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Article ; Online: Epigenetic liquid biopsies: a novel putative biomarker in immunology and inflammation.

Fox-Fisher, Ilana / Shemer, Ruth / Dor, Yuval

2023 Volume 44, Issue 5, Page(s) 356–364

Abstract: Immune and inflammatory processes occurring within tissues are often undetectable by blood cell counts, standard circulating biomarkers, or imaging, representing an unmet biomedical need. Here, we outline recent advances indicating that liquid biopsies ... ...

Abstract	Immune and inflammatory processes occurring within tissues are often undetectable by blood cell counts, standard circulating biomarkers, or imaging, representing an unmet biomedical need. Here, we outline recent advances indicating that liquid biopsies can broadly inform human immune system dynamics. Nucleosome-size fragments of cell-free DNA (cfDNA) released from dying cells into blood contain rich epigenetic information such as methylation, fragmentation, and histone mark patterns. This information allows to infer the cfDNA cell of origin, as well as pre-cell death gene expression patterns. We propose that the analysis of epigenetic features of immune cell-derived cfDNA can shed light on immune cell turnover dynamics in healthy people, and inform the study and diagnosis of cancer, local inflammation, infectious or autoimmune diseases, as well as responses to vaccination.
MeSH term(s)	Humans ; DNA Methylation ; Liquid Biopsy/methods ; Biomarkers ; Cell-Free Nucleic Acids/genetics ; Inflammation/genetics ; Epigenesis, Genetic
Chemical Substances	Biomarkers ; Cell-Free Nucleic Acids
Language	English
Publishing date	2023-04-01
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2023.03.005
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Article: Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing

Katsman, Efrat / Orlanski, Shari / Martignano, Filippo / Fox-Fisher, Ilana / Shemer, Ruth / Dor, Yuval / Zick, Aviad / Eden, Amir / Petrini, Iacopo / Conticello, Silvestro G. / Berman, Benjamin P.

Genome biology. 2022 Dec., v. 23, no. 1

2022

Abstract: The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT ... ...

Abstract	The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNAs) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy.
Keywords	DNA ; DNA methylation ; biopsy ; feasibility studies ; genome ; nanopores ; neoplasms ; point-of-care systems
Language	English
Dates of publication	2022-12
Size	p. 158.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-022-02710-1
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Article ; Online: Chronic graft-versus-host disease detected by tissue-specific cell-free DNA methylation biomarkers.

Avni, Batia / Neiman, Daniel / Shaked, Elior / Gal-Rosenberg, Ofer / Grisariu, Sigal / Kuzli, Mona / Avni, Ilai / Fracchia, Andrea / Stepensky, Polina / Zuckerman, Tsila / Lev-Sagie, Ahinoam / Fox-Fisher, Ilana / Piyanzin, Sheina / Moss, Joshua / Salpeter, Seth J / Glaser, Benjamin / Shemer, Ruth / Dor, Yuval

The Journal of clinical investigation

2024 Volume 134, Issue 2

Abstract: Background: Accurate detection of graft-versus-host disease (GVHD) is a major challenge in the management of patients undergoing hematopoietic stem cell transplantation (HCT). Here, we demonstrated the use of circulating cell-free DNA (cfDNA) for ... ...

Abstract	Background: Accurate detection of graft-versus-host disease (GVHD) is a major challenge in the management of patients undergoing hematopoietic stem cell transplantation (HCT). Here, we demonstrated the use of circulating cell-free DNA (cfDNA) for detection of tissue turnover and chronic GVHD (cGVHD) in specific organs. Methods: We established a cocktail of tissue-specific DNA methylation markers and used it to determine the concentration of cfDNA molecules derived from the liver, skin, lungs, colon, and specific immune cells in 101 patients undergoing HCT. Results: Patients with active cGVHD showed elevated concentrations of cfDNA, as well as tissue-specific methylation markers that agreed with clinical scores. Strikingly, transplanted patients with no clinical symptoms had abnormally high levels of tissue-specific markers, suggesting hidden tissue turnover even in the absence of evident clinical pathology. An integrative model taking into account total cfDNA concentration, monocyte/macrophage cfDNA levels and alanine transaminase was able to correctly identify GVHD with a specificity of 86% and precision of 89% (AUC of 0.8). Conclusion: cfDNA markers can be used for the detection of cGVHD, opening a window into underlying tissue dynamics in patients that receive allogeneic stem cell transplants. Funding: This work was supported by grants from the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation and the Helmsley Charitable Trust (to YD).
MeSH term(s)	Humans ; Bronchiolitis Obliterans Syndrome ; DNA Methylation ; Cell-Free Nucleic Acids/genetics ; Graft vs Host Disease/diagnosis ; Biomarkers ; Hematopoietic Stem Cell Transplantation ; Genetic Markers ; Chronic Disease
Chemical Substances	Cell-Free Nucleic Acids ; Biomarkers ; Genetic Markers
Language	English
Publishing date	2024-01-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI163541
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Article ; Online: Insights Image for "Treatment of severe Kaposiform Lymphangiomatosis positive for NRAS mutation by MEK-inhibition".

