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145 results on '"Nair, Jayakumar R."'

1. The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

Author

Giudice, Elena, Huang, Tzu-Ting, Nair, Jayakumar R., Zurcher, Grant, McCoy, Ann, Nousome, Darryl, Radke, Marc R., Swisher, Elizabeth M., Lipkowitz, Stanley, Ibanez, Kristen, Donohue, Duncan, Malys, Tyler, Lee, Min-Jung, Redd, Bernadette, Levy, Elliot, Rastogi, Shraddha, Sato, Nahoko, Trepel, Jane B., and Lee, Jung-Min

Published
2024
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10. BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancer

Author

Gupta, Nitasha, primary, Huang, Tzu-Ting, additional, Nair, Jayakumar R., additional, An, Daniel, additional, Zurcher, Grant, additional, Lampert, Erika J., additional, McCoy, Ann, additional, Cimino-Mathews, Ashley, additional, Swisher, Elizabeth M., additional, Radke, Marc R., additional, Lockwood, Christina M., additional, Reichel, Jonathan B., additional, Chiang, Chih-Yuan, additional, Wilson, Kelli M., additional, Cheng, Ken Chih-Chien, additional, Nousome, Darryl, additional, and Lee, Jung-Min, additional

Published
2023
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12. Supplementary Data from Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study

Author

Lampert, Erika J., primary, Zimmer, Alexandra, primary, Padget, Michelle, primary, Cimino-Mathews, Ashley, primary, Nair, Jayakumar R., primary, Liu, Yingmiao, primary, Swisher, Elizabeth M., primary, Hodge, James W., primary, Nixon, Andrew B., primary, Nichols, Erin, primary, Bagheri, Mohammad H., primary, Levy, Elliott, primary, Radke, Marc R., primary, Lipkowitz, Stanley, primary, Annunziata, Christina M., primary, Taube, Janis M., primary, Steinberg, Seth M., primary, and Lee, Jung-Min, primary

Published
2023
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15. BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA-mutant ovarian cancer

Author

Gupta, Nitasha, primary, Huang, Tzu-Ting, additional, Nair, Jayakumar R., additional, An, Daniel, additional, Zurcher, Grant, additional, Lampert, Erika J., additional, McCoy, Ann, additional, Cimino-Mathews, Ashley, additional, Swisher, Elizabeth M., additional, Radke, Marc R., additional, Lockwood, Christina M, additional, Reichel, Jonathan B., additional, Chiang, Chih-Yuan, additional, Wilson, Kelli M., additional, Cheng, Ken Chih-Chien, additional, Nousome, Darryl, additional, and Lee, Jung-Min, additional

Published
2022
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21. Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study

Author

Lampert, Erika J., primary, Zimmer, Alexandra, additional, Padget, Michelle, additional, Cimino-Mathews, Ashley, additional, Nair, Jayakumar R., additional, Liu, Yingmiao, additional, Swisher, Elizabeth M., additional, Hodge, James W., additional, Nixon, Andrew B., additional, Nichols, Erin, additional, Bagheri, Mohammad H., additional, Levy, Elliott, additional, Radke, Marc R., additional, Lipkowitz, Stanley, additional, Annunziata, Christina M., additional, Taube, Janis M., additional, Steinberg, Seth M., additional, and Lee, Jung-Min, additional

Published
2020
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23. Comparative genomic analysis reveals a novel mitochondrial isoform of human rTS protein and unusual phylogenetic distribution of the rTS gene

Author

McGuire John J, Song Lei, Nair Jayakumar R, Liang Ping, and Dolnick Bruce J

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The rTS gene (ENOSF1), first identified in Homo sapiens as a gene complementary to the thymidylate synthase (TYMS) mRNA, is known to encode two protein isoforms, rTSα and rTSβ. The rTSβ isoform appears to be an enzyme responsible for the synthesis of signaling molecules involved in the down-regulation of thymidylate synthase, but the exact cellular functions of rTS genes are largely unknown. Results Through comparative genomic sequence analysis, we predicted the existence of a novel protein isoform, rTS, which has a 27 residue longer N-terminus by virtue of utilizing an alternative start codon located upstream of the start codon in rTSβ. We observed that a similar extended N-terminus could be predicted in all rTS genes for which genomic sequences are available and the extended regions are conserved from bacteria to human. Therefore, we reasoned that the protein with the extended N-terminus might represent an ancestral form of the rTS protein. Sequence analysis strongly predicts a mitochondrial signal sequence in the extended N-terminal of human rTSγ, which is absent in rTSβ. We confirmed the existence of rTS in human mitochondria experimentally by demonstrating the presence of both rTSγ and rTSβ proteins in mitochondria isolated by subcellular fractionation. In addition, our comprehensive analysis of rTS orthologous sequences reveals an unusual phylogenetic distribution of this gene, which suggests the occurrence of one or more horizontal gene transfer events. Conclusion The presence of two rTS isoforms in mitochondria suggests that the rTS signaling pathway may be active within mitochondria. Our report also presents an example of identifying novel protein isoforms and for improving gene annotation through comparative genomic analysis.

