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2. Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy

Author

Chen, Jonathan H., Nieman, Linda T., Spurrell, Maxwell, Jorgji, Vjola, Elmelech, Liad, Richieri, Peter, Xu, Katherine H., Madhu, Roopa, Parikh, Milan, Zamora, Izabella, Mehta, Arnav, Nabel, Christopher S., Freeman, Samuel S., Pirl, Joshua D., Lu, Chenyue, Meador, Catherine B., Barth, Jaimie L., Sakhi, Mustafa, Tang, Alexander L., Sarkizova, Siranush, Price, Colles, Fernandez, Nicolas F., Emanuel, George, He, Jiang, Van Raay, Katrina, Reeves, Jason W., Yizhak, Keren, Hofree, Matan, Shih, Angela, Sade-Feldman, Moshe, Boland, Genevieve M., Pelka, Karin, Aryee, Martin J., Mino-Kenudson, Mari, Gainor, Justin F., Korsunsky, Ilya, and Hacohen, Nir

Published
2024
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3. Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer

Author

You, Eunae, Danaher, Patrick, Lu, Chenyue, Sun, Siyu, Zou, Luli, Phillips, Ildiko E., Rojas, Alexandra S., Ho, Natalie I., Song, Yuhui, Raabe, Michael J., Xu, Katherine H., Richieri, Peter M., Li, Hao, Aston, Natalie, Porter, Rebecca L., Patel, Bidish K., Nieman, Linda T., Schurman, Nathan, Hudson, Briana M., North, Khrystyna, Church, Sarah E., Deshpande, Vikram, Liss, Andrew S., Kim, Tae K., Cui, Yi, Kim, Youngmi, Greenbaum, Benjamin D., Aryee, Martin J., and Ting, David T.

Published
2024
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5. A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

Author

Liu, Chunhong, Nagashima, Hiroyuki, Fernando, Nilisha, Bass, Victor, Gopalakrishnan, Jaanam, Signorella, Sadie, Montgomery, Will, Lim, Ai Ing, Harrison, Oliver, Reich, Lauren, Yao, Chen, Sun, Hong-Wei, Brooks, Stephen R., Jiang, Kan, Nagarajan, Vijayaraj, Zhao, Yongbing, Jung, Seolkyoung, Philips, Rachael, Mikami, Yohei, Lareau, Caleb A., Kanno, Yuka, Jankovic, Dragana, Aryee, Martin J., Pękowska, Aleksandra, Belkaid, Yasmine, O’Shea, John, and Shih, Han-Yu

Published
2024
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7. DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs

Author

Guo, Hongshan, Vuille, Joanna A., Wittner, Ben S., Lachtara, Emily M., Hou, Yu, Lin, Maoxuan, Zhao, Ting, Raman, Ayush T., Russell, Hunter C., Reeves, Brittany A., Pleskow, Haley M., Wu, Chin-Lee, Gnirke, Andreas, Meissner, Alexander, Efstathiou, Jason A., Lee, Richard J., Toner, Mehmet, Aryee, Martin J., Lawrence, Michael S., Miyamoto, David T., Maheswaran, Shyamala, and Haber, Daniel A.

Published
2023
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9. Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

Author

Ligorio, Matteo, Sil, Srinjoy, Malagon-Lopez, Jose, Nieman, Linda T, Misale, Sandra, Di Pilato, Mauro, Ebright, Richard Y, Karabacak, Murat N, Kulkarni, Anupriya S, Liu, Ann, Vincent Jordan, Nicole, Franses, Joseph W, Philipp, Julia, Kreuzer, Johannes, Desai, Niyati, Arora, Kshitij S, Rajurkar, Mihir, Horwitz, Elad, Neyaz, Azfar, Tai, Eric, Magnus, Neelima KC, Vo, Kevin D, Yashaswini, Chittampalli N, Marangoni, Francesco, Boukhali, Myriam, Fatherree, Jackson P, Damon, Leah J, Xega, Kristina, Desai, Rushil, Choz, Melissa, Bersani, Francesca, Langenbucher, Adam, Thapar, Vishal, Morris, Robert, Wellner, Ulrich F, Schilling, Oliver, Lawrence, Michael S, Liss, Andrew S, Rivera, Miguel N, Deshpande, Vikram, Benes, Cyril H, Maheswaran, Shyamala, Haber, Daniel A, Fernandez-Del-Castillo, Carlos, Ferrone, Cristina R, Haas, Wilhelm, Aryee, Martin J, and Ting, David T

