36 results on '"Shringarpure, Reshma"'
Search Results
2. A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis
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Harrison, Stephen A., Ruane, Peter J., Freilich, Bradley, Neff, Guy, Patil, Rashmee, Behling, Cynthia, Hu, Chen, Shringarpure, Reshma, de Temple, Brittany, Fong, Erica, Tillman, Erik J., Rolph, Timothy, Cheng, Andrew, and Yale, Kitty
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- 2023
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3. Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis
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Loomba, Rohit, Sanyal, Arun J., Kowdley, Kris V., Terrault, Norah, Chalasani, Naga P., Abdelmalek, Manal F., McCullough, Arthur J., Shringarpure, Reshma, Ferguson, Beatrice, Lee, Lois, Chen, Jianfen, Liberman, Alexander, Shapiro, David, and Neuschwander-Tetri, Brent A.
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- 2019
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4. Transcriptional Signature of Histone Deacetylase Inhibition in Multiple Myeloma: Biological and Clinical Implications
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Mitsiades, Constantine S., Mitsiades, Nicholas S., McMullan, Ciaran J., Poulaki, Vassiliki, Shringarpure, Reshma, Hideshima, Teru, Akiyama, Masaharu, Chauhan, Dharminder, Munshi, Nikhil, Gu, Xuesong, Bailey, Charles, Joseph, Marie, Libermann, Towia A., Richon, Victoria M., Marks, Paul A., and Anderson, Kenneth C.
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- 2004
5. Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341
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Chauhan, Dharminder, Li, Guilan, Hideshima, Teru, Podar, Klaus, Shringarpure, Reshma, Mitsiades, Constantine, Munshi, Nikhil, Yew, P Renee, and Anderson, Kenneth C
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- 2004
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6. Antimyeloma activity of heat shock protein-90 inhibition
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Mitsiades, Constantine S., Mitsiades, Nicholas S., McMullan, Ciaran J., Poulaki, Vassiliki, Kung, Andrew L., Davies, Faith E., Morgan, Gareth, Akiyama, Masaharu, Shringarpure, Reshma, Munshi, Nikhil C., Richardson, Paul G., Hideshima, Teru, Chauhan, Dharminder, Gu, Xuesong, Bailey, Charles, Joseph, Marie, Libermann, Towia A., Rosen, Neal S., and Anderson, Kenneth C.
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- 2006
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7. Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells
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Tassone, Pierfrancesco, Goldmacher, Victor S., Neri, Paola, Gozzini, Antonella, Shammas, Masood A., Whiteman, Kathleen R., Hylander-Gans, Linda L., Carrasco, Daniel R., Hideshima, Teru, Shringarpure, Reshma, Shi, Jialan, Allam, Charles K., Wijdenes, John, Venuta, Salvatore, Munshi, Nikhil C., and Anderson, Kenneth C.
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- 2004
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8. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment
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Podar, Klaus, Catley, Laurence P., Tai, Yu-Tzu, Shringarpure, Reshma, Carvalho, Pedro, Hayashi, Toshiaki, Burger, Renate, Schlossman, Robert L., Richardson, Paul G., Pandite, Lini N., Kumar, Rakesh, Hideshima, Teru, Chauhan, Dharminder, and Anderson, Kenneth C.
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- 2004
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9. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti–multiple myeloma (MM) activity and overcome bortezomib resistance
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Chauhan, Dharminder, Li, Guilan, Podar, Klaus, Hideshima, Teru, Shringarpure, Reshma, Catley, Laurence, Mitsiades, Constantine, Munshi, Nikhil, Tai, Yu Tzu, Suh, Nanjoo, Gribble, Gordon W., Honda, Tadashi, Schlossman, Robert, Richardson, Paul, Sporn, Michael B., and Anderson, Kenneth C.
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- 2004
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10. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors
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Mitsiades, Constantine S, Mitsiades, Nicholas S, McMullan, Ciaran J, Poulaki, Vassiliki, Shringarpure, Reshma, Akiyama, Masaharu, Hideshima, Teru, Chauhan, Dharminder, Joseph, Marie, Libermann, Towia A, Garcı́a-Echeverrı́a, Carlos, Pearson, Mark A, Hofmann, Francesco, Anderson, Kenneth C, and Kung, Andrew L
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- 2004
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11. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma
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Catley, Laurence, Weisberg, Ellen, Tai, Yu-Tzu, Atadja, Peter, Remiszewski, Stacy, Hideshima, Teru, Mitsiades, Nicholas, Shringarpure, Reshma, LeBlanc, Richard, Chauhan, Dharminder, Munshi, Nikhil C., Schlossman, Robert, Richardson, Paul, Griffin, James, and Anderson, Kenneth C.
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- 2003
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12. 334 OBETICHOLIC ACID IMPROVES EXPERIMENTAL NON-INVASIVE MARKERS OF NON-ALCOHOLIC STEATOHEPATITIS AND ADVANCED FIBROSIS; RESULTS OF A SECONDARY ANALYSIS FROM THE MONTH-18 INTERIM ANALYSIS OF THE REGENERATE STUDY
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Boursier, Jerome, Loomba, Rohit, Anstee, Quentin M., Harrison, Stephen, Sanyal, Arun J., Rinella, Mary E., Younossi, Zobair M., Goodman, Zachary, Bedossa, Pierre, Fournier, Celine, Stenkilsson, Michael B., Shringarpure, Reshma, Zaru, Luna, Venugopal, Aditya, MacConell, Leigh, and Ratziu, Vlad
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- 2020
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13. Su1508 - Treatment with Obeticholic Acid in Patients with NASH Does not Show Increased Markers of Liver Toxicity Based on Evaluation of Drug-Induced Serious Hepatotoxicity (EDISH)
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Sanyal, Arun J., Pockros, Paul J., Shah, Amrik, Shringarpure, Reshma, Shapiro, David, and MacConell, Leigh
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- 2018
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14. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway
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LeBlanc, Richard, Hideshima, Teru, Catley, Laurence P., Shringarpure, Reshma, Burger, Renate, Mitsiades, Nicholas, Mitsiades, Constantine, Cheema, Puneet, Chauhan, Dharminder, Richardson, Paul G., Anderson, Kenneth C., and Munshi, Nikhil C.