Published
2005
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25. Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8+ T cells compared with women with BRCA wild-type disease during the early disease course.

Author

Lee, Jung-Min, Botesteanu, Dana-Adriana, Tomita, Yusuke, Yuno, Akira, Lee, Min-Jung, Kohn, Elise C., Annunziata, Christina M., Matulonis, Ursula, MacDonald, Lauren A., Nair, Jayakumar R., Macneill, Kimberley M., and Trepel, Jane B.

Subjects
T cells, SUPPRESSOR cells, DISEASE progression, BLOOD cells, APOPTOSIS
Abstract

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8+ T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed cell death protein 1 (PD-1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45+ PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post-diagnosis. CD8+ T cells among viable CD45+ PBMCs and CTLA-4+/CD8+ T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post-diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM-3 expression on Tregs was associated with poor progression-free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8+ T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post-diagnosis decade. [ABSTRACT FROM AUTHOR]

Published
2019
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28. CD28 Expressed on Malignant Plasma Cells Induces A Pro-Survival and Immunosuppressive Microenvironment1

Author

Nair, Jayakumar R., Carlson, Louise M., Koorella, Chandana, Rozanski, Cheryl H., Byrne, Gerald E., Bergsagel, P. Leif, Shaughnessy, John P., Boise, Lawrence H., Chanan-Khan, Asher, and Lee, Kelvin P.

Subjects
Cell Survival, Plasma Cells, Article, Coculture Techniques, CD28 Antigens, Antigens, Neoplasm, Disease Progression, Immune Tolerance, Tumor Cells, Cultured, Tumor Microenvironment, Humans, Myeloid Cells, Stromal Cells, Multiple Myeloma
Abstract

Interactions between the malignant plasma cells of multiple myeloma (MM) and stromal cells within the bone marrow (BM) microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal BM-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce pro-survival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor prognosis subgroups, and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell (DC) directly transduces a pro-survival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal DC to produce the pro-survival cytokine IL-6 (involving novel crosstalk with the Notch pathway) and the immunosuppressive enzyme indoleamine 2, 3 dioxygenase (IDO). These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, and point to similar interaction for normal plasma cells as well as suggesting novel therapeutic strategies to target malignant and pathogenic (e.g. in allergy and autoimmunity) plasma cells.

Published
2011

29. CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif

Author

Rozanski, Cheryl H., primary, Utley, Adam, additional, Carlson, Louise M., additional, Farren, Matthew R., additional, Murray, Megan, additional, Russell, Lisa M., additional, Nair, Jayakumar R., additional, Yang, ZhengYu, additional, Brady, William, additional, Garrett-Sinha, Lee Ann, additional, Schoenberger, Stephen P., additional, Green, Jonathan M., additional, Boise, Lawrence H., additional, and Lee, Kelvin P., additional

Published
2015
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33. BLMoverexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA-mutant ovarian cancer

Author

Gupta, Nitasha, Huang, Tzu-Ting, Nair, Jayakumar R., An, Daniel, Zurcher, Grant, Lampert, Erika J., McCoy, Ann, Cimino-Mathews, Ashley, Swisher, Elizabeth M., Radke, Marc R., Lockwood, Christina M., Reichel, Jonathan B., Chiang, Chih-Yuan, Wilson, Kelli M., Cheng, Ken Chih-Chien, Nousome, Darryl, and Lee, Jung-Min

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)–mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (BLM) and cyclin E1 (CCNE1) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCAreversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork–related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.

Published
2023
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40. Under one roof

Author

Nair, Jayakumar R., primary, Rozanski, Cheryl H., additional, and Lee, Kelvin P., additional

Published
2012
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42. Sustained Antibody Responses Depend on CD28 Function in Bone Marrow Resident Plasma Cells

Author

Rozanski, Cheryl H, primary, Dodson, Lindzy F, additional, Arens, Ramon, additional, Carlson, Louise M, additional, Russell, Lisa M, additional, Nair, Jayakumar R, additional, Chanan-Khan, Asher, additional, Garrett-Sinha, Lee Ann, additional, Green, Jonathan M, additional, Schoenberger, Stephen P, additional, Boise, Lawrence H., additional, and Lee, Kelvin P, additional

Published
2011
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50. Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8 + T cells compared with women with BRCA wild-type disease during the early disease course.

Author

Lee JM, Botesteanu DA, Tomita Y, Yuno A, Lee MJ, Kohn EC, Annunziata CM, Matulonis U, MacDonald LA, Nair JR, Macneill KM, and Trepel JB

Abstract

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8 + T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed cell death protein 1 (PD-1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45 + PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post-diagnosis. CD8 + T cells among viable CD45 + PBMCs and CTLA-4 + /CD8 + T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post-diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM-3 expression on Tregs was associated with poor progression-free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8 + T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post-diagnosis decade.

Published
2019
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