9 results on '"James Butler"'
Search Results
2. Classical Hematology Referrals at an NCI-Designated Cancer Center: Lessons Learned
- Author
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Chase West, Matthew James Butler, Supreet Kaur, and Anand Karnad
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Combination of Phosphodiesterase 4 (PDE4) Inhibitor Roflumilast and R-CHOP As First-Line Therapy for High-Risk Diffuse Large B Cell Lymphoma Patients
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Ricardo C.T. Aguiar, Adolfo E Diaz, Anand B. Karnad, and Matthew James Butler
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Cardiotoxicity ,Bevacizumab ,business.industry ,Immunology ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphoma ,Leukemia ,chemistry.chemical_compound ,chemistry ,hemic and lymphatic diseases ,Ibrutinib ,medicine ,Cancer research ,business ,Diffuse large B-cell lymphoma ,Roflumilast ,medicine.drug - Abstract
R-CHOP remains the standard therapy for diffuse large B cell lymphoma (DLBCL), even though long-term disease free survival is achieved in only ~60-70% of the patients. One approach to improve on this cure rate is to implement rationally devised therapeutic strategies that capitalize on a better understanding of lymphoma biology, and on robust pre-clinical data. Still, in many instances clinical translation is limited by the difficulty in inhibiting key lymphomagenic proteins (e.g., MYC), or by subpar clinical responses and/or toxicity associated with the use of inhibitors to well-validated targets (e.g., SYK, BTK, PI3K, VEGF, etc.). Using genome-wide studies, we identified high expression of phosphodiesterase 4B (PDE4B) in fatal DLBCLs (Nat Med. PMID: 11786909). PDE4 hydroxylases cyclic adenosine monophosphate (cAMP) thus terminating its inhibitory signals and promoting B lymphocytes survival. Using in vitro and in vivo models, we showed that PDE4 inhibition augments cAMP signals and suppresses PI3K-AKT activity in DLBCL (Blood, PMID: 15331441). We mapped these events to SYK inhibition downstream of the B cell receptor (BCR) (Blood, PMID: 19369227). PDE4 inhibitors also suppress the pro-angiogenic lymphoma microenvironment by directly inhibiting the endothelium, and by decreasing VEGF production/secretion by the lymphoma cells, as we showed in a mouse engineered to develop lymphoma in a Pde4b KO background (Leukemia, PMID: 26503641). Earlier, we built on these pre-clinical data to test the safety and pharmacodynamics of the PDE4 inhibitor roflumilast (FDA-approved for COPD) in patients with relapsed/refractory mature B cell malignancies. In that first-in-cancer drug-repurposing study (NCT01888952), we found that roflumilast was well tolerated, clinically active, and that it suppressed PI3K activity, which correlated with the degree of clinical response (Clin. Cancer Res PMID: 27542768). Aberrant BCR signaling and angiogenesis are integral to the pathogenesis of DLBCL. Yet, combination of either ibrutinib or bevacizumab with R-CHOP was not beneficial in this disease. Thus, considering the pleiotropic anti-lymphoma properties of PDE4 inhibitors (seeBloodPMID: 27756749), which includes BCR suppression and anti-angiogenesis, we opened a trial to test the combination of roflumilast with R-CHOP in treatment naïve DLBCLs (NCT03458546). This is a single center, phase Ib, open label, non-randomized single arm study of roflumilast + R-CHOP (RR-CHOP) aimed at untreated high-risk DLBCL patients. Key eligibility criteria include: non-GCB DLBCL (Han's algorithm), NCCN-IPI risk score of ≥ 2, Ann Arbor stage II-IV; key exclusion criteria include active CNS involvement and documented history of severe depression (a specific concern related to the use of roflumilast). Patients will receive R-CHOP every 21 days for 6 cycles, and roflumilast PO daily (500 mcg) throughout the 18-week treatment period. Given the anti-angiogenic properties of PDE4 inhibitors that we documented pre-clinically, and the prohibitive cardiotoxicity of bevacizumab + R-CHOP combination, we will monitor serum levels of troponin and B-type natriuretic peptide, as biomarkers for cardiac toxicity. In addition, PBMC, plasma and urine samples will be collected for measurement SYK/PI3K/AKT activity and VEGF levels at baseline and before cycles 3 and 6. Exome sequencing of germline and tumor DNA is to be performed too. Adverse events will be assessed and documented according to the CTCAE version 4.03 criteria. Eligible patients will be included in the intent-to-treat analysis. The primary objective of this study is to test safety and tolerability of RR-CHOP; the secondary objectives are to preliminarily assess anti-tumor efficacy of the combination and the biomarker potential of SYK/PI3K/AKT activity and VEGF levels. Given its exploratory nature, this study was designed for a cohort of 10 patients, in which no statistical assessment of response or sample size calculation was included. To date, we have met ~50% of the target accrual, with half of those patients being of Hispanics ethnicity. If RR-CHOP is proven safe, the next step will be to initiate a randomized trial that compares RR-CHOP to R-CHOP in untreated DLBCL patients, which should conclusively validate (or refute) our extensive, biologically-informed, pre-clinically data on the benefits of PDE4 inhibitors for the treatment of mature B cell malignancies. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: roflumilast - PDE4 inhibitor, FDA-approved for COPD patients.