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- 2004
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15. A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program.
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Tong, Kenneth, Nicandro, Jean Paul, Shringarpure, Reshma, Chuang, Emil, and Chang, Lin
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- 2013
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16. Enhanced Weight Loss With Pramlintide/Metreleptin: An Integrated Neurohormonal Approach to Obesity Pharmacotherapy.
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Ravussin, Eric, Smith, Steven R., Mitchell, Julie A., Shringarpure, Reshma, Shan, Kevin, Maier, Holly, Koda, Joy E., and Weyer, Christian
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WEIGHT loss ,DRUG efficacy ,OBESITY treatment ,DRUG therapy ,DIET therapy - Abstract
The neurohormonal control of body weight involves a complex interplay between long-term adiposity signals (e.g., leptin), and short-term satiation signals (e.g., amylin). In diet-induced obese (DIO) rodents, amylin/leptin combination treatment led to marked, synergistic, fat-specific weight loss. To evaluate the weight-lowering effect of combined amylin/leptin agonism (with pramlintide/metreleptin) in human obesity, a 24-week, randomized, double-blind, active-drug-controlled, proof-of-concept study was conducted in obese or overweight subjects (N = 177; 63% female; 39 ± 8 years; BMI 32.0 ± 2.1 kg/m
2 ; 93.3 ± 13.2 kg; mean ± s.d.). After a 4-week lead-in period with pramlintide (180 µg b.i.d. for 2 weeks, 360 µg b.i.d. thereafter) and diet (40% calorie deficit), subjects achieving 2–8% weight loss were randomized 1:2:2 to 20 weeks of treatment with metreleptin (5 mg b.i.d.), pramlintide (360 µg b.i.d.), or pramlintide/metreleptin (360 µg/5 mg b.i.d.). Combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (−12.7 ± 0.9%; least squares mean ± s.e.) than treatment with pramlintide (−8.4 ± 0.9%; P < 0.001) or metreleptin (−8.2 ± 1.3%; P < 0.01) alone (evaluable, N = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time. These results support further development of pramlintide/metreleptin as a novel, integrated neurohormonal approach to obesity pharmacotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2009
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17. Tu1392 Psychological Variables Add Incremental Value to Biological Markers in Differentiating IBS From Healthy Volunteers
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Jones, Michael P., Chey, William D., Gong, Hua, Shringarpure, Reshma, Chuang, Emil, Singh, Sharat, and Talley, Nicholas J.
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- 2012
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18. Tu1393 Real-World use of Alosetron: Results of a Multi-Center Observational Study
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Lacy, Brian E., Shringarpure, Reshma, and Chuang, Emil
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- 2012
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19. Tu1386 Alosetron Treatment Reduced Health Care Utilization and Improved Symptoms More Effectively Than Traditional Therapy in Women With Severe IBS-D
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Chey, William D., Shringarpure, Reshma, Nicandro, Jean Paul A., Chuang, Emil, and Olden, Kevin
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- 2012
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20. Ubiquitin Conjugation Is Not Required for the Degradation of Oxidized Proteins by Proteasome.
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Shringarpure, Reshma, Grune, Tilman, Mehlhase, Jana, and Davies, Kelvin J.A.
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UBIQUITIN , *PROTEINS , *ADENOSINE triphosphate - Abstract
Determines whether ubiquitin conjugation is necessary for the degradation of oxidized proteins in intact cells. Inhibition of degradation by proteasome inhibitors; Rates of oxidized protein degradation by cell lysates; Presence of adenosine triphosphate; Tendency of a protein to be ubiquitinylated.
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- 2003
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21. M1058 Alosetron is Associated With Improvements in Treatment Satisfaction and Quality of Life
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Nicandro, Jean Paul A., Shin, Paul, Shringarpure, Reshma, Chuang, Emil, and Pan, Henry
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- 2010
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22. 116-LB: Efruxifermin Is Associated with Improved Glucose Metabolism in Patients with NASH and Type 2 Diabetes.
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FRIAS, JUAN PABLO, SHRINGARPURE, RESHMA, TILLMAN, ERIK J., HU, CHEN, FONG, ERICA, DE TEMPLE, BRITTANY, ROLPH, TIMOTHY, CHENG, ANDREW, YALE, KITTY, and HARRISON, STEPHEN A.
- Abstract
A third of patients with type 2 diabetes (T2D) are estimated to have nonalcoholic steatohepatitis (NASH). There is a high unmet need for safe and effective therapies that can address liver health and metabolic comorbidities in NASH patients. Efruxifermin (EFX), a long-acting Fc-FGF21 fusion protein, demonstrated robust reductions in liver fat content, markers of liver injury and fibrosis, and improved lipid and glucose metabolism in patients with NASH and fibrosis stage 1-3.1 Patients (N=80) were randomized to receive placebo or 28, 50, or 70mg EFX for 16 weeks, and continued on their existing antidiabetic medications. The aim of this analysis was to evaluate the effects of EFX on markers of glucose metabolism in patients with NASH and in the subgroup with T2D (N=41). Mean age, BMI and HbA1c at baseline were 52y, 37.6 kg/m2 and 6.3% in the overall study population, and 53y, 38.1 kg/m2, and 7.0% in the T2D subgroup. Clinically meaningful improvements in glycemic control were observed in the T2D subgroup (Table B), consistent with improvements in markers of glucose metabolism in the overall population (Table A), and with the insulin-sensitizing actions of EFX. Considering the prevalence of T2D in NASH, the ability to improve glycemic control over existing medications is a desirable attribute for future NASH therapies. 1Harrison et. al. 2020. Hepatology, 72; 1S; 6A Disclosure: J. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker's Bureau; Self; Merck & Co., Inc., Sanofi. S. A. Harrison: Consultant; Self; Axcella Health Inc. R. Shringarpure: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. E. J. Tillman: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. C. Hu: None. E. Fong: Employee; Self; Akero Therapeutics, Inc. B. De temple: Employee; Self; Akero Therapeutics, Inc. T. Rolph: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Pfizer Inc. A. Cheng: Employee; Self; Akero Therapeutics, Inc. K. Yale: Employee; Self; Akero Therapeutics, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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23. 119-LB: Increased Adiponectin following Efruxifermin Treatment Is Associated with Improvements in Dyslipidemia, Glucose Metabolism, and Liver Health in a 16-Week, Randomized, Placebo-Controlled NASH Trial.
