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1. Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels

Author: Joshua Moss, Roni Ben-Ami, Ela Shai, Ofer Gal-Rosenberg, Yosef Kalish, Agnes Klochendler, Gordon Cann, Benjamin Glaser, Ariela Arad, Ruth Shemer, and Yuval Dor
Subjects: Science
Abstract: Abstract Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determine that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (~26%), while erythroblasts contribute 1–4% of cfDNA in healthy individuals. Surprisingly, we discover that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.
Published: 2023
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2. Liquid biopsy reveals collateral tissue damage in cancer

Author: Asael Lubotzky, Hai Zemmour, Daniel Neiman, Marc Gotkine, Netanel Loyfer, Sheina Piyanzin, Bracha-Lea Ochana, Roni Lehmann-Werman, Daniel Cohen, Joshua Moss, Judith Magenheim, Maureen F. Loftus, Lauren Brais, Kimmie Ng, Raul Mostoslavsky, Brian M. Wolpin, Aviad Zick, Myriam Maoz, Albert Grinshpun, Anatoli Kustanovich, Chen Makranz, Jonathan E. Cohen, Tamar Peretz, Ayala Hubert, Mark Temper, Azzam Salah, Shani Avniel-Polak, Simona Grozinsky-Glasberg, Kirsty L. Spalding, Ariel Rokach, Tommy Kaplan, Benjamin Glaser, Ruth Shemer, and Yuval Dor
Subjects: Cell biology, Oncology, Medicine
Abstract: Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases. In addition, patients with localized pancreatic or colon cancer showed elevated hepatocyte cfDNA, suggesting liver damage inflicted by micrometastatic disease, by primary pancreatic tumor pressing the bile duct, or by a systemic response to the primary tumor. We also identified elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA in a subpopulation of patients with brain metastases compared with cancer patients without brain metastasis. Cell type–specific cfDNA methylation markers enable the identification of collateral tissue damage in cancer, revealing the presence of metastases in specific locations and potentially assisting in early cancer detection.
Published: 2022
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3. Remote immune processes revealed by immune-derived circulating cell-free DNA

Author: Ilana Fox-Fisher, Sheina Piyanzin, Bracha Lea Ochana, Agnes Klochendler, Judith Magenheim, Ayelet Peretz, Netanel Loyfer, Joshua Moss, Daniel Cohen, Yaron Drori, Nehemya Friedman, Michal Mandelboim, Marc E Rothenberg, Julie M Caldwell, Mark Rochman, Arash Jamshidi, Gordon Cann, David Lavi, Tommy Kaplan, Benjamin Glaser, Ruth Shemer, and Yuval Dor
Subjects: biomarker, liquid biopsy, DNA methylation, cell-free DNA, vaccination, lymphoma, Medicine, Science, Biology (General), QH301-705.5
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.
Published: 2021
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4. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Author: Joshua Moss, Judith Magenheim, Daniel Neiman, Hai Zemmour, Netanel Loyfer, Amit Korach, Yaacov Samet, Myriam Maoz, Henrik Druid, Peter Arner, Keng-Yeh Fu, Endre Kiss, Kirsty L. Spalding, Giora Landesberg, Aviad Zick, Albert Grinshpun, A. M. James Shapiro, Markus Grompe, Avigail Dreazan Wittenberg, Benjamin Glaser, Ruth Shemer, Tommy Kaplan, and Yuval Dor
Subjects: Science
Abstract: The methylation status of circulating cell-free DNA (cfDNA) can be informative about recent cell death events. Here the authors present an approach to determine the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types, and find that cfDNA from patients reveals tissue contributions that agree with clinical findings.
Published: 2018
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5. Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA

Author: Hai Zemmour, David Planer, Judith Magenheim, Joshua Moss, Daniel Neiman, Dan Gilon, Amit Korach, Benjamin Glaser, Ruth Shemer, Giora Landesberg, and Yuval Dor
Subjects: Science
Abstract: The detection of cardiomyocyte death is a critical aspect in the diagnosis and monitoring of heart diseases. Here the authors show that cardiomyocyte-specific methylation patterns of circulating cell-free DNA may serve as a biomarker of cardiac cell death in infarcted and septic patients.
Published: 2018
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6. Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability

Author: Cornelia Jäkel, Frank Bergmann, Reka Toth, Yassen Assenov, Daniel van der Duin, Oliver Strobel, Thomas Hank, Günter Klöppel, Craig Dorrell, Markus Grompe, Joshua Moss, Yuval Dor, Peter Schirmacher, Christoph Plass, Odilia Popanda, and Peter Schmezer
Subjects: Science
Abstract: Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, the authors perform genome- and epigenome-wide analyses from normal and ACC pancreatic tissue that identify aberrations in genome stability and cell cycle control.
Published: 2017
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7. A Study of the Radiation Tolerance of CVD Diamond to 70 MeV Protons, Fast Neutrons and 200 MeV Pions

Author: Lukas Bäni, Andreas Alexopoulos, Marina Artuso, Felix Bachmair, Marcin Ryszard Bartosik, Helge Christoph Beck, Vincenzo Bellini, Vladimir Belyaev, Benjamin Bentele, Alexandre Bes, Jean-Marie Brom, Gabriele Chiodini, Dominik Chren, Vladimir Cindro, Gilles Claus, Johann Collot, John Cumalat, Sébastien Curtoni, Anne Evelyn Dabrowski, Raffaello D’Alessandro, Denis Dauvergne, Wim De Boer, Christian Dorfer, Marc Dünser, Gerald Eigen, Vladimir Eremin, Jacopo Forneris, Laurent Gallin-Martel, Marie-Laure Gallin-Martel, Kock Kiam Gan, Martin Gastal, Abderrahman Ghimouz, Mathieu Goffe, Joel Goldstein, Alexander Golubev, Andrej Gorišek, Eugene Grigoriev, Jörn Grosse-Knetter, Aidan Grummer, Bojan Hiti, Dmitry Hits, Martin Hoeferkamp, Jérôme Hosselet, Fabian Hügging, Chris Hutson, Jens Janssen, Harris Kagan, Keida Kanxheri, Richard Kass, Mladen Kis, Gregor Kramberger, Sergey Kuleshov, Ana Lacoste, Stefano Lagomarsino, Alessandro Lo Giudice, Ivan López Paz, Eric Lukosi, Chaker Maazouzi, Igor Mandić, Sara Marcatili, Alysia Marino, Cédric Mathieu, Mauro Menichelli, Marko Mikuž, Arianna Morozzi, Francesco Moscatelli, Joshua Moss, Raymond Mountain, Alexander Oh, Paolo Olivero, Daniele Passeri, Heinz Pernegger, Roberto Perrino, Federico Picollo, Michal Pomorski, Renato Potenza, Arnulf Quadt, Fatah Rarbi, Alessandro Re, Michael Reichmann, Shaun Roe, Olivier Rossetto, Diego Alejandro Sanz Becerra, Christian J. Schmidt, Stephen Schnetzer, Silvio Sciortino, Andrea Scorzoni, Sally Seidel, Leonello Servoli, Dale Shane Smith, Bruno Sopko, Vit Sopko, Stefania Spagnolo, Stefan Spanier, Kevin Stenson, Robert Stone, Bjarne Stugu, Concetta Sutera, Michael Traeger, William Trischuk, Marco Truccato, Cristina Tuvè, Jaap Velthuis, Stephen Wagner, Rainer Wallny, Jianchun Wang, Norbert Wermes, Jayashani Wickramasinghe, Mahfoud Yamouni, Justas Zalieckas, Marko Zavrtanik, Kazuhiko Hara, Yoichi Ikegami, Osamu Jinnouchi, Takashi Kohriki, Shingo Mitsui, Ryo Nagai, Susumu Terada, and Yoshinobu Unno
Subjects: Chemical Vapor Deposition, single-crystalline diamond, polycrystalline diamond, charge collection distance, mean drift path, schubweg, Chemical technology, TP1-1185
Abstract: We measured the radiation tolerance of commercially available diamonds grown by the Chemical Vapor Deposition process by measuring the charge created by a 120 GeV hadron beam in a 50 μm pitch strip detector fabricated on each diamond sample before and after irradiation. We irradiated one group of samples with 70 MeV protons, a second group of samples with fast reactor neutrons (defined as energy greater than 0.1 MeV), and a third group of samples with 200 MeV pions, in steps, to (8.8±0.9) × 1015 protons/cm2, (1.43±0.14) × 1016 neutrons/cm2, and (6.5±1.4) × 1014 pions/cm2, respectively. By observing the charge induced due to the separation of electron–hole pairs created by the passage of the hadron beam through each sample, on an event-by-event basis, as a function of irradiation fluence, we conclude all datasets can be described by a first-order damage equation and independently calculate the damage constant for 70 MeV protons, fast reactor neutrons, and 200 MeV pions. We find the damage constant for diamond irradiated with 70 MeV protons to be 1.62±0.07(stat)±0.16(syst)× 10−18 cm2/(p μm), the damage constant for diamond irradiated with fast reactor neutrons to be 2.65±0.13(stat)±0.18(syst)× 10−18 cm2/(n μm), and the damage constant for diamond irradiated with 200 MeV pions to be 2.0±0.2(stat)±0.5(syst)× 10−18 cm2/(π μm). The damage constants from this measurement were analyzed together with our previously published 24 GeV proton irradiation and 800 MeV proton irradiation damage constant data to derive the first comprehensive set of relative damage constants for Chemical Vapor Deposition diamond. We find 70 MeV protons are 2.60 ± 0.29 times more damaging than 24 GeV protons, fast reactor neutrons are 4.3 ± 0.4 times more damaging than 24 GeV protons, and 200 MeV pions are 3.2 ± 0.8 more damaging than 24 GeV protons. We also observe the measured data can be described by a universal damage curve for all proton, neutron, and pion irradiations we performed of Chemical Vapor Deposition diamond. Finally, we confirm the spatial uniformity of the collected charge increases with fluence for polycrystalline Chemical Vapor Deposition diamond, and this effect can also be described by a universal curve.
Published: 2020
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8. A universal cell‐free <scp>DNA</scp> approach for response prediction to preoperative chemoradiation in rectal cancer