- Published
- 2019
4. Short survival of phosphatidylserine-exposing red blood cells in murine sickle cell anemia
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Renee K. Emerson, Narla Mohandas, Kitty de Jong, James Butler, Jacob Bastacky, and Frans A. Kuypers
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Male ,Hemolytic anemia ,Erythrocytes ,Recombinant Fusion Proteins ,Hemoglobin, Sickle ,Immunology ,Mice, Transgenic ,Spleen ,Anemia, Sickle Cell ,Phosphatidylserines ,Biology ,Biochemistry ,Membrane Lipids ,Mice ,Reticulocyte ,medicine ,Animals ,Humans ,Biotinylation ,Erythropoiesis ,Red Cell ,Erythrocyte Membrane ,beta-Thalassemia ,Erythrocyte Aging ,Cell Biology ,Hematology ,Flow Cytometry ,medicine.disease ,Sickle cell anemia ,Globins ,Oxygen ,Red blood cell ,medicine.anatomical_structure ,Models, Animal ,Cancer research ,Female ,Bone marrow - Abstract
Several transgenic murine models for sickle cell anemia have been developed that closely reproduce the biochemical and physiological disorders in the human disease. A comprehensive characterization is described of hematologic parameters of mature red blood cells, reticulocytes, and red cell precursors in the bone marrow and spleen of a murine sickle cell model in which erythroid cells expressed exclusively human α, γ, and βS globin. Red cell survival was dramatically decreased in these anemic animals, partially compensated by considerable enhancement in erythropoietic activity. As in humans, these murine sickle cells contain a subpopulation of phosphatidylserine-exposing cells that may play a role in their premature removal. Continuous in vivo generation of this phosphatidylserine-exposing subset may have a significant impact on the pathophysiology of sickle cell disease.
- Published
- 2001
5. Molecular characterization of a transformation from primary myelofibrosis into polycythemia vera: a case report
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Matthew James Butler, Paul Roda, and Patrick Dorion
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Transformation (genetics) ,Polycythemia vera ,business.industry ,Immunology ,medicine ,Cancer research ,Cell Biology ,Hematology ,medicine.disease ,business ,Myelofibrosis ,Biochemistry - Abstract
To the editor: Transformation of polycythemia vera (PV) into post-PV myelofibrosis (MF) occurs at a rate of 5.1 per 1000 person-years.[1][1] The reverse of this transformation, from MF to PV, has been described[2][2][⇓][3][⇓][4]-[5][5] but is rare, and these cases predate testing for the
- Published
- 2013
6. An RNAi-Therapeutic Targeting Tmprss6, in Conjunction With Oral Chelator Therapy, Ameliorates Anemia and Additively Diminishes Secondary Iron Overload In a Mouse Model Of β-Thalassemia Intermedia
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Paul J. Schmidt, Tim Racie, James Butler, Mark D. Fleming, and Kevin Fitzgerald
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Ineffective erythropoiesis ,medicine.medical_specialty ,Reticulocytosis ,Anemia ,Thalassemia ,Immunology ,Cell Biology ,Hematology ,Biology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Hepcidin ,Internal medicine ,medicine ,biology.protein ,HAMP ,medicine.symptom ,Deferiprone ,Hemojuvelin - Abstract
β-Thalassemias are a group of inherited blood disorders caused by loss of β-globin synthesis and are characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis leading to secondary iron overload. Increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (HAMP). The membrane serine protease Matriptase-2 (TMPRSS6) attenuates BMP-mediated HAMP induction by cleaving the BMP co-receptor, hemojuvelin (HJV). Previously, we demonstrated that an RNAi-therapeutic targeting Tmprss6 elevates hepcidin expression and reduces disease severity in the Hbbth3/+ mouse model of β-Thalassemia intermedia (Blood. 