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Wang H, Wang Y, Zhang D, Li P. Circulating nucleosomes as potential biomarkers for cancer diagnosis and treatment monitoring. Int J Biol Macromol 2024; 262:130005. [PMID: 38331061 DOI: 10.1016/j.ijbiomac.2024.130005] [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] [Received: 11/29/2023] [Revised: 01/03/2024] [Accepted: 02/04/2024] [Indexed: 02/10/2024]
Abstract
Nucleosomes play a crucial role in regulating gene expression through their composition and post-translational modifications. When cells die, intracellular endonucleases are activated and cleave chromatin into oligo- and mono-nucleosomes, which are then released into the body fluids. Studies have shown that the levels of nucleosomes are increased in serum and plasma in various cancer types, suggesting that analysis of circulating nucleosomes can provide an initial assessment of carcinogenesis. However, it should be noted that elevated serum nucleosome levels may not accurately diagnose certain tumor types, as increased cell death may occur in different pathological conditions. Nevertheless, detection of circulating nucleosomes and their histone modifications, along with specific tumor markers, can help diagnose certain types of cancer. Furthermore, monitoring changes in circulating nucleosome levels during chemotherapy or radiotherapy in patients with malignancies can provide valuable insights into clinical outcomes and therapeutic efficacy. The utilization of circulating nucleosomes as biomarkers is an exciting and emerging area of research, with the potential for early detection of various diseases and monitoring of treatment response. Integrating nucleosome-based biomarkers with existing ones may improve the specificity and sensitivity of current assays, offering the possibility of personalized precision medical treatment for patients.
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Affiliation(s)
- Huawei Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, 1 Ningde Road, Qingdao 266073, China.
| | - Yin Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, 1 Ningde Road, Qingdao 266073, China.
| | - Dejiu Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, 1 Ningde Road, Qingdao 266073, China.
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, 1 Ningde Road, Qingdao 266073, China.
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Chen Z, Li C, Zhou Y, Yao Y, Liu J, Wu M, Su J. Liquid biopsies for cancer: From bench to clinic. MedComm (Beijing) 2023; 4:e329. [PMID: 37492785 PMCID: PMC10363811 DOI: 10.1002/mco2.329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 07/27/2023] Open
Abstract
Over the past two decades, liquid biopsy has been increasingly used as a supplement, or even, a replacement to the traditional biopsy in clinical oncological practice, due to its noninvasive and early detectable properties. The detections can be based on a variety of features extracted from tumor‑derived entities, such as quantitative alterations, genetic changes, and epigenetic aberrations, and so on. So far, the clinical applications of cancer liquid biopsy mainly aimed at two aspects, prediction (early diagnosis, prognosis and recurrent evaluation, therapeutic response monitoring, etc.) and intervention. In spite of the rapid development and great contributions achieved, cancer liquid biopsy is still a field under investigation and deserves more clinical practice. To better open up future work, here we systematically reviewed and compared the latest progress of the most widely recognized circulating components, including circulating tumor cells, cell-free circulating DNA, noncoding RNA, and nucleosomes, from their discovery histories to clinical values. According to the features applied, we particularly divided the contents into two parts, beyond epigenetics and epigenetic-based. The latter was considered as the highlight along with a brief overview of the advances in both experimental and bioinformatic approaches, due to its unique advantages and relatively lack of documentation.
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Affiliation(s)
- Zhenhui Chen
- School of Biomedical EngineeringSchool of Ophthalmology & Optometry and Eye HospitalWenzhou Medical UniversityWenzhouZhejiangChina
- Oujiang LaboratoryZhejiang Lab for Regenerative MedicineVision and Brain HealthWenzhouZhejiangChina
| | - Chenghao Li
- School of Biomedical EngineeringSchool of Ophthalmology & Optometry and Eye HospitalWenzhou Medical UniversityWenzhouZhejiangChina
| | - Yue Zhou
- School of Biomedical EngineeringSchool of Ophthalmology & Optometry and Eye HospitalWenzhou Medical UniversityWenzhouZhejiangChina
- Oujiang LaboratoryZhejiang Lab for Regenerative MedicineVision and Brain HealthWenzhouZhejiangChina
| | - Yinghao Yao
- Oujiang LaboratoryZhejiang Lab for Regenerative MedicineVision and Brain HealthWenzhouZhejiangChina
| | - Jiaqi Liu
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Min Wu
- Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiangChina
| | - Jianzhong Su
- School of Biomedical EngineeringSchool of Ophthalmology & Optometry and Eye HospitalWenzhou Medical UniversityWenzhouZhejiangChina
- Oujiang LaboratoryZhejiang Lab for Regenerative MedicineVision and Brain HealthWenzhouZhejiangChina
- Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiangChina
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Main SC, Cescon DW, Bratman SV. Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:727-748. [PMID: 36176758 PMCID: PMC9511796 DOI: 10.20517/cdr.2022.37] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/04/2022] [Accepted: 05/25/2022] [Indexed: 06/16/2023]
Abstract
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. However, some patients do not respond to this treatment, and patients inevitably develop resistance, such that novel biomarkers are needed to predict primary resistance, monitor treatment response for acquired resistance, and personalize treatment strategies. Circumventing the spatial and temporal limitations of tissue biopsy, newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test. Studies on circulating tumor DNA (ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers, but emerging epigenetic ctDNA methodologies hold promise for further discovery. The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.
