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1. Boosting corrects a memory B cell defect in SARS-CoV-2 mRNA–vaccinated patients with inflammatory bowel disease

Author

Kathryn A. Pape, Thamotharampillai Dileepan, William E. Matchett, Charles Ellwood, Samuel Stresemann, Amanda J. Kabage, Daria Kozysa, Clayton Evert, Michael Matson, Sharon Lopez, Peter D. Krueger, Carolyn T. Graiziger, Byron P. Vaughn, Eugenia Shmidt, Joshua Rhein, Timothy W. Schacker, Tyler D. Bold, Ryan A. Langlois, Alexander Khoruts, and Marc K. Jenkins

Subjects
COVID-19, Immunology, Medicine
Abstract

Immunosuppressed patients with inflammatory bowel disease (IBD) generate lower amounts of SARS-CoV-2 spike antibodies after mRNA vaccination than healthy controls. We assessed SARS-CoV-2 spike S1 receptor binding domain–specific (S1-RBD–specific) B lymphocytes to identify the underlying cellular defects. Patients with IBD produced fewer anti–S1-RBD antibody–secreting B cells than controls after the first mRNA vaccination and lower amounts of total and neutralizing antibodies after the second. S1-RBD–specific memory B cells were generated to the same degree in IBD and control groups and were numerically stable for 5 months. However, the memory B cells in patients with IBD had a lower S1-RBD–binding capacity than those in controls, which is indicative of a defect in antibody affinity maturation. Administration of a third shot to patients with IBD elevated serum antibodies and generated memory B cells with a normal antigen-binding capacity. These results show that patients with IBD have defects in the formation of antibody-secreting B cells and affinity-matured memory B cells that are corrected by a third vaccination.

Published
2022
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3. '… or equivalent combination of experience and education'

Author

Charles Ellwood Jones

Subjects
Career development, Archeology, Education, Higher, Archaeology, Professional development, Pedagogy, Conservation, Sociology
Abstract

Published in the Journal of Eastern Mediterranean Archaeology and Heritage Studies, Vol. 3, No. 3, 2015. This contribution was part of FORUM Investing in the Future of the Past: Alternative Careers for Mediterranean Archaeologists.

Published
2015
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4. Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1

Author

Guillaume Médard, Stephen P. Schmidt, Raman Narukulla, Emanuela Gancia, Jason Halladay, Sarah Major, Sharon Yee, Brenda Burton, Ping Wu, Lorraine Axford, Simon Charles Goodacre, Michael Flagella, Eileen Mary Seward, Joy Drobnick, Joanne Hewitt, Charles Ellwood, Lewis J. Gazzard, Judi Ramiscal, Samuel Kintz, Matthew Gill, Calum Macleod, Hazel Hunt, Kerry Chapman, Shiva Malek, Peter H. Crackett, Huifen Chen, Christian Wiesmann, Ivana Yen, Jennifer Epler, Karen Williams, Elizabeth Blackwood, and Joseph P. Lyssikatos

Subjects
Models, Molecular, Aché, DNA damage, Carbazoles, Mice, Nude, Pharmacology, Crystallography, X-Ray, Mice, Dogs, In vivo, Cell Line, Tumor, Neoplasms, Drug Discovery, medicine, Potency, Animals, Humans, CHEK1, Protein Kinase Inhibitors, Aza Compounds, Chemistry, Gemcitabine, In vitro, language.human_language, Rats, Biochemistry, Cell culture, Checkpoint Kinase 1, language, Acetylcholinesterase, Molecular Medicine, Cholinesterase Inhibitors, Protein Kinases, medicine.drug
Abstract

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

Published
2015

5. Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2

Author

Kathy Barrett, Paul Gibbons, Steven Shia, Jane R. Kenny, Mark Zak, Charles Ellwood, Sharada Labadie, Richard James Bull, Chris Hamman, Peter H. Crackett, Peter Gribling, Peter S. Dragovich, Scott Savage, Jiangpeng Liao, Jason DeVoss, Christine Chang, Paroma Chakravarty, Mercedesz Balazs, Wyne P. Lee, Tony Johnson, Rebecca Pulk, Michael F. T. Koehler, Gauri Deshmukh, Marya Liimatta, Janusz J. Kulagowski, Pawan Bir Kohli, Anne van Abbema, Austin John Reeve, Rohan Mendonca, Adam R. Johnson, Ignacio Aliagas, Simon Gaines, Charles Eigenbrot, Yisong Xiao, Nico Ghilardi, Jing Yang, Christopher A. Hurley, Philippe Bergeron, Wade S. Blair, Peter Hewitt, Stuart Ward, Eric Harstad, Micah Steffek, Barbara Avitabile-Woo, Stefan Gradl, Raman Narukulla, and Savita Ubhayakar

Subjects
Models, Molecular, Cell Membrane Permeability, Membrane permeability, Stereochemistry, Pyridines, Administration, Oral, Biological Availability, Stereoisomerism, Crystallography, X-Ray, Protein–protein interaction, Madin Darby Canine Kidney Cells, Dogs, Drug Discovery, Moiety, Animals, Humans, Pyrroles, Whole blood, Molecular Structure, Chemistry, Imidazoles, Haplorhini, Janus Kinase 1, Janus Kinase 2, Ligand (biochemistry), Arthritis, Experimental, Bioavailability, Rats, Isoenzymes, Antirheumatic Agents, Microsomes, Liver, Molecular Medicine, Collagen, Selectivity, Heterocyclic Compounds, 3-Ring
Abstract

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

Published
2013

8. LETTERS.

Author

Jones, Charles Ellwood, Eakin, Hugh, Harman, Mark, Vallier, Jean, White, Edmund, McGegan, Nicholas, Bowersock, G. W., and Jamison, Kay Redfield

Subjects
*LETTERS to the editor, *DISASTERS, *CULTURAL property, *IDENTITY (Psychology)
Abstract

Several letters to the editor are presented in response to articles in previous issues including "The Devastation of Iraq's Past," by Hugh Eakin in the August 14, 2008 issue, a review of Louis Begley's biographical essay on Kafka in the July 17, 2008 issue, and a review of Judith Herin's book on Byzantium in the September 25, 2008 issue.

Published
2008

9. ETANA: Electronic Tools and Ancient Near Eastern Archives.

Author

Jones, Charles Ellwood

Subjects
INFORMATION technology, INFORMATION resources, WEBSITES, JOINT ventures, SCALABILITY, HIGH technology
Abstract

The article informs that Electronic Tools and Ancient Near Eastern Archives (ETANA) is a cooperative venture of a consortium of scholarly societies and universities to develop and maintain a comprehensive Internet site for the study of the ancient Near East. Academic, library and technical staff of the partner organizations will collaborate to share intellectual and technical resources in the development of the project. Funded in the first instance by generous grants from the Andrew W. Mellon Foundation, ETANA has subsequently received substantial additional funding from the Information Technology Research division of the National Science Foundation and from the American Theological Library Association's Cooperative Digital Resources Initiative.

Published
2004

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