5 results on '"John H. Baird"'
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2. Bleeding and Thrombosis Are Associated with Endothelial Dysfunction in CAR-T Cell Therapy and Are Increased in Patients Experiencing Neurologic Toxicity
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Matthew J. Frank, Andrew R. Rezvani, Robert Lowsky, Surbhi Sidana, Andrew Johnsrud, Laura Johnston, Sally Arai, Robert S. Negrin, David B. Miklos, Parveen Shiraz, Juliana Craig, Crystal L. Mackall, Wen-Kai Weng, James L. Zehnder, John H. Baird, Judith A. Shizuru, Everett Meyer, Theresa Latchford, Jay Y. Spiegel, and Lori Muffly
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Transplantation ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Thrombin time ,medicine.disease ,Biochemistry ,Thrombosis ,Lymphoma ,Cytokine release syndrome ,Internal medicine ,Cohort ,medicine ,Coagulopathy ,Molecular Medicine ,Immunology and Allergy ,Platelet ,business - Abstract
Background Treatment with chimeric antigen receptor (CAR) T cell therapies have shown dramatic, often durable responses for relapsed/refractory B-cell malignancies. However, it can be associated with significant side effects such as cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS) and life-threatening consumptive coagulopathies. The underlying pathobiology of such hemostatic defects and their distinct clinical sequelae remains obscure. This retrospective study aims at quantifying CAR T therapy associated bleeding and thrombotic complications and their association with CRS, ICANS, and laboratory derangements. Methods 130 adult patients with DLBCL or B-ALL treated between 2017-2020 with CD19 CAR-T therapy axicabtagene ciloleucel (N=90) or a bispecific CD 19/22 CAR construct utilizing 4-1BB costimulatory domains (N=40) were analyzed to determine dynamics of coagulation parameters and platelet counts as well as incidences of bleeding or thrombosis in the first three months after CAR T infusion. Events were included if graded ≥ 2 or if intervention was required. Platelet counts and coagulation parameters were collected prior to lymphodepletion (pre-LD), day 0, 3, 7, 14, 21, 28, 60 and 90. Results 12 (9.2%) and 8 (6.2%) patients developed bleeding and thrombotic complications in the first three months after CAR-T infusion, respectively. Events are characterized in Figure 1. All bleeding events occurred between days 0-30 (median 17.5, range 8-30), while thrombotic events occurred between days 2-91 (median day 29, range, 2-91). Two (1.5%) patients experienced both bleeding and thrombosis. Bleeding events coincided with the onset of thrombocytopenia and hypofibrinogenemia, and patients who bled had lower platelet (median 22.5 vs. 47 K/uL; p=0.03) and fibrinogen (median 151 vs. 351 ug/mL; p=0.007) nadirs in the first 30 days compared to those without bleeding. Temporally, the lowest median platelet nadir occurred at day 7 in patients with bleeding events vs. day 21 in patients without bleeding, while timing of fibrinogen nadirs were at day 21 in both. Patients with bleeding episodes were more likely to be older (median age: 70 vs. 60 yrs, p=0.03), have thrombocytopenia prior to lymphodepletion therapy (median 117.5 vs. 174.5 K/uL, p=0.01), and have elevated LDH (lymphoma subgroup; p=0.07). Other lab derangements in the first 30 days seen more frequently in patients with bleeding included prolonged thrombin time (TT) (21% vs. 6%; p=0.02), PT (16% vs. 5%; p=0.06), and elevated d-dimer (16% vs. 3%; p=0.01) indicative of a consumptive process. Thrombotic events were not significantly associated with elevated or peak d-dimer values (median 4.97 vs. 2.37 ug/mL, p=0.20). Interestingly, occurrence or severity of CRS was not associated with bleeding or thrombotic events, nor was it associated with marked derangements in coagulation abnormalities. However, higher grade ICANS (grade > 3) was associated with bleeding (42% vs. 15%; p=0.038), thrombosis (50% vs. 16%; p=0.03), and evidence of endothelial activation including PT prolongation (78% vs. 35%; p 13 (10%) patients received anticoagulation for prophylaxis or therapeutic indications that predated CAR T infusion. Four started anticoagulation secondarily for thrombotic events after CAR-T infusion, and one received tissue plasminogen activator (tPA) for an acute stroke. In this group, no patients developed bleeding complications from anticoagulation. Conclusion Both bleeding (9.2%), and thrombotic (6.2%) events are observed after CAR T cell therapy, with bleeding limited to the first month in our cohort. Notably, ICANS was uniquely associated with PT prolongation, hypofibrinogenemia, and increased fibrin degradation, in addition to both bleeding and thrombosis. These results suggest that a systemic coagulopathy coincides with high grade ICANS and whether these neurologic events truly represent sequelae of widespread vascular dysfunction warrants further investigation. Anticoagulation was safe in the patients whom it was indicated. Risk factors for bleeding and thrombotic complications should be studied prospectively to develop risk-assessment models and clinical guidelines for management of bleeding and thrombosis (including prophylaxis) during CAR T therapy. Disclosures Muffly: Adaptive: Research Funding; Servier: Research Funding; Amgen: Consultancy. Negrin:BioEclipse Therapeutics: Current equity holder in private company; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; Amgen: Consultancy; UpToDate: Honoraria. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Meyer:Orca Bio: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Rezvani:Pharmacyclics: Research Funding. Mackall:Apricity Health: Consultancy, Current equity holder in private company; NeoImmune Tech: Consultancy; Nektar Therapeutics: Consultancy; Allogene: Current equity holder in publicly-traded company; BMS: Consultancy; Lyell Immunopharma: Consultancy, Current equity holder in private company. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Sidana:Janssen: Consultancy.
