13 results on '"Yakup Batlevi"'
Search Results
2. Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging
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Yakup Batlevi and Albert R. La Spada
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Autophagy ,Macroautophagy ,Mitophagy ,Lysosome ,Parkin ,PINK1 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Macroautophagy is a cellular process by which cytosolic components and organelles are degraded in double-membrane bound structures upon fusion with lysosomes. A pathway for selective degradation of mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to neurons, because of the constant need for high levels of energy production in this cell type. Although much remains to be learned about mitophagy, it appears that the regulation of mitophagy shares key steps with the macroautophagy pathway, while exhibiting distinct regulatory steps specific for mitochondrial autophagic turnover. Mitophagy is emerging as an important pathway in neurodegenerative disease, and has been linked to the pathogenesis of Parkinson's disease through the study of recessively inherited forms of this disorder, involving PINK1 and Parkin. Recent work indicates that PINK1 and Parkin together maintain mitochondrial quality control by regulating mitophagy. In the Purkinje cell degeneration (pcd) mouse, altered mitophagy may contribute to the dramatic neuron cell death observed in the cerebellum, suggesting that over-active mitophagy or insufficient mitophagy can both be deleterious. Finally, mitophagy has been linked to aging, as impaired macroautophagy over time promotes mitochondrial dysfunction associated with the aging process. Understanding the role of mitophagy in neural function, neurodegenerative disease, and aging represents an essential goal for future research in the autophagy field. This article is part of a Special Issue entitled “Autophagy and protein degradation in neurological diseases.”
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- 2011
- Full Text
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3. Impact and safety of chimeric antigen receptor T-cell therapy in older, vulnerable patients with relapsed/refractory large B-cell lymphoma
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Yakup Batlevi, Soo Jung Kim, Molly Maloy, Connie Lee Batlevi, Arela Noy, Theresa A. Elko, Stephanie Lobaugh, Elena Mead, Gunjan L. Shah, Sergio Giralt, Miguel-Angel Perales, Michael Scordo, Parastoo B. Dahi, Josel D. Ruiz, Beatriz Korc-Grodzicki, Richard J. Lin, Craig S. Sauter, Hei Ton Chan, Martina Pennisi, Mari Lynne Silverberg, Bianca Santomasso, Paul A. Hamlin, Chelsea A Brooklyn, Sean M. Devlin, and M. Lia Palomba
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medicine.medical_treatment ,Antigens, CD19 ,Cell- and Tissue-Based Therapy ,Receptors, Antigen, T-Cell ,Immunotherapy, Adoptive ,CD19 ,Antigen ,medicine ,Humans ,Letters to the Editor ,B-cell lymphoma ,Receptor ,Aged ,Receptors, Chimeric Antigen ,biology ,business.industry ,Hematology ,Immunotherapy ,medicine.disease ,Lymphoma ,Relapsed refractory ,biology.protein ,Cancer research ,Chimeric Antigen Receptor T-Cell Therapy ,Lymphoma, Large B-Cell, Diffuse ,business - Published
- 2020
4. Comparing Car T Cells Toxicities Grading Systems: Application of Astct Grading System and Implications for Management
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Yakup Batlevi, Gunjan L. Shah, Roni Shouval, Craig S. Sauter, Miguel Perales, Jae H. Park, Miriam Sanchez-Escamilla, Elena Mead, Sean M. Devlin, Parastoo B. Dahi, Bianca Santomasso, Michael Scordo, Molly Maloy, Connie W. Batlevi, Martina Pennisi, Mari Lynne Silverberg, M. Lia Palomba, Tania Jain, Sergio Giralt, Claudia Diamonte, Renier J. Brentjens, and Elizabeth Halton
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Transplantation ,medicine.medical_specialty ,Immune effector ,business.industry ,Fda approval ,Hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Management implications ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,B Acute Lymphoblastic Leukemia ,Car t cells ,Grading (education) ,business ,Diffuse large B-cell lymphoma ,030215 immunology - Abstract