Author: Albert Grinshpun, Anatoli Kustanovich, Daniel Neiman, Roni Lehmann‐Werman, Aviad Zick, Karen Meir, Elez Vainer, Roy Z. Granit, Amit Arad, Noa Daskal, Ruth Schwartz, Eli Sapir, Myriam Maoz, Esther Tahover, Joshua Moss, Iddo Z. Ben‐Dov, Tamar Peretz, Ayala Hubert, Ruth Shemer, and Yuval Dor
Subjects: Cancer Research, Oncology
Abstract: The standard treatment approach for stage II/III rectal cancer is neoadjuvant chemoradiation therapy (nCRT) followed by surgery. In recent years, new treatment approaches have led to higher rates of complete tumor eradication combined with organ-preservation strategies. However, better tools are still needed to personalize therapy for the individual patient. In this prospective observational study, we analyzed colon-derived cell-free (cf)DNA (c-cfDNA) using a tissue-specific DNA methylation signature, and its association with therapy outcomes. Analyzing plasma samples (n = 303) collected during nCRT from 37 patients with locally advanced rectal cancer (LARC), we identified colon-specific methylation markers that discriminated healthy individuals from patients with untreated LARC (area under the curve, 0.81; 95% confidence interval, 0.70-0.92; P 0.0001). Baseline c-cfDNA predicted tumor response, with increased levels linked to larger residual cancer. c-cfDNA measured after the first week of therapy identified patients with maximal response and complete cancer eradication, who had significantly lower c-cfDNA compared with those who had residual disease (8.6 vs 57.7 average copies/mL, respectively; P = 0.013). Increased c-cfDNA after one week of therapy was also associated with disease recurrence. Methylation-based liquid biopsy can predict nCRT outcomes and facilitate patient selection for escalation and de-escalation strategies.
Published: 2022
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9. Megakaryocyte and erythroblast DNA in plasma and platelets

Author: Joshua Moss, Roni Ben-Ami, Ela Shai, Yosef Kalish, Agnes Klochender, Gordon Cann, Benjamin Glaser, Ariela Arad, Ruth Shemer, and Yuval Dor
Abstract: Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determined that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (∼26%), while erythroblasts contribute 1-4% of cfDNA in healthy individuals. Surprisingly, we discovered that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with Thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as novel biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.GRAPHICAL ABSTRACT
Published: 2022
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10. The DNA methylome of human vascular endothelium and its use in liquid biopsies

Author: Ayelet Peretz, Netanel Loyfer, Sheina Piyanzin, Bracha Lea Ochana, Daniel Neiman, Judith Magenheim, Agnes Klochendler, Zeina Drawshy, Ilana Fox-Fisher, Ori Fridlich, Joshua Moss, Daniel Cohen, Hai Zemmour, Gordon Cann, Joerg Bredno, Oliver Venn, Batia Avni, Tural Alekberli, Yaacov Samet, Amit Korach, Ori Wald, Vladimir Yutkin, Uzi Izhar, Nir Pillar, Markus Grompe, Zvi Fridlender, Ariel Rokach, David Planer, Giora Landesberg, Benjamin Glaser, Ruth Shemer, Tommy Kaplan, and Yuval Dor
Subjects: General Medicine
Published: 2023
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11. Abstract PS5-43: Senescence-related methylation changes following therapy as potential biomarker for CDK4/6 inhibitor activity

Author: Yael Gabai, Yuval Dor, Ittai Ben-Porath, Joshua Moss, Albert Grinshpun, and Anatoli Kustanovich
Subjects: Senescence, Cancer Research, Oncology, Potential biomarkers, Cancer research, Methylation, Biology
Abstract: IntroductionClassically, cancer therapy approaches lead to tumor cell death or an alternative fate such as senescence. Senescent cells remain viable but without proliferation markers. Senescent cells secrete factors with diverse actions that influence surrounding cells, the extracellular matrix (ECM) and the immune system, a phenomenon termed the senescence-associated secretory phenotype (SASP). Cyclin-dependent kinase 4/6 inhibitors (CDKi) are game-changers in the therapy of metastatic hormone receptor-positive, HER2-negative breast cancer. A potential mechanism of the action of these agents is induction of senescence in breast tumor cells, going beyond cell cycle arrest. However, senescence can be studied mainly using invasive biopsies, and therefore the prevalence and importance of senescence in patients are largely unknown. Moreover, only few circulating biomarkers exist to predict activity or measure CDKi effects. In order to develop a correlative liquid biopsy for CDKi activity, we have analyzed epigenetic (methylation) changes following therapy-induced senescence in vitro. We sought to identify (un)methylated loci that will be affected by different approaches and later can be discovered in circulating cell-free DNA. MethodsWe have treated luminal breast cancer MCF-7 cells with Doxorubicin, CDKi (Palbociclib) or by irradiation. This protocol resulted in up to 80% of cells with senescence-related beta-galactosidase activity. DNA methylation was profiled using Illumina Infinium MethylationEPIC 850K BeadChip. Differentially methylated loci (mDNA) were identified using GenomeStudio and Minfi. Analyses were done using GREAT, CSGene, and Reactome databases. Methylation age was analyzed using the Horvath Methylation Calculator. Statistical significance was defined as p ResultsSignificantly differentially methylated sites (in comparison to untreated cells) were revealed as following: 9111 sites in Doxorubicin treated cells, 3828 sites in Palbociclib treated cells, and 694 sites in irradiated cells. These loci comprise 1%, 0.45%, and 0.08% of analyzed methylation sites, respectively. 324 loci were similarly changed following the three treatment options ('common sites'). We found that the 'geographic' distribution of intragenic and intergenic methylation sites (5' UTR, gene body etc.) in all treated cells was similar. Gene set over-representation analysis revealed that sites associated with genes of the 'collagen metabolic process' set were significantly altered in drug-treated cells. Pathway investigation of the 324 'common sites' revealed that ECM-related 'focal adhesion assembly' is the most significant pathway involved. Specific analysis of senescence-related gene sets showed that 15.1% (76/503) of senescence genes changed after Doxorubicin treatment, 6.2% (31/503) after Palbociclib and 1% (5/503) after irradiation. Pathway analysis of these genes showed that drugs affected the 'oxidative stress-induced senescence' pathway, while irradiated cells had SASP-related genes affected.Despite the above mentioned methylation changes, age calculation based on methylation clock showed that all samples had similar age (6), regardless of manipulation. ConclusionSingle treatment of MCF-7 cells with known senescence inducers results in changes in methylation patterns. A significant number of common loci changed following all types of treatments, suggesting them as potential surrogate loci of senescence. Also, we have reproduced the well-known interplay between collagen and senescence/SASP.This preliminary data sheds light on epigenetic changes following treatment-induced senescence. Further studies are needed to validate whether these methylation changes can be found in vivo in tumors and in patients’ cell-free DNA following therapy with CDKi. Citation Format: Albert Grinshpun, Anatoli Kustanovich, Joshua Moss, Yael Gabai, Yuval Dor, Ittai Ben-Porath. Senescence-related methylation changes following therapy as potential biomarker for CDK4/6 inhibitor activity [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-43.
Published: 2021
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12. Chronic Graft Versus Host Disease Detected By Tissue-Specific Cell-Free DNA Methylation Biomarkers

Author: Batia Avni, Daniel Neiman, Elior Shaked, Sigal Grisariu Greenzaid, Mona Kuzli, Andrea Fracchia, Polina Stepensky, Tsila Zuckerman, Ahinoam Lev-Sagie, Ilana Fox-Fisher, Sheina Piyanzin, Joshua Moss, Benjamin Glaser, Ruth Shemer, and Yuval Dor
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022
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13. Abstract P1-10-10: Non-personalized detection of circulating breast-derived DNA for monitoring of preoperative breast cancer treatment

Author: Bracha Ohana, Yuval Dor, Einat Carmon, Ruth Shemer, Ofri Abraham, Myriam Maoz, Joshua Moss, Lili Germansky, Beatrice Uziely, Albert Grinshpun, Benjamin Glaser, and Aviad Zick
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, Methylation, medicine.disease, Metastatic breast cancer, Breast cancer, CpG site, Internal medicine, DNA methylation, medicine, Biomarker (medicine), Epigenetics, business
Abstract: Background: Cell-free DNA (cfDNA) molecules circulating in blood are emerging as important non-invasive biomarkers for monitoring physiological and pathological processes. Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection of multiple cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist in only a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast derived cfDNA, using a breast-specific DNA methylation signature. Methods: In order to identify regions of the genome with unique methylation patterns in breast epithelium, we compared genome-wide methylation profiles of normal breast tissue and breast cancer to genome-wide methylation profiles of other normal and cancerous tissues and aimed to identify CpG sites that are uniquely hypermethylated or hypomethylated in the breast. By quantifying the proportion of molecules in a sample that harbored 3 chosen breast-specific methylation sites, we could obtain an estimate of the proportion of the sample derived from breast epithelial cells. We have collected plasma prospectively from healthy women, metastatic breast cancer patients and patients with localized (stage II-III) breast cancer who were assigned to preoperative chemotherapy at our cancer institute. In the latter cohort, samples were collected before and throughout treatment until surgery. The trial was approved by the Institutional Ethics Committee and all patients gave written informed consent. Results: All three markers clearly distinguished between the plasma of healthy donors (n=64) and patients with metastatic disease (n=14, p-value Conclusion: A breast-unique epigenetic signature in circulating cell-free DNA can be used as a universal biomarker for breast cancer, to allow sensitive detection and monitoring of localized breast cancer treatment outcomes. Further research will aid to evaluate this promising and affordable method in additional clinical scenarios. Citation Format: Albert Grinshpun, Aviad Zick, Joshua Moss, Einat Carmon, Myriam Maoz, Bracha Ohana, Ofri Abraham, Lili Germansky, Benjamin Glaser, Ruth Shemer, Yuval Dor, Beatrice Uziely. Non-personalized detection of circulating breast-derived DNA for monitoring of preoperative breast cancer treatment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-10.
Published: 2020
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14. Development of methylation-based biomarkers for breast cancer detection by model training and validation in synthetic cell-free DNA

Author: Sophie Marion de Procé, Martyna Adamowicz, Prasun Dutta, Sophie J. Warlow, Joshua Moss, Ruth Shemer, Yuval Dor, Christelle Robert, and Timothy J. Aitman
Abstract: Circulating tumour-derived DNA (ctDNA) carries the genetic and epigenetic characteristics of the tumour from which it is derived and can give information about the biology and tissue origins of the underlying tumour. DNA methylation is an epigenetic mark that is specific to individual tissues and, as methylation profiles are disrupted in tumours, they can indicate the tissue of origin and cancer type of ctDNA. We have developed a set of methylation biomarkers for detecting breast cancer in plasma cell-free DNA (cfDNA). First, we mined publicly available methylation datasets to create synthetic methylation profiles that were modelled to reflect cfDNA from healthy subjects and cancer patients. These profiles were restricted to the most differentially methylated CpGs between breast tumour samples and haematopoietic cells. Regularised logistic regression models were trained using 10-fold cross-validation on synthetic cfDNA datasets with distinct fractions of breast tumour DNA spiked in silico into healthy cfDNA with the addition of 10% of a mix of different tissues. Initial validation with synthetic cfDNA permitted detection of breast cancer-derived DNA with as little as 0.25% tumour DNA spiked in silico into healthy subject cfDNA with an area under ROC curve (AUC) of 0.63. Performances of classifiers increased with increased fractions of spike-in tumour DNA (AUCs 0.77 and 0.93 at tumour DNA fractions 0.5% and 1% respectively). We then combined the most discriminative CpG markers from our models with methylation markers of breast cancer that had already been published to obtain a single marker set. In vitro testing of MCF-7 breast cancer cell line DNA spiked into leukocyte DNA showed highly significant correlation for individual markers between laboratory-measured and published methylation data for MCF-7 and leukocytes (R > 0.89, P < 2.2 × 10−16). These preliminary data indicate promising results for detection of breast cancer cell line DNA using this methylation marker set, which now require testing in cfDNA from breast cancer patients and healthy controls.
Published: 2022
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15. A human DNA methylation atlas reveals principles of cell type-specific methylation and identifies thousands of cell type-specific regulatory elements