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Rare Diseases, Genetics, Digestive Diseases, Stem Cell Research, Pancreatic Cancer, Cancer, Stem Cell Research - Nonembryonic - Human, 2.1 Biological and endogenous factors, Aetiology, Animals, Cancer-Associated Fibroblasts, Carcinoma, Pancreatic Ductal, Cell Proliferation, Coculture Techniques, Epithelial-Mesenchymal Transition, Female, HEK293 Cells, Heterografts, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Mitogen-Activated Protein Kinases, Pancreatic Neoplasms, RNA-Seq, STAT3 Transcription Factor, Stromal Cells, Transfection, Tumor Microenvironment, mass spectrometry, pancreatic cancer, pancreatic ductal adenocarcinoma, single cell RNA-sequencing, single cell spatial analysis, stromal microenvironment, tumor architecture, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

Published
2019

10. Interrogation of human hematopoiesis at single-cell and single-variant resolution

Author

Ulirsch, Jacob C, Lareau, Caleb A, Bao, Erik L, Ludwig, Leif S, Guo, Michael H, Benner, Christian, Satpathy, Ansuman T, Kartha, Vinay K, Salem, Rany M, Hirschhorn, Joel N, Finucane, Hilary K, Aryee, Martin J, Buenrostro, Jason D, and Sankaran, Vijay G

Subjects
Human Genome, Genetics, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, Biotechnology, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, Generic health relevance, Cell Lineage, Chromatin, Chromosome Mapping, Epigenomics, Genome-Wide Association Study, Hematopoiesis, Humans, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. For regulatory variants, we explore patterns of developmental enhancer activity, predict molecular mechanisms, and identify likely target genes. In several instances, we localize multiple independent variants to the same regulatory element or gene. We further observe that variants with pleiotropic effects preferentially act in common progenitor populations to direct the production of distinct lineages. Finally, we leverage fine-mapped variants in conjunction with continuous epigenomic annotations to identify trait-cell type enrichments within closely related populations and in single cells. Our study provides a comprehensive framework for single-variant and single-cell analyses of genetic associations.

Published
2019

11. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment

Author

Hwang, William L., Jagadeesh, Karthik A., Guo, Jimmy A., Hoffman, Hannah I., Yadollahpour, Payman, Reeves, Jason W., Mohan, Rahul, Drokhlyansky, Eugene, Van Wittenberghe, Nicholas, Ashenberg, Orr, Farhi, Samouil L., Schapiro, Denis, Divakar, Prajan, Miller, Eric, Zollinger, Daniel R., Eng, George, Schenkel, Jason M., Su, Jennifer, Shiau, Carina, Yu, Patrick, Freed-Pastor, William A., Abbondanza, Domenic, Mehta, Arnav, Gould, Joshua, Lambden, Conner, Porter, Caroline B. M., Tsankov, Alexander, Dionne, Danielle, Waldman, Julia, Cuoco, Michael S., Nguyen, Lan, Delorey, Toni, Phillips, Devan, Barth, Jaimie L., Kem, Marina, Rodrigues, Clifton, Ciprani, Debora, Roldan, Jorge, Zelga, Piotr, Jorgji, Vjola, Chen, Jonathan H., Ely, Zackery, Zhao, Daniel, Fuhrman, Kit, Fropf, Robin, Beechem, Joseph M., Loeffler, Jay S., Ryan, David P., Weekes, Colin D., Ferrone, Cristina R., Qadan, Motaz, Aryee, Martin J., Jain, Rakesh K., Neuberg, Donna S., Wo, Jennifer Y., Hong, Theodore S., Xavier, Ramnik, Aguirre, Andrew J., Rozenblatt-Rosen, Orit, Mino-Kenudson, Mari, Castillo, Carlos Fernandez-del, Liss, Andrew S., Ting, David T., Jacks, Tyler, and Regev, Aviv