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FRIAS, JUAN PABLO, TILLMAN, ERIK J., SHRINGARPURE, RESHMA, FONG, ERICA, DE TEMPLE, BRITTANY, ROLPH, TIMOTHY, CHENG, ANDREW, YALE, KITTY, and HARRISON, STEPHEN A.
- Abstract
FGF21, an endocrine hormone that regulates whole-body metabolism during energy imbalance, is a promising therapeutic target. Efruxifermin (EFX), an Fc-FGF21 analog, is a balanced FGFR1c, 2c, and 3c agonist under investigation as a potential treatment for nonalcoholic steatohepatitis (NASH). In a clinical trial in biopsy-confirmed NASH, EFX significantly reduced liver fat content (LFC), ALT, and AST, and increased adiponectin.
1 Activating FGFR1c in adipose tissue increases circulating adiponectin; the aim of this analysis was to evaluate correlations between changes in adiponectin and markers of dyslipidemia, glucose metabolism and liver health following EFX treatment. Patients (N=80) were randomized to placebo or 28, 50, or 70mg EFX. Larger increases in adiponectin correlated with greater improvements in lipid profiles, including decreases in triglycerides and increases in HDL-C, as well as decreases in LFC (Table). Increases in adiponectin also correlated strongly with markers of improved glucose metabolism, and greater reductions in markers of liver injury and fibrosis. These data suggest adipose tissue-mediated effects of EFX contribute substantially to restoration of liver health, healthy lipoprotein profiles, insulin sensitivity and glucose tolerance.1 Harrison 2020 Hepatol 72 1S; 6A Disclosure: J. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker's Bureau; Self; Merck & Co., Inc., Sanofi. E. J. Tillman: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. R. Shringarpure: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. E. Fong: Employee; Self; Akero Therapeutics, Inc. B. De temple: Employee; Self; Akero Therapeutics, Inc. T. Rolph: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Pfizer Inc. A. Cheng: Employee; Self; Akero Therapeutics, Inc. K. Yale: Employee; Self; Akero Therapeutics, Inc. S. A. Harrison: Consultant; Self; Axcella Health Inc. [ABSTRACT FROM AUTHOR]- Published
- 2021
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24. Caveolin-1 Is Required for VEGF- Triggered Multiple Myeloma Cell Migration and Is Targeted by Bortezomib (Velcade®).
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Podar, Klaus, Shringarpure, Reshma, Tai, Yu-Tzu, Simoncini, Melissa, Sattler, Martin, Ishitsuka, Kenji, Richardson, Paul G., Hideshima, Teru, Chauhan, Dharminder, and Kenneth, Anderson C.
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- 2004
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25. NVP-AEW541: A Selective Small Molecule IGF-1R Tyrosine Kinase Inhibitor Is Active Against Multiple Myeloma and Other Hematologic Neoplasias and Solid Tumors.
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Mitsiades, Nicholas, McMullan, Ciaran J., Poulaki, Vassiliki, Shringarpure, Reshma, Libermann, Towia A., Hideshima, Teru, Chauhan, Dharminder, Schlossman, Robert L., Richardson, Paul G., Munshi, Nikhil C., Garcia-Echeverria, Carlos, Hoffmann, Francesco, Anderson, Kenneth C., and Mitsiades, Constantine S.
- Published
- 2004
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26. Inhibition of Human Plasmacytoma Cell Growth by a Novel JAK Kinase Inhibitor.
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Burger, Renate, Legouill, Steven, Tai, Yu-Tzu, Shringarpure, Reshma, Podar, Klaus, Catley, Laurence, Tassone, Pierfrancesco, Neri, Paola, Hideshima, Teru, Chauhan, Dharminder, Fridman, Jordan S., and Anderson, Kenneth C.
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- 2004
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27. Increased TCF-4 Expression Correlates with Reduced Caspase-3 Induction and Confers Resistance to Bortezomib.
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Shringarpure, Reshma, Bhole, Deepak, Burger, Renate, Catley, Laurence, Podar, Klaus, Tai, Yu-Tzu, Hideshima, Teru, Mitsiades, Constantine, Munshi, Nikhil C., Chauhan, Dharminder, and Anderson, Kenneth C.