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Affiliation(s)
- Sasha C Main
- Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C1, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto M5G 1L7, Ontario, Canada
| | - David W Cescon
- Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C1, Ontario, Canada
- Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto M5S 1A8, Ontario, Canada
| | - Scott V Bratman
- Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C1, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto M5G 1L7, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto M5T 1P5, Ontario, Canada
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Abstract
Cell-free DNA (cfDNA) has the potential to enable non-invasive detection of disease states and progression. Beyond its sequence, cfDNA also represents the nucleosomal landscape of cell(s)-of-origin and captures the dynamics of the epigenome. In this review, we highlight the emergence of cfDNA epigenomic methods that assess disease beyond the scope of mutant tumour genotyping. Detection of tumour mutations is the gold standard for sequencing methods in clinical oncology. However, limitations inherent to mutation targeting in cfDNA, and the possibilities of uncovering molecular mechanisms underlying disease, have made epigenomics of cfDNA an exciting alternative. We discuss the epigenomic information revealed by cfDNA, and how epigenomic methods exploit cfDNA to detect and characterize cancer. Future applications of cfDNA epigenomic methods to act complementarily and orthogonally to current clinical practices has the potential to transform cancer management and improve cancer patient outcomes.
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Affiliation(s)
| | | | - Srinivas Ramachandran
- RNA Bioscience Initiative, and Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Mail Stop: 8101, 12801 East 17th Avenue L18–9102, Aurora, CO 80045, USA
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Vad-Nielsen J, Meldgaard P, Sorensen BS, Nielsen AL. Cell-free Chromatin Immunoprecipitation (cfChIP) from blood plasma can determine gene-expression in tumors from non-small-cell lung cancer patients. Lung Cancer 2020; 147:244-251. [PMID: 32759018 DOI: 10.1016/j.lungcan.2020.07.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/03/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Lung cancer is the leading cause of cancer related death worldwide. Accurate molecular diagnostics from a tumor biopsy is paramount for correct diagnosis, treatment strategy, and prediction of outcome. However, a tumor biopsy can be misleading due to tumor heterogeneity and consecutive biopsies are rarely achievable. Importantly, tumor-specific genetic information concerning mutations and translocations, can also be obtained from liquid biopsies, e.g. blood plasma, containing cell-free DNA (cfDNA) with both systemic and tumor origin. Tumor-specific gene-expression information can also be determined from liquid biopsies using cfDNA methylation and cell-free RNA analyses. However, supplementary methodologies that can determine gene-expression patterns in lung tumors from liquid biopsies could also have diagnostic impact. MATERIALS AND METHODS We here present the method cell-free chromatin Immunoprecipitation (cfChIP), which for genes having high expression specifically in the tumor, can determine such gene-expression from blood plasma. In cfChIP cell-free nucleosomes modified with histone H3 lysine 36 tri-methylation (H3K36me3), a mark quantitatively correlated with the transcription of the underlying gene, are isolated, and associated cfDNA quantified. RESULTS We demonstrate that cfChIP from lung cancer patient blood plasma can successfully quantify the level of H3K36me3 associated with circulating cell-free nucleosomes and thereby quantify the transcriptional level of genes associated with these nucleosomes. Moreover, as a proof-of-principle we show that in blood plasma from 14 lung cancer patients, H3K36me3 cfChIP can replicate the expected higher expression of KRT6 in lung squamous cell carcinoma relative to adenocarcinoma. CONCLUSION This work shows that for genes with a high expression specifically in tumor, cfChIP can determine this gene-expression pattern from blood plasma. cfChIP is a method that determine gene-expression at the transcriptional level and accordingly can supplement cfDNA methylation and cell-free RNA analyses.