Published
2022
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12. CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer’s disease PSEN1 M146L mutation

Author

Konstantinidis, Evangelos, Molisak, Agnieszka, Perrin, Florian, Streubel-Gallasch, Linn, Fayad, Sarah, Kim, Daniel Y., Petri, Karl, Aryee, Martin J., Aguilar, Ximena, György, Bence, Giedraitis, Vilmantas, Joung, J. Keith, Pattanayak, Vikram, Essand, Magnus, Erlandsson, Anna, Berezovska, Oksana, and Ingelsson, Martin

Published
2022
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13. Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1

Author

Ludwig, Leif S., Lareau, Caleb A., Bao, Erik L., Liu, Nan, Utsugisawa, Taiju, Tseng, Alex M., Myers, Samuel A., Verboon, Jeffrey M., Ulirsch, Jacob C., Luo, Wendy, Muus, Christoph, Fiorini, Claudia, Olive, Meagan E., Vockley, Christopher M., Munschauer, Mathias, Hunter, Abigail, Ogura, Hiromi, Yamamoto, Toshiyuki, Inada, Hiroko, Nakagawa, Shinichiro, Ohzono, Shuichi, Subramanian, Vidya, Chiarle, Roberto, Glader, Bertil, Carr, Steven A., Aryee, Martin J., Kundaje, Anshul, Orkin, Stuart H., Regev, Aviv, McCavit, Timothy L., Kanno, Hitoshi, and Sankaran, Vijay G.

Published
2022
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16. EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

Author

Möller, Emely, Praz, Viviane, Rajendran, Sanalkumar, Dong, Rui, Cauderay, Alexandra, Xing, Yu-Hang, Lee, Lukuo, Fusco, Carlo, Broye, Liliane C., Cironi, Luisa, Iyer, Sowmya, Rengarajan, Shruthi, Awad, Mary E., Naigles, Beverly, Letovanec, Igor, Ormas, Nicola, Finzi, Giovanna, La Rosa, Stefano, Sessa, Fausto, Chebib, Ivan, Petur Nielsen, G., Digklia, Antonia, Spentzos, Dimitrios, Cote, Gregory M., Choy, Edwin, Aryee, Martin, Stamenkovic, Ivan, Boulay, Gaylor, Rivera, Miguel N., and Riggi, Nicolò

Published
2022
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19. STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Author

Adane, Biniam, Alexe, Gabriela, Seong, Bo Kyung A., Lu, Diana, Hwang, Elizabeth E., Hnisz, Denes, Lareau, Caleb A., Ross, Linda, Lin, Shan, Dela Cruz, Filemon S., Richardson, Melissa, Weintraub, Abraham S., Wang, Sarah, Iniguez, Amanda Balboni, Dharia, Neekesh V., Conway, Amy Saur, Robichaud, Amanda L., Tanenbaum, Benjamin, Krill-Burger, John M., Vazquez, Francisca, Schenone, Monica, Berman, Jason N., Kung, Andrew L., Carr, Steven A., Aryee, Martin J., Young, Richard A., Crompton, Brian D., and Stegmaier, Kimberly

Published
2021
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20. OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma

Author

Boulay, Gaylor, Awad, Mary E, Riggi, Nicolo, Archer, Tenley C, Iyer, Sowmya, Boonseng, Wannaporn E, Rossetti, Nikki E, Naigles, Beverly, Rengarajan, Shruthi, Volorio, Angela, Kim, James C, Mesirov, Jill P, Tamayo, Pablo, Pomeroy, Scott L, Aryee, Martin J, and Rivera, Miguel N

Subjects
Rare Diseases, Pediatric Cancer, Genetics, Neurosciences, Biotechnology, Brain Disorders, Brain Cancer, Pediatric, Cancer, Human Genome, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Tumor, Cell Survival, Cerebellar Neoplasms, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Humans, Medulloblastoma, Mesenchymal Stem Cells, NIMA-Related Kinases, Otx Transcription Factors, Oncology and Carcinogenesis
Abstract