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- 2004
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28. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial
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Zobair M Younossi, Vlad Ratziu, Rohit Loomba, Mary Rinella, Quentin M Anstee, Zachary Goodman, Pierre Bedossa, Andreas Geier, Susanne Beckebaum, Philip N Newsome, David Sheridan, Muhammad Y Sheikh, James Trotter, Whitfield Knapple, Eric Lawitz, Manal F Abdelmalek, Kris V Kowdley, Aldo J Montano-Loza, Jerome Boursier, Philippe Mathurin, Elisabetta Bugianesi, Giuseppe Mazzella, Antonio Olveira, Helena Cortez-Pinto, Isabel Graupera, David Orr, Lise Lotte Gluud, Jean-Francois Dufour, David Shapiro, Jason Campagna, Luna Zaru, Leigh MacConell, Reshma Shringarpure, Stephen Harrison, Arun J Sanyal, Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Cindy Cai, Amy Calderon, José Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrión, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Charlote Costentin, Kathleen Corey, Lynsey Corless, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Mamie Dong, Jean-François Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Marek Hartleb, Tarek Hassanein, Dieter Häussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Hyder Hussaini, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Shoba Joshi, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Scott Kuwada, Damien Labarriere, Michelle Lai, Wim Laleman, Pietro Lampertico, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Velimir Anthony Christopher Luketic, Yoav Lurie, Guilherme Macedo, Joana Magalhaes, Mihály Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Linda Martinez, Marlyn Mayo, Mark McCullen, William McLaughlin, Uta Merle, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Amilcar Morales Cardona, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Müller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Hans Orlent, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Sonali Paul, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Joseph Pisegna, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Justin Reynolds, Andres Riera, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Sandor Romero, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jörn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Albert Tran, Michael Trauner, Christian Trautwein, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Julia Wattacheril, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin, Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z., Bedossa P., Geier A., Beckebaum S., Newsome P.N., Sheridan D., Sheikh M.Y., Trotter J., Knapple W., Lawitz E., Abdelmalek M.F., Kowdley K.V., Montano-Loza A.J., Boursier J., Mathurin P., Bugianesi E., Mazzella G., Olveira A., Cortez-Pinto H., Graupera I., Orr D., Gluud L.L., Dufour J.-F., Shapiro D., Campagna J., Zaru L., MacConell L., Shringarpure R., Harrison S., Sanyal A.J., Abdelmalek M., Abrams G., Aguilar H., Ahmed A., Aigner E., Aithal G., Ala A., Alazawi W., Albillos A., Allison M., Al-Shamma S., Andrade R., Andreone P., Angelico M., Ankoma-Sey V., Anstee Q., Anty R., Araya V., Arenas Ruiz J.I., Arkkila P., Arora M., Asselah T., Au J., Ayonrinde O., Bailey R.J., Balakrishnan M., Bambha K., Bansal M., Barritt S., Bate J., Beato J., Behari J., Bellot P., Ben Ari Z., Bennett M., Berenguer M., Beretta-Piccoli B.T., Berg T., Bonacini M., Bonet L., Borg B., Bourliere M., Bowman W., Bradley D., Brankovic M., Braun M., Bronowicki J.-P., Bruno S., Cai C., Calleja Panero J.L., Carey E., Carmiel M., Carrion J.A., Cave M., Chagas C., Chami T., Chang A., Coates A., Cobbold J., Corey K., Corless L., Crespo J., Cruz Pereira O., de Ledinghen V., deLemos A., Diago M., Dugalic P., Dunn W., Elkhashab M., Epstein M., Escudero-Garcia M.D., Etzion O., Evans L., Falcone R., Fernandez C., Ferreira J., Fink S., Finnegan K., Firpi-Morell R., Floreani A., Fontanges T., Ford R., Forrest E., Fowell A., Fracanzani A.L., Francque S., Freilich B., Frias J., Fuchs M., Fuentes J., Galambos M., Gallegos J., Geerts A., George J., Ghali M., Ghalib R., Gholam P., Gines P., Gitlin N., Goeser T., Goff J., Gordon S., Gordon F., Goria O., Greer S., Grigorian A., Gronbaek H., Guillaume M., Gunaratnam N., Halegoua-De Marzio D., Hameed B., Hametner S., Hamilton J., Hartleb M., Hassanein T., Haussinger D., Hellstern P., Herring R., Heurich E., Hezode C., Hinrichsen H., Holland Fischer P., Horsmans Y., Huang J., Jakiche A., Jeffers L., Jones B., Jorge R., Jorquera F., Kahraman A., Kaita K., Karyotakis N., Kayali Z., Kechagias S., Kepczyk T., Khalili M., Khallafi H., Kluwe J., Kohli A., Korenblat K., Kowdley K., Krag A., Krause R., Kremer A., Krok K., Krstic M., Kugelmas M., Kumar S., Labarriere D., Lai M., Lampertico P., Lee A., Leroy V., Lidofsky S., Lim T.H., Lim J., Lipkis D., Little E., Lonardo A., Long M., Lurie Y., Macedo G., Makara M., Maliakkal B., Manns M., Manousou P., Mantry P., Marchesini G., Marinho C., Marotta P., Marschall H.-U., Mayo M., McCullen M., McLaughlin W., Merriman R., Modi A., Molina E., Montano-Loza A., Monteverde C., Moreea S., Moreno C., Morisco F., Mubarak A., Muellhaupt B., Mukherjee S., Muller T., Nagorni A., Naik J., Neff G., Nevah M., Newsome P., Nguyen-Khac E., Noureddin M., Oben J., Orlent H., Orr J., Ortiz-Lasanta G., Ozenne V., Pandya P., Paredes A., Park J., Patel J., Patel K., Uta M., Patton H., Peck-Radosavljevic M., Petta S., Pianko S., Piekarska A., Pimstone N., Pockros P., Pol S., Porayko M., Poulos J., Pound D., Pouzar J., Presa Ramos J., Pyrsopoulos N., Rafiq N., Muller K., Ramji A., Ravinuthala R., Reddy C., Reddy K G G., Reddy K R K.R., Regenstein F., Reindollar R., Riera A., Rivera Acosta J., Robaeys G., Roberts S., Rodriguez-Perez F., Romero-Gomez M., Rubin R., Rumi M., Rushbrook S., Rust C., Ryan M., Safadi R., Said A., Salminen K., Samuel D., Santoro J., Sanyal A., Sarkar S., Schaeffer C., Schattenberg J., Schiefke I., Schiff E., Schmidt W., Schneider J., Schouten J., Schultz M., Sebastiani G., Semela D., Sepe T., Sheikh A., Sheikh M., Sherman K., Shibolet O., Shiffman