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- 2021
3. Anti-CD22 CAR T-Cell Therapy Mediates Durable Complete Responses in Adults with Relapsed or Refractory Large B-Cell Lymphoma after Failure of Anti-CD19 CAR T-Cell Therapy and High Response Rates in Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia
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Steven R. Feldman, Juliana Craig, Kara L. Davis, Robert Lowsky, Zachary Ehlinger, Sheren F. Younes, Robert S. Negrin, David B. Miklos, Sally Arai, Parveen Shiraz, Crystal L. Mackall, Liora M. Schultz, Bita Sahaf, Yasodha Natkunam, John H. Baird, Wen-Kai Weng, Surbhi Sidana, Sneha Ramakrishna, Lori Muffly, Laura Johnston, Jean Oak, Shabnum Patel, Warren D. Reynolds, Matthew J. Frank, Andrew R. Rezvani, and Jay Y. Spiegel
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Transplantation ,business.industry ,Anti cd19 ,Cell Biology ,Hematology ,B-cell acute lymphoblastic leukemia ,medicine.disease ,Cell therapy ,Refractory ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,CAR T-cell therapy ,Medicine ,business ,CD22 CAR-T ,B-cell lymphoma - Published
- 2021
4. Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARγ Activation to Decrease Diet-Induced Obesity
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Fong Fu-Hsu, Babak Razani, Clay F. Semenkovich, Haowei Song, Anne P.L. Jensen-Urstad, Katsuhiko Funai, Meral K. El Ramahi, Trey Coleman, Li Yin, John H. Baird, John Turk, and Irfan J. Lodhi
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medicine.medical_specialty ,Physiology ,Blotting, Western ,Adipose tissue ,Peroxisome proliferator-activated receptor ,Biology ,Article ,Mass Spectrometry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,Adipocyte ,medicine ,Animals ,Immunoprecipitation ,Obesity ,Cloning, Molecular ,Molecular Biology ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Lipogenesis ,Lipid metabolism ,Thermogenesis ,3T3 Cells ,Cell Biology ,Enzyme Activation ,PPAR gamma ,Fatty acid synthase ,Endocrinology ,chemistry ,Adipose Tissue ,Adipogenesis ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,biology.protein ,Body Composition ,Fatty Acid Synthases ,Energy Metabolism ,Sugar Alcohol Dehydrogenases - Abstract
SummaryDe novo lipogenesis in adipocytes, especially with high fat feeding, is poorly understood. We demonstrate that an adipocyte lipogenic pathway encompassing fatty acid synthase (FAS) and PexRAP (peroxisomal reductase activating PPARγ) modulates endogenous PPARγ activation and adiposity. Mice lacking FAS in adult adipose tissue manifested increased energy expenditure, increased brown fat-like adipocytes in subcutaneous adipose tissue, and resistance to diet-induced obesity. FAS knockdown in embryonic fibroblasts decreased PPARγ transcriptional activity and adipogenesis. FAS-dependent alkyl ether phosphatidylcholine species were associated with PPARγ and treatment of 3T3-L1 cells with one such ether lipid increased PPARγ transcriptional activity. PexRAP, a protein required for alkyl ether lipid synthesis, was associated with peroxisomes and induced during adipogenesis. PexRAP knockdown in cells decreased PPARγ transcriptional activity and adipogenesis. PexRAP knockdown in mice decreased expression of PPARγ-dependent genes and reduced diet-induced adiposity. These findings suggest that inhibiting PexRAP or related lipogenic enzymes could treat obesity and diabetes.
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- 2012
- Full Text
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5. Some Aspects of Dietetics in The Veterans Administration1
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Col. John H. Baird
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Nutrition and Dietetics ,Food Science - Published
- 1945
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