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1
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Cai P, Yang Q, Lu J, Dai X, Xiong J. Fecal bacterial biomarkers and blood biochemical indicators as potential key factors in the development of colorectal cancer. mSystems 2025; 10:e0004325. [PMID: 40013832 PMCID: PMC11915818 DOI: 10.1128/msystems.00043-25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/06/2025] [Indexed: 02/28/2025] Open
Abstract
The incidence of colorectal cancer (CRC) has been increasing in recent decades. Current methods for CRC screening have their own drawbacks, thus there is an urgent need to identify the key microbes that drive the development of CRC for wider application in the early detection and prevention of CRC. To address this issue, we performed fecal microbiome analysis by high-throughput sequencing of 16S rRNA gene combined with blood biochemical indicators in patients with CRC stages I, II, III, and IV, healthy people, and patients with polyps. Fecal microbiota of patients with CRC was disturbed, as evidenced by significantly reduced α-diversity in patients with CRC stage IV and markedly different β-diversity. The random forest model identified the top 25 genera from 174 training data, resulting in a diagnostic accuracy of 87.95%. Further, by combining with differential genera analysis, we screened out 11 biomarkers that significantly changed in different groups. Peptostreptococcus, Parvimonas, Shewanella, Oscillibacter, Eggerthella, and Gemella associated with the development of CRC were significantly enriched, while Fenollaria, Staphylococcus, Ezakiella, Finegoldia, and Neisseria associated with the remission of CRC were significantly suppressed in patients with CRC. Importantly, carcinoembryonic antigen (CEA) was significantly correlated with these 11 microbial biomarkers, and carbohydrate antigen 19-9 (CA 19-9) was markedly correlated with Oscillibacter. Notably, co-occurrence network analysis at the genus level exhibited that the microbial co-occurrence network of CRC IV was the most complex and stable. These results suggested that CEA, CA 19-9 and 11 microbial biomarkers may be co-biomarkers for the disease occurrence and development, and non-invasive diagnosis of CRC. IMPORTANCE Identifying the key microbes that drive the development of colorectal cancer (CRC) has been important in this field. We delved into the research on the association between CRC and fecal microbiota in this study, providing a detailed analysis of the characteristics of fecal microbiota during the transition from normal intestine to polyps to cancer. Fecal bacterial biomarkers and blood biochemical indicators may be co-biomarkers in the development of CRC.
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Affiliation(s)
- Ping Cai
- Ningbo No.2 Hospital, Ningbo, China
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Qingzhen Yang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University, Xi’an, China
| | - Jiaqi Lu
- Zhejiang KinGene Bio-technology Co., Ltd, Ningbo, China
| | | | - Jinbo Xiong
- Institute of One Health, School of Marine Sciences, Ningbo University, Ningbo, China
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2
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Lee PY, Osman J, Low TY. Immunoaffinity Depletion of High-Abundance Proteins from Serum/Plasma for Proteomic Analysis. Methods Mol Biol 2025; 2884:1-12. [PMID: 39715993 DOI: 10.1007/978-1-0716-4298-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024]
Abstract
Mass spectrometry-based proteomics is widely applied to human blood serum or plasma in the search of biomarkers for various diseases. However, the enormous complexity and dynamic range of protein concentrations in these samples render a significant analytical challenge, particularly for detecting low-abundance candidate biomarkers. As a result, strategies for enriching low-abundance proteins and improving their identification in serum or plasma proteomics are commonly used. Here, we describe an immunodepletion technique that is routinely used in our lab for removing high-abundance proteins from human serum/plasma.
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Affiliation(s)
- Pey Yee Lee
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Junaida Osman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
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3
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Rivas-Macho A, Romeo MV, Rackles E, Olabarria G, Falcon-Perez JM, Berganza-Granda J, Cortajarena AL, Goñi-de-Cerio F. Potential use of heat shock protein 90 as a biomarker for the diagnosis of human diseases. Expert Rev Mol Diagn 2023; 23:875-884. [PMID: 37577928 DOI: 10.1080/14737159.2023.2246883] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/27/2023] [Accepted: 08/08/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION The heat shock protein 90 (Hsp90) is a protein involved in many different biological processes and especially in cell survival. Some of these functions require the participation of other biological molecules, so Hsp90 is a chaperone that takes part in many protein-protein interactions working as a critical signaling hub protein. As a member of the heat shock protein family, Hsp90 expression is regulated under certain environmental and/or stressful situations, therefore Hsp90 concentration can be monitored and linked to these effects. AREAS COVERED This review discusses the Hsp90 expression in samples from individuals affected by different diseases (from infectious to cancer origin), and the biological consequences of these disorders, including the potential use of Hsp90 as a biomarker for the diagnosis of human diseases. EXPERT OPINION The potential of Hsp90 as a biomarker disease has been demonstrated in several studies in relation to infectious diseases and especially cancer. However, further research in this field is still needed, mainly to validate in statistically significant clinical studies that the detection of Hsp90 protein allows the diagnosis of some cancers at an early stage and also that it can act as a biomarker for monitoring the efficacy of their therapies.
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Affiliation(s)
- Ane Rivas-Macho
- GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Spain
| | - María V Romeo
- GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Spain
- Centre for Cooperative Research in Biomaterials (CICbiomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia-San Sebastián, Spain
| | - Elisabeth Rackles
- Exosomes Laboratory. Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park 801, Derio, Spain
| | - Garbiñe Olabarria
- GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Spain
| | - Juan Manuel Falcon-Perez
- Exosomes Laboratory. Centre for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park 801, Derio, Spain
- Centro de Investigación Biomédica e Red de enfermedades hepáticas y digestivas (CIBRehd), Madrid, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Jesús Berganza-Granda
- GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Spain
| | - Aitziber L Cortajarena
- Centre for Cooperative Research in Biomaterials (CICbiomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia-San Sebastián, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Felipe Goñi-de-Cerio
- GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Spain
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Agostini M, Traldi P, Hamdan M. Mass Spectrometry Contribution to Pediatric Cancers Research. Medicina (B Aires) 2023; 59:medicina59030612. [PMID: 36984613 PMCID: PMC10053507 DOI: 10.3390/medicina59030612] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
For over four decades, mass spectrometry-based methods have provided a wealth of information relevant to various challenges in the field of cancers research. These challenges included identification and validation of novel biomarkers for various diseases, in particular for various forms of cancer. These biomarkers serve various objectives including monitoring patient response to the various forms of therapy, differentiating subgroups of the same type of cancer, and providing proteomic data to complement datasets generated by genomic, epigenetic, and transcriptomic methods. The same proteomic data can be used to provide prognostic information and could guide scientists and medics to new and innovative targeted therapies The past decade has seen a rapid emergence of epigenetics as a major contributor to carcinogenesis. This development has given a fresh momentum to MS-based proteomics, which demonstrated to be an unrivalled tool for the analyses of protein post-translational modifications associated with chromatin modifications. In particular, high-resolution mass spectrometry has been recently used for systematic quantification of chromatin modifications. Data generated by this approach are central in the search for new therapies for various forms of cancer and will help in attempts to decipher antitumor drug resistance. To appreciate the contribution of mass spectrometry-based proteomics to biomarkers discovery and to our understanding of mechanisms behind the initiation and progression of various forms of cancer, a number of recent investigations are discussed. These investigations also include results provided by two-dimensional gel electrophoresis combined with mass spectrometry.
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Musyoka Wayua D, Kalambuka Angeyo H, Dehayem-Kamadjeu A, Amiga Kaduki K. Direct Analysis of Blood for Diagnostic Metals for Malaria by Peak-Free Laser-Induced Breakdown Spectroscopy (LIBS) with Artificial Neural Networks (ANN) and Partial Least Squares (PLS). ANAL LETT 2022. [DOI: 10.1080/00032719.2022.2067862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
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Cameron JM, Rinaldi C, Rutherford SH, Sala A, G Theakstone A, Baker MJ. Clinical Spectroscopy: Lost in Translation? APPLIED SPECTROSCOPY 2022; 76:393-415. [PMID: 34041957 DOI: 10.1177/00037028211021846] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
This Focal Point Review paper discusses the developments of biomedical Raman and infrared spectroscopy, and the recent strive towards these technologies being regarded as reliable clinical tools. The promise of vibrational spectroscopy in the field of biomedical science, alongside the development of computational methods for spectral analysis, has driven a plethora of proof-of-concept studies which convey the potential of various spectroscopic approaches. Here we report a brief review of the literature published over the past few decades, with a focus on the current technical, clinical, and economic barriers to translation, namely the limitations of many of the early studies, and the lack of understanding of clinical pathways, health technology assessments, regulatory approval, clinical feasibility, and funding applications. The field of biomedical vibrational spectroscopy must acknowledge and overcome these hurdles in order to achieve clinical efficacy. Current prospects have been overviewed with comment on the advised future direction of spectroscopic technologies, with the aspiration that many of these innovative approaches can ultimately reach the frontier of medical diagnostics and many clinical applications.
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Affiliation(s)
| | - Christopher Rinaldi
- WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, Glasgow, UK
| | - Samantha H Rutherford
- WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, Glasgow, UK
| | - Alexandra Sala
- WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, Glasgow, UK
| | - Ashton G Theakstone
- WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, Glasgow, UK
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Fazal Y, Zohaib M, Syed B, Ansari SH, Hashim Z, Ahmed A, Zarina S. Prenatal diagnosis of maternal serum from mothers carrying β-thalassemic fetus. Pediatr Int 2022; 64:e14999. [PMID: 34559910 DOI: 10.1111/ped.14999] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/03/2021] [Accepted: 09/13/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND This study focuses on the discovery of protein biomarkers from the maternal serum of β-thalassemic trait mothers carrying the normal fetus and β-thalassemic major fetus. METHODS Serum samples from β-thalassemic trait mothers carrying major (N = 5) and normal fetuses (N = 5) were studied. The IVS1-5 thalassemia mutation was common among β-thalassemic trait mothers who were carrying a homozygous β-thalassemic fetus (IVS1-5/ IVS1-5 mutation) or a normal fetus (no mutation). We employed two-dimensional gel electrophoresis and mass spectrometry analysis to explore differentially expressed maternal serum proteins from thalassemia carrier couples with the same β-thalassemia mutation. Western blotting was performed for one of the identified proteins to validate our data. RESULTS Ten proteins were identified in the maternal serum of β-thalassemic trait mothers carrying the β-thalassemic major fetus and normal fetus. Among these, serotransferrin, haptoglobin, α-1 anti-trypsin, apo-lipoprotein A1, and the fibrinogen-β chain were found to be upregulated in mothers carrying major fetuses and are known to be associated with pregnancy-related disorders. The expression of α-1 anti-trypsin was validated through western blotting. CONCLUSIONS Proteins identified in the current study from maternal serum are reported to contribute to hereditary disorders. We suggest that these can serve as putative screening markers for non-invasive prenatal diagnosis in β-thalassemic pregnancies.