2013; 14;121(7):1200-8). To further interrogate the efficacy of this therapeutic approach, Hbbth3/+ animals were treated with a siRNA directed against Tmprss6 on a replete 50ppm iron diet, a low iron diet (3-5ppm iron) or a 50ppm iron diet containing deferiprone. Systemic administration of an siRNA directed against Tmprss6 in the three diet conditions leads to significant inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ mice with concomitant elevation in hepcidin expression. In correspondence with earlier studies, we demonstrate here that Tmprss6 silencing in animals under each of the three diet regimens leads to a significant improvement in the anemia of Hbbth3/+ mice as evidenced by increased total hemoglobin. Furthermore, hallmarks of ineffective erythropoiesis, including splenomegaly and reticulocytosis, were decreased in all Tmprss6 silenced Hbbth3/+ animals. If untreated, excessive iron loading in humans with β-Thalassemia leads to tissue iron deposition and eventual organ damage and failure. Importantly, here we demonstrate that the total body iron burden of Hbbth3/+ mice, as assessed by non-heme liver iron, is decreased by almost 30% in animals chelated with oral deferiprone and treated with Tmprss6 siRNA. A similar diminution of iron deposition is not evident in animals on a low iron diet or in mice fed deferiprone alone. Taken together, this data suggest that siRNA suppression of Tmprss6, in conjunction with chelation therapy, may provide an improved modality for treatment of the anemia and secondary iron loading seen in hemoglobinopathies such as β-Thalassemia. Disclosures: Racie: Alnylam Pharmaceutical, Inc: Employment. Butler:Alnylam Pharmaceutical, Inc: Employment. Fitzgerald:Alnylam: Employment. Fleming:Alnylam Pharmaceutical, Inc: Research Funding.
- Published
- 2013
7. Development Of RNAi Therapeutics Targeting The Complement Pathway
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Shannon Fishman, Rajeev G. Kallanthottathil, Andrew Sprague, James Butler, Muthiah Manoharan, Satya Kuchimanchi, Kevin Fitzgerald, Akshay Vaishnaw, Anna Borodovsky, Kristina Yucius, Tuyen Nguyen, Martin Maier, and Rachel Meyers
- Subjects
Small interfering RNA ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Complement factor B ,Molecular biology ,RNAi Therapeutics ,Complement system ,Classical complement pathway ,Alternative complement pathway ,Cancer research ,Gene silencing ,Complement C3 Convertases - Abstract
The complement system is a pivotal player in multiple hematological conditions. Antibody blockade of the C5 component of complement has been approved as a treatment for both paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS), validating C5 as an important therapeutic target. Recently, we developed a robust RNAi therapeutics platform for the delivery of siRNAs to the liver using trivalent GalNAc conjugates, enabling silencing of hepatocyte-expressed genes following subcutaneous (SC) injection. The liver is a major source of C5 and other complement pathway components. The GalNAc conjugate technology allows rapid development of siRNAs targeting multiple members of the complement cascade and evaluation of their silencing in pre-clinical models. To examine the utility of the siRNA approach for targeting complement pathway components we designed and synthesized GalNAc conjugated siRNAs targeting rodent, primate and human C5. Potent siRNA duplexes, showing greater than 95% silencing of C5 mRNA were selected using in vitro screening in human cell lines and mouse primary hepatocytes. C5 silencing and serum hemolytic activity inhibition were evaluated in rodents using single and multi-dose SC treatment regimens. A C5-targeting siRNA conjugate demonstrated a single dose ED50 of 0.625 mg/kg in the mouse with greater than 90% silencing of serum C5 achievable at higher doses. Serum C5 silencing was durable, with recovery starting two weeks after a single SC injection We went on to examine the efficacy of C5 silencing in the rat and observed robust lowering of serum C5 with 2.5 and 5 mg/kg multi-dose regimens, resulting in up to ∼90% inhibition of complement classical pathway hemolytic activity. Evaluation of the translation of this approach to higher species is in progress. Since PNH erythrocyte lysis is thought to be mediated by the activation of the alternative pathway of complement we initiated work on the development of siRNA conjugates targeting Factor B, an essential component of the