42 results on '"Navenot, Jean-Marc"'
Search Results
2. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial
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D'Angelo, Sandra P, Araujo, Dejka M, Abdul Razak, Albiruni R, Agulnik, Mark, Attia, Steven, Blay, Jean-Yves, Carrasco Garcia, Irene, Charlson, John A, Choy, Edwin, Demetri, George D, Druta, Mihaela, Forcade, Edouard, Ganjoo, Kristen N, Glod, John, Keedy, Vicki L, Le Cesne, Axel, Liebner, David A, Moreno, Victor, Pollack, Seth M, Schuetze, Scott M, Schwartz, Gary K, Strauss, Sandra J, Tap, William D, Thistlethwaite, Fiona, Valverde Morales, Claudia Maria, Wagner, Michael J, Wilky, Breelyn A, McAlpine, Cheryl, Hudson, Laura, Navenot, Jean-Marc, Wang, Tianjiao, Bai, Jane, Rafail, Stavros, Wang, Ruoxi, Sun, Amy, Fernandes, Lilliam, Van Winkle, Erin, Elefant, Erica, Lunt, Colin, Norry, Elliot, Williams, Dennis, Biswas, Swethajit, and Van Tine, Brian A
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- 2024
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3. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial
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Hong, David S., Van Tine, Brian A., Biswas, Swethajit, McAlpine, Cheryl, Johnson, Melissa L., Olszanski, Anthony J., Clarke, Jeffrey M., Araujo, Dejka, Blumenschein, Jr, George R., Kebriaei, Partow, Lin, Quan, Tipping, Alex J., Sanderson, Joseph P., Wang, Ruoxi, Trivedi, Trupti, Annareddy, Thejo, Bai, Jane, Rafail, Stavros, Sun, Amy, Fernandes, Lilliam, Navenot, Jean-Marc, Bushman, Frederic D., Everett, John K., Karadeniz, Derin, Broad, Robyn, Isabelle, Martin, Naidoo, Revashnee, Bath, Natalie, Betts, Gareth, Wolchinsky, Zohar, Batrakou, Dzmitry G., Van Winkle, Erin, Elefant, Erica, Ghobadi, Armin, Cashen, Amanda, Grand’Maison, Anne, McCarthy, Philip, Fracasso, Paula M., Norry, Elliot, Williams, Dennis, Druta, Mihaela, Liebner, David A., Odunsi, Kunle, and Butler, Marcus O.
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- 2023
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4. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma
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Ramachandran, Indu, Lowther, Daniel E., Dryer-Minnerly, Rebecca, Wang, Ruoxi, Fayngerts, Svetlana, Nunez, Daniel, Betts, Gareth, Bath, Natalie, Tipping, Alex J., Melchiori, Luca, Navenot, Jean-Marc, Glod, John, Mackall, Crystal L., D’Angelo, Sandra P., Araujo, Dejka M., Chow, Warren A., Demetri, George D., Druta, Mihaela, Van Tine, Brian A., Grupp, Stephan A., Abdul Razak, Albiruni R., Wilky, Breelyn, Iyengar, Malini, Trivedi, Trupti, Winkle, Erin Van, Chagin, Karen, Amado, Rafael, Binder, Gwendolyn K., and Basu, Samik
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- 2019
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5. Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists
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Mandawat, Aditya, Fiskus, Warren, Buckley, Kathleen M., Robbins, Kelly, Rao, Rekha, Balusu, Ramesh, Navenot, Jean-Marc, Wang, Zi-Xuan, Ustun, Celalettin, Chong, Daniel G., Atadja, Peter, Fujii, Nobutaka, Peiper, Stephen C., and Bhalla, Kapil
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- 2010
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6. Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors.
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Hong, David S., Butler, Marcus O., Pachynski, Russell K., Sullivan, Ryan, Kebriaei, Partow, Boross-Harmer, Sarah, Ghobadi, Armin, Frigault, Matthew J., Dumbrava, Ecaterina E., Sauer, Amy, Brophy, Francine, Navenot, Jean-Marc, Fayngerts, Svetlana, Wolchinsky, Zohar, Broad, Robyn, Batrakou, Dzmitry G., Wang, Ruoxi, Solis, Luisa M., Duose, Dzifa Yawa, and Sanderson, Joseph P.
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MELANOMA ,HEAD & neck cancer ,ANTINEOPLASTIC agents ,T cells ,CYTOKINE release syndrome ,HLA histocompatibility antigens ,CLINICAL trials - Abstract
Background: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://clinicaltrials.gov : NCT02989064). Methods: Eligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1×10
9 and >1.2 to 6×109 transduced cells, respectively, and an expansion group receiving 1.2 to 15×109 transduced cells. Results: Ten patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade ≥3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group. Conclusions: ADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing. [ABSTRACT FROM AUTHOR]- Published
- 2022
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7. Structure–activity relationship study on small peptidic GPR54 agonists
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Tomita, Kenji, Niida, Ayumu, Oishi, Shinya, Ohno, Hiroaki, Cluzeau, Jérôme, Navenot, Jean-Marc, Wang, Zi-xuan, Peiper, Stephen C., and Fujii, Nobutaka
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- 2006
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8. Requirement of KISS1 Secretion for Multiple Organ Metastasis Suppression and Maintenance of Tumor Dormancy
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Nash, Kevin T., Phadke, Pushkar A., Navenot, Jean-Marc, Hurst, Douglas R., Accavitti-Loper, Mary Ann, Sztul, Elizabeth, Vaidya, Kedar S., Frost, Andra R., Kappes, John C., Peiper, Stephen C., and Welch, Danny R.
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- 2007
9. Characterization of the receptor binding residues of kisspeptins by positional scanning using peptide photoaffinity probes
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Misu, Ryosuke, Oishi, Shinya, Setsuda, Shohei, Noguchi, Taro, Kaneda, Masato, Ohno, Hiroaki, Evans, Barry, Navenot, Jean-Marc, Peiper, Stephen C., and Fujii, Nobutaka
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- 2013
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10. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.
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O'Rourke, Donald M., Nasrallah, MacLean P., Desai, Arati, Melenhorst, Jan J., Mansfield, Keith, Morrissette, Jennifer J. D., Martinez-Lage, Maria, Brem, Steven, Maloney, Eileen, Shen, Angela, Isaacs, Randi, Mohan, Suyash, Plesa, Gabriela, Lacey, Simon F., Navenot, Jean-Marc, Zhaohui Zheng, Levine, Bruce L., Hideho Okada, June, Carl H., and Brogdon, Jennifer L.