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Affiliation(s)
- Yumna Fazal
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, Pakistan
| | | | - Basir Syed
- Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, USA
| | - Saqib H Ansari
- Omair Sana Foundation, Gulshan-e-Iqbal, Karachi, Pakistan
| | - Zehra Hashim
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, Pakistan
| | - Aftab Ahmed
- Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, USA
| | - Shamshad Zarina
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, Pakistan
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Ma W, Zhong C, Lin J, Chen Z, Li G, Tong W, Wu Y, Zhang L, Lin Z. Copper(II) ions-immobilized virus-like hollow covalent organic frameworks for highly efficient capture and sensitive analysis of amyloid beta-peptide 1-42 by MALDI-MS. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.01.047] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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9
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Yaari Z, Yang Y, Apfelbaum E, Cupo C, Settle AH, Cullen Q, Cai W, Roche KL, Levine DA, Fleisher M, Ramanathan L, Zheng M, Jagota A, Heller DA. A perception-based nanosensor platform to detect cancer biomarkers. SCIENCE ADVANCES 2021; 7:eabj0852. [PMID: 34797711 PMCID: PMC8604403 DOI: 10.1126/sciadv.abj0852] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 09/14/2021] [Indexed: 05/15/2023]
Abstract
Conventional molecular recognition elements, such as antibodies, present issues for developing biomolecular assays for use in certain technologies, such as implantable devices. Additionally, antibody development and use, especially for highly multiplexed applications, can be slow and costly. We developed a perception-based platform based on an optical nanosensor array that leverages machine learning algorithms to detect multiple protein biomarkers in biofluids. We demonstrated this platform in gynecologic cancers, often diagnosed at advanced stages, leading to low survival rates. We investigated the detection of protein biomarkers in uterine lavage samples, which are enriched with certain cancer markers compared to blood. We found that the method enables the simultaneous detection of multiple biomarkers in patient samples, with F1-scores of ~0.95 in uterine lavage samples from patients with cancer. This work demonstrates the potential of perception-based systems for the development of multiplexed sensors of disease biomarkers without the need for specific molecular recognition elements.
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Affiliation(s)
- Zvi Yaari
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Yoona Yang
- Lehigh University, Bethlehem, PA 18015, USA
| | - Elana Apfelbaum
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Christian Cupo
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Alex H. Settle
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Quinlan Cullen
- Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
| | - Winson Cai
- Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
| | - Kara Long Roche
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | | | - Martin Fleisher
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | | | - Ming Zheng
- National Institute of Standards and Technology, Gaithersburg, MD 20899, USA
| | | | - Daniel A. Heller
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
- Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
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10
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Peng X, Ma Y, Wang Q, Gao Y, Li G, Jiang C, Gao Y, Feng Y. Serum Amyloid A Correlates With the Osteonecrosis of Femoral Head by Affecting Bone Metabolism. Front Pharmacol 2021; 12:767243. [PMID: 34733165 PMCID: PMC8559508 DOI: 10.3389/fphar.2021.767243] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/27/2021] [Indexed: 11/13/2022] Open
Abstract
Osteonecrosis of femoral head (ONFH) is a progressive hip joint disease without disease-modifying treatment. Lacking understanding of the pathophysiological process of ONFH has become the humper to develop therapeutic approach. Serum amyloid A (SAA) is an acute phase lipophilic protein during inflammation and we found that SAA is increased for the first time in the serum of ONFH patients through proteomic studies and quantitatively verified by ELISA. Treating rBMSCs with SAA inhibited the osteogenic differentiation via Wnt/β-catenin signaling pathway deactivation and enhanced the adipogenic differentiation via MAPK/PPARγ signaling pathway activation. Finally, bilateral critical-sized calvarial-defect rat model which received SAA treated rBMSCs demonstrated reduction of bone formation when compared to untreated rBMSCs implantation control. Hence, SAA is a vital protein in the physiological process of ONFH and can act as a potential therapeutic target to treat ONFH.
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Affiliation(s)
- Xiaoyuan Peng
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yiyang Ma
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Qiyang Wang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yanchun Gao
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Guangyi Li
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chenyi Jiang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yun Gao
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yong Feng
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Vásquez X, Sánchez-Gómez P, Palma V. Netrin-1 in Glioblastoma Neovascularization: The New Partner in Crime? Int J Mol Sci 2021; 22:8248. [PMID: 34361013 PMCID: PMC8348949 DOI: 10.3390/ijms22158248] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive and common primary tumor of the central nervous system. It is characterized by having an infiltrating growth and by the presence of an excessive and aberrant vasculature. Some of the mechanisms that promote this neovascularization are angiogenesis and the transdifferentiation of tumor cells into endothelial cells or pericytes. In all these processes, the release of extracellular microvesicles by tumor cells plays an important role. Tumor cell-derived extracellular microvesicles contain pro-angiogenic molecules such as VEGF, which promote the formation of blood vessels and the recruitment of pericytes that reinforce these structures. The present study summarizes and discusses recent data from different investigations suggesting that Netrin-1, a highly versatile protein recently postulated as a non-canonical angiogenic ligand, could participate in the promotion of neovascularization processes in GBM. The relevance of determining the angiogenic signaling pathways associated with the interaction of Netrin-1 with its receptors is posed. Furthermore, we speculate that this molecule could form part of the microvesicles that favor abnormal tumor vasculature. Based on the studies presented, this review proposes Netrin-1 as a novel biomarker for GBM progression and vascularization.
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Affiliation(s)
- Ximena Vásquez
- Laboratory of Stem Cells and Developmental Biology, Faculty of Sciences, Universidad de Chile, Santiago 7800003, Chile;
| | - Pilar Sánchez-Gómez
- Neurooncology Unit, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain
| | - Verónica Palma
- Laboratory of Stem Cells and Developmental Biology, Faculty of Sciences, Universidad de Chile, Santiago 7800003, Chile;
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Dunphy K, O’Mahoney K, Dowling P, O’Gorman P, Bazou D. Clinical Proteomics of Biofluids in Haematological Malignancies. Int J Mol Sci 2021; 22:ijms22158021. [PMID: 34360786 PMCID: PMC8348619 DOI: 10.3390/ijms22158021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/25/2022] Open
Abstract
Since the emergence of high-throughput proteomic techniques and advances in clinical technologies, there has been a steady rise in the number of cancer-associated diagnostic, prognostic, and predictive biomarkers being identified and translated into clinical use. The characterisation of biofluids has become a core objective for many proteomic researchers in order to detect disease-associated protein biomarkers in a minimally invasive manner. The proteomes of biofluids, including serum, saliva, cerebrospinal fluid, and urine, are highly dynamic with protein abundance fluctuating depending on the physiological and/or pathophysiological context. Improvements in mass-spectrometric technologies have facilitated the in-depth characterisation of biofluid proteomes which are now considered hosts of a wide array of clinically relevant biomarkers. Promising efforts are being made in the field of biomarker diagnostics for haematologic malignancies. Several serum and urine-based biomarkers such as free light chains, β-microglobulin, and lactate dehydrogenase are quantified as part of the clinical assessment of haematological malignancies. However, novel, minimally invasive proteomic markers are required to aid diagnosis and prognosis and to monitor therapeutic response and minimal residual disease. This review focuses on biofluids as a promising source of proteomic biomarkers in haematologic malignancies and a key component of future diagnostic, prognostic, and disease-monitoring applications.
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Affiliation(s)
- Katie Dunphy
- Department of Biology, National University of Ireland, W23 F2K8 Maynooth, Ireland; (K.D.); (P.D.)
| | - Kelly O’Mahoney
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland; (K.O.); (P.O.)
| | - Paul Dowling
- Department of Biology, National University of Ireland, W23 F2K8 Maynooth, Ireland; (K.D.); (P.D.)
| | - Peter O’Gorman
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland; (K.O.); (P.O.)
| | - Despina Bazou
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland; (K.O.); (P.O.)
- Correspondence:
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13
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Guo Y, Li K, Gao Y, Zhao S, Shi M, Li J, Liu Z, Wang Z, He L. CLEC3B Identified as a Potential Lung Cancer Biomarker in Serum by Aptamer‐Capture Technology. ChemistrySelect 2021. [DOI: 10.1002/slct.202100605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Yuanbin Guo
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Kun Li
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Yue Gao
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Shuhua Zhao
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Ming Shi
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Jian Li
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Zhiwei Liu
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Zhaoxia Wang
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
| | - Lei He
- College of Environment & Chemical Engineering Yanshan University Qinhuangdao Hebei Province 066004 China
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14
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Byrne HJ, Behl I, Calado G, Ibrahim O, Toner M, Galvin S, Healy CM, Flint S, Lyng FM. Biomedical applications of vibrational spectroscopy: Oral cancer diagnostics. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 252:119470. [PMID: 33503511 DOI: 10.1016/j.saa.2021.119470] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/09/2021] [Accepted: 01/10/2021] [Indexed: 06/12/2023]
Abstract
Vibrational spectroscopy, based on either infrared absorption or Raman scattering, has attracted increasing attention for biomedical applications. Proof of concept explorations for diagnosis of oral potentially malignant disorders and cancer are reviewed, and recent advances critically appraised. Specific examples of applications of Raman microspectroscopy for analysis of histological, cytological and saliva samples are presented for illustrative purposes, and the future prospects, ultimately for routine, chairside in vivo screening are discussed.