alternative pathway C3 convertase. siRNAs targeting rodent, primate and human Factor B were identified by in vitro screening and demonstrate >90% silencing of Factor B mRNA in human cell lines and primary mouse hepatocytes. Evaluation of Factor B silencing in rodent models is ongoing. siRNA-mediated silencing of liver-derived complement components is a promising novel therapeutic approach for inhibiting the activity of C5 and other complement pathway targets, with the potential to enable subcutaneous treatment for patients with PNH and related disorders. Disclosures: Borodovsky: Alnylam: Employment. Yucius:Alnylam: Employment. Sprague:Alnylam: Employment. Butler:Alnylam: Employment. Fishman:Alnylam: Employment. Nguyen:Alnylam: Employment. Vaishnaw:Alnylam: Employment. Maier:Alnylam: Employment. Kallanthottathil:Alnylam: Employment. Kuchimanchi:Alnylam: Employment. Manoharan:Alnylam: Employment. Meyers:Alnylam: Employment. Fitzgerald:Alnylam: Employment.
- Published
- 2013
8. Aln-TMP: A Subcutaneously Administered RNAi Therapeutic Targeting Tmprss6 For The Treatment Of β-Thalassemia
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Julia Hettinger, Tim Racie, James Butler, Brian Bettencourt, Klaus Charisse, Kevin Fitzgerald, and Shannon Fishman
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Regulation of gene expression ,Ineffective erythropoiesis ,biology ,medicine.diagnostic_test ,Transferrin saturation ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Animal data ,Hepcidin ,hemic and lymphatic diseases ,medicine ,biology.protein ,Serum iron ,Gene silencing ,Hemojuvelin - Abstract
The b-Thalassemias are a group of hereditary blood disorders resulting from insufficient beta globin production, ultimately giving rise to the signature clinical sequelae associated with β-Thalassemia which includes anemia, ineffective erythropoiesis, and secondary iron overload. Previously, we demonstrated that intravenous administration of an siRNA targeting hepatic Tmprss6 expression significantly ameliorated the disease phenotype in the Hbbth3/+ mouse model of Thalassemia Intermedia (Blood. 2013; 14;121(7):1200-8). The Tmprss6 gene encodes for the protein Matriptase-2 which negatively regulates Hepcidin gene expression by cleaving the Hepcidin regulatory protein Hemojuvelin; RNAi-mediated suppression of Tmprss6 removes this negative regulator, ultimately leading to an increase in Hepcidin expression. Increased Hepcidin expression leads to a significant decrease in serum iron concentration and Transferrin Saturation (TfSat), which in the β-Thalassemia disease setting, corrects ineffective erythropoiesis, ameliorates anemia, and mitigates secondary iron overload. The role of Tmprss6 in iron metabolism has been extensively characterized in animal and human studies and, together with the observation in the Hbbth3/+ mouse, represents an attractive therapeutic target for the treatment of β-Thalassemia. To this end, we developed ALN-TMP, a subcutaneous RNAi therapeutic targeting hepatic Tmprss6 for the treatment of β-Thalassemia. ALN-TMP employs the GalNAc conjugate siRNA delivery platform that safely and effectively delivers siRNA to the liver for hepatic gene silencing. Preclinical animal data demonstrate ALN-TMP exhibits robust and durable dose-dependent gene suppression as single dose administration of ALN-TMP leads to > 80% Tmprss6 gene suppression for up to 3 weeks post-dose. This leads to concomitant increases in Hepcidin gene expression (>2x baseline levels) and subsequent decreases in total serum iron and TfSat (>50% decrease from baseline). The degree to which ALN-TMP modulates Hepcidin and serum iron mobilization is nearly identical to that observed in the previous Hbbth3/+ mouse studies and suggests ALN-TMP is a potent RNAi therapeutic with the potential of producing disease modifying effects in β-Thalassemia. Disclosures: Butler: Alnylam: Employment. Fishman:Alnylam: Employment. Racie:Alnylam Pharmaceutical, Inc: Employment. Hettinger:Alnylam Pharmaceuticals: Employment. Bettencourt:Alnylam Pharmaceuticals: Employment. Charisse:Alnylam Pharmaceuticals: Employment. Fitzgerald:Alnylam: Employment.