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T cells ,LYMPHOCYTES ,GENETIC mutation ,PROTEIN-tyrosine kinases ,CHIMERIC antigen receptors ,EPIDERMAL growth factor receptors - Abstract
The article discusses the first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). It reveals that manufacturing and infusion of CAR-modified T cell (CART)–EGFRvIII cells are feasible and safe even without evidence of off-tumor toxicity or cytokine release syndrome.
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- 2017
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11. Preliminary clinical outcomes of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in patients with advanced urothelial cancer.
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Aggen, David H, Hong, David S., Clarke, Jeffrey Melson, Asch, Adam Steven, Calvo, Emiliano, Zugazagoitia, Jon, Butler, Marcus O., Moreno, Victor, Cervantes, Andres, Van Tine, Brian Andrew, Lawrence, Donald P., Johnson, Melissa Lynne, Brophy, Francine Elizabeth, Broad, Robyn, Isabelle, Martin, Gunn, Alasdair, Navenot, Jean-Marc, Saro, Jose, Norry, Elliot, and Charlson, John A.
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- 2023
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12. Safety and efficacy from the phase 1 SURPASS trial of ADP-A2M4CD8, a next-generation T-cell receptor T-cell therapy, in patients with advanced esophageal, esophagogastric junction, or gastric cancer.
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Blum Murphy, Mariela A., Ajani, Jaffer A., Van Tine, Brian Andrew, Clarke, Jeffrey Melson, Butler, Marcus O., Lawrence, Donald P., Johnson, Melissa Lynne, Cervantes, Andres, Moreno, Victor, Hong, David S., Brophy, Francine Elizabeth, Navenot, Jean-Marc, Lin, Quan, Saro, Jose, and Norry, Elliot
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- 2023
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13. Expression and distribution of complement regulatory proteins in Duchenne Muscular Dystrophy, Polymyositis, and X-linked Vacuolated myopathy
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Louboutin, Jean-Pierre, Navenot, Jean-Marc, Rouger, Karl, Blanchard, Dominique, Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, and ProdInra, Archive Ouverte
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[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
absent
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- 2005
14. Heme Oxygenase-1 Gene Promoter Polymorphism Is Associated With the Development of Necrotizing Acute Pancreatitis.
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Gulla, Aiste, Evans, Barry J., Navenot, Jean Marc, Pundzius, Juozas, Barauskas, Giedrius, Gulbinas, Antanas, Dambrauskas, Zilvinas, Arafat, Hwyda, and Wang, Zi-Xuan
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- 2014
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15. Design and synthesis of downsized metastin (45–54) analogs with maintenance of high GPR54 agonistic activity
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Niida, Ayumu, Wang, Zixuan, Tomita, Kenji, Oishi, Shinya, Tamamura, Hirokazu, Otaka, Akira, Navenot, Jean-Marc, Broach, James R., Peiper, Stephen C., and Fujii, Nobutaka
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- 2006
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16. Characterization of Constitutively Active Mutants of G Protein-Coupled Receptors.
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Walker, John M., Ali, Hydar, Haribabu, Bodduluri, Navenot, Jean-Marc, Zi-xuan Wang, and Peiper, Stephen C.
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The ability of G protein-coupled receptors to transduce signaling typically is induced by the binding of an appropriate ligand (agonist), resulting in a conformational change of the receptor and the subsequent interaction with the G protein heterotrimer. Some mutants of G protein-coupled receptors, known as constitutively active mutants, have the capac-ity to activate the G protein-signaling cascade even in the absence of ligand. In this chapter, we describe three methods that most directly allow characterization of constitu-tively active mutants and discriminate them from the wild-type receptors. All methods are based on the spontaneous signaling function in the absence of ligand and its conse-quences on the receptor. [ABSTRACT FROM AUTHOR]
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- 2006
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17. Paradoxical Downregulationof CXC Chemokine Receptor4 Induced by Polyphemusin II-Derived Antagonists.
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Masuda, Ryo, Oishi, Shinya, Tanahara, Noriko, Ohno, Hiroaki, Hirasawa, Akira, Tsujimoto, Gozoh, Yano, Yoshiaki, Matsuzaki, Katsumi, Navenot, Jean-Marc, Peiper, Stephen C., and Fujii, Nobutaka
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- 2012
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18. The metastasis suppressor KISS1 lacks antimetastatic activity in the C8161.9 xenograft model of melanoma.
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Navenot, Jean-Marc, Evans, Barry, Oishi, Shinya, Setsuda, Shohei, Fujii, Nobutaka, and Peiper, Stephen C.
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- 2012
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19. Heat Shock Response in CHO Mammalian Cells Is Controlled by a Nonlinear Stochastic Process.
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Lipan, Ovidiu, Navenot, Jean-Marc, Wang, Zixuan, Huang, Lei, and Peiper, Stephen C.
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CELL populations , *MAMMALS , *PHYSIOLOGICAL control systems , *NONLINEAR theories , *STOCHASTIC processes , *HAMSTERS as laboratory animals - Abstract
In many biological systems, the interactions that describe the coupling between different units in a genetic network are nonlinear and stochastic. We study the interplay between stochasticity and nonlinearity using the responses of Chinese hamster ovary (CHO) mammalian cells to different temperature shocks. The experimental data show that the mean value response of a cell population can be described by a mathematical expression (empirical law) which is valid for a large range of heat shock conditions. A nonlinear stochastic theoretical model was developed that explains the empirical law for the mean response. Moreover, the theoretical model predicts a specific biological probability distribution of responses for a cell population. The prediction was experimentally confirmed by measurements at the single-cell level. The computational approach can be used to study other nonlinear stochastic biological phenomena. [ABSTRACT FROM AUTHOR]
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- 2007
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20. Constitutive Activation of CCR5 and CCR2 Induced by Conformational Changes in the Conserved TXP Motif in Transmembrane Helix 2.
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Arias, Diana Alvarez, Navenot, Jean-Marc, Wen-bo Zhang, Jean-Marc, Broach, James, and Peiper, Stephen C.
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G proteins , *YEAST - Abstract
Investigates the constitutive activation of CCR5, a G protein-couple receptor for RANTES MIP-1alpha, MIP01beta and MCP-2, and CCR2 induced by conformational changes in the conserved TXP motif in transmembrane helix2. Finding that the expression of CCR5 and CCR2 in yeast and the availability of variants with autonomous signaling represent critical tools for characterizing receptor antagonists and developing approaches to block their role in human disease.