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Affiliation(s)
- Hugh J Byrne
- FOCAS Research Institute, Technological University Dublin, City Campus, Dublin 8, Ireland.
| | - Isha Behl
- School of Physics and Clinical and Optometric Sciences, Technological University Dublin, City Campus, Dublin 8, Ireland; Radiation and Environmental Science Centre, FOCAS Research Institute, Technological University Dublin, City Campus, Dublin 8, Ireland
| | - Genecy Calado
- School of Physics and Clinical and Optometric Sciences, Technological University Dublin, City Campus, Dublin 8, Ireland; Radiation and Environmental Science Centre, FOCAS Research Institute, Technological University Dublin, City Campus, Dublin 8, Ireland
| | - Ola Ibrahim
- School of Dental Science, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland
| | - Mary Toner
- Central Pathology Laboratory, St. James Hospital, James Street, Dublin 8, Ireland
| | - Sheila Galvin
- Oral Medicine Unit, Dublin Dental University Hospital, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland
| | - Claire M Healy
- Oral Medicine Unit, Dublin Dental University Hospital, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland
| | - Stephen Flint
- Oral Medicine Unit, Dublin Dental University Hospital, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland
| | - Fiona M Lyng
- School of Physics and Clinical and Optometric Sciences, Technological University Dublin, City Campus, Dublin 8, Ireland; Radiation and Environmental Science Centre, FOCAS Research Institute, Technological University Dublin, City Campus, Dublin 8, Ireland
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15
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Sengupta A, Naresh G, Mishra A, Parashar D, Narad P. Proteome analysis using machine learning approaches and its applications to diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 127:161-216. [PMID: 34340767 DOI: 10.1016/bs.apcsb.2021.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
With the tremendous developments in the fields of biological and medical technologies, huge amounts of data are generated in the form of genomic data, images in medical databases or as data on protein sequences, and so on. Analyzing this data through different tools sheds light on the particulars of the disease and our body's reactions to it, thus, aiding our understanding of the human health. Most useful of these tools is artificial intelligence and deep learning (DL). The artificially created neural networks in DL algorithms help extract viable data from the datasets, and further, to recognize patters in these complex datasets. Therefore, as a part of machine learning, DL helps us face all the various challenges that come forth during protein prediction, protein identification and their quantification. Proteomics is the study of such proteins, their structures, features, properties and so on. As a form of data science, Proteomics has helped us progress excellently in the field of genomics technologies. One of the major techniques used in proteomics studies is mass spectrometry (MS). However, MS is efficient with analysis of large datasets only with the added help of informatics approaches for data analysis and interpretation; these mainly include machine learning and deep learning algorithms. In this chapter, we will discuss in detail the applications of deep learning and various algorithms of machine learning in proteomics.
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Affiliation(s)
- Abhishek Sengupta
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - G Naresh
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Astha Mishra
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Diksha Parashar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Priyanka Narad
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India.
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16
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Xing X, Yuan H, Liu H, Tan X, Zhao B, Wang Y, Ouyang J, Lin M, Liu X, Huang A. Quantitative Secretome Analysis Reveals Clinical Values of Carbonic Anhydrase II in Hepatocellular Carcinoma. GENOMICS, PROTEOMICS & BIOINFORMATICS 2021; 19:94-107. [PMID: 33662630 PMCID: PMC8498920 DOI: 10.1016/j.gpb.2020.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 05/15/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022]
Abstract
Early detection and intervention are key strategies to reduce mortality, increase long-term survival, and improve the therapeutic effects of hepatocellular carcinoma (HCC) patients. Herein, the isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomic strategy was used to study the secretomes in conditioned media from HCC cancerous tissues, surrounding noncancerous tissues, and distal noncancerous tissues to identify diagnostic and prognostic biomarkers for HCC. In total, 22 and 49 dysregulated secretory proteins were identified in the cancerous and surrounding noncancerous tissues, respectively, compared with the distal noncancerous tissues. Among these proteins, carbonic anhydrase II (CA2) was identified to be significantly upregulated in the secretome of cancerous tissues; correspondingly, the serum concentrations of CA2 were remarkably increased in HCC patients compared with that in normal populations. Interestingly, a significant increase of serum CA2 in recurrent HCC patients after radical resection was also confirmed compared with HCC patients without recurrence, and the serum level of CA2 could act as an independent prognostic factor for time to recurrence and overall survival. Regarding the mechanism, the secreted CA2 enhances the migration and invasion of HCC cells by activating the epithelial mesenchymal transition pathway. Taken together, this study identified a novel biomarker for HCC diagnosis and prognosis, and provided a valuable resource of HCC secretome for investigating serological biomarkers.
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Affiliation(s)
- Xiaohua Xing
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou 350004, China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Hui Yuan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Hongzhi Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Xionghong Tan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Jiahe Ouyang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Minjie Lin
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Xiaolong Liu
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou 350004, China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China.
| | - Aimin Huang
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou 350004, China.
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17
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Theakstone AG, Rinaldi C, Butler HJ, Cameron JM, Confield LR, Rutherford SH, Sala A, Sangamnerkar S, Baker MJ. Fourier‐transform infrared spectroscopy of biofluids: A practical approach. TRANSLATIONAL BIOPHOTONICS 2021. [DOI: 10.1002/tbio.202000025] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Ashton G. Theakstone
- WestCHEM, Department of Pure and Applied Chemistry Technology and Innovation Centre Glasgow UK
| | - Christopher Rinaldi
- WestCHEM, Department of Pure and Applied Chemistry Technology and Innovation Centre Glasgow UK
| | | | | | - Lily Rose Confield
- WestCHEM, Department of Pure and Applied Chemistry Technology and Innovation Centre Glasgow UK
- CDT Medical Devices, Department of Biomedical Engineering Wolfson Centre Glasgow UK
| | - Samantha H. Rutherford
- WestCHEM, Department of Pure and Applied Chemistry Technology and Innovation Centre Glasgow UK
| | - Alexandra Sala
- WestCHEM, Department of Pure and Applied Chemistry Technology and Innovation Centre Glasgow UK
- ClinSpec Diagnostics Ltd, Royal College Building Glasgow UK
| | - Sayali Sangamnerkar
- WestCHEM, Department of Pure and Applied Chemistry Technology and Innovation Centre Glasgow UK
| | - Matthew J. Baker
- WestCHEM, Department of Pure and Applied Chemistry Technology and Innovation Centre Glasgow UK
- ClinSpec Diagnostics Ltd, Royal College Building Glasgow UK
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18
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Chatterjee B, Bhatia Y, Mondal G, Islam S, Ghosh R, Dutta S, Ghosh S, Duseja A, Panda C. Phospho zinc finger protein: A promising serum biomolecule as noninvasive diagnostic marker of chronic Hepatitis B related liver diseases including liver cancer. JOURNAL OF RADIATION AND CANCER RESEARCH 2021. [DOI: 10.4103/jrcr.jrcr_31_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Abstract
State of the art of quantitative Vibrational Spectroscopic analysis of human blood serum is reviewed. Technical considerations for infrared absorption and Raman analysis are discussed. Quantitative analyses of Endogenous and Exogenous constituents are presented. The potential for clinical translation of spectroscopic serology is argued. Analysis of bodily fluids using vibrational spectroscopy has attracted increasing attention in recent years. In particular, infrared spectroscopic screening of blood products, particularly blood serum, for disease diagnostics has been advanced considerably, attracting commercial interests. However, analyses requiring quantification of endogenous constituents or exogenous agents in blood are less well advanced. Recent advances towards this end are reviewed, focussing on infrared and Raman spectroscopic analyses of human blood serum. The importance of spectroscopic analysis in the native aqueous environment is highlighted, and the relative merits of infrared absorption versus Raman spectroscopy are considered, in this context. It is argued that Raman spectroscopic analysis is more suitable to quantitative analysis in liquid samples, and superior performance for quantification of high and low molecular weight components, is demonstrated. Applications for quantitation of viral loads, and therapeutic drug monitoring are also discussed.
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20
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Harberts E, Liang T, Yoon SH, Opene BN, McFarland MA, Goodlett DR, Ernst RK. Toll-like Receptor 4-Independent Effects of Lipopolysaccharide Identified Using Longitudinal Serum Proteomics. J Proteome Res 2020; 19:1258-1266. [PMID: 32037835 DOI: 10.1021/acs.jproteome.9b00765] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Sepsis remains one of the most lethal and costly conditions treated in U.S. hospitals, with approximately 50% of cases caused by Gram-negative bacterial infections. Septic shock is induced when lipopolysaccharide (LPS), the main component of Gram-negative outer bacterial membrane, signals through the Toll-like receptor 4 (TLR4) complex. Lethal endotoxemia, a model for septic shock, was induced in WT C57BL6 and TLR4-/- mice by administration of Escherichia coli LPS. WT LPS treated mice showed high morbidity, while PBS treated LPS and treated TLR4-/- mice did not. ANOVA analysis of label-free quantification of longitudinal serum proteome revealed 182 out of 324 proteins in LPS injected WT mice that were significantly changed across four time points (0, 6, 12, and 18 h). No significant changes were identified in the two control groups. From the 182 identified proteins, examples of known sepsis biomarkers were validated by ELISA, which showed similar trends as MS proteomics data. Longitudinal analysis within individual mice produced 3-fold more significantly changed proteins than pair-wise comparison. A subsequent global analysis of WT and TLR4-/- mice identified pathways activated independent of TLR4. These pathways represent possible compensatory mechanisms that allow for control of Gram-negative bacterial infection regardless of host immune status.
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Affiliation(s)
- Erin Harberts
- Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, Maryland 21201, United States
| | - Tao Liang
- Department of Pharmaceutical Science, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States
| | - Sung Hwan Yoon
- Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, Maryland 21201, United States
| | - Belita N Opene
- Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, Maryland 21201, United States
| | - Melinda A McFarland
- Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland 21201, United States
| | - David R Goodlett
- Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, Maryland 21201, United States.,University of Gdansk, International Centre for Cancer Vaccine Science, 80-308 Gdansk, Poland, EU
| | - Robert K Ernst
- Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, Maryland 21201, United States
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21
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Wu J, Yang Y, Cheng L, Wu J, Xi L, Ma Y, Zhang P, Xu X, Zhang D, Li S. GCdiscrimination: identification of gastric cancer based on a milliliter of blood. Brief Bioinform 2020; 22:536-544. [PMID: 32010933 DOI: 10.1093/bib/bbaa006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/22/2019] [Accepted: 11/21/2019] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) continues to be one of the major causes of cancer deaths worldwide. Meanwhile, liquid biopsies have received extensive attention in the screening and detection of cancer along with better understanding and clinical practice of biomarkers. In this work, 58 routine blood biochemical indices were tentatively used as integrated markers, which further expanded the scope of liquid biopsies and a discrimination system for GC consisting of 17 top-ranked indices, elaborated by random forest method was constructed to assist in preliminary assessment prior to histological and gastroscopic diagnosis based on the test data of a total of 2951 samples. The selected indices are composed of eight routine blood indices (MO%, IG#, IG%, EO%, P-LCR, RDW-SD, HCT and RDW-CV) and nine blood biochemical indices (TP, AMY, GLO, CK, CHO, CK-MB, TG, ALB and γ-GGT). The system presented a robust classification performance, which can quickly distinguish GC from other stomach diseases, different cancers and healthy people with sensitivity, specificity, total accuracy and area under the curve of 0.9067, 0.9216, 0.9138 and 0.9720 for the cross-validation set, respectively. Besides, this system can not only provide an innovative strategy to facilitate rapid and real-time GC identification, but also reveal the remote correlation between GC and these routine blood biochemical parameters, which helped to unravel the hidden association of these parameters with GC and serve as the basis for subsequent studies of the clinical value in prevention program and surveillance management for GC. The identification system, called GC discrimination, is now available online at http://lishuyan.lzu.edu.cn/GC/.
