50 results on '"G. Carreño-Tarragona"'
Search Results
2. P716: OUTCOMES AND PATTERNS OF TREATMENT IN CHRONIC MYELOID LEUKEMIA, A GLOBAL PERSPECTIVE BASED ON A REAL-WORLD DATA GLOBAL NETWORK
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A. Sanz, R. Ayala, G. Hernández, N. López, D. Gil, R. Gil, R. Colmenares, G. Carreño-Tarragona, J. M. Sánchez Pina, R. A. Alonso, N. García Barrio, D. Pérez-Rey, L. Meloni, M. Calbacho, M. Pedrera-Jiménez, P. Serrano-Balazote, J. de la Cruz, and J. Martínez-López
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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3. Papain-treated panels are a simple method for the identification of alloantibodies in multiple myeloma patients treated with anti-CD38-based therapies
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G, Carreño-Tarragona, T, Cedena, L, Montejano, R, Alonso, F, Miras, A, Valeri, A, Rivero, J J, Lahuerta, and J, Martinez-Lopez
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Adult ,Aged, 80 and over ,Male ,Antibodies, Monoclonal ,Transfusion Reaction ,Middle Aged ,Antibodies, Monoclonal, Humanized ,Coombs Test ,Isoantibodies ,Papain ,Humans ,Blood Transfusion ,Female ,Multiple Myeloma ,Aged - Abstract
To report our 2 years of experience navigating the interference of anti-CD38 monoclonal antibodies (MAs) in 33 patients and describe papain-treated panels as a complementary method to dithiothreitol (DTT).Novel anti-CD38 MAs are now approved or undergoing clinical trials to evaluate their activity in patients with multiple myeloma. A concern with the use of these drugs is that they interfere with blood bank tests in a group of patients who often require blood transfusions.Clinical data and whole blood samples were collected from patients receiving daratumumab or isatuximab. Routine blood bank serological tests were performed.A total of 9·1% of patients presented with alloantibodies prior to treatment. All patients exhibited nonspecific reactivity in indirect antiglobulin tests, and 26% had positive direct antiglobulin tests after beginning treatment. This interference disappeared in all patients after discontinuing treatment. Papain panels avoided this reactivity and allowed us to identify alloantibodies. Phenotyped blood units were transfused, and no patient suffered any transfusion-related complications.Anti-CD38 MAs produce nonspecific interference in blood bank tests. This interference can be overcome by various methods, including DTT or papain treatment as proposed here. These methods have limitations that can be resolved using phenotyped blood units.
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- 2017
4. PF664 46/1 HAPLOTYPE IS ASSOCIATED WITH A HIGHER MONOCYTE/LYMPHOCYTE RATIO IN HEALTHY INDIVIDUALS
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G. Carreño-Tarragona, J.M. García-Ruiz, J. Martínez-López, N.C. P. Cross, A.J. Chase, R. Rouco, J.C. Silla, F. Sánchez-Cabo, B. Oliva, V. Fuster, R. Ayala, and M. Manzanares
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medicine.anatomical_structure ,Healthy individuals ,Monocyte ,Lymphocyte ,Haplotype ,Immunology ,medicine ,Hematology ,Biology - Published
- 2019
5. P1009: PREDICTORS OF HOSPITALIZATION AND SEVERE OUTCOMES IN PATIENTS WITH MPN AND COVID-19
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T. Barbui, A. Carobbio, A. Masciulli, A. Iurlo, M. A. Sobas, E. M. Elli, E. Rumi, V. De Stefano, F. Lunghi, M. Marchetti, R. Daffini, M. Gasior Kabat, B. Cuevas, M. L. Fox, M. M. Andrade Campos, F. Palandri, P. Guglielmelli, G. Benevolo, C. Harrison, M. A. Foncillas, M. Bonifacio, A. Alvarez-Larran, J.-J. Kiladjian, E. Bolanos Calderon, A. Patriarca, K. S. Quiroz Cervantes, M. Griesshammer, V. Garcia-Gutierrez, A. Marin Sanchez, E. Magro Mazo, M. Ruggeri, J. C. Hernandez-Boluda, S. Osorio, G. Carreno-Tarragona, M. Sagues Serrano, R. Kusec, B. Navas Elorza, A. Angona, B. Xicoy Cirici, E. Lopez Abadia, S. Koschmieder, E. Cichocka, A. Kulikowska de Nałęcz, M. Bellini, D. Cattaneo, C. Bucelli, F. Cavalca, O. Borsani, S. Betti, N. Curto-Garcia, S. Carbonell, L. Benajiba, A. Rambaldi, and A. M. Vannucchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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6. Prognostic value of response to first-line hydroxyurea according to IPSET stratification in essential thrombocythemia.
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Santaliestra M, Garrote M, Noya MS, Pérez-Encinas M, Senín A, Pérez-López R, Ferrer-Marín F, Carreño-Tarragona G, Caballero G, Magro E, Vélez P, Cortés Vázquez MÁ, Moretó A, Angona A, Pastor-Galán I, Guerra JM, García Hernández C, Mata MI, Stuckey R, Gómez-Casares MT, Fox L, Cuevas B, García-Gutiérrez V, Triguero A, Arellano-Rodrigo E, Hernández-Boluda JC, and Alvarez-Larrán A
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Hydroxyurea (HU) constitutes the first-line treatment in most patients with essential thrombocythemia (ET), but criteria for changing therapy are not clearly established. The prognostic value of complete hematological response (CHR) and resistance/intolerance to HU was assessed in 1080 patients from the Spanish Registry of ET, classified according to revised IPSET-Thrombosis stratification (Very low- n = 61, Low- n = 83, Intermediate- n = 261, and High-risk n = 675). With a median therapy duration of 5 years, CHR was registered in 720 (67%) patients (1-year probability 51%) and resistance/intolerance in 219 (20%) patients (5-years probability 13%). After correction by other risk factors, High-risk patients achieving CHR showed a reduced risk of arterial thrombosis (HR: 0.35, 95%CI: 0.2-0.6, p = 0.001) and a trend towards lower risk of venous thrombosis (HR: 0.45, 95%CI: 0.2-1.02, p = 0.06) whereas no association was observed for intermediate- or low-risk patients. In comparison with non-responders, intermediate- and high-risk patients achieving CHR had longer survival and lower myelofibrosis incidence. Development of resistance/intolerance to HU, mainly cytopenia, was associated with higher probability of myelofibrosis but no effect on survival or thrombotic risk was demonstrated. In conclusion, CHR with HU is associated with better outcomes and might be an early indicator for selecting candidates to second-line clinical trials., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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7. Real-World Impact of Deep Targeted Sequencing on Erythrocytosis and Thrombocytosis Diagnosis: A Reference Centre Experience.
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Blanco-Sánchez A, Gil-Manso R, de Nicolás R, López-Muñoz N, Colmenares R, Mas R, Sánchez R, Rapado I, Martínez-López J, Díaz RA, and Carreño-Tarragona G
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Despite advances in diagnosis of erythrocytosis and thrombocytosis due to driver mutation testing, many cases remain classified as "idiopathic". This can be explained by the absence of an evident secondary cause, inconclusive bone marrow biopsy or neglection of family history. Analysis of a broad panel of genes through next-generation sequencing (NGS) could improve diagnostic work-up identifying underlying genetic causes. We reviewed the results of NGS performed in our laboratory and its diagnostic impact on 117 patients with unexplained erythrocytosis and 58 with unexplained thrombocytosis; six patients (5.1%) were diagnosed with polycythaemia vera (PV) and 8 (6.8%) with familial erythrocytosis after NGS testing. Low EPO and a family history seemed to predict a positive result, respectively. However, a greater percentage of patients were ultimately diagnosed with secondary erythrocytosis (36%), remained as idiopathic (28.2%) or were self-limited (15%). The yield of NGS was shown to be slightly higher in patients with thrombocytosis, as 15 (25.9%) were diagnosed with essential thrombocythemia (ET) or familial thrombocytosis after variant detection; previous research has shown similar results, but most of them carried out NGS retrospectively, while the present study exhibits the performance of this test in a real-world setting. Overall, the low rate of variant detection and its poor impact on diagnostic work-up highlights the need for a thorough screening prior to NGS, in order to improve its yield.