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- 2003
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21. Heme Oxygenase-1 Gene Promoter Polymorphism and Acute Pancreatitis
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Pupine, Aiste, Evans, Barry J., Navenot, Jean-Marc, Wang, Zi-Xuan, Pundzius, Juozas, Barauskas, Giedrius, Dambrauskas, Zilvinas, and Arafat, Hwyda A.
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- 2011
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22. X-linked vacuolated myopathy: membrane attack complex deposition on the surface membrane of injured muscle fibers is not accompanied by S-protein.
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Louboutin, Jean-Pierre, Navenot, Jean-Marc, Villanova, Marcello, Rouger, Karl, Merlini, Luciano, Fardeau, Michel, Louboutin, J P, Navenot, J M, Villanova, M, Rouger, K, Merlini, L, and Fardeau, M
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- 1998
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23. Expression of CD59, a regulator of the membrane attack complex of complement, on human skeletal muscle fibers.
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Navenot, Jean-Marc, Villanova, Marcello, Lucas-Héron, Brigitte, Malandrini, Alessandro, Blanchard, Dominique, Louboutin, Jean-Pierre, Navenot, J M, Villanova, M, Lucas-Héron, B, Malandrini, A, Blanchard, D, and Louboutin, J P
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- 1997
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24. PROTECTION OF RAT ENDOTHELIAL CELLS FROM PRIMATE COMPLEMENT-MEDIATED LYSIS BY EXPRESSION OF HUMAN CD59 AND/OR DECAY-ACCELERATING FACTOR.
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Charreau, BÉatrice, Cassard, Armelle, Tesson, Laurent, Mauff, Brigitte Le, Navenot, Jean-Marc, Blanchard, Dominique, Lublin, Douglas, Soulillou, Jean-Paul, and Anegon, Ignacio
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- 1994
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25. Cytolytic effect of human anti-Gal IgM and complement on porcine endothelial cells: A kinetic analysis.
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Borche, Luis, Thibaudeau, Karen, Navenot, Jean-Marc, Soulillou, Jean-Paul, and Blanchard, Dominique
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- 1994
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26. Role of CD4 Hinge Region in GP120 Utilization by Immunoglobulin Domain 1
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Murray, James L., Hu, Qin-xue, Navenot, Jean-Marc, and Peiper, Stephen C.
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IMMUNOGLOBULINS , *HIV infections , *GLYCOPROTEINS - Abstract
Immunoglobulin-like domain 1 of CD4 (D1-CD4) promotes HIV infection by binding the envelope glycoprotein (ENV) and exposing its coreceptor-binding site. To study CD4-ENV-coreceptor interactions, we characterized hybrid receptors having domains 1 and 2 of CD4 (D1D2-CD4) joined to the N-terminus of chemokine receptors CCR5, CXCR4, CXCR2, and DARC. Hybrid receptors showed conserved ENV-coreceptor specificity in cell-cell fusion assays. Although D1D2-CD4-CCR5 was sufficient to permit ENV-mediated fusion, D1-CD4-CCR5 and human D1/mouse D2-CD4-CCR5 lacked CD4 function and binding to a neutralizing antibody mapped to D1-CD4. Chimeric D1D2-CD4 joined to CCR5 revealed that the C-terminal 20 residues of human D2-CD4 are required for efficient ENV-mediated fusion. Mutagenesis of hybrid receptors showed the importance of residues forming D1-D2 CD4 interdomain contacts and hinge region proximal residues. Mutagenesis of WT human CD4 confirmed that residues forming D1-D2 interdomain contacts and hinge-region proximal residues contribute positively to CD4 activity in the full-length receptor. [Copyright &y& Elsevier]
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- 2002
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27. Physical association of GPR54 C-terminal with protein phosphatase 2A
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Evans, Barry J., Wang, Zixuan, Mobley, La’Tonya, Khosravi, Davood, Fujii, Nobutaka, Navenot, Jean-Marc, and Peiper, Stephen C.
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PHOSPHOPROTEIN phosphatases , *METASTASIS , *TUMOR suppressor genes , *G proteins , *RECEPTOR-ligand complexes , *PROTEIN-protein interactions - Abstract
Abstract: KiSS1 was discovered as a metastasis suppressor gene and subsequently found to encode kisspeptins (KP), ligands for a G protein coupled receptor (GPCR), GPR54. This ligand-receptor pair was later shown to play a critical role in the neuro-endocrine regulation of puberty. The C-terminal cytoplasmic (C-ter) domain of GPR54 contains a segment rich in proline and arginine residues that corresponds to the primary structure of four overlapping SH3 binding motifs. Yeast two hybrid experiments identified the catalytic subunit of protein phosphatase 2A (PP2A-C) as an interacting protein. Pull-down experiments with GST fusion proteins containing the GPR54 C-ter confirmed binding to PP2A-C in cell lysates and these complexes contained phosphatase activity. The proline arginine rich segment is necessary for these interactions. The GPR54 C-ter bound directly to purified recombinant PP2A-C, indicating the GPR54 C-ter may form complexes involving the catalytic subunit of PP2A that regulate phosphorylation of critical signaling intermediates. [Copyright &y& Elsevier]
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- 2008
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28. Phase I clinical trial evaluating the safety and efficacy of ADP-A2M10 SPEAR T cells in patients with MAGE-A10 + advanced non-small cell lung cancer.
