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3. Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

Author

Song, Yun-Jeong, Choi, In Ah., Meylan, Françoise, Demoruelle, M. Kristen, Farley, Taylor, Richard, Arianne C., Hawley, Eric, Botson, John, Hong, Yoo Jin, Lee, Eun Young, Mian, Sabina R., Hamilton, Bartlett C., Thiele, Geoffrey M., Mikuls, Ted R., Gara, Naveen, Ward, Chris D., Lamberth, Sarah, Deane, Kevin D., Heller, Theo, Ward, Michael M., Lee, David M., Migone, Thi-Sau, Stohl, William, O’Dell, James R., Norris, Jill M., Holers, V. Michael, Gregersen, Peter, Song, Yeong-Wook, and Siegel, Richard M.

Published
2020
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5. Cybersecurity and disaster recovery issues for law firms.

Author

Hawley, Eric A.

Subjects
Data security -- Methods, Disaster recovery (Computers) -- Methods, Employee training -- Management, Data encryption -- Management, Encryption, Company business management, Disaster recovery, Data security issue
Abstract

Practicing law in the 21st Century means that you have more sensitive data in your possession or access to such data than any other lawyer has had in history. The [...]

Published
2016

7. PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2)

Author

Hawley, Eric, primary, Gehlhausen, Jeffrey, additional, Karchugina, Sofiia, additional, Chow, Hoi-Yee, additional, Araiza-Olivera, Daniela, additional, Radu, Maria, additional, Smith, Abbi, additional, Burks, Ciersten, additional, Jiang, Li, additional, Li, Xiaohong, additional, Bessler, Waylan, additional, Masters, Andrea, additional, Edwards, Donna, additional, Burgin, Callie, additional, Jones, David, additional, Yates, Charles, additional, Clapp, D Wade, additional, Chernoff, Jonathan, additional, and Park, Su-Jung, additional

Published
2021
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9. Correction: Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 17

Author

Mund, Julie A., primary, Park, SuJung, additional, Smith, Abbi E., additional, He, Yongzheng, additional, Jiang, Li, additional, Hawley, Eric, additional, Roberson, Michelle J., additional, Mitchell, Dana K., additional, Abu-Sultanah, Mohannad, additional, Yuan, Jin, additional, Bessler, Waylan K., additional, Sandusky, George, additional, Chen, Shi, additional, Zhang, Chi, additional, Rhodes, Steven D., additional, and Clapp, D.Wade, additional

Published
2020
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11. Additional file 1 of Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

Author

Yun-Jeong Song, Choi, In Ah., Meylan, Françoise, M. Kristen Demoruelle, Farley, Taylor, Richard, Arianne C., Hawley, Eric, Botson, John, Hong, Yoo Jin, Lee, Eun Young, Mian, Sabina R., Bartlett C. Hamilton, Thiele, Geoffrey M., Mikuls, Ted R., Gara, Naveen, Ward, Chris D., Lamberth, Sarah, Deane, Kevin D., Heller, Theo, Ward, Michael M., Lee, David M., Thi-Sau Migone, Stohl, William, O’Dell, James R., Norris, Jill M., V. Michael Holers, Gregersen, Peter, Yeong-Wook Song, and Siegel, Richard M.

Subjects
musculoskeletal diseases
Abstract

Additional file 1: Figure S1. Analysis of effect of methotrexate on TL1A levels from a second independent patient cohort. TL1A was measured in serum from an independent cohort of patients with RA treated with MTX for 4 months (66 good/moderate EULAR responders, 18 non-responders).

Published
2020
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12. Additional file 2 of Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

Author

Yun-Jeong Song, Choi, In Ah., Meylan, Françoise, M. Kristen Demoruelle, Farley, Taylor, Richard, Arianne C., Hawley, Eric, Botson, John, Hong, Yoo Jin, Lee, Eun Young, Mian, Sabina R., Bartlett C. Hamilton, Thiele, Geoffrey M., Mikuls, Ted R., Gara, Naveen, Ward, Chris D., Lamberth, Sarah, Deane, Kevin D., Heller, Theo, Ward, Michael M., Lee, David M., Thi-Sau Migone, Stohl, William, O’Dell, James R., Norris, Jill M., V. Michael Holers, Gregersen, Peter, Yeong-Wook Song, and Siegel, Richard M.