Introduction Cytokine release syndrome (CRS) and immune effector cells associated neurotoxicity syndrome (ICANS) are common CAR T cells toxicities. Various grading systems that attribute different grades of severity to symptoms are currently used, preventing comparisons of different products and possibly leading to management implications. Methods We included 53 patients (pts) with B acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T cells (NCT01044069) and 49 pts with diffuse large B cell lymphoma (DLBCL) who received axicabtagene ciloleucel (axi-cel, n=36) or tisagenlecleucel (tisa-cel, n=13) after FDA approval. CRS and ICANS were retrospectively graded according to the new ASTCT consensus grading system, for comparison with other available systems: Lee, Penn, Memorial Sloan Kettering Cancer Center, CARTOX and CTCAEv5.0 for CRS; CTCAEv4.03 and CARTOX for ICANS. We then used ASTCT grades to predict management according to current guidelines for DLBCL pts (axi-cel and tisa-cel insert packages, CARTOX and NCCN guidelines) and compare it to the actual treatment received at our center. Results According to the ASTCT grading, B-ALL pts had 87% CRS (28% grade ≥3), while DLBCL pts had 86% CRS (14% grade ≥3) with axi-cel, and 54% (no grade ≥3) with tisa-cel. B-ALL pts had 55% ICANS (45% grade ≥3), while DLBCL pts had 55% ICANS (33% grade ≥3) with axi-cel, and 15% with tisa-cel (no grade ≥3) (fig. 1). When comparing grading systems, agreement on CRS and ICANS diagnosis was found in 99% and 91% cases, respectively. However, when evaluating toxicities grade by grade, only 27% pts had the same grade in each system for CRS, and 55% for ICANS (fig. 2). When predicting management for DLBCL pts, we found some relevant differences across current guidelines (fig. 3). At our center 58% and 13% of patients with CRS received tocilizumab (toci) and steroids, respectively, similarly to what predicted according to axi-cel's, CARTOX and NCCN guidelines, but differently from tisa-cel's label (10% and 5%). For ICANS, while tisa-cel's label does not provide any recommendations, other guidelines-based predictions were mostly overlapping. Indications for treatment vary across current guidelines, which were developed on single products and different grading systems, thus, should not be universally applied. This discrepancy becomes particularly relevant for cases with discordant CRS/ICANS grades. As such, we gave toci to 66% pts upgraded to grade 3 by Penn (grade 2 by ASTCT), while they would receive both toci and steroids according to axi-cel/CARTOX/NCCN guidelines, but would not be treated according to tisa-cel's. Conclusions Different grading systems provide inconsistent CRS/ICANS scores. To avoid discrepancies in assessing and managing toxicities of different products, a unified grading should be used and paired management guidelines with product-specific indications should be developed.
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- 2020
5. Safety and Feasibility of Chimeric Antigen Receptor T Cell Therapy after Allogeneic Hematopoietic Cell Transplantation in Relapsed/ Refractory B Cell Non-Hodgkin’s Lymphoma
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Gunjan L. Shah, Yakup Batlevi, Craig S. Sauter, Michael Scordo, Molly Maloy, Jason E. Chan, Miguel-Angel Perales, Connie W. Batlevi, Parastoo B. Dahi, Scott T. Avecilla, M. Lia Palomba, Tania Jain, and Sergio Giralt
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Adult ,Male ,Cancer Research ,Lymphoma, B-Cell ,medicine.medical_treatment ,Immunotherapy, Adoptive ,Article ,medicine ,Humans ,Receptor ,Aged ,B-Lymphocytes ,Receptors, Chimeric Antigen ,Hematopoietic cell ,business.industry ,Lymphoma, Non-Hodgkin ,Hematopoietic Stem Cell Transplantation ,Hematology ,Immunotherapy ,Middle Aged ,medicine.disease ,Lymphoma ,Transplantation ,Oncology ,Relapsed refractory ,B-Cell Non-Hodgkin Lymphoma ,Cancer research ,Feasibility Studies ,Chimeric Antigen Receptor T-Cell Therapy ,Female ,Neoplasm Recurrence, Local ,business - Published
- 2019
6. Chimeric Antigen Receptor T Cells for Lymphomas: Methods, Data, and Challenges
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Craig S. Sauter and Yakup Batlevi
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biology ,business.industry ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,CD19 ,Tumor antigen ,Lymphoma ,Antigen ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Cancer research ,biology.protein ,Rituximab ,business ,medicine.drug - Abstract
Antigen 16 (CD19) is an optimal target for targeted cellular therapy against all B-cell non-Hodgkin lymphomas (B-NHL)/chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B-cell acute lymphoblastic leukemia (B-ALL). However, targeting CD19 can result in prolonged B-cell aplasia. Given the clinical experience with the anti-CD20 monoclonal antibody rituximab with temporary B-cell aplasia, severe clinical consequence has not been observed. Intravenous gamma globulin has proven to effectively supplement humoral immunity in hypogammaglobulinemic patients. Genetically engineered recombinant T-cell receptors directed against a specific tumor antigen (chimeric antigen receptors, CARs) can recognize and kill tumor cell targets. This review will focus on the clinical experience of targeting CD19 with CAR-modified T cells (19-CAR-T) for B-cell lymphomas, excluding CLL/SLL and multiple myeloma which are covered in other chapters of this book.