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- 2024
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8. DNMT3A/TET2/ASXL1 Mutations are an Age-independent Thrombotic Risk Factor in Polycythemia Vera Patients: An Observational Study.
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Segura-Díaz A, Stuckey R, Florido Y, Sobas M, Álvarez-Larrán A, Ferrer-Marín F, Pérez-Encinas M, Carreño-Tarragona G, Fox ML, Tazón Vega B, Cuevas B, López Rodríguez JF, Sánchez-Farías N, González-Martín JM, Gómez-Casares MT, and Bilbao-Sieyro C
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- Humans, Male, Female, Middle Aged, Risk Factors, Aged, Age Factors, Case-Control Studies, Adult, Europe epidemiology, Incidence, Genetic Predisposition to Disease, Risk Assessment, Kaplan-Meier Estimate, Aged, 80 and over, Dioxygenases, Thrombosis genetics, Mutation, DNA Methyltransferase 3A, Polycythemia Vera genetics, Polycythemia Vera complications, Repressor Proteins genetics, Proto-Oncogene Proteins genetics, DNA (Cytosine-5-)-Methyltransferases genetics, DNA-Binding Proteins genetics
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Background: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes ( DNMT3A, TET2, and ASXL1 ). The objective of this study was to confirm this observation in a larger series of PV patients., Methods: PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias., Results: Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort ( p = 0.007), as well as in low-risk patients ( p = 0.039) and older patients ( p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation., Conclusion: Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
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- 2024
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9. Author Correction: Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA.
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Sánchez R, Dorado S, Ruíz-Heredia Y, Martín-Muñoz A, Rosa-Rosa JM, Ribera J, García O, Jimenez-Ubieto A, Carreño-Tarragona G, Linares M, Rufián L, Juárez A, Carrillo J, Espino MJ, Cáceres M, Expósito S, Cuevas B, Vanegas R, Casado LF, Torrent A, Zamora L, Mercadal S, Coll R, Cervera M, Morgades M, Hernández-Rivas JÁ, Bravo P, Serí C, Anguita E, Barragán E, Sargas C, Ferrer-Marín F, Sánchez-Calero J, Sevilla J, Ruíz E, Villalón L, Del Mar Herráez M, Riaza R, Magro E, Steegman JL, Wang C, de Toledo P, García-Gutiérrez V, Ayala R, Ribera JM, Barrio S, and Martínez-López J
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- 2024
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10. NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.
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Hurtado-Navarro L, Cuenca-Zamora EJ, Zamora L, Bellosillo B, Such E, Soler-Espejo E, Martínez-Banaclocha H, Hernández-Rivas JM, Marco-Ayala J, Martínez-Alarcón L, Linares-Latorre L, García-Ávila S, Amat-Martínez P, González T, Arnan M, Pomares-Marín H, Carreño-Tarragona G, Chen-Liang TH, Herranz MT, García-Palenciano C, Morales ML, Jerez A, Lozano ML, Teruel-Montoya R, Pelegrín P, and Ferrer-Marín F
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- Humans, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Symptom Burden, Interleukin-1 metabolism, Inflammasomes genetics, Inflammasomes metabolism, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic genetics
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Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRAS
G12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers., Competing Interests: Declaration of interests P.P. is consultant of Viva In Vitro Diagnostics SL. P.P., H.M.-B., and C.G.-P. are inventors on patent PCT/EP2020/056729. L.H.-N., L.M.-A., H.M.-B., C.G.-P., and P.P. are co-founders of Viva In Vitro Diagnostics SL but declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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11. Should we move to a genomic classification of neutrophilic myeloid neoplasms?
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Carreño-Tarragona G, Álvarez-Larrán A, Hernández-Boluda JC, Ayala R, and Cross NCP
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- Humans, Genomics, Neoplasms, Myeloproliferative Disorders genetics
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- 2023
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12. Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia.
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Morales ML, García-Vicente R, Rodríguez-García A, Reyes-Palomares A, Vincelle-Nieto Á, Álvarez N, Ortiz-Ruiz A, Garrido-García V, Giménez A, Carreño-Tarragona G, Sánchez R, Ayala R, Martínez-López J, and Linares M
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- Humans, Sulfonamides pharmacology, Sulfonamides therapeutic use, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, RNA Splicing, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytarabine pharmacology, Cytarabine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism
- Abstract
Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation were altered during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis were significantly lower in responder than non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes. Notably, splicing inhibitors were therapeutically effective in treating sensitive and resistant AML cells as monotherapy or combination with other approved drugs. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML., (© 2023. The Author(s).)
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- 2023
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13. Multidisciplinary management in chronic myeloid leukemia improves cardiovascular risk measured by SCORE.
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Blanco Sánchez A, Gil Manso R, Carreño-Tarragona G, Paredes Ruiz D, González Olmedo J, Martínez-López J, Díaz Pedroche C, and Ayala R
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Introduction: Cardiovascular events are one of the main long-term complications in patients with chronic myeloid leukemia (CML) receiving treatment with tyrosine kinase inhibitors (TKIs). The proper choice of TKI and the adequate management of risk factors may reduce cardiovascular comorbidity in this population. Methods: This study evaluated the cardiovascular risk of a cohort of patients with CML at diagnosis and after follow-up in a specialized cardiovascular risk consultation. In order to do this, we performed data analysis from 35 patients who received TKIs and were referred to the aforementioned consultation between 2015 and 2018 at our center. Cardiovascular risk factors were analyzed separately, as well as integrated into the cardiovascular SCORE, both at diagnosis and at the last visit to the specialized consultation. Results: At the time of diagnosis, 60% had some type of risk factor, 20% had a high or very high risk SCORE, 40% had an intermediate risk, and 40% belonged to the low risk category. During follow-up, the main cardiovascular adverse event observed was hypertension (diagnosed in 8 patients, 23%). 66% of patients quit smoking, achieving control of blood pressure in 95%, diabetes in 50%, weight in 76%, and dyslipidemia in 92%. 5.7% of patients suffered a thrombotic event and a significant percentage of patients showed a reduction in their SCORE. Conclusion: Our study shows the benefit of controlling cardiovascular risk factors through follow-up in a specialized consultation for patients with CML treated with TKI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Blanco Sánchez, Gil Manso, Carreño-Tarragona, Paredes Ruiz, González Olmedo, Martínez-López, Díaz Pedroche and Ayala.)
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- 2023
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14. Application of IPSET-thrombosis in 1366 Patients Prospectively Followed From the Spanish Registry of Essential Thrombocythemia.