Subjects
musculoskeletal diseases
Abstract

Additional file 2: Figure S2. Micro-CT Scoring system for erosions and joint damage (MCTS). A scoring system was devised for micro-CT measurements of hind paw joint scores incorporating a score for the ankle/tarsus, MTP, and distal joints with a total score of 0–30 points.

Published
2020
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13. Additional file 3 of Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

Author

Yun-Jeong Song, Choi, In Ah., Meylan, Françoise, M. Kristen Demoruelle, Farley, Taylor, Richard, Arianne C., Hawley, Eric, Botson, John, Hong, Yoo Jin, Lee, Eun Young, Mian, Sabina R., Bartlett C. Hamilton, Thiele, Geoffrey M., Mikuls, Ted R., Gara, Naveen, Ward, Chris D., Lamberth, Sarah, Deane, Kevin D., Heller, Theo, Ward, Michael M., Lee, David M., Thi-Sau Migone, Stohl, William, O’Dell, James R., Norris, Jill M., V. Michael Holers, Gregersen, Peter, Yeong-Wook Song, and Siegel, Richard M.

Abstract

Additional file 3: Table S1. Demographic characteristics of SNUH cohort (data shown in Fig. 2 D-F and Fig. 3 B-D). Sr, serum; SF, synovial fluid; ESR, erythrocyte sedimentation rate; hsCRP, high sensitive C-reactive protein; RF, rheumatoid factor. Table S2. Demographic characteristics of patient subgroups from the SERA cohort.

Published
2020
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14. Ketotifen Modulates Mast Cell Chemotaxis to Kit-Ligand, but Does Not Impact Mast Cell Numbers, Degranulation, or Tumor Behavior in Neurofibromas of Nf1-Deficient Mice

Author

Burks, Ciersten A., primary, Rhodes, Steven D., additional, Bessler, Waylan K., additional, Chen, Shi, additional, Smith, Abbi, additional, Gehlhausen, Jeffrey R., additional, Hawley, Eric T., additional, Jiang, Li, additional, Li, Xiaohong, additional, Yuan, Jin, additional, Lu, Qingbo, additional, Jacobsen, Max, additional, Sandusky, George E., additional, Jones, David R., additional, Clapp, D. Wade, additional, and Blakeley, Jaishri O., additional

Published
2019
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15. Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

Author

Chang, Long-Sheng, Oblinger, Janet L., Smith, Abbi E., Ferrer, Marc, Angus, Steven P., Hawley, Eric, Petrilli, Alejandra M., Beauchamp, Roberta L., Riecken, Lars Björn, Erdin, Serkan, Poi, Ming, Huang, Jie, Bessler, Waylan K., Zhang, Xiaohu, Guha, Rajarshi, Thomas, Craig, Burns, Sarah S., Gilbert, Thomas S. K., Jiang, Li, and Li, Xiaohong

Subjects
PROTEIN-tyrosine kinases, FOCAL adhesion kinase, HIGH throughput screening (Drug development), KINASES, NEUROFIBROMATOSIS 2, TYROSINE, TUMOR suppressor genes
Abstract

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies. [ABSTRACT FROM AUTHOR]

Published
2021
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17. A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Author

Gehlhausen, Jeffrey R, primary, Hawley, Eric, additional, Wahle, Benjamin Mark, additional, He, Yongzheng, additional, Edwards, Donna, additional, Rhodes, Steven D, additional, Lajiness, Jacquelyn D, additional, Staser, Karl, additional, Chen, Shi, additional, Yang, Xianlin, additional, Yuan, Jin, additional, Li, Xiaohong, additional, Jiang, Li, additional, Smith, Abbi, additional, Bessler, Waylan, additional, Sandusky, George, additional, Stemmer-Rachamimov, Anat, additional, Stuhlmiller, Timothy J, additional, Angus, Steven P, additional, Johnson, Gary L, additional, Nalepa, Grzegorz, additional, Yates, Charles W, additional, Wade Clapp, D, additional, and Park, Su-Jung, additional

Published
2018
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19. Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

Author

Wahle, Benjamin M., primary, Hawley, Eric T., additional, He, Yongzheng, additional, Smith, Abbi E., additional, Yuan, Jin, additional, Masters, Andi R., additional, Jones, David R., additional, Gehlhausen, Jeffrey R., additional, Park, Su-Jung, additional, Conway, Simon J., additional, Clapp, D. Wade, additional, and Yates, Charles W., additional

