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Santos JMD, Touguinha L, Bridi R, Andreazza AC, Bick DLU, Davidson CB, Dos Santos AF, Machado KA, Scariot FJ, Delamare LAP, Salvador M, Branco CS. Could the inhibition of systemic NLRP3 inflammasome mediate central redox effects of yerba mate? An in silico and pre-clinical translational approach. JOURNAL OF ETHNOPHARMACOLOGY 2025; 344:119518. [PMID: 39987999 DOI: 10.1016/j.jep.2025.119518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/13/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Empirically, Ilex paraguariensis A. St. Hil, or yerba-mate, has been used by natives of South America as a stimulant. Nowadays, this plant has gained popularity due to its neuroprotective effects. However, there are few studies on the biochemical-molecular mechanisms of action involved in its effect. AIM OF THE STUDY Chemically characterize an aqueous extract of yerba mate (YME) and evaluate if it could suppress the aberrant inflammatory response related to neurodegeneration. MATERIALS AND METHODS Macrophages and microglia cells were exposed to lipopolysaccharide (LPS; 100 ng/mL) plus nigericin (100 μM) or quinolinic acid (QA; 5 mM). Cellular viability, oxidative, and inflammatory markers were evaluated. Chemical matrix (HPLC - DAD), antioxidant activity, safety profile in vitro and in vivo, and an in silico docking of main targets were also assessed. RESULTS Pre-treatment with YME (15 μg/mL) prevented impairments in redox metabolism and inflammatory markers in BV-2 cells. In macrophages, YME showed similar results to MCC950, an inflammasome inhibitor. YME presented 282.88 mg EAG/g total phenolic content and a redox capacity of 32.94 ± 1.30 μg/mL (IC50), and its major compounds were chlorogenic acid > rutin > ferulic acid > catechin > sinapic acid. Chlorogenic acid and rutin presented a high affinity to the MCC950 region. Additionally, YME did not cause genotoxicity and was safe in vivo. CONCLUSION YME has significantly affected macrophages and microglia by regulating the NLRP3 inflammatory pathway.
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Affiliation(s)
- Júlia Maiara Dos Santos
- Oxidative Stress & Antioxidants Laboratory, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco Getúlio Vargas, 1130, Caxias Do Sul, Rio Grande do Sul, 95070-560, Brazil.
| | - Luciana Touguinha
- Oxidative Stress & Antioxidants Laboratory, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco Getúlio Vargas, 1130, Caxias Do Sul, Rio Grande do Sul, 95070-560, Brazil.
| | - Raquel Bridi
- Departamento de Química Farmocológica y Toxicológica, Universidad de Chile, Calle Dr. Carlos Lorca Tobar, 964, Región Metropolitana, Santiago, 8380494, Chile.
| | - Ana Cristina Andreazza
- Pharmacology & Toxicology Department, University of Toronto, Medical Sciences Building, 1 King's College Cir Room 4207, Toronto, Ontario, ON M5S 1A8, Canada.
| | - Djenifer Leticia Ulrich Bick
- Cell Culture & Bioactive Effects Laboratory, Franciscan University, Rua Silva Jardim, 1323, Santa Maria, Rio Grande do Sul, 97010-492, Brazil.
| | - Carolina Bordin Davidson
- Cell Culture & Bioactive Effects Laboratory, Franciscan University, Rua Silva Jardim, 1323, Santa Maria, Rio Grande do Sul, 97010-492, Brazil.
| | - André Flores Dos Santos
- Advanced Laboratory for Research and Development in Computational Nanotechnology and Virtual Reality, Franciscan University, Rua Silva Jardim, 1323, Santa Maria, Rio Grande do Sul, 97010-492, Brazil.
| | - Kolinski Alencar Machado
- Cell Culture & Bioactive Effects Laboratory, Franciscan University, Rua Silva Jardim, 1323, Santa Maria, Rio Grande do Sul, 97010-492, Brazil.
| | - Fernando Joel Scariot
- Enology and Applied Microbiology Laboratory, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco Getúlio Vargas, 1130, Caxias Do Sul, Rio Grande do Sul, 95070-560, Brazil.
| | - Longaray Ana Paula Delamare
- Enology and Applied Microbiology Laboratory, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco Getúlio Vargas, 1130, Caxias Do Sul, Rio Grande do Sul, 95070-560, Brazil.
| | - Mirian Salvador
- Oxidative Stress & Antioxidants Laboratory, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco Getúlio Vargas, 1130, Caxias Do Sul, Rio Grande do Sul, 95070-560, Brazil.
| | - Catia Santos Branco
- Oxidative Stress & Antioxidants Laboratory, Institute of Biotechnology, University of Caxias do Sul, Rua Francisco Getúlio Vargas, 1130, Caxias Do Sul, Rio Grande do Sul, 95070-560, Brazil.
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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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Armakolas A, Kotsari M, Koskinas J. Liquid Biopsies, Novel Approaches and Future Directions. Cancers (Basel) 2023; 15:1579. [PMID: 36900369 PMCID: PMC10000663 DOI: 10.3390/cancers15051579] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/22/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Cancer is among the leading causes of death worldwide. Early diagnosis and prognosis are vital to improve patients' outcomes. The gold standard of tumor characterization leading to tumor diagnosis and prognosis is tissue biopsy. Amongst the constraints of tissue biopsy collection is the sampling frequency and the incomplete representation of the entire tumor bulk. Liquid biopsy approaches, including the analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating miRNAs, and tumor-derived extracellular vesicles (EVs), as well as certain protein signatures that are released in the circulation from primary tumors and their metastatic sites, present a promising and more potent candidate for patient diagnosis and follow up monitoring. The minimally invasive nature of liquid biopsies, allowing frequent collection, can be used in the monitoring of therapy response in real time, allowing the development of novel approaches in the therapeutic management of cancer patients. In this review we will describe recent advances in the field of liquid biopsy markers focusing on their advantages and disadvantages.
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Affiliation(s)
- Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Maria Kotsari
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - John Koskinas
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece
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Cell-Free DNA as a New Biomarker of IVF Success, Independent of Any Infertility Factor, Including Endometriosis. Diagnostics (Basel) 2023; 13:diagnostics13020208. [PMID: 36673018 PMCID: PMC9858053 DOI: 10.3390/diagnostics13020208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/31/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023] Open
Abstract
Cell-free DNA fragments detected in blood and in other biological fluids are released from apoptotic/necrotic cells. In this study, we analyzed cfDNA levels in follicular fluid (FF) samples from patients with infertility. Samples were collected from 178 infertile women and cfDNA was extracted and quantified by qPCR, using ALU115 and ALU247 primers, and statistical correlations were performed. We found that cfDNA concentration was significantly higher in FF pools from women aged 35 and over than in women under 35 years of age (p = 0.017). We also found that q247 cfDNA levels were significantly higher in women with an associated female factor, such as endometriosis, PCOS and POF, compared with women with no specific cause of infertility (p = 0.033). The concentration of cfDNA did not vary significantly in each group of women with an associated female factor. The concentration of cfDNA was significantly higher in the FF of women that obtained embryos with a high fragmentation rate, compared to embryos with a low fragmentation rate (p = 0.007). Finally, we found that women who did not become pregnant during IVF treatments had higher q247 cfDNA levels (p = 0.043). The quantification of cfDNA could be an important biomarker of follicular micro-environment quality to predict embryo quality and the success of IVF, making them more specific and effective.
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Chen H, Xu C, Fang Z, Mao S. Cell-Free DNA, MicroRNAs, Proteins, and Peptides as Liquid Biopsy Biomarkers in Prostate Cancer and Bladder Cancer. Methods Mol Biol 2023; 2695:165-179. [PMID: 37450118 DOI: 10.1007/978-1-0716-3346-5_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Liquid biopsy, as a novel noninvasive tool for biomarker discovery, has gained a lot of attention and represents a significant innovation in precision medicine. Due to its minimally invasive nature, liquid biopsy has fewer complications and can be scheduled more frequently to provide individualized snapshots of the disease at successive time points. This is particularly valuable in providing simultaneous measurements of tumor burden during treatment and early detection of tumor recurrence or drug resistance. Blood-based liquid biopsy is an attractive, minimally invasive alternative, which has shown promise in diagnosis, risk stratification, disease monitoring, and more. Urine has gained popularity due to its less invasive sampling, the ability to easily repeat samples, and the ability to track tumor evolution in real time, making it a powerful tool for diagnosis and treatment monitoring, especially in urologic cancers. In this review, we provide a detailed discussion on the potential clinical applications of prostate cancer (PCa) and bladder cancer (BCa), with cell-free DNA (cfDNA), microRNAs (miRNAs), proteins, and peptides as liquid biopsy biomarkers.