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Alvarez-Larrán A, Cuevas B, Velez P, Noya S, Caballero-Navarro G, Ferrer-Marín F, Carbonell S, Pérez-Encinas M, Gómez-Casares MT, Pérez-López R, Magro E, Moretó A, Pastor-Galán I, Angona A, Mata-Vázquez MI, Guerrero-Fernández L, Guerra JM, Carreño-Tarragona G, Fox L, Murillo I, García-Gutiérrez V, Mora E, Stuckey R, Arellano-Rodrigo E, Hernández-Boluda JC, and Pereira A
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The International Prognostic Score of thrombosis in Essential Thrombocythemia (IPSET-thrombosis) and its revised version have been proposed to guide thrombosis prevention strategies. We evaluated both classifications to prognosticate thrombosis in 1366 contemporary essential thrombocythemia (ET) patients prospectively followed from the Spanish Registry of ET. The cumulative incidence of thrombosis at 10 years, taking death as a competing risk, was 11.4%. The risk of thrombosis was significantly higher in the high-risk IPSET-thrombosis and high-risk revised IPSET-thrombosis, but no differences were observed among the lower risk categories. Patients allocated in high-risk IPSET-thrombosis (subdistribution hazard ratios [SHR], 3.7 [95% confidence interval, CI, 1.6-8.7]) and high-risk revised IPSET-thrombosis (SHR, 3.2 [95% CI, 1.4-7.45]) showed an increased risk of arterial thrombosis, whereas both scoring systems failed to predict venous thrombosis. The incidence rate of thrombosis in intermediate risk revised IPSET-thrombosis (aged >60 years, JAK2 -negative, and no history of thrombosis) was very low regardless of the treatment administered (0.9% and 0% per year with and without cytoreduction, respectively). Dynamic application of the revised IPSET-thrombosis showed a low rate of thrombosis when patients without history of prior thrombosis switched to a higher risk category after reaching 60 years of age. In conclusion, IPSET-thrombosis scores are useful for identifying patients at high risk of arterial thrombosis, whereas they fail to predict venous thrombosis. Controlled studies are needed to determine the appropriate treatment of ET patients assigned to the non-high-risk categories., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
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- 2023
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15. CNL and aCML should be considered as a single entity based on molecular profiles and outcomes.
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Carreño-Tarragona G, Álvarez-Larrán A, Harrison C, Martínez-Ávila JC, Hernández-Boluda JC, Ferrer-Marín F, Radia DH, Mora E, Francis S, González-Martínez T, Goddard K, Pérez-Encinas M, Narayanan S, Raya JM, Singh V, Gutiérrez X, Toth P, Amat-Martínez P, Mcilwaine L, Alobaidi M, Mayani K, McGregor A, Stuckey R, Psaila B, Segura A, Alvares C, Davidson K, Osorio S, Cutting R, Sweeney CP, Rufián L, Moreno L, Cuenca I, Smith J, Morales ML, Gil-Manso R, Koutsavlis I, Wang L, Mead AJ, Rozman M, Martínez-López J, Ayala R, and Cross NCP
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- Humans, Epigenesis, Genetic, Mutation, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative diagnosis, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative genetics, Leukemia, Neutrophilic, Chronic diagnosis, Leukemia, Neutrophilic, Chronic genetics, Myelodysplastic-Myeloproliferative Diseases genetics
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Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (β = 2.26, hazard ratio [HR] = 9.54, P = .003), EZH2 (β = 1.12, HR = 3.062, P = .009), NRAS (β = 1.29, HR = 3.63, P = .048), and U2AF1 (β = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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16. Janus kinase inhibitor ruxolitinib in combination with nilotinib and prednisone in patients with myelofibrosis (RuNiC study): A phase Ib, multicenter study.
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Ayala R, Fernández RA, García-Gutiérrez V, Alvarez-Larrán A, Osorio S, Sánchez-Pina JM, Carreño-Tarragona G, Álvarez N, Gómez-Casares MT, Duran A, Gorrochategi J, Hernández-Boluda JC, and Martínez-López J
- Abstract
This phase Ib, non-randomized, open-label study evaluates the safety and tolerability of ruxolitinib in combination with nilotinib and prednisone in patients with naïve or ruxolitinib-resistant myelofibrosis (MF). A total of 15 patients with primary or secondary MF received the study treatment; 13 patients had received prior ruxolitinib treatment (86.7%). Eight patients completed seven cycles (53.3%) and six patients completed twelve cycles of treatment (40%). All the patients experienced at least one adverse event (AE) during the study (the most common AEs were hyperglycemia, asthenia, and thrombocytopenia), and 14 patients registered at least one treatment-related AE (the most common treatment-related AEs were hyperglycemia (22.2%; three grade 3 cases). Five treatment-related serious AEs (SAEs) were reported in two patients (13.3%). No deaths were registered throughout the study. No dose-limiting toxicity was observed. Four out of fifteen (27%) patients experienced a 100% spleen size reduction at Cycle 7, and two additional patients achieved a >50% spleen size reduction, representing an overall response rate of 40% at Cycle 7. In conclusion, the tolerability of this combination was acceptable, and hyperglycemia was the most frequent treatment-related AE. Ruxolitinib in combination with nilotinib and prednisone showed relevant clinical activity in patients with MF. This trial was registered with EudraCT Number 2016-005214-21., Competing Interests: J.M‐L. declares honoraria for lectures; membership on advisory boards with Janssen, BMS, Sanofi, Novartis, Incyte, Roche, and Amgen; and membership on the boards of directors of Hosea and Altum Sequencing. R.A. is an advisory board member for Novartis and Incyte; received speaker honoraria from Astellas, Celgene, and Novartis; and is a member on the board of directors of Altum Sequencing. The remaining authors declare no competing financial interests., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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17. Cell Count Differentials by Cytomorphology and Next-Generation Flow Cytometry in Bone Marrow Aspirate: An Evidence-Based Approach.
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Ríos-Tamayo R, Sánchez MJ, Gómez-Rojas S, Rodríguez-Barranco M, Segura GP, Redondo-Sánchez D, Carreño-Tarragona G, Nicolás AR, Ruiz-Cabello F, Jiménez P, Alonso R, Lahuerta JJ, Martínez-López J, and Duarte RF
- Abstract
Despite a lack of evidence, a bone marrow aspirate differential of 500 cells is commonly used in the clinical setting. We aimed to test the performance of 200-cell counts for daily hematological workup. In total, 660 consecutive samples were analyzed recording differentials at 200 and 500 cells. Additionally, immunophenotype results and preanalytical issues were also evaluated. Clinical and statistical differences between both cutoffs and both methods were checked. An independent control group of 122 patients was included. All comparisons between both cutoffs and both methods for all relevant types of cells did not show statistically significant differences. No significant diagnostic discrepancies were demonstrated in the contingency table analysis. This is a real-life study, and some limitations may be pointed out, such as a different sample sizes according to the type of cell in the immunophenotype analysis, the lack of standardization of some preanalytical events, and the relatively small sample size of the control group. The comparisons of differentials by morphology on 200 and 500 cells, as well as by morphology (both cutoffs) and by immunophenotype, are equivalent from the clinical and statistical point of view. The preanalytical issues play a critical role in the assessment of bone marrow aspirate samples.
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- 2023
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18. Impact of FLT3-ITD Mutation Status and Its Ratio in a Cohort of 2901 Patients Undergoing Upfront Intensive Chemotherapy: A PETHEMA Registry Study.