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Wimmer K, Sachet M, Oehler R. Circulating biomarkers of cell death. Clin Chim Acta 2019; 500:87-97. [PMID: 31655053 DOI: 10.1016/j.cca.2019.10.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 10/02/2019] [Accepted: 10/03/2019] [Indexed: 12/15/2022]
Abstract
Numerous disease states are associated with cell death. For many decades, apoptosis and accidental necrosis have been assumed to be the two ways how a cell can die. The recent discovery of additional cell death processes such as necroptosis, ferroptosis or pyroptosis revealed a complex interplay between cell death mechanisms and diseases. Depending on the particular cell death pathway, cells secrete distinct molecular patterns, which differ between cell death types. This review focusses on released molecules, detectable in the blood flow, and their potential role as circulating biomarkers of cell death. We elucidate the molecular background of different biomarkers and give an overview on their correlation with disease stage, therapy response and prognosis in patients.
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Affiliation(s)
- Kerstin Wimmer
- Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Monika Sachet
- Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Rudolf Oehler
- Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
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Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum. Cancers (Basel) 2018; 10:cancers10040101. [PMID: 29614786 PMCID: PMC5923356 DOI: 10.3390/cancers10040101] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 03/23/2018] [Accepted: 03/27/2018] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic modifications are an early event in carcinogenesis, with the epigenetic landscape continuing to change during tumor progression and metastasis—these observations suggest that specific epigenetic modifications could be used as diagnostic and prognostic biomarkers for many cancer types. DNA methylation, post-translational histone modifications, and non-coding RNAs are all dysregulated in cancer and are detectable to various degrees in liquid biopsies such as sputum, urine, stool, and blood. Here, we will focus on the application of liquid biopsies, as opposed to tissue biopsies, because of their potential as non-invasive diagnostic tools and possible use in monitoring therapy response and progression to metastatic disease. This includes a discussion of septin-9 (SEPT9) DNA hypermethylation for detecting colorectal cancer, which is by far the most developed epigenetic biomarker assay. Despite their potential as prognostic and diagnostic biomarkers, technical issues such as inconsistent methodology between studies, overall low yield of epigenetic material in samples, and the need for improved histone and non-coding RNA purification methods are limiting the use of epigenetic biomarkers. Once these technical limitations are overcome, epigenetic biomarkers could be used to monitor cancer development, disease progression, therapeutic response, and recurrence across the entire cancer care continuum.
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Reddy D, Khade B, Pandya R, Gupta S. A novel method for isolation of histones from serum and its implications in therapeutics and prognosis of solid tumours. Clin Epigenetics 2017; 9:30. [PMID: 28360947 PMCID: PMC5372264 DOI: 10.1186/s13148-017-0330-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 03/20/2017] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Dysregulation in post-translational modifications of histones and their modifiers are now well-recognized as a hallmark of cancer and can be used as biomarkers and potential therapeutic targets for disease progression and prognosis. In most solid tumours, a biopsy is challenging, costly, painful or potentially risky for the patient. Therefore, non-invasive methods like 'liquid biopsy' for analysis of histone modifications and their modifiers if possible will be helpful in the better clinical management of cancer patients. METHODS Here, we have developed a cost-effective and time-efficient protocol for isolation of circulating histones from serum of solid tumor, HCC, called Dual Acid Extraction (DAE) protocol and have confirmed by mass spectrometry. Also, we measured the activity of HDACs and HATs in serum samples. RESULTS The serum purified histones were profiled for changes in histone PTMs and have shown a comparable pattern of modifications like acetylation (H4K16Ac), methylation (H4K20Me3, H3K27Me3, H3K9Me3) and phosphorylation (γ-H2AX and H3S10P) to paired cancer tissues. Profiling for the histone PTM changes in various other organs of normal and tumor bearing animal suggests that the changes in the histone PTMs observed in the tumor serum is indeed due to changes in the tumor tissue only. Further, we demonstrate that the observed hypo-acetylation of histone H4 in tissue and serum samples of tumor bearing animals corroborated with the elevated HDAC activity in both samples compared to normal. Interestingly, human normal and tumor serum samples also showed elevated HDAC activity with no significant changes in HAT activity. CONCLUSIONS Our study provides the first evidence in the context of histone PTMs and modifiers that liquid biopsy is a valuable predictive tool for monitoring disease progression. Importantly, with the advent of drugs that target specific enzymes involved in the epigenetic regulation of gene expression, liquid biopsy-based 'real time' monitoring will be useful for subgrouping of the patients for epi-drug treatment, predicting response to therapy, early relapse and prognosis.