Author: Netanel Loyfer, Judith Magenheim, Ayelet Peretz, Gordon Cann, Joerg Bredno, Agnes Klochendler, Ilana Fox-Fisher, Sapir Shabi-Porat, Merav Hecht, Tsuria Pelet, Joshua Moss, Zeina Drawshy, Hamed Amini, Patriss Moradi, Sudharani Nagaraju, Dvora Bauman, David Shveiky, Shay Porat, Gurion Rivkin, Omer Or, Nir Hirshoren, Einat Carmon, Alon Pikarsky, Abed Khalaileh, Gideon Zamir, Ronit Grinboim, Machmud Abu Gazala, Ido Mizrahi, Noam Shussman, Amit Korach, Ori Wald, Uzi Izhar, Eldad Erez, Vladimir Yutkin, Yaacov Samet, Devorah Rotnemer Golinkin, Kirsty L. Spalding, Henrik Druid, Peter Arner, A.M. James Shapiro, Markus Grompe, Alex Aravanis, Oliver Venn, Arash Jamshidi, Ruth Shemer, Yuval Dor, Benjamin Glaser, and Tommy Kaplan
Abstract: DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 207 healthy tissue samples.Replicates of the same cell-type are >99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hyper-methylated loci are rare and are enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping. The atlas provides an essential resource for interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.Summary paragraphDNA methylation, a fundamental epigenetic mark, governs chromatin organization and gene expression1, thus defining the molecular identity of cells and providing a window into developmental processes with wide-ranging physiologic and clinical ramifications. Current DNA methylation datasets have limitations, typically including only a fraction of methylation sites, many from cell lines that underwent massive changes in culture or from tissues containing unspecified mixtures of cells2–6.We present a human methylome atlas based on deep whole-genome bisulfite sequencing of 39 sorted, primary cell types and use this dataset to address fundamental questions in developmental biology, physiology and pathology. Biological replicates are >99.5% identical, demonstrating unappreciated robustness to genetic variation and environmental perturbations. Clustering recapitulates key elements of tissue ontogeny, identifying methylation patterns retained since gastrulation. Loci uniquely unmethylated in individual cell types identify novel transcriptional enhancers and are enriched for tissue-specific transcription factors binding motifs. In contrast, loci uniquely hyper-methylated in specific cell types are rare, enriched for CpG islands and polycomb targets, and overlap CTCF binding sites, suggesting a novel role in shaping cell-type-specific chromatin looping. Finally, the atlas facilitates fragment-level deconvolution of tissue and plasma methylomes across thousands of cell-type specific regions to quantify their individual components at unprecedented resolution.The human cell-type-specific methylation atlas provides an essential resource for studying gene regulation by defining cell-type-specific distal enhancers and regulators of 3D organization, for identifying pathological changes in DNA methylation, and for the interpretation of methylation-based liquid biopsies.A deep methylation atlas of 39 human cell types, sorted from healthy samplesMethylomes record developmental history of cellsThousands of novel cell type-specific methylation markersHypo-methylation uncovers cell type-specific regulatory map of distal enhancersHyper-methylation across CTCF sitesCell type-specific biomarkers facilitate fragment-level deconvolution of tissues and cfDNA
Published: 2022
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16. A DNA methylation atlas of normal human cell types

Author: Netanel Loyfer, Judith Magenheim, Ayelet Peretz, Gordon Cann, Joerg Bredno, Agnes Klochendler, Ilana Fox-Fisher, Sapir Shabi-Porat, Merav Hecht, Tsuria Pelet, Joshua Moss, Zeina Drawshy, Hamed Amini, Patriss Moradi, Sudharani Nagaraju, Dvora Bauman, David Shveiky, Shay Porat, Uri Dior, Gurion Rivkin, Omer Or, Nir Hirshoren, Einat Carmon, Alon Pikarsky, Abed Khalaileh, Gideon Zamir, Ronit Grinbaum, Machmud Abu Gazala, Ido Mizrahi, Noam Shussman, Amit Korach, Ori Wald, Uzi Izhar, Eldad Erez, Vladimir Yutkin, Yaacov Samet, Devorah Rotnemer Golinkin, Kirsty L. Spalding, Henrik Druid, Peter Arner, A. M. James Shapiro, Markus Grompe, Alex Aravanis, Oliver Venn, Arash Jamshidi, Ruth Shemer, Yuval Dor, Benjamin Glaser, and Tommy Kaplan
Subjects: Multidisciplinary
Abstract: DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2–5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.
Published: 2021

17. Author response: Remote immune processes revealed by immune-derived circulating cell-free DNA

Author: Ilana Fox-Fisher, Sheina Piyanzin, Bracha Lea Ochana, Agnes Klochendler, Judith Magenheim, Ayelet Peretz, Netanel Loyfer, Joshua Moss, Daniel Cohen, Yaron Drori, Nehemya Friedman, Michal Mandelboim, Marc E Rothenberg, Julie M Caldwell, Mark Rochman, Arash Jamshidi, Gordon Cann, David Lavi, Tommy Kaplan, Benjamin Glaser, Ruth Shemer, and Yuval Dor
Published: 2021
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18. Universal lung epithelium DNA methylation markers for detection of lung damage in liquid biopsies

Author: Judith Magenheim, Ariel Rokach, Ayelet Peretz, Netanel Loyfer, Gordon Cann, Hamed Amini, Patriss Moradi, Sudharani Nagaraju, Wafa Sameer, Assaf Cohen, Ophir Fogel, Rottem Kuint, Avraham Abutbul, Aiman Abu Rmeileh, Mutaz Karameh, Polina Cohen Goichman, Ori Wald, Amit Korach, Daniel Neiman, Ilana Fox-Fisher, Joshua Moss, Daniel Cohen, Sheina Piyanzin, Roni Ben Ami, Ahmad Quteineh, Eliahu Golomb, Ruth Shemer, Benjamin Glaser, Tommy Kaplan, Zvi G. Fridlender, and Yuval Dor
Subjects: Pulmonary and Respiratory Medicine, Lung Neoplasms, Liquid Biopsy, Biomarkers, Tumor, Humans, DNA Methylation, respiratory system, Cell-Free Nucleic Acids, Lung, Biomarkers, Epithelium, respiratory tract diseases
Abstract: BackgroundCirculating 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.MethodsWe 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.ResultsLoci 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.ConclusionsUniversal 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.
Published: 2022
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19. Key role for liquid biopsy in the elimination of breast cancer surgery following neoadjuvant therapy

Author: Beatrice Uziely, Joshua Moss, and Albert Grinshpun
Subjects: Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, MEDLINE, Liquid Biopsy, Breast Neoplasms, Hematology, medicine.disease, Neoadjuvant Therapy, Breast cancer, Internal medicine, medicine, Humans, Breast, Liquid biopsy, business, Neoadjuvant therapy, Mastectomy
Published: 2020

20. Multiplexing DNA methylation markers to detect circulating cell-free DNA derived from human pancreatic β cells

Author: Saar Hashavia, Ori Fridlich, Ruth Shemer, Yuval Dor, Tal Oron, Benjamin Glaser, Desmond A. Schatz, Daniel Neiman, Cate Speake, Olle Korsgren, Gun Forsander, Oskar Skog, David Gillis, Dan Cohen, Mark A. Atkinson, Floris Levy-Khademi, Frida Sundberg, Carla J. Greenbaum, Jennifer Hosford, Dan Arbel, A. M. James Shapiro, Sheina Piyanzin, Aviad Zick, Amanda L. Posgai, and Joshua Moss
Subjects: 0301 basic medicine, Adult, Male, Adolescent, medicine.medical_treatment, Cell, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Insulin-Secreting Cells, medicine, Humans, Insulin, Epigenetics, Child, Cell damage, Aged, Chemistry, General Medicine, DNA Methylation, Middle Aged, medicine.disease, Molecular biology, Circulating Cell-Free DNA, Transplantation, 030104 developmental biology, medicine.anatomical_structure, Diabetes Mellitus, Type 1, 030220 oncology & carcinogenesis, Child, Preschool, DNA methylation, Female, Cell-Free Nucleic Acids, DNA, Biomarkers, Research Article
Abstract: It has been proposed that unmethylated insulin promoter fragments in plasma derive exclusively from β cells, reflect their recent demise, and can be used to assess β cell damage in type 1 diabetes. Herein we describe an ultrasensitive assay for detection of a β cell–specific DNA methylation signature, by simultaneous assessment of 6 DNA methylation markers, that identifies β cell DNA in mixtures containing as little as 0.03% β cell DNA (less than 1 β cell genome equivalent). Based on this assay, plasma from nondiabetic individuals (N = 218, aged 4–78 years) contained on average only 1 β cell genome equivalent/mL. As expected, cell-free DNA (cfDNA) from β cells was significantly elevated in islet transplant recipients shortly after transplantation. We also detected β cell cfDNA in a patient with KATP congenital hyperinsulinism, in which substantial β cell turnover is thought to occur. Strikingly, in contrast to previous reports, we observed no elevation of β cell–derived cfDNA in autoantibody-positive subjects at risk for type 1 diabetes (N = 32), individuals with recent-onset type 1 diabetes (4 months, N = 38). We discuss the utility of sensitive β cell cfDNA analysis and potential explanations for the lack of a β cell cfDNA signal in type 1 diabetes.
Published: 2020

21. Role of transcription complexes in the formation of the basal methylation pattern in early development

Author: Ofra Sabag, Ilana Keshet, Amalia Tabib, Howard Cedar, Razi Greenfield, Joshua Moss, and Alon Goren
Subjects: 0301 basic medicine, Transcription, Genetic, Mice, Transgenic, Transgenic, Histones, Mice, 03 medical and health sciences, chemistry.chemical_compound, Genetic, Transcription (biology), histomodification, Genetics, Animals, inheritance, Developmental, Epigenetics, development, Pediatric, Multidisciplinary, epigenetics, biology, Chemistry, Mammalian, Prevention, Human Genome, Gene Expression Regulation, Developmental, DNA-Directed RNA Polymerases, Methylation, Biological Sciences, DNA Methylation, Embryo, Mammalian, Stem Cell Research, Cell biology, 030104 developmental biology, Histone, Gene Expression Regulation, CpG site, Embryo, Blastocyst Inner Cell Mass, DNA methylation, biology.protein, H3K4me3, CpG Islands, Generic health relevance, Transcription, DNA, Transcription Factors
Abstract: Following erasure in the blastocyst, the entire genome undergoes de novo methylation at the time of implantation, with CpG islands being protected from this process. This bimodal pattern is then preserved throughout development and the lifetime of the organism. Using mouse embryonic stem cells as a model system, we demonstrate that the binding of an RNA polymerase complex on DNA before de novo methylation is predictive of it being protected from this modification, and tethering experiments demonstrate that the presence of this complex is, in fact, sufficient to prevent methylation at these sites. This protection is most likely mediated by the recruitment of enzyme complexes that methylate histone H3K4 over a local region and, in this way, prevent access to the de novo methylation complex. The topological pattern of H3K4me3 that is formed while the DNA is as yet unmethylated provides a strikingly accurate template for modeling the genome-wide basal methylation pattern of the organism. These results have far-reaching consequences for understanding the relationship between RNA transcription and DNA methylation.
Published: 2018
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22. Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA