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Ayala R, Carreño-Tarragona G, Barragán E, Boluda B, Larráyoz MJ, Chillón MC, Carrillo-Cruz E, Bilbao C, Sánchez-García J, Bernal T, Martinez-Cuadron D, Gil C, Serrano J, Rodriguez-Medina C, Bergua J, Pérez-Simón JA, Calbacho M, Alonso-Domínguez JM, Labrador J, Tormo M, Amigo ML, Herrera-Puente P, Rapado I, Sargas C, Vazquez I, Calasanz MJ, Gomez-Casares T, García-Sanz R, Sanz MA, Martínez-López J, and Montesinos P
- Abstract
FLT3−ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3−ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3−ITD mutations. In multivariate analyses, patients with an FLT3−ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3−ITD-mutated patients, median OS gradually decreased according to FLT3−ITD status and ratio (34.3 months FLT3−ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months ≥ 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3−ITD-mutated AML regardless of pre-established AR cutoff (≤0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3−ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3−ITD status in all patients, and we found that the group of FLT3−ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3−ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3−ITD mutations.
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- 2022
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19. Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA.
- Author
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Sánchez R, Dorado S, Ruíz-Heredia Y, Martín-Muñoz A, Rosa-Rosa JM, Ribera J, García O, Jimenez-Ubieto A, Carreño-Tarragona G, Linares M, Rufián L, Juárez A, Carrillo J, Espino MJ, Cáceres M, Expósito S, Cuevas B, Vanegas R, Casado LF, Torrent A, Zamora L, Mercadal S, Coll R, Cervera M, Morgades M, Hernández-Rivas JÁ, Bravo P, Serí C, Anguita E, Barragán E, Sargas C, Ferrer-Marín F, Sánchez-Calero J, Sevilla J, Ruíz E, Villalón L, Del Mar Herráez M, Riaza R, Magro E, Steegman JL, Wang C, de Toledo P, García-Gutiérrez V, Ayala R, Ribera JM, Barrio S, and Martínez-López J
- Subjects
- DNA, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl genetics, Genomics, High-Throughput Nucleotide Sequencing methods, Humans, Mutation, Protein Kinase Inhibitors pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
The screening of the BCR::ABL1 kinase domain (KD) mutation has become a routine analysis in case of warning/failure for chronic myeloid leukemia (CML) and B-cell precursor acute lymphoblastic leukemia (ALL) Philadelphia (Ph)-positive patients. In this study, we present a novel DNA-based next-generation sequencing (NGS) methodology for KD ABL1 mutation detection and monitoring with a 1.0E-4 sensitivity. This approach was validated with a well-stablished RNA-based nested NGS method. The correlation of both techniques for the quantification of ABL1 mutations was high (Pearson r = 0.858, p < 0.001), offering DNA-DeepNGS a sensitivity of 92% and specificity of 82%. The clinical impact was studied in a cohort of 129 patients (n = 67 for CML and n = 62 for B-ALL patients). A total of 162 samples (n = 86 CML and n = 76 B-ALL) were studied. Of them, 27 out of 86 harbored mutations (6 in warning and 21 in failure) for CML, and 13 out of 76 (2 diagnostic and 11 relapse samples) did in B-ALL patients. In addition, in four cases were detected mutation despite BCR::ABL1 < 1%. In conclusion, we were able to detect KD ABL1 mutations with a 1.0E-4 sensitivity by NGS using DNA as starting material even in patients with low levels of disease., (© 2022. The Author(s).)
- Published
- 2022
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20. Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea.
- Author
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Alvarez-Larrán A, Garrote M, Ferrer-Marín F, Pérez-Encinas M, Mata-Vazquez MI, Bellosillo B, Arellano-Rodrigo E, Gómez M, García R, García-Gutiérrez V, Gasior M, Cuevas B, Angona A, Gómez-Casares MT, Martínez CM, Magro E, Ayala R, Del Orbe-Barreto R, Pérez-López R, Fox ML, Raya JM, Guerrero L, García-Hernández C, Caballero G, Murillo I, Xicoy B, Ramírez MJ, Carreño-Tarragona G, Hernández-Boluda JC, and Pereira A
- Subjects
- Hemorrhage chemically induced, Humans, Hydroxyurea adverse effects, Nitriles, Pyrazoles, Pyrimidines, Retrospective Studies, Leukemia, Myeloid, Acute drug therapy, Neoplasms, Second Primary drug therapy, Polycythemia Vera drug therapy, Primary Myelofibrosis drug therapy, Thrombosis chemically induced, Thrombosis drug therapy, Thrombosis prevention & control
- Abstract
Background: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown., Methods: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT., Results: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups., Conclusions: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis., Lay Summary: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
- Published
- 2022
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21. Outcomes and patterns of treatment in chronic myeloid leukemia, a global perspective based on a real-world data global network.
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Sanz A, Ayala R, Hernández G, Lopez N, Gil-Alos D, Gil R, Colmenares R, Carreño-Tarragona G, Sánchez-Pina J, Alonso RA, García-Barrio N, Pérez-Rey D, Meloni L, Calbacho M, Cruz-Rojo J, Pedrera-Jiménez M, Serrano-Balazote P, de la Cruz J, and Martínez-López J
- Subjects
- Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology, Leukemia, Myeloid
- Published
- 2022
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22. MPL S505C enhances driver mutations at W515 in essential thrombocythemia.
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Varghese LN, Carreño-Tarragona G, Levy G, Gutiérrez-López de Ocáriz X, Rapado I, Martínez-López J, Ayala R, and Constantinescu SN
- Subjects
- Aged, 80 and over, Amino Acid Substitution, Female, Humans, Receptors, Thrombopoietin metabolism, Thrombocythemia, Essential metabolism, Mutation, Missense, Receptors, Thrombopoietin genetics, Thrombocythemia, Essential genetics
- Published
- 2021
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23. A typical acute lymphoblastic leukemia JAK2 variant, R683G, causes an aggressive form of familial thrombocytosis when germline.
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Carreño-Tarragona G, Varghese LN, Sebastián E, Gálvez E, Marín-Sánchez A, López-Muñoz N, Nam-Cha S, Martínez-López J, Constantinescu SN, Sevilla J, and Ayala R
- Subjects
- Adult, Child, Female, Humans, Male, Pedigree, Thrombocytosis etiology, Thrombocytosis metabolism, Young Adult, Germ-Line Mutation, Janus Kinase 2 genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Thrombocytosis pathology
- Published
- 2021
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24. Monitoring of clonal evolution of acute myeloid leukemia identifies the leukemia subtype, clinical outcome and potential new drug targets for post-remission strategies or relapse.
- Author
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Onecha E, Rapado I, Luz Morales M, Carreño-Tarragona G, Martinez-Sanchez P, Gutierrez X, Sáchez Pina JM, Linares M, Gallardo M, Martinez-López J, and Ayala R
- Subjects
- Clonal Evolution genetics, Humans, Neoplasm, Residual, Prognosis, Recurrence, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Pharmaceutical Preparations
- Abstract
In cases of treatment failure in acute myeloid leukemia (AML), the utility of mutational profiling in primary refractoriness and relapse is not established. We undertook a perspective study using next-generation sequencing (NGS) of clinical follow-up samples (n=91) from 23 patients with AML with therapeutic failure to cytarabine plus idarubicin or fludarabine. Cases of primary refractoriness to treatment were associated with a lower number of DNA variants at diagnosis than cases of relapse (median 1.67 and 3.21, respectively, p=0.029). The most frequently affected pathways in patients with primary refractoriness were signaling, transcription and tumor suppression, whereas methylation and splicing pathways were mainly implicated in relapsed patients. New therapeutic targets, either by an approved drug or within clinical trials, were not identified in any of the cases of refractoriness (0/10); however, 8 potential new targets were found in 5 relapsed patients (5/13) (p=0.027): 1 IDH2, 3 SF3B1, 2 KRAS, 1 KIT and 1 JAK2. Sixty-five percent of all variants detected at diagnosis were not detected at complete response (CR). Specifically, 100% of variants in EZH2, RUNX1, VHL, FLT3, ETV6, U2AF1, PHF6 and SF3B1 disappeared at CR, indicating their potential use as markers to evaluate minimal residual disease (MRD) for follow-up of AML. Molecular follow-up using a custom NGS myeloid panel of 32 genes in the post-treatment evaluation of AML can help in the stratification of prognostic risk, the selection of MRD markers to monitor the response to treatment and guide post-remission strategies targeting AML, and the selection of new drugs for leukemia relapse.