M., Siddique A., Sieberhagen C., Sigal S., Sikorska K., Simon K., Sinclair M., Skoien R., Solis J., Sood S., Souder B., Spivey J., Stal P., Stinton L., Strasser S., Svorcan P., Szabo G., Talal A., Tam E., Tetri B., Thuluvath P., Tobias H., Tomasiewicz K., Torres D., Trauner M., Trautwein C., Tsochatzis E., Unitt E., Vargas V., Varkonyi I., Veitsman E., Vespasiani Gentilucci U., Victor D., Vierling J., Vincent C., Vincze A., von der Ohe M., Von Roenn N., Vuppalanchi R., Waters M., Watt K., Weltman M., Wieland A., Wiener G., Williams A A., Williams J J., Wilson J., Yataco M., Yoshida E., Younes Z., Yuan L., Zivony A., Zogg D., Zoller H., Zoulim F., Zuckerman E., Zuin M., Repositório da Universidade de Lisboa, Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. -F., Shapiro, D., Campagna, J., Zaru, L., Macconell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., Al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. -P., Bruno, S., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrion, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Crespo, J., Cruz Pereira, O., de Ledinghen, V., Delemos, A., Diago, M., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-De Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Hartleb, M., Hassanein, T., Haussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. -U., Mayo, M., Mccullen, M., Mclaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Muller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Orlent, H., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., Von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., Zuin, M., Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andrea, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, Jame, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francoi, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert Jame, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thoma, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Mariu, Bronowicki, Jean-Pierre, Bruno, Savino, Cai, Cindy, Calleja Panero, José Lui, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Corey, Kathleen, Corless, Lynsey, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moise, Dufour, Jean-Françoi, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparado, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Goeser, Tobia, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, Jame, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yve, Huang, Jonathan, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nichola, Kayali, Zeid, Kechagias, Stergio, Kepczyk, Thoma, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johanne, Kohli, Anita, Korenblat, Kevin, Kowdley, Kri, Krag, Aleksander, Krause, Richard, Kremer, Andrea, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Labarriere, Damien, Lai, Michelle, Lampertico, Pietro, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Lurie, Yoav, Macedo, Guilherme, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Mayo, Marlyn, McCullen, Mark, McLaughlin, William, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlo, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobia, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moise, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Orlent, Han, Orr, Jame, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, Jame, Patel, Joykumar, Patel, Keyur, Uta, Merle, Patton, Heather, Peck-Radosavljevic, Marku, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pockros, Paul, Pol, Stanisla, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolao, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Riera, Andre, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thoma, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, Jame, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Trauner, Michael, Trautwein, Christian, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, Zuin, Massimo, and REGENERATE Study Investigators
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Male ,Biopsy ,Clinical Trial, Phase III ,Administration, Oral ,030204 cardiovascular system & hematology ,Chronic liver disease ,Settore MED/04 ,Biomarkers/analysis ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,Liver Function Tests ,Non-alcoholic Fatty Liver Disease ,Clinical endpoint ,Medicine ,030212 general & internal medicine ,610 Medicine & health ,Chenodeoxycholic Acid/administration & dosage ,education.field_of_study ,Liver Function Test ,Research Support, Non-U.S. Gov't ,Fatty liver ,Obeticholic acid ,NASH, OBETICHOLIC ACID ,General Medicine ,Middle Aged ,Multicenter Study ,Randomized Controlled Trial ,Administration ,Female ,Biomarkers ,Chenodeoxycholic Acid ,Double-Blind Method ,Humans ,Human ,Oral ,medicine.medical_specialty ,Population ,Placebo ,03 medical and health sciences ,Research Support, N.I.H., Extramural ,Internal medicine ,Journal Article ,education ,Intention-to-treat analysis ,business.industry ,Biomarker ,Interim analysis ,medicine.disease ,Non-alcoholic Fatty Liver Disease/drug therapy ,chemistry ,Human medicine ,business - Abstract
© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.
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- 2019
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29. A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis.
- Author
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Harrison SA, Ruane PJ, Freilich B, Neff G, Patil R, Behling C, Hu C, Shringarpure R, de Temple B, Fong E, Tillman EJ, Rolph T, Cheng A, and Yale K
- Abstract