Author: Yuval Dor, Daniel Neiman, Hai Zemmour, Ruth Shemer, Joshua Moss, Benjamin Glaser, Amit Korach, Giora Landesberg, Judith Magenheim, Dan Gilon, and David Planer
Subjects: Adult, 0301 basic medicine, medicine.medical_specialty, Heart Diseases, Heart disease, Science, General Physics and Astronomy, Polymerase Chain Reaction, Article, General Biochemistry, Genetics and Molecular Biology, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Reference Values, Internal medicine, medicine, Humans, Myocytes, Cardiac, Myocardial infarction, lcsh:Science, Creatine Kinase, Multidisciplinary, Cell Death, biology, business.industry, General Chemistry, DNA Methylation, medicine.disease, Troponin, 3. Good health, Cardiovascular physiology, 030104 developmental biology, Case-Control Studies, 030220 oncology & carcinogenesis, DNA methylation, Cardiology, biology.protein, ST Elevation Myocardial Infarction, Biomarker (medicine), Creatine kinase, lcsh:Q, business, Cell-Free Nucleic Acids, Biomarkers
Abstract: Detection of cardiomyocyte death is crucial for the diagnosis and treatment of heart disease. Here we use comparative methylome analysis to identify genomic loci that are unmethylated specifically in cardiomyocytes, and develop these as biomarkers to quantify cardiomyocyte DNA in circulating cell-free DNA (cfDNA) derived from dying cells. Plasma of healthy individuals contains essentially no cardiomyocyte cfDNA, consistent with minimal cardiac turnover. Patients with acute ST-elevation myocardial infarction show a robust cardiac cfDNA signal that correlates with levels of troponin and creatine phosphokinase (CPK), including the expected elevation-decay dynamics following coronary angioplasty. Patients with sepsis have high cardiac cfDNA concentrations that strongly predict mortality, suggesting a major role of cardiomyocyte death in mortality from sepsis. A cfDNA biomarker for cardiomyocyte death may find utility in diagnosis and monitoring of cardiac pathologies and in the study of normal human cardiac physiology and development., The detection of cardiomyocyte death is a critical aspect in the diagnosis and monitoring of heart diseases. Here the authors show that cardiomyocyte-specific methylation patterns of circulating cell-free DNA may serve as a biomarker of cardiac cell death in infarcted and septic patients.
Published: 2018
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23. Contribution of epigenetic mechanisms to variation in cancer risk among tissues

Author: Michael Klutstein, Howard Cedar, Joshua Moss, and Tommy Kaplan
Subjects: Male, Risk, 0301 basic medicine, Aging, Population, Biology, medicine.disease_cause, Epigenesis, Genetic, 03 medical and health sciences, Neoplasms, Morphogenesis, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, education, Genetics, education.field_of_study, Mutation, Models, Statistical, Multidisciplinary, Models, Genetic, Stem Cells, Cell Differentiation, Methylation, Biological Sciences, DNA Methylation, Cell Transformation, Neoplastic, 030104 developmental biology, Variation (linguistics), CpG site, Organ Specificity, DNA methylation, CpG Islands, Female, Cancer risk, Cell Division
Abstract: Significance It is well-known that the risk of cancer varies widely between different tissues of the body with some cell types (e.g., colon, breast) being prone to cancer, whereas others (e.g., brain, bone) only rarely develop tumors, but the mechanism of this phenomenon has not been elucidated. Recently, it was shown that this risk coefficient may actually be related to the inherent number of stem-cell divisions that go into generating each individual cell type during development. In this work, we demonstrate that cancer risk is highly correlated with the degree of aberrant age-dependent methylation in normal tissues, clearly supporting the idea that cell-type tumor susceptibility may be influenced by biologically intrinsic epigenetic factors.
Published: 2017
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24. Circulating breast-derived DNA allows universal detection and monitoring of localized breast cancer

Author: Einat Carmon, Karen Meir, Joshua Moss, Ofri Abraham, B.L. Ochana, Albert Grinshpun, Myriam Maoz, Yuval Dor, O. Arieli, L. Germansky, Ruth Shemer, Beatrice Uziely, Benjamin Glaser, and Aviad Zick
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Breast Neoplasms, Disease, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Biomarkers, Tumor, Humans, skin and connective tissue diseases, Chemotherapy, business.industry, Cancer, Hematology, DNA, DNA, Neoplasm, DNA Methylation, medicine.disease, Chemotherapy regimen, Circulating Cell-Free DNA, 030104 developmental biology, 030220 oncology & carcinogenesis, Localized disease, DNA methylation, Mutation, business, Cell-Free Nucleic Acids
Abstract: Background Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection of several cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist only in a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast-derived cfDNA using a breast-specific DNA methylation signature. Patients and methods We collected plasma from patients with localized breast cancer before and throughout treatment with neoadjuvant chemotherapy and surgery (N = 235 samples). Results Pretreatment breast cfDNA was detected in patients with localized disease with a sensitivity of 80% at 97% specificity. High breast cfDNA levels were associated with aggressive molecular tumor profiles and metabolic activity of the disease. During neoadjuvant chemotherapy, breast cfDNA levels decreased dramatically. Importantly, the presence of breast cfDNA towards the end of the chemotherapy regimen reflected the existence of residual disease. Conclusion We propose that breast-specific cfDNA is a universal and powerful marker for the detection and monitoring of breast cancer.
Published: 2019

25. Mechanistic Study of Formation of Ring-retaining and Ring-opening Products from Oxidation of Aromatic Compounds under Urban Atmospheric Conditions

Author: Alexander Zaytsev, Abigail R. Koss, Martin Breitenlechner, Jordan E. Krechmer, Kevin J. Nihill, Christopher Y. Lim, James C. Rowe, Joshua L. Cox, Joshua Moss, Joseph R. Roscioli, Manjula R. Canagaratna, Douglas R. Worsnop, Jesse H. Kroll, and Frank N. Keutsch
Abstract: Aromatic hydrocarbons make up a large fraction of anthropogenic volatile organic compounds and contribute significantly to the production of tropospheric ozone and secondary organic aerosol (SOA). A series of toluene and 1,2,4-trimethylbenzene (1,2,4-TMB) photooxidation experiments were performed in an environmental chamber under relevant polluted conditions (NOx ~ 10 ppb). An extensive suite of instrumentation including two Proton-Transfer Reaction Mass-Spectrometers (PTR-MS) and two Chemical Ionization Mass-Spectrometers (NH4+ CIMS and I- CIMS) allowed for quantification of reactive carbon in multiple generations of oxidation. Hydroxyl radical (OH)-initiated oxidation of both species produces ring-retaining products such as cresols, benzaldehydes, and bicyclic intermediate compounds, as well as ring scission products such as epoxides, and dicarbonyls. We show that the oxidation of bicyclic intermediate products leads to formation of compounds with high oxygen content (O:C ratio up to 1.1). These compounds, previously identified as highly oxygenated molecules (HOMs), are produced by more than one pathway with differing numbers of reaction steps with OH, including both autooxidation and phenolic pathways. We report the elemental composition of these compounds formed under relevant urban high-NO conditions. We show that ring-retaining products for these two precursors are more diverse and abundant than predicted by current mechanisms. We present speciated elemental composition of SOA for both precursors and confirm that highly oxygenated products make up a significant fraction of SOA. Ring scission products are also detected in both the gas and particle phases, and their yields and speciation overall agree with the kinetic model prediction.
Published: 2019
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26. Supplementary material to 'Mechanistic Study of Formation of Ring-retaining and Ring-opening Products from Oxidation of Aromatic Compounds under Urban Atmospheric Conditions'

Author: Alexander Zaytsev, Abigail R. Koss, Martin Breitenlechner, Jordan E. Krechmer, Kevin J. Nihill, Christopher Y. Lim, James C. Rowe, Joshua L. Cox, Joshua Moss, Joseph R. Roscioli, Manjula R. Canagaratna, Douglas R. Worsnop, Jesse H. Kroll, and Frank N. Keutsch
Published: 2019
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27. Characterization of patients with allergic reactions to iodinated contrast media during CT scan

Author: Alon Y. Hershko, Aviv Talmon, Yuval Tal, Dorith Shaham, and Joshua Moss
Subjects: Iodinated contrast media, medicine.diagnostic_test, business.industry, Immunology, Immunology and Allergy, Medicine, Computed tomography, Nuclear medicine, business
Published: 2020
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28. Specific detection of cell-free DNA derived from intestinal epithelial cells using methylation patterns

Author: Daniel Neiman, Miriam Maoz, Sheina Piyanzin, Hadar Golan, Eran Israeli, Talia Golan, Yuval Dor, Eran Segal, Alon J. Pikarsky, Ayala Hubert, Markus Grompe, Matan Fischer, Tal Davidy, Cloud P. Paweletz, Roni Lehmann-Werman, Ruth Shemer, Joshua Moss, Judith Magenheim, Aviad Zick, Benjamin Glaser, Brian M. Wolpin, and Marisa W. Welch
Subjects: Colorectal cancer, Disease, Methylation, Biology, medicine.disease, Inflammatory bowel disease, digestive system diseases, chemistry.chemical_compound, Cell-free fetal DNA, chemistry, Genetic marker, medicine, Cancer research, Developmental biology, DNA
Abstract: Epithelial cells of the intestine undergo rapid turnover and are thought to be cleared via stool. Disruption of tissue architecture, as occurs in colorectal cancer (CRC), results in the release of material from dying intestinal epithelial cells to blood. This phenomenon could be utilized for diagnosis and monitoring of intestinal diseases, if circulating cell-free DNA (cfDNA) derived from intestinal cells could be specifically identified. Here we describe two genomic loci that are unmethylated specifically in intestinal epithelial cells, allowing for sensitive and specific detection of DNA derived from such cells. As expected, intestinal DNA is found in stool, but not in plasma, of healthy individuals. Patients with inflammatory bowel disease (IBD) have minimal amounts of intestinal cfDNA in the plasma, whereas patients with advanced CRC show a strong signal. The intestinal markers are not elevated in plasma samples from patients with pancreatic ductal adenocarcinoma (PDAC), and a combination of intestine- and pancreas-specific markers allowed for robust differentiation between plasma cfDNA derived from CRC and PDAC patients. Intestinal DNA markers provide a mutation-independent tool for monitoring intestinal dynamics in health and disease.
Published: 2018
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29. Monitoring liver damage using hepatocyte-specific methylation markers in cell-free circulating DNA