- Published
- 2021
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25. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma.
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Leivas A, Valeri A, Córdoba L, García-Ortiz A, Ortiz A, Sánchez-Vega L, Graña-Castro O, Fernández L, Carreño-Tarragona G, Pérez M, Megías D, Paciello ML, Sánchez-Pina J, Pérez-Martínez A, Lee DA, Powell DJ Jr, Río P, and Martínez-López J
- Subjects
- Animals, Cell Line, Tumor, Humans, Male, Mice, Inbred NOD, Mice, Immunotherapy, Adoptive methods, Killer Cells, Natural transplantation, Multiple Myeloma therapy, NK Cell Lectin-Like Receptor Subfamily K therapeutic use
- Abstract
CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA
- T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM., (© 2021. The Author(s).)- Published
- 2021
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26. Author Correction: Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia.
- Author
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Lozano ML, Mingot-Castellano ME, Perera MM, Jarque I, Campos-Alvarez RM, González-López TJ, Carreño-Tarragona G, Bermejo N, Lopez-Fernandez MF, de Andrés A, Valcarcel D, Casado-Montero LF, Alvarez-Roman MT, Orts MI, Novelli S, Revilla N, González-Porras JR, Bolaños E, Rodríguez-López MA, Orna-Montero E, and Vicente V
- Published
- 2021
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27. The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial.
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Ayala R, Rapado I, Onecha E, Martínez-Cuadrón D, Carreño-Tarragona G, Bergua JM, Vives S, Algarra JL, Tormo M, Martinez P, Serrano J, Herrera P, Ramos F, Salamero O, Lavilla E, Gil C, López Lorenzo JL, Vidriales MB, Labrador J, Falantes JF, Sayas MJ, Paiva B, Barragán E, Prosper F, Sanz MÁ, Martínez-López J, Montesinos P, and On Behalf Of The Programa Para El Estudio de la Terapeutica En Hemopatias Malignas Pethema Cooperative Study Group
- Abstract
We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1.014; p = 0.030) and lower TP53 VAF (OR, 0.981; p = 0.003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1.9, p = 0.005) and TP53 (HR, 2.6, p = 9.8 × 10
-7 ) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3.6, p = 0.0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low-intermediate cytogenetic risk (HR, 1.51, p = 0.045) and mutated NRAS (HR, 3.66, p = 0.047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4.71, p = 0.009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials.gov as NCT02319135.- Published
- 2021
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28. Do myeloproliferative neoplasms and multiple myeloma share the same genetic susceptibility loci?
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Macauda A, Giaccherini M, Sainz J, Gemignani F, Sgherza N, Sánchez-Maldonado JM, Gora-Tybor J, Martinez-Lopez J, Carreño-Tarragona G, Jerez A, Spadano R, Gołos A, Jurado M, Hernández-Mohedo F, Mazur G, Tavano F, Butrym A, Várkonyi J, Canzian F, and Campa D
- Subjects
- Aged, Female, Genetic Loci, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Genetic Predisposition to Disease, Multiple Myeloma genetics, Myeloproliferative Disorders genetics
- Abstract
Myeloproliferative neoplasms (MPNs) are a group of diseases that cause myeloid hematopoietic cells to overproliferate. Epidemiological and familial studies suggest that genetic factors contribute to the risk of developing MPN, but the genetic susceptibility of MPN is still not well known. Indeed, only few loci are known to have a clear role in the predisposition to this disease. Some studies reported a diagnosis of MPNs and multiple myeloma (MM) in the same patients, but the biological causes are still unclear. We tested the hypothesis that the two diseases share at least partly the same genetic risk loci. In the context of a European multicenter study with 460 cases and 880 controls, we analyzed the effect of the known MM risk loci, individually and in a polygenic risk score (PRS). The most significant result was obtained among patients with chronic myeloid leukemia (CML) for PS0RS1C1-rs2285803, which showed to be associated with an increased risk (OR = 3.28, 95% CI 1.79-6.02, P = .00012, P = .00276 when taking into account multiple testing). Additionally, the PRS showed an association with MPN risk when comparing the last with the first quartile of the PRS (OR = 2.39, 95% CI 1.64-3.48, P = 5.98 × 10
-6 ). In conclusion, our results suggest a potential common genetic background between MPN and MM, which needs to be further investigated., (© 2020 UICC.)- Published
- 2021
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29. Cytoreductive treatment in patients with CALR-mutated essential thrombocythaemia: a study comparing indications and efficacy among genotypes from the Spanish Registry of Essential Thrombocythaemia.
- Author
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Alvarez-Larrán A, Angona A, Andrade-Campos M, Soledad Noya M, Teresa Gómez-Casares M, Cuevas B, Caballero G, García-Hernández C, García-Gutiérrez V, Palomino A, Ferrer-Marín F, Isabel Mata-Vázquez M, Moretó A, Magro E, Murillo I, Manuel Alonso-Domínguez J, María Guerra J, Guerrero L, María Raya J, Pérez-Encinas M, Carreño-Tarragona G, Fox L, Pastor-Galán I, Bellosillo B, and Hernández-Boluda JC
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Substitution, Child, Female, Follow-Up Studies, Humans, Janus Kinase 2 genetics, Male, Middle Aged, Spain, Calreticulin genetics, Genotype, Hydroxyurea administration & dosage, Mutation, Missense, Quinazolines administration & dosage, Registries, Thrombocythemia, Essential drug therapy, Thrombocythemia, Essential genetics
- Abstract
The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2021
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30. Genomic characterization of patients with polycythemia vera developing resistance to hydroxyurea.
- Author
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Alvarez-Larrán A, Díaz-González A, Such E, Mora E, Andrade-Campos M, García-Hernández C, Gómez-Casares MT, García-Gutiérrez V, Carreño-Tarragona G, Garrote M, Fernández-Ibarrondo L, Cervera J, Bellosillo B, Cervantes F, and Hernández-Boluda JC
- Subjects
- Humans, Polycythemia Vera drug therapy, Polycythemia Vera pathology, Prognosis, Survival Rate, Antineoplastic Agents pharmacology, Biomarkers, Tumor genetics, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic drug effects, Genomics methods, Hydroxyurea pharmacology, Polycythemia Vera genetics
- Published
- 2021
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31. A decade of changes in management of immune thrombocytopenia, with special focus on elderly patients.
