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1. Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression

Author

Wortzel, Inbal, Seo, Yura, Akano, Ife, Shaashua, Lee, Tobias, Gabriel Cardial, Hebert, Jakob, Kim, Kyung-A, Kim, DooA, Dror, Shani, Liu, Yanshen, Azrak, Griffin Campbell, Cioffi, Michele, Johnson, Kofi Ennu, Hennika, Tammy, Twerski, Meshulam Zisha, Kushner, Alexis, Math, Robert, Han, Yoon Dae, Han, Dai Hoon, Jung, Minsun, Park, Juyeong, Paik, Soonmyung, Shin, Jeon-Soo, Lee, Min Goo, Russo, Marco Vincenzo, Zakheim, Daniel, Barnes, Jesse, Mehta, Sunjoy, Manova, Katia, Schwartz, Robert E., Thakur, Basant Kumar, Boudreau, Nancy, Matei, Irina, Zhang, Haiying, Sidoli, Simone, Bromberg, Jacqueline, David, Yael, Kim, Han Sang, and Lyden, David

Published
2024
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3. Space radiation damage rescued by inhibition of key spaceflight associated miRNAs

Author

McDonald, J. Tyson, Kim, JangKeun, Farmerie, Lily, Johnson, Meghan L., Trovao, Nidia S., Arif, Shehbeel, Siew, Keith, Tsoy, Sergey, Bram, Yaron, Park, Jiwoon, Overbey, Eliah, Ryon, Krista, Haltom, Jeffrey, Singh, Urminder, Enguita, Francisco J., Zaksas, Victoria, Guarnieri, Joseph W., Topper, Michael, Wallace, Douglas C., Meydan, Cem, Baylin, Stephen, Meller, Robert, Muratani, Masafumi, Porterfield, D. Marshall, Kaufman, Brett, Mori, Marcelo A., Walsh, Stephen B., Sigaudo-Roussel, Dominique, Mebarek, Saida, Bottini, Massimo, Marquette, Christophe A., Wurtele, Eve Syrkin, Schwartz, Robert E., Galeano, Diego, Mason, Christopher E., Grabham, Peter, and Beheshti, Afshin

Published
2024
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4. Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer

Author

Bojmar, Linda, Zambirinis, Constantinos P., Hernandez, Jonathan M., Chakraborty, Jayasree, Shaashua, Lee, Kim, Junbum, Johnson, Kofi Ennu, Hanna, Samer, Askan, Gokce, Burman, Jonas, Ravichandran, Hiranmayi, Zheng, Jian, Jolissaint, Joshua S., Srouji, Rami, Song, Yi, Choubey, Ankur, Kim, Han Sang, Cioffi, Michele, van Beek, Elke, Sigel, Carlie, Jessurun, Jose, Velasco Riestra, Paulina, Blomstrand, Hakon, Jönsson, Carolin, Jönsson, Anette, Lauritzen, Pernille, Buehring, Weston, Ararso, Yonathan, Hernandez, Dylanne, Vinagolu-Baur, Jessica P., Friedman, Madison, Glidden, Caroline, Firmenich, Laetitia, Lieberman, Grace, Mejia, Dianna L., Nasar, Naaz, Mutvei, Anders P., Paul, Doru M., Bram, Yaron, Costa-Silva, Bruno, Basturk, Olca, Boudreau, Nancy, Zhang, Haiying, Matei, Irina R., Hoshino, Ayuko, Kelsen, David, Sagi, Irit, Scherz, Avigdor, Scherz-Shouval, Ruth, Yarden, Yosef, Oren, Moshe, Egeblad, Mikala, Lewis, Jason S., Keshari, Kayvan, Grandgenett, Paul M., Hollingsworth, Michael A., Rajasekhar, Vinagolu K., Healey, John H., Björnsson, Bergthor, Simeone, Diane M., Tuveson, David A., Iacobuzio-Donahue, Christine A., Bromberg, Jaqueline, Vincent, C. Theresa, O’Reilly, Eileen M., DeMatteo, Ronald P., Balachandran, Vinod P., D’Angelica, Michael I., Kingham, T. Peter, Allen, Peter J., Simpson, Amber L., Elemento, Olivier, Sandström, Per, Schwartz, Robert E., Jarnagin, William R., and Lyden, David

Published
2024
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5. A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

Author

Narayanan, S. Anand, Jamison, Jr, David A., Guarnieri, Joseph W., Zaksas, Victoria, Topper, Michael, Koutnik, Andrew P., Park, Jiwoon, Clark, Kevin B., Enguita, Francisco J., Leitão, Ana Lúcia, Das, Saswati, Moraes-Vieira, Pedro M., Galeano, Diego, Mason, Christopher E., Trovão, Nídia S., Schwartz, Robert E., Schisler, Jonathan C., Coelho-dos-Reis, Jordana G. A., Wurtele, Eve Syrkin, and Beheshti, Afshin