Author: Ruth Shemer, Daniel Neiman, Hai Zemmour, Markus Grompe, Kim M. Olthoff, Benjamin Glaser, Judith Magenheim, Ofri Abraham, Sheina Piyanzin, Giora Landesberg, Roni Lehmann-Werman, Joshua Moss, Bao Li Loza, Ilana Fox, Talya Dor, Yuval Dor, and Abraham Shaked
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Bisulfite sequencing, Proteinase Inhibitory Proteins, Secretory, Liver transplantation, Sensitivity and Specificity, Receptor, IGF Type 2, 03 medical and health sciences, Internal medicine, Hepatectomy, Humans, Medicine, Aspartate Aminotransferases, Epigenetics, Glycoproteins, Cell Death, business.industry, Liver Diseases, Liver cell, High-Throughput Nucleotide Sequencing, Alanine Transaminase, Blood Proteins, General Medicine, DNA Methylation, Hepatology, Molecular biology, Liver Transplantation, 3. Good health, Transplantation, 030104 developmental biology, medicine.anatomical_structure, Liver, Technical Advance, Hepatocyte, Toxicity, Hepatocytes, business, Cell-Free Nucleic Acids, Biomarkers
Abstract: Liver damage is typically inferred from serum measurements of cytoplasmic liver enzymes. DNA molecules released from dying hepatocytes are an alternative biomarker, unexplored so far, potentially allowing for quantitative assessment of liver cell death. Here we describe a method for detecting acute hepatocyte death, based on quantification of circulating, cell-free DNA (cfDNA) fragments carrying hepatocyte-specific methylation patterns. We identified 3 genomic loci that are unmethylated specifically in hepatocytes, and used bisulfite conversion, PCR, and massively parallel sequencing to quantify the concentration of hepatocyte-derived DNA in mixed samples. Healthy donors had, on average, 30 hepatocyte genomes/ml plasma, reflective of basal cell turnover in the liver. We identified elevations of hepatocyte cfDNA in patients shortly after liver transplantation, during acute rejection of an established liver transplant, and also in healthy individuals after partial hepatectomy. Furthermore, patients with sepsis had high levels of hepatocyte cfDNA, which correlated with levels of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Duchenne muscular dystrophy patients, in which elevated AST and ALT derive from damaged muscle rather than liver, did not have elevated hepatocyte cfDNA. We conclude that measurements of hepatocyte-derived cfDNA can provide specific and sensitive information on hepatocyte death, for monitoring human liver dynamics, disease, and toxicity.
Published: 2018
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30. Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers

Author: Sheina Piyanzin, Yuval Dor, Ruth Shemer, A. M. James Shapiro, Judith Magenheim, Howard Cedar, Joshua Moss, Aharon Razin, Merav Hecht, Eelco J.P. de Koning, Daniel Neiman, and Hubrecht Institute for Developmental Biology and Stem Cell Research
Subjects: 0301 basic medicine, endocrine system, Medical Sciences, endocrine system diseases, β-cells, 030209 endocrinology & metabolism, Biology, Development, Cell Line, Epigenesis, Genetic, Mice, 03 medical and health sciences, 0302 clinical medicine, Insulin-Secreting Cells, Gene expression, Journal Article, Animals, Humans, Epigenetics, Promoter Regions, Genetic, Enhancer, General, Gene, development, Cells, Cultured, islets, Mice, Inbred ICR, Multidisciplinary, DNA methylation, Epigenetic, Cell Differentiation, Promoter, Methylation, Biological Sciences, Cell biology, Enhancer Elements, Genetic, 030104 developmental biology, Glucagon-Secreting Cells, beta-cells, Islets, Reprogramming, epigenetic
Abstract: Significance We have studied the dynamics of DNA methylation in pancreatic α- and β-cells and reached surprising insights into the establishment of islet cell identity. Different islet cell types share lack of methylation in cell-type–specific gene promoters, while DNA methylation differences between islet cell types are concentrated in enhancer regions. The findings support the fundamental role of enhancer methylation in determining cell identity, and have implications for the understanding of islet cell plasticity in diabetes., DNA methylation at promoters is an important determinant of gene expression. Earlier studies suggested that the insulin gene promoter is uniquely unmethylated in insulin-expressing pancreatic β-cells, providing a classic example of this paradigm. Here we show that islet cells expressing insulin, glucagon, or somatostatin share a lack of methylation at the promoters of the insulin and glucagon genes. This is achieved by rapid demethylation of the insulin and glucagon gene promoters during differentiation of Neurogenin3+ embryonic endocrine progenitors, regardless of the specific endocrine cell-type chosen. Similar methylation dynamics were observed in transgenic mice containing a human insulin promoter fragment, pointing to the responsible cis element. Whole-methylome comparison of human α- and β-cells revealed generality of the findings: genes active in one cell type and silent in the other tend to share demethylated promoters, while methylation differences between α- and β-cells are concentrated in enhancers. These findings suggest an epigenetic basis for the observed plastic identity of islet cell types, and have implications for β-cell reprogramming in diabetes and diagnosis of β-cell death using methylation patterns of circulating DNA.
Published: 2017

31. Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability

Author: Reka Toth, Günter Klöppel, Odilia Popanda, Thomas Hank, Peter Schmezer, Cornelia Jäkel, Daniel van der Duin, Christoph Plass, Yassen Assenov, Yuval Dor, Oliver Strobel, Peter Schirmacher, Markus Grompe, Frank Bergmann, Craig Dorrell, and Joshua Moss
Subjects: 0301 basic medicine, Genome instability, Science, Gene Dosage, General Physics and Astronomy, Biology, medicine.disease_cause, behavioral disciplines and activities, General Biochemistry, Genetics and Molecular Biology, Genomic Instability, Article, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, CDKN2A, medicine, Acinar cell, Humans, Genes, Tumor Suppressor, Epigenetics, lcsh:Science, Gene, Genetics, Chromosome Aberrations, Mutation, Multidisciplinary, Carcinoma, Acinar Cell, General Chemistry, Cell Cycle Checkpoints, Pancreatic Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, lcsh:Q, Carcinogenesis, Pancreatic Acinar Cell Carcinoma, Carcinoma, Pancreatic Ductal
Abstract: Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, to identify potential targets for personalized treatment, we perform integrative genome-wide and epigenome-wide analyses. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are detected. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies promising therapeutic targets in ACC for drugs recently approved for precision cancer therapy., Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, the authors perform genome- and epigenome-wide analyses from normal and ACC pancreatic tissue that identify aberrations in genome stability and cell cycle control.
Published: 2017

32. Picturing the Past: Gender inNational GeographicReconstructions of Prehistoric Life

Author: Joshua Moss and Julie Solometo
Subjects: 010506 paleontology, Archeology, History, 060102 archaeology, Anthropology, Interpretation (philosophy), media_common.quotation_subject, Museology, 06 humanities and the arts, 01 natural sciences, Prehistory, Arts and Humanities (miscellaneous), 0601 history and archaeology, Societal Factors, Narrative, Temporal change, Ideology, 0105 earth and related environmental sciences, media_common
Abstract: Artistic reconstructions of ancient life are powerful blends of archaeological interpretation and imagination. Like other narratives about the past, they can project contemporary gender roles and relations on ancient peoples, and can reinforce or transform ideas about gender in the present. This article examines the construction of gender ideologies inNational Geographicillustrations of prehistoric life. Our analysis of 204 pictorial reconstructions from 1936 to 2007 reveals that women and women’s work are significantly underrepresented and undervalued, while exhibiting evidence of temporal change in response to societal factors and editorial influences. A vigorous archaeology of gender has had little impact on the magazine’s imagined past; in some respects, the ancient women depicted in the last twenty years are just as scarce, passive, and subordinate as they were in the postwar “backlash” of the 1950s.
Published: 2013
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33. Establishment of methylation patterns in ES cells

Author: Ofra Sabag, Ilana Keshet, Ayelet Zamir, Howard Cedar, Merav Hecht, Amalia Tabib, Guy Ludwig, and Joshua Moss
Subjects: 0303 health sciences, DNA Repair, Methylation, DNA Methylation, Biology, Molecular biology, Embryonic stem cell, MBD4, Mice, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, 030220 oncology & carcinogenesis, DNA methylation, Animals, Molecular Biology, RNA-Directed DNA Methylation, Reprogramming, Embryonic Stem Cells, Amination, 030304 developmental biology, Demethylation, Nucleotide excision repair
Abstract: After erasure in the early animal embryo, a new bimodal DNA methylation pattern is regenerated at implantation. We have identified a demethylation pathway in mouse embryonic cells that uses hydroxymethylation (Tet1), deamination (Aid), glycosylation (Mbd4) and excision repair (Gadd45a) genes. Surprisingly, this demethylation system is not necessary for generating the overall bimodal methylation pattern but does appear to be involved in resetting methylation patterns during somatic-cell reprogramming.
Published: 2013
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34. Test of the universality of $\tau$ and $\mu$ lepton couplings in $W$-boson decays from $t\bar{t}$ events with the ATLAS detector