- Author
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Lozano ML, Mingot-Castellano ME, Perera MM, Jarque I, Campos-Alvarez RM, González-López TJ, Carreño-Tarragona G, Bermejo N, Lopez-Fernandez MF, de Andrés A, Valcarcel D, Casado-Montero LF, Alvarez-Roman MT, Orts MI, Novelli S, González-Porras JR, Bolaños E, López-Ansoar E, Orna-Montero E, and Vicente V
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Disease Management, Female, Humans, Male, Middle Aged, Purpura, Thrombocytopenic, Idiopathic epidemiology, Retrospective Studies, Treatment Outcome, Young Adult, Purpura, Thrombocytopenic, Idiopathic therapy, Receptors, Thrombopoietin agonists
- Abstract
Background: Ten years after their availability, thrombopoietin receptor agonists (TPO-RA) have heralded a paradigm shift in the treatment of immune thrombocytopenia (ITP). This study was aimed to analyze the implementation of current recommendations in the standard practice of adult ITP patients, and how age may influence those changes., Methods: We included 121 adult patients (> 65 years, n = 54; younger individuals, n = 67) who initiated treatment with TPO-RA between January 2012 and December 2014., Results: Patients older than 65 years treated with TPO-RA presented at diagnosis with significantly higher platelet counts, less bleeding, and a more prothrombotic profile than younger ones. The high efficacy rates of TPO-RA, preferentially used during the last decade in non-chronic phases, precluded from further therapies in the majority of ITP patients. Their administration was associated with a sharp decline in the last decade in the use of splenectomy and intravenous immunoglobulin, especially in younger ITP individuals., Conclusion: These results confirm (1) that there is a preferential use of TPO-RAs in elderly ITP patients with fewer bleeding complications but more unfavorable prothrombotic conditions than in younger individuals, and (2) that early use of these agents has been established as an effective therapeutic alternative to other second line therapies., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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32. Immunogenetic characterization of clonal plasma cells in systemic light-chain amyloidosis.
- Author
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Cuenca I, Alameda D, Sanchez-Vega B, Gomez-Sanchez D, Alignani D, Lasa M, Onecha E, Lecumberri R, Prosper F, Ocio EM, González ME, García de Coca A, De La Rubia J, Gironella M, Palomera L, Oriol A, Casanova M, Cabañas V, Taboada F, Pérez-Montaña A, De Arriba F, Puig N, Carreño-Tarragona G, Barrio S, Enrique de la Puerta J, Ramirez-Payer A, Krsnik I, Bargay JJ, Lahuerta JJ, Mateos MV, San-Miguel JF, Paiva B, and Martinez-Lopez J
- Subjects
- Biomarkers, Disease Management, Genetic Predisposition to Disease, Humans, Immunoglobulin Light-chain Amyloidosis diagnosis, Immunoglobulin Light-chain Amyloidosis metabolism, Mutation, Plasma Cells pathology, Clonal Evolution genetics, Clonal Evolution immunology, Disease Susceptibility, Immunoglobulin Light-chain Amyloidosis etiology, Plasma Cells immunology, Plasma Cells metabolism
- Published
- 2021
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33. Clinical course and risk factors for mortality from COVID-19 in patients with haematological malignancies.
- Author
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Sanchez-Pina JM, Rodríguez Rodriguez M, Castro Quismondo N, Gil Manso R, Colmenares R, Gil Alos D, Paciello ML, Zafra D, Garcia-Sanchez C, Villegas C, Cuellar C, Carreño-Tarragona G, Zamanillo I, Poza M, Iñiguez R, Gutierrez X, Alonso R, Rodríguez A, Folgueira MD, Delgado R, Ferrari JM, Lizasoain M, Aguado JM, Ayala R, Martinez-Lopez J, and Calbacho M
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, COVID-19 blood, Case-Control Studies, Female, Hematologic Neoplasms blood, Humans, Leukemia, Lymphocytic, Chronic, B-Cell complications, Lymphoma complications, Male, Middle Aged, Multiple Myeloma complications, Multivariate Analysis, Pandemics, Risk Factors, SARS-CoV-2, Spain epidemiology, COVID-19 complications, COVID-19 mortality, Hematologic Neoplasms complications
- Abstract
Background: The impact of coronavirus disease 2019 (COVID-19) in haematological patients (HP) has not been comprehensively reported., Methods: We analysed 39 patients with SARS-CoV-2 infection and haematological malignancies. Clinical characteristics and outcomes were compared to a matched control group of 53 non-cancer patients with COVID-19. Univariate and multivariate analyses were carried out to assess the risk factors associated with poor outcome., Results: The most frequent haematological diseases were lymphoma (30%) and multiple myeloma (30%). Eighty-seven % HP developed moderate or severe disease. Patients with haematological malignancies had a significantly higher mortality rate compared to non-cancer patients (35.9% vs 13.2%; P = .003 (odds ratio 6.652). The worst outcome was observed in chronic lymphocytic leukaemia patients. Only age >70 years and C reactive protein >10 mg/dl at admission were associated with higher risk of death (odds ratio 34.86, P = .003 and 13.56,P = .03). Persistent viral sheddind was detected in 5 HP. Active chemotherapy, viral load at diagnosis and COVID-19 therapy were not predictors of outcome., Conclusion: Mortality of COVID-19 is significantly higher in patients with haematological malignancies compared to non-cancer patients. The impact of persistent viral shedding must be considered in order to re-start therapies and maintain infectious control measures., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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34. Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels.
- Author
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Snyder TM, Gittelman RM, Klinger M, May DH, Osborne EJ, Taniguchi R, Zahid HJ, Kaplan IM, Dines JN, Noakes MT, Pandya R, Chen X, Elasady S, Svejnoha E, Ebert P, Pesesky MW, De Almeida P, O'Donnell H, DeGottardi Q, Keitany G, Lu J, Vong A, Elyanow R, Fields P, Greissl J, Baldo L, Semprini S, Cerchione C, Nicolini F, Mazza M, Delmonte OM, Dobbs K, Laguna-Goya R, Carreño-Tarragona G, Barrio S, Imberti L, Sottini A, Quiros-Roldan E, Rossi C, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Tompkins MF, Alba C, Dalgard C, Sambri V, Martinelli G, Goldman JD, Heath JR, Su HC, Notarangelo LD, Paz-Artal E, Martinez-Lopez J, Carlson JM, and Robins HS
- Abstract
T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in clinical diagnostics as well as in vaccine development and monitoring.
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- 2020
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35. A large-scale database of T-cell receptor beta (TCRβ) sequences and binding associations from natural and synthetic exposure to SARS-CoV-2.
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Nolan S, Vignali M, Klinger M, Dines JN, Kaplan IM, Svejnoha E, Craft T, Boland K, Pesesky M, Gittelman RM, Snyder TM, Gooley CJ, Semprini S, Cerchione C, Mazza M, Delmonte OM, Dobbs K, Carreño-Tarragona G, Barrio S, Sambri V, Martinelli G, Goldman JD, Heath JR, Notarangelo LD, Carlson JM, Martinez-Lopez J, and Robins HS
- Abstract
We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 135,000 high-confidence SARS-CoV-2-specific TCRs. This database is made freely available, and the data contained in it can be downloaded and analyzed online or offline to assist with the global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions., Competing Interests: Conflict of Interest Statement S.N, M.V., M.K., J.D., I.M.K., E.S., T.C., K.B., M.P, R.M.G., T.M.S. and H.S.R. have a financial interest in Adaptive Biotechnologies. C. J. G. and J.M.C. have a financial interest in Microsoft. Dr. Martinez-Lopez is a consultant for Adaptive Biotechnologies in projects outside of COVID-19. Funding for the ISB INCOV project from BARDA was managed by Merck, Merck had no role in planning the research or writing the paper. All other authors declare no competing interests.
- Published
- 2020
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36. Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia.
