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262 results on '"Joshua M. So"'

13. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity

Author

Weisser, Nina E., Sanches, Mario, Escobar-Cabrera, Eric, O’Toole, Jason, Whalen, Elizabeth, Chan, Peter W. Y., Wickman, Grant, Abraham, Libin, Choi, Kate, Harbourne, Bryant, Samiotakis, Antonios, Rojas, Andrea Hernández, Volkers, Gesa, Wong, Jodi, Atkinson, Claire E., Baardsnes, Jason, Worrall, Liam J., Browman, Duncan, Smith, Emma E., Baichoo, Priya, Cheng, Chi Wing, Guedia, Joy, Kang, Sohyeong, Mukhopadhyay, Abhishek, Newhook, Lisa, Ohrn, Anders, Raghunatha, Prajwal, Zago-Schmitt, Matteo, Schrag, Joseph D., Smith, Joel, Zwierzchowski, Patricia, Scurll, Joshua M., Fung, Vincent, Black, Sonia, Strynadka, Natalie C. J., Gold, Michael R., Presta, Leonard G., Ng, Gordon, and Dixit, Surjit

Published
2023
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16. Mapping the landscape of genetic dependencies in chordoma

Author

Sharifnia, Tanaz, Wawer, Mathias J., Goodale, Amy, Lee, Yenarae, Kazachkova, Mariya, Dempster, Joshua M., Muller, Sandrine, Levy, Joan, Freed, Daniel M., Sommer, Josh, Kalfon, Jérémie, Vazquez, Francisca, Hahn, William C., Root, David E., Clemons, Paul A., and Schreiber, Stuart L.

Published
2023
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17. Analysis of SARS-CoV-2 Antibodies in COVID-19 Convalescent Blood using a Coronavirus Antigen Microarray

Author

de Assis, Rafael R, Jain, Aarti, Nakajima, Rie, Jasinskas, Algis, Felgner, Jiin, Obiero, Joshua M, Adenaiye, Oluwasanmi, Tai, Sheldon, Hong, Filbert, Norris, Philip J, Stone, Mars, Simmons, Graham, Bagri, Anil, Schreiber, Martin, Buser, Andreas, Holbro, Andreas, Battegay, Manuel, Hosimer, Philip, Noesen, Charles, Milton, Donald K, Group, Prometheus Study, Davies, D Huw, Contestable, Paul, Corash, Laurence M, Busch, Michael P, Felgner, Philip L, and Khan, Saahir

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Vaccine Related, Emerging Infectious Diseases, Lung, Prevention, Infectious Diseases, Pneumonia, Biodefense, Pneumonia & Influenza, Clinical Research, Infection, Good Health and Well Being, Prometheus Study Group
Abstract

The current practice for diagnosis of COVID-19, based on SARS-CoV-2 PCR testing of pharyngeal or respiratory specimens in a symptomatic patient at high epidemiologic risk, likely underestimates the true prevalence of infection. Serologic methods can more accurately estimate the disease burden by detecting infections missed by the limited testing performed to date. Here, we describe the validation of a coronavirus antigen microarray containing immunologically significant antigens from SARS-CoV-2, in addition to SARS-CoV, MERS-CoV, common human coronavirus strains, and other common respiratory viruses. A comparison of antibody profiles detected on the array from control sera collected prior to the SARS-CoV-2 pandemic versus convalescent blood specimens from virologically confirmed COVID-19 cases demonstrates complete discrimination of these two groups. This array can be used as a diagnostic tool, as an epidemiologic tool to more accurately estimate the disease burden of COVID-19, and as a research tool to correlate antibody responses with clinical outcomes.

Published
2021

18. Pathway and network analysis of more than 2500 whole cancer genomes.

Author

Reyna, Matthew A, Haan, David, Paczkowska, Marta, Verbeke, Lieven PC, Vazquez, Miguel, Kahraman, Abdullah, Pulido-Tamayo, Sergio, Barenboim, Jonathan, Wadi, Lina, Dhingra, Priyanka, Shrestha, Raunak, Getz, Gad, Lawrence, Michael S, Pedersen, Jakob Skou, Rubin, Mark A, Wheeler, David A, Brunak, Søren, Izarzugaza, Jose MG, Khurana, Ekta, Marchal, Kathleen, von Mering, Christian, Sahinalp, S Cenk, Valencia, Alfonso, PCAWG Drivers and Functional Interpretation Working Group, Reimand, Jüri, Stuart, Joshua M, Raphael, Benjamin J, and PCAWG Consortium