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Affiliation(s)
| | | | | | | | - Lili Xi
- First Hospital of Lanzhou University
| | - Ying Ma
- physician in Gansu Provincial Maternity and Child-care Hospital
| | | | - Xiaoying Xu
- physician of First Hospital of Lanzhou University
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22
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Dixit A, Mehta R, Singh AK. Proteomics in Human Parkinson's Disease: Present Scenario and Future Directions. Cell Mol Neurobiol 2019; 39:901-915. [PMID: 31190159 PMCID: PMC11457823 DOI: 10.1007/s10571-019-00700-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 06/04/2019] [Indexed: 12/26/2022]
Abstract
Parkinson's disease (PD) is an age-related, threatening neurodegenerative disorder with no reliable treatment till date. Identification of specific and reliable biomarker is a major challenge for disease diagnosis and designing effective therapeutic strategy against it. PD pathology at molecular level involves abnormal expression and function of several proteins, including alpha-synuclein. These proteins affect the normal functioning of neurons through various post-translational modifications and interaction with other cellular components. The role of protein anomalies during PD pathogenesis can be better understood by the application of proteomics approach. A number of proteomic studies conducted on brain tissue, blood, and cerebrospinal fluid of PD patients have identified a wide array of protein alterations underlying disease pathogenesis. However, these studies are limited by the types of brain regions or biofluids utilized in the research. For a complete understanding of PD mechanism and discovery of reliable protein biomarkers, it is essential to analyze the proteome of different PD-associated brain regions and easily accessible biofluids such as saliva and urine. The present review summarizes the major advances in the field of PD research in humans utilizing proteomic techniques. Moreover, potential samples for proteomic analysis and limitations associated with the analyses of different types of samples have also been discussed.
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Affiliation(s)
- Anubhuti Dixit
- Amity Institute of Neuropsychology and Neurosciences, Amity University, Sector-125, Noida, Uttar Pradesh, 201313, India.
| | - Rachna Mehta
- Amity Institute of Neuropsychology and Neurosciences, Amity University, Sector-125, Noida, Uttar Pradesh, 201313, India
| | - Abhishek Kumar Singh
- Amity Institute of Neuropsychology and Neurosciences, Amity University, Sector-125, Noida, Uttar Pradesh, 201313, India
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23
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Djureinovic D, Pontén V, Landelius P, Al Sayegh S, Kappert K, Kamali-Moghaddam M, Micke P, Ståhle E. Multiplex plasma protein profiling identifies novel markers to discriminate patients with adenocarcinoma of the lung. BMC Cancer 2019; 19:741. [PMID: 31357969 PMCID: PMC6664554 DOI: 10.1186/s12885-019-5943-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 07/16/2019] [Indexed: 12/12/2022] Open
Abstract
Background The overall prognosis of non-small cell lung cancer (NSCLC) is poor, and currently only patients with localized disease are potentially curable. Therefore, preferably non-invasively determined biomarkers that detect NSCLC patients at early stages of the disease are of high clinical relevance. The aim of this study was to identify and validate novel protein markers in plasma using the highly sensitive DNA-assisted multiplex proximity extension assay (PEA) to discriminate NSCLC from other lung diseases. Methods Plasma samples were collected from a total of 343 patients who underwent surgical resection for different lung diseases, including 144 patients with lung adenocarcinoma (LAC), 68 patients with non-malignant lung disease, 83 patients with lung metastasis of colorectal cancers and 48 patients with typical carcinoid. One microliter of plasma was analyzed using PEA, allowing detection and quantification of 92 established cancer related proteins. The concentrations of the plasma proteins were compared between disease groups. Results The comparison between LAC and benign samples revealed significantly different plasma levels for four proteins; CXCL17, CEACAM5, VEGFR2 and ERBB3 (adjusted p-value < 0.05). A multi-parameter classifier was developed to discriminate between samples from LAC patients and from patients with non-malignant lung conditions. With a bootstrap aggregated decision tree algorithm (TreeBagger), a sensitivity of 93% and specificity of 64% was achieved to detect LAC in this risk population. Conclusions By applying the highly sensitive PEA, reliable protein profiles could be determined in microliter amounts of plasma. We further identified proteins that demonstrated different plasma concentration in defined disease groups and developed a signature that holds potential to be included in a screening assay for early lung cancer detection. Electronic supplementary material The online version of this article (10.1186/s12885-019-5943-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dijana Djureinovic
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden.
| | - Victor Pontén
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden
| | - Per Landelius
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Sahar Al Sayegh
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden
| | - Kai Kappert
- Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Masood Kamali-Moghaddam
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Patrick Micke
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden
| | - Elisabeth Ståhle
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Parachalil DR, Bruno C, Bonnier F, Blasco H, Chourpa I, Baker MJ, McIntyre J, Byrne HJ. Analysis of bodily fluids using vibrational spectroscopy: a direct comparison of Raman scattering and infrared absorption techniques for the case of glucose in blood serum. Analyst 2019; 144:3334-3346. [DOI: 10.1039/c9an00125e] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Analysis of biomarkers present in the blood stream can potentially deliver crucial information on patient health and indicate the presence of numerous pathologies.
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Affiliation(s)
- Drishya Rajan Parachalil
- FOCAS Research Institute
- Technological University Dublin
- Dublin 8
- Ireland
- School of Physics and Optometric & Clinical Sciences
| | - Clément Bruno
- Université de Tours
- UFR sciences pharmaceutiques
- EA 6295 Nanomédicaments et Nanosondes
- 37200 Tours
- France
| | - Franck Bonnier
- Université de Tours
- UFR sciences pharmaceutiques
- EA 6295 Nanomédicaments et Nanosondes
- 37200 Tours
- France
| | - Hélène Blasco
- CHRU de Tours
- Laboratoire de Biochimie et Biologie Moléculaire
- Tours
- France
- WestCHEM
| | - Igor Chourpa
- Université de Tours
- UFR sciences pharmaceutiques
- EA 6295 Nanomédicaments et Nanosondes
- 37200 Tours
- France
| | - Matthew J. Baker
- WestCHEM
- Department of Pure & Applied Chemistry
- Technology and Innovation Centre
- University of Strathclyde
- Glasgow
| | - Jennifer McIntyre
- FOCAS Research Institute
- Technological University Dublin
- Dublin 8
- Ireland
| | - Hugh J. Byrne
- FOCAS Research Institute
- Technological University Dublin
- Dublin 8
- Ireland
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Soler M, Huertas CS, Lechuga LM. Label-free plasmonic biosensors for point-of-care diagnostics: a review. Expert Rev Mol Diagn 2018; 19:71-81. [PMID: 30513011 DOI: 10.1080/14737159.2019.1554435] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Introduction: Optical biosensors, particularly those based on nanoplasmonics technology, have emerged in recent decades as a potential solution for disease diagnostics and therapy follow-up at the point-of-care (POC). These biosensor platforms could overcome some of the challenges faced in conventional diagnosis techniques offering label-free assays with immediate results and employing small and user-friendly devices. Areas covered: In this review, we will provide a critical overview of the recent advances in the development of nanoplasmonic biosensors for the POC diagnostics. We focus on those systems with demonstrated capabilities for integration in portable platforms, highlighting some of the most relevant diagnostics applications targeting proteins, nucleic acids, and cells as disease biomarkers. Expert commentary: Despite the attractive features of label-free nanoplasmonic sensors in terms of miniaturization and analytical robustness, the route toward an effective clinical implementation involves the integration of fully automated microfluidic systems for sample processing and analysis, and the optimization of surface biofunctionalization procedures. Additionally, the development of multiplexed sensors for high-throughput analysis and including specific neoantigens and novel biomarkers in detection panels will provide the means for delivering a powerful analytical technology for an accurate and improved medical diagnosis.
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Affiliation(s)
- Maria Soler
- a Nanobiosensors and Bioanalytical Applications Group , Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, BIST and CIBER-BBN , Bellaterra , Barcelona , Spain
| | - Cesar S Huertas
- a Nanobiosensors and Bioanalytical Applications Group , Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, BIST and CIBER-BBN , Bellaterra , Barcelona , Spain.,b School of Engineering , RMIT University , Melbourne , Australia
| | - Laura M Lechuga
- a Nanobiosensors and Bioanalytical Applications Group , Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, BIST and CIBER-BBN , Bellaterra , Barcelona , Spain
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26
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Bortz E, Wu TT, Patel P, Whitelegge JP, Sun R. Proteomics of Bronchoalveolar Lavage Fluid Reveals a Lung Oxidative Stress Response in Murine Herpesvirus-68 Infection. Viruses 2018; 10:v10120670. [PMID: 30486363 PMCID: PMC6316452 DOI: 10.3390/v10120670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 11/15/2018] [Accepted: 11/20/2018] [Indexed: 12/25/2022] Open
Abstract
Murine herpesvirus-68 (MHV-68) productively infects mouse lungs, exhibiting a complex pathology characteristic of both acute viral infections and chronic respiratory diseases. We sought to discover proteins differentially expressed in bronchoalveolar lavage (BAL) from mice infected with MHV-68. Mice were infected intranasally with MHV-68. After nine days, as the lytic phase of infection resolved, differential BAL proteins were identified by two-dimensional (2D) electrophoresis and mass spectrometry. Of 23 unique proteins, acute phase proteins, vitamin A transport, and oxidative stress response factors Pdx6 and EC-SOD (Sod3) were enriched. Correspondingly, iNOS2 was induced in lung tissue by seven days post-infection. Oxidative stress was partly a direct result of MHV-68 infection, as reactive oxygen species (ROS) were induced in cultured murine NIH3T3 fibroblasts and human lung A549 cells infected with MHV-68. Finally, mice infected with a recombinant MHV-68 co-expressing inflammatory cytokine murine interleukin 6 (IL6) showed exacerbated oxidative stress and soluble type I collagen characteristic of tissue recovery. Thus, oxidative stress appears to be a salient feature of MHV-68 pathogenesis, in part caused by lytic replication of the virus and IL6. Proteins and small molecules in lung oxidative stress networks therefore may provide new therapeutic targets to ameliorate respiratory virus infections.