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Lozano ML, Mingot-Castellano ME, Perera MM, Jarque I, Campos-Alvarez RM, González-López TJ, Carreño-Tarragona G, Bermejo N, Lopez-Fernandez MF, de Andrés A, Valcarcel D, Casado-Montero LF, Alvarez-Roman MT, Orts MI, Novelli S, Revilla N, González-Porras JR, Bolaños E, Rodríguez-López MA, Orna-Montero E, and Vicente V
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Purpura, Thrombocytopenic, Idiopathic blood, Retrospective Studies, Survival Rate, Young Adult, Benzoates therapeutic use, Hydrazines therapeutic use, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombocytopenic, Idiopathic pathology, Pyrazoles therapeutic use, Receptors, Fc therapeutic use, Receptors, Thrombopoietin agonists, Recombinant Fusion Proteins therapeutic use, Thrombopoietin therapeutic use
- Abstract
Very few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 10
9 /l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs. eltrombopag (P = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs. 2.2%, P < 0.001), and to previous splenectomy in younger patients (100% vs. 33%, P = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA.- Published
- 2019
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37. The use of PanDrugs to prioritize anticancer drug treatments in a case of T-ALL based on individual genomic data.
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Fernández-Navarro P, López-Nieva P, Piñeiro-Yañez E, Carreño-Tarragona G, Martinez-López J, Sánchez Pérez R, Aroca Á, Al-Shahrour F, Cobos-Fernández MÁ, and Fernández-Piqueras J
- Subjects
- Adolescent, Alternative Splicing genetics, Exome genetics, Gene Fusion genetics, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation genetics, RNA-Seq, Spain, Transcriptome genetics, Antineoplastic Agents therapeutic use, Genome, Human genetics, Genomics methods, Precision Medicine methods, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Background: Acute T-cell lymphoblastic leukaemia (T-ALL) is an aggressive disorder derived from immature thymocytes. The variability observed in clinical responses on this type of tumours to treatments, the high toxicity of current protocols and the poor prognosis of patients with relapse or refractory make it urgent to find less toxic and more effective therapies in the context of a personalized medicine of precision., Methods: Whole exome sequencing and RNAseq were performed on DNA and RNA respectively, extracted of a bone marrow sample from a patient diagnosed with tumour primary T-ALL and double negative thymocytes from thymus control samples. We used PanDrugs, a computational resource to propose pharmacological therapies based on our experimental results, including lists of variants and genes. We extend the possible therapeutic options for the patient by taking into account multiple genomic events potentially sensitive to a treatment, the context of the pathway and the pharmacological evidence already known by large-scale experiments., Results: As a proof-of-principle we used next-generation-sequencing technologies (Whole Exome Sequencing and RNA-Sequencing) in a case of diagnosed Pro-T acute lymphoblastic leukaemia. We identified 689 disease-causing mutations involving 308 genes, as well as multiple fusion transcript variants, alternative splicing, and 6652 genes with at least one principal isoform significantly deregulated. Only 12 genes, with 27 pathogenic gene variants, were among the most frequently mutated ones in this type of lymphoproliferative disorder. Among them, 5 variants detected in CTCF, FBXW7, JAK1, NOTCH1 and WT1 genes have not yet been reported in T-ALL pathogenesis., Conclusions: Personalized genomic medicine is a therapeutic approach involving the use of an individual's information data to tailor drug therapy. Implementing bioinformatics platform PanDrugs enables us to propose a prioritized list of anticancer drugs as the best theoretical therapeutic candidates to treat this patient has been the goal of this article. Of note, most of the proposed drugs are not being yet considered in the clinical practice of this type of cancer opening up the approach of new treatment possibilities.
- Published
- 2019
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38. Protein Carbonylation in Patients with Myelodysplastic Syndrome: An Opportunity for Deferasirox Therapy.
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Rodríguez-García A, Morales ML, Garrido-García V, García-Baquero I, Leivas A, Carreño-Tarragona G, Sánchez R, Arenas A, Cedena T, Ayala RM, Bautista JM, Martínez-López J, and Linares M
- Abstract
Control of oxidative stress in the bone marrow (BM) is key for maintaining the interplay between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an indicator of oxidative stress in the BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox (DFX). As expected, differences in the pattern of protein carbonylation were observed in BM samples between MDS patients and controls, with an increase in protein carbonylation in the former. Strikingly, patients under DFX treatment had lower levels of protein carbonylation in BM with respect to untreated patients. Proteomic analysis identified four proteins with high carbonylation levels in MDS BM cells. Finally, as oxidative stress-related signaling pathways can modulate the cell cycle through p53, we analyzed the expression of the p53 target gene p21 in BM cells, finding that it was significantly upregulated in patients with MDS and was significantly downregulated after DFX treatment. Overall, our results suggest that the fine-tuning of oxidative stress levels in the BM of patients with MDS might control malignant progression.
- Published
- 2019
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39. Papain-treated panels are a simple method for the identification of alloantibodies in multiple myeloma patients treated with anti-CD38-based therapies.
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Carreño-Tarragona G, Cedena T, Montejano L, Alonso R, Miras F, Valeri A, Rivero A, Lahuerta JJ, and Martinez-Lopez J
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Female, Humans, Male, Middle Aged, Antibodies, Monoclonal administration & dosage, Blood Transfusion, Coombs Test, Isoantibodies blood, Multiple Myeloma blood, Multiple Myeloma therapy, Papain chemistry, Transfusion Reaction blood
- Abstract
Objectives: To report our 2 years of experience navigating the interference of anti-CD38 monoclonal antibodies (MAs) in 33 patients and describe papain-treated panels as a complementary method to dithiothreitol (DTT)., Background: Novel anti-CD38 MAs are now approved or undergoing clinical trials to evaluate their activity in patients with multiple myeloma. A concern with the use of these drugs is that they interfere with blood bank tests in a group of patients who often require blood transfusions., Methods: Clinical data and whole blood samples were collected from patients receiving daratumumab or isatuximab. Routine blood bank serological tests were performed., Results: A total of 9·1% of patients presented with alloantibodies prior to treatment. All patients exhibited nonspecific reactivity in indirect antiglobulin tests, and 26% had positive direct antiglobulin tests after beginning treatment. This interference disappeared in all patients after discontinuing treatment. Papain panels avoided this reactivity and allowed us to identify alloantibodies. Phenotyped blood units were transfused, and no patient suffered any transfusion-related complications., Conclusion: Anti-CD38 MAs produce nonspecific interference in blood bank tests. This interference can be overcome by various methods, including DTT or papain treatment as proposed here. These methods have limitations that can be resolved using phenotyped blood units., (© 2018 British Blood Transfusion Society.)
- Published
- 2019
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40. The pluripotency factor NANOG controls primitive hematopoiesis and directly regulates Tal1 .
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Sainz de Aja J, Menchero S, Rollan I, Barral A, Tiana M, Jawaid W, Cossio I, Alvarez A, Carreño-Tarragona G, Badia-Careaga C, Nichols J, Göttgens B, Isern J, and Manzanares M
- Subjects
- Animals, Cell Differentiation, Embryo, Mammalian metabolism, Embryonic Development, Embryonic Stem Cells metabolism, Female, Gene Expression Regulation, Developmental, Male, Mice, Mice, Transgenic, Pluripotent Stem Cells metabolism, T-Cell Acute Lymphocytic Leukemia Protein 1 genetics, Cell Lineage, Embryo, Mammalian cytology, Embryonic Stem Cells cytology, Hematopoiesis, Nanog Homeobox Protein physiology, Pluripotent Stem Cells cytology, T-Cell Acute Lymphocytic Leukemia Protein 1 metabolism
- Abstract
Progenitors of the first hematopoietic cells in the mouse arise in the early embryo from Brachyury -positive multipotent cells in the posterior-proximal region of the epiblast, but the mechanisms that specify primitive blood cells are still largely unknown. Pluripotency factors maintain uncommitted cells of the blastocyst and embryonic stem cells in the pluripotent state. However, little is known about the role played by these factors during later development, despite being expressed in the postimplantation epiblast. Using a dual transgene system for controlled expression at postimplantation stages, we found that Nanog blocks primitive hematopoiesis in the gastrulating embryo, resulting in a loss of red blood cells and downregulation of erythropoietic genes. Accordingly, Nanog -deficient embryonic stem cells are prone to erythropoietic differentiation. Moreover, Nanog expression in adults prevents the maturation of erythroid cells. By analysis of previous data for NANOG binding during stem cell differentiation and CRISPR/Cas9 genome editing, we found that Tal1 is a direct NANOG target. Our results show that Nanog regulates primitive hematopoiesis by directly repressing critical erythroid lineage specifiers., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2019
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41. Essential thrombocythaemia with mutation in MPL : clinicopathological correlation and comparison with JAK 2V617F-mutated and CALR- mutated genotypes.