- Published
- 2013
9. RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and Secondary Iron Overload in a Mouse Model of β-Thalassemia Intermedia and Decreases Iron Overload in Hfe−/− Mice
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Anoop K. Sendamarai, David Bumcrot, James Butler, Mark D. Fleming, Paul J. Schmidt, Ivanka Toudjarska, and Tim Racie
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Ineffective erythropoiesis ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,Anemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Endocrinology ,Hepcidin ,Internal medicine ,Hereditary hemochromatosis ,medicine ,biology.protein ,Serum iron ,Erythropoiesis ,Hemochromatosis ,Hemojuvelin - Abstract
Abstract 1018 β-Thalassemia intermedia (TI), an inherited hemoglobinopathy caused by partial loss of β-globin synthesis, is characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis as well as secondary iron overload. Hereditary hemochromatosis (HH) is most frequently caused by mutations in HFE and is marked by excess uptake of dietary iron with concomitant tissue iron overload. In both diseases, increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (encoded by Hamp1). The membrane serine protease Matriptase-2 (encoded by Tmprss6) attenuates BMP-mediated Hamp1 induction by cleaving the BMP co-receptor, hemojuvelin. Previously, it has been shown that elevating Hamp1 expression by genetic inactivation of Tmprss6 reduces disease severity in the Hbbth3/+ mouse model of TI and prevents iron overload in Hfe−/− mice. Therefore, a therapeutic approach comprising specific inhibition of Tmprss6 could prove efficacious in TI and HH. Here we show that systemic administration of a potent lipid nanoparticle (LNP) formulated siRNA directed against Tmprss6 leads to >80% inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ and Hfe−/− mice with concomitant >2-fold elevation in Hamp1 expression. In the TI model, Tmprss6 silencing leads to ∼30% reductions in serum iron and non-heme liver iron. In Hfe−/− mice, serum iron and non-heme liver iron are similarly reduced, and Perls staining of peri-portal iron is diminished. Remarkably, the partial iron restriction induced by Tmprss6 inhibition in Hbbth3/+ mice leads to dramatic improvements in the hematological aspects of the disease phenotype: the severity of the anemia is decreased as evidenced by an approximately 1 g/dL increase in total hemoglobin and a 50% decrease in circulating erythropoietin levels. As in the human disease, Hbbth3/+ mice exhibit the hallmarks of ineffective erythropoiesis including splenomegaly, decreased erythrocyte survival and marked reticulocytosis. Treatment with LNP formulated Tmprss6 siRNA leads to a dramatic 2–3 fold decrease in spleen size, a 3–4 fold decrease in reticulocyte counts and a >7-day increase in RBC half-life. Histological analysis of spleens from Tmprss6 siRNA treated animals demonstrates restoration of normal splenic architecture, as well as a reduction in the number of Tfr1-positive erythrocyte precursors in the spleen. Furthermore, as evidenced by the near normalization of blood smears, the overall quality of erythropoiesis in treated animals is vastly improved. Taken together, these data demonstrate that RNAi-mediated silencing of liver Tmprss6 elevates Hamp1 expression and reduces iron overload in both TI and HH model mice. More significantly, Tmprss6 siRNA treatment ameliorates all aspects of the disease phenotype in the TI mouse model. These results support the development of an RNAi therapeutic targeting TMPRSS6 for the treatment of TI, HH and potentially other disorders characterized by excess iron absorption due to physiologically inappropriately low levels of hepcidin. Disclosures: Racie: Alnylam Pharmaceuticals: Employment. Butler:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership.
- Published
- 2012
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