Subjects
PCAWG Drivers and Functional Interpretation Working Group, PCAWG Consortium, Humans, Neoplasms, Computational Biology, Chromatin Assembly and Disassembly, Gene Expression Regulation, Neoplastic, RNA Splicing, Mutation, Genome, Human, Databases, Genetic, Metabolic Networks and Pathways, Promoter Regions, Genetic
Abstract

The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

Published
2020

19. Biological process activity transformation of single cell gene expression for cross-species alignment.

Author

Ding, Hongxu, Blair, Andrew, Yang, Ying, and Stuart, Joshua M

Subjects
Leukocytes, Mononuclear, Animals, Zebrafish, Humans, Mice, Gene Expression Profiling, Sequence Analysis, RNA, Computational Biology, Systems Biology, Gene Expression, Gene Expression Regulation, Developmental, Single-Cell Analysis, Signal-To-Noise Ratio, Mouse Embryonic Stem Cells, Gene Expression Regulation, Developmental, Leukocytes, Mononuclear, Sequence Analysis, RNA
Abstract

The maintenance and transition of cellular states are controlled by biological processes. Here we present a gene set-based transformation of single cell RNA-Seq data into biological process activities that provides a robust description of cellular states. Moreover, as these activities represent species-independent descriptors, they facilitate the alignment of single cell states across different organisms.

Published
2019

25. Author Correction: Pathway and network analysis of more than 2500 whole cancer genomes

Author

Reyna, Matthew A., Haan, David, Paczkowska, Marta, Verbeke, Lieven P. C., Vazquez, Miguel, Kahraman, Abdullah, Pulido-Tamayo, Sergio, Barenboim, Jonathan, Wadi, Lina, Dhingra, Priyanka, Shrestha, Raunak, Getz, Gad, Lawrence, Michael S., Pedersen, Jakob Skou, Rubin, Mark A., Wheeler, David A., Brunak, Søren, Izarzugaza, Jose M. G., Khurana, Ekta, Marchal, Kathleen, von Mering, Christian, Sahinalp, S. Cenk, Valencia, Alfonso, Reimand, Jüri, Stuart, Joshua M., and Raphael, Benjamin J.

Published
2022
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26. A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses

Author

Amarilla, Alberto A., Sng, Julian D. J., Parry, Rhys, Deerain, Joshua M., Potter, James R., Setoh, Yin Xiang, Rawle, Daniel J., Le, Thuy T., Modhiran, Naphak, Wang, Xiaohui, Peng, Nias Y. G., Torres, Francisco J., Pyke, Alyssa, Harrison, Jessica J., Freney, Morgan E., Liang, Benjamin, McMillan, Christopher L. D., Cheung, Stacey T. M., Guevara, Darwin J. Da Costa, Hardy, Joshua M., Bettington, Mark, Muller, David A., Coulibaly, Fasséli, Moore, Frederick, Hall, Roy A., Young, Paul R., Mackenzie, Jason M., Hobson-Peters, Jody, Suhrbier, Andreas, Watterson, Daniel, and Khromykh, Alexander A.

Published
2021
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27. Common and cell-type specific responses to anti-cancer drugs revealed by high throughput transcript profiling.

Author

Niepel, Mario, Hafner, Marc, Duan, Qiaonan, Wang, Zichen, Paull, Evan O, Chung, Mirra, Lu, Xiaodong, Stuart, Joshua M, Golub, Todd R, Subramanian, Aravind, Ma'ayan, Avi, and Sorger, Peter K

Subjects
Cell Line, Tumor, Humans, Antineoplastic Agents, Gene Expression Profiling, Drug Synergism, High-Throughput Screening Assays, Genetics, Cancer, Pediatric Research Initiative, 5.1 Pharmaceuticals, 1.1 Normal biological development and functioning, Cell Line, Tumor, MD Multidisciplinary
Abstract

More effective use of targeted anti-cancer drugs depends on elucidating the connection between the molecular states induced by drug treatment and the cellular phenotypes controlled by these states, such as cytostasis and death. This is particularly true when mutation of a single gene is inadequate as a predictor of drug response. The current paper describes a data set of ~600 drug cell line pairs collected as part of the NIH LINCS Program ( http://www.lincsproject.org/ ) in which molecular data (reduced dimensionality transcript L1000 profiles) were recorded across dose and time in parallel with phenotypic data on cellular cytostasis and cytotoxicity. We report that transcriptional and phenotypic responses correlate with each other in general, but whereas inhibitors of chaperones and cell cycle kinases induce similar transcriptional changes across cell lines, changes induced by drugs that inhibit intra-cellular signaling kinases are cell-type specific. In some drug/cell line pairs significant changes in transcription are observed without a change in cell growth or survival; analysis of such pairs identifies drug equivalence classes and, in one case, synergistic drug interactions. In this case, synergy involves cell-type specific suppression of an adaptive drug response.