Background & Aims: Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis., Methods: Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy., Results: Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] -9 μg/L efruxifermin vs. -3.4 μg/L placebo; p = 0.0130) and ELF score (-0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB -5.7 kPa efruxifermin vs. -1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients., Conclusions: Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies., Lay Summary: Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH., Clinical Trial Number: NCT03976401., Competing Interests: Stephen A. Harrison holds a leadership or fiduciary role at, advises, consults for, receives grants or contracts from Northsea Therapeutics. He advises, consults for, receives grants or contracts, support for attending meetings and/or travel from Madrigal Pharmaceuticals, Inc. He advises, consults for, and receives grants or contracts from Akero Therapeutics, Inc. He advises, consults for, and receives grants or contracts from Axcella Health, Inc., Cymabay Therapeutics, Inc., Galectin Therapeutics, Inc., Hepion Pharmaceuticals, Inc., Hightide Therapeutics, Inc., Intercept Pharmaceuticals, Inc., Metacrine Inc., NGM Biopharmaceuticals Inc., Genfit Corp, Novo Nordisk, Poxel, Sagimet Biosciences. He advises and receives grants or contracts from Gilead Sciences, Inc., Galmed Research & Dev. LTD., and Novartis Pharmaceuticals Corp. He consults for and receives grants or contracts from Viking Therapeutics, Inc. and Enyo Pharma S.A. He advises and consults for Altimmune, Echosens North America Inc. Foresite Labs, LLC, HistoIndex PTE LTD, Medpace Inc., Prometic, Pharma SMT LTD, Ridgeline and Sonic Incytes Medical Corp, Terns Inc. He advises for 89bio, Arrowhead, Chronwell, CiVi, Indalo, PathAI, and Theratechnologies. He consults for AgomAB, Alentis Therapeutics AG, Alimentiv, Inc, Boston Pharmaceuticals, B Riley FBR Inc. BVF Partners LP, Cohbar, Inc. Canfite, Corcept Therapeutics, Inc, Fibronostics, Fortress Biotech, Inc GNS, Inipharm, Ionis, Kowa Research Institute, Microba, Nutrasource, Perspectum Diagnostics, and Piper Sandler. He receives grants or contracts from Cirius Therapeutics, Inc., and CiVi Biopharma Inc. He holds stock or stock options at Akero Therapeutics, Inc., Chronwell Inc., Cirius Therapeutics, Inc, Galectin Therapeutics, Inc., Genfit Corp, Hepion Pharmaceuticals Inc., HistoIndex PTE LTD, Metacrine Inc., NGM Biopharmaceuticals., Northsea Therapeutics B.V, and Sonic Incytes Medical Corp. Peter J. Ruane: none. Bradley Freilich: none. Guy Neff has received payment or honoraria from Intercept Pharmaceuticals. Rashmee Patil has received grants to institution from 89 Bio, AltImmune, Boehringer Ingelheim, Bristol Myers Squibb, Corcept Therapeutics, Fibronostics, Galectin Therapeutics, Genentech, Gilead, Helio Health, Hepagene, Madrigal Pharmaceuticals, NGMBio, NorthSea Therapeutics, Poxel, Sagimet Biosciences, and Viking Therapeutics. He consults for Intercept Pharmaceuticals. Cynthia Behling has received payment via Pacific Rim Pathology for liver biopsy scoring. She has received grants as a co-investigator under N100 K U01 DK61734. She has received honoraria for lectures from Pfizer and Alimentev. She is a co-chair on NASH CRN Pathology Committee. Chen Hu: none. Reshma Shringarpure, Brittany de Temple, Erica Fong, Erik J. Tillman, Timothy Rolph, Andrew Cheng, and Kitty Yale are employees of Akero Therapeutics and own stock and/or stock options of Akero Therapeutics. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)
- Published
- 2022
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30. Janus kinase inhibitor INCB20 has antiproliferative and apoptotic effects on human myeloma cells in vitro and in vivo.
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Burger R, Le Gouill S, Tai YT, Shringarpure R, Tassone P, Neri P, Podar K, Catley L, Hideshima T, Chauhan D, Caulder E, Neilan CL, Vaddi K, Li J, Gramatzki M, Fridman JS, and Anderson KC
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Bone Marrow Cells drug effects, Bone Marrow Cells enzymology, Cell Proliferation drug effects, Cells, Cultured, Coculture Techniques, Cytoprotection drug effects, Dexamethasone pharmacology, Humans, Interleukin-6 genetics, Interleukin-6 metabolism, Janus Kinases genetics, Janus Kinases metabolism, Mice, Multiple Myeloma drug therapy, Phosphorylation drug effects, Protein Kinase Inhibitors therapeutic use, STAT3 Transcription Factor metabolism, Stromal Cells drug effects, Stromal Cells enzymology, Substrate Specificity, Survival Rate, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Apoptosis drug effects, Janus Kinases antagonists & inhibitors, Multiple Myeloma enzymology, Multiple Myeloma pathology, Protein Kinase Inhibitors pharmacology
- Abstract
Protein tyrosine kinases of the Janus kinase (JAK) family are associated with many cytokine receptors, which, on ligand binding, regulate important cellular functions such as proliferation, survival, and differentiation. In multiple myeloma, JAKs may be persistently activated due to a constant stimulation by interleukin (IL)-6, which is produced in the bone marrow environment. INCB20 is a synthetic molecule that potently inhibits all members of the JAK family with a 100- to 1,000-fold selectivity for JAKs over >70 other kinases. Treatment of multiple myeloma cell lines and patient tumor cells with INCB20 resulted in a significant and dose-dependent inhibition of spontaneous as well as IL-6-induced cell growth. Importantly, multiple myeloma cell growth was inhibited in the presence of bone marrow stromal cells. The IL-6 dependent cell line INA-6 was particularly sensitive to the drug (IC50<1 micromol/L). Growth suppression of INA-6 correlated with an increase in the percentage of apoptotic cells and inhibition of signal transducer and activator of transcription 3 phosphorylation. INCB20 also abrogated the protective effect of IL-6 against dexamethasone by blocking phosphorylation of SHP-2 and AKT. In contrast, AKT phosphorylation induced by insulin-like growth factor-I remained unchanged, showing selectivity of the compound. In a s.c. severe combined immunodeficient mouse model with INA-6, INCB20 significantly delayed INA-6 tumor growth. Our studies show that disruption of JAKs and downstream signaling pathways may both inhibit multiple myeloma cell growth and survival and overcome cytokine-mediated drug resistance, thereby providing the preclinical rationale for the use of JAK inhibitors as a novel therapeutic approach in multiple myeloma.
- Published
- 2009
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31. Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells.