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- 2018
7. Easix and Modified-Easix Are Early Predictors of Severe Cytokine Release Syndrome and Neurotoxicity in Patients Treated with Chimeric Antigen Receptor T Cells
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Miguel-Angel Perales, Jae H. Park, Michael Scordo, Bianca Santomasso, Gunjan L. Shah, Jessica Flynn, Molly Maloy, Yakup Batlevi, Elizabeth Halton, Roni Shouval, Sean M. Devlin, Sergio Giralt, Tania Jain, Craig S. Sauter, Maria Lia Palomba, Connie Lee Batlevi, Parastoo B. Dahi, Martina Pennisi, Mari Lynne Silverberg, Elena Mead, Miriam Sanchez-Escamilla, Claudia Diamonte, and Renier J. Brentjens
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medicine.medical_specialty ,education.field_of_study ,Stress index ,business.industry ,Lymphoblastic Leukemia ,Fda approval ,Immunology ,Population ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Cytokine release syndrome ,Internal medicine ,medicine ,In patient ,education ,business ,Hemodynamic instability - Abstract
Introduction Chimeric Antigen Receptor (CAR) T cells are associated with unique toxicities, including cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS). Patients (pts) with severe CRS and ICANS exhibit hemodynamic instability and coagulopathy with evidence of endothelial activation and increased blood brain barrier permeability. Increases in inflammatory cytokines and biomarkers of endothelial activation in serum and CSF have been associated with severe CRS and ICANS. The EASIX (Endothelial Activation and Stress Index) score [lactate dehydrogenase (LDH) (U/L) × creatinine (mg/dl) / platelets (PLT) (109 cells/L)] correlates with severe fluid overload and survival in allogeneic transplant pts. Elevated LDH and low PLT levels have been associated with severe ICANS development, and high IL-6 levels are seen in severe CRS and ICANS. We hypothesized that the EASIX and a newly proposed version of it, the modified-EASIX (mEASIX), in which creatinine is replaced by CRP (mg/dL) as an easily available surrogate for IL6, would be associated with CRS and ICANS in CAR T cells pts. Methods We analyzed 2 different populations of adult CAR T cells pts treated at our institution: 1) B-cell acute lymphoblastic leukemia (B-ALL) pts treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) aggressive diffuse large B-cell lymphoma (DLBCL) pts treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval starting from 2018. EASIX and mEASIX scores were calculated for each patient daily from start of lymphodepletion conditioning to day +14. A log transformation using base 2 (log2) was applied to all EASIX/mEASIX variables to reduce skew. CRS and ICANS were graded according to the ASTCT grading system. Results 87 pts, B-ALL (n=53) and DLBCL (n=34), were analyzed. According to ASTCT grading, 83% (72/87) experienced CRS and 54% (47/87) developed ICANS, grade ≥3 in 23% (20/87) and 40% (35/87) of pts, respectively. When analyzed by disease, CRS and ICANS rates were 87% (46/53) and 55% (29/53) for B-ALL and 76% (26/34) and 53% (18/34) for DLBCL, respectively. CRS and ICANS were grade ≥3 in 28% (15/53) and 45% (24/53) of B-ALL pts and in 15% (5/34) and 32% (11/34) of DLBCL pts, respectively. Median time of onset of CRS after CAR T cell infusion was day +2 and median onset of ICANS was day +6 for the overall population and the subgroups. High EASIX and mEASIX scores at start of conditioning were both associated with development of any grade CRS [OR=1.81 (95% CI 1.09-3.36) p=0.038 and OR=1.94 (95% CI 1.32-3.38) p=0.005] and grade ≥3 CRS [OR=1.47 (95% CI 1.05-2.29) p=0.049 and OR=1.34 (95% CI 1.07-1.80) p=0.024], respectively (Table). Following CAR T cell infusion, high scores of both EASIX [OR=1.60 (95% CI 1.12-2.43) p=0.017] and mEASIX [OR=1.32 (95% CI 1.07-1.69) p=0.014] on day +1 were associated with development of grade ≥3 CRS. Moreover, both high EASIX [OR=1.43 (95% CI 1.08-1.96) p=0.018] and mEASIX [OR=1.29 (95% CI 1.07-1.60) p=0.010] scores on day +3 were associated with grade ≥3 ICANS. When analyzed by disease, results were confirmed for severe CRS and ICANS in B-ALL patients, while in the DLBCL group only mEASIX at start of conditioning and at day +1 was associated with development of any grade CRS. EASIX and mEASIX scores were not associated with response rates to CAR T cells therapy. Conclusions EASIX and mEASIX scores calculated at baseline (before lymphodepletion) are associated with development of CRS and severe CRS. Moreover, both high EASIX and mEASIX scores on day +1 and day +3 are associated with occurrence of grade ≥3 CRS and grade ≥3 ICANS, respectively. We conclude that EASIX and mEASIX, as markers of endothelial damage and inflammation, could be useful as early predictors in guiding treatment decisions before the onset of severe symptoms. Table Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brentjens:JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy. Giralt:Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Kite: Consultancy. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy. Santomasso:Kite/Gilead: Consultancy; Juno/Celgene: Consultancy; Novartis: Consultancy. Sauter:GSK: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Perales:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: 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, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees.
