11 results on '"Brady Stein"'
Search Results
2. Supplementary Table from LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms
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John D. Crispino, Ayalew Tefferi, Grant A. Challen, Raajit K. Rampal, Ross L. Levine, Navdeep S. Chandel, Panagiotis Ntziachristos, Naseema Gangat, Ronald Hoffman, Scott T. Younger, David E. Root, Sandeep Gurbuxani, Michael Schieber, Brady Stein, Noushin Farnoud, Christopher A. Famulare, Richard P. Koche, Terra Lasho, Marinka Bulic, Te Ling, Qiang Jeremy Wen, Andrew Volk, Hamza Celik, Praveen Suraneni, and Christian Marinaccio more...
- Abstract
Supplementary Table from LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms
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- 2023
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Catalog
3. Data from LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms
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John D. Crispino, Ayalew Tefferi, Grant A. Challen, Raajit K. Rampal, Ross L. Levine, Navdeep S. Chandel, Panagiotis Ntziachristos, Naseema Gangat, Ronald Hoffman, Scott T. Younger, David E. Root, Sandeep Gurbuxani, Michael Schieber, Brady Stein, Noushin Farnoud, Christopher A. Famulare, Richard P. Koche, Terra Lasho, Marinka Bulic, Te Ling, Qiang Jeremy Wen, Andrew Volk, Hamza Celik, Praveen Suraneni, and Christian Marinaccio more...
- Abstract
The myeloproliferative neoplasms (MPN) frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/Stk11 led to enhanced in vitro self-renewal of murine MPN cells. Deletion of Stk11 in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis, and an accumulation of immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells in vivo. LKB1 loss was associated with increased mitochondrial reactive oxygen species and stabilization of HIF1α, and downregulation of LKB1 and increased levels of HIF1α were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that STK11 is a tumor suppressor in the MPNs.Significance:Progression of the myeloproliferative neoplasms to acute myeloid leukemia occurs in a substantial number of cases, but the genetic basis has been unclear. We discovered that loss of LKB1/STK11 leads to stabilization of HIF1a and promotes disease progression. This observation provides a potential therapeutic avenue for targeting progression.This article is highlighted in the In This Issue feature, p. 1307 more...
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- 2023
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4. Data from Aurora Kinase A Inhibition Provides Clinical Benefit, Normalizes Megakaryocytes, and Reduces Bone Marrow Fibrosis in Patients with Myelofibrosis: A Phase I Trial
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John D. Crispino, Brady Stein, Ayalew Tefferi, Francis J. Giles, Raajit K. Rampal, Peng Ji, Juehua Gao, Amber Thomassen, Dalissa Tejera, Juan Carlos Nobrega, Shradha Patel, Kristen Englund Prahl, Yvonne Trang Dinh, Aref Al-kali, Mrinal M. Patnaik, Darci Zblewski, Amy Handlogten, Amy Graf, Stephanie Barath, Rangit R. Vallapureddy, Roberto Tapia, Akshar Patel, Christopher A. Famulare, Noushin Farnoud, Qiang Jeremy Wen, Jessica K. Altman, Olga Frankfurt, Angela J. Fought, Alfred Rademaker, Sandeep Gurbuxani, Justin M. Watts, Ronan Swords, Christian Marinaccio, and Naseema Gangat more...
- Abstract
Purpose:Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis.Patients and Methods:Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis.Results:In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients.Conclusions:Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.See related commentary by Piszczatowski and Steidl, p. 4868 more...
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- 2023
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5. Supplementary Data from Aurora Kinase A Inhibition Provides Clinical Benefit, Normalizes Megakaryocytes, and Reduces Bone Marrow Fibrosis in Patients with Myelofibrosis: A Phase I Trial
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John D. Crispino, Brady Stein, Ayalew Tefferi, Francis J. Giles, Raajit K. Rampal, Peng Ji, Juehua Gao, Amber Thomassen, Dalissa Tejera, Juan Carlos Nobrega, Shradha Patel, Kristen Englund Prahl, Yvonne Trang Dinh, Aref Al-kali, Mrinal M. Patnaik, Darci Zblewski, Amy Handlogten, Amy Graf, Stephanie Barath, Rangit R. Vallapureddy, Roberto Tapia, Akshar Patel, Christopher A. Famulare, Noushin Farnoud, Qiang Jeremy Wen, Jessica K. Altman, Olga Frankfurt, Angela J. Fought, Alfred Rademaker, Sandeep Gurbuxani, Justin M. Watts, Ronan Swords, Christian Marinaccio, and Naseema Gangat more...