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Affiliation(s)
- Eric Bortz
- Department of Biological Sciences, University of Alaska Anchorage, Anchorage, AK 99508, USA.
| | - Ting-Ting Wu
- Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
| | - Parthive Patel
- Center for Molecular Biology and German Cancer Research Center (DKFZ), University of Heidelberg (ZMBH), 69120 Heidelberg, Germany.
| | - Julian P Whitelegge
- The Pasarow Mass Spectrometry Laboratory & the Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
| | - Ren Sun
- Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
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Contribution of the plasma and lymph Degradome and Peptidome to the MHC Ligandome. Immunogenetics 2018; 71:203-216. [PMID: 30343358 DOI: 10.1007/s00251-018-1093-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 10/09/2018] [Indexed: 12/15/2022]
Abstract
Every biological fluid, blood, interstitial fluid and lymph, urine, saliva, lacrimal fluid, nipple aspirate, and spinal fluid, contains a peptidome-degradome derived from the cellular secretome along with byproducts of the metabolic/catabolic activities of each parenchymal organ. Clement et al. (J Proteomics 78:172-187, 2013), Clement et al. (J Biol Chem 291:5576-5595, 2016), Clement et al. (PLoS One 5:e9863, 2010), Clement et al. (Trends Immunol 32:6-11, 2011), Clement et al. (Front Immunol 4:424, 2013), Geho et al. (Curr Opin Chem Biol 10, 50-55, 2006), Interewicz et al. (Lymphology 37:65‑72, 2004), Leak et al. (Proteomics 4:753‑765, 2004), Popova et al. (PLoS One 9:e110873, 2014), Zhou et al. (Electrophoresis 25:1289‑1298, 2004), D'Alessandro et al. (Shock 42:509‑517, 2014), Dzieciatkowska et al. (Shock 42:485‑498, 2014), Dzieciatkowska et al. (Shock 35:331‑338, 2011), Jordan et al. (J Surg Res 143:130‑135, 2007), Peltz et al. (Surgery 146:347‑357, 2009), Zurawel et al. (Clin Proteomics 8:1, 2011), Ling et al. (Clin Proteomics 6:175‑193, 2010), Sturm et al. (Nat Commun 4:1616, 2013). Over the last decade, qualitative and quantitative analysis of the biological fluids peptidome and degradome have provided a dynamic measurement of tissue homeostasis as well as the tissue response to pathological damage. Proteomic profiling has mapped several of the proteases and resulting degradation by-products derived from cell cycle progression, organ/tissue remodeling and cellular growth, physiological apoptosis, hemostasis, and angiogenesis. Currently, a growing interest lies in the degradome observed during pathological conditions such as cancer, autoimmune diseases, and immune responses to pathogens as a way to exploit biological fluids as liquid biopsies for biomarker discovery Dzieciatkowska et al. (Shock 42:485-498, 2014), Dzieciatkowska et al. (Shock 35:331-338, 2011), Ling et al. (Clin Proteomics 6:175-193, 2010), Ugalde et al. (Methods Mol Biol 622:3-29, 2010), Quesada et al. (Nucleic Acids Res 37:D239‑243, 2009), Cal et al. (Front Biosci 12, 4661-4669, 2007), Shen et al. (PLoS One 5:e13133, 2010a), Antwi et al. (Mol Immunol 46:2931-2937, 2009a), Antwi et al. (J Proteome Res 8:4722‑4731, 2009b), Bedin et al. (J Cell Physiol 231, 915‑925, 2016), Bery et al. (Clin Proteomics 11:13, 2014), Bhalla et al. (Sci Rep 7:1511, 2017), Fan et al. (Diagn Pathol 7:45, 2012a), Fang et al. (Shock 34:291‑298, 2010), Fiedler et al. (Clin Cancer Res 15:3812‑3819, 2009), Fredolini et al. (AAPS J 12:504‑518, 2010), Greening et al. (Enzymes 42:27‑64, 2017), He et al. (PLoS One 8:e63724, 2013), Huang et al. (Int J Gynecol Cancer 28:355‑362, 2018), Hashiguchi et al. (Med Hypotheses 73:760‑763, 2009), Liotta and Petricoin (J Clin Invest 116:26‑30, 2006), Petricoin et al. (Nat Rev Cancer 6:961‑967, 2006), Shen et al. (J Proteome Res 9:2339‑2346, 2010a), Shen et al. (J Proteome Res 5:3154‑3160, 2006), Smith (Clin Proteomics 11:23, 2014), Wang et al. (Oncotarget 8:59376‑59386, 2017), Yang et al. (Clin Exp Med 12:79‑87, 2012a), Yang et al. (J Clin Lab Anal 26:148‑154, 2012b), Yang et al. (Anat Rec (Hoboken) 293:2027‑2033, 2010), Zapico-Muniz et al. (Pancreas 39:1293‑1298, 2010), Villanueva et al. (Mol Cell Proteomics 5:1840‑1852, 2006), Robbins et al. (J Clin Oncol 23:4835‑4837, 2005), Klupczynska et al. (Int J Mol Sci 17:410, 2016). In this review, we focus on the current knowledge of the degradome/peptidome observed in two main biological fluids (plasma and lymph) during physiological and pathological conditions and its importance for immune surveillance.
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Manchanda S, Meyer M, Li Q, Liang K, Li Y, Kong N. On Comprehensive Mass Spectrometry Data Analysis for Proteome Profiling of Human Blood Samples. JOURNAL OF HEALTHCARE INFORMATICS RESEARCH 2018; 2:305-318. [DOI: 10.1007/s41666-018-0022-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 04/15/2018] [Accepted: 04/20/2018] [Indexed: 10/16/2022]
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Greco V, Piras C, Pieroni L, Ronci M, Putignani L, Roncada P, Urbani A. Applications of MALDI-TOF mass spectrometry in clinical proteomics. Expert Rev Proteomics 2018; 15:683-696. [PMID: 30058389 DOI: 10.1080/14789450.2018.1505510] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION The development of precision medicine requires advanced technologies to address the multifactorial disease stratification and to support personalized treatments. Among omics techniques, proteomics based on Mass Spectrometry (MS) is becoming increasingly relevant in clinical practice allowing a phenotypic characterization of the dynamic functional status of the organism. From this perspective, Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) MS is a suitable platform for providing a high-throughput support to clinics. Areas covered: This review aims to provide an updated overview of MALDI-TOF MS applications in clinical proteomics. The most relevant features of this analysis have been discussed, highlighting both pre-analytical and analytical factors that are crucial in proteomics studies. Particular emphasis is placed on biofluids proteomics for biomarkers discovery and on recent progresses in clinical microbiology, drug monitoring, and minimal residual disease (MRD). Expert commentary: Despite some analytical limitations, the latest technological advances together with the easiness of use, the low time and low cost consuming and the high throughput are making MALDI-TOF MS instruments very attractive for the clinical practice. These features offer a significant potential for the routine of the clinical laboratory and ultimately for personalized medicine.
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Affiliation(s)
- Viviana Greco
- a Institute of Biochemistry and Clinical Biochemistry , Università Cattolica del Sacro Cuore , Rome , Italy.,b Department of Laboratory Diagnostic and Infectious Diseases , Fondazione Policlinico Universitario Agostino Gemelli-IRCCS , Rome , Italy
| | - Cristian Piras
- c Dipartimento di Medicina Veterinaria , Università degli studi di Milano , Milano , Italy
| | - Luisa Pieroni
- d Proteomics and Metabonomics Unit , IRCCS-Fondazione Santa Lucia , Rome , Italy
| | - Maurizio Ronci
- d Proteomics and Metabonomics Unit , IRCCS-Fondazione Santa Lucia , Rome , Italy.,e Department of Medical, Oral and Biotechnological Sciences , University "G. D'Annunzio" of Chieti-Pescara , Chieti , Italy
| | - Lorenza Putignani
- f Unit of Parasitology Bambino Gesù Children's Hospital , IRCCS , Rome , Italy.,g Unit of Human Microbiome , Bambino Gesù Children's Hospital, IRCCS , Rome , Italy
| | - Paola Roncada
- h Dipartimento di Scienze della Salute , Università degli studi "Magna Græcia" di Catanzaro , Catanzaro , Italy
| | - Andrea Urbani
- a Institute of Biochemistry and Clinical Biochemistry , Università Cattolica del Sacro Cuore , Rome , Italy.,b Department of Laboratory Diagnostic and Infectious Diseases , Fondazione Policlinico Universitario Agostino Gemelli-IRCCS , Rome , Italy
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Pereira RL, Nascimento IC, Santos AP, Ogusuku IEY, Lameu C, Mayer G, Ulrich H. Aptamers: novelty tools for cancer biology. Oncotarget 2018; 9:26934-26953. [PMID: 29928493 PMCID: PMC6003562 DOI: 10.18632/oncotarget.25260] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 03/22/2018] [Indexed: 02/07/2023] Open
Abstract
Although the term ‘cancer’ was still over two thousand years away of being coined, the first known cases of the disease date back to about 3000BC, in ancient Egypt. Five thousand years later, still lacking a cure, it has become one of the leading causes of death, killing over half a dozen million people yearly. So far, monoclonal antibodies are the most successful immune-therapy tools when it comes to fighting cancer. The number of clinical trials that use them has been increasing steadily during the past few years, especially since the Food and Drug Administration greenlit the use of the first immune-checkpoint blockade antibodies. However, albeit successful, this approach does come with the cost of auto-inflammatory toxicity. Taking this into account, the development of new therapeutic reagents with low toxicity becomes evident, particularly ones acting in tandem with the tools currently at our disposal. Ever since its discovery in the early nineties, aptamer technology has been used for a wide range of diagnostic and therapeutic applications. With similar properties to those of monoclonal antibodies, such as high-specificity of recognition and high-affinity binding, and the advantages of being developed using in vitro selection procedures, aptamers quickly became convenient building blocks for the generation of multifunctional constructs. In this review, we discuss the steps involved in the in vitro selection process that leads to functional aptamers - known as Systematic Evolution of Ligands by Exponential Enrichment - as well as the most recent applications of this technology in diagnostic and treatment of oncological illnesses. Moreover, we also suggest ways to improve such use.
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Affiliation(s)
- Ricardo L Pereira
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Isis C Nascimento
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Ana P Santos
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Isabella E Y Ogusuku
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Claudiana Lameu
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Günter Mayer
- Chemical Biology and Chemical Genetics, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53121, Bonn, Germany.,Center of Aptamer Research and Development (CARD), University of Bonn, 53121, Bonn, Germany
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-900, Brazil
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Pang WW, Abdul-Rahman PS, Wan-Ibrahim WI, Hashim OH. Can the Acute-Phase Reactant Proteins be Used as Cancer Biomarkers? Int J Biol Markers 2018; 25:1-11. [DOI: 10.1177/172460081002500101] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The association between the acute-phase reactant proteins (APRPs) and cancer has long been established. There have been numerous reports correlating altered levels of various APRPs with different types of cancers. However, researchers are often quick to dismiss the use of these APRPs as potential biomarkers for the diagnosis and monitoring of cancer because alterations in APRP concentrations are observed in a wide range of diseases. Recent progress in proteomics studies which profiled the serum proteins of cancer patients and those of normal individuals indicated that the altered APRP expressions were different for distinct types, subtypes, and even stages of cancer. Interestingly, these data are in agreement with those observed earlier using immunochemical and biochemical assays. In view of this compelling association of different patterns of APRPs with various types of cancers and in an apparent shift of paradigm, we present in this review some indications that APRP fingerprinting may be used as complementary cancer biomarkers.