Published
2024
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6. Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication

Author

Yaron, Tomer M, Heaton, Brook E, Levy, Tyler M, Johnson, Jared L, Jordan, Tristan X, Cohen, Benjamin M, Kerelsky, Alexander, Lin, Ting-Yu, Liberatore, Katarina M, Bulaon, Danielle K, Van Nest, Samantha J, Koundouros, Nikos, Kastenhuber, Edward R, Mercadante, Marisa N, Shobana-Ganesh, Kripa, He, Long, Schwartz, Robert E, Chen, Shuibing, Weinstein, Harel, Elemento, Olivier, Piskounova, Elena, Nilsson-Payant, Benjamin E, Lee, Gina, Trimarco, Joseph D, Burke, Kaitlyn N, Hamele, Cait E, Chaparian, Ryan R, Harding, Alfred T, Tata, Aleksandra, Zhu, Xinyu, Tata, Purushothama Rao, Smith, Clare M, Possemato, Anthony P, Tkachev, Sasha L, Hornbeck, Peter V, Beausoleil, Sean A, Anand, Shankara K, Aguet, François, Getz, Gad, Davidson, Andrew D, Heesom, Kate, Kavanagh-Williamson, Maia, Matthews, David A, tenOever, Benjamin R, Cantley, Lewis C, Blenis, John, and Heaton, Nicholas S

Subjects
Pneumonia & Influenza, Prevention, Immunization, Biotechnology, Vaccine Related, Lung, Emerging Infectious Diseases, Infectious Diseases, Infection, Good Health and Well Being, Animals, Humans, SARS-CoV-2, Phosphorylation, COVID-19, Glycogen Synthase Kinase 3, Virus Replication, Nucleocapsid Proteins, Nucleocapsid, Serine, Threonine, Mammals, Protein Serine-Threonine Kinases, Biochemistry and Cell Biology
Abstract

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

Published
2022

7. Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection

Author

Yang, Liuliu, Han, Yuling, Zhang, Tuo, Dong, Xue, Ge, Jian, Roy, Aadita, Zhu, Jiajun, Lu, Tiankun, Jeya Vandana, J., de Silva, Neranjan, Robertson, Catherine C., Xiang, Jenny Z., Pan, Chendong, Sun, Yanjie, Que, Jianwen, Evans, Todd, Liu, Chengyang, Wang, Wei, Naji, Ali, Parker, Stephen C.J., Schwartz, Robert E., and Chen, Shuibing

Published
2024
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9. Author Correction: Identification of SARS-CoV-2 inhibitors using lung and colonic organoids

Author

Han, Yuling, Duan, Xiaohua, Yang, Liuliu, Nilsson-Payant, Benjamin E., Wang, Pengfei, Duan, Fuyu, Tang, Xuming, Yaron, Tomer M., Zhang, Tuo, Uhl, Skyler, Bram, Yaron, Richardson, Chanel, Zhu, Jiajun, Zhao, Zeping, Redmond, David, Houghton, Sean, Nguyen, Duc-Huy T., Xu, Dong, Wang, Xing, Jessurun, Jose, Borczuk, Alain, Huang, Yaoxing, Johnson, Jared L., Liu, Yuru, Xiang, Jenny, Wang, Hui, Cantley, Lewis C., tenOever, Benjamin R., Ho, David D., Pan, Fong Cheng, Evans, Todd, Chen, Huanhuan Joyce, Schwartz, Robert E., and Chen, Shuibing

Published
2024
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11. SARS-CoV-2 infection causes dopaminergic neuron senescence

Author

Yang, Liuliu, Kim, Tae Wan, Han, Yuling, Nair, Manoj S., Harschnitz, Oliver, Zhu, Jiajun, Wang, Pengfei, Koo, So Yeon, Lacko, Lauretta A., Chandar, Vasuretha, Bram, Yaron, Zhang, Tuo, Zhang, Wei, He, Feng, Pan, Chendong, Wu, Junjie, Huang, Yaoxing, Evans, Todd, van der Valk, Paul, Titulaer, Maarten J., Spoor, Jochem K.H., Furler O’Brien, Robert L., Bugiani, Marianna, D.J. Van de Berg, Wilma, Schwartz, Robert E., Ho, David D., Studer, Lorenz, and Chen, Shuibing

Published
2024
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12. Epinephrine inhibits PI3Kα via the Hippo kinases

Author

Lin, Ting-Yu, Ramsamooj, Shakti, Perrier, Tiffany, Liberatore, Katarina, Lantier, Louise, Vasan, Neil, Karukurichi, Kannan, Hwang, Seo-Kyoung, Kesicki, Edward A., Kastenhuber, Edward R., Wiederhold, Thorsten, Yaron, Tomer M., Huntsman, Emily M., Zhu, Mengmeng, Ma, Yilun, Paddock, Marcia N., Zhang, Guoan, Hopkins, Benjamin D., McGuinness, Owen, Schwartz, Robert E., Ersoy, Baran A., Cantley, Lewis C., Johnson, Jared L., and Goncalves, Marcus D.