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Affiliation(s)
- Haoran Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenyang Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zujun Fang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Shanhua Mao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
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Shields MD, Chen K, Dutcher G, Patel I, Pellini B. Making the Rounds: Exploring the Role of Circulating Tumor DNA (ctDNA) in Non-Small Cell Lung Cancer. Int J Mol Sci 2022; 23:ijms23169006. [PMID: 36012272 PMCID: PMC9408840 DOI: 10.3390/ijms23169006] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/03/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Advancements in the clinical practice of non-small cell lung cancer (NSCLC) are shifting treatment paradigms towards increasingly personalized approaches. Liquid biopsies using various circulating analytes provide minimally invasive methods of sampling the molecular content within tumor cells. Plasma-derived circulating tumor DNA (ctDNA), the tumor-derived component of cell-free DNA (cfDNA), is the most extensively studied analyte and has a growing list of applications in the clinical management of NSCLC. As an alternative to tumor genotyping, the assessment of oncogenic driver alterations by ctDNA has become an accepted companion diagnostic via both single-gene polymerase chain reactions (PCR) and next-generation sequencing (NGS) for advanced NSCLC. ctDNA technologies have also shown the ability to detect the emerging mechanisms of acquired resistance that evolve after targeted therapy. Furthermore, the detection of minimal residual disease (MRD) by ctDNA for patients with NSCLC after curative-intent treatment may serve as a prognostic and potentially predictive biomarker for recurrence and response to therapy, respectively. Finally, ctDNA analysis via mutational, methylation, and/or fragmentation multi-omic profiling offers the potential for improving early lung cancer detection. In this review, we discuss the role of ctDNA in each of these capacities, namely, for molecular profiling, treatment response monitoring, MRD detection, and early cancer detection of NSCLC.
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Affiliation(s)
- Misty Dawn Shields
- Department of Internal Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA
| | - Kevin Chen
- Department of Radiation Oncology, Division of Cancer Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Giselle Dutcher
- Department of Medicine, Division of Solid Tumor Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ishika Patel
- Department of Public Health, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Bruna Pellini
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- Correspondence:
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7
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Tutanov O, Tamkovich S. The Influence of Proteins on Fate and Biological Role of Circulating DNA. Int J Mol Sci 2022; 23:7224. [PMID: 35806228 PMCID: PMC9266439 DOI: 10.3390/ijms23137224] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 11/17/2022] Open
Abstract
Circulating DNA has already proven itself as a valuable tool in translational medicine. However, one of the overlooked areas of circulating DNA research is its association with different proteins, despite considerable evidence that this association might impact DNA's fate in circulation and its biological role. In this review, we attempt to shed light on current ideas about circulating DNA origins and forms of circulation, known biological effects, and the clinical potential of circulating tumor deoxyribonucleoprotein complexes.
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Affiliation(s)
| | - Svetlana Tamkovich
- V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia;
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8
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Wu X, Zeng H, Cai L, Chen G. Role of the Extracellular Traps in Central Nervous System. Front Immunol 2021; 12:783882. [PMID: 34868063 PMCID: PMC8635093 DOI: 10.3389/fimmu.2021.783882] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/26/2021] [Indexed: 12/20/2022] Open
Abstract
It has been reported that several immune cells can release chromatin and granular proteins into extracellular space in response to the stimulation, forming extracellular traps (ETs). The cells involved in the extracellular trap formation are recognized including neutropils, macrophages, basophils, eosinophils, and mast cells. With the development of research related to central nervous system, the role of ETs has been valued in neuroinflammation, blood–brain barrier, and other fields. Meanwhile, it has been found that microglial cells as the resident immune cells of the central nervous system can also release ETs, updating the original understanding. This review aims to clarify the role of the ETs in the central nervous system, especially in neuroinflammation and blood–brain barrier.
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Affiliation(s)
- Xinyan Wu
- Department of Neurological Surgery The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hanhai Zeng
- Department of Neurological Surgery The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingxin Cai
- Department of Neurological Surgery The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Gao Chen
- Department of Neurological Surgery The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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9
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Larribère L, Martens UM. Advantages and Challenges of Using ctDNA NGS to Assess the Presence of Minimal Residual Disease (MRD) in Solid Tumors. Cancers (Basel) 2021; 13:5698. [PMID: 34830853 PMCID: PMC8616165 DOI: 10.3390/cancers13225698] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 12/22/2022] Open
Abstract
The ability to detect minimal residual disease (MRD) after a curative-intent surgery or treatment is of paramount importance, because it offers the possibility to help guide the clinical decisions related adjuvant therapy. Thus, the earlier MRD is detected, the earlier potentially beneficial treatment can be proposed to patients who might need it. Liquid biopsies, and in particular the next-generation sequencing of circulating tumor DNA (ctDNA) in the blood, have been the focus of an increasing amount of research in the past years. The ctDNA detection at advanced cancer stages is practicable for several solid tumors, and complements molecular information on acquired therapy resistance. In the context of MRD, it is by definition more challenging to detect ctDNA, but it is technically achievable and provides information on treatment response and probability of relapse significantly earlier than standard imaging methods. The clinical benefit of implementing this new technique in the routine is being tested in interventional clinical trials at the moment. We propose here an update of the current use of ctDNA detection by NGS as a tool to assess the presence of MRD and improve adjuvant treatment of solid tumors. We also discuss the main limitations and medium-term perspectives of this process in the clinic.
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Affiliation(s)
- Lionel Larribère
- Department of Hematology and Oncology, Cancer Center Heilbronn-Franken, SLK Clinics Heilbronn GmbH, 74078 Heilbronn, Germany;
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany
| | - Uwe M. Martens
- Department of Hematology and Oncology, Cancer Center Heilbronn-Franken, SLK Clinics Heilbronn GmbH, 74078 Heilbronn, Germany;
- MOLIT Institute for Personalized Medicine GmbH, 74076 Heilbronn, Germany
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Haupts A, Vogel A, Foersch S, Hartmann M, Maderer A, Wachter N, Huber T, Kneist W, Roth W, Lang H, Moehler M, Hartmann N. Comparative analysis of nuclear and mitochondrial DNA from tissue and liquid biopsies of colorectal cancer patients. Sci Rep 2021; 11:16745. [PMID: 34408162 PMCID: PMC8373949 DOI: 10.1038/s41598-021-95006-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/20/2021] [Indexed: 01/05/2023] Open
Abstract
The current standard for molecular profiling of colorectal cancer (CRC) is using resected or biopsied tissue specimens. However, they are limited regarding sampling frequency, representation of tumor heterogeneity, and sampling can expose patients to adverse side effects. The analysis of cell-free DNA (cfDNA) from blood plasma, which is part of a liquid biopsy, is minimally invasive and in principle enables detection of all tumor-specific mutations. Here, we analyzed cfDNA originating from nucleus and mitochondria and investigated their characteristics and mutation status in a cohort of 18 CRC patients and 10 healthy controls using targeted next-generation sequencing (NGS) and digital PCR. Longitudinal analyses of nuclear cfDNA level and size during chemotherapy revealed a decreasing cfDNA content and a shift from short to long fragments, indicating an appropriate therapy response, while shortened cfDNAs and increased cfDNA content corresponded with tumor recurrence. Comparative NGS analysis of nuclear tissue and plasma DNA demonstrated a good patient-level concordance and cfDNA revealed additional variants in three of the cases. Analysis of mitochondrial cfDNA surprisingly revealed a higher plasma copy number in healthy subjects than in CRC patients. These results highlight the potential clinical utility of liquid biopsies in routine diagnostics and surveillance of CRC patients as complementation to tissue biopsies or as an attractive alternative in cases where tissue biopsies are risky or the quantity/quality does not allow testing.
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Affiliation(s)
- Anna Haupts
- Institute of Pathology, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
| | - Anne Vogel
- Institute of Pathology, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Sebastian Foersch
- Institute of Pathology, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Monika Hartmann
- Department of Internal Medicine I, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Annett Maderer
- Department of Internal Medicine I, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Nicolas Wachter
- Department of General, Visceral and Transplantation Surgery, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Tobias Huber
- Department of General, Visceral and Transplantation Surgery, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Werner Kneist
- Department of General, Visceral and Transplantation Surgery, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.,Department of General and Visceral Surgery, St. Georg Hospital Eisenach gGmbH, Mühlhäuser Straße 94, 99817, Eisenach, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplantation Surgery, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Markus Moehler
- Department of Internal Medicine I, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Nils Hartmann
- Institute of Pathology, University Medical Center JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
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Nagasaka M, Uddin MH, Al-Hallak MN, Rahman S, Balasubramanian S, Sukari A, Azmi AS. Liquid biopsy for therapy monitoring in early-stage non-small cell lung cancer. Mol Cancer 2021; 20:82. [PMID: 34074295 PMCID: PMC8170728 DOI: 10.1186/s12943-021-01371-1] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 05/13/2021] [Indexed: 12/19/2022] Open
Abstract
Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).
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Affiliation(s)
- Misako Nagasaka
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA.
- Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
| | - Mohammed Hafiz Uddin
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA
| | - Mohammed Najeeb Al-Hallak
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA
| | - Sarah Rahman
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, 49401, USA
| | - Suresh Balasubramanian
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA
| | - Ammar Sukari
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA
| | - Asfar S Azmi
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA
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Circulating tumor DNA in lung cancer: real-time monitoring of disease evolution and treatment response. Chin Med J (Engl) 2021; 133:2476-2485. [PMID: 32960843 PMCID: PMC7575184 DOI: 10.1097/cm9.0000000000001097] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Lung cancer is one of the leading causes of all cancer-related deaths. Circulating tumor DNA (ctDNA) is released from apoptotic and necrotic tumor cells. Several sensitive techniques have been invented and adapted to quantify ctDNA genomic alterations. Applications of ctDNA in lung cancer include early diagnosis and detection, prognosis prediction, detecting mutations and structural alterations, minimal residual disease, tumor mutational burden, and tumor evolution tracking. Compared to surgical biopsy and radiographic imaging, the advantages of ctDNA are that it is a non-invasive procedure, allows real-time monitoring, and has relatively high sensitivity and specificity. Given the massive research on non-small cell lung cancer, attention should be paid to small cell lung cancer.
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13
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Cell-Free DNA Analysis by Whole-Exome Sequencing for Hepatocellular Carcinoma: A Pilot Study in Thailand. Cancers (Basel) 2021; 13:cancers13092229. [PMID: 34066484 PMCID: PMC8125351 DOI: 10.3390/cancers13092229] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Liquid biopsy for cell-free DNA (cfDNA) is a non-invasive technique to characterize the genetic profile of a tumor. Despite being a valuable tool, there is no mutational profile of cfDNA from hepatocellular carcinoma (HCC) in patients from Thailand, where HCC is prevalent. The present study aimed to demonstrate the utility of using whole-exome sequencing of cfDNA to define the somatic mutation profiles of HCC in Thai patients who underwent nonoperative therapies. The level of cfDNA was higher in HCC patients than in chronic hepatitis patients. Single nucleotide variations were present in somatic genes in cfDNA, including in ZNF814, HRNR, ZNF492, ADAMTS12, FLG, OBSCN, TP53, and TTN. The co-occurrence of HRNR and TTN mutations in cfDNA was associated with shorter overall survival. These findings indicate that the mutational profiles of cfDNA reflected those of HCC tissue, and cfDNA could serve as a useful biomarker for diagnosis and prognosis in HCC patients. Abstract Cell-free DNA (cfDNA) has been used as a non-invasive biomarker for detecting cancer-specific mutations. However, the mutational profile of cfDNA in Thai patients with hepatocellular carcinoma (HCC) has not been investigated. Here, we demonstrated the utility of using whole-exome sequencing (WES) of cfDNA to define the somatic mutation profiles of HCC in Thai patients. The comprehensive profile of cfDNA was determined with WES to identify variants in matched cfDNA and germline DNA from 30 HCC patients in Thailand who underwent nonoperative therapies. The level of cfDNA was higher in HCC patients compared with chronic hepatitis patients (p-value < 0.001). Single nucleotide variants were present in somatic genes in cfDNA, including in ZNF814 (27%), HRNR (20%), ZNF492 (20%), ADAMTS12 (17%), FLG (17%), OBSCN (17%), TP53 (17%), and TTN (17%). These same mutations were matched to HCC mutation data from The Cancer Genome Atlas (TCGA) and a previous Thai HCC study. The co-occurrence of HRNR and TTN mutations in cfDNA was associated with shorter overall survival in HCC patients (hazard ratio = 1.60, p-value = 0.0196). These findings indicate that the mutational profile of cfDNA accurately reflected that of HCC tissue and suggest that cfDNA could serve as a useful biomarker for diagnosis and prognosis in Thai HCC patients. In addition, we demonstrated the use of the pocket-sized sequencer of Oxford Nanopore Technology to detect copy-number variants in HCC tissues that could be applied for onsite clinical detection/monitoring of HCC.
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Martins I, Ribeiro IP, Jorge J, Gonçalves AC, Sarmento-Ribeiro AB, Melo JB, Carreira IM. Liquid Biopsies: Applications for Cancer Diagnosis and Monitoring. Genes (Basel) 2021; 12:349. [PMID: 33673461 PMCID: PMC7997281 DOI: 10.3390/genes12030349] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
The minimally-or non-invasive detection of circulating tumor-derived components in biofluids, such as blood, liquid biopsy is a revolutionary approach with significant potential for the management of cancer. Genomic and transcriptomic alterations can be accurately detected through liquid biopsies, which provide a more comprehensive characterization of the heterogeneous tumor profile than tissue biopsies alone. Liquid biopsies could assist diagnosis, prognosis, and treatment selection, and hold great potential to complement current surveilling strategies to monitor disease evolution and treatment response in real-time. In particular, these are able to detect minimal residual disease, to predict progression, and to identify mechanisms of resistance, allowing to re-orient treatment strategies in a timelier manner. In this review we gathered current knowledge regarding the role and potential of liquid biopsies for the diagnosis and follow-up of cancer patients. The presented findings emphasize the strengths of liquid biopsies, revealing their chance of improving the diagnosis and monitoring of several tumor types in the near future. However, despite growing evidence supporting their value as a management tool in oncology, some limitations still need to be overcome for their implementation in the routine clinical setting.
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Affiliation(s)
- Ivana Martins
- Cytogenetics and Genomics Laboratory, Faculty of Medicine University of Coimbra, Institute of Cellular and Molecular Biology, University of Coimbra, 3004-531 Coimbra, Portugal; (I.M.); (I.P.R.); (J.B.M.)
| | - Ilda Patrícia Ribeiro
- Cytogenetics and Genomics Laboratory, Faculty of Medicine University of Coimbra, Institute of Cellular and Molecular Biology, University of Coimbra, 3004-531 Coimbra, Portugal; (I.M.); (I.P.R.); (J.B.M.)
- Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3004-531 Coimbra, Portugal; (J.J.); (A.C.G.); (A.B.S.-R.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-531 Coimbra, Portugal
| | - Joana Jorge
- Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3004-531 Coimbra, Portugal; (J.J.); (A.C.G.); (A.B.S.-R.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-531 Coimbra, Portugal
- Laboratory of Oncobiology and Haematology and University Clinic of Haematology, Faculty of Medicine, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Ana Cristina Gonçalves
- Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3004-531 Coimbra, Portugal; (J.J.); (A.C.G.); (A.B.S.-R.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-531 Coimbra, Portugal
- Laboratory of Oncobiology and Haematology and University Clinic of Haematology, Faculty of Medicine, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Ana Bela Sarmento-Ribeiro
- Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3004-531 Coimbra, Portugal; (J.J.); (A.C.G.); (A.B.S.-R.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-531 Coimbra, Portugal
- Laboratory of Oncobiology and Haematology and University Clinic of Haematology, Faculty of Medicine, University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Haematology Department, Coimbra University Hospital Centre (CHUC), 3004-531 Coimbra, Portugal
| | - Joana Barbosa Melo
- Cytogenetics and Genomics Laboratory, Faculty of Medicine University of Coimbra, Institute of Cellular and Molecular Biology, University of Coimbra, 3004-531 Coimbra, Portugal; (I.M.); (I.P.R.); (J.B.M.)
- Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3004-531 Coimbra, Portugal; (J.J.); (A.C.G.); (A.B.S.-R.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-531 Coimbra, Portugal
| | - Isabel Marques Carreira
- Cytogenetics and Genomics Laboratory, Faculty of Medicine University of Coimbra, Institute of Cellular and Molecular Biology, University of Coimbra, 3004-531 Coimbra, Portugal; (I.M.); (I.P.R.); (J.B.M.)
- Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3004-531 Coimbra, Portugal; (J.J.); (A.C.G.); (A.B.S.-R.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-531 Coimbra, Portugal
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Yoo TK. Liquid Biopsy in Breast Cancer: Circulating Tumor Cells and Circulating Tumor DNA. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1187:337-361. [PMID: 33983587 DOI: 10.1007/978-981-32-9620-6_17] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer is associated with gene mutations, and the analysis of tumor-associated mutations is increasingly used for diagnostic, prognostic, and treatment purposes. These molecular landscapes of solid tumors are currently obtained from surgical or biopsy specimens. However, during cancer progression and treatment, selective pressures lead to additional genetic changes as tumors acquire drug resistance. Tissue sampling cannot be performed routinely owing to its invasive nature and a single biopsy only provides a limited snapshot of a tumor, which may fail to reflect spatial and temporal heterogeneity. This dilemma may be solved by analyzing cancer cells or cancer cell-derived DNA from blood samples, called liquid biopsy. Liquid biopsy is one of the most rapidly advancing fields in cancer diagnostics and recent technological advances have enabled the detection and detailed characterization of circulating tumor cells and circulating tumor DNA in blood samples.Liquid biopsy is an exciting area with rapid advances, but we are still at the starting line with many challenges to overcome. In this chapter we will explore how tumor cells and tumor-associated mutations detected in the blood can be used in the clinic. This will include detection of cancer, prediction of prognosis, monitoring systemic therapies, and stratification of patients for therapeutic targets or resistance mechanisms.