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Affiliation(s)
- Divya Reddy
- 0000 0004 1769 5793grid.410871.bEpigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi, Mumbai, 410210 MH India
- 0000 0004 1775 9822grid.450257.1Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India
| | - Bharat Khade
- 0000 0004 1769 5793grid.410871.bEpigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi, Mumbai, 410210 MH India
| | - Riddhi Pandya
- 0000 0004 1769 5793grid.410871.bEpigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi, Mumbai, 410210 MH India
| | - Sanjay Gupta
- 0000 0004 1769 5793grid.410871.bEpigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi, Mumbai, 410210 MH India
- 0000 0004 1775 9822grid.450257.1Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India
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Yörüker EE, Holdenrieder S, Gezer U. Blood-based biomarkers for diagnosis, prognosis and treatment of colorectal cancer. Clin Chim Acta 2016; 455:26-32. [PMID: 26797671 DOI: 10.1016/j.cca.2016.01.016] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/15/2016] [Accepted: 01/16/2016] [Indexed: 02/07/2023]
Abstract
The global burden of colorectal cancer (CRC)-associated morbidity and mortality is increasing, in part due to a lack of early detection. Direct structural examination techniques, such as colonoscopy, are invasive and can therefore affect the willingness of patients to participate in screening. Recently, the use of "liquid biopsy" has gained considerable attention as a novel source of biomarkers. Blood-based biomarkers could prove to be practical tools for CRC detection, as the monitoring of biomarkers in biological fluids offers many advantages, including minimal invasiveness and easy accessibility. Biomarkers with high specificity and sensitivity can enable the detection of CRC at an early stage, thereby improving prognosis, prediction of treatment response, and recurrence risk. In this review, we summarize that the biomarkers currently thought to have potential for the early detection and monitoring of CRC, including circulating tumor cells, DNA, RNA and proteins.
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Affiliation(s)
- Ebru E Yörüker
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
| | - Stefan Holdenrieder
- Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Ugur Gezer
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey.
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Khan SA, Reddy D, Gupta S. Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis and treatment? World J Biol Chem 2015; 6:333-345. [PMID: 26629316 PMCID: PMC4657128 DOI: 10.4331/wjbc.v6.i4.333] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/10/2015] [Accepted: 10/08/2015] [Indexed: 02/05/2023] Open
Abstract
Global alterations in epigenetic landscape are now recognized as a hallmark of cancer. Epigenetic mechanisms such as DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs are proven to have strong association with cancer. In particular, covalent post-translational modifications of histone proteins are known to play an important role in chromatin remodeling and thereby in regulation of gene expression. Further, histone modifications have also been associated with different aspects of carcinogenesis and have been studied for their role in the better management of cancer patients. In this review, we will explore and discuss how histone modifications are involved in cancer diagnosis, prognosis and treatment.
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Hudler P. Challenges of deciphering gastric cancer heterogeneity. World J Gastroenterol 2015; 21:10510-10527. [PMID: 26457012 PMCID: PMC4588074 DOI: 10.3748/wjg.v21.i37.10510] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/19/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is in decline in most developed countries; however, it still accounts for a notable fraction of global mortality and morbidity related to cancer. High-throughput methods are rapidly changing our view and understanding of the molecular basis of gastric carcinogenesis. Today, it is widely accepted that the molecular complexity and heterogeneity, both inter- and intra-tumour, of gastric adenocarcinomas present significant obstacles in elucidating specific biomarkers for early detection of the disease. Although genome-wide sequencing and gene expression studies have revealed the intricate nature of the molecular changes that occur in tumour landscapes, the collected data and results are complex and sometimes contradictory. Several aberrant molecules have already been tested in clinical trials, although their diagnostic and prognostic utilities have not been confirmed thus far. The gold standard for the detection of sporadic gastric cancer is still the gastric endoscopy, which is considered invasive. In addition, genome-wide association studies have confirmed that genetic variations are important contributors to increased cancer risk and could participate in the initiation of malignant transformation. This hypothesis could in part explain the late onset of sporadic gastric cancers. The elaborate interplay of polymorphic low penetrance genes and lifestyle and environmental risk factors requires additional research to decipher their relative impacts on tumorigenesis. The purpose of this article is to present details of the molecular heterogeneity of sporadic gastric cancers at the DNA, RNA, and proteome levels and to discuss issues relevant to the translation of basic research data to clinically valuable tools. The focus of this work is the identification of relevant molecular changes that could be detected non-invasively.