Chowers, Guy / Abebe-Campino, Gadi / Golan, Hana / Vivante, Asaf / Greenberger, Shoshana / Soudack, Michalle / Barkai, Galia / Fox-Fisher, Ilana / Li, Dong / March, Michael / Battig, Mark R / Hakonarson, Hakon / Adams, Denise / Dori, Yoav / Dagan, Adi

Pediatric research

2023 Volume 94, Issue 6, Page(s) 2117

MeSH term(s)	Mutation ; Apoptosis ; Mitogen-Activated Protein Kinase Kinases
Chemical Substances	Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2023-08-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	4411-8
ISSN	1530-0447 ; 0031-3998
ISSN (online)	1530-0447
ISSN	0031-3998
DOI	10.1038/s41390-023-02755-3
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Article ; Online: Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing.

Katsman, Efrat / Orlanski, Shari / Martignano, Filippo / Fox-Fisher, Ilana / Shemer, Ruth / Dor, Yuval / Zick, Aviad / Eden, Amir / Petrini, Iacopo / Conticello, Silvestro G / Berman, Benjamin P

Genome biology

2022 Volume 23, Issue 1, Page(s) 158

Abstract	The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNAs) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy.
MeSH term(s)	Cell-Free Nucleic Acids ; Circulating Tumor DNA ; DNA Methylation ; High-Throughput Nucleotide Sequencing ; Humans ; Nanopore Sequencing ; Neoplasms/genetics
Chemical Substances	Cell-Free Nucleic Acids ; Circulating Tumor DNA
Language	English
Publishing date	2022-07-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-022-02710-1
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Article ; Online: Elevated cfDNA after exercise is derived primarily from mature polymorphonuclear neutrophils, with a minor contribution of cardiomyocytes.

Fridlich, Ori / Peretz, Ayelet / Fox-Fisher, Ilana / Pyanzin, Sheina / Dadon, Ziv / Shcolnik, Eilon / Sadeh, Ronen / Fialkoff, Gavriel / Sharkia, Israa / Moss, Joshua / Arpinati, Ludovica / Nice, Shachar / Nogiec, Christopher D / Ahuno, Samuel Terkper / Li, Rui / Taborda, Eddie / Dunkelbarger, Sonia / Fridlender, Zvi G / Polak, Paz /

Kaplan, Tommy / Friedman, Nir / Glaser, Benjamin / Shemer, Ruth / Constantini, Naama / Dor, Yuval

Cell reports. Medicine

2023 Volume 4, Issue 6, Page(s) 101074

Abstract: Strenuous physical exercise causes a massive elevation in the concentration of circulating cell-free DNA (cfDNA), which correlates with effort intensity and duration. The cellular sources and physiological drivers of this phenomenon are unknown. Using ... ...

Abstract	Strenuous physical exercise causes a massive elevation in the concentration of circulating cell-free DNA (cfDNA), which correlates with effort intensity and duration. The cellular sources and physiological drivers of this phenomenon are unknown. Using methylation patterns of cfDNA and associated histones, we show that cfDNA in exercise originates mostly in extramedullary polymorphonuclear neutrophils. Strikingly, cardiomyocyte cfDNA concentration increases after a marathon, consistent with elevated troponin levels and indicating low-level, delayed cardiac cell death. Physical impact, low oxygen levels, and elevated core body temperature contribute to neutrophil cfDNA release, while muscle contraction, increased heart rate, β-adrenergic signaling, or steroid treatment fail to cause elevation of cfDNA. Physical training reduces neutrophil cfDNA release after a standard exercise, revealing an inverse relationship between exercise-induced cfDNA release and training level. We speculate that the release of cfDNA from neutrophils in exercise relates to the activation of neutrophils in the context of exercise-induced muscle damage.
MeSH term(s)	Neutrophils ; Myocytes, Cardiac ; Cell-Free Nucleic Acids ; Exercise/physiology ; Histones
Chemical Substances	Cell-Free Nucleic Acids ; Histones
Language	English
Publishing date	2023-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2023.101074
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Article ; Online: Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition.