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Blumenschein GR, Devarakonda S, Johnson M, Moreno V, Gainor J, Edelman MJ, Heymach JV, Govindan R, Bachier C, Doger de Spéville B, Frigault MJ, Olszanski AJ, Lam VK, Hyland N, Navenot JM, Fayngerts S, Wolchinsky Z, Broad R, Batrakou D, Pentony MM, Sanderson JP, Gerry A, Marks D, Bai J, Holdich T, Norry E, and Fracasso PM
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- Aged, Female, Genetic Engineering, Humans, Lymphocyte Depletion, Male, Middle Aged, Antigens, Neoplasm immunology, Carcinoma, Non-Small-Cell Lung therapy, Immunotherapy, Adoptive adverse effects, Lung Neoplasms therapy, Neoplasm Proteins immunology, Receptors, Antigen, T-Cell immunology, T-Lymphocytes immunology
- Abstract
Background: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10
+ tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577)., Methods: Eligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08-0.12×109 (dose group 1), 0.5-1.2×109 (dose group 2), and 1.2-15×109 (dose group 3/expansion) transduced cells., Results: Eleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m2 on days -5 to -2 and cyclophosphamide 1800 mg/m2 on days -5 to -4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10., Conclusions: ADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing., Competing Interests: Competing interests: AG holds stock options in Adaptimmune. AJO has received research contracts from Alkermes, Antegene, Astellas, Checkmate, Gan & Lee, GlycoNex, InstilBio, Intensity, Istari, Kadmon, Kartos, NeoImmune, NGM, OncoSec, Sound Bio, SpringBank, Takeda; has received payment for advisory board roles from Merck, BMS, Pfizer, Takeda, Sanofi, Eisai. DB, DM, EN, JB, J-MN, JPS, MMP, NH, RB, SF are or were employees of Adaptimmune at the time of the study. GRB has received grants/contracts from Amgen, Bayer, Adaptimmune, Elelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Xcovery, Tmunity Therapeutics, Regeneron, Beigene, Repertoire Immune Medicines, Verastem; consulting fees from Abbvie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics; has participated on a Data Safety Monitoring Board or Advisory Board for Virogen Biotech, Maverick Therapeutics; holds stock or stock options in Virogin Biotech; and has other financial or non-financial interests in Johnson & Johnson/Janssen (immediate family member employed). JG has been a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, Jounce, Karyopharm, GlydeBio, Mirati, AstraZeneca, Regeneron, Oncorus, Helsinn, Array, and Clovis Oncology; has been an employee (immediate family member) with equity in Ironwood Pharmaceuticals; has received research funding from Novartis, Genentech/Roche, and Ariad/Takeda; has received institutional research support from Tesaro, Moderna, Blueprint, Scholar Rock, BMS, Array, Adaptimmune, Novartis, Genentech/Roche, Alexo and Merck. JVH has received grants/contracts from AstraZeneca, GlaxoSmithKline and Spectrum; holds royalty/licenses in Spectrum; has received consulting fees from AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion; has received honoraria from Medlinker, Peerview, Nexus Health Medicine, Targeted Oncology, MJH Events; has received support for attending meetings from IASLC Targeted Therapies, IASLC World Conference on Lung Cancer; has been in a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Mechanisms of Cancer Therapeutics-1 (MCT1) (Study Section – Chair). MJ has received research funding from AbbVie, Acerta, Adaptimmune, Apexigen, Array BioPharma, AstraZeneca, Atreca, BeiGene, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dynavax, Lilly, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals, Sanofi, Seven and Eight Biopharmaceuticals, Shattuck Labs, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, University of Michigan, WindMIL, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, Amgen; has held a consulting/advisory role (spouse) for Astellas, Otsuka Pharmaceuticals; has held a consulting/advisory role (self) for AbbVie, Achilles Therapeutics, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Genentech, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, Association of Community Cancer Center; has received food/beverage/travel expenses from Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol Myers Squibb, Exelixis, Genentech/Roche, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm, Janssen, Lilly, Novartis, Sanofi. MJE has received research funding from GlaxoSmithKline, Mersana, Amgen, Windmil, Nektar, Apexigen, Adaptimmune; has received consulting fees from Kanaph, Flame; has received honoraria from Sanofi; has been a member of DSMB for AstraZeneca, Seattle Genetics, GlaxoSmithKline, Takeda; has been a consultant/on an advisory board for Windmil, Regeneron, Syndax; has been the Chair, Scientific Advisory board for Lung Cancer Foundation of America; has been the Deputy Editor of 'Lung Cancer'; has received stock options from Biomarker strategies; Creatv Biotech. MJF has been a consultant for Arcellx, BMS, Novartis, Kite, Iovance. PMF is an employee of Adaptimmune; holds stock in Adaptimmune and Bristol-Myers Squib; has received compensation for travel and congress meetings. RG has received consulting fees from BMS, Abbvie, Geneplus; has participated on a Data Safety Monitoring Board or Advisory Board for Roche Genentech. SD has been a consultant for Jacobio pharmaceuticals (without financial compensation). TH was an employee of Adaptimmune at the time of the study; has been a consultant for Adaptimmune. VKL has been in a consulting or advisory role for Takeda, Bristol-Myers Squibb, Seattle Genetics; has received research funding from GlaxoSmithKline, Bristol-Myers Squibb, Guardant Health, Takeda. VM has received consulting fees from Roche, Bayer, Pieris, BMS, Janssen and Basilea. BDdS, CB, ZW have nothing to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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29. Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma.
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Stadtmauer EA, Faitg TH, Lowther DE, Badros AZ, Chagin K, Dengel K, Iyengar M, Melchiori L, Navenot JM, Norry E, Trivedi T, Wang R, Binder GK, Amado R, and Rapoport AP
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Cytokines metabolism, Female, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Membrane Proteins antagonists & inhibitors, Middle Aged, Receptors, Antigen, T-Cell genetics, Receptors, Chimeric Antigen genetics, Transplantation, Autologous, Treatment Outcome, Young Adult, Antigens, Neoplasm immunology, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Membrane Proteins immunology, Multiple Myeloma immunology, Multiple Myeloma therapy, Receptors, Antigen, T-Cell metabolism, Receptors, Chimeric Antigen metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1
c259 TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 1010 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells. Objective response rate (International Myeloma Working Group consensus criteria) was 80% at day 42 (95% confidence interval [CI], 0.59-0.93), 76% at day 100 (95% CI, 0.55-0.91), and 44% at 1 year (95% CI, 0.24-0.65). At year 1, 13/25 patients were disease progression-free (52%); 11 were responders (1 stringent complete response, 1 complete response, 8 very good partial response, 1 partial response). Three patients remained disease progression-free at 38.6, 59.2, and 60.6 months post-NY-ESO-1 SPEAR T-cell infusion. Median progression-free survival was 13.5 months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 months). Infusions were well tolerated; cytokine release syndrome was not reported. No fatal serious adverse events occurred during study conduct. NY-ESO-1 SPEAR T cells expanded in vivo, trafficked to bone marrow, demonstrated persistence, and exhibited tumor antigen-directed functionality. In this MM patient population, NY-ESO-1 SPEAR T-cell therapy in the context of ASCT was associated with antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01352286., (© 2019 by The American Society of Hematology.)- Published
- 2019
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30. Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259 T Cells in Synovial Sarcoma.