Author: Georges Aad, Braden Abbott, Abbott, Dale Charles, Adam Abed Abud, Kira Abeling, Deshan Abhayasinghe, Syed Haider Abidi, Ossama Sherif Alexander AbouZeid, Abraham, Nicola, Halina Abramowicz, Abreu, Henso, Yiming Abulaiti, Bobby Acharya, Baida Achkar, Lennart Adam, Claire Bourdarios, Leszek Adamczyk, Lukas Adamek, Jahred Adelman, Adersberger, Michael, Aytul Adiguzel, Sofia Adorni Braccesi Chiassi, Tim Adye, Anthony Affolder, Yoav Afik, Christina Agapopoulou, Merve Nazlim Agaras, Anamika Aggarwal, Agheorghiesei, Catalin, Juan Antonio Aguilar Saavedra, Ahmad, Ammara, Faig Ahmadov, waleed syed ahmed, Xiaocong Ai, Giulio Aielli, Shunichi Akatsuka, Melike Akbiyik, Torsten Akesson, ECE AKILLI, Andrey Akimov, konie al khoury, Gian Luigi Alberghi, Justin Albert, Maria Josefina Alconada Verzini, Sara Alderweireldt, Martin Aleksa, Igor Alexandrov, Calin Alexa, Alexopoulos, Theodoros, Alice Alfonsi, FABRIZIO ALFONSI, Muhammad Alhroob, Babar Ali, Shahzad Ali, Malik Aliev, Gianluca Alimonti, Corentin Allaire, Benedict Allbrooke, Benjamin Allen, Philip Allport, Alberto Aloisio, Francisco Alonso, Cristiano Alpigiani, Alunno Camelia, Elio, Manuel Alvarez Estevez, Mariagrazia Alviggi, Yara Coutinho, Alessandro Ambler, Luca Ambroz, Amelung, Christoph, Dante Amidei, Susana Amor Santos, Simone Amoroso, Amrouche, Cherifa Sabrina, Fenfen An, Christos Anastopoulos, Nansi Andari, Timothy Andeen, John Anders, Stefio Yosse Andrean, Andreazza, Attilio, Andrei, George Victor, Anelli, Christopher Ryan, Stylianos Angelidakis, Aaron Angerami, Alexey Anisenkov, Alberto Annovi, Claire Antel, Matthew Anthony, Egor Antipov, Mario Antonelli, Daniel Antrim, Fabio Anulli, Masato Aoki, Aparisi Pozo, Javier Alberto, Aparo, Marco, Ludovica Aperio Bella, Nordin Aranzabal, Victor Araujo Ferraz, Araujo Pereira, Rodrigo, Chiara Arcangeletti, Ayana Holloway Arce, Arduh, Francisco Anuar, Jean-Francois Arguin, Spyridon Argyropoulos, Jan-Hendrik Arling, Aaron Armbruster, Alexander Armstrong, Olivier Arnaez, Hannah Arnold, Arrubarrena Tame, Zulit Paola, Giacomo Artoni, Haruka Asada, Asai, Kanae, Shoji Asai, Asawatavonvanich, Thanawat, Nedaa Alexandra Asbah, Eleni Myrto Asimakopoulou, lily asquith, Jihad Assahsah, Assamagan, Ketevi, Robert Astalos, Ryan Atkin, Atkinson, Markus, Naim Bora Atlay, Atmani, Hicham, Kamil Augsten, Volker Andreas Austrup, Giuseppe Avolio, Mohamad Kassem Ayoub, Georges Azuelos, Henri Bachacou, Konstantinos Bachas, Backman, Filip, Paolo Bagnaia, Marzieh Bahmani, Baluch Bahrasemani, Sina, Adam Bailey, Virginia Bailey, John Baines, Bakalis, Christos, Oliver Baker, Pepijn Bakker, Evelin Bakos, Debottam BakshiGupta, Shyam Balaji, Rahul Balasubramanian, Evgenii Baldin, Petr Balek, Fabrice Balli, William Balunas, Johannes Balz, Elżbieta Banaś, Marilena Bandieramonte, Anjishnu Bandyopadhyay, swagato banerjee, Liron Barak, William Barbe, Elisabetta Barberio, Dario Barberis, Marlon, Barbour, Gregory, Barillari Teresa, Martin Barisits, Jason Barkeloo, Timothy Barklow, Barnea, 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M. S., Saleh Sultansoy, Toshi Sumida, Siyuan Sun, Xiaohu Sun, Carl Joseph Edmund Suster, Mark Sutton, Shota Suzuki, Michal Svatos, Maximilian Swiatlowski, Swift, Stewart Patrick, Thorben Swirski, Sydorenko, Alexander, Ivan Sykora, Martin Sykora, Tomáš Sýkora, Duc Bao Ta, Kerstin Tackmann, Kinghorn-Taenzer, Joseph Peter, Anyes Taffard, Reda Tafirout, Emin Tagiev, Takashima, Ryuichi, Kosuke Takeda, Tohru Takeshita, Emily Takeva, Yosuke Takubo, Mossadek Talby, Talyshev, Alexey, Tam, Kai Chung, Tamir, Nadav Michael, Junichi Tanaka, Reisaburo Tanaka, Sebastian Tapia, Stefan Tapprogge, Ahmed Tarek Abouelfadl Mohamed, Shlomit Tarem, Khuram Tariq, Grigore Tarna, Giuseppe Francesco Tartarelli, Petr Tas, Marek Tasevsky, Tassi, Enrico, Tavares Delgado, Ademar, yahya tayalati, Alan Taylor, GEOFFREY TAYLOR, Wendy Taylor, Teagle, Hamish, Tee, Amy Selvi, Rafael Teixeira de Lima, Pedro Teixeira-Dias, Ten Kate, Herman, Jia Jian Teoh, Koji Terashi, JUAN TERRON, Stefano Terzo, Marianna Testa, Richard Teuscher, Savannah Thais, Neofytos Themistokleous, Timothée Theveneaux-Pelzer, Thiele, Fabian A. J., Thomas, David William, Thomas, James Oscar, Juergen Thomas, Emily Anne Thompson, Paul Thompson, Evelyn Thomson, Edward Thorpe, Royer Edson Ticse Torres, Vladimir Tikhomirov, Yuriy Tikhonov, Timoshenko, Sergey, Paul Tipton, Sylvain Tisserant, Kazuki Todome, Sarka Todorova, Todt, Stefanie, Junji Tojo, Stanislav Tokar, Katsuo Tokushuku, Emma Tolley, Rupert Tombs, Kehinde Tomiwa, Makoto Tomoto, Lauren Tompkins, Peter Tornambe, Eric Torrence, Heberth Torres, Emma Torro Pastor, Mariana Toscani, Cecilia Tosciri, Jozsef Toth, Daniel Tovey, Traeet, Are Sivertsen, Colleen Treado, Thomas Trefzger, Fabio Tresoldi, Alessandro, Isabel Trigger, Sophie Trincaz-Duvoid, Dominique Trischuk, Trischuk, William, Trocme, Benjamin, Artur Trofymov, Clara Troncon, Fabrizio Trovato, Thi Ngoc Loan Truong, Maciej Trzebinski, Adam Trzupek, Fang-Ying Tsai, Jeffrey Tseng, Tsiareshka, Pavel, Apostolos Tsirigotis, Vakhtang Tsiskaridze, Tskhadadze, Edisher, MARIA EVANTHIA TSOPOULOU, Ilya Tsukerman, Vakhtang Tsulaia, Soshi Tsuno, Dmitri Tsybychev, Tu, Y., Alexandra Tudorache, Valentina Tudorache, Tulbure, Traian Tiberiu, Alexander Tuna, Semen Turchikhin, Daniel Turgeman, Turk Cakir, Ilkay, Turner, Russell James, Ruggero Turra, Philip Tuts, Tzamarias, Spyros, Eftychia Tzovara, Uchida, Kenta, Fumihiko Ukegawa, Guillaume Unal, Mesut Ünal, Alexander Undrus, Unel, Gokhan, Francesca Ungaro, Yoshinobu Unno, Kenta Uno, Jozef Urban, PHILLIP URQUIJO, Giulio Usai, zekeriya uysal, Vacek, Vaclav, Brigitte Vachon, Knut Oddvar Høie Vadla, Theodoros Vafeiadis, Amal Vaidya, Chrysostomos Valderanis, Eduardo Valdes Santurio, Marco Valente, Sara Valentinetti, Alberto Valero, Loïc Valéry, Robert Vallance, Vallier, Alexis Roger Louis, Valls Ferrer, Juan Antonio, Tal van Daalen, Peter van Gemmeren, Samuel Van Stroud, Ivo van Vulpen, Marco Vanadia, Wainer Vandelli, Maxence Vandenbroucke, Evan Van de Wall, Aleksandr Vanyashin, damiano vannicola, Riccardo Vari, Erich Varnes, Carlo Varni, Tulin Varol, Dimitris Varouchas, Kevin Varvell, Matei-Eugen Vasile, Gerardo Vasquez, François Vazeille, David Vázquez Furelos, Tamara Vazquez Schroeder, Jason Veatch, Valentina Vecchio, Michiel Veen, Laurelle Maria Veloce, Filipe Veloso, Stefano Veneziano, Andrea Ventura, Andrii Verbytskyi, Valerio Vercesi, Monica Verducci, Vergel Infante, Carlos Miguel, Christos Vergis, Verkerke, Wouter, Ambrosius Vermeulen, Jos Vermeulen, Caterina Vernieri, Pim Verschuuren, Michel Vetterli, Nicolás Viaux, Trevor Vickey, Oana Vickey Boeriu, Georg Viehhauser, Luigi Vigani, Mauro Villa, Miguel Villaplana Perez, Villhauer, Elena Michelle, Elisabetta Vilucchi, Manuella Vincter, Govindraj Singh Virdee, Akanksha Vishwakarma, Camilla Vittori, Iacopo Vivarelli, Marcelo Vogel, Petr Vokac, Stefan von Buddenbrock, Eckhard von Toerne, Vít Vorobel, Konstantin Vorobev, Marcel Vos, Joost Vossebeld, Vozak, Matous, Nenad Vranjes, Marija Vranjes Milosavljevic, Vrba, Vaclav, Vreeswijk, Marcel, Ngoc Khanh Vu, Vuillermet, Raphael, Ilija Vukotic, Sayaka 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Yi-Lin Yang, Yang, Zhe, Wei-Ming Yao, Yee Chinn Yap, Elena Yatsenko, Hanfei Ye, Jingbo Ye, Shuwei Ye, Ivan Yeletskikh, Melissa Yexley, Efe Yigitbasi, Pengqi Yin, Kohei Yorita, Keisuke Yoshihara, Christopher Young, Charles Young, Jie Yu, Rui Yuan, Xiaoguang Yue, Mohamed Zaazoua, Bartłomiej Żabiński, Georgios Zacharis, Ettore Zaffaroni, Jad Mathieu Sardain, Alexandre Zaitsev, Tamar Zakareishvili, Nataliia Zakharchuk, Stefano Zambito, Daniele Zanzi, Sonja Verena Zeißner, Christian Zeitnitz, Gabija Zemaityte, Jian Cong Zeng, Oleg Zenin, Tibor Zenis, Dirk Zerwas, Miha Zgubic, Zhang, Bowen, Dengfeng Zhang, Gang Zhang, Jinlong Zhang, Kaili Zhang, Lei Zhang, Liqing Zhang, Matt Zhang, Rui Zhang, Zhang, Shuzhou, Xiangke Zhang, xueyao zhang, Yu Zhang, Zhang, Zhidong, Zhiqing Zhang, Pingchuan Zhao, Zhao, Zhengguo, Alexey Zhemchugov, Zheng, Zhi, Dewen Zhong, Zhou, Bing, Chen Zhou, Hao Zhou, Maosen Zhou, Mingliang Zhou, Ning Zhou, Zhou, You, chengguang zhu, Chenzheng Zhu, Heling Zhu, Hongbo Zhu, Junjie Zhu, Yingchun Zhu, Xuai Zhuang, Konstantin Zhukov, Vladimir Zhulanov, Daria Zieminska, Nikolai Zimine, Stephanie Zimmermann, Zinonos, Zinonas, Ziolkowski, Michael, Lidija Zivkovic, Georg Zobernig, Antonio Zoccoli, Knut Zoch, Theodore Georgio Zorbas, Rui Zou, and Lukasz Zwalinski