Pediatric research

2022 Volume 94, Issue 6, Page(s) 1911–1915

Abstract: Background: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the ... ...

Abstract	Background: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. Methods: The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. Results: Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. Conclusions: Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. Impact: This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
MeSH term(s)	Child ; Humans ; Endothelial Cells ; Phosphatidylinositol 3-Kinases ; Mutation ; Treatment Outcome ; Lymphatic Abnormalities ; Mitogen-Activated Protein Kinase Kinases/genetics ; Membrane Proteins/genetics ; GTP Phosphohydrolases/genetics
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; NRAS protein, human (EC 3.6.1.-) ; Membrane Proteins ; GTP Phosphohydrolases (EC 3.6.1.-)
Language	English
Publishing date	2022-03-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	4411-8
ISSN	1530-0447 ; 0031-3998
ISSN (online)	1530-0447
ISSN	0031-3998
DOI	10.1038/s41390-022-01986-0
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Article ; Online: The DNA methylome of human vascular endothelium and its use in liquid biopsies.

Peretz, Ayelet / Loyfer, Netanel / Piyanzin, Sheina / Ochana, Bracha Lea / Neiman, Daniel / Magenheim, Judith / Klochendler, Agnes / Drawshy, Zeina / Fox-Fisher, Ilana / Fridlich, Ori / Moss, Joshua / Cohen, Daniel / Zemmour, Hai / Cann, Gordon / Bredno, Joerg / Venn, Oliver / Avni, Batia / Alekberli, Tural / Samet, Yaacov /

Korach, Amit / Wald, Ori / Yutkin, Vladimir / Izhar, Uzi / Pillar, Nir / Grompe, Markus / Fridlender, Zvi / Rokach, Ariel / Planer, David / Landesberg, Giora / Glaser, Benjamin / Shemer, Ruth / Kaplan, Tommy / Dor, Yuval

Med (New York, N.Y.)

2023 Volume 4, Issue 4, Page(s) 263–281.e4

Abstract: Background: Vascular endothelial cells (VECs) are an essential component of each tissue, contribute to multiple pathologies, and are targeted by important drugs. Yet, there is a shortage of biomarkers to assess VEC turnover.: Methods: To develop DNA ... ...

Abstract	Background: Vascular endothelial cells (VECs) are an essential component of each tissue, contribute to multiple pathologies, and are targeted by important drugs. Yet, there is a shortage of biomarkers to assess VEC turnover. Methods: To develop DNA methylation-based liquid biopsies for VECs, we determined the methylome of VECs isolated from freshly dissociated human tissues. Findings: A comparison with a human cell-type methylome atlas yielded thousands of loci that are uniquely unmethylated in VECs. These sites are typically gene enhancers, often residing adjacent to VEC-specific genes. We also identified hundreds of genomic loci that are differentially methylated in organotypic VECs, indicating that VECs feeding specific organs are distinct cell types with a stable epigenetic identity. We established universal and lung-specific VEC markers and evaluated their presence in circulating cell-free DNA (cfDNA). Nearly 2.5% of cfDNA in the plasma of healthy individuals originates from VECs. Sepsis, graft versus host disease, and cardiac catheterization are associated with elevated levels of VEC-derived cfDNA, indicative of vascular damage. Lung-specific VEC cfDNA is selectively elevated in patients with chronic obstructive pulmonary disease (COPD) or lung cancer, revealing tissue-specific vascular turnover. Conclusions: VEC cfDNA biomarkers inform vascular dynamics in health and disease, potentially contributing to early diagnosis and monitoring of pathologies, and assessment of drug activity. Funding: This work was supported by the Beutler Research Program, Helmsley Charitable Trust, JDRF, Grail and the DON Foundation (to Y.D.). Y.D holds the Walter & Greta Stiel Chair in heart studies. B.G., R.S., J.M., D.N., T.K., and Y.D. filed patents on cfDNA analysis.
MeSH term(s)	Humans ; Epigenome ; Endothelium, Vascular ; Endothelial Cells/metabolism ; Biomarkers/metabolism ; Cell-Free Nucleic Acids ; Liquid Biopsy
Chemical Substances	Biomarkers ; Cell-Free Nucleic Acids
Language	English
Publishing date	2023-04-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2666-6340
ISSN (online)	2666-6340
DOI	10.1016/j.medj.2023.03.006
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Article ; Online: Remote immune processes revealed by immune-derived circulating cell-free DNA.

eLife

2021 Volume 10

Abstract: Blood cell counts often fail to report on immune processes occurring in remote tissues. Here, we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA ... ...