Medulloblastoma is the most frequent malignant pediatric brain tumor and is divided into at least four subgroups known as WNT, SHH, Group 3, and Group 4. Here, we characterized gene regulation mechanisms in the most aggressive subtype, Group 3 tumors, through genome-wide chromatin and expression profiling. Our results show that most active distal sites in these tumors are occupied by the transcription factor OTX2. Highly active OTX2-bound enhancers are often arranged as clusters of adjacent peaks and are also bound by the transcription factor NEUROD1. These sites are responsive to OTX2 and NEUROD1 knockdown and could also be generated de novo upon ectopic OTX2 expression in primary cells, showing that OTX2 cooperates with NEUROD1 and plays a major role in maintaining and possibly establishing regulatory elements as a pioneer factor. Among OTX2 target genes, we identified the kinase NEK2, whose knockdown and pharmacologic inhibition decreased cell viability. Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.Significance: The gene regulation mechanisms that drive medulloblastoma are not well understood. Using chromatin profiling, we find that the transcription factor OTX2 acts as a pioneer factor and, in cooperation with NEUROD1, controls the Group 3 medulloblastoma active enhancer landscape. OTX2 itself or its target genes, including the mitotic kinase NEK2, represent attractive targets for future therapies. Cancer Discov; 7(3); 288-301. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235.

Published
2017

30. Dysregulated Repeat Element Viral-like Immune Response in Hepatocellular Carcinoma

Author

Coley, Avril K., primary, Lu, Chenyue, additional, Pankaj, Amaya, additional, Emmett, Matthew J., additional, Lang, Evan R., additional, Song, Yuhui, additional, Xu, Katherine H., additional, Xu, Nova, additional, Patel, Bidish K., additional, Chougule, Abhijit, additional, Nieman, Linda T., additional, Aryee, Martin J., additional, Ferrone, Cristina R., additional, Deshpande, Vikram, additional, Franses, Joseph W., additional, and Ting, David T., additional

Published
2023
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34. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors

Author

Grünewald, Julian, Zhou, Ronghao, Garcia, Sara P., Iyer, Sowmya, Lareau, Caleb A., Aryee, Martin J., and Joung, J. Keith

Subjects
Methods, Analysis, Usage, Genetic aspects, RNA processing -- Methods -- Analysis, CRISPR-Cas technology -- Usage, Cytosine -- Genetic aspects -- Usage
Abstract

Author(s): Julian Grünewald [sup.1] [sup.2] [sup.3] [sup.4] , Ronghao Zhou [sup.1] [sup.2] [sup.3] , Sara P. Garcia [sup.1] , Sowmya Iyer [sup.1] , Caleb A. Lareau [sup.1] [sup.5] , Martin [...], CRISPR-Cas base-editor technology enables targeted nucleotide alterations, and is being increasingly used for research and potential therapeutic applications.sup.1,2. The most widely used cytosine base editors (CBEs) induce deamination of DNA cytosines using the rat APOBEC1 enzyme, which is targeted by a linked Cas protein-guide RNA complex.sup.3,4. Previous studies of the specificity of CBEs have identified off-target DNA edits in mammalian cells.sup.5,6. Here we show that a CBE with rat APOBEC1 can cause extensive transcriptome-wide deamination of RNA cytosines in human cells, inducing tens of thousands of C-to-U edits with frequencies ranging from 0.07% to 100% in 38-58% of expressed genes. CBE-induced RNA edits occur in both protein-coding and non-protein-coding sequences and generate missense, nonsense, splice site, and 5' and 3' untranslated region mutations. We engineered two CBE variants bearing mutations in rat APOBEC1 that substantially decreased the number of RNA edits (by more than 390-fold and more than 3,800-fold) in human cells. These variants also showed more precise on-target DNA editing than the wild-type CBE and, for most guide RNAs tested, no substantial reduction in editing efficiency. Finally, we show that an adenine base editor.sup.7 can also induce transcriptome-wide RNA edits. These results have implications for the use of base editors in both research and clinical settings, illustrate the feasibility of engineering improved variants with reduced RNA editing activities, and suggest the need to more fully define and characterize the RNA off-target effects of deaminase enzymes in base editor platforms. CRISPR DNA base editors induce transcriptome-wide off-target RNA editing, which can be reduced by using engineered variants that retain on-target DNA editing activities.