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Affiliation(s)
- Tae-Kyung Yoo
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Utility of circulating cell-free Mycobacterium tuberculosis DNA for the improved diagnosis of abdominal tuberculosis. PLoS One 2020; 15:e0238119. [PMID: 32845896 PMCID: PMC7449497 DOI: 10.1371/journal.pone.0238119] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/09/2020] [Indexed: 12/13/2022] Open
Abstract
Abdominal tuberculosis (ATB) continues to pose a major diagnostic challenge for clinicians due to its nonspecific clinical presentation, variable anatomical location and lack of sensitive diagnostic tools. In spite of the development of several assays till date; no single test has proved to be adequate for ATB diagnosis. In this study, we for the first time report the detection of circulating cell-free Mycobacterium tuberculosis (M. tuberculosis) DNA (cfMTB-DNA) in ascitic fluid (AF) samples and its utility in ATB diagnosis. Sixty-five AF samples were included in the study and processed for liquid culture, cytological, biochemical and molecular assays. A composite reference standard (CRS) was formulated to categorize the patients into 'Definite ATB' (M. tuberculosis culture positive, n = 2), 'Probable ATB' (n = 16), 'Possible ATB' (n = 13) and 'Non-TB' category (n = 34). Two molecular assays were performed, namely, the novel cfMTB-DNA qPCR assay targeting M. tuberculosis devR gene and Xpert MTB/RIF assay (Xpert), and their diagnostic accuracy was assessed using CRS as reference standard. Clinical features such as fever, loss of weight, abdominal distension and positive Mantoux were found to be strongly associated with ATB disease (p<0.05). cfMTB-DNA qPCR had a sensitivity of 66.7% (95% CI:40.9,86.7) with 97.1% specificity (95% CI:84.7,99.9) in 'Definite ATB' and 'Probable ATB' group collectively. The sensitivity increased to 70.9% (95% CI:51.9,85.8) in the combined 'Definite', 'Probable' and 'Possible' ATB group with similar specificity. The cfMTB-DNA qPCR assay performed significantly better than the Xpert assay which demonstrated a poor sensitivity of ≤16.7% with 100% (95% CI:89.7,100) specificity (p<0.001). We conclude that cfMTB-DNA qPCR assay is an accurate molecular test that can provide direct evidence of M. tuberculosis etiology and has promise to pave the way for improving ATB diagnosis.
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Synthesis and Evaluation of Diindole-Based MRI Contrast Agent for In Vivo Visualization of Necrosis. Mol Imaging Biol 2019; 22:593-601. [PMID: 31332630 DOI: 10.1007/s11307-019-01399-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PURPOSE Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage. PROCEDURES The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM. RESULTS The Log P value and T1 relaxivity of Gd-DIM is - 2.15 ± 0.01 and 6.61 mM-1 s-1, respectively. Gd-DIM showed predominant necrosis avidity in vitro and in vivo. Clear visualization of the tumor necrosis induced by CA4P was achieved at 60 min after administration of Gd-DIM. DNA binding study indicated that the necrosis-avidity mechanism of Gd-DIM may be due to its binding to exposed DNA in necrotic cells. CONCLUSION Gd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.
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Extracellular DNA traps in inflammation, injury and healing. Nat Rev Nephrol 2019; 15:559-575. [PMID: 31213698 DOI: 10.1038/s41581-019-0163-2] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2019] [Indexed: 12/14/2022]
Abstract
Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is especially prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathological roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of pathology associated with the release of extracellular DNA traps is mainly determined by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
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Coras R, Narasimhan R, Guma M. Liquid biopsies to guide therapeutic decisions in rheumatoid arthritis. Transl Res 2018; 201:1-12. [PMID: 30092207 PMCID: PMC6309446 DOI: 10.1016/j.trsl.2018.07.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 06/29/2018] [Accepted: 07/10/2018] [Indexed: 12/18/2022]
Abstract
Rheumatoid arthritis (RA) is a systemic, immune-mediated inflammatory disease that has transitioned from a debilitating disease to a chronic, controllable disease. This has been possible due to the introduction of new treatment strategies like "treat-to-target," in which the clinician treats the patient aggressively enough to reach low disease activity or remission, and the introduction of new therapeutic agents, such as biological therapies, which can lead to the prevention of damage by early diagnosis and initiation of treatment. Attention is now being directed toward identifying the optimal treatment for each patient, one that will be the most efficient and have the least number of side effects. Much work has been done to find serologic and synovial biomarkers of response to various RA treatments. Proteomics, genomics and, in the past few years, metabolomics, have all been used in the quest of identifying these biomarkers. Blood-based liquid biopsies provide a minimally invasive alternative to synovial biopsies to identify cellular and molecular signatures that can be used to longitudinally monitor response and allow for personalized medicine approach. Liquid biopsies are comprised of cell-free DNA, immune circulating cells, and extracellular vesicles, and are being increasingly and successfully used in the field of oncology for diagnosis, progression, prognosis, and prediction of response to treatment. Recently, researchers have also begun investigating the usefulness of liquid biopsies in the field of rheumatology; in this review, we will focus on the potential of liquid biopsy blood samples as biomarkers of response to treatment in patients with RA.
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Affiliation(s)
- Roxana Coras
- Department of Medicine, School of Medicine, La Jolla, California; University of California San Diego, San Diego, California; Department of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
| | - Rekha Narasimhan
- Department of Medicine, School of Medicine, La Jolla, California; University of California San Diego, San Diego, California
| | - Monica Guma
- Department of Medicine, School of Medicine, La Jolla, California; University of California San Diego, San Diego, California; Department of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain.
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Leão R, Ahmad AE, Hamilton RJ. Testicular Cancer Biomarkers: A Role for Precision Medicine in Testicular Cancer. Clin Genitourin Cancer 2018; 17:e176-e183. [PMID: 30497810 DOI: 10.1016/j.clgc.2018.10.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/11/2018] [Accepted: 10/14/2018] [Indexed: 12/16/2022]
Abstract
Testicular germ cell tumors (TGCTs) represent the most common solid tumors among men aged 15 to 34 years. Fortunately, recent advances have made testicular cancer a highly curable disease. Despite the high cure rates, there are still several areas in testis cancer care where treatment decisions are controversial and guided only with clinical factors and historic serum tumor markers. Unfortunately, unlike other genitourinary malignancies, modern research techniques have not been widely tested or applied to germ cell tumors, perhaps as a result of excellent prognosis in this cohort of young men. Despite this, there remain numerous challenges and pitfalls in testis cancer care that need to be addressed. A reliable set of biomarkers could be extremely useful in helping risk-stratify patients, detect relapse early, guide surgical decision-making, and tailor follow-up. Current tumor markers (Alpha-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase) have low accuracy and low sensitivity when used not only as diagnostic but also as prognostic and predictive markers. In twenty-first century medicine, there is a role for further prognostic stratification and the development of novel biomarkers that offer greater sensitivity and specificity for TGCTs. Despite the initial promising results, the majority of preclinical biomarkers do not, as yet have a proven validated role in clinical practice, and future prospective trials are needed to support and confirm the results of cohort studies. In this narrative review, we aimed to highlight the recent innovations in the development and implementation of novel testicular tumor markers and discuss their clinical applications and limitations in the management of this disease.
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Affiliation(s)
- Ricardo Leão
- Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CUF Department of Urology, Lisbon, Portugal
| | - Ardalan E Ahmad
- Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Robert J Hamilton
- Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
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SPECT Imaging of Treatment-Related Tumor Necrosis Using Technetium-99m-Labeled Rhein. Mol Imaging Biol 2018; 21:660-668. [DOI: 10.1007/s11307-018-1285-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Wills B, Gorse E, Lee V. Role of liquid biopsies in colorectal cancer. Curr Probl Cancer 2018; 42:593-600. [PMID: 30268335 DOI: 10.1016/j.currproblcancer.2018.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/27/2018] [Accepted: 08/08/2018] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, with a global incidence of over 1 million cases. In the era of personalized medicine, tumor sampling is essential for characterizing the molecular profile of individual tumors. This provides pivotal information regarding optimal sequencing of therapy and emergence of drug resistance, allowing for timely therapy adjustment. However, tumor tissue sampling offers static information in a single time point and area of disease at the time of biopsy, which may not entirely represent the heterogeneity of molecular alterations. Moreover, tumor biopsies often involve invasive procedures with potential risks to patients. Less invasive, safer, and real-time methods such as liquid biopsies have generated increasing interest as a surrogate of solid tumor biopsies. Liquid biopsy allows for noninvasive survey with detection of cell-free circulating tumor DNA (ctDNA) or circulating tumor cells. Blood-based assays are the most widely studied. Additionally, the quantity of ctDNA detected has been shown to correlate with tumor burden and enables assessment of tumor heterogeneity. In this article, we discuss the concept of liquid biopsies including ctDNA and circulating tumor cell, and their current application in the diagnosis and management of CRC. We suggest that liquid biopsies can be successfully used to characterize the molecular profile of CRC, monitor disease, detect minimal residual disease after surgery, and identify therapeutic targets and mechanisms of drug resistance. This strategy could potentially imply an early change in treatment, sparing unnecessary side effects, and minimizing health costs. Combined radiological and liquid biopsy assessments will likely become more standard in CRC oncology. However, large prospective studies are needed to definitively establish the role of liquid biopsy.