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- 2019
8. Impact and Safety of Chimeric Antigen Receptor T Cell Therapy in Vulnerable Older Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma
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Molly Maloy, Michael Scordo, Yakup Batlevi, Maria Lia Palomba, Bianca Santomasso, Sergio Giralt, Gunjan L. Shah, Theresa A. Elko, Jason T Chan, Craig S. Sauter, Stephanie Lobaugh, Connie Lee Batlevi, Richard J. Lin, Elena Mead, Chelsea A Brooklyn, Beatriz Korc-Grodzicki, Ariela Noy, Parastoo B. Dahi, Sean M. Devlin, Josel D. Ruiz, Martina Pennisi, Mari Lynne Silverberg, Soo Jung Kim, and Miguel-Angel Perales
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0301 basic medicine ,medicine.medical_specialty ,Immunology ,Context (language use) ,Small sample ,Cell Biology ,Hematology ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Older patients ,Family medicine ,Charlson comorbidity index ,Honorarium ,Relapsed refractory ,medicine ,Clinical staff ,Medicaid ,health care economics and organizations ,030215 immunology - Abstract
The development of chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of relapsed refractory diffuse large b-cell lymphoma (DLBCL). However, its impact in vulnerable older patients, especially those with multi-morbidity and functional limitations, has not been explored. Moreover, the Centers for Medicare & Medicaid Services (CMS) has recently proposed Coverage with Evidence Development for CAR T, emphasizing the need for evidence in older patients. We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Forty-two consecutive older patients (≥65yo) were included in the analysis of post-relapse (last documented relapse or refractory state) overall survival (PR-OS) accounting for time of CAR T entry. Geriatric assessment, including comorbidity, basic and instrumental activities of daily living, prior falls, and weight loss, was performed either by a geriatrician prior to admission, or by interdisciplinary clinical staff on the day of admission. In parallel, we compared the safety and toxicities of CAR T between older (≥65yo, n=24) and younger ( Among the 42 patients ≥65yo, 18 did not receive CAR T due to clinical ineligibility and/or death during the pre-requisite clinical evaluation. Their gender distribution, comorbidity burden, measured by Deyo/Charlson Comorbidity Index (DCI/CCI), and Karnofsky Performance Status (KPS) were comparable to the 24 older patients who received a CAR T product. With a median follow-up of 291 days (range 162 - 572) for survivors, the PR-OS favored the group of older patients who had received CAR T with estimated 1-year PR-OS of 0.67 (95% CI: 0.43, 0.99) versus 0.44 (95% CI: 0.27, 0.75) for patients who did not receive CAR T (p=0.04) (Figure). We next compared the safety and toxicity profiles among older (≥65yo, n=24) versus younger patients ( Although limited by small sample size, retrospective design, and possible patient selection bias regarding disease biology, our results highlight potential benefits of CAR T in selected older patients even with functional limitation, multi-morbidity, and significant tumor burden; and the lack of excessive CRS, NT, and other high-grade toxicities. These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and support that, with meticulous management of CAR T toxicities, older patients should not be excluded from CAR T based on chronologic age alone. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Jazz Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Kite: Consultancy. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Santomasso:Kite/Gilead: Consultancy; Novartis: Consultancy; Juno/Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: 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, Research Funding; Kyte/Gilead: Research Funding; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2019
9. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS
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Dan Garza, J. Paul Taylor, Brett A. McCray, Tso-Pang Yao, Oren Schuldiner, Yakup Batlevi, Melanie Knight, Marc Hild, Charlotte Hubbert, Nicholas A. Diprospero, Ranjani Padmanabhan, Eric H. Baehrecke, Natalia B. Nedelsky, Zhiping Nie, Stephanie L. Schwartz, Deborah L. Berry, Udai Bhan Pandey, and Gillian P. Ritson
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Proteasome Endopeptidase Complex ,Histone Deacetylase 6 ,Histone Deacetylases ,Ubiquitin ,Conditional gene knockout ,Autophagy ,medicine ,Animals ,Drosophila Proteins ,Humans ,Receptor ,Multidisciplinary ,biology ,Neurodegeneration ,Neurodegenerative Diseases ,HDAC6 ,biology.organism_classification ,medicine.disease ,Muscular Disorders, Atrophic ,Cell biology ,Disease Models, Animal ,Drosophila melanogaster ,Proteasome ,Receptors, Androgen ,Immunology ,biology.protein ,Peptides - Abstract
A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.