Published
2019
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37. Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia

Author

Gaiti, Federico, Chaligne, Ronan, Gu, Hongcang, Brand, Ryan M., Kothen-Hill, Steven, Schulman, Rafael C., Grigorev, Kirill, Risso, Davide, Kim, Kyu-Tae, Pastore, Alessandro, Huang, Kevin Y., Alonso, Alicia, Sheridan, Caroline, Omans, Nathaniel D., Biederstedt, Evan, Clement, Kendell, Wang, Lili, Felsenfeld, Joshua A., Bhavsar, Erica B., Aryee, Martin J., Allan, John N., Furman, Richard, Gnirke, Andreas, Wu, Catherine J., Meissner, Alexander, and Landau, Dan A.

Published
2019
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39. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

Author

Lim, Stephen S, Vos, Theo, Flaxman, Abraham D, Danaei, Goodarz, Shibuya, Kenji, Adair-Rohani, Heather, AlMazroa, Mohammad A, Amann, Markus, Anderson, H Ross, Andrews, Kathryn G, Aryee, Martin, Atkinson, Charles, Bacchus, Loraine J, Bahalim, Adil N, Balakrishnan, Kalpana, Balmes, John, Barker-Collo, Suzanne, Baxter, Amanda, Bell, Michelle L, Blore, Jed D, Blyth, Fiona, Bonner, Carissa, Borges, Guilherme, Bourne, Rupert, Boussinesq, Michel, Brauer, Michael, Brooks, Peter, Bruce, Nigel G, Brunekreef, Bert, Bryan-Hancock, Claire, Bucello, Chiara, Buchbinder, Rachelle, Bull, Fiona, Burnett, Richard T, Byers, Tim E, Calabria, Bianca, Carapetis, Jonathan, Carnahan, Emily, Chafe, Zoe, Charlson, Fiona, Chen, Honglei, Chen, Jian Shen, Cheng, Andrew Tai-Ann, Child, Jennifer Christine, Cohen, Aaron, Colson, K Ellicott, Cowie, Benjamin C, Darby, Sarah, Darling, Susan, Davis, Adrian, Degenhardt, Louisa, Dentener, Frank, Jarlais, Don C Des, Devries, Karen, Dherani, Mukesh, Ding, Eric L, Dorsey, E Ray, Driscoll, Tim, Edmond, Karen, Ali, Suad Eltahir, Engell, Rebecca E, Erwin, Patricia J, Fahimi, Saman, Falder, Gail, Farzadfar, Farshad, Ferrari, Alize, Finucane, Mariel M, Flaxman, Seth, Fowkes, Francis Gerry R, Freedman, Greg, Freeman, Michael K, Gakidou, Emmanuela, Ghosh, Santu, Giovannucci, Edward, Gmel, Gerhard, Graham, Kathryn, Grainger, Rebecca, Grant, Bridget, Gunnell, David, Gutierrez, Hialy R, Hall, Wayne, Hoek, Hans W, Hogan, Anthony, Hosgood, H Dean, Hoy, Damian, Hu, Howard, Hubbell, Bryan J, Hutchings, Sally J, Ibeanusi, Sydney E, Jacklyn, Gemma L, Jasrasaria, Rashmi, Jonas, Jost B, Kan, Haidong, Kanis, John A, Kassebaum, Nicholas, Kawakami, Norito, Khang, Young-Ho, Khatibzadeh, Shahab, Khoo, Jon-Paul, and Kok, Cindy

Subjects
Tobacco Smoke and Health, Prevention, Tobacco, Burden of Illness, Nutrition, Pediatric, 2.2 Factors relating to the physical environment, 2.3 Psychological, social and economic factors, Aetiology, Respiratory, Cardiovascular, Good Health and Well Being, Clean Water and Sanitation, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Global Health, Humans, Infant, Infant, Newborn, Male, Middle Aged, Mortality, Quality-Adjusted Life Years, Risk Assessment, Risk Factors, Sex Factors, Young Adult, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundQuantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.MethodsWe estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden.FindingsIn 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania.InterpretationWorldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.FundingBill & Melinda Gates Foundation.