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Affiliation(s)
- Beatriz Wills
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD.
| | - Egal Gorse
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD
| | - Valerie Lee
- Department of GI Oncology, Johns Hopkins Hospital, Baltimore, MD
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Khatami F, Larijani B, Tavangar SM. The presence of tumor extrachomosomal circular DNA (ecDNA) as a component of liquid biopsy in blood. Med Hypotheses 2018; 114:5-7. [PMID: 29602465 DOI: 10.1016/j.mehy.2018.02.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 02/19/2018] [Indexed: 12/12/2022]
Abstract
In molecular biology covalently closed circular DNAs are able to passthrough double layer of eukaryotic cellular membrane. Very recently the presence of circular extra chromosomal DNA (ecDNA) has been shown which are different in seventeen different types of cancers. In fact, ecDNA are the tricky way of oncogenes to increase their copy number. We hypothesis the presence of ecDNA in the blood of cancer patients as a subpopulation of liquid biopsy. On the occasion of their presence in blood they will be very beneficial to cover the small amount of cell frees DNA (cfDNA). Isolation and characterization of ecDNA will be possible by a sensitive method entitled Circle-Seq. The origin of tumor more than its prognosis and diagnosis will be possible in the easiest way by using ecDNA.
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Affiliation(s)
- Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Pathology, Doctor Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Dendritic cell recruitment and activation in autoimmunity. J Autoimmun 2017; 85:126-140. [DOI: 10.1016/j.jaut.2017.07.012] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 07/26/2017] [Indexed: 12/11/2022]
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Zhang W, Xia W, Lv Z, Ni C, Xin Y, Yang L. Liquid Biopsy for Cancer: Circulating Tumor Cells, Circulating Free DNA or Exosomes? Cell Physiol Biochem 2017; 41:755-768. [PMID: 28214887 DOI: 10.1159/000458736] [Citation(s) in RCA: 158] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 12/08/2016] [Indexed: 01/02/2023] Open
Abstract
Precision medicine and personalized medicine are based on the development of biomarkers, and liquid biopsy has been reported to be able to detect biomarkers that carry information on tumor development and progression. Compared with traditional 'solid biopsy', which cannot always be performed to determine tumor dynamics, liquid biopsy has notable advantages in that it is a noninvasive modality that can provide diagnostic and prognostic information prior to treatment, during treatment and during progression. In this review, we describe the source, characteristics, technology for detection and current situation of circulating tumor cells, circulating free DNA and exosomes used for diagnosis, recurrence monitoring, prognosis assessment and medication planning.
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Prikhodko AS, Vitushkina MV, Zinovkina LA, Popova EN, Zinovkin RA. Priming of Human Neutrophils Is Necessary for Their Activation by Extracellular DNA. BIOCHEMISTRY (MOSCOW) 2017; 81:609-14. [PMID: 27301289 DOI: 10.1134/s0006297916060079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Extracellular plasma DNA is thought to act as a damage-associated molecular pattern causing activation of immune cells. However, purified preparations of mitochondrial and nuclear DNA were unable to induce neutrophil activation in vitro. Thus, we examined whether granulocyte-macrophage colony-stimulating factor (GM-CSF) acting as a neutrophil priming agent can promote the activation of neutrophils by different types of extracellular DNA. GM-CSF pretreatment greatly increased p38 MAPK phosphorylation and promoted CD11b/CD66b expression in human neutrophils treated with mitochondrial and, to a lesser extent, with nuclear DNA. Our experiments clearly indicate that GM-CSF-induced priming of human neutrophils is necessary for their subsequent activation by extracellular DNA.
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Affiliation(s)
- A S Prikhodko
- Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, 119991, Russia
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Vasilyeva I, Bespalov V, Baranova A. Radioprotective combination of α-tocopherol and ascorbic acid promotes apoptosis that is evident by release of low-molecular weight DNA fragments into circulation. Int J Radiat Biol 2015; 91:872-7. [PMID: 26473391 DOI: 10.3109/09553002.2015.1087066] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE Genotoxic stresses, including irradiation, lead to the apoptosis of damaged cells and the release of DNA fragments into circulation. Both α-tocopherol acetate and ascorbic acid possess antioxidant and radioprotective properties. Interestingly, depending on a particular experimental system, the treatment with vitamins may demonstrate either apoptosis-promoting or apoptosis-suppressing effects. MATERIALS AND METHODS Adult Wistar male rats received total body irradiation with 2-100 Gy doses, while non-irradiated rats served as controls. Oral gavages with vitamins were administered either 10 min or 1 h before irradiation. Control groups were similarly treated with water. Blood samples were collected at 5 h post irradiation. The levels and the composition of circulating DNA were profiled. Chromosomal aberrations were assessed 24 h after irradiation. RESULTS A substantial dose-dependent increase in circulating low-molecular weight (LMW) DNA levels was observed after whole body irradiation. An order-of-magnitude increase in the proportion of bone marrow cells with chromosomal abnormalities was observed after irradiation at 2 Gy. Single vitamin preparations were not protective, while the combination of α-tocopherol (10 mg/kg) and ascorbic acid (20 mg/kg) displayed a protective effect evident from marked decrease in chromosomal aberrations. In animals treated with a combination of the vitamins only, substantial increases in the release of LMW DNA were observed. CONCLUSIONS Radioprotective combination of α-tocopherol and ascorbic acid promotes apoptosis that is evident by release of low-molecular weight DNA into circulation. We hypothesize that the pretreatment with vitamins provides radioprotection, at least in part, by aiding non-inflammatory, apoptotic elimination of most damaged cells. The microevolutionary nature of observed adaptive response provides mechanistic foundation for the phenomenon of hormesis.
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Affiliation(s)
- Irina Vasilyeva
- a N. N. Petrov Research Institute of Oncology, Ministry of Public Health , St. Petersburg.,b International Research Center 'Biotechnologies of the Third Millennium' ITMO University 191002 , St. Petersburg , Russia
| | - Vladimir Bespalov
- a N. N. Petrov Research Institute of Oncology, Ministry of Public Health , St. Petersburg.,b International Research Center 'Biotechnologies of the Third Millennium' ITMO University 191002 , St. Petersburg , Russia
| | - Ancha Baranova
- c Center for the Study of Chronic Metabolic Diseases, School of Systems Biology, College of Science, George Mason University , Fairfax , VA , USA.,d Moscow Institute of Physics and Technology , Dolgoprudny , Moscow Region.,e Federal State Budgetary Institution 'Research Centre for Medical Genetics' under the Russian Academy of Medical Sciences , Moscow , Russia
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Almeida M, Garc�a-Montero AC, Orfao A. Cell Purification: A New Challenge for Biobanks. Pathobiology 2015; 81:261-275. [DOI: 10.1159/000358306] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Bryzgunova O, Laktionov P. Generation of blood circulating DNA: the sources, peculiarities of circulation and structure. ACTA ACUST UNITED AC 2015; 61:409-26. [DOI: 10.18097/pbmc20156104409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Extracellular nucleic acids (exNA) were described in blood of both healthy and illness people as early as in 1948, but staied overlooked until middle 60-th. Starting from the beginning of new millennium and mainly in the last 5 years exNA are intensively studied. Main attention is directed to investigation of exNA as the source of diagnostic material whereas the mechanisms of their generation, as well as mechanisms to providing long-term circulation of exNA in the bloodstream are not established unambiguously. According to some authors, the main source of circulating nucleic acids in blood are the processes of apoptosis and necrosis, while others refer to the possible nucleic acid secretion by healthy and tumor cells. Circulating DNA were found to be stable in the blood for a long time, escaping from the action of DNA hydrolyzing enzymes and are apparently packed in different supramolecular complexes. This review presents the opinions of various authors and evidence in favor of all the theories describingappearance of extracellular DNA, the features of the circulation and structure of the extracellular DNA and factors affecting the time of DNA circulation in blood
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Affiliation(s)
- O.E. Bryzgunova
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
| | - P.P. Laktionov
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
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Changing the paradigm: circulating tumor DNA as a ‘liquid biopsy’ for clinical biomarker assessments. ACTA ACUST UNITED AC 2014. [DOI: 10.4155/cli.14.93] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Induction of cytokine production in cholesteatoma keratinocytes by extracellular high-mobility group box chromosomal protein 1 combined with DNA released by apoptotic cholesteatoma keratinocytes. Mol Cell Biochem 2014; 400:189-200. [PMID: 25416861 DOI: 10.1007/s11010-014-2275-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 11/15/2014] [Indexed: 10/24/2022]
Abstract
High-mobility group box chromosomal protein 1 (HMGB-1), a nuclear DNA binding protein, was recently rediscovered as a new proinflammatory cytokine. The purpose of this study was to determine HMGB-1 expression in vivo and to identify the effect of extracellular HMGB-1 in inflammatory process associated with bone destruction in cholesteatoma. We investigated the expression and location of HMGB-1 in the cholesteatoma and healthy skin using an immunofluorescence assay. We also detected apoptosis and DNA fragments in the cholesteatoma by TUNEL staining. HMGB-1 concentration in apoptotic supernatants from UV light-treated cells, culture supernatants and its translocation in cholesteatoma keratinocytes stimulated by supernatants from UV light-treated cells were measured by immunoblot analysis and immunofluorescence assay. Cultures of human cholesteatoma keratinocytes were exposed to CpG-DNA, HMGB-1, or CpG-DNA complexed to HMGB-1 for 24 h. Cytokines in the culture supernatant were measured by ELISA. In addition, levels of proinflammatory cytokines released by cholesteatoma keratinocytes stimulated by supernatants from UV light-treated cells with or without anti-HMGB-1 antibodies and supernatants from UV light-treated cells with DNase 1 were measured by enzyme-linked immunosorbent assay. The expression of HMGB-1 in cholesteatoma increased and it translocated both to the cytoplasm and extracellular space. Furthermore, the HMGB-1 concentration in supernatants increased significantly after addition of supernatants from UV light-treated cells. TNF-α and IL-1β can be induced by purified HMGB-1 combined with CpG-DNA in the cholesteatoma keratinocytes. In addition, supernatants of apoptotic cells containing HMGB-1-DNA were effective in inducing TNF-α and IL-1β secretion. This study suggested that persistent expression of extracellular HMGB-1 and DNA fragments in cholesteatoma leads to TNF-α and IL-1β production, causing bone resorption and destruction. Thus, we have implicated that HMGB-1-DNA complexes might act as a key molecule involved in bone resorption associated with cholesteatoma.