Published
2023
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15. Shotgun transcriptome, spatial omics, and isothermal profiling of SARS-CoV-2 infection reveals unique host responses, viral diversification, and drug interactions

Author

Butler, Daniel, Mozsary, Christopher, Meydan, Cem, Foox, Jonathan, Rosiene, Joel, Shaiber, Alon, Danko, David, Afshinnekoo, Ebrahim, MacKay, Matthew, Sedlazeck, Fritz J, Ivanov, Nikolay A, Sierra, Maria, Pohle, Diana, Zietz, Michael, Gisladottir, Undina, Ramlall, Vijendra, Sholle, Evan T, Schenck, Edward J, Westover, Craig D, Hassan, Ciaran, Ryon, Krista, Young, Benjamin, Bhattacharya, Chandrima, Ng, Dianna L, Granados, Andrea C, Santos, Yale A, Servellita, Venice, Federman, Scot, Ruggiero, Phyllis, Fungtammasan, Arkarachai, Chin, Chen-Shan, Pearson, Nathaniel M, Langhorst, Bradley W, Tanner, Nathan A, Kim, Youngmi, Reeves, Jason W, Hether, Tyler D, Warren, Sarah E, Bailey, Michael, Gawrys, Justyna, Meleshko, Dmitry, Xu, Dong, Couto-Rodriguez, Mara, Nagy-Szakal, Dorottya, Barrows, Joseph, Wells, Heather, O’Hara, Niamh B, Rosenfeld, Jeffrey A, Chen, Ying, Steel, Peter AD, Shemesh, Amos J, Xiang, Jenny, Thierry-Mieg, Jean, Thierry-Mieg, Danielle, Iftner, Angelika, Bezdan, Daniela, Sanchez, Elizabeth, Campion, Thomas R, Sipley, John, Cong, Lin, Craney, Arryn, Velu, Priya, Melnick, Ari M, Shapira, Sagi, Hajirasouliha, Iman, Borczuk, Alain, Iftner, Thomas, Salvatore, Mirella, Loda, Massimo, Westblade, Lars F, Cushing, Melissa, Wu, Shixiu, Levy, Shawn, Chiu, Charles, Schwartz, Robert E, Tatonetti, Nicholas, Rennert, Hanna, Imielinski, Marcin, and Mason, Christopher E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Vaccine Related, Biodefense, Rare Diseases, Emerging Infectious Diseases, Clinical Research, Prevention, Lung, Pneumonia & Influenza, Aetiology, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Adult, Aged, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Antiviral Agents, COVID-19, COVID-19 Nucleic Acid Testing, Drug Interactions, Female, Gene Expression Profiling, Genome, Viral, HLA Antigens, Host Microbial Interactions, Humans, Male, Middle Aged, Molecular Diagnostic Techniques, New York City, Nucleic Acid Amplification Techniques, Pandemics, RNA-Seq, SARS-CoV-2, COVID-19 Drug Treatment
Abstract

In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin-angiotensin-aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies.

Published
2021

16. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors

Author

Cheong, Jin-Gyu, Ravishankar, Arjun, Sharma, Siddhartha, Parkhurst, Christopher N., Grassmann, Simon A., Wingert, Claire K., Laurent, Paoline, Ma, Sai, Paddock, Lucinda, Miranda, Isabella C., Karakaslar, Emin Onur, Nehar-Belaid, Djamel, Thibodeau, Asa, Bale, Michael J., Kartha, Vinay K., Yee, Jim K., Mays, Minh Y., Jiang, Chenyang, Daman, Andrew W., Martinez de Paz, Alexia, Ahimovic, Dughan, Ramos, Victor, Lercher, Alexander, Nielsen, Erik, Alvarez-Mulett, Sergio, Zheng, Ling, Earl, Andrew, Yallowitz, Alisha, Robbins, Lexi, LaFond, Elyse, Weidman, Karissa L., Racine-Brzostek, Sabrina, Yang, He S., Price, David R., Leyre, Louise, Rendeiro, André F., Ravichandran, Hiranmayi, Kim, Junbum, Borczuk, Alain C., Rice, Charles M., Jones, R. Brad, Schenck, Edward J., Kaner, Robert J., Chadburn, Amy, Zhao, Zhen, Pascual, Virginia, Elemento, Olivier, Schwartz, Robert E., Buenrostro, Jason D., Niec, Rachel E., Barrat, Franck J., Lief, Lindsay, Sun, Joseph C., Ucar, Duygu, and Josefowicz, Steven Z.