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- 2007
10. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA
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Helen C. Miranda, Constanza J. Cortes, Albert R. La Spada, Harald Frankowski, Gwenn A. Garden, Bryce L. Sopher, Jessica E. Young, Nishi Ivanov, Cassiano Carromeu, Yakup Batlevi, Amy Le, and Alysson R. Muotri
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Male ,Basic helix-loop-helix leucine zipper transcription factors ,Neurodegenerative ,Transgenic ,Androgen ,Transactivation ,Mice ,Phagosomes ,Receptors ,2.1 Biological and endogenous factors ,Psychology ,Aetiology ,Induced pluripotent stem cell ,Motor Neurons ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,General Neuroscience ,Neurodegeneration ,Cellular Reprogramming ,Muscular Disorders, Atrophic ,Cell biology ,Receptors, Androgen ,Neurological ,Female ,Cognitive Sciences ,medicine.medical_specialty ,Induced Pluripotent Stem Cells ,Mice, Transgenic ,Biology ,Rare Diseases ,Internal medicine ,medicine ,Autophagy ,Animals ,Humans ,Atrophic ,Neurology & Neurosurgery ,Animal ,Neurosciences ,Fibroblasts ,medicine.disease ,Stem Cell Research ,Brain Disorders ,Androgen receptor ,Disease Models, Animal ,Spinal and bulbar muscular atrophy ,Muscular Disorders ,Orphan Drug ,Endocrinology ,Disease Models ,TFEB ,Peptides ,Neuroscience - Abstract
Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis.
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- 2014
11. Identification of factors that function in Drosophila salivary gland cell death during development using proteomics
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Eric H. Baehrecke, Jahda H Hill, Cheng S. Lee, Yakup Batlevi, Xueping Fang, Charles Nelson, Brian M. Balgley, and Christina K. McPhee
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Proteomics ,Programmed cell death ,Proteasome Endopeptidase Complex ,Proteome ,Apoptosis ,DNA Fragmentation ,Salivary Glands ,medicine ,Animals ,Drosophila Proteins ,RNA, Small Interfering ,Molecular Biology ,Ubiquitins ,Caspase ,Original Paper ,biology ,Salivary gland ,COP9 Signalosome Complex ,Autophagy ,Cell Biology ,Cell biology ,medicine.anatomical_structure ,Proteasome ,Larva ,Multiprotein Complexes ,biology.protein ,Drosophila ,RNA Interference ,Drosophila Protein ,Heparan Sulfate Proteoglycans ,Peptide Hydrolases - Abstract
Proteasome inhibitors induce cell death and are used in cancer therapy, but little is known about the relationship between proteasome impairment and cell death under normal physiological conditions. Here, we investigate the relationship between proteasome function and larval salivary gland cell death during development in Drosophila. Drosophila larval salivary gland cells undergo synchronized programmed cell death requiring both caspases and autophagy (Atg) genes during development. Here, we show that ubiquitin proteasome system (UPS) function is reduced during normal salivary gland cell death, and that ectopic proteasome impairment in salivary gland cells leads to early DNA fragmentation and salivary gland condensation in vivo. Shotgun proteomic analyses of purified dying salivary glands identified the UPS as the top category of proteins enriched, suggesting a possible compensatory induction of these factors to maintain proteolysis during cell death. We compared the proteome following ectopic proteasome impairment to the proteome during developmental cell death in salivary gland cells. Proteins that were enriched in both populations of cells were screened for their function in salivary gland degradation using RNAi knockdown. We identified several factors, including trol, a novel gene CG11880, and the cop9 signalsome component cop9 signalsome 6, as required for Drosophila larval salivary gland degradation.