35. Two-particle Bose-Einstein correlations in pp collisions at ${\sqrt{s} = 13}$ TeV measured with the ATLAS detector at the LHC

Author: Georges Aad, Braden Abbott, Dale Abbott, Adam Abed Abud, Kira Abeling, Deshan Abhayasinghe, Syed Haider Abidi, Ossama Sherif Alexander AbouZeid, Abraham, Nicola Louise, Halina Abramowicz, Abreu, Henso, Yiming Abulaiti, Bobby Acharya, Baida Achkar, SHUNSUKE ADACHI, Lennart Adam, Claire Bourdarios, Leszek Adamczyk, Lukas Adamek, Jahred Adelman, Adersberger, Michael, Aytul Adiguzel, Sofia Adorni Braccesi Chiassi, Tim Adye, Anthony Affolder, Yoav Afik, Christina Agapopoulou, Merve Nazlim Agaras, Anamika Aggarwal, Agheorghiesei, Catalin, Juan Antonio Aguilar Saavedra, Faig Ahmadov, waleed syed ahmed, Xiaocong Ai, Giulio Aielli, Shunichi Akatsuka, Torsten Akesson, ECE AKILLI, Andrey Akimov, konie al khoury, Gian Luigi Alberghi, Justin Albert, Maria Josefina Alconada Verzini, Sara Alderweireldt, Martin Aleksa, Igor Alexandrov, Calin Alexa, Alexandre, Didier, Theodoros Alexopoulos, Alice Alfonsi, Muhammad Alhroob, Babar Ali, Gianluca Alimonti, John Alison, Alkire, Steve, Corentin Allaire, Benedict Allbrooke, Benjamin Allen, Philip Allport, Alberto Aloisio, Alejandro Alonso, Francisco Alonso, Cristiano Alpigiani, Alshehri, Azzah Aziz, Manuel Alvarez Estevez, Damián Álvarez Piqueras, Mariagrazia Alviggi, Yara Coutinho, Alessandro Ambler, Luca Ambroz, Amelung, Christoph, Dante Amidei, Susana Amor Santos, Simone Amoroso, Amrouche, Cherifa Sabrina, Fenfen An, Christos Anastopoulos, Nansi Andari, Timothy Andeen, Christoph Falk Anders, John Anders, Andreazza, Attilio, Andrei, Victor, Anelli, Christopher Ryan, Stylianos Angelidakis, Aaron Angerami, Alexey Anisenkov, Alberto Annovi, Claire Antel, Matthew Anthony, Mario Antonelli, Daniel Antrim, Fabio Anulli, Masato Aoki, Javier Alberto Aparisi Pozo, Ludovica Aperio Bella, Arabidze, Giorgi, Juan Pedro Araque Espinosa, Victor Araujo Ferraz, Pereira, Rodrigo, Chiara Arcangeletti, Ayana Holloway Arce, Arduh, Francisco Anuar, Jean-Francois Arguin, Spyridon Argyropoulos, Jan-Hendrik Arling, Aaron Armbruster, Alexander Armstrong, Olivier Arnaez, Hannah Arnold, Giacomo Artoni, Artz, Sebastian, Shoji Asai, Nedaa Alexandra Asbah, Eleni Myrto Asimakopoulou, lily asquith, Assamagan, Ketevi Adikle, Robert Astalos, Ryan Atkin, Atkinson, Markus Julian, Naim Bora Atlay, Atmani, Hicham, Kamil Augsten, Giuseppe Avolio, Rachel Maria Avramidou, Mohamad Kassem Ayoub, Azoulay, Adam, Georges Azuelos, Baca, Matt, Henri Bachacou, Konstantinos Bachas, Moritz Backes, Filip Backman, Paolo Bagnaia, Bahrasemani, Sina, Adam Bailey, Virginia Bailey, John Baines, Milena Bajic, Christos Bakalis, Oliver Baker, Pepijn Bakker, Debottam BakshiGupta, Shyam Balaji, Evgenii Baldin, Petr Balek, Fabrice Balli, William Balunas, Johannes Balz, Elżbieta Banaś, Anjishnu Bandyopadhyay, swagato banerjee, Arwa Bannoura, Liron Barak, William Barbe, Elisabetta Barberio, Dario Barberis, Marlon, Barillari Teresa, Martin Barisits, Jason Barkeloo, Timothy Barklow, Barnea, Rotem, Barnes, Sarah Louise, Bruce Barnett, Michael Barnett, Zuzana Blenessy, Antonio Baroncelli, Gaetano Barone, Alan Barr, Laura Barranco Navarro, Fernando Barreiro, Joao Guimaraes da Costa, Sergey Barsov, Rainer Bartoldus, Giovanni Bartolini, Adam Barton, Pavol Bartos, Artem Basalaev, Ahmed Bassalat, richard bates, Batista, Santiago, Batlamous, Souad, Richard Batley, Binish Batool, Battaglia, Marco, Matteo Bauce, Florian Bauer, Bauer, Kevin Thomas, Bawa, Harinder Singh, James Beacham, Tristan Beau, Pierre-Hugues Beauchemin, Fabian Becherer, Philip Bechtle, Beck, Helge Christoph, Hans Peter Beck, Kathrin Becker, Becker, Maurice, Cyril Becot, Beddall, Ayda, Andrew Beddall, Vadim Bednyakov, Matteo Bedognetti, Christopher Bee, Thomas Beermann, Marcia Begalli, Michael Begel, Arabinda Behera, Katharina Behr, J., Florian Beisiegel, Andrew Bell, Gideon Bella, Lorenzo Bellagamba, Alain Bellerive, Panagiotis Bellos, Konstantin Beloborodov, Konstantin Belotsky, Nikita Belyaev, Driss Benchekroun, Nektarios Benekos, yan benhammou, Douglas Benjamin, Mathieu Benoit, James Bensinger, Stan Bentvelsen, Lydia Beresford, Matteo Mario Beretta, David Berge, Elin Bergeaas Kuutmann, Nicolas Berger, Benedikt Ludwig Bergmann, Laura, Juerg Beringer, Simon, Nathan Bernard, Gregorio Bernardi, Catrin Bernius, Florian Bernlochner, Tracey Berry, Peter Berta, Claudia Bertella, Iain Alexander Bertram, Geert-Jan Besjes, Olga Bessidskaia Bylund, Nathalie Besson, Agni Bethani, Siegfried Bethke, Alessandra Betti, Adrian Bevan, Julien-Christopher Beyer, Bi, Runyu, Riccardo Maria Bianchi, Otmar Biebel, Dustin Biedermann, Rafal Bielski, Katharina Bierwagen, Nicolò Vladi Biesuz, Michela Biglietti, Thomas Billoud, Marcello Bindi, Ahmet Bingul, Cesare Bini, Silvia Biondi, Mattias Birman, Bisanz, Tobias, Jyoti Prakash Biswal, Diptaparna Biswas, Alexander Bitadze, Carsten Bittrich, Kristian Bjørke, Kevin Black, Tomas Blazek, Ingo Bloch, Craig Blocker, Andrew Blue, Ulla Blumenschein, gerard jan bobbink, Viktor Bobrovnikov, Bocchetta, Simona, Andrea Bocci, Danijela Bogavac, Alexander Bogdanchikov, Bohm, Christian, Veronique Boisvert, Petar Bokan, Tomasz Bold, Alexey Boldyrev, Arthur Eugen Bolz, Marco Bomben, Marcella Bona, Johan Bonilla, Maarten Boonekamp, Hanna Borecka-Bielska, Borisov, Anatoli, Guennadi Borissov, Jonathan Bortfeldt, Daniela Bortoletto, Bortolotto, Valerio, Davide Boscherini, Martine Bosman, Jonathan David Bossio Sola, Khalil Bouaouda, Joseph Boudreau, Evelina Bouhova-Thacker, Boumediene, Djamel, Sarah Boutle, Antonio Boveia, James Boyd, Diallo Boye, Igor Boyko, Adam Bozson, Juraj Bracinik, Brahimi, Nihal, Gerhard Immanuel Brandt, Oleg Brandt, Früd Braren, Benjamin Brau, Brau, James E., Breaden Madden, Will, Kurt Brendlinger, Lydia Brenner, Richard Brenner, Shikma Bressler, Bernard Brickwedde, Daniel Briglin, David Britton, Britzger Daniel, Ian Brock, Raymond Brock, Gustaaf Brooijmans, William Brooks, Elizabeth Brost, James Broughton, Pawel Bruckman de Renstrom, Dusan Bruncko, Alessia Bruni, Graziano Bruni, Lucrezia Stella Bruni, Salvatore bruno, Benjamin Brunt, Marco Bruschi, Nello Bruscino, Patrick Bryant, Lene Kristian Bryngemark, Trygve Buanes, Quentin Buat, Peter Buchholz, Andy Buckley, Ioulian Budagov, Magnar Kopangen Bugge, Felix Bührer, Oleg Bulekov, Tyler James Burch, Sergey Burdin, Carsten Burgard, Angela Burger, Blake Burghgrave, Jonathan Burr, Jackson Burzynski, Volker Buescher, Buschmann, Eric, peter bussey, John Butler, Craig Buttar, Jonathan Butterworth, Butti, Pierfrancesco, William Buttinger, Adrian Buzatu, Alexey Buzykaev, Grazia Cabras, Susana Cabrera Urbán, Davide Caforio, Huacheng Cai, Valentina Maria Martina Cairo, Cakir, Orhan, Noemi Calace, Paolo Calafiura, Calandri Alessandro, Giovanni Calderini, Philippe Calfayan, Giuseppe Callea, Caloba, Luiz, Sergio Calvente Lopez, David Calvet, Samuel Calvet, Thomas Calvet, Milene Calvetti, Reina Coromoto Camacho Toro, Stefano Camarda, Daniel Camarero, Paolo Camarri, David Cameron, Roger Caminal Armadans, Clément Camincher, Campana, Simone, Mario Campanelli, Alessandra Camplani, Angel Campoverde, Vincenzo Canale, Auriane Canesse, Marc Bret Cano, Josu Cantero García, Tingting Cao, Yumeng Cao, Mar Capeans, Marcella Capua, Roberto Cardarelli, Fabio Cardillo, Giovandomenico Carducci, Ina Carli, Tancredi Carli, Gianpaolo Carlino, Benjamin Carlson, LEONARDO CARLO CARMINATI, Rebecca Carney, Sascha, Edson Carquin, SONIA CARRA, Joseph Carter, María Pilar Casado Lechuga, Casha, Albert Francis, David Casper, Castelijn, Remco Johannes, Florencia Luciana Castillo, Maria Victoria Castillo, Nuno Castro, Andrea Catinaccio, James Catmore, Cattai, Ariella, Julien Caudron, Viviana Cavaliere, Emanuele Cavallaro, Vincenzo Cavasinni, Emre Celebi, Leonor Cerda Alberich, Karel Černý, Augusto Cerqueira, alessandro cerri, Lucio Cerrito, Fabio Cerutti, Alberto Cervelli, SERKANT ALİ ÇETİN, Zakaria Chadi, dhiman chakraborty, Chan, Stephen Kam-Wah, Wing Sheung Chan, Chan, Wai Yuen, John Chapman, Bakar Chargeishvili, David Charlton, Thomas Charman, Chav Chhiv Chau, Siinn Che, Chegwidden, Andrew Mc Rae, Sergei Chekanov, Sergey Chekulaev, SHELKOV GEORGY, Magda Anna Chelstowska, Boping Chen, Chen, Cheng, Chunhui Chen, Hucheng Chen, Jing Chen, jue chen, Shion Chen, Shenjian Chen, Xin Chen, Ye Chen, Chen Yu-Heng, Hok-Chuen Cheng, Huajie Cheng, Alexander Cheplakov, Evgeniya Cheremushkina, Rajaa Cherkaoui El Moursli, Elliott Cheu, Kingman Cheung, Thibault Chevalerias, laurent chevalier, Vitaliano Chiarella, Giorgio Chiarelli, Gabriele Chiodini, Andrew Chisholm, Adrian Chitan, Chiu, I-Huan, Yu Him Justin Chiu, Mihail Chizhov, KYUNGEON CHOI, Arthur Chomont, Chouridou, Sofia, Chow, Edwin, Ming-chung Chu, Xiaotong Chu, Jiri Chudoba, Annabelle Chuinard, Janusz Chwastowski, Chytka, Ladislav, Krzysztof Cieśla, Diane Cinca, Vladimir Cindro, Irina Cioara, Alessandra Ciocio, Francesco Cirotto, Zvi Citron, Mauro Citterio, Ciubotaru, Dan Andrei, Bianca Ciungu, Allan Clark, Michael Clark, Philip Clark, Christophe Clement, Yann Coadou, marina cobal, Andrea Coccaro, Cochran Jr, James Herbert, Cohen, Hadar, Artur Coimbra, Luca Colasurdo, Brian Cole, Colijn, Auke-Pieter, Johann Collot, Conde Muino, P., Elias Coniavitis, Simon Connell, Ian Connelly, Constantinescu, Serban, Francesco Alessandro Conventi, Amanda Cooper-Sarkar, Felix Cormier, Cormier, Kyle James Read, Louie Corpe, Massimo Corradi, Eric Edward Corrigan, Francois Corriveau, Costa Mezquita, Francesco Costanza, Davide Costanzo, Glen Cowan, James Cowley, Jonathan Crane, Kyle Cranmer, Crawley, Samuel Joseph, Rachael Creager, Sabine Crépé-Renaudin, Francesco Crescioli, Markus Cristinziani, Vincent Alexander Croft, Nanni Crosetti, Ana Rosario Cueto Gómez, Tulay Cuhadar Donszelmann, Aviv Cukierman, Sabina Czekierda, Patrick Czodrowski, Mário José Cunha Sargedas Sousa, JOAO VICTOR DA FONSECA PINTO, Cinzia Da Via, Wladyslaw Dabrowski, Tomas Dado, Salah-eddine Dahbi, Tiesheng Dai, Carlo Dallapiccola, Mogens Dam, Amen, Gabriele D., Amico, Valerio D., Johannes Damp, Jeffrey Dandoy, Maria Florencia Daneri, Nguyen Phuong Dang, Nick Dann, Matthias Danninger, Valerio Dao, Giovanni Darbo, Dartsi, Olympia, Aparajita Dattagupta, Daubney, Thomas, Auria, Saverio D., William Davey, Claire David, Tomas Davidek, Douglas Davis, Ian Dawson, Kaushik De, Riccardo De Asmundis, Marc de Beurs, Stefano De Castro, Sandro De Cecco, Nicolo de Groot, Paul de Jong, Hector de la Torre Perez, Antonio De Maria, Daniele De Pedis, Alessandro De Salvo, Umberto De Sanctis, Maurizio De Santis, Antonella De Santo, Vasconcelos Corga, Kevin, Jean-Baptiste de Vivie, Chiara Debenedetti, Dedovich, Dmitri, Allison McCarn Deiana, Del Gaudio, Michela, Jose del Peso, Yasiel Delabat Diaz, David Delgove, Frederic Deliot, Chris Malena Delitzsch, Massimo Della Pietra, Domenico Della Volpe, Andrea Dell’Acqua, Lidia Dell'Asta, Marco Delmastro, Delporte, Charles Eliaz, Pierre-Antoine Delsart, David DeMarco, Sarah Demers, Mikhail Demichev, Demontigny, Gabriel, Sergei Denisov, Denys Denysiuk, Eramo, Louis D., Dominik Derendarz, Jamal Eddine Derkaoui, Derue, Frédéric, Paul Dervan, Klaus Desch, Cécile Deterre, Karola Dette, Christopher Deutsch, Devesa, Maria Roberta, Pier-Olivier Deviveiros, Alastair Dewhurst, Dhaliwal, Saminder, Francesco Armando Di Bello, Anna Di Ciaccio, Lucia Di Ciaccio, William DiClemente, Camilla Di Donato, Alessandro Di Girolamo, Giulia Di Gregorio, Biagio Di Micco, Roberto Di Nardo, Karri Folan Di Petrillo, Riccardo Di Sipio, David Di Valentino, Cristinel Diaconu, Flavia De Almeida Dias, Tiago Vale, Marco Aurelio Diaz, Jennet Dickinson, Edward Diehl, Janet Dietrich, Sergio Diez Cornell, Aleksandra Dimitrievska, Wei Ding, Jochen Dingfelder, Fridolin Dittus, Farès Djama, Tamar Djobava, Julia Isabell Djuvsland, Maria Aline Vale, Monica Dobre, David Dodsworth, Caterina Doglioni, Jiří Dolejší, Zdeněk Doležal, Marisilvia Donadelli, Binbin Dong, Julien Donini, Onofrio, Adelina D., Onofrio, Monica D., Jens Dopke, Alessandra Doria, María Teresa Dova, Anthony Doyle, Eric Drechsler, Etienne Dreyer, Timo Dreyer, Alec Drobac, Duan, Yanyun, Filipp, Michal Dubovsky, Arnaud Dubreuil, Ehud Duchovni, Guenter Duckeck, Audrey Ducourthial, Otilia Ducu, Dominik Duda, Alexey Dudarev, Andreas Düdder, Duffield, Emily Marie, Laurent Duflot, Michael Duehrssen-Debling, Carsten Dülsen, Mirta Dumancic, Dumitriu Ana Elena, Anna Duncan, Monica Dunford, Arnaud Duperrin, Hatice, Michael Düren, Archil Durglishvili, Duschinger, Dirk Uwe, Baishali Dutta, Damir Duvnjak, Brianna Dwyer, George Ian Dyckes, Mateusz Dyndal, Samuel Dysch, Bartosz Dziedzic, Ecker, Katharina Maria, Edgar, Ryan Christopher, Eggleston, Michael Glenn, Till Eifert, Gerald Eigen, Kevin Einsweiler, Tord Ekelof, Hassnae El Jarrari, El Kacimi, Mohamed, El Kosseifi, Rima, Venugopal Ellajosyula, Mattias Ellert, Frank Ellinghaus, Alison Elliot, Nicolas Ellis, Johannes Elmsheuser, Markus Elsing, Dmitry Emeliyanov, Alexander Emerman, Yuji Enari, Matthew Epland, Johannes Erdmann, Antonio Ereditato, Martin Errenst, Marc Escalier, Carlos Escobar Ibáñez, Oscar Estrada Pastor, Erez Etzion, Harold Evans, Alexey Ezhilov, Federica Fabbri, Laura Fabbri, Veronica Fabiani, Gabriel Facini, Rui Pereira, Rinat Fakhrutdinov, Speranza Falciano, Peter Johannes Falke, Saskia Falke, Jana Faltova, Yi Fang, Yaquan Fang, GEORGIOS FANOURAKIS, MARCELLO FANTI, Mohammed Faraj, Amir Farbin, Addolorata Farilla, Edoardo Maria Farina, Trisha Farooque, Steven Farrell, Sinead Farrington, Philippe Farthouat, Farida Fassi, Patrick Fassnacht, Dimitris Fassouliotis, Michele Faucci Giannelli, William Fawcett, Louis Fayard, Oleg Fedin, Wojciech Fedorko, Matthew Feickert, Simon Feigl, Lorenzo Feligioni, Alexandra Fell, Cunfeng Feng, Eric Feng, Minyu Feng, Michael Fenton, Fenyuk, Alexandre, James Ferrando, Ferrante, Andrew, arnaud ferrari, Pamela, Pamela Ferrari, Ferrari, Roberto Ferrari, Danilo Enoque Ferreira de Lima, Antonio Ferrer, Didier Ferrere, Claudio Ferretti, Frank Fiedler, Andrej Filipčič, Frank Filthaut, Kevin Finelli, Miguel Fiolhais, Luca 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Vladimir Zhulanov, Daria Zieminska, Nikolai Zimine, Stephanie Zimmermann, Zinonos, Zinonas, Michael Ziolkowski, Lidija Zivkovic, Georg Zobernig, Antonio Zoccoli, Knut Zoch, Theodore Georgio Zorbas, Rui Zou, and Lukasz Zwalinski

36. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Author: Benjamin Glaser, Henrik Druid, Tommy Kaplan, Amit Korach, Judith Magenheim, Aviad Zick, Yuval Dor, Myriam Maoz, Albert Grinshpun, Daniel Neiman, Netanel Loyfer, Peter Arner, Endre Kiss, Yaacov Samet, Ruth Shemer, Kirsty L. Spalding, Hai Zemmour, A. M. James Shapiro, Avigail Dreazan Wittenberg, Joshua Moss, Giora Landesberg, Keng Yeh Fu, and Markus Grompe
Subjects: 0301 basic medicine, Cell type, Programmed cell death, Erythrocytes, Lung Neoplasms, In silico, Science, General Physics and Astronomy, Breast Neoplasms, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Prostate, Sepsis, medicine, Biomarkers, Tumor, Leukocytes, Humans, Progenitor cell, Promoter Regions, Genetic, lcsh:Science, Cells, Cultured, Multidisciplinary, Endothelial Cells, General Chemistry, Methylation, DNA Methylation, Circulating Cell-Free DNA, 3. Good health, Transplantation, 030104 developmental biology, medicine.anatomical_structure, DNA methylation, Colonic Neoplasms, Cancer research, Hepatocytes, CpG Islands, lcsh:Q, DNA microarray, Cell-Free Nucleic Acids, Algorithms
Abstract: Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics., The methylation status of circulating cell-free DNA (cfDNA) can be informative about recent cell death events. Here the authors present an approach to determine the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types, and find that cfDNA from patients reveals tissue contributions that agree with clinical findings.
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