Published
2017

28. Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography

Author

Ubah, Obinna C., Lake, Eric W., Gunaratne, Gihan S., Gallant, Joseph P., Fernie, Marie, Robertson, Austin J., Marchant, Jonathan S., Bold, Tyler D., Langlois, Ryan A., Matchett, William E., Thiede, Joshua M., Shi, Ke, Yin, Lulu, Moeller, Nicholas H., Banerjee, Surajit, Ferguson, Laura, Kovaleva, Marina, Porter, Andrew J., Aihara, Hideki, LeBeau, Aaron M., and Barelle, Caroline J.

Published
2021
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34. Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Author

Giddings, Emily L., Champagne, Devin P., Wu, Meng-Han, Laffin, Joshua M., Thornton, Tina M., Valenca-Pereira, Felipe, Culp-Hill, Rachel, Fortner, Karen A., Romero, Natalia, East, James, Cao, Phoebe, Arias-Pulido, Hugo, Sidhu, Karatatiwant S., Silverstrim, Brian, Kam, Yoonseok, Kelley, Shana, Pereira, Mark, Bates, Susan E., Bunn, Janice Y., Fiering, Steven N., Matthews, Dwight E., Robey, Robert W., Stich, Domink, D’Alessandro, Angelo, and Rincon, Mercedes

Published
2021
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38. CD8+ T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs.

Author

Palmeri, Joseph R., Lax, Brianna M., Peters, Joshua M., Duhamel, Lauren, Stinson, Jordan A., Santollani, Luciano, Lutz, Emi A., Pinney III, William, Bryson, Bryan D., and Wittrup, K. Dane

Abstract

Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of a ɑ4-1BB antibody fused to the collagen-binding protein LAIR. While combination treatment with an antitumor antibody (TA99) shows only modest efficacy, simultaneous depletion of CD4+ T cells boosts cure rates to over 90% of mice. Mechanistically, this synergy depends on ɑCD4 eliminating tumor draining lymph node regulatory T cells, resulting in priming and activation of CD8+ T cells which then infiltrate the tumor microenvironment. The cytotoxic program of these newly primed CD8+ T cells is then supported by the combined effect of TA99 and ɑ4-1BB-LAIR. The combination of TA99 and ɑ4-1BBLAIR with a clinically approved ɑCTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of ɑCTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Published
2024
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43. Agreement between two large pan-cancer CRISPR-Cas9 gene dependency data sets

Author

Dempster, Joshua M., Pacini, Clare, Pantel, Sasha, Behan, Fiona M., Green, Thomas, Krill-Burger, John, Beaver, Charlotte M., Younger, Scott T., Zhivich, Victor, Najgebauer, Hanna, Allen, Felicity, Gonçalves, Emanuel, Shepherd, Rebecca, Doench, John G., Yusa, Kosuke, Vazquez, Francisca, Parts, Leopold, Boehm, Jesse S., Golub, Todd R., Hahn, William C., Root, David E., Garnett, Mathew J., Tsherniak, Aviad, and Iorio, Francesco

Published
2019
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45. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity

Author

Nina E. Weisser, Mario Sanches, Eric Escobar-Cabrera, Jason O’Toole, Elizabeth Whalen, Peter W. Y. Chan, Grant Wickman, Libin Abraham, Kate Choi, Bryant Harbourne, Antonios Samiotakis, Andrea Hernández Rojas, Gesa Volkers, Jodi Wong, Claire E. Atkinson, Jason Baardsnes, Liam J. Worrall, Duncan Browman, Emma E. Smith, Priya Baichoo, Chi Wing Cheng, Joy Guedia, Sohyeong Kang, Abhishek Mukhopadhyay, Lisa Newhook, Anders Ohrn, Prajwal Raghunatha, Matteo Zago-Schmitt, Joseph D. Schrag, Joel Smith, Patricia Zwierzchowski, Joshua M. Scurll, Vincent Fung, Sonia Black, Natalie C. J. Strynadka, Michael R. Gold, Leonard G. Presta, Gordon Ng, and Surjit Dixit

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.