Published
2017
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20. The TNF-family ligand TL1A and its receptor DR3 promote T-cell mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9 producing T cells1

Author

Richard, Arianne C., Tan, Cuiyan, Hawley, Eric T., Gomez-Rodriguez, Julio, Goswami, Ritobrata, Yang, Xiang-ping, Cruz, Anthony C., Penumetcha, Pallavi, Hayes, Erika T., Pelletier, Martin, Gabay, Odile, Walsh, Matthew, Ferdinand, John R., Keane-Myers, Andrea, Choi, Yongwon, O'Shea, John J., Al-Shamkhani, Aymen, Kaplan, Mark H., Gery, Igal, Siegel, Richard M., and Meylan, Françoise

Subjects
Article
Abstract

The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation, and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3 deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. Here we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.

Published
2015

22. Proposed interoperability readiness level assessment for mission critical interfaces during Navy acquisition

Author

Cavolowsky, Mark, Foley, Kyle, Garcia, Jesus, Gorospe, John, Guerao, Alex, Hawley, Eric, Holt, Janet, Phan, Tien, Pimsarn, Chirana, Possehl, Steven, Rogers, Peggy, Tegtmeyer, Steve, Thrift, Michael, Trinh, Phong, and Systems Engineering (SE)

Subjects
Mission Critical, Development Testing, Defense Acquisition Systems Engineering Process, Operational Test and Evaluation
Abstract

The current Department of the Navy (DoN) system development and acquisition system has documented instances of programs failing to detect critical interoperability failures prior to operational level testing. The authors investigated methods of improving capturing, monitoring, implementing and testing the requirements critical to ensuring mission success. Improvements to the DoN systems engineering processes were developed to ensure that these requirements are identified and promulgated through key program documents and design reviews. There was a down selection of alternatives that examined several candidate options for solutions. This down selection incorporated an evaluation of cost and benefits for each alternative. This included an assessment of how the requirements and testing of the system would have changed if this modified review process had been performed. The current process is improved upon by introducing I/ORLs. These enhanced processes were simulated on a representative DoN system in a tabletop exercise to provide an example of how this modified process could be performed. The additional information provided to programs in the form of I/ORL requirements and clarifying definitions will help to improve interoperability in system development and reduce Operational Test failures. http://archive.org/details/proposedinterope109456954 Approved for public release; distribution is unlimited.

Published
2010

23. Correction: The TNF-Family Ligand TL1A and Its Receptor DR3 Promote T Cell–Mediated Allergic Immunopathology by Enhancing Differentiation and Pathogenicity of IL-9–Producing T Cells

Author

Richard, Arianne C., primary, Tan, Cuiyan, additional, Hawley, Eric T., additional, Gomez-Rodriguez, Julio, additional, Goswami, Ritobrata, additional, Yang, Xiang-Ping, additional, Cruz, Anthony C., additional, Penumetcha, Pallavi, additional, Hayes, Erika T., additional, Pelletier, Martin, additional, Gabay, Odile, additional, Walsh, Matthew, additional, Ferdinand, John R., additional, Keane-Myers, Andrea, additional, Choi, Yongwon, additional, O’Shea, John J., additional, Al-Shamkhani, Aymen, additional, Kaplan, Mark H., additional, Gery, Igal, additional, Siegel, Richard M., additional, and Meylan, FranÇoise, additional

Published
2015
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24. The TNF-family ligand TL1A and its receptor DR3 promote T cell mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9 producing T cells (HYP2P.333)

Author

Meylan, Francoise, primary, Richard, Arianne, additional, Tan, Cuiyan, additional, Hawley, Eric, additional, Gomez-Rodriguez, Julio, additional, Goswami, Ritobrata, additional, Yang, Xiangping, additional, Cruz, Anthony, additional, Penumetcha, Pallavi, additional, Hayes, Erika, additional, Pelletier, Martin, additional, Gabay, Odile, additional, Walsh, Matthew, additional, Ferdinand, John, additional, Keane-Myers, Andrea, additional, Choi, Yongwon, additional, O'Shea, John, additional, Al-Shamkhani, Aymen, additional, Kaplan, Mark, additional, Gery, Igal, additional, and Siegel, Richard, additional

Published
2015
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25. The TNF-Family Ligand TL1A and Its Receptor DR3 Promote T Cell–Mediated Allergic Immunopathology by Enhancing Differentiation and Pathogenicity of IL-9–Producing T Cells