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Cantone L, Angelici L, Bollati V, Bonzini M, Apostoli P, Tripodi A, Bertazzi PA, Baccarelli AA. Extracellular histones mediate the effects of metal-rich air particles on blood coagulation. ENVIRONMENTAL RESEARCH 2014; 132:76-82. [PMID: 24742731 PMCID: PMC4387237 DOI: 10.1016/j.envres.2014.03.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 02/10/2014] [Accepted: 03/10/2014] [Indexed: 05/04/2023]
Abstract
BACKGROUND Epidemiological studies have shown associations of particulate matter (PM) exposure with hypercoagulability and thrombosis. Extracellular circulating histones have recently been identified as novel mediators of inflammatory and procoagulant responses. The potential roles of extracellular histones in PM-related hypercoagulability have yet not been investigated. OBJECTIVES In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (H3K4me3 and H3K9ac); and the association of H3K4me3 and H3K9ac with coagulation markers. METHODS Extracellular H3K4me3 and H3K9ac were determined in plasma through enzyme-linked immunosorbent assays. Coagulation markers included endogenous thrombin potentials (ETPs), tissue-type plasminogen activator antigen (t-PA) and D-dimer. Exposure to PM with aerodynamic diameters <1 μm (PM1) or <10 μm (PM10) and PM10 metal components were estimated for each participant. RESULTS The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (β=107.84, p=0.03), PM10 (β=83.06, p=0.02), and zinc (β=75.14, p=0.03); and a marginal association with iron (β=122.58, p=0.07). Additional PM effects were observed on t-PA, D-dimer, and ETP TM+. PM1 exposure was associated with increased plasma H3K4me3 and H3K9ac (β=0.20, p=0.02; β=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (β=0.13, p=0.03) and iron (β=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (β=0.50, p=0.05) and H3K9ac (β=0.54, p=0.05). CONCLUSIONS This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.
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Affiliation(s)
- L Cantone
- Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - L Angelici
- Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - V Bollati
- Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - M Bonzini
- Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
| | - P Apostoli
- Occupational Medicine and Industrial Hygiene, University of Brescia, Department of Experimental and Applied Medicine, Brescia, Italy
| | - A Tripodi
- Angelo Bianchi-Bonomi Haemophilia and Thrombosis Centre, Department of Medicine and Medical Specialties, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy
| | - P A Bertazzi
- Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - A A Baccarelli
- Laboratory of Environmental Epigenetics, Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA.
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Dilek AR, Dilek N, Saral Y, Yüksel D. The relationship between severity of the disease and circulating nucleosomes in psoriasis patients. Arch Dermatol Res 2013; 305:483-7. [PMID: 23567920 DOI: 10.1007/s00403-013-1347-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 03/20/2013] [Accepted: 03/22/2013] [Indexed: 12/11/2022]
Abstract
Psoriasis was initially considered to represent a disease of abnormal epidermal keratinocyte proliferation. Proliferation of keratinocytes is restricted by apoptotic cell death to maintain a constant thickness of epidermis. Nucleosomes are mainly released by apoptotic cells. Tumor necrosis factor-α (TNF-α) is an important factor affecting the apoptosis. In the present study, the relationship between TNF-α, nucleosome and the Psoriasis Area and Severity Index (PASI) score was investigated. The patients were divided according to PASI score into three groups (mild, moderately, severe). Serum TNF-α and nucleosome levels were measured using Enzyme-linked immunosorbent assay (ELISA) method. Our findings show a correct relationship between PASI scores and TNF-α and an inverse relationship between nucleosome and PASI score. According to the results obtained from the study, we believe that serum nucleosome levels can be used as a new indicator in follow-up of patients with psoriasis and monitoring of the effectiveness of drugs which used in the treatment of psoriasis.
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Affiliation(s)
- Aziz Ramazan Dilek
- Microbiology Department of Recep Tayyip Erdoğan University, Medical Faculty Hospital, Rize, 53000, Turkey.