- Abstract
Figure S1: Alisertib treatment did not result in a consistent cytokine response. Figure S2: Alisertib did not have a consistent effect on TGF-b levels. Figure S3: Alisertib induced GATA1 expression in the SET2 megakaryocytic cell line. Figure S4: AURKA inhibition induces megakaryocytic gene expression. Figure S5: Alisertib increases GATA1 expression in the bone marrow of patients on therapy. Table S1: Correlation of Genotype and prior JAK inhibitor therapy with response and adverse events Table S2: Summary of Treatment Related Adverse Events Table S3: Association between GATA1 staining, degree of fibrosis and clinical response more...
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- 2023
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6. LKB1
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Christian, Marinaccio, Praveen, Suraneni, Hamza, Celik, Andrew, Volk, Qiang Jeremy, Wen, Te, Ling, Marinka, Bulic, Terra, Lasho, Richard P, Koche, Christopher A, Famulare, Noushin, Farnoud, Brady, Stein, Michael, Schieber, Sandeep, Gurbuxani, David E, Root, Scott T, Younger, Ronald, Hoffman, Naseema, Gangat, Panagiotis, Ntziachristos, Navdeep S, Chandel, Ross L, Levine, Raajit K, Rampal, Grant A, Challen, Ayalew, Tefferi, and John D, Crispino more...
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Mice, Inbred C57BL ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,Mice ,Myeloproliferative Disorders ,Mutation ,Disease Progression ,food and beverages ,Animals ,Genes, Tumor Suppressor ,AMP-Activated Protein Kinases ,Article - Abstract
The myeloproliferative neoplasms frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/Stk11 led to enhanced in vitro self-renewal of murine MPN cells. Deletion of Stk11 in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis and an accumulation immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells in vivo. LKB1 loss was associated with increased mitochondrial ROS and stabilization of HIF1a, and downregulation of LKB1 and increased levels of HIF1a were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that STK11 is a tumor suppressor in the MPNs. more...
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- 2020
7. Novel Therapies in the Classical BCR-ABL Negative Myeloproliferative Neoplasms
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Brady Stein
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- 2015
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8. Phase 1/2 Study of NS-018, an Oral JAK2 Inhibitor, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (postPV MF), or Post-Essential Thrombocythemia Myelofibrosis (postET MF)
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Srdan Verstovsek, Moshe Talpaz, Ellen K. Ritchie, Martha Wadleigh, Olatoyosi Odenike, Catriona Jamieson, Brady Stein, Candido E. Rivera, Tomonori Uno, and Ruben A. Mesa
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2).In the previously-reported Phase 1 portion, patients with myelofibrosis (MF) who received NS-018 achieved steady-state plasma levels above the IC50 for JAK2 at all doses (75mg QD - 400 mg BID). 300 mg QD was chosen as the recommended dose (RD) for Phase 2 portion of the study. OBJECTIVE: The purpose of this study was to determine the safety, tolerability and efficacy of orally-administered NS-018 in patients with PMF, post-PV MF, or post-ET MF. METHODS: This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, post-PV MF, or post-ET MF. NS-018 was dosed orally daily (QD) or twice daily (BID) in 28-day cycles. In Phase 1, changes in spleen size were assessed by manual palpation, quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF), and responses according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis was evaluated by biopsy, according to standard practice at the sites. Changes from baseline in grade of BM fibrosis were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study is complete. In the ongoing Phase 2 portion, spleen size is being assessed by palpation and by centrally-read MRI, and quality of life evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). RESULTS: 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID) in Phase 1. Patient characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF; median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor. The data cutoff for this analysis was June 30, 2016 (median follow-up time of 279.5 [range 5-1806] days from screening), at which time 10 patients remained on treatment. The median number of treatment cycles was 10 (1-65). Reasons for treatment discontinuation were disease progression (PD, n = 13), adverse events (AE, n = 8), physician consideration (n = 6), patient request (n = 4), and protocol non-compliance (n = 1). The 300 mg QD dose was selected as the phase 2 recommended dose (P2RD) in terms of tolerability and efficacy. For the 48 