Published
2023

48. Engineering the lymph node environment promotes antigen-specific efficacy in type 1 diabetes and islet transplantation

Author

Joshua M. Gammon, Sean T. Carey, Vikas Saxena, Haleigh B. Eppler, Shannon J. Tsai, Christina Paluskievicz, Yanbao Xiong, Lushen Li, Marian Ackun-Farmmer, Lisa H. Tostanoski, Emily A. Gosselin, Alexis A. Yanes, Xiangbin Zeng, Robert S. Oakes, Jonathan S. Bromberg, and Christopher M. Jewell

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune signal targeting and integration, limiting efficacy and causing systemic non-specific suppression. Here we use intra-lymph node injection of diffusion-limited degradable microparticles that encapsulate self-antigens with the immunomodulatory small molecule, rapamycin. We show this strategy potently inhibits disease during pre-clinical type 1 diabetes and allogenic islet transplantation. Antigen and rapamycin are required for maximal efficacy, and tolerance is accompanied by expansion of antigen-specific regulatory T cells in treated and untreated lymph nodes. The antigen-specific tolerance in type 1 diabetes is systemic but avoids non-specific immune suppression. Further, microparticle treatment results in the development of tolerogenic structural microdomains in lymph nodes. Finally, these local structural and functional changes in lymph nodes promote memory markers among antigen-specific regulatory T cells, and tolerance that is durable. This work supports intra-lymph node injection of tolerogenic microparticles as a powerful platform to promote antigen-dependent efficacy in type 1 diabetes and allogenic islet transplantation.

Published
2023

49. Enhancing CAR-T cell functionality in a patient-specific manner

Author

David K. Y. Zhang, Kwasi Adu-Berchie, Siddharth Iyer, Yutong Liu, Nicoletta Cieri, Joshua M. Brockman, Donna Neuberg, Catherine J. Wu, and David J. Mooney

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

Patient responses to autologous CD19 chimeric antigen receptor (CAR) T-cell therapies are limited by insufficient and inconsistent cellular functionality. Here, we show that controlling the precise level of stimulation during T-cell activation to accommodate individual differences in the donor cells will dictate the functional attributes of CAR-T cell products. The functionality of CAR-T cell products, consisting of a diverse set of blood samples derived from healthy donors, acute lymphoblastic leukemia (ALL), and chronic lymphocytic lymphoma (CLL) patient samples, representing a range of patient health status, is tested upon culturing on artificial antigen-presenting cell scaffolds to deliver T-cell stimulatory ligands (anti-CD3/anti-CD28) at highly defined densities. A clear relationship is observed between the dose of stimulation, the phenotype of the T-cell blood sample prior to T-cell activation, and the functionality of the resulting CAR-T cell products. We present a model, based on this dataset, that predicts the precise stimulation needed to manufacture a desired CAR-T cell product, given the input T-cell attributes in the initial blood sample. These findings demonstrate a simple approach to enhance CAR-T functionality by personalizing the level of stimulation during T-cell activation to enable flexible manufacturing of more consistent and potent CAR-T cells.

Published
2023

50. Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface

Author

Joshua M. Weiss, Miranda V. Hunter, Reuben Moncada, Itai Yanai, and Richard M. White

Subjects
Cancer microenvironment, Cell type, Science, General Physics and Astronomy, Article, General Biochemistry, Genetics and Molecular Biology, Neoplasms, Tumor Microenvironment, medicine, Animals, Humans, RNA-Seq, Cancer models, Melanoma, Zebrafish, Transcription factor, Tumor microenvironment, Multidisciplinary, biology, Gene Expression Profiling, Cilium, RNA sequencing, General Chemistry, biology.organism_classification, medicine.disease, Computational biology and bioinformatics, Cell biology, Gene Expression Regulation, Neoplastic, Disease Models, Animal, Tumor progression, Cancer cell, Transcriptome
Abstract

During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct “interface” cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments., During tumor progression, cancer cells contact different neighboring cell types, but it is unclear how these interactions affect cancer cell behavior. Here, the authors use spatially resolved transcriptomics and single-cell RNA-seq to study the role of cilia at the tumormicroenvironment interface.

Published
2021

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