Abstract	Blood cell counts often fail to report on immune processes occurring in remote tissues. Here, we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA released from specific immune cell types in healthy individuals (N = 242), cross sectionally and longitudinally. Immune cfDNA levels had no individual steady state as opposed to blood cell counts, suggesting that cfDNA concentration reflects adjustment of cell survival to maintain homeostatic cell numbers. We also observed selective elevation of immune-derived cfDNA upon perturbations of immune homeostasis. Following influenza vaccination (N = 92), B-cell-derived cfDNA levels increased prior to elevated B-cell counts and predicted efficacy of antibody production. Patients with eosinophilic esophagitis (N = 21) and B-cell lymphoma (N = 27) showed selective elevation of eosinophil and B-cell cfDNA, respectively, which were undetectable by cell counts in blood. Immune-derived cfDNA provides a novel biomarker for monitoring immune responses to physiological and pathological processes that are not accessible using conventional methods.
MeSH term(s)	Adult ; Aged ; Biomarkers, Tumor/metabolism ; Cell-Free Nucleic Acids/metabolism ; DNA Methylation ; Female ; Humans ; Immunity ; Male ; Middle Aged ; Young Adult
Chemical Substances	Biomarkers, Tumor ; Cell-Free Nucleic Acids
Language	English
Publishing date	2021-11-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.70520
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Article ; Online: Universal lung epithelium DNA methylation markers for detection of lung damage in liquid biopsies.

Magenheim, Judith / Rokach, Ariel / Peretz, Ayelet / Loyfer, Netanel / Cann, Gordon / Amini, Hamed / Moradi, Patriss / Nagaraju, Sudharani / Sameer, Wafa / Cohen, Assaf / Fogel, Ophir / Kuint, Rottem / Abutbul, Avraham / Abu Rmeileh, Aiman / Karameh, Mutaz / Cohen Goichman, Polina / Wald, Ori / Korach, Amit / Neiman, Daniel /

Fox-Fisher, Ilana / Moss, Joshua / Cohen, Daniel / Piyanzin, Sheina / Ben Ami, Roni / Quteineh, Ahmad / Golomb, Eliahu / Shemer, Ruth / Glaser, Benjamin / Kaplan, Tommy / Fridlender, Zvi G / Dor, Yuval

The European respiratory journal

2022 Volume 60, Issue 5

Abstract: Background: Circulating biomarkers for lung damage are lacking. Lung epithelium-specific DNA methylation patterns can potentially report the presence of lung-derived cell-free DNA (cfDNA) in blood, as an indication of lung cell death.: Methods: We ... ...

Abstract	Background: Circulating biomarkers for lung damage are lacking. Lung epithelium-specific DNA methylation patterns can potentially report the presence of lung-derived cell-free DNA (cfDNA) in blood, as an indication of lung cell death. Methods: We sorted human lung alveolar and bronchial epithelial cells from surgical specimens, and obtained their methylomes using whole-genome bisulfite sequencing. We developed a PCR sequencing assay determining the methylation status of 17 loci with lung-specific methylation patterns, and used it to assess lung-derived cfDNA in the plasma of healthy volunteers and patients with lung disease. Results: Loci that are uniquely unmethylated in alveolar or bronchial epithelial cells are enriched for enhancers controlling lung-specific genes. Methylation markers extracted from these methylomes revealed that normal lung cell turnover probably releases cfDNA into the air spaces, rather than to blood. People with advanced lung cancer show a massive elevation of lung cfDNA concentration in blood. Among individuals undergoing bronchoscopy, lung-derived cfDNA is observed in the plasma of those later diagnosed with lung cancer, and to a lesser extent in those diagnosed with other lung diseases. Lung cfDNA is also elevated in patients with acute exacerbation of COPD compared with patients with stable disease, and is associated with future exacerbation and mortality in these patients. Conclusions: Universal cfDNA methylation markers of normal lung epithelium allow for mutation-independent, sensitive and specific detection of lung-derived cfDNA, reporting on ongoing lung injury. Such markers can find broad utility in the study of normal and pathologic human lung dynamics.
MeSH term(s)	Humans ; DNA Methylation ; Cell-Free Nucleic Acids/genetics ; Liquid Biopsy ; Biomarkers ; Epithelium ; Lung ; Lung Neoplasms/genetics ; Biomarkers, Tumor/genetics
Chemical Substances	Cell-Free Nucleic Acids ; Biomarkers ; Biomarkers, Tumor
Language	English
Publishing date	2022-11-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.03056-2021
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