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D'Angelo SP, Melchiori L, Merchant MS, Bernstein D, Glod J, Kaplan R, Grupp S, Tap WD, Chagin K, Binder GK, Basu S, Lowther DE, Wang R, Bath N, Tipping A, Betts G, Ramachandran I, Navenot JM, Zhang H, Wells DK, Van Winkle E, Kari G, Trivedi T, Holdich T, Pandite L, Amado R, and Mackall CL
- Subjects
- Adoptive Transfer, Adult, CD8-Positive T-Lymphocytes metabolism, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Pilot Projects, Sarcoma, Synovial immunology, T-Lymphocytes immunology, Treatment Outcome, Young Adult, Antigens, Neoplasm immunology, Membrane Proteins immunology, Receptors, Antigen, T-Cell metabolism, Sarcoma, Synovial therapy, T-Lymphocytes transplantation
- Abstract
We evaluated the safety and activity of autologous T cells expressing NY-ESO-1
c259 , an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259 T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259 T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259 T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259 T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259 T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects. Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259 T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944-57. ©2018 AACR. See related commentary by Keung and Tawbi, p. 914 This article is highlighted in the In This Issue feature, p. 899 ., (©2018 American Association for Cancer Research.)- Published
- 2018
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31. Paradoxical downregulation of CXC chemokine receptor 4 induced by polyphemusin II-derived antagonists.
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Masuda R, Oishi S, Tanahara N, Ohno H, Hirasawa A, Tsujimoto G, Yano Y, Matsuzaki K, Navenot JM, Peiper SC, and Fujii N
- Subjects
- Amino Acid Sequence, Animals, CHO Cells, Chemokine CXCL12 metabolism, Cricetulus, Down-Regulation drug effects, HIV-1 drug effects, Humans, Models, Molecular, Molecular Sequence Data, Receptors, CXCR4 analysis, Receptors, CXCR4 metabolism, Structure-Activity Relationship, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Antimicrobial Cationic Peptides chemistry, Antimicrobial Cationic Peptides pharmacology, Receptors, CXCR4 antagonists & inhibitors
- Abstract
CXC chemokine receptor 4 (CXCR4) is a G protein-coupled receptor implicated in cell entry of T-cell line-tropic HIV-1 strains. CXCR4 and its ligand stromal cell derived factor-1 (SDF-1)/CXCL12 play pivotal parts in many physiological processes and pathogenetic conditions (e.g., immune cell-homing and cancer metastasis). We previously developed the potent CXCR4 antagonist T140 from structure-activity relationship studies of the antimicrobial peptide polyphemusin II. T140 and its derivatives have been exploited in biological and biomedical studies for the SDF-1/CXCR4 axis. We investigated receptor localization upon ligand stimulation using fluorescent SDF-1 and T140 derivatives as well as a specific labeling technique for cellular-membrane CXCR4. Fluorescent T140 derivatives induced translocation of CXCR4 into the perinuclear region as observed by treatment with fluorescent SDF-1. T140 derivative-mediated internalization of CXCR4 was also monitored by the coiled-coil tag-probe system. These findings demonstrated that the CXCR4 antagonistic activity and anti-HIV activity of T140 derivatives were derived (at least in part) from antagonist-mediated receptor internalization.
- Published
- 2012
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32. MicroRNA profiling in lung cancer reveals new molecular markers for diagnosis.
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Solomides CC, Evans BJ, Navenot JM, Vadigepalli R, Peiper SC, and Wang ZX
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- Adenocarcinoma genetics, Adult, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Squamous Cell genetics, Humans, Lung Neoplasms genetics, Oligonucleotide Array Sequence Analysis, Prognosis, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Adenocarcinoma diagnosis, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Squamous Cell diagnosis, Gene Expression Profiling, Lung Neoplasms diagnosis, MicroRNAs genetics
- Abstract
Objective: To identify new molecular diagnostic markers for non-small cell lung carcinoma (NSCLC) by analyzing microRNA (miRNA) expression profile differences in samples from NSCLC patients and adults with nonneoplastic diseases., Study Design: miRNA expression was studied in archival formalin-fixed, paraffin-embedded tissues by microarray and confirmed by real-time PCR analysis of NSCLC and normal lung tissues. An algorithm for discriminating normal, squamous cell carcinoma (SQCC), and adenocarcinoma (ADC) tissue was derived from miRNA expression studies and applied towards characterization of poorly differentiated NSCLC samples., Results: Microarray data from a genome-wide scan revealed 34 differentially expressed miRNAs, 5 of which enabled algorithmic discrimination of normal tissue from carcinoma (SQCC or ADC), as well as SQCC from ADC. Expression of miR-21 was significantly increased in both tumor types, whereas levels of miR-451 and miR-486-5p were reduced. SQCC was distinguished from normal tissue and ADC by high-level miR-205 expression and decreased miR-26b. Comparison of miRNA profiles to histological and immunohistochemical findings in 19 poorly differentiated specimens demonstrated the potential clinical utility of miRNA profiling to provide important insights into the classification of SQCC and ADC., Conclusion: This study presents a novel algorithm for specimen classification in cases of poorly differentiated NSCLC., (Copyright © 2012 S. Karger AG, Basel.)
- Published
- 2012
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33. Activation of Rho and Rho-associated kinase by GPR54 and KiSS1 metastasis suppressor gene product induces changes of cell morphology and contributes to apoptosis.
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Navenot JM, Fujii N, and Peiper SC
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- Cell Adhesion, Cell Line, Cell Shape, Cell Surface Extensions ultrastructure, Cytoskeleton ultrastructure, Enzyme Activation, Humans, Kisspeptins, Oligopeptides pharmacology, Receptors, Kisspeptin-1, Apoptosis, Receptors, G-Protein-Coupled physiology, Tumor Suppressor Proteins physiology, rho GTP-Binding Proteins metabolism, rho-Associated Kinases metabolism
- Abstract
The mechanism of action of the metastasis suppressor KiSS1 and its receptor GPR54 is still incompletely characterized. Although the loss of KiSS1 expression by tumor cells has been associated with a metastatic phenotype, the nature of the cellular target of the secreted kisspeptins is unknown. Although an autocrine model of action has been generally assumed, metastasis suppression by KiSS1 has also been shown in cells that do not express GPR54, suggesting a paracrine mechanism in which kisspeptins affect cells in the metastatic niche. Activation of GPR54 was shown to inhibit cell motility and invasion of tumor cells, induce the formation of stress fibers, and reduce the expression of matrix metalloproteinase 9. We showed previously that the activation of GPR54 by kisspeptin-10 suppressed CXCR4-mediated chemotaxis in response to stromal cell-derived factor 1/CXCL12 and abolished the phosphorylation of Akt by CXCR4. We also demonstrated that activation of GPR54 inhibited Akt phosphorylation after the activation of epidermal growth factor receptor and the insulin receptor and triggered apoptosis in epithelial and lymphoid cell lines through a mechanism involving extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase. We show here that the activation of GPR54 induced immediate and profound changes of cell morphology, including cytoplasmic condensation and formation of unpolarized plasma membrane protrusions. These events were dependent on Rho and Rho-Associated Kinase (ROCK) activation. The activation of ROCK also contributed to GPR54-mediated apoptosis in 293 cells, and its effect was additive to and independent of ERK activation. These results suggest that RhoA and ROCK are additional key components of the antimetastatic effect of kisspeptins.