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Affiliation(s)
- Wei Wei Pang
- University of Malaya Centre for Proteomics Research, University of Malaya, Kuala Lumpur - Malaysia
| | - Puteri Shafinaz Abdul-Rahman
- University of Malaya Centre for Proteomics Research, University of Malaya, Kuala Lumpur - Malaysia
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur - Malaysia
| | - Wan Izlina Wan-Ibrahim
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur - Malaysia
| | - Onn Haji Hashim
- University of Malaya Centre for Proteomics Research, University of Malaya, Kuala Lumpur - Malaysia
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur - Malaysia
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Abstract
This review will highlight our current understanding of the formation, circulation, and immunological role of lymphatic fluid. The formation of the extracellular fluid depends on the net balance between the hydrostatic and osmotic pressure gradients effective in the capillary beds. Lymph originates from the extracellular fluid and its composition combines the ultrafiltrated plasma proteins with the proteome generated by the metabolic activities of each parenchymal tissue. Several analyses have indicated how the lymph composition reflects the organs' physiological and pathological states. The collected lymphatic fluid moves from the capillaries into progressively larger collectors toward the draining lymph node aided by the lymphangion contractility and unidirectional valves, which prevent backflow. The proteomic composition of the lymphatic fluid is reflected in the MHC II peptidome presented by nodal antigen-presenting cells. Taken together, the past few years have generated new interest in the formation, transport, and immunological role of the lymphatic fluid.
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Versura P, Giannaccare G, Vukatana G, Mulè R, Malavolta N, Campos EC. Predictive role of tear protein expression in the early diagnosis of Sjögren’s syndrome. Ann Clin Biochem 2018; 55:561-570. [DOI: 10.1177/0004563217750679] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background The contribution of tear protein expression in patients with presumed diagnosis of Sjögren syndrome is underestimated. We aimed to evaluate the role of tear proteins in the Sjögren syndrome early diagnosis. Methods Charts from 110 patients suspected of Sjögren syndrome were analysed and the subsequent diagnosis retrieved. Subjective symptoms (ocular surface disease index, OSDI), tear film break-up time (TFBUT), Schirmer test, Jones test, tear clearance (TC), corneal (NEI score) and conjunctival staining (van Bjerstelveldt score), esthesiometry, cytology, tear protein analysis (total protein [TP] content, lysozyme-C [LYS-C], lactoferrin [LACTO], lipocalin-1 [LIPOC-1] and albumin [ALB]) were analysed. The diagnostic performance with area under the curve (AUC) and odds ratio (OR) for each parameter were calculated. Results Thirty-five patients (31.8%) had been diagnosed as affected by Sjögren syndrome. Clinical tests showed lower diagnostic performance (OSDI > 44 [AUC 0.57], Schirmer ≤ 5 mm [0.59], TFBUT ≤ 3 s [0.72], TC > 1/16 [0.68], Jones ≤ 4 mm [0.68], corneal staining > 2 [0.51], conjunctival staining > 2 [0.78]) compared with tear proteins (LYS-C ≤ 1.5 mg/mL [0.79], LACTO ≤ 20% [0.94], LIPOC-1 ≤ 10% [0.89], ALB ≥ 15% [0.79]). LYS-C, LACTO, LIPOC-1 and ALB showed a significant association in predicting Sjögren syndrome vs. not-Sjögren syndrome dry eye (OR, respectively, 4.9, 5.5, 7.2, 6.7). Conclusions Tear proteins’ concentrations showed a significant higher accuracy compared with the traditional ocular clinical tests for reaching Sjögren syndrome’s diagnosis. In particular, LACTO and LIPOC-1 provided an excellent diagnostic performance and thus could likely be considered promising biomarkers of Sjögren syndrome.
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Affiliation(s)
- Piera Versura
- Ophthalmology Unit, DIMES, University of Bologna, Bologna, Italy
| | | | - Gentiana Vukatana
- Rheumatology Unit, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | - Rita Mulè
- Rheumatology Unit, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | | | - Emilio C Campos
- Ophthalmology Unit, DIMES, University of Bologna, Bologna, Italy
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Röthlisberger S, Pedroza-Diaz J. Urine protein biomarkers for detection of cardiovascular disease and their use for the clinic. Expert Rev Proteomics 2017; 14:1091-1103. [DOI: 10.1080/14789450.2017.1394188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Sarah Röthlisberger
- Grupo de Investigación e Innovación Biomédica, Instituto Tecnológico Metropolitano, Medellín, Colombia
| | - Johanna Pedroza-Diaz
- Grupo de Investigación e Innovación Biomédica, Instituto Tecnológico Metropolitano, Medellín, Colombia
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Murphy S, Dowling P, Zweyer M, Henry M, Meleady P, Mundegar RR, Swandulla D, Ohlendieck K. Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy. Int J Mol Med 2017; 39:1357-1370. [PMID: 28440464 PMCID: PMC5428965 DOI: 10.3892/ijmm.2017.2952] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 03/29/2017] [Indexed: 12/12/2022] Open
Abstract
X-linked muscular dystrophy is caused by primary abnormalities in the Dmd gene and is characterized by the almost complete loss of the membrane cytoskeletal protein dystrophin, which triggers sarcolemmal instability, abnormal calcium homeostasis, increased proteolysis and impaired excitation-contraction coupling. In addition to progressive necrosis, crucial secondary pathologies are represented by myofibrosis and the invasion of immune cells in damaged muscle fibres. In order to determine whether these substantial changes within the skeletal musculature are reflected by an altered rate of protein release into the circulatory system or other plasma fluctuations, we used label-free mass spectrometry to characterize serum from the mdx-4cv model of Duchenne muscular dystrophy. Comparative proteomics revealed a large number of increased vs. decreased protein species in mdx-4cv serum. A serum component with greatly elevated levels was identified as the inflammation-inducible plasma marker haptoglobin. This acute phase response protein is usually secreted in relation to tissue damage and sterile inflammation. Both immunoblot analyses and enzyme-linked immunosorbent assays confirmed the increased concentration of haptoglobin in crude mdx-4cv serum. This suggests that haptoglobin, in conjunction with other altered serum proteins, represents a novel diagnostic, prognostic and/or therapy-monitoring biomarker candidate to evaluate the inflammatory response in the mdx-4cv animal model of dystrophinopathy.
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Affiliation(s)
- Sandra Murphy
- Department of Biology, Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland
| | - Paul Dowling
- Department of Biology, Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland
| | - Margit Zweyer
- Department of Physiology II, University of Bonn, D‑53115 Bonn, Germany
| | - Michael Henry
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Paula Meleady
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Rustam R Mundegar
- Department of Physiology II, University of Bonn, D‑53115 Bonn, Germany
| | - Dieter Swandulla
- Department of Physiology II, University of Bonn, D‑53115 Bonn, Germany
| | - Kay Ohlendieck
- Department of Biology, Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland
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Hmmier A, O'Brien ME, Lynch V, Clynes M, Morgan R, Dowling P. Proteomic analysis of bronchoalveolar lavage fluid (BALF) from lung cancer patients using label-free mass spectrometry. BBA CLINICAL 2017; 7:97-104. [PMID: 28331811 PMCID: PMC5357681 DOI: 10.1016/j.bbacli.2017.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 02/08/2017] [Accepted: 03/01/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related mortality in both men and women throughout the world. The need to detect lung cancer at an early, potentially curable stage, is essential and may reduce mortality by 20%. The aim of this study was to identify distinct proteomic profiles in bronchoalveolar fluid (BALF) and plasma that are able to discriminate individuals with benign disease from those with non-small cell lung cancer (NSCLC). METHODS Using label-free mass spectrometry analysis of BALF during discovery-phase analysis, a significant number of proteins were found to have different abundance levels when comparing control to adenocarcinoma (AD) or squamous cell lung carcinoma (SqCC). Validation of candidate biomarkers identified in BALF was performed in a larger cohort of plasma samples by detection with enzyme-linked immunoassay. RESULTS Four proteins (Cystatin-C, TIMP-1, Lipocalin-2 and HSP70/HSPA1A) were selected as a representative group from discovery phase mass spectrometry BALF analysis. Plasma levels of TIMP-1, Lipocalin-2 and Cystatin-C were found to be significantly elevated in AD and SqCC compared to control. CONCLUSION The results presented in this study indicate that BALF is an important proximal biofluid for the discovery and identification of candidate lung cancer biomarkers. GENERAL SIGNIFICANCE There is good correlation between the trend of protein abundance levels in BALF and that of plasma which validates this approach to develop a blood biomarker to aid lung cancer diagnosis, particularly in the era of lung cancer screening. The protein signatures identified also provide insight into the molecular mechanisms associated with lung malignancy.
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Affiliation(s)
- Abduladim Hmmier
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland; BioNano Integration Research Group, Biotechnology Research Centre, Tripoli, Libya
| | | | - Vincent Lynch
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Martin Clynes
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Ross Morgan
- Department of Respiratory Medicine, Beaumont Hospital, Dublin 9, Ireland
| | - Paul Dowling
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
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Novel biotechnology approaches in colorectal cancer diagnosis and therapy. Biotechnol Lett 2017; 39:785-803. [DOI: 10.1007/s10529-017-2303-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 02/07/2017] [Indexed: 12/17/2022]
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Impact and influence of “omics” technology on hyper tension studies. Int J Cardiol 2017; 228:1022-1034. [DOI: 10.1016/j.ijcard.2016.11.179] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 11/06/2016] [Indexed: 12/14/2022]
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Bhosale SD, Moulder R, Kouvonen P, Lahesmaa R, Goodlett DR. Mass Spectrometry-Based Serum Proteomics for Biomarker Discovery and Validation. Methods Mol Biol 2017; 1619:451-466. [PMID: 28674903 DOI: 10.1007/978-1-4939-7057-5_31] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Blood protein measurements are used frequently in the clinic in the assessment of patient health. Nevertheless, there remains the need for new biomarkers with better diagnostic specificities. With the advent of improved technology for bioanalysis and the growth of biobanks including collections from specific disease risk cohorts, the plasma proteome has remained a target of proteomics research toward the characterization of disease-related biomarkers. The following protocol presents a workflow for serum/plasma proteomics including details of sample preparation both with and without immunoaffinity depletion of the most abundant plasma proteins and methodology for selected reaction monitoring mass spectrometry validation.