Published
2023
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17. Recent Developments and Therapeutic Strategies against Hepatocellular Carcinoma

Author

Yarchoan, Mark, Agarwal, Parul, Villanueva, Augusto, Rao, Shuyun, Dawson, Laura A, Karasic, Thomas, Llovet, Josep M, Finn, Richard S, Groopman, John D, El-Serag, Hashem B, Monga, Satdarshan P, Wang, Xin Wei, Karin, Michael, Schwartz, Robert E, Tanabe, Kenneth K, Roberts, Lewis R, Gunaratne, Preethi H, Tsung, Allan, Brown, Kimberly A, Lawrence, Theodore S, Salem, Riad, Singal, Amit G, Kim, Amy K, Rabiee, Atoosa, Resar, Linda, Meyer, Jeffrey, Hoshida, Yujin, He, Aiwu Ruth, Ghoshal, Kalpana, Ryan, Patrick B, Jaffee, Elizabeth M, Guha, Chandan, Mishra, Lopa, Coleman, C Norman, and Ahmed, Mansoor M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Liver Disease, Liver Cancer, Cancer, Orphan Drug, Rare Diseases, Chronic Liver Disease and Cirrhosis, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Anilides, Antibodies, Monoclonal, Humanized, Carcinoma, Hepatocellular, Chemoembolization, Therapeutic, Clinical Trials as Topic, Humans, Immunotherapy, Liver Neoplasms, Molecular Targeted Therapy, Mutation, Phenylurea Compounds, Protein Kinase Inhibitors, Pyridines, Quinolines, beta Catenin, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2-5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

Published
2019

18. A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants

Author

Han, Yuling, Tan, Lei, Zhou, Ting, Yang, Liuliu, Carrau, Lucia, Lacko, Lauretta A., Saeed, Mohsan, Zhu, Jiajun, Zhao, Zeping, Nilsson-Payant, Benjamin E., Lira Neto, Filipe Tenorio, Cahir, Clare, Giani, Alice Maria, Chai, Jin Chou, Li, Yang, Dong, Xue, Moroziewicz, Dorota, Paull, Daniel, Zhang, Tuo, Koo, Soyeon, Tan, Christina, Danziger, Ron, Ba, Qian, Feng, Lingling, Chen, Zhengming, Zhong, Aaron, Wise, Gilbert J., Xiang, Jenny Z., Wang, Hui, Schwartz, Robert E., tenOever, Benjamin R., Noggle, Scott A., Rice, Charles M., Qi, Qibin, Evans, Todd, and Chen, Shuibing

Published
2022
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19. CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction

Author

Yang, Dapeng, Cho, Hyunwoo, Tayyebi, Zakieh, Shukla, Abhijit, Luo, Renhe, Dixon, Gary, Ursu, Valeria, Stransky, Stephanie, Tremmel, Daniel M., Sackett, Sara D., Koche, Richard, Kaplan, Samuel J., Li, Qing V., Park, Jiwoon, Zhu, Zengrong, Rosen, Bess P., Pulecio, Julian, Shi, Zhong-Dong, Bram, Yaron, Schwartz, Robert E., Odorico, Jon S., Sidoli, Simone, Wright, Christopher V., Leslie, Christina S., and Huangfu, Danwei

Published
2022
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24. Cardiomyocytes recruit monocytes upon SARS-CoV-2 infection by secreting CCL2

Author

Yang, Liuliu, Nilsson-Payant, Benjamin E., Han, Yuling, Jaffré, Fabrice, Zhu, Jiajun, Wang, Pengfei, Zhang, Tuo, Redmond, David, Houghton, Sean, Møller, Rasmus, Hoagland, Daisy, Carrau, Lucia, Horiuchi, Shu, Goff, Marisa, Lim, Jean K., Bram, Yaron, Richardson, Chanel, Chandar, Vasuretha, Borczuk, Alain, Huang, Yaoxing, Xiang, Jenny, Ho, David D., Schwartz, Robert E., tenOever, Benjamin R., Evans, Todd, and Chen, Shuibing

Published
2021
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26. Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms

Author

Livanos, Alexandra E., Jha, Divya, Cossarini, Francesca, Gonzalez-Reiche, Ana S., Tokuyama, Minami, Aydillo, Teresa, Parigi, Tommaso L., Ladinsky, Mark S., Ramos, Irene, Dunleavy, Katie, Lee, Brian, Dixon, Rebekah E., Chen, Steven T., Martinez-Delgado, Gustavo, Nagula, Satish, Bruce, Emily A., Ko, Huaibin M., Glicksberg, Benjamin S., Nadkarni, Girish, Pujadas, Elisabet, Reidy, Jason, Naymagon, Steven, Grinspan, Ari, Ahmad, Jawad, Tankelevich, Michael, Bram, Yaron, Gordon, Ronald, Sharma, Keshav, Houldsworth, Jane, Britton, Graham J., Chen-Liaw, Alice, Spindler, Matthew P., Plitt, Tamar, Wang, Pei, Cerutti, Andrea, Faith, Jeremiah J., Colombel, Jean-Frederic, Kenigsberg, Ephraim, Argmann, Carmen, Merad, Miriam, Gnjatic, Sacha, Harpaz, Noam, Danese, Silvio, Cordon-Cardo, Carlos, Rahman, Adeeb, Schwartz, Robert E., Kumta, Nikhil A., Aghemo, Alessio, Bjorkman, Pamela J., Petralia, Francesca, van Bakel, Harm, Garcia-Sastre, Adolfo, and Mehandru, Saurabh