Published
2012

40. Comprehensive methylome map of lineage commitment from haematopoietic progenitors

Author

Ji, Hong, Ehrlich, Lauren IR, Seita, Jun, Murakami, Peter, Doi, Akiko, Lindau, Paul, Lee, Hwajin, Aryee, Martin J, Irizarry, Rafael A, Kim, Kitai, Rossi, Derrick J, Inlay, Matthew A, Serwold, Thomas, Karsunky, Holger, Ho, Lena, Daley, George Q, Weissman, Irving L, and Feinberg, Andrew P

Subjects
Stem Cell Research, Genetics, Human Genome, Regenerative Medicine, Stem Cell Research - Embryonic - Non-Human, Stem Cell Research - Nonembryonic - Non-Human, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Cell Line, Cell Lineage, CpG Islands, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Genome, Hematopoiesis, Hematopoietic Stem Cells, Lymphocytes, Metabolome, Metabolomics, Mice, Myeloid Cells, Pluripotent Stem Cells, General Science & Technology
Abstract

Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.

Published
2010

41. 655 Dissecting pancreatic cancer tumor-immune microenvironment crosstalk using spatial transcriptomics

Author

Pankaj, Amaya, primary, Mehta, Arnav, additional, Raabe, Michael J, additional, Koenig, Julie L, additional, Patel, Bidish, additional, Lang, Evan R, additional, Kocher, Joshua, additional, Xu, Katherine, additional, Nieman, Linda, additional, Kimmelman, Alec, additional, Ryan, David, additional, Hwang, William, additional, Aryee, Martin, additional, Hong, Theodore, additional, Parikh, Aparna R, additional, and Ting, David, additional

Published
2023
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42. High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion dynamics

Author

Sept, Corriene E., primary, Tak, Y. Esther, additional, Cerda-Smith, Christian G., additional, Hutchinson, Haley M., additional, Goel, Viraat, additional, Blanchette, Marco, additional, Bhakta, Mital S., additional, Hansen, Anders S., additional, Joung, J. Keith, additional, Johnstone, Sarah, additional, Eyler, Christine E., additional, and Aryee, Martin J., additional

Published
2023
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43. IntegrativePTENEnhancer Discovery Reveals a New Model of Enhancer Organization

Author

Cerda-Smith, Christian G., primary, Hutchinson, Haley M., additional, Liu, Annie, additional, Goel, Viraat Y., additional, Sept, Corriene, additional, Kim, Holly, additional, Casaní-Galdón, Salvador, additional, Burkman, Katherine G., additional, Bassil, Christopher F., additional, Hansen, Anders S., additional, Aryee, Martin J., additional, Johnstone, Sarah E., additional, Eyler, Christine E., additional, and Wood, Kris C., additional

Published
2023
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46. In vivo CRISPR editing with no detectable genome-wide off-target mutations

Author

Akcakaya, Pinar, Bobbin, Maggie L., Guo, Jimmy A., Malagon-Lopez, Jose, Clement, Kendell, Garcia, Sara P., Fellows, Mick D., Porritt, Michelle J., Firth, Mike A., Carreras, Alba, Baccega, Tania, Seeliger, Frank, Bjursell, Mikael, Tsai, Shengdar Q., Nguyen, Nhu T., Nitsch, Roberto, Mayr, Lorenz M., Pinello, Luca, Bohlooly-Y, Mohammad, Aryee, Martin J., Maresca, Marcello, and Joung, J. Keith

Published
2018
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47. P1207: SERIAL SINGLE-CELL PROFILING OF MANTLE CELL LYMPHOMA REVEALS FUNCTIONAL AND MOLECULAR CORRELATES OF RESISTANCE TO BTK INHIBITOR-INCLUSIVE TRIPLET THERAPY

Author

Debaize, Lydie, primary, Zhang, Ye, additional, Ramseier, Michelle, additional, Zhang, Mingzeng, additional, Langenbucher, Adam, additional, Winter, Peter S., additional, Xu, Ran, additional, Senhaji, Nezha, additional, Redd, Robert A, additional, Aryee, Martin J., additional, Branch, Paul H., additional, Kim, Austin I., additional, Weinstock, David M., additional, Shalek, Alex, additional, Manalis, Scott R., additional, and Murakami, Mark A., additional

Published
2023
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