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- 2012
12. Dynein light chain 1 is required for autophagy, protein clearance, and cell death in Drosophila
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J. Paul Taylor, Yakup Batlevi, Claudio R. Simon, Damali N. Martin, Eric H. Baehrecke, Christine M. Powers, and Udai Bhan Pandey
- Subjects
Cytoplasmic Dyneins ,Programmed cell death ,Atg1 ,Motility ,Salivary Glands ,Animals, Genetically Modified ,medicine ,Autophagy ,In Situ Nick-End Labeling ,Animals ,Drosophila Proteins ,Caspase ,Conserved Sequence ,Crosses, Genetic ,Multidisciplinary ,biology ,Cell Death ,Neurodegeneration ,Pupa ,DNA ,Biological Sciences ,medicine.disease ,Cell biology ,Mutagenesis, Insertional ,Caspases ,Larva ,Mutation ,Nerve Degeneration ,Synapses ,biology.protein ,Ectopic expression ,Drosophila ,Drosophila Protein - Abstract
Autophagy is a catabolic pathway that is important for turnover of long-lived proteins and organelles, and has been implicated in cell survival, tumor progression, protection from infection, neurodegeneration, and cell death. Autophagy and caspases are required for type II autophagic cell death of Drosophila larval salivary glands during development, but the mechanisms that regulate these degradation pathways are not understood. We conducted a forward genetic screen for genes that are required for salivary gland cell death, and here we describe the identification of Drosophila dynein light chain 1 ( ddlc1 ) as a gene that is required for type II cell death. Autophagy is attenuated in ddlc1 mutants, but caspases are active in these cells. ddlc1 mutant salivary glands develop large fibrillar protein inclusions that stain positive for amyloid-specific dyes and ubiquitin. Ectopic expression of Atg1 is sufficient to induce autophagy, clear protein inclusions, and rescue degradation of ddlc1 mutant salivary glands. Furthermore, ddlc1 mutant larvae have decreased motility, and mutations in ddlc1 enhance the impairment of motility that is observed in a Drosophila model of neurodegenerative disease. Significantly, this decrease in larval motility is associated with decreased clearance of protein with polyglutamine expansion, the accumulation of p62 in neurons and muscles, and fewer synaptic boutons. These results indicate that DDLC1 is required for protein clearance by autophagy that is associated with autophagic cell death and neurodegeneration.
- Published
- 2010
13. HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration
- Author
-
J. Paul Taylor, Udai Bhan Pandey, Eric H. Baehrecke, and Yakup Batlevi
- Subjects
Proteasome Endopeptidase Complex ,Biology ,Histone Deacetylase 6 ,Neuroprotection ,Histone Deacetylases ,medicine ,Autophagy ,Animals ,Drosophila Proteins ,Humans ,Molecular Biology ,Ubiquitin ,Neurodegeneration ,Cell Biology ,HDAC6 ,medicine.disease ,Phenotype ,Cell biology ,Disease Models, Animal ,Drosophila melanogaster ,Mechanism of action ,Proteasome ,Mutation ,Nerve Degeneration ,medicine.symptom ,Intracellular - Abstract
The two major intracellular catabolic pathways, the ubiquitin-proteasome system (UPS) and macroautophagy (autophagy), have each been implicated as playing roles in neurodegenerative proteinopathies. 1,2 We have investigated the relationship between the UPS and autophagy using Drosophila models of neurodegenerative diseases. We identified histone deacetylase 6 (HDAC6) as a genetic modifier of polyglutamine-induced neurodegeneration and determined that its mechanism of action is autophagy-dependent. 3 The ability of HDAC6 to suppress degeneration has been extended to additional neurodegenerative disease models, including a fly model expressing pathological Aβ fragments, presented here, but is not a universal modifier of degenerative phenotypes. Importantly, HDAC6 was also found to suppress degeneration associated with proteasome mutations in an autophagy-dependent manner, revealing a compensatory relationship between these two degradation pathways. Our findings indicate that HDAC6 facilitates degradation of potentially noxious protein substrates, contributing vitally to the neuroprotective role of autophagy.
- Published
- 2007
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