Author

Richard, Arianne C., primary, Tan, Cuiyan, additional, Hawley, Eric T., additional, Gomez-Rodriguez, Julio, additional, Goswami, Ritobrata, additional, Yang, Xiang-Ping, additional, Cruz, Anthony C., additional, Penumetcha, Pallavi, additional, Hayes, Erika T., additional, Pelletier, Martin, additional, Gabay, Odile, additional, Walsh, Matthew, additional, Ferdinand, John R., additional, Keane-Myers, Andrea, additional, Choi, Yongwon, additional, O’Shea, John J., additional, Al-Shamkhani, Aymen, additional, Kaplan, Mark H., additional, Gery, Igal, additional, Siegel, Richard M., additional, and Meylan, Françoise, additional

Published
2015
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26. Understanding Unfolding Change and the Value of Strategic Unification in Recent USU Information Technology Functional Realignment

Author

Hawley, Eric S.

Subjects
Technology, Information, Managment, Change, Reorganization, Organization, Information Science, Other Computer Sciences
Abstract

This is a qualitative case study of the 2005-2008 Utah State University Information Technology reorganization from the perspective of key change advocates. The study identified and documented the unfolding change process involved in the reorganization in terms of dissatisfaction, executive changes, internal executive strategic planning, implementation and initial impacts, and continuous "in situ" strategic planning. The study also answered a set of supporting concluding questions indicating increased value to the institution in areas of customer service and confidence, organization, financial resources, planning and policy, security, and increased/improved services and service functions.

Published
2008
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27. The TNF family member TL1A promotes Th9 differentiation and Th9-mediated immunopathology (LYM3P.733)

Author

Richard, Arianne, primary, Tan, Cuiyan, additional, Hawley, Eric, additional, Gomez-Rodriguez, Julio, additional, Goswami, Ritobrata, additional, Yang, Xiangping, additional, Cruz, Anthony, additional, Penumetcha, Pallavi, additional, Hayes, Erika, additional, Pelletier, Martin, additional, Gabay, Odile, additional, Walsh, Matthew, additional, Ferdinand, John, additional, Keane-Myers, Andrea, additional, Choi, Yongwon, additional, O'Shea, John, additional, Al-Shamkhani, Aymen, additional, Kaplan, Mark, additional, Gery, Igal, additional, Siegel, Richard, additional, and Meylan, Francoise, additional

Published
2014
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28. Proposed interoperability readiness level assessment for mission critical interfaces during Navy acquisition

Author

Systems Engineering (SE), Cavolowsky, Mark, Foley, Kyle, Garcia, Jesus, Gorospe, John, Guerao, Alex, Hawley, Eric, Holt, Janet, Phan, Tien, Pimsarn, Chirana, Possehl, Steven, Rogers, Peggy, Tegtmeyer, Steve, Thrift, Michael, Trinh, Phong, Systems Engineering (SE), Cavolowsky, Mark, Foley, Kyle, Garcia, Jesus, Gorospe, John, Guerao, Alex, Hawley, Eric, Holt, Janet, Phan, Tien, Pimsarn, Chirana, Possehl, Steven, Rogers, Peggy, Tegtmeyer, Steve, Thrift, Michael, and Trinh, Phong

Abstract

The current Department of the Navy (DoN) system development and acquisition system has documented instances of programs failing to detect critical interoperability failures prior to operational level testing. The authors investigated methods of improving capturing, monitoring, implementing and testing the requirements critical to ensuring mission success. Improvements to the DoN systems engineering processes were developed to ensure that these requirements are identified and promulgated through key program documents and design reviews. There was a down selection of alternatives that examined several candidate options for solutions. This down selection incorporated an evaluation of cost and benefits for each alternative. This included an assessment of how the requirements and testing of the system would have changed if this modified review process had been performed. The current process is improved upon by introducing I/ORLs. These enhanced processes were simulated on a representative DoN system in a tabletop exercise to provide an example of how this modified process could be performed. The additional information provided to programs in the form of I/ORL requirements and clarifying definitions will help to improve interoperability in system development and reduce Operational Test failures., http://archive.org/details/proposedinterope109456954, Approved for public release; distribution is unlimited.