- Published
- 2009
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34. KiSS1 metastasis suppressor gene product induces suppression of tyrosine kinase receptor signaling to Akt, tumor necrosis factor family ligand expression, and apoptosis.
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Navenot JM, Fujii N, and Peiper SC
- Subjects
- ErbB Receptors physiology, Extracellular Signal-Regulated MAP Kinases physiology, Humans, Jurkat Cells, Kisspeptins, Oligopeptides pharmacology, Receptor, Insulin physiology, Receptors, Kisspeptin-1, Apoptosis, Proto-Oncogene Proteins c-akt physiology, Receptors, G-Protein-Coupled physiology, Signal Transduction, Tumor Necrosis Factor-alpha metabolism, Tumor Suppressor Proteins physiology
- Abstract
The powerful metastasis suppressor function of KiSS1 gene products has been demonstrated in both clinical studies and experimental models, but its mechanism is still incompletely understood. Studies on the antimetastatic function of KiSS1 and GPR54 largely focused on the autocrine inhibition of cell motility, despite experimental evidence of an alternative post-migratory effect. We showed previously that the activation of its cognate receptor GPR54 by kisspeptin-10 suppressed the capacity of the prometastatic chemokine receptor CXCR4 to induce chemotaxis in response to stromal cell derived factor 1 and abolished the activation of Akt by CXCR4. We demonstrate here that activation of GPR54 can also abolish the activation of Akt by the tyrosine kinase receptors for epidermal growth factor and insulin. The signaling of GPR54 was sufficient to trigger apoptosis in epithelial and lymphoid cell lines. Surprisingly, this phenomenon depended largely on the activation of extracellular signal-regulated kinase (ERK) rather than the inhibition of Akt. Activation of GPR54 resulted in the ERK-dependent expression of tumor necrosis factor-alpha and FasL in a lymphoid cell line, the latter being the main trigger of apoptosis. These data provide novel mechanisms relevant to a potential autocrine metastasis suppression effect of KiSS1 on GPR54-positive tumor cells. More importantly, they also establish an experimental basis for a paracrine mode of action by which kisspeptins suppress the metastatic potential of tumor cells lacking expression of the receptor, as observed in several animal models of metastasis. The action on stromal cells significantly broadens the clinical relevance of this metastasis suppressor.
- Published
- 2009
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35. Association of nucleophosmin negatively regulates CXCR4-mediated G protein activation and chemotaxis.
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Zhang W, Navenot JM, Frilot NM, Fujii N, and Peiper SC
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Cytosol metabolism, Humans, Molecular Sequence Data, Nuclear Proteins chemistry, Nucleophosmin, Protein Conformation, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Receptors, CXCR4 chemistry, Receptors, CXCR4 genetics, Chemotaxis, GTP-Binding Proteins metabolism, Nuclear Proteins metabolism, Receptors, CXCR4 metabolism
- Abstract
CXCR4, the primary receptor for CXCL12, plays a critical role in the development of hematopoietic, vascular, central nervous, and immune systems by mediating directional migration of precursor cells. This mechanism promotes homing of tumor cells to metastatic sites that secrete CXCL12, and CXCR4 expression is a negative prognostic factor in acute myelogenous leukemia (AML). To elucidate mechanisms that regulate CXCR4 signaling, we used a proteomic approach to identify proteins physically associated with CXCR4. Analysis of CXCR4 immune complexes identified nucleophosmin (NPM), which was confirmed by reciprocal coimmunoprecipitation for NPM. Constitutively active CXCR4 variants bound higher levels of NPM than the wild-type receptor, which was reversed by T140, an inverse agonist. NPM binding to CXCR4 localized interactions to the C terminus and cytoplasmic loop (CL)-3, but not CL-1 or CL-2. Alanine scanning mutagenesis demonstrated that positively charged amino acids in CL-3 were critical for NPM binding. Recombinant NPM decreased GTP binding in membrane fractions after activation of CXCR4 by CXCL12. Suppression of NPM expression enhanced chemotactic responses to CXCL12, and, conversely, overexpression of a cytosolic NPM mutant reduced chemotaxis induced by CXCL12. This study provides evidence for a novel role for NPM as a negative regulator of CXCR4 signaling induced by CXCL12 that may be relevant to the biology of AML.
- Published
- 2007
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36. SAR and QSAR studies on the N-terminally acylated pentapeptide agonists for GPR54.
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Tomita K, Oishi S, Cluzeau J, Ohno H, Navenot JM, Wang ZX, Peiper SC, Akamatsu M, and Fujii N
- Subjects
- Acylation, Animals, CHO Cells, Cricetinae, Cricetulus, Models, Molecular, Quantitative Structure-Activity Relationship, Receptors, Kisspeptin-1, Structure-Activity Relationship, Oligopeptides pharmacology, Receptors, G-Protein-Coupled agonists
- Abstract
Kisspeptins (KPs) play important roles in the regulation of physiological and pathological states through activation of the cognate receptor GPR54. Our previous studies to downsize KP agonists to the essential GPR54 pharmacophore identified peptides 1-3 as low molecular weight GPR54 agonists. In this study, the effect of N-terminal acyl groups on the activity of a series of analogues (R-Phe-Gly-Leu-Arg-Trp-NH2) was investigated in order to develop novel potent GPR54 agonists. Among the compounds developed, the most potent agonistic activity for GPR54 was observed for N-terminal 4-fluorobenzoyl analogue 29. Using quantitative structure-activity relationship studies, it was demonstrated that the inductively negative and small substituents were preferred at the 4-position of N-terminal benzoyl groups.
- Published
- 2007
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37. Characterization of constitutively active mutants of G protein-coupled receptors.