Published
2021
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27. A molecular single-cell lung atlas of lethal COVID-19

Author

Melms, Johannes C., Biermann, Jana, Huang, Huachao, Wang, Yiping, Nair, Ajay, Tagore, Somnath, Katsyv, Igor, Rendeiro, André F., Amin, Amit Dipak, Schapiro, Denis, Frangieh, Chris J., Luoma, Adrienne M., Filliol, Aveline, Fang, Yinshan, Ravichandran, Hiranmayi, Clausi, Mariano G., Alba, George A., Rogava, Meri, Chen, Sean W., Ho, Patricia, Montoro, Daniel T., Kornberg, Adam E., Han, Arnold S., Bakhoum, Mathieu F., Anandasabapathy, Niroshana, Suárez-Fariñas, Mayte, Bakhoum, Samuel F., Bram, Yaron, Borczuk, Alain, Guo, Xinzheng V., Lefkowitch, Jay H., Marboe, Charles, Lagana, Stephen M., Del Portillo, Armando, Tsai, Emily J., Zorn, Emmanuel, Markowitz, Glen S., Schwabe, Robert F., Schwartz, Robert E., Elemento, Olivier, Saqi, Anjali, Hibshoosh, Hanina, Que, Jianwen, and Izar, Benjamin

Published
2021
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28. The spatial landscape of lung pathology during COVID-19 progression

Author

Rendeiro, André F., Ravichandran, Hiranmayi, Bram, Yaron, Chandar, Vasuretha, Kim, Junbum, Meydan, Cem, Park, Jiwoon, Foox, Jonathan, Hether, Tyler, Warren, Sarah, Kim, Youngmi, Reeves, Jason, Salvatore, Steven, Mason, Christopher E., Swanson, Eric C., Borczuk, Alain C., Elemento, Olivier, and Schwartz, Robert E.

Subjects
Lung diseases -- Development and progression, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Recent studies have provided insights into the pathology of and immune response to COVID-19.sup.1-8. However, a thorough investigation of the interplay between infected cells and the immune system at sites of infection has been lacking. Here we use high-parameter imaging mass cytometry.sup.9 that targets the expression of 36 proteins to investigate the cellular composition and spatial architecture of acute lung injury in humans (including injuries derived from SARS-CoV-2 infection) at single-cell resolution. These spatially resolved single-cell data unravel the disordered structure of the infected and injured lung, alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyperinflammatory cell state that is associated with lung damage. We leverage the temporal range of fatal outcomes of COVID-19 in relation to the onset of symptoms, which reveals increased macrophage extravasation and increased numbers of mesenchymal cells and fibroblasts concomitant with increased proximity between these cell types as the disease progresses--possibly as a result of attempts to repair the damaged lung tissue. Our data enable us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. We use this landscape to characterize the pathophysiology of the human lung from its macroscopic presentation to the single-cell level, which provides an important basis for understanding COVID-19 and lung pathology in general. Imaging mass cytometry of the human lung reveals the cellular composition and spatial architecture during COVID-19 and other acute injuries, enabling the characterization of lung pathophysiology from structural, immunological and clinical perspectives., Author(s): André F. Rendeiro [sup.1] [sup.2] , Hiranmayi Ravichandran [sup.2] [sup.3] [sup.4] , Yaron Bram [sup.5] , Vasuretha Chandar [sup.5] , Junbum Kim [sup.1] , Cem Meydan [sup.1] [sup.4] , [...]

Published
2021
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31. Evolution of antibody immunity to SARS-CoV-2

Author

Gaebler, Christian, Wang, Zijun, Lorenzi, Julio C. C., Muecksch, Frauke, Finkin, Shlomo, Tokuyama, Minami, Cho, Alice, Jankovic, Mila, Schaefer-Babajew, Dennis, Oliveira, Thiago Y., Cipolla, Melissa, Viant, Charlotte, Barnes, Christopher O., Bram, Yaron, Breton, Gaëlle, Hägglöf, Thomas, Mendoza, Pilar, Hurley, Arlene, Turroja, Martina, Gordon, Kristie, Millard, Katrina G., Ramos, Victor, Schmidt, Fabian, Weisblum, Yiska, Jha, Divya, Tankelevich, Michael, Martinez-Delgado, Gustavo, Yee, Jim, Patel, Roshni, Dizon, Juan, Unson-O’Brien, Cecille, Shimeliovich, Irina, Robbiani, Davide F., Zhao, Zhen, Gazumyan, Anna, Schwartz, Robert E., Hatziioannou, Theodora, Bjorkman, Pamela J., Mehandru, Saurabh, Bieniasz, Paul D., Caskey, Marina, and Nussenzweig, Michel C.