Published
2012

29. Proposed Interoperability Readiness Level Assessment for Mission Critical Interfaces During Navy Acquisition

Author

NAVAL POSTGRADUATE SCHOOL MONTEREY CA DEPT OF SYSTEMS ENGINEERING, Cavolowsky, Mark, Foley, Kyle, Garcia, Jesus, Gorospe, John, Guerao, Alex, Hawley, Eric, Holt, Janet, Phan, Tien, Pimsarn, Chirana, Possehl, Steven, NAVAL POSTGRADUATE SCHOOL MONTEREY CA DEPT OF SYSTEMS ENGINEERING, Cavolowsky, Mark, Foley, Kyle, Garcia, Jesus, Gorospe, John, Guerao, Alex, Hawley, Eric, Holt, Janet, Phan, Tien, Pimsarn, Chirana, and Possehl, Steven

Abstract

The current Department of the Navy (DoN) system development and acquisition system has documented instances of programs failing to detect critical interoperability failures prior to operational level testing. The authors investigated methods of improving capturing, monitoring, implementing and testing the requirements critical to ensuring mission success. Improvements to the DoN systems engineering processes were developed to ensure that these requirements are identified and promulgated through key program documents and design reviews. There was a down selection of alternatives that examined several candidate options for solutions. This down selection incorporated an evaluation of cost and benefits for each alternative. This included an assessment of how the requirements and testing of the system would have changed if this modified review process had been performed. The current process is improved upon by introducing I/ORLs. These enhanced processes were simulated on a representative DoN system in a tabletop exercise to provide an example of how this modified process could be performed. The additional information provided to programs in the form of I/ORL requirements and clarifying definitions will help to improve interoperability in system development and reduce Operational Test failures., The original document contains color images.

Published
2010

30. Proposed interoperability readiness level assessment for mission critical interfaces during Navy acquisition

Author

Systems Engineering (SE), Cavolowsky, Mark, Foley, Kyle, Garcia, Jesus, Gorospe, John, Guerao, Alex, Hawley, Eric, Holt, Janet, Phan, Tien, Pimsarn, Chirana, Possehl, Steven, Rogers, Peggy, Tegtmeyer, Steve, Thrift, Michael, Trinh, Phong, Systems Engineering (SE), Cavolowsky, Mark, Foley, Kyle, Garcia, Jesus, Gorospe, John, Guerao, Alex, Hawley, Eric, Holt, Janet, Phan, Tien, Pimsarn, Chirana, Possehl, Steven, Rogers, Peggy, Tegtmeyer, Steve, Thrift, Michael, and Trinh, Phong

Abstract

The current Department of the Navy (DoN) system development and acquisition system has documented instances of programs failing to detect critical interoperability failures prior to operational level testing. The authors investigated methods of improving capturing, monitoring, implementing and testing the requirements critical to ensuring mission success. Improvements to the DoN systems engineering processes were developed to ensure that these requirements are identified and promulgated through key program documents and design reviews. There was a down selection of alternatives that examined several candidate options for solutions. This down selection incorporated an evaluation of cost and benefits for each alternative. This included an assessment of how the requirements and testing of the system would have changed if this modified review process had been performed. The current process is improved upon by introducing I/ORLs. These enhanced processes were simulated on a representative DoN system in a tabletop exercise to provide an example of how this modified process could be performed. The additional information provided to programs in the form of I/ORL requirements and clarifying definitions will help to improve interoperability in system development and reduce Operational Test failures.

Published
2010

31. 180

Author

Meylan, Françoise, primary, Hawley, Eric, additional, Barron, Luke, additional, Barlow, Jillian, additional, Tan, Cuyian, additional, Penumetcha, Pallavi, additional, Richard, Arianne, additional, Chen, Xi, additional, Paul, William E., additional, Wynn, Thomas A., additional, Gery, Igal, additional, McKenzie, Andrew, additional, and Siegel, Richard M., additional

Published
2013
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37. Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease

Author

Richard, Arianne C, Peters, James E, Savinykh, Natalia, Lee, James C, Hawley, Eric T, Meylan, Françoise, Siegel, Richard M, Lyons, Paul A, and Smith, Kenneth GC

Subjects
Adult, Male, Tumor Necrosis Factor Ligand Superfamily Member 15, Macrophages, Primary Cell Culture, Quantitative Trait Loci, Middle Aged, Polymorphism, Single Nucleotide, digestive system diseases, Monocytes, 3. Good health, Young Adult, Crohn Disease, Haplotypes, Humans, Colitis, Ulcerative, Female, Genetic Predisposition to Disease, Alleles, Cells, Cultured
Abstract

Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a "recall-by-genotype" bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD.