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Mayer J, Beck J, Soller JT, Wemheuer W, Schütz E, Brenig B. Analysis of circulating DNA distribution in pregnant and nonpregnant dairy cows. Biol Reprod 2013; 88:29. [PMID: 23255334 DOI: 10.1095/biolreprod.112.103168] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Circulating nucleic acids (CNAs) are free-floating, cell-free DNA and RNA molecules in the circulation of healthy and diseased humans and animals. The aim of this study was to identify differences in CNA distribution in serum samples from multiparous pregnant (n = 24) and nonpregnant (n = 16) dairy cows at different days of gestation (Days 0, 20, and 40). A modified serial analysis of gene expression procedure was used to generate concatemerized short sequence tags from isolated serum DNA. A total of 6.1 × 10(6) tags were recovered from analyzed samples (n = 40). Significant differences between the pregnant and nonpregnant groups were detected in chromosomal regions, protein-coding sequences, and single genes (P < 0.05). Approximately 23% (1.4 × 10(6) tags) of the total sequence pool were present exclusively in the analyzed serum samples of pregnant cows. Of these tag sequences, seven originated from genomic regions and 13 from repetitive elements. Comparative BLAST analysis identified the repetitive tags as BovB (non-long terminal repeat retrotransposons/long interspersed nuclear elements), Art2A, BovA2, and Bov-tA2 (short interspersed nuclear elements). To our knowledge, this is the first study to comprehensively characterize the circulating, cell-free DNA profile in sera from pregnant and nonpregnant cows across early gestation.
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Affiliation(s)
- Jennifer Mayer
- Institute of Veterinary Medicine, University of Göttingen, Göttingen, Germany
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Characterization of H3K9me3- and H4K20me3-associated circulating nucleosomal DNA by high-throughput sequencing in colorectal cancer. Tumour Biol 2012; 34:329-36. [PMID: 23086575 DOI: 10.1007/s13277-012-0554-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 10/03/2012] [Indexed: 12/23/2022] Open
Abstract
Modified histone tails in nucleosomes circulating in the blood bear the potential as cancer biomarkers. Recently, using chromatin immunopecipitation (ChIP)-related quantitative PCR, we described reduced plasma levels of the two pericentric heterochromatin-specific histone methylation marks H3K9me3 and H4K20me3 in patients with colorectal cancer (CRC). Here, by utilizing ChIP-related high-throughput sequencing, we further characterized these modifications in circulation. Plasma DNA from nucleosomes immunoprecipitated by H3K9me3- and H4K20me3-specific antibodies from patients with CRC (N = 15) and healthy subjects (N = 15) was subjected to the Roche 454 FLX sequencing, and the generated array of ChIP-enriched sequences were compared to the human reference genome. The total number of nucleosomes, of sequence reads and of diverse DNA repetitive elements were statistically compared between the study groups. Total nucleosome amount was not different in both groups. Concerning both histone modifications, lower numbers of sequence reads were detected in CRC patients as compared with healthy controls (medians in H3K9me3: 32 vs. 61; p < 0.01; in H4K20me3: 54 vs. 88; p < 0.01). Size of fragments was not different in both groups. Most abundant sequences were repetitive LINE and SINE elements while simple repeats, LTR, DNA, SAT, and low complexity elements were less frequent. Best discrimination between both groups was achieved by total number of H3K9me3 reads (AUC 0.90) and H3K9me3 LINE elements L1 (AUC 0.93) und L2 (AUC 0.91). The present results confirm earlier findings of lower H3K9me3 levels in CRC and show LINE elements to be the most frequent and best discriminative markers on modified histones.
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Pasic MD, Olkhov E, Bapat B, Yousef GM. Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there. Biol Chem 2012; 393:319-30. [PMID: 22505515 DOI: 10.1515/hsz-2011-0273] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 01/20/2012] [Indexed: 11/15/2022]
Abstract
The human kallikreins are a cluster of 15 kallikreins and kallikrein-related peptidases (KLKs). Evidence shows the involvement of KLKs in a wide range of pathophysiological processes, and underscores their potential contribution to cancer, skin and neurodegenerative disorders. The control of KLK expression is not fully elucidated. Understanding the mechanisms controlling KLK expression is an essential step towards exploring the pathogenesis of several diseases and the use of KLKs as disease biomarkers and/or therapeutic targets. Recently, epigenetic changes (including methylation, histone modification and microRNAs [miRNAs]) have drawn attention as a new dimension for controlling KLK expression. Reports showed the effect of methylation on the expression of KLK genes. This was also shown to have potential utility as a prognostic marker in cancer. miRNAs are small RNAs that control the expression of their targets at the post-transcriptional level. Target prediction showed that KLKs are potential targets of miRNAs that are dysregulated in tumors, including prostate, kidney and ovarian cancers, with downstream effect on tumor proliferation. Experimental validation remains an essential step to confirm the KLK-miRNA interaction. Epigenetic regulation of KLKs holds promise for an array of therapeutic applications in many diseases including cancer.