Published
2021
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32. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids

Author

Han, Yuling, Duan, Xiaohua, Yang, Liuliu, Nilsson-Payant, Benjamin E., Wang, Pengfei, Duan, Fuyu, Tang, Xuming, Yaron, Tomer M., Zhang, Tuo, Uhl, Skyler, Bram, Yaron, Richardson, Chanel, Zhu, Jiajun, Zhao, Zeping, Redmond, David, Houghton, Sean, Nguyen, Duc-Huy T., Xu, Dong, Wang, Xing, Jessurun, Jose, Borczuk, Alain, Huang, Yaoxing, Johnson, Jared L., Liu, Yuru, Xiang, Jenny, Wang, Hui, Cantley, Lewis C., tenOever, Benjamin R., Ho, David D., Pan, Fong Cheng, Evans, Todd, Chen, Huanhuan Joyce, Schwartz, Robert E., and Chen, Shuibing

Published
2021
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33. Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis

Author

Palikuqi, Brisa, Nguyen, Duc-Huy T., Li, Ge, Schreiner, Ryan, Pellegata, Alessandro F., Liu, Ying, Redmond, David, Geng, Fuqiang, Lin, Yang, Gómez-Salinero, Jesus M., Yokoyama, Masataka, Zumbo, Paul, Zhang, Tuo, Kunar, Balvir, Witherspoon, Mavee, Han, Teng, Tedeschi, Alfonso M., Scottoni, Federico, Lipkin, Steven M., Dow, Lukas, Elemento, Olivier, Xiang, Jenny Z., Shido, Koji, Spence, Jason R., Zhou, Qiao J., Schwartz, Robert E., De Coppi, Paolo, Rabbany, Sina Y., and Rafii, Shahin

Published
2020
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37. Banning carbon nanotubes would be scientifically unjustified and damaging to innovation

Author

Heller, Daniel A., Jena, Prakrit V., Pasquali, Matteo, Kostarelos, Kostas, Delogu, Lucia G., Meidl, Rachel E., Rotkin, Slava V., Scheinberg, David A., Schwartz, Robert E., Terrones, Mauricio, Wang, YuHuang, Bianco, Alberto, Boghossian, Ardemis A., Cambré, Sofie, Cognet, Laurent, Corrie, Simon R., Demokritou, Philip, Giordani, Silvia, Hertel, Tobias, Ignatova, Tetyana, Islam, Mohammad F., Iverson, Nicole M., Jagota, Anand, Janas, Dawid, Kono, Junichiro, Kruss, Sebastian, Landry, Markita P., Li, Yan, Martel, Richard, Maruyama, Shigeo, Naumov, Anton V., Prato, Maurizio, Quinn, Susan J., Roxbury, Daniel, Strano, Michael S., Tour, James M., Weisman, R. Bruce, Wenseleers, Wim, and Yudasaka, Masako

Published
2020
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38. A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

Author

Narayanan, S. Anand, primary, Jamison, David A., additional, Guarnieri, Joseph W., additional, Zaksas, Victoria, additional, Topper, Michael, additional, Koutnik, Andrew P., additional, Park, Jiwoon, additional, Clark, Kevin B., additional, Enguita, Francisco J., additional, Leitão, Ana Lúcia, additional, Das, Saswati, additional, Moraes-Vieira, Pedro M., additional, Galeano, Diego, additional, Mason, Christopher E., additional, Trovão, Nídia S., additional, Schwartz, Robert E., additional, Schisler, Jonathan C., additional, Coelho-dos-Reis, Jordana G. A., additional, Wurtele, Eve Syrkin, additional, and Beheshti, Afshin, additional

Published
2023
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39. LETHAL COVID-19 ASSOCIATES WITH RAAS-INDUCED INFLAMMATION FOR MULTIPLE ORGAN DAMAGE INCLUDING MEDIASTINAL LYMPH NODES