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Altun M, Galardy PJ, Shringarpure R, Hideshima T, LeBlanc R, Anderson KC, Ploegh HL, and Kessler BM
- Subjects
- Animals, Bone Marrow immunology, Bortezomib, Cell Line, Tumor, Cytokines pharmacology, HeLa Cells, Humans, Interferon-gamma pharmacology, Mice, Multiple Myeloma immunology, Boronic Acids pharmacology, Multiple Myeloma drug therapy, Multiple Myeloma enzymology, Protease Inhibitors pharmacology, Proteasome Endopeptidase Complex metabolism, Proteasome Inhibitors, Pyrazines pharmacology
- Abstract
Multiple myeloma is a B-cell malignancy for which no curative therapies exist to date, despite enormous research efforts. The remarkable activity of the proteasome inhibitor bortezomib (PS-341, Velcade) observed in clinical trials of patients with relapsed refractory myeloma has led to investigations of the role of the ubiquitin-proteasome pathway in the pathogenesis of myeloma. Here we report a biochemical analysis of proteasome activity and composition in myeloma cells exposed to PS-341 in the presence or absence of cytokines present in the bone marrow milieu. We observed that the myeloma cell lines MM1.S, RPMI8226, and U266 contain active immunoproteasomes, the amount of which is enhanced by IFN-gamma and tumor necrosis factor-alpha. Using a radiolabeled active site-directed probe specific for proteasome catalytic subunits, we show that PS-341 targets the beta5 and beta1 subunits in a concentration-dependent manner. Furthermore, PS-341 also targeted the corresponding catalytic subunits of the immunoproteasome, beta5i and beta1i, respectively. These data suggest that PS-341 targets both normal and immunoproteasome species to a similar extent in myeloma cells.
- Published
- 2005
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32. Proteasomal degradation of topoisomerase I is preceded by c-Jun NH2-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage in SN38-mediated cytotoxicity against multiple myeloma.
- Author
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Catley L, Tai YT, Shringarpure R, Burger R, Son MT, Podar K, Tassone P, Chauhan D, Hideshima T, Denis L, Richardson P, Munshi NC, and Anderson KC
- Subjects
- Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Apoptosis physiology, Bone Marrow Cells drug effects, Bone Marrow Cells pathology, Boronic Acids administration & dosage, Boronic Acids pharmacology, Bortezomib, Cell Communication drug effects, Cell Line, Tumor, DNA, Neoplasm biosynthesis, Doxorubicin administration & dosage, Doxorubicin pharmacology, Drug Synergism, Enzyme Activation, Humans, Irinotecan, Lymphoma drug therapy, Lymphoma enzymology, Lymphoma genetics, Lymphoma pathology, Multiple Myeloma enzymology, Multiple Myeloma genetics, Multiple Myeloma pathology, Pyrazines administration & dosage, Pyrazines pharmacology, Signal Transduction drug effects, Signal Transduction physiology, Stromal Cells drug effects, Stromal Cells pathology, Up-Regulation drug effects, fas Receptor genetics, fas Receptor immunology, Camptothecin analogs & derivatives, Camptothecin pharmacology, DNA Topoisomerases, Type I metabolism, JNK Mitogen-Activated Protein Kinases metabolism, Multiple Myeloma drug therapy, Poly(ADP-ribose) Polymerases metabolism, Proteasome Endopeptidase Complex metabolism, fas Receptor biosynthesis
- Abstract
Topoisomerase I inhibitors are effective anticancer therapies and have shown activity in hematologic malignancies. Here we show for the first time that SN38, the potent active metabolite of irinotecan, induces c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and caspase 8-mediated apoptosis in multiple myeloma (MM) cells. Proteasomal degradation of nuclear topoisomerase I has been proposed as a resistance mechanism in solid malignancies. SN38-induced proteasomal degradation of topoisomerase I was observed during SN38-mediated cytotoxicity against MM.1S myeloma cell line but occurred after c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage and failed to protect cells from apoptosis. Differential toxicity was observed against MM cells versus bone marrow stromal cells, and SN38 inhibited adhesion-induced up-regulation of MM cell proliferation when MM cells adhere to bone marrow stromal cells. In addition, SN38 directly inhibited constitutive and inducible interleukin 6 and vascular endothelial growth factor secretion by bone marrow stromal cells. Synergy was observed when SN38 was used in combination with doxorubicin, bortezomib, as well as poly(ADP-ribose) polymerase inhibitor NU1025 and Fas-activator CH11. These findings have clinical significance, because identification of downstream apoptotic signaling after topoisomerase I inhibition will both elucidate mechanisms of resistance and optimize future combination chemotherapy against MM.
- Published
- 2004
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33. Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib.
- Author
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Podar K, Shringarpure R, Tai YT, Simoncini M, Sattler M, Ishitsuka K, Richardson PG, Hideshima T, Chauhan D, and Anderson KC
- Subjects
- Bone Marrow metabolism, Bortezomib, Caveolin 1, Caveolins biosynthesis, Caveolins genetics, Cell Line, Tumor, Cell Movement drug effects, Cell Movement physiology, Crk-Associated Substrate Protein, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Humans, Multiple Myeloma genetics, Multiple Myeloma metabolism, Multiple Myeloma pathology, Phosphorylation, Proteins metabolism, Recombinant Proteins pharmacology, Retinoblastoma-Like Protein p130, Transfection, Tyrosine metabolism, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, src-Family Kinases metabolism, Antineoplastic Agents pharmacology, Boronic Acids pharmacology, Caveolins metabolism, Pyrazines pharmacology, Vascular Endothelial Growth Factor A pharmacology
- Abstract
We recently demonstrated that caveolae, vesicular flask-shaped invaginations of the plasma membrane, represent novel therapeutic targets in multiple myeloma. In the present study, we demonstrate that vascular endothelial growth factor (VEGF) triggers Src-dependent phosphorylation of caveolin-1, which is required for p130(Cas) phosphorylation and multiple myeloma cell migration. Conversely, depletion of caveolin-1 by antisense methodology abrogates p130(Cas) phosphorylation and VEGF-triggered multiple myeloma cell migration. The proteasome inhibitor bortezomib both inhibited VEGF-triggered caveolin-1 phosphorylation and markedly decreased caveolin-1 expression. Consequently, bortezomib inhibited VEGF-induced multiple myeloma cell migration. Bortezomib also decreased VEGF secretion in the bone marrow microenvironment and inhibited VEGF-triggered tyrosine phosphorylation of caveolin-1, migration, and survival in human umbilical vascular endothelial cells. Taken together, these studies demonstrate the requirement of caveolae for VEGF-triggered multiple myeloma cell migration and identify caveolin-1 in multiple myeloma cells and human umbilical vascular endothelial cells as a molecular target of bortezomib.