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Navenot JM, Wang ZX, and Peiper SC
- Subjects
- Animals, CHO Cells, Cricetinae, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Humans, Ligands, Phosphorylation, Protein Binding, Receptors, CXCR4 genetics, Receptors, CXCR4 metabolism, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled genetics, Mutation, Receptors, G-Protein-Coupled metabolism, Second Messenger Systems physiology
- Abstract
The ability of G protein-coupled receptors to transduce signaling typically is induced by the binding of an appropriate ligand (agonist), resulting in a conformational change of the receptor and the subsequent interaction with the G protein heterotrimer. Some mutants of G protein-coupled receptors, known as constitutively active mutants, have the capacity to activate the G protein-signaling cascade even in the absence of ligand. In this chapter, we describe three methods that most directly allow characterization of constitutively active mutants and discriminate them from the wild-type receptors. All methods are based on the spontaneous signaling function in the absence of ligand and its consequences on the receptor.
- Published
- 2006
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38. Kisspeptin-10-induced signaling of GPR54 negatively regulates chemotactic responses mediated by CXCR4: a potential mechanism for the metastasis suppressor activity of kisspeptins.
- Author
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Navenot JM, Wang Z, Chopin M, Fujii N, and Peiper SC
- Subjects
- Animals, CHO Cells, Calcium metabolism, Chemokine CXCL12, Chemokines, CXC, Chemotaxis drug effects, Cricetinae, Enzyme Induction, HeLa Cells, Humans, Kisspeptins, MAP Kinase Signaling System drug effects, Mitogen-Activated Protein Kinases biosynthesis, Mitogen-Activated Protein Kinases genetics, Mitogen-Activated Protein Kinases metabolism, Oncogene Protein v-akt antagonists & inhibitors, Oncogene Protein v-akt biosynthesis, Phosphorylation drug effects, Receptors, CXCR4 biosynthesis, Receptors, CXCR4 physiology, Receptors, G-Protein-Coupled, Receptors, Kisspeptin-1, Receptors, Neuropeptide genetics, Receptors, Neuropeptide metabolism, Signal Transduction drug effects, Transfection, Oligopeptides pharmacology, Receptors, CXCR4 antagonists & inhibitors, Receptors, Neuropeptide physiology
- Abstract
The product of the KiSS-1 gene is absent or expressed at low level in metastatic melanoma and breast cancer compared with their nonmetastatic counterparts. A polypeptide derived from the KiSS-1 product, designated kisspeptin-10 (Kp-10), activates a receptor coupled to Galphaq subunits (GPR54 or KiSS-1R). To study the mechanism by which Kp-10 antagonizes metastatic spread, the effect on CXCR4-mediated signaling, which has been shown to direct organ-specific migration of tumor cells, was determined. Kp-10 blocked chemotaxis of tumor cells expressing CXCR4 in response to low and high concentrations of SDF-1/CXCL12 and inhibited mobilization of calcium ions induced by this ligand. Pretreatment with Kp-10 did not induce down-modulation of cell surface CXCR4 expression, reduce affinity for SDF-1/CXCL12, or alter Galphai subunit activation stimulated by this ligand. Although Kp-10 stimulated prolonged phosphorylation of extracellular signal-regulated kinase 1/2, it inhibited the phosphorylation of Akt induced by SDF-1. The ability of Kp-10 to inhibit signaling and chemotaxis induced by SDF-1 indicates that activation of GPR54 signaling may negatively regulate the role of CXCR4 in programming tumor metastasis.
- Published
- 2005
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39. Constitutive activation of CCR5 and CCR2 induced by conformational changes in the conserved TXP motif in transmembrane helix 2.
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Alvarez Arias D, Navenot JM, Zhang WB, Broach J, and Peiper SC
- Subjects
- Amino Acid Motifs, Animals, CHO Cells, Cell Movement, Chemokine CCL5 metabolism, Chemotaxis, Cricetinae, Dose-Response Relationship, Drug, Gene Library, Genes, Reporter, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Humans, Ligands, Mutation, Open Reading Frames, Plasmids metabolism, Protein Binding, Protein Conformation, Receptors, CCR2, Signal Transduction, Threonine chemistry, Receptors, CCR5 metabolism, Receptors, Chemokine metabolism
- Abstract
CCR5 is a G protein-coupled receptor for RANTES, MIP-1alpha, MIP-1beta, and MCP-2 that functions as the front line coreceptor for human immunodeficiency virus type 1 infection. To elucidate the mechanism for CCR5 activation, this coreceptor was expressed in yeast coupled to the pheromone response pathway and a constitutively active mutant (CAM) was derived by random mutagenesis. Conversion of Thr-82 in the highly conserved TXP motif in transmembrane helix 2 to Pro, His, Tyr, Arg, or Lys conferred autonomous signaling activity in yeast and mammalian cells. This substitution also imparted constitutive signaling to CCR2 in yeast and mammalian cells, but not CCR1, CCR3, CCR4, CXCR2, or CXCR4. The CCR5-CAM, but not the CCR2-CAM had a reduction in ligand binding affinity. Whereas the amplitude of calcium mobilization induced by RANTES stimulation was lower in the CCR5-CAM than the wild-type (WT) receptor, MCP-1 induced a higher signal in the CCR2-CAM than in CCR2-WT. The chemotactic response of CCR5-CAM(T82P) to RANTES was similar to that of CCR5-WT, but CCR5-CAM(T82K) was dramatically decreased. The chemotactic response of CCR2-WT and CCR2-CAM(T94K) were similar. These findings extend insight into the role of the TXP motif in the mechanism for CCR5 signaling. CCR2, the receptor most closely genetically related to CCR5, shared a similar signaling mechanism, but other receptors containing the TXP motif did not. The expression of CCR5 and CCR2 in yeast and the availability of variants with autonomous signaling represent critical tools for characterizing receptor antagonists and developing approaches to block their role in human diseases.
- Published
- 2003
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40. S-protein is expressed in necrotic fibers in Duchenne muscular dystrophy and polymyositis.