Author

Guarnieri, Joseph W, primary, Topper, Michael, additional, Beigel, Katherine, additional, Haltoom, Jeff A, additional, Chadburn, Amy, additional, Frere, Justin, additional, An, Julia, additional, Cope, Henry, additional, Borczuk, Alain, additional, Sinha, Saloni, additional, Lim, Christine, additional, Kim, JangKeun, additional, Park, Jiwoon, additional, Meydan, Cem, additional, Foox, Jonathan, additional, Mozsary, Christopher, additional, Bram, Yaron, additional, Richard, Stephanie, additional, Epsi, Nusrat, additional, Agan, Brian, additional, Chenoweth, Josh, additional, Simons, Mark, additional, Tribble, David, additional, Burgess, Timothy, additional, Dalgard, Clifton L., additional, Heise, Mark T., additional, Moorman, Nathaniel, additional, Baxter, Victoria, additional, Madden, Emily A., additional, Taft-Benz, Sharon, additional, Anderson, Elizabeth, additional, Sanders, Wes A., additional, Dickmander, Rebekah J., additional, Widjaja, Gabrielle A., additional, Janssen, Kevin, additional, Lie, Timothy, additional, Murdock, Deborah G, additional, Angelin, Alessia, additional, Albrecht, Yentli E. S., additional, Olali, Arnold, additional, Dybas, Joseph M., additional, Priebe, Waldemar, additional, Emmett, Mark R., additional, Best, Sonja, additional, Johnson, Maya Kelsey, additional, Trovao, Nidia S., additional, Clark, Kevin B., additional, Zaksiene, Viktoria, additional, Miller, Rob, additional, Grabhamr, Peter, additional, Schisler, Jonathan C, additional, Moraes-vieira, Pedro, additional, Pollett, Simon, additional, Mason, Christopher E., additional, Wurtele, Eve Syrkin, additional, Taylor, Deanne, additional, Schwartz, Robert E., additional, Beheshti, Afshin, additional, Wallace, Douglas C., additional, and Baylin, Stephen B., additional

Published
2023
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40. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts

Author

Guarnieri, Joseph W., primary, Dybas, Joseph M., additional, Fazelinia, Hossein, additional, Kim, Man S., additional, Frere, Justin, additional, Zhang, Yuanchao, additional, Soto Albrecht, Yentli, additional, Murdock, Deborah G., additional, Angelin, Alessia, additional, Singh, Larry N., additional, Weiss, Scott L., additional, Best, Sonja M., additional, Lott, Marie T., additional, Zhang, Shiping, additional, Cope, Henry, additional, Zaksas, Victoria, additional, Saravia-Butler, Amanda, additional, Meydan, Cem, additional, Foox, Jonathan, additional, Mozsary, Christopher, additional, Bram, Yaron, additional, Kidane, Yared, additional, Priebe, Waldemar, additional, Emmett, Mark R., additional, Meller, Robert, additional, Demharter, Sam, additional, Stentoft-Hansen, Valdemar, additional, Salvatore, Marco, additional, Galeano, Diego, additional, Enguita, Francisco J., additional, Grabham, Peter, additional, Trovao, Nidia S., additional, Singh, Urminder, additional, Haltom, Jeffrey, additional, Heise, Mark T., additional, Moorman, Nathaniel J., additional, Baxter, Victoria K., additional, Madden, Emily A., additional, Taft-Benz, Sharon A., additional, Anderson, Elizabeth J., additional, Sanders, Wes A., additional, Dickmander, Rebekah J., additional, Baylin, Stephen B., additional, Wurtele, Eve Syrkin, additional, Moraes-Vieira, Pedro M., additional, Taylor, Deanne, additional, Mason, Christopher E., additional, Schisler, Jonathan C., additional, Schwartz, Robert E., additional, Beheshti, Afshin, additional, and Wallace, Douglas C., additional

Published
2023
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41. Author Correction: A molecular single-cell lung atlas of lethal COVID-19

Author

Melms, Johannes C., Biermann, Jana, Huang, Huachao, Wang, Yiping, Nair, Ajay, Tagore, Somnath, Katsyv, Igor, Rendeiro, André F., Amin, Amit Dipak, Schapiro, Denis, Frangieh, Chris J., Luoma, Adrienne M., Filliol, Aveline, Fang, Yinshan, Ravichandran, Hiranmayi, Clausi, Mariano G., Alba, George A., Rogava, Meri, Chen, Sean W., Ho, Patricia, Montoro, Daniel T., Kornberg, Adam E., Han, Arnold S., Bakhoum, Mathieu F., Anandasabapathy, Niroshana, Suárez-Fariñas, Mayte, Bakhoum, Samuel F., Bram, Yaron, Borczuk, Alain, Guo, Xinzheng V., Lefkowitch, Jay H., Marboe, Charles, Lagana, Stephen M., Del Portillo, Armando, Tsai, Emily J., Zorn, Emmanuel, Markowitz, Glen S., Schwabe, Robert F., Schwartz, Robert E., Elemento, Olivier, Saqi, Anjali, Hibshoosh, Hanina, Que, Jianwen, and Izar, Benjamin

Published
2021
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47. Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Author