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Scalici E, Traver S, Mullet T, Ferrières A, Monforte M, Vintejoux E, Hamamah S. Acides nucléiques circulants et fécondation in vitro. ACTA ACUST UNITED AC 2014; 42:696-701. [DOI: 10.1016/j.gyobfe.2014.07.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Accepted: 07/07/2014] [Indexed: 12/22/2022]
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Scalici E, Traver S, Molinari N, Mullet T, Monforte M, Vintejoux E, Hamamah S. Cell-free DNA in human follicular fluid as a biomarker of embryo quality. Hum Reprod 2014; 29:2661-9. [DOI: 10.1093/humrep/deu238] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Bryzgunova OE, Laktionov PP. Generation of blood circulating DNAs: Sources, features of struction and circulation. BIOCHEMISTRY MOSCOW-SUPPLEMENT SERIES B-BIOMEDICAL CHEMISTRY 2014. [DOI: 10.1134/s1990750814030020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Traver S, Assou S, Scalici E, Haouzi D, Al-Edani T, Belloc S, Hamamah S. Cell-free nucleic acids as non-invasive biomarkers of gynecological cancers, ovarian, endometrial and obstetric disorders and fetal aneuploidy. Hum Reprod Update 2014; 20:905-23. [PMID: 24973359 DOI: 10.1093/humupd/dmu031] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Proper folliculogenesis is fundamental to obtain a competent oocyte that, once fertilized, can support the acquisition of embryo developmental competence and pregnancy. MicroRNAs (miRNAs) are crucial regulators of folliculogenesis, which are expressed in the cumulus-oocyte complex and in granulosa cells and some can also be found in the bloodstream. These circulating miRNAs are intensively studied and used as diagnostic/prognostic markers of many diseases, including gynecological and pregnancy disorders. In addition, serum contains small amounts of cell-free DNA (cfDNA), presumably resulting from the release of genetic material from apoptotic/necrotic cells. The quantification of nucleic acids in serum samples could be used as a diagnostic tool for female infertility. METHODS An overview of the published literature on miRNAs, and particularly on the use of circulating miRNAs and cfDNA as non-invasive biomarkers of gynecological diseases, was performed (up to January 2014). RESULTS In the past decade, cell-free nucleic acids have been studied for potential use as biomarkers in many diseases, particularly in gynecological cancers, ovarian and endometrial disorders, as well as in pregnancy-related pathologies and fetal aneuploidy. The data strongly suggest that the concentration of cell-free nucleic acids in serum from IVF patients or in embryo culture medium could be related to the ovarian hormone status and embryo quality, respectively, and be used as a non-invasive biomarker of IVF outcome. CONCLUSIONS The profiling of circulating nucleic acids, such as miRNAs and cfDNA, opens new perspectives for the diagnosis/prognosis of ovarian disorders and for the prediction of IVF outcomes, namely (embryo quality and pregnancy).
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Affiliation(s)
- S Traver
- CHU Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, INSERM U1040, Montpellier, France
| | - S Assou
- CHU Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, INSERM U1040, Montpellier, France Université Montpellier 1, UFR de Médecine, Montpellier, France
| | - E Scalici
- CHU Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, INSERM U1040, Montpellier, France Université Montpellier 1, UFR de Médecine, Montpellier, France
| | - D Haouzi
- CHU Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, INSERM U1040, Montpellier, France
| | - T Al-Edani
- CHU Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, INSERM U1040, Montpellier, France Université Montpellier 1, UFR de Médecine, Montpellier, France
| | - S Belloc
- Eylau-Unilabs Laboratory, Paris, France
| | - S Hamamah
- CHU Montpellier, Institute for Research in Biotherapy, Hôpital Saint-Eloi, INSERM U1040, Montpellier, France Université Montpellier 1, UFR de Médecine, Montpellier, France ART-PGD Department, Hôpital Arnaud de Villeneuve, CHU Montpellier, Montpellier, France
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Tsujiura M, Ichikawa D, Konishi H, Komatsu S, Shiozaki A, Otsuji E. Liquid biopsy of gastric cancer patients: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol 2014; 20:3265-3286. [PMID: 24696609 PMCID: PMC3964398 DOI: 10.3748/wjg.v20.i12.3265] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/27/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
To improve the clinical outcomes of cancer patients, early detection and accurate monitoring of diseases are necessary. Numerous genetic and epigenetic alterations contribute to oncogenesis and cancer progression, and analyses of these changes have been increasingly utilized for diagnostic, prognostic and therapeutic purposes in malignant diseases including gastric cancer (GC). Surgical and/or biopsy specimens are generally used to understand the tumor-associated alterations; however, those approaches cannot always be performed because of their invasive characteristics and may fail to reflect current tumor dynamics and drug sensitivities, which may change during the therapeutic process. Therefore, the importance of developing a non-invasive biomarker with the ability to monitor real-time tumor dynamics should be emphasized. This concept, so called “liquid biopsy”, would provide an ideal therapeutic strategy for an individual cancer patient and would facilitate the development of “tailor-made” cancer management programs. In the blood of cancer patients, the presence and potent utilities of circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) such as DNA, mRNA and microRNA have been recognized, and their clinical relevance is attracting considerable attention. In this review, we discuss recent developments in this research field as well as the relevance and future perspectives of CTCs and cfNAs in cancer patients, especially focusing on GC.
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Janmey PA, Slochower DR, Wang YH, Wen Q, Cēbers A. Polyelectrolyte properties of filamentous biopolymers and their consequences in biological fluids. SOFT MATTER 2014; 10:1439-49. [PMID: 24651463 PMCID: PMC4009494 DOI: 10.1039/c3sm50854d] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Anionic polyelectrolyte filaments are common in biological cells. DNA, RNA, the cytoskeletal filaments F-actin, microtubules, and intermediate filaments, and polysaccharides such as hyaluronan that form the pericellular matrix all have large net negative charge densities distributed over their surfaces. Several filamentous viruses with diameters and stiffnesses similar to those of cytoskeletal polymers also have similar negative charge densities. Extracellular protein filaments such collagen, fibrin and elastin, in contrast, have notably smaller charge densities and do not behave as highly charged polyelectrolytes in solution. This review summarizes data that demonstrate generic counterion-mediated effects on four structurally unrelated biopolymers of similar charge density: F-actin, vimentin, Pf1 virus, and DNA, and explores the possible biological and pathophysiological consequences of the polyelectrolyte properties of biological filaments.