- Author
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Louboutin JP, Navenot JM, Rouger K, and Blanchard D
- Subjects
- Antibodies, Monoclonal, Antibody Specificity, Humans, Membrane Glycoproteins analysis, Membrane Glycoproteins immunology, Muscle Fibers, Skeletal chemistry, Muscle Fibers, Skeletal pathology, Muscular Dystrophy, Duchenne pathology, Necrosis, Polymyositis pathology, Vitronectin, Membrane Glycoproteins biosynthesis, Muscle Fibers, Skeletal metabolism, Muscular Dystrophy, Duchenne metabolism, Polymyositis metabolism
- Abstract
Complement regulatory proteins (CD55, CD59) and a fluid-phase complement regulator (S-protein) expression and distribution were studied in Duchenne muscular dystrophy (DMD) and polymyositis by Western blots and immunocytochemistry. In muscle samples from control subjects, no specific signal was detected for CD55 or S-protein, and CD59 was present on the sarcolemma of the muscle fibers. In DMD and polymyositis, Western blots demonstrated a 18-20 kDa band corresponding to CD59, as well as a signal corresponding to S-protein. Immunocytochemistry showed a colocalization between complement membrane attack complex (MAC), a molecule previously demonstrated in necrotic muscle fibers in DMD and polymyositis, and S-protein in necrotic fibers of DMD and polymyositis. Necrotic muscle fibers were more numerous in muscle biopsies of DMD patients with stronger signals for S-protein in Western blots. These results suggest that S-protein is not able to prevent the full assembly of MAC in necrotic fibers of patients with DMD and polymyositis, but might instead inactivate MAC deposits present inside necrotic fibers or participate in the clearance of MAC-attacked muscle fibers.
- Published
- 2003
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41. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion.
- Author
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Libura J, Drukala J, Majka M, Tomescu O, Navenot JM, Kucia M, Marquez L, Peiper SC, Barr FG, Janowska-Wieczorek A, and Ratajczak MZ
- Subjects
- Apoptosis, Bone Neoplasms, Breast Neoplasms, Cell Division physiology, Chemokine CXCL12, Chemokines, CXC genetics, Chemokines, CXC physiology, Female, Fibronectins physiology, Flow Cytometry, Humans, Laminin physiology, Melanoma, Phosphorylation, RNA, Messenger genetics, Receptors, CXCR4 genetics, Reverse Transcriptase Polymerase Chain Reaction, Rhabdomyosarcoma pathology, Sarcoma, Stromal Cells physiology, Tumor Cells, Cultured, Cell Adhesion physiology, Cell Movement physiology, Chemotaxis physiology, Receptors, CXCR4 physiology, Rhabdomyosarcoma physiopathology, Signal Transduction physiology
- Abstract
We hypothesized that the CXC chemokine receptor-4 (CXCR4)-stromal-derived factor-1 (SDF-1) axis may be involved in metastasis of CXCR4(+) tumor cells into the bone marrow and lymph nodes, which secrete the alpha-chemokine SDF-1. To explore this hypothesis, we phenotyped by fluorescence-activated cell sorter analysis various human tumor cell lines for expression of CXCR4 and found that it was highly expressed on several rhabdomyosarcoma (RMS) cell lines. We also observed that cell lines derived from alveolar RMS, which is characterized by recurrent PAX3- and PAX7-FKHR gene fusions and is associated with a poor prognosis, expressed higher levels of CXCR4 than lines derived from embryonal RMS. Furthermore, transfer of a PAX3-FKHR gene into embryonal RMS cell activates CXCR4 expression. Because alveolar RMS frequently metastasizes to the bone marrow and lymph nodes, it seems that the CXCR4-SDF-1 axis could play an important role in this process. These findings prompted us to determine whether SDF-1 regulates the metastatic behavior of RMS cells. Accordingly, we found that, although SDF-1 did not affect proliferation or survival of these cell lines, it induced in several of them (1) phosphorylation of mitogen-activated protein kinase p42/44; (2) locomotion; (3) directional chemotaxis across membranes covered by laminin, fibronectin, or Matrigel; (4) adhesion to laminin, fibronectin, and endothelial cells; and (5) increased MMP-2 and diminished tissue inhibitors of metalloproteinases secretion. The small-molecule CXCR4-specific inhibitor, T140, effectively blocked the in vitro responses of RMS cells to SDF-1. On the basis of these observations we suggest that the CXCR4-SDF-1 axis may play an important role in tumor spread and metastasis of RMS cells to bone marrow and that molecular strategies aimed at inhibiting this axis could thus prove to be useful therapeutic measures.
- Published
- 2002
- Full Text
- View/download PDF
42. A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists.
- Author
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Zhang WB, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A, Pei G, Manfredi JP, Fujii N, Broach JR, and Peiper SC
- Subjects
- Amino Acid Substitution, Animals, Anti-HIV Agents pharmacology, Benzylamines, CHO Cells, Cricetinae, Cyclams, GTP-Binding Proteins metabolism, Genes, Reporter, Genetic Variation, Humans, Open Reading Frames, Protein Conformation, Receptors, CXCR4 agonists, Receptors, CXCR4 antagonists & inhibitors, Receptors, CXCR4 metabolism, Recombinant Proteins metabolism, Saccharomyces cerevisiae drug effects, Saccharomyces cerevisiae genetics, Signal Transduction, Transfection, Heterocyclic Compounds pharmacology, Oligopeptides pharmacology, Point Mutation, Receptors, CXCR4 genetics, Saccharomyces cerevisiae physiology
- Abstract
CXCR4 is a G protein-coupled receptor for stromal-derived factor 1 (SDF-1) that plays a critical role in leukocyte trafficking, metastasis of mammary carcinoma, and human immunodeficiency virus type-1 infection. To elucidate the mechanism for CXCR4 activation, a constitutively active mutant (CAM) was derived by coupling the receptor to the pheromone response pathway in yeast. Conversion of Asn-119 to Ser or Ala, but not Asp or Lys, conferred autonomous CXCR4 signaling in yeast and mammalian cells. SDF-1 induced signaling in variants with substitution of Asn-119 to Ser, Ala, or Asp, but not Lys. These variants had similar cell surface expression and binding affinity for SDF-1. CXCR4-CAMs were constitutively phosphorylated and present in cytosolic inclusions. Analysis of antagonists revealed that exposure to AMD3100 or ALX40-4C induced G protein activation by CXCR4 wild type, which was greater in the CAM, whereas T140 decreased autonomous signaling. The affinity of AMD3100 and ALX40-4C binding to CAMs was less than to wild type, providing evidence of a conformational shift. These results illustrate the importance of transmembrane helix 3 in CXCR4 signaling. Insight into the mechanism for CXCR4 antagonists will allow for the development of a new generation of agents that lack partial agonist activity that may induce toxicities, as observed for AMD3100.
- Published
- 2002
- Full Text
- View/download PDF
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