Wang, Gang, Li, Jianlong, Bojmar, Linda, Chen, Haiyan, Li, Zhong, Tobias, Gabriel C., Hu, Mengying, Homan, Edwin A., Lucotti, Serena, Zhao, Fengbo, Posada, Valentina, Oxley, Peter R., Cioffi, Michele, Kim, Han Sang, Wang, Huajuan, Lauritzen, Pernille, Boudreau, Nancy, Shi, Zhanjun, Burd, Christin E., Zippin, Jonathan H., Lo, James C., Pitt, Geoffrey S., Hernandez, Jonathan, Zambirinis, Constantinos P., Hollingsworth, Michael A., Grandgenett, Paul M., Jain, Maneesh, Batra, Surinder K., DiMaio, Dominick J., Grem, Jean L., Klute, Kelsey A., Trippett, Tanya M., Egeblad, Mikala, Paul, Doru, Bromberg, Jacqueline, Kelsen, David, Rajasekhar, Vinagolu K., Healey, John H., Matei, Irina R., Jarnagin, William R., Schwartz, Robert E., Zhang, Haiying, Lyden, David, Wang, Gang, Li, Jianlong, Bojmar, Linda, Chen, Haiyan, Li, Zhong, Tobias, Gabriel C., Hu, Mengying, Homan, Edwin A., Lucotti, Serena, Zhao, Fengbo, Posada, Valentina, Oxley, Peter R., Cioffi, Michele, Kim, Han Sang, Wang, Huajuan, Lauritzen, Pernille, Boudreau, Nancy, Shi, Zhanjun, Burd, Christin E., Zippin, Jonathan H., Lo, James C., Pitt, Geoffrey S., Hernandez, Jonathan, Zambirinis, Constantinos P., Hollingsworth, Michael A., Grandgenett, Paul M., Jain, Maneesh, Batra, Surinder K., DiMaio, Dominick J., Grem, Jean L., Klute, Kelsey A., Trippett, Tanya M., Egeblad, Mikala, Paul, Doru, Bromberg, Jacqueline, Kelsen, David, Rajasekhar, Vinagolu K., Healey, John H., Matei, Irina R., Jarnagin, William R., Schwartz, Robert E., Zhang, Haiying, and Lyden, David

Abstract

Cancer alters the function of multiple organs beyond those targeted by metastasis(1,2). Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy., Funding Agencies|National Cancer Institute; Thompson Family Foundation; Tortolani Foundation; Pediatric Oncology Experimental Therapeutics Investigators Consortium; Malcolm Hewitt Weiner Foundation; Manning Foundation; Sohn Foundation; AHEPA Vth District Cancer Research Foundation; Childrens Cancer and Blood Foundation; Hartwell Foundation; National Institutes of Health; United States Department of Defense; Paul G. Allen Family Foundation; National Natural Science Foundation of China; Guangdong Foundation of Medical Science and Technology; China Scholarship Council (CSC) [CA232093, CA163117, CA207983, CA218513]; Swedish Cancer Society Pancreatic Cancer Fellowship; Lions International Postdoctoral fellowship; Sweden-America stipend; Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of Memorial Sloan Kettering Cancer Center; NIH/NCI Cancer Center Support Grant; [R01CA234614]; [2R01AI107301]; [R01DK121072]; [R01CA237213]; [R01CA254036]; [W81XWH-21-1-0978]; [UWSC13448]; [81902730]; [A2019213]; [202008440567]; [P30 CA008748]

Published
2023
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49. Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Author

Wang, Gang, primary, Li, Jianlong, additional, Bojmar, Linda, additional, Chen, Haiyan, additional, Li, Zhong, additional, Tobias, Gabriel C., additional, Hu, Mengying, additional, Homan, Edwin A., additional, Lucotti, Serena, additional, Zhao, Fengbo, additional, Posada, Valentina, additional, Oxley, Peter R., additional, Cioffi, Michele, additional, Kim, Han Sang, additional, Wang, Huajuan, additional, Lauritzen, Pernille, additional, Boudreau, Nancy, additional, Shi, Zhanjun, additional, Burd, Christin E., additional, Zippin, Jonathan H., additional, Lo, James C., additional, Pitt, Geoffrey S., additional, Hernandez, Jonathan, additional, Zambirinis, Constantinos P., additional, Hollingsworth, Michael A., additional, Grandgenett, Paul M., additional, Jain, Maneesh, additional, Batra, Surinder K., additional, DiMaio, Dominick J., additional, Grem, Jean L., additional, Klute, Kelsey A., additional, Trippett, Tanya M., additional, Egeblad, Mikala, additional, Paul, Doru, additional, Bromberg, Jacqueline, additional, Kelsen, David, additional, Rajasekhar, Vinagolu K., additional, Healey, John H., additional, Matei, Irina R., additional, Jarnagin, William R., additional, Schwartz, Robert E., additional, Zhang, Haiying, additional, and Lyden, David, additional

Published
2023
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50. Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines

Author

Licht-Murava, Avital, primary, Meadows, Samantha M., additional, Palaguachi, Fernando, additional, Song, Soomin C., additional, Jackvony, Stephanie, additional, Bram, Yaron, additional, Zhou, Constance, additional, Schwartz, Robert E., additional, Froemke, Robert C., additional, Orr, Adam L., additional, and Orr, Anna G., additional

Published
2023
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