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Affiliation(s)
- Maria D Pasic
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
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Epigenetic biomarkers in prostate cancer: Current and future uses. Cancer Lett 2012; 342:248-56. [PMID: 22391123 DOI: 10.1016/j.canlet.2012.02.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Revised: 02/10/2012] [Accepted: 02/11/2012] [Indexed: 12/18/2022]
Abstract
Epigenome alterations are characteristic of nearly all human malignancies and include changes in DNA methylation, histone modifications and microRNAs (miRNAs). However, what induces these epigenetic alterations in cancer is largely unknown and their mechanistic role in prostate tumorigenesis is just beginning to be evaluated. Identification of the epigenetic modifications involved in the development and progression of prostate cancer will not only identify novel therapeutic targets but also prognostic and diagnostic markers. This review will focus on the use of epigenetic modifications as biomarkers for prostate cancer.
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Gezer U, Mert U, Ozgür E, Yörüker EE, Holdenrieder S, Dalay N. Correlation of histone methyl marks with circulating nucleosomes in blood plasma of cancer patients. Oncol Lett 2012; 3:1095-1098. [PMID: 22783398 DOI: 10.3892/ol.2012.600] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 02/06/2012] [Indexed: 12/14/2022] Open
Abstract
Circulating DNA is present in plasma/serum, mainly complexed with histones as nucleosomes. The detection of circulating nucleosomes (cNUCs) in the peripheral blood may be a diagnostic modality for cancer-associated changes of modified histone tails in blood circulation. In the present study, we investigated the correlation between the trimethylation of H3 lysine 9 (H3K9me3) and H4 lysine 20 (H4K20me3), which are hallmarks of pericentric heterochromatin, and cNUCs in healthy subjects and patients with colorectal cancer (CRC) and multiple myeloma (MM). The plasma concentration of cNUCs was measured using the Cell-Death Detection ELISA kit. Histone methylation marks were detected using chromatin immunoprecipitation (ChIP), followed by quantitative PCR with pericentric satellite 2 as the target sequence. The results showed a high variation in the concentrations of cNUCs, with healthy subjects exhibiting the lowest levels (median 0.194), the CRC patients intermediate (median 0.25) and the MM patients the highest levels (median 0.648). However, the differences between the groups did not reach statistical significance (p>0.05). Analysis using the Pearson's correlation test revealed a significant positive correlation between the concentration of cNUCs and H3K9me3 and H4K20me3 in the whole study group (N=57, p<0.001 for both histone marks). A study of the correlation between cNUCs and histone marks in the individual study groups demonstrated the correlation between cNUCs and H3K9me3 in CRC patients to be weak (p=0.046), indicating that circulating H3K9me3 may be modified in CRC patients. The histone marks were normalized using the values of cNUCs. In agreement with the weak correlation between cNUCs and H3K9me3 in CRC patients, H3K9me3 levels (median 0.047) were lowest in this group compared with the other two groups (0.06 in healthy subjects, 0.2 in MM patients, p = not significant). For H4K20me3, the median values were 0.022 in healthy subjects, 0.052 in CRC patients and 0.056 in MM patients. In conclusion, our findings indicate a marked correlation between cNUCs and histone methyl marks.
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Affiliation(s)
- Ugur Gezer
- Department of Basic Oncology, Oncology Institute, Istanbul University, Capa 34390, Istanbul, Turkey
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Abstract
It is now widely recognized that epigenetic events are important mechanisms underlying cancer development and progression. Epigenetic information in chromatin includes covalent modifications (such as acetylation, methylation, phosphorylation, and ubiquitination) of core nucleosomal proteins (histones). A recent progress in the field of histone modifications and chromatin research has tremendously enhanced our understanding of the mechanisms underlying the control of key physiological and pathological processes. Histone modifications and other epigenetic mechanisms appear to work together in establishing and maintaining gene activity states, thus regulating a wide range of cellular processes. Different histone modifications themselves act in a coordinated and orderly fashion to regulate cellular processes such as gene transcription, DNA replication, and DNA repair. Interest in histone modifications has further grown over the last decade with the discovery and characterization of a large number of histone-modifying molecules and protein complexes. Alterations in the function of histone-modifying complexes are believed to disrupt the pattern and levels of histone marks and consequently deregulate the control of chromatin-based processes, ultimately leading to oncogenic transformation and the development of cancer. Consistent with this notion, aberrant patterns of histone modifications have been associated with a large number of human malignancies. In this chapter, we discuss recent advances in our understanding of the mechanisms controlling the establishment and maintenance of histone marks and how disruptions of these chromatin-based mechanisms contribute to tumorigenesis. We also suggest how these advances may facilitate the development of novel strategies to prevent, diagnose, and treat human malignancies.