- Published
- 2004
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34. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance.
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Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Catley L, Tai YT, Hayashi T, Shringarpure R, Burger R, Munshi N, Ohtake Y, Saxena S, and Anderson KC
- Subjects
- Apoptosis drug effects, Caspase 3, Caspase 9, Caspases metabolism, Cell Line, Tumor, HSP27 Heat-Shock Proteins, Humans, Immunomagnetic Separation, Interleukin-6 pharmacology, Molecular Chaperones, Multiple Myeloma metabolism, Neoplasm Proteins physiology, Oligonucleotides, Antisense pharmacology, Tumor Cells, Cultured, Dexamethasone pharmacology, Drug Resistance, Neoplasm, Heat-Shock Proteins physiology, Multiple Myeloma pathology
- Abstract
Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.
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- 2003
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35. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells.
- Author
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Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T, and Anderson KC
- Subjects
- Apoptosis drug effects, Bortezomib, Cell Line, Tumor, Cell Survival drug effects, Cysteine Endopeptidases, Drug Resistance, Neoplasm, HSP27 Heat-Shock Proteins, Humans, Leupeptins pharmacology, Lymphoma enzymology, Lymphoma genetics, Lymphoma pathology, Molecular Chaperones, Multienzyme Complexes antagonists & inhibitors, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Neoplasm Proteins physiology, Proteasome Endopeptidase Complex, RNA, Messenger genetics, RNA, Messenger metabolism, Transfection, Boronic Acids pharmacology, Heat-Shock Proteins, Lymphoma drug therapy, Neoplasm Proteins antagonists & inhibitors, Pyrazines pharmacology
- Abstract
Bortezomib (PS-341), a selective inhibitor of proteasome, induces apoptosis in various tumor cells, but its mechanism of action is unclear. Treatment with PS-341 induces apoptosis in SUDHL6 (DHL6), but not SUDHL4 (DHL4), lymphoma cells. Microarray analysis shows high RNA levels of heat shock protein-27 (Hsp27) in DHL4 versus DHL6 cells, which correlates with Hsp27 protein expression. Blocking Hsp27 using an antisense strategy restores the apoptotic response to PS-341 in DHL4 cells; conversely, ectopic expression of wild-type Hsp27 renders PS-341-sensitive DHL6 cells resistant to PS-341. These findings provide the first evidence that Hsp27 confers PS-341 resistance.
- Published
- 2003
36. Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3'-kinase/AKT signaling.
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Tai YT, Podar K, Catley L, Tseng YH, Akiyama M, Shringarpure R, Burger R, Hideshima T, Chauhan D, Mitsiades N, Richardson P, Munshi NC, Kahn CR, Mitsiades C, and Anderson KC
- Subjects
- Antibodies, Monoclonal pharmacology, Cell Adhesion drug effects, Cell Adhesion physiology, Cell Line, Tumor, Cell Movement drug effects, Cell Movement physiology, Enzyme Activation, Fibronectins metabolism, Humans, Insulin-Like Growth Factor I antagonists & inhibitors, Insulin-Like Growth Factor I pharmacology, Integrin beta1 metabolism, Membrane Glycoproteins metabolism, Membrane Microdomains metabolism, Mitogen-Activated Protein Kinase 1 antagonists & inhibitors, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinases metabolism, Oligopeptides pharmacology, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors, Proteoglycans metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Receptor Cross-Talk physiology, Receptor, IGF Type 1 metabolism, Receptor, IGF Type 1 physiology, Signal Transduction physiology, Syndecan-1, Syndecans, Insulin-Like Growth Factor I physiology, Integrin beta1 physiology, Multiple Myeloma enzymology, Multiple Myeloma pathology, Phosphatidylinositol 3-Kinases physiology, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins physiology
- Abstract
Insulin-like growth factor-1 (IGF-I) is a growth and survival factor in human multiple myeloma (MM) cells. Here we examine the effect of IGF-I on MM cell adhesion and migration, and define the role of beta1 integrin in these processes. IGF-I increases adhesion of MM.1S and OPM6 MM cells to fibronectin (FN) in a time- and dose-dependent manner, as a consequence of IGF-IR activation. Conversely, blocking anti-beta1 integrin monoclonal antibody, RGD peptide, and cytochalasin D inhibit IGF-I-induced cell adhesion to FN. IGF-I rapidly and transiently induces association of IGF-IR and beta1 integrin, with phosphorylation of IGF-IR, IRS-1, and p85(PI3-K). IGF-I also triggers phosphorylation of AKT and ERK significantly. Both IGF-IR and beta1 integrin colocalize to lipid rafts on the plasma membrane after IGF-I stimulation. In addition, IGF-I triggers polymerization of F-actin, induces phosphorylation of p125(FAK) and paxillin, and enhances beta1 integrin interaction with these focal adhesion proteins. Importantly, using pharmacological inhibitors of phosphatidylinositol 3'-kinase (PI3-K) (LY294002 and wortmannin) and extracellular signal-regulated kinase (PD98059), we demonstrate that IGF-I-induced MM cell adhesion to FN is achieved only when PI3-K/AKT is activated. IGF-I induces a 1.7-2.2 (MM.1S) and 2-2.5-fold (OPM6) increase in migration, whereas blocking anti-IGF-I and anti-beta1 integrin monoclonal antibodies, PI3-K inhibitors, as well as cytochalasin D abrogate IGF-I-induced MM cell transmigration. Finally, IGF-I induces adhesion of CD138+ patient MM cells. Therefore, these studies suggest a role for IGF-I in trafficking and localization of MM cells in the bone marrow microenvironment. Moreover, they define the functional association of IGF-IR and beta1 integrin in mediating MM cell homing, providing the preclinical rationale for novel treatment strategies targeting IGF-I/IGF-IR in MM.
- Published
- 2003
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