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including patients with priorJAK2 inhibitor treatment. Among 36 splenic-evaluable patients with baseline splenomegaly > 5 cm and treatment for > 1 cycle, 20 (56%) showed > 50% reduction in spleen size (confirmed for > 8 weeks in 16 patients), including 9/19 (47%) patients with prior JAK2 treatment. According to IWG criteria, 14/36 (39%) patients showed splenic clinical improvement for > 8 weeks, 4 with hemoglobin CI, and 1 with platelet CI. Twenty-nine patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Patient characteristics: 13 PMF, 12 post-PV MF, 4 post-ET MF; median age (range) 67 yrs (48-86). The reason for discontinuation of prior JAK2 inhibitor treatment: AEs (62%) and PD (38%). To date, the median number of treatment cycles is 6 (1-20). The majority of grade 3/4 AEs were hematologic and the most common hematologic toxicities were anemia (21%) and thrombocytopenia (17%). Non-hematologic AEs were mostly grade 1/2, and the other AEs shown in > 10% of patients was nausea (14%). Updated Phase 2 efficacy and safety data will be presented at the meeting. CONCLUSIONS: The RP2D dose of NS-018 was 300 mg QD. This dose provided a durable dosing schedule, an acceptable safety profile, splenic size reductions and clinical symptom improvement. Phase 2 is ongoing and includes patients previously treated with a different JAK2 inhibitor. Disclosures Talpaz: Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Ritchie:Pfizer: Honoraria; Arian: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Honoraria; Incyte: Speakers Bureau. Odenike:Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jamieson:GlaxoSmithKline: Research Funding; CTI Biopharma: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. more...
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- 2016
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9. Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis
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Rita Rastogi, Kalyani, Brady, Stein, Ritu, Valiyil, Rebecca, Manno, Janet W, Maynard, and Deidra C, Crews
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Aged, 80 and over ,Male ,Dietary Supplements ,Humans ,Accidental Falls ,Female ,Vitamins ,Vitamin D ,Aged - Abstract
To systematically review and quantitatively synthesize the effect of vitamin D therapy on fall prevention in older adults.Systematic review and meta-analysis.MEDLINE, CINAHL, Web of Science, EMBASE, Cochrane Library, LILACS, bibliographies of selected articles, and previous systematic reviews through February 2009 were searched for eligible studies.Older adults (agedor = 60) who participated in randomized controlled trials that both investigated the effectiveness of vitamin D therapy in the prevention of falls and used an explicit fall definition.Two authors independently extracted data, including study characteristics, quality assessment, and outcomes. The I(2) statistic was used to assess heterogeneity in a random-effects model.Of 1,679 potentially relevant articles, 10 met inclusion criteria. In pooled analysis, vitamin D therapy (200-1,000 IU) resulted in 14% (relative risk (RR)=0.86, 95% confidence interval (CI)=0.79-0.93; I(2)=7%) fewer falls than calcium or placebo (number needed to treat =15). The following subgroups had significantly fewer falls: community-dwelling (aged80), adjunctive calcium supplementation, no history of fractures or falls, duration longer than 6 months, cholecalciferol, and dose of 800 IU or greater. Meta-regression demonstrated no linear association between vitamin D dose or duration and treatment effect. Post hoc analysis including seven additional studies (17 total) without explicit fall definitions yielded smaller benefit (RR=0.92, 95% CI=0.87-0.98) and more heterogeneity (I(2)=36%) but found significant intergroup differences favoring adjunctive calcium over none (P=.001).Vitamin D treatment effectively reduces the risk of falls in older adults. Future studies should investigate whether particular populations or treatment regimens may have greater benefit. more...
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- 2010
10. First impressions
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Kristi V. Mizelle, Ritu Valiyil, Brady Stein, and Allan C. Gelber
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Adult ,Male ,Behcet Syndrome ,Anti-Inflammatory Agents ,Humans ,Prednisone ,General Medicine ,Colchicine ,Methylprednisolone - Published
- 2008
11. Alisertib in Treating Patients With Myelofibrosis or Relapsed or Refractory Acute Megakaryoblastic Leukemia
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The Leukemia and Lymphoma Society, Millennium Pharmaceuticals, Inc., National Cancer Institute (NCI), and Brady Stein, Principal Investigator
- Published
- 2021
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