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Affiliation(s)
- Paul A Janmey
- Institute for Medicine and Engineering, University of Pennsylvania, 1010 Vagelos Laboratories, 3340 Smith Walk, Philadelphia, PA 19104, USA
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38
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Chi Z, Wang Z, Wang K, Zhu Y, Qin S. Cathelicidin Antimicrobial Peptide LL-37 in Cholesteatoma Enables Keratinocyte Reactivity with Cytosolic DNA. Scand J Immunol 2014; 79:214-21. [PMID: 24383796 DOI: 10.1111/sji.12149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 12/16/2013] [Indexed: 12/21/2022]
Affiliation(s)
- Z. Chi
- Department of Otolaryngology; Eye & ENT Hospital; Fudan University; Shanghai China
| | - Z. Wang
- Department of Otolaryngology; Eye & ENT Hospital; Fudan University; Shanghai China
| | - K. Wang
- Department of Otolaryngology; Eye & ENT Hospital; Fudan University; Shanghai China
| | - Y. Zhu
- Department of Otolaryngology; Eye & ENT Hospital; Fudan University; Shanghai China
| | - S. Qin
- Department of Otolaryngology; Eye & ENT Hospital; Fudan University; Shanghai China
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Rigby RE, Webb LM, Mackenzie KJ, Li Y, Leitch A, Reijns MAM, Lundie RJ, Revuelta A, Davidson DJ, Diebold S, Modis Y, MacDonald AS, Jackson AP. RNA:DNA hybrids are a novel molecular pattern sensed by TLR9. EMBO J 2014; 33:542-58. [PMID: 24514026 PMCID: PMC3989650 DOI: 10.1002/embj.201386117] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The sensing of nucleic acids by receptors of the innate immune system is a key component of antimicrobial immunity. RNA:DNA hybrids, as essential intracellular replication intermediates generated during infection, could therefore represent a class of previously uncharacterised pathogen-associated molecular patterns sensed by pattern recognition receptors. Here we establish that RNA:DNA hybrids containing viral-derived sequences efficiently induce pro-inflammatory cytokine and antiviral type I interferon production in dendritic cells. We demonstrate that MyD88-dependent signalling is essential for this cytokine response and identify TLR9 as a specific sensor of RNA:DNA hybrids. Hybrids therefore represent a novel molecular pattern sensed by the innate immune system and so could play an important role in host response to viruses and the pathogenesis of autoimmune disease.
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Affiliation(s)
- Rachel E Rigby
- MRC Human Genetics Unit, MRC IGMM, University of EdinburghEdinburgh, UK
- MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC WIMM, University of OxfordOxford, UK
| | - Lauren M Webb
- Institute of Immunology and Infection Research, University of EdinburghEdinburgh, UK
- Manchester Collaborative Centre for Inflammation Research, University of ManchesterManchester, UK
| | - Karen J Mackenzie
- MRC Human Genetics Unit, MRC IGMM, University of EdinburghEdinburgh, UK
| | - Yue Li
- Department of Molecular Biophysics and Biochemistry, Yale UniversityNew Haven, CT, USA
| | - Andrea Leitch
- MRC Human Genetics Unit, MRC IGMM, University of EdinburghEdinburgh, UK
| | - Martin A M Reijns
- MRC Human Genetics Unit, MRC IGMM, University of EdinburghEdinburgh, UK
| | - Rachel J Lundie
- Institute of Immunology and Infection Research, University of EdinburghEdinburgh, UK
| | - Ailsa Revuelta
- MRC Human Genetics Unit, MRC IGMM, University of EdinburghEdinburgh, UK
| | - Donald J Davidson
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of EdinburghEdinburgh, UK
| | - Sandra Diebold
- Division of Immunology, Infection and Inflammatory Disease, King's College LondonLondon, UK
| | - Yorgo Modis
- Department of Molecular Biophysics and Biochemistry, Yale UniversityNew Haven, CT, USA
| | - Andrew S MacDonald
- Institute of Immunology and Infection Research, University of EdinburghEdinburgh, UK
- Manchester Collaborative Centre for Inflammation Research, University of ManchesterManchester, UK
- *Corresponding author. Tel: +44 161 275 1504; E-mail:
| | - Andrew P Jackson
- MRC Human Genetics Unit, MRC IGMM, University of EdinburghEdinburgh, UK
- **Corresponding author. Tel: +44 131 332 2471; Fax: +44 131 467 8456;
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Marzese DM, Hirose H, Hoon DSB. Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients. Expert Rev Mol Diagn 2013; 13:827-844. [PMID: 24127721 DOI: 10.1586/14737159.2013.845088] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Qualitative and quantitative analysis of circulating cell-free DNA (cfDNA) is an emerging non-invasive blood biomarker utilized to assess tumor progression and to evaluate prognosis, diagnosis and response to treatment. There is a need to develop cfDNA biomarkers to avoid complex risk-prone biopsy procedures for primary or metastatic tumors. Given the challenges associated with inter- and intra-tumor heterogeneity, the implementation of genome-wide cfDNA analysis will become an important avenue to understand tumor progression and therapeutic settings, not only for predominant, but also for under-represented tumor subclones with specific genomic aberrations. We summarize the latest publications in cfDNA analysis, including a metric analysis of clinical trials and new high-throughput technology applied to cfDNA analysis in clinical oncology.
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Affiliation(s)
- Diego M Marzese
- Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA
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Abstract
Cancer is associated with mutated genes, and analysis of tumour-linked genetic alterations is increasingly used for diagnostic, prognostic and treatment purposes. The genetic profile of solid tumours is currently obtained from surgical or biopsy specimens; however, the latter procedure cannot always be performed routinely owing to its invasive nature. Information acquired from a single biopsy provides a spatially and temporally limited snap-shot of a tumour and might fail to reflect its heterogeneity. Tumour cells release circulating free DNA (cfDNA) into the blood, but the majority of circulating DNA is often not of cancerous origin, and detection of cancer-associated alleles in the blood has long been impossible to achieve. Technological advances have overcome these restrictions, making it possible to identify both genetic and epigenetic aberrations. A liquid biopsy, or blood sample, can provide the genetic landscape of all cancerous lesions (primary and metastases) as well as offering the opportunity to systematically track genomic evolution. This Review will explore how tumour-associated mutations detectable in the blood can be used in the clinic after diagnosis, including the assessment of prognosis, early detection of disease recurrence, and as surrogates for traditional biopsies with the purpose of predicting response to treatments and the development of acquired resistance.
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Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 2013; 10:472-84. [PMID: 23836314 DOI: 10.1038/nrclinonc.2013.110] [Citation(s) in RCA: 1290] [Impact Index Per Article: 107.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cancer is associated with mutated genes, and analysis of tumour-linked genetic alterations is increasingly used for diagnostic, prognostic and treatment purposes. The genetic profile of solid tumours is currently obtained from surgical or biopsy specimens; however, the latter procedure cannot always be performed routinely owing to its invasive nature. Information acquired from a single biopsy provides a spatially and temporally limited snap-shot of a tumour and might fail to reflect its heterogeneity. Tumour cells release circulating free DNA (cfDNA) into the blood, but the majority of circulating DNA is often not of cancerous origin, and detection of cancer-associated alleles in the blood has long been impossible to achieve. Technological advances have overcome these restrictions, making it possible to identify both genetic and epigenetic aberrations. A liquid biopsy, or blood sample, can provide the genetic landscape of all cancerous lesions (primary and metastases) as well as offering the opportunity to systematically track genomic evolution. This Review will explore how tumour-associated mutations detectable in the blood can be used in the clinic after diagnosis, including the assessment of prognosis, early detection of disease recurrence, and as surrogates for traditional biopsies with the purpose of predicting response to treatments and the development of acquired resistance.
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Affiliation(s)
- Emily Crowley
- Department of Oncology, University of Turin, Institute for Cancer Research and Treatment, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Turin, Italy
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Cho H, Guo Y, Sosnovik DE, Josephson L. Imaging DNA with fluorochrome bearing metals. Inorg Chem 2013; 52:12216-22. [PMID: 23646914 DOI: 10.1021/ic400404g] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Molecules that fluoresce upon binding DNA are widely used in assaying and visualizing DNA in cells and tissues. However, using light to visualize DNA in animals is limited by the attenuation of light transmission by biological tissues. Moreover, it is now clear that DNA is an important mediator of dead cell clearance, coagulation reactions, and an immunogen in autoimmune lupus. Attaching metals (e.g., superparamagnetic nanoparticles, gadolinium ions, radioactive metal ions) to DNA-binding fluorochromes provides a way of imaging DNA in whole animals, and potentially humans, without light. Imaging metal-bearing, DNA-binding fluorochromes and their target DNA by magnetic resonance imaging may shed light on the many key roles of DNA in health and disease beyond the storage of genetic information.
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Affiliation(s)
- Hoonsung Cho
- Center for Translational Nuclear Medicine and Molecular Imaging, ‡Martinos Center for Biomedical Imaging, Department of Radiology, and §Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts 02114, United States
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Guéry L, Hugues S. Tolerogenic and activatory plasmacytoid dendritic cells in autoimmunity. Front Immunol 2013; 4:59. [PMID: 23508732 PMCID: PMC3589693 DOI: 10.3389/fimmu.2013.00059] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 02/19/2013] [Indexed: 11/30/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are a particular subset of DCs that link innate and adaptive immunity. They are responsible for the substantial production of type 1 interferon (IFN-I) in response to viral RNA or DNA through activation of TLR7 and 9. Furthermore, pDCs present antigens (Ag) and induce naïve T cell differentiation. It has been demonstrated that pDCs can induce immunogenic T cell responses through differentiation of cytotoxic CD8+ T cells and effector CD4+ T cells. Conversely, pDCs exhibit strong tolerogenic functions by inducing CD8+ T cell deletion, CD4+ T cell anergy, and Treg differentiation. However, since IFN-I produced by pDCs efficiently activates and recruits conventional DCs, B cells, T cells, and NK cells, pDCs also indirectly affect the nature and the amplitude of adaptive immune responses. As a consequence, the precise role of Ag-presenting functions of pDCs in adaptive immunity has been difficult to dissect in vivo. Additionally, different experimental procedures led to conflicting results regarding the outcome of T cell responses induced by pDCs. During the development of autoimmunity, pDCs have been shown to play both immunogenic and tolerogenic functions depending on disease, disease progression, and the experimental conditions. In this review, we will discuss the relative contribution of innate and adaptive pDC functions in modulating T cell responses, particularly during the development of autoimmunity.