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Affiliation(s)
| | - Robert Moulder
- Turku Centre for Biotechnology, University of Turku, Turku, Finland
| | - Petri Kouvonen
- Turku Centre for Biotechnology, University of Turku, Turku, Finland
| | - Riitta Lahesmaa
- Turku Centre for Biotechnology, University of Turku, Turku, Finland
| | - David R Goodlett
- Turku Centre for Biotechnology, University of Turku, Turku, Finland. .,Department of Pharmaceutical Science, University of Maryland, 20 North Pine Street, Baltimore, MD, 21201, USA.
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Anjos L, Morgado I, Guerreiro M, Cardoso JCR, Melo EP, Power DM. Cartilage acidic protein 1, a new member of the beta-propeller protein family with amyloid propensity. Proteins 2016; 85:242-255. [DOI: 10.1002/prot.25210] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 11/06/2016] [Accepted: 11/09/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Liliana Anjos
- Comparative Endocrinology and Integrative Biology Group (CEIB), Centro de Ciencias do Mar (CCMAR), University of Algarve; Campus de Gambelas Faro 8005-139 Portugal
| | - Isabel Morgado
- Comparative Endocrinology and Integrative Biology Group (CEIB), Centro de Ciencias do Mar (CCMAR), University of Algarve; Campus de Gambelas Faro 8005-139 Portugal
| | - Marta Guerreiro
- Comparative Endocrinology and Integrative Biology Group (CEIB), Centro de Ciencias do Mar (CCMAR), University of Algarve; Campus de Gambelas Faro 8005-139 Portugal
| | - João C. R. Cardoso
- Comparative Endocrinology and Integrative Biology Group (CEIB), Centro de Ciencias do Mar (CCMAR), University of Algarve; Campus de Gambelas Faro 8005-139 Portugal
| | - Eduardo P. Melo
- Campus de Gambelas, Center for Biomedical Research, University of Algarve; Faro 8005-139 Portugal
| | - Deborah M. Power
- Comparative Endocrinology and Integrative Biology Group (CEIB), Centro de Ciencias do Mar (CCMAR), University of Algarve; Campus de Gambelas Faro 8005-139 Portugal
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Liang K, Wu H, Hu TY, Li Y. Mesoporous silica chip: enabled peptide profiling as an effective platform for controlling bio-sample quality and optimizing handling procedure. Clin Proteomics 2016; 13:34. [PMID: 27895544 PMCID: PMC5120552 DOI: 10.1186/s12014-016-9134-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 11/10/2016] [Indexed: 12/11/2022] Open
Abstract
Background High quality clinical samples are critical for meaningful interpretation of data obtained in both basic and translational medicine. More specifically, optimized pre-analysis handling to bio-sample is crucial for avoiding biased analysis in a clinical setting. A universally applicable method for the evaluation of sample quality and pre-analysis handling is therefore in great demand. Methods The fingerprint pattern of low molecular weight (LMW) peptides in sera is directly associated with sample quality and handling process. Previous studies for enrichment/isolation of LMW peptides have shown that LMW peptides can be enriched by silica meso-porous material in a sensitive and high-throughput manner. Here, a peptide profile approach utilizing mesoporous silica chip-based sample preparation combined with MALDI MS analysis was used as a new platform for evaluation of bio-sample quality. Rat sera were selected as model sample and analyzed according to their LMW peptide fingerprint spectra. Results This novel method can complete the entire sample preparation procedure in a short period of time (<40 min), requires minimum amounts of sample (<10 µL), is of high sensitivity (LOD 10 ng/mL) as well as high reproducibility (CV% < 15%). According to the acquired LMW peptide spectra, we were able to distinguish the serum samples processed under different conditions (including different storage temperature, time, and freezing/thaw cycles) with the help of bioinformatics tools (principle composition analysis and significant difference analysis), and identify the samples that had significantly changed due to the inappropriate processing. Based on the percentage of significantly changed peaks in LMW peptide mass spectrum after handling, a judgment standard was established that can be used to evaluate the status of preservation of a biological sample. In addition, our principle study established recommendations for storage time, storage temperature and freeze/thaw conditions. Conclusion Our novel method for analysis of bio-samples allows for effective identification of variations in composition within samples, and provides a cost-effective tool for simple sample manipulation in a clinical setting.
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Affiliation(s)
- Kai Liang
- Laboratory of Interdisciplinary Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101 China
| | - Hongmei Wu
- Laboratory of Interdisciplinary Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101 China ; GuangDong Bio-healtech Advanced Co., Ltd, Foshan City, 52800 GuangDong Province China
| | - Tony Y Hu
- Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX 77030 USA ; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 445 E. 69th Street, New York, NY 10021 USA
| | - Yan Li
- Laboratory of Interdisciplinary Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101 China
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42
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Wu W, Yong WW, Chung MCM. A simple biomarker scoring matrix for early gastric cancer detection. Proteomics 2016; 16:2921-2930. [PMID: 27488579 DOI: 10.1002/pmic.201600194] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 07/25/2016] [Accepted: 07/27/2016] [Indexed: 12/31/2022]
Abstract
Gastric cancer (GC) is a major cause of death in many parts of the world. While 90% of early GC is curable by resection, only about 5% of patients diagnosed in the late stages survive beyond five years. This provides strong impetus to push for early GC detection through the use of non-invasive biomarkers, before metastatic complications arise. It is also of strong medical interest to identify patients of the diffuse subtype at the earliest time possible, since the disease variant progresses very rapidly and is associated with much higher mortality rate. In this study, we compared quantitatively the gastric fluid proteome of 70 GC patients to 17 individuals with benign gastritis in search of potential biomarkers that aid in GC diagnosis, prognosis and subtype stratification. We report that as much as half of the gastric fluid proteome is subject to regulation in diseased states, and propose a simple biomarker panel scoring matrix for early GC detection with diagnostic sensitivity of 95.7%. We also demonstrate as proof-of-concept that a digitised record generated with SWATH-MS based on 380 protein abundance signatures from the gastric fluid could segregate patients with diffuse-type GC.
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Affiliation(s)
- Wei Wu
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wen Wei Yong
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maxey C M Chung
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
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43
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Qian EN, Han SY, Ding SZ, Lv X. Expression and diagnostic value of CCT3 and IQGAP3 in hepatocellular carcinoma. Cancer Cell Int 2016; 16:55. [PMID: 27390551 PMCID: PMC4936258 DOI: 10.1186/s12935-016-0332-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 06/23/2016] [Indexed: 12/14/2022] Open
Abstract
Background To evaluate plasma chaperonin containing TCP1 complex subunit 3 (CCT3) and IQ-motif-containing GTPase-activating protein-3 (IQGAP3) as biomarker for hepatocellular carcinoma (HCC) screening and diagnosis. Methods Blood samples were collected from 126 HCC patients with HCC, 88 patients with cirrhosis and 50 healthy volunteers to detect plasma α-fetoprotein (AFP), CCT3 and IQGAP3 levels. Plasma AFP, CCT3 and IQGAP3 protein levels were measured by enzyme linked immunosorbent assay (ELISA). Results In the plasma of HCC patients, both CCT3 and IQGAP3 were significantly higher than in patients with cirrhosis and in healthy controls (P < 0.01). CCT3 and IQGAP3 protein level correlated well with HCC etiology, tumor size, TNM stage, and child-pugh classification. CCT3 protein had higher sensitivity in the diagnosis of HCC when compared with AFP (87.3 vs 69.8 %). In addition, CCT3 and IQGAP3 protein were able to complement AFP in detecting AFP-negative HCC patients with sensitivity and specificity of 92.1 and 70.5 % and 81.6 and 71.6 %, respectively. In the small HCC group, CCT3 and IQGAP3 protein had sensitivity of 76.6 and 74.5 %, respectively. The combination of AFP + CCT3 + IQGAP3 (0.954) had significantly superior discriminative ability than AFP alone (0.815; P < 0.01). Conclusions CCT3 and IQGAP3 are novel complementary biomarkers for HCC screening and diagnosis, especially for AFP-negative and small HCC patients.
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Affiliation(s)
- E-Na Qian
- Department of Gastroenterology and Hepatology, People's Hospital of Zhengzhou University, No. 7 Wei Wu Road, Zhengzhou, 450003 Henan China
| | - Shuang-Yin Han
- Department of Gastroenterology and Hepatology, People's Hospital of Zhengzhou University, No. 7 Wei Wu Road, Zhengzhou, 450003 Henan China
| | - Song-Ze Ding
- Department of Gastroenterology and Hepatology, People's Hospital of Zhengzhou University, No. 7 Wei Wu Road, Zhengzhou, 450003 Henan China
| | - Xun Lv
- Department of Gastroenterology and Hepatology, People's Hospital of Zhengzhou University, No. 7 Wei Wu Road, Zhengzhou, 450003 Henan China
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44
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Ma Y, Xiao T, Xu Q, Shao X, Wang H. iTRAQ-based quantitative analysis of cancer-derived secretory proteome reveals TPM2 as a potential diagnostic biomarker of colorectal cancer. Front Med 2016; 10:278-85. [PMID: 27283175 DOI: 10.1007/s11684-016-0453-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 05/11/2016] [Indexed: 01/24/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. We aimed to find novel molecules as potential biomarkers for the early diagnosis of CRC. A serum-free conditioned medium was successfully collected from three pairs of CRC tissue and adjacent normal tissue. iTRAQ-based quantitative proteomic analysis was applied to compare the differences in secretome between primary CRC mucosa and adjacent normal mucosa. A total of 145 kinds of proteins were identified. Of these proteins, 29 were significantly different between CRC and normal tissue. Tropomyosin 2 β (TPM2) exhibited the most significant differences; as such, this protein was selected for further validation. Quantitative real-time PCR indicated that the mRNA expression of TPM2 significantly decreased in the CRC tissue compared with the paired adjacent normal tissue. Immunohistochemical analysis also confirmed that TPM2 was barely detected at protein levels in the CRC tissue. In summary, this study revealed potential molecules for future biomarker applications and provided an efficient approach for the differential analysis of cancer-associated secretome. TPM2 may be valuable for the early diagnosis of CRC.