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Affiliation(s)
- Carla Sawan
- Epigenetics Group, International Agency for Research on Cancer ,69008 Lyon, France
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Post-treatment circulating plasma BMP6 mRNA and H3K27 methylation levels discriminate metastatic prostate cancer from localized disease. Clin Chim Acta 2010; 411:1452-6. [PMID: 20573596 DOI: 10.1016/j.cca.2010.05.040] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Revised: 05/27/2010] [Accepted: 05/27/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND We evaluated the utility of post-treatment plasma levels of the circulating bone-morphogenetic protein-6-specific mRNA (cBMP6 mRNA), cell-free DNA (cf-DNA), apoptotic nucleosomes and Histone H3 lysine 27 trimethylation (H3K27me3), in discriminating metastatic prostate cancer (PCa) from organ confined, locally controlled disease. METHODS Peripheral blood was taken from the patients at the end of therapy, and quantitative PCR was performed to amplify cBMP6 mRNA or cf-DNA from plasma while apoptotic nucleosomes and H3K27me3 were determined by ELISA-based approaches. Following blinded measurements, the markers were compared between the patients with local (n=22), local advanced (n=11) or metastatic disease (n=28). RESULTS Of the four markers investigated, the cBMP6 mRNA and H3K27me3 levels revealed significant differences between the three subgroups. We found higher levels of cBMP6 mRNA in the patients with metastases than in those with localized (p=0.001) or local advanced disease (p=0.05). When compared to cBMP6, H3K27me3 displayed an inverse distribution and was significantly lower in the patients with metastatic disease than in those with localized (p=0.05) or local advanced disease (p=0.024). There was no correlation between the different markers and total PSA levels or Gleason score at diagnosis. CONCLUSION Our study provides evidence that post-treatment analysis of cBMP6 mRNA and H3K27me3 may be used to distinguish metastatic PCa from organ confined, locally controlled disease.
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Beck J, Urnovitz HB, Mitchell WM, Schütz E. Next generation sequencing of serum circulating nucleic acids from patients with invasive ductal breast cancer reveals differences to healthy and nonmalignant controls. Mol Cancer Res 2010; 8:335-42. [PMID: 20215424 DOI: 10.1158/1541-7786.mcr-09-0314] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Circulating nucleic acids (CNA) isolated from serum or plasma are increasingly recognized as biomarkers for cancers. Recently developed next generation sequencing provides high numbers of DNA sequences to detect the trace amounts of unique serum biomarkers associated with breast carcinoma. Serum CNA of 38 women with ductal carcinoma was extracted and sequenced on a 454/Roche high-throughput GS-FLX platform and compared with healthy controls and patients with other medical conditions. Repetitive elements present in CNA were detected and classified, and each repetitive element was normalized based on total sequence count or repeat count. Multivariate regression models were calculated using an information-theoretical approach and multimodel inference. A total of 423,150 and 953,545 sequences for the cancer patients and controls, respectively, were obtained. Data from 26 patients with stages II to IV tumors and from 67 apparently healthy female controls were used as the training data set. Using a bootstrap method to avoid sampling bias, a five-parameter model was developed. When this model was applied to a validation data set consisting of patients with tumor stage I (n = 10) compared with healthy and nonmalignant disease controls (n = 87; 1,261,561 sequences) a sensitivity of 70% at a specificity of 100% was obtained. At a diagnostic specificity level of 95%, a sensitivity of 90% was calculated. Identification of specific breast cancer-related CNA sequences provides the basis for the development of a serum-based routine laboratory test for breast cancer screening and monitoring.
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Affiliation(s)
- Julia Beck
- Chronix Biomedical GmbH, Goettingen, Germany
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Holdenrieder S, Kolligs FT, Stieber P. New Horizons for Diagnostic Applications of Circulating Nucleosomes in Blood? Clin Chem 2008; 54:1104-6. [DOI: 10.1373/clinchem.2008.108688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Stefan Holdenrieder
- Institute of Clinical Chemistry, University Hospital Munich-Grosshadern, Munich, Germany
| | - Frank T Kolligs
- Medical Clinic II, University Hospital Munich-Grosshadern, Munich, Germany
| | - Petra Stieber
- Institute of Clinical Chemistry, University Hospital Munich-Grosshadern, Munich, Germany
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