38. Brain-Numbingly Strategic.

Author

HAWLEY, ERIC

Subjects
*CHIEF information officers, *UNIVERSITIES & colleges, *INFORMATION technology, *COMPUTER software industry, *HIGHER education
Abstract

The author describes his responsibilities as a chief information officer (CIO) at a research university. Topics discussed include suggestions for information technology (IT) leaders, some tips for working in IT departments in higher education, and the importance of building partnerships and good relationships.

Published
2014

39. Cloning and expression of a zebrafish 5-HT2C receptor gene

Author

Schneider, Henning, Fritzky, Luke, Williams, Jesse, Heumann, Christine, Yochum, Marissa, Pattar, Kala, Noppert, Grace, Mock, Vanessa, and Hawley, Eric

Subjects
*SEROTONIN receptors, *ZEBRA danio, *GENE expression, *POLYMERASE chain reaction, *ANTISENSE DNA, *MOLECULAR cloning
Abstract

Abstract: The 5-HT2C receptor is one of 14 different serotonin (5-HT) receptors that control neural function and behavior. Here, we present the entire sequence of a zebrafish 5-HT2C receptor cDNA including the 3′ untranslated region and the previously unknown 5′ untranslated region. The cloned 5-HT2C receptor gene is located on chromosome 7, is approximately 202kbp long, and contains six exons. The coding region of the gene is 1557bp long and flanked by a 504bp 5′ UTR and a 1474bp 3′ UTR. The deduced protein sequence of 518 amino acids aligns with orthologs of other vertebrates and is 54% identical to the human and mouse 5-HT2C receptor protein sequences. The region of the cDNA that encodes the 2nd cytoplasmic loop of the protein shows a 66% identity with vertebrate orthologs and clearly identifies the gene as a 5-HT2C receptor gene. Coupling sites for beta-arrestin and calmodulin are conserved in zebrafish. In-situ hybridization shows that the receptor is expressed in the brain and spinal cord including areas such as the olfactory bulb, the dorsal thalamus, the posterior tuberculum, the hypothalamus and the medulla oblongata. Reverse Transcriptase-PCR experiments indicate that the receptor gene can also be active in other tissues such as skin, ovaries, and axial muscle of adult zebrafish. Expression of the 5-HT2C receptor during ontogeny was found as early as 2.5hpf. Five edited adenines in the region of the human, rat and mouse mRNA that encodes the 2nd cytoplasmic loop are conserved in the zebrafish transcript. However, RNA editing was not detected in the zebrafish. The results characterize the zebrafish 5-HT2C receptor gene and gene expression pattern for the first time. The similarities to mammalian 5-HT2C receptor genes suggest the use of zebrafish for the study of 5-HT2C receptor function in behavior, development and drug discovery. [Copyright &y& Elsevier]

Published
2012
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40. A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas.

Author

Gehlhausen JR, Hawley E, Wahle BM, He Y, Edwards D, Rhodes SD, Lajiness JD, Staser K, Chen S, Yang X, Yuan J, Li X, Jiang L, Smith A, Bessler W, Sandusky G, Stemmer-Rachamimov A, Stuhlmiller TJ, Angus SP, Johnson GL, Nalepa G, Yates CW, Wade Clapp D, and Park SJ

Subjects
Animals, Autocrine Communication genetics, Carcinogenesis genetics, Caspase 1 genetics, Cell Proliferation genetics, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Hepatocyte Growth Factor genetics, Humans, Mice, Molecular Targeted Therapy, NF-kappa B genetics, Neurilemmoma complications, Neurilemmoma drug therapy, Neurilemmoma pathology, Neurofibromatosis 2 complications, Neurofibromatosis 2 drug therapy, Neurofibromatosis 2 pathology, Proteasome Endopeptidase Complex genetics, Proto-Oncogene Mas, Proto-Oncogene Proteins c-met genetics, Schwann Cells, Signal Transduction genetics, NF-kappaB-Inducing Kinase, Neurilemmoma genetics, Neurofibromatosis 2 genetics, Neurofibromin 2 genetics, Protein Serine-Threonine Kinases genetics
Abstract

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

Published
2019
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