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Affiliation(s)
- Leslie Guéry
- Department of Pathology and Immunology, University of Geneva Medical School Geneva, Switzerland
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Tomlinson MJ, Tomlinson S, Yang XB, Kirkham J. Cell separation: Terminology and practical considerations. J Tissue Eng 2012; 4:2041731412472690. [PMID: 23440031 PMCID: PMC3578272 DOI: 10.1177/2041731412472690] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Cell separation is a powerful tool in biological research. Increasing usage, particularly within the tissue engineering and regenerative medicine communities, means that researchers from a diverse range of backgrounds are utilising cell separation technologies. This review aims to offer potential solutions to cell sorting problems and to clarify common ambiguities in terminology and experimental design. The frequently used cell separation terms of 'purity', 'recovery' and 'viability' are discussed, and attempts are made to reach a consensus view of their sometimes ambiguous meanings. The importance of appropriate experimental design is considered, with aspects such as marker expression, tissue isolation and original cell population analysis discussed. Finally, specific technical issues such as cell clustering, dead cell removal and non-specific antibody binding are considered and potential solutions offered. The solutions offered may provide a starting point to improve the quality of cell separations achieved by both the novice and experienced researcher alike.
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Affiliation(s)
- Matthew J Tomlinson
- Department of Oral Biology, Leeds Dental Institute, University of Leeds, Leeds, UK
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Jylhävä J, Lyytikäinen LP, Kähönen M, Hutri-Kähönen N, Kettunen J, Viikari J, Raitakari OT, Lehtimäki T, Hurme M. A genome-wide association study identifies UGT1A1 as a regulator of serum cell-free DNA in young adults: The Cardiovascular Risk in Young Finns Study. PLoS One 2012; 7:e35426. [PMID: 22511988 PMCID: PMC3325226 DOI: 10.1371/journal.pone.0035426] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Accepted: 03/16/2012] [Indexed: 01/13/2023] Open
Abstract
Introduction Circulating cell-free DNA (cf-DNA) is a useful indicator of cell death, and it can also be used to predict outcomes in various clinical disorders. Several innate immune mechanisms are known to be involved in eliminating DNA and chromatin-related material as part of the inhibition of potentially harmful autoimmune responses. However, the exact molecular mechanism underlying the clearance of circulating cf-DNA is currently unclear. Methods To examine the mechanisms controlling serum levels of cf-DNA, we carried out a genome-wide association analysis (GWA) in a cohort of young adults (aged 24–39 years; n = 1841; 1018 women and 823 men) participating in the Cardiovascular Risk in Young Finns Study. Genotyping was performed with a custom-built Illumina Human 670 k BeadChip. The Quant-iTTM high sensitivity DNA assay was used to measure cf-DNA directly from serum. Results The results revealed that 110 single nucleotide polymorphisms (SNPs) were associated with serum cf-DNA with genome-wide significance (p<5×10−8). All of these significant SNPs were localised to chromosome 2q37, near the UDP-glucuronosyltransferase 1 (UGT1) family locus, and the most significant SNPs localised within the UGT1 polypeptide A1 (UGT1A1) gene region. Conclusion The UGT1A1 enzyme catalyses the detoxification of several drugs and the turnover of many xenobiotic and endogenous compounds by glucuronidating its substrates. These data indicate that UGT1A1-associated processes are also involved in the regulation of serum cf-DNA concentrations.
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Affiliation(s)
- Juulia Jylhävä
- Department of Microbiology and Immunology, School of Medicine, University of Tampere, Tampere, Finland.
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Radic M, Herrmann M, van der Vlag J, Rekvig OP. Regulatory and pathogenetic mechanisms of autoantibodies in SLE. Autoimmunity 2011; 44:349-56. [PMID: 21231891 DOI: 10.3109/08916934.2010.536794] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In the 53 years since the discovery of anti-DNA autoantibodies in lupus [1, 2, 3] , recalcitrant questions have been pondered and possible answers have been debated. The discovery of anti-DNA autoantibodies presented many puzzles: How is immunological tolerance to native B-form DNA broken? What elicits characteristic systemic lupus erythematosus (SLE) autoantibodies? Which of the diverse anti-nuclear reactivities are pathogenic? What is the role of autoantibodies in the clinical presentation of disease? How do genetic predisposition and environmental triggers contribute to SLE? These questions were brought into focus by Professor David Stollar in an introductory presentation to an intense, three-day meeting set among the rugged and inspiring scenery of the Norwegian arctic coastline (the Scientific Program is included as supplemental File 1). Other participants presented and discussed topics directed to understanding the origin and clinico-pathological impact of autoantibodies to chromatin and phospholipid antigens. In the following, several aspects of the workshop are discussed.
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Affiliation(s)
- Marko Radic
- Department of Molecular Sciences, University of Tennessee Health Science Center , Memphis, TN 38163, USA.
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High-mobility group box 1 (HMGB1) as a master regulator of innate immunity. Cell Tissue Res 2010; 343:189-99. [PMID: 20835834 DOI: 10.1007/s00441-010-1033-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Accepted: 08/03/2010] [Indexed: 02/08/2023]
Abstract
Damage-associated molecular patterns (DAMPs) comprise intracellular molecules characterized by the ability to reach the extracellular environment, where they prompt inflammation and tissue repair. The high-mobility box group 1 (HMGB1) protein is a prototypic DAMP and is highly conserved in evolution. HMGB1 is released upon cell and tissue necrosis and is actively produced by immune cells. Evidence suggests that HMGB1 acts as a key molecule of innate immunity, downstream of persistent tissue injury, orchestrating inflammation, stem cell recruitment/activation, and eventual tissue remodeling.
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Dasari M, Lee S, Sy J, Kim D, Lee S, Brown M, Davis M, Murthy N. Hoechst-IR: an imaging agent that detects necrotic tissue in vivo by binding extracellular DNA. Org Lett 2010; 12:3300-3. [PMID: 20597468 PMCID: PMC2929653 DOI: 10.1021/ol100923d] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Cell necrosis is central to the progression of numerous diseases, and imaging agents that can detect necrotic tissue have great clinical potential. We demonstrate here that a small molecule, termed Hoechst-IR, composed of the DNA binding dye Hoechst and the near-infrared dye IR-786, can image necrotic tissue in vivo via fluorescence imaging. Hoechst-IR detects necrosis by binding extracellular DNA released from necrotic cells and was able to image necrosis generated from a myocardial infarction and lipopolysaccharide/d-galactosamine (LPS-GalN) induced sepsis.
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Affiliation(s)
- Madhuri Dasari
- The Wallace H. Coulter Department of Biomedical Engineering and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Sungmun Lee
- The Wallace H. Coulter Department of Biomedical Engineering and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Jay Sy
- The Wallace H. Coulter Department of Biomedical Engineering and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Dongin Kim
- The Wallace H. Coulter Department of Biomedical Engineering and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Seungjun Lee
- The Wallace H. Coulter Department of Biomedical Engineering and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Milton Brown
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Michael Davis
- The Wallace H. Coulter Department of Biomedical Engineering and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Niren Murthy
- The Wallace H. Coulter Department of Biomedical Engineering and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
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Okuya K, Tamura Y, Saito K, Kutomi G, Torigoe T, Hirata K, Sato N. Spatiotemporal regulation of heat shock protein 90-chaperoned self-DNA and CpG-oligodeoxynucleotide for type I IFN induction via targeting to static early endosome. THE JOURNAL OF IMMUNOLOGY 2010; 184:7092-9. [PMID: 20483722 DOI: 10.4049/jimmunol.1000490] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Recent studies have suggested that TLR9 signaling in early endosomes leads to IFN-alpha production by plasmacytoid dendritic cells (pDCs), whereas TLR9 signaling in late endosomes induces pDC maturation, IL-6, and TNF-alpha secretion. In this study, we show that human DNA as well as CpG-oligodeoxynucleotides (ODNs) in complex with heat shock protein 90 (Hsp90) stimulate pDCs to produce large quantities of IFN-alpha. The Hsp90-CpG-A complexes are targeted into the Rab5+, early endosomal Ag 1+-static early endosome postinternalization by DCs, suggesting that preferential sorting of Hsp90-chaperoned self-DNA/CpG-ODNs to the static endosome is required for signaling through TLR9 for IFN-alpha production. Interestingly, Hsp90-mediated preferential static early endosomal translocation of CpG-ODNs triggers robust IFN-alpha production from murine conventional DCs. Thus, extracellular Hsp90 converts inert self-DNA/CpG-ODNs into a potent trigger of IFN-alpha production via spatiotemporal regulation.
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Affiliation(s)
- Koichi Okuya
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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