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Affiliation(s)
- Yiming Ma
- State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Quan Xu
- Department of Gastrointestinal Cancer Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xinxin Shao
- Department of Gastrointestinal Cancer Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hongying Wang
- State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Gorelik A, Illes K, Superti-Furga G, Nagar B. Structural Basis for Nucleotide Hydrolysis by the Acid Sphingomyelinase-like Phosphodiesterase SMPDL3A. J Biol Chem 2016; 291:6376-85. [PMID: 26792860 DOI: 10.1074/jbc.m115.711085] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Indexed: 11/06/2022] Open
Abstract
Sphingomyelin phosphodiesterase, acid-like 3A (SMPDL3A) is a member of a small family of proteins founded by the well characterized lysosomal enzyme, acid sphingomyelinase (ASMase). ASMase converts sphingomyelin into the signaling lipid, ceramide. It was recently discovered that, in contrast to ASMase, SMPDL3A is inactive against sphingomyelin and, surprisingly, can instead hydrolyze nucleoside diphosphates and triphosphates, which may play a role in purinergic signaling. As none of the ASMase-like proteins has been structurally characterized to date, the molecular basis for their substrate preferences is unknown. Here we report crystal structures of murine SMPDL3A, which represent the first structures of an ASMase-like protein. The catalytic domain consists of a central mixed β-sandwich surrounded by α-helices. Additionally, SMPDL3A possesses a unique C-terminal domain formed from a cluster of four α-helices that appears to distinguish this protein family from other phosphoesterases. We show that SMDPL3A is a di-zinc-dependent enzyme with an active site configuration that suggests a mechanism of phosphodiester hydrolysis by a metal-activated water molecule and protonation of the leaving group by a histidine residue. Co-crystal structures of SMPDL3A with AMP and α,β-methylene ADP (AMPCP) reveal that the substrate binding site accommodates nucleotides by establishing interactions with their base, sugar, and phosphate moieties, with the latter the major contributor to binding affinity. Our study provides the structural basis for SMPDL3A substrate specificity and sheds new light on the function of ASMase-like proteins.
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Affiliation(s)
- Alexei Gorelik
- From the Department of Biochemistry and Groupe de Recherche Axe sur la Structure des Proteines, Faculty of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada and
| | - Katalin Illes
- From the Department of Biochemistry and Groupe de Recherche Axe sur la Structure des Proteines, Faculty of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada and
| | - Giulio Superti-Furga
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, A-1090 Vienna, Austria
| | - Bhushan Nagar
- From the Department of Biochemistry and Groupe de Recherche Axe sur la Structure des Proteines, Faculty of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada and
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46
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Clement CC, Becerra A, Yin L, Zolla V, Huang L, Merlin S, Follenzi A, Shaffer SA, Stern LJ, Santambrogio L. The Dendritic Cell Major Histocompatibility Complex II (MHC II) Peptidome Derives from a Variety of Processing Pathways and Includes Peptides with a Broad Spectrum of HLA-DM Sensitivity. J Biol Chem 2016; 291:5576-5595. [PMID: 26740625 DOI: 10.1074/jbc.m115.655738] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Indexed: 12/26/2022] Open
Abstract
The repertoire of peptides displayed in vivo by MHC II molecules derives from a wide spectrum of proteins produced by different cell types. Although intracellular endosomal processing in dendritic cells and B cells has been characterized for a few antigens, the overall range of processing pathways responsible for generating the MHC II peptidome are currently unclear. To determine the contribution of non-endosomal processing pathways, we eluted and sequenced over 3000 HLA-DR1-bound peptides presented in vivo by dendritic cells. The processing enzymes were identified by reference to a database of experimentally determined cleavage sites and experimentally validated for four epitopes derived from complement 3, collagen II, thymosin β4, and gelsolin. We determined that self-antigens processed by tissue-specific proteases, including complement, matrix metalloproteases, caspases, and granzymes, and carried by lymph, contribute significantly to the MHC II self-peptidome presented by conventional dendritic cells in vivo. Additionally, the presented peptides exhibited a wide spectrum of binding affinity and HLA-DM susceptibility. The results indicate that the HLA-DR1-restricted self-peptidome presented under physiological conditions derives from a variety of processing pathways. Non-endosomal processing enzymes add to the number of epitopes cleaved by cathepsins, altogether generating a wider peptide repertoire. Taken together with HLA-DM-dependent and-independent loading pathways, this ensures that a broad self-peptidome is presented by dendritic cells. This work brings attention to the role of "self-recognition" as a dynamic interaction between dendritic cells and the metabolic/catabolic activities ongoing in every parenchymal organ as part of tissue growth, remodeling, and physiological apoptosis.
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Affiliation(s)
| | | | | | | | | | - Simone Merlin
- the School of Medicine, University of Piemonte Orientale, 28100 Novara, Italy
| | - Antonia Follenzi
- From the Departments of Pathology and; the School of Medicine, University of Piemonte Orientale, 28100 Novara, Italy
| | - Scott A Shaffer
- Biochemistry and Molecular Pharmacology and; the Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, Massachusetts 01655, and
| | - Lawrence J Stern
- the Departments of Pathology and; Biochemistry and Molecular Pharmacology and
| | - Laura Santambrogio
- From the Departments of Pathology and; Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York 10461,.
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Wan-Ibrahim WI, Singh VA, Hashim OH, Abdul-Rahman PS. Biomarkers for Bone Tumors: Discovery from Genomics and Proteomics Studies and Their Challenges. Mol Med 2015; 21:861-872. [PMID: 26581086 DOI: 10.2119/molmed.2015.00183] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 11/12/2015] [Indexed: 01/07/2023] Open
Abstract
Diagnosis of bone tumor currently relies on imaging and biopsy, and hence, the need to find less invasive ways for its accurate detection. More recently, numerous promising deoxyribonucleic acid (DNA) and protein biomarkers with significant prognostic, diagnostic and/or predictive abilities for various types of bone tumors have been identified from genomics and proteomics studies. This article reviewed the putative biomarkers for the more common types of bone tumors (that is, osteosarcoma, Ewing sarcoma, chondrosarcoma [malignant] and giant cell tumor [benign]) that were unveiled from the studies. The benefits and drawbacks of these biomarkers, as well as the technology platforms involved in the research, were also discussed. Challenges faced in the biomarker discovery studies and the problems in their translation from the bench to the clinical settings were also addressed.
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Affiliation(s)
- Wan I Wan-Ibrahim
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Vivek A Singh
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Onn H Hashim
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,University of Malaya Centre of Proteomics Research (UMCPR), University of Malaya, Kuala Lumpur, Malaysia
| | - Puteri S Abdul-Rahman
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,University of Malaya Centre of Proteomics Research (UMCPR), University of Malaya, Kuala Lumpur, Malaysia
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48
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Kim SY, Lee HM, Kim KS, Kim HS, Moon A. Noninvasive Biomarker Candidates for Cadmium-Induced Nephrotoxicity by 2DE/MALDI-TOF-MS and SILAC/LC-MS Proteomic Analyses. Toxicol Sci 2015; 148:167-182. [PMID: 26259607 DOI: 10.1093/toxsci/kfv172] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2024] Open
Abstract
Cadmium (Cd(2+)) is a major environmental pollutant that induces cytotoxicity by heavy-metal accumulation. Prolonged Cd(2+) exposure leads to cell damage by oxidative stress mainly in the kidneys, a critical organ for detoxification. To identify reliable on invasive protein biomarkers for Cd(2+)-induced nephrotoxicity, we performed 2-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization time of flight mass spectra and stable isotope labeling by amino acids in cell culture/liquid chromatography-mass spectrometry analyses using conditioned media (CM) of HK-2 human kidney epithelial cells treated with CdCl2. Here, we identified heat shock cognate 71 kDa protein isoform1 (HSPA8) and α-enolase (ENO1) as potential biomarker candidates for the evaluation of Cd(2+)-induced nephrotoxicity. Treatment with CdCl2 increased the protein level of HSPA8 in CM and lysates of HK-2 cells. The mRNA level of HSPA8 was also increased by CdCl2 treatment, indicating transcriptional regulation. The level of ENO1 was increased in CM, but not in lysates of CdCl2-treated HK-2 cells. CdCl2 did not affect the mRNA level of ENO1. We provide evidence that the increases of HSPA8 and ENO1 in CM were due to Cd(2+)-induced cell death through oxidative stress. The increases of HSPA8 and ENO1 levels were also detected in CM of HK-2 cells treated with other nephrotoxic agents, such as HgCl2, NaAsO2, cisplatin, amphotericin B, and cyclosporine A. Urine and kidney tissues of CdCl2-treated rats showed increased levels of HSPA8. Taken together, this study identified HSPA8 and ENO1 as noninvasive biomarker candidates by 2 comparative proteomic analyses. These new biomarker candidates may have potential as alternatives to traditional biomarkers for the efficient and sensitive assessment of nephrotoxicity.
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Affiliation(s)
- Sun Young Kim
- *College of Pharmacy, Duksung Women's University, Seoul 132-714, Republic of Korea; and
| | - Hye Min Lee
- *College of Pharmacy, Duksung Women's University, Seoul 132-714, Republic of Korea; and
| | - Kyeong Seok Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
| | - Aree Moon
- *College of Pharmacy, Duksung Women's University, Seoul 132-714, Republic of Korea; and
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Enrichment of phosphorylated peptides and proteins by selective precipitation methods. Bioanalysis 2015; 7:243-52. [PMID: 25587840 DOI: 10.4155/bio.14.281] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Protein phosphorylation is one of the most prominent post-translational modifications involved in the regulation of cellular processes. Fundamental understanding of biological processes requires appropriate bioanalytical methods for selectively enriching phosphorylated peptides and proteins. Most of the commonly applied enrichment approaches include chromatographic materials including Fe(3+)-immobilized metal-ion affinity chromatography or metal oxides. In the last years, the introduction of several non-chromatographic isolation technologies has increasingly attracted the interest of many scientists. Such approaches are based on the selective precipitation of phosphorylated peptides and proteins by applying various metal cations. The excellent performance of precipitation-based enrichment methods can be explained by the absence of any stationary phase, resin or sorbent, which usually leads to unspecific binding. This review provides an overview of recently published methods for the selective precipitation of phosphorylated peptides and proteins.
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50
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Scumaci D, Tammè L, Fiumara CV, Pappaianni G, Concolino A, Leone E, Faniello MC, Quaresima B, Ricevuto E, Costanzo FS, Cuda G. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications. PLoS One 2015; 10:e0129762. [PMID: 26061043 PMCID: PMC4465499 DOI: 10.1371/journal.pone.0129762] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 05/13/2015] [Indexed: 12/16/2022] Open
Abstract
Background Breast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC. Methods To perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19), previously reported by our group, with the aim to identify specific signatures. Results The comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker. Conclusions Further analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer.
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Affiliation(s)
- Domenica Scumaci
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
- * E-mail:
| | - Laura Tammè
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Claudia Vincenza Fiumara
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Giusi Pappaianni
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Antonio Concolino
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Emanuela Leone
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Maria Concetta Faniello
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Barbara Quaresima
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Enrico Ricevuto
- Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Francesco Saverio Costanzo
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
| | - Giovanni Cuda
- Dpt. of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Salvatore Venuta University Campus, Catanzaro, Italy
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