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Alvarez-Larran A, Martínez D, Arenillas L, Rubio A, Arellano-Rodrigo E, Hernández Boluda JC, Papaleo N, Caballero G, Martínez C, Ferrer-Marín F, Mata MI, Pérez-Encinas M, Durán MA, Alonso JM, Carreño-Tarragona G, Alonso JM, Noya S, Magro E, Pérez R, López-Guerra M, Pastor-Galán I, Cervantes F, Besses C, Colomo L, and Rozman M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biopsy, Bone Marrow Examination, Cell Proliferation, Child, DNA Mutational Analysis, Female, Genetic Markers, Genetic Predisposition to Disease, Hemoglobins analysis, Humans, Male, Megakaryocytes pathology, Middle Aged, Phenotype, Platelet Count, Primary Myelofibrosis blood, Primary Myelofibrosis pathology, Prognosis, Thrombocythemia, Essential blood, Thrombocythemia, Essential pathology, Young Adult, Calreticulin genetics, Janus Kinase 2 genetics, Mutation, Primary Myelofibrosis genetics, Receptors, Thrombopoietin genetics, Thrombocythemia, Essential genetics
- Abstract
Aim: To characterise the clinical and histological features of MPL -mutated essential thrombocythaemia (ET)., Patients and Methods: Bone marrow biopsies of 175 patients with ET were centrally reviewed according to the 2016 WHO classification, including 42 cases with MPL mutation, 98 JAK2 V617F-mutated and 35 CALR -mutated. Clinical and histological features were compared among the three genotypes included in the current 2016 WHO classification and among the different types of MPL mutations., Results: Patients with MPL -mutated ET were significantly older than those with the other genotypes. Haematological values at diagnosis were similar among MPL -mutated and CALR -mutated ET, with both genotypes showing higher platelet counts and lower haemoglobin values than ET with JAK2 V617F genotype. In the bone marrow, the median number of megakaryocytes was higher in MPL and CALR than in JAK2 V617F genotype (16, 19 and 14 megakaryocytes per ×20 power field, respectively, p=0.004). Histological features of prefibrotic myelofibrosis were rarely observed in MPL genotype, whereas sinusoidal hyperplasia, dense clusters of megakaryocytes and reticulin fibrosis were more frequent in CALR -mutated ET, with 11% of such cases fulfilling WHO 2016 histological criteria of prefibrotic myelofibrosis. With a median follow-up of 3.5 years, no significant differences were seen among genotypes regarding survival, vascular complications or myelofibrotic transformation. There were no significant differences in the clinical data or in the histological characteristics depending on the type of MPL mutation., Conclusion: MPL and CALR ET genotypes share clinical and histological characteristics. In contrast to CALR genotype, features of prefibrotic myelofibrosis are uncommon in MPL -mutated ET., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2018
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42. Dramatic resolution of disseminated pyoderma gangrenosum associated with monoclonal gammopathy after therapy with bortezomib and dexamethasone.
- Author
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Velasco-Tamariz V, Carreño-Tarragona G, Tous-Romero F, Gil-de la Cruz E, Martín-Clavero E, and Rivera-Díaz R
- Subjects
- Adult, Anti-Inflammatory Agents therapeutic use, Antineoplastic Agents therapeutic use, Female, Humans, Middle Aged, Treatment Outcome, Bortezomib therapeutic use, Dexamethasone therapeutic use, Multiple Myeloma drug therapy, Paraproteinemias drug therapy, Pyoderma Gangrenosum drug therapy, Skin Ulcer drug therapy, Sweet Syndrome drug therapy
- Abstract
Pyoderma gangrenosum (PG) is an uncommon inflammatory and ulcerative skin disorder, which is commonly associated with systemic conditions such as inflammatory bowel disease, arthritis and haematological malignancies. It is widely stated that control of the underlying diseases may lead to resolution of PG. However, standard of care dictates that patients suffering with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (MM) should not receive therapy unless they progress to symptomatic MM. Here, we report a woman in her 40s with a disseminated corticodependent PG, resistant to any treatment attempted, including anti-tumoral necrosis factor (TNF) therapy in which bortezomib-dexamethasone regimen results in dramatic healing of all lesions in only a month. This case supports the belief that treatment of the underlying monoclonal gammopathy could be necessary when PG presents as an aggressive, non-responding skin disease., (© 2017 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)
- Published
- 2017
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43. Effects of early overnutrition on the renal response to Ang II and expression of RAAS components in rat renal tissue.
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Granado M, Amor S, Fernández N, Carreño-Tarragona G, Iglesias-Cruz MC, Martín-Carro B, Monge L, and García-Villalón AL
- Subjects
- Adipose Tissue drug effects, Adipose Tissue metabolism, Adipose Tissue physiopathology, Age Factors, Animal Nutritional Physiological Phenomena, Animals, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Gene Expression Regulation, Nitric Oxide Synthase Type III genetics, Nitric Oxide Synthase Type III metabolism, Nutritional Status, Overnutrition genetics, Overnutrition physiopathology, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1 genetics, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 2 genetics, Receptor, Angiotensin, Type 2 metabolism, Renal Artery metabolism, Renal Artery physiopathology, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Angiotensin II pharmacology, Kidney blood supply, Overnutrition metabolism, Renal Artery drug effects, Renin-Angiotensin System drug effects, Vasoconstriction drug effects, Vasoconstrictor Agents pharmacology
- Abstract
Background and Aims: The aim of this study was to analyze the effects of early overnutrition (EON) on the expression of the renin angiotensin aldosterone system (RAAS) components in renal cortex, renal arteries and renal perivascular adipose tissue (PVAT), as well as the vascular response of renal arteries to Angiotensin II (Ang II)., Methods and Results: On birth day litters were adjusted to twelve (L12-control) or three (L3-overfed) pups per mother. Half of the animals were sacrificed at weaning (21 days old) and the other half at 5 months of age. Ang II-induced vasoconstriction of renal artery segments increased in young overfed rats and decreased in adult overfed rats. EON decreased the gene expression of angiotensinogen (Agt), Ang II receptors AT1 and AT2 and eNOS in renal arteries of young rats, while it increased the mRNA levels of AT-2 and ET-1 in adult rats. In renal PVAT EON up-regulated the gene expression of COX-2 and TNF-α in young rats and the mRNA levels of renin receptor both in young and in adult rats. On the contrary, Ang II receptors mRNA levels were downregulated at both ages. Renal cortex of overfed rats showed increased gene expression of Agt in adult rats and of AT1 in young rats. However the mRNA levels of AT1 were decreased in the renal cortex of overfed adult rats., Conclusion: EON is associated with alterations in the vascular response of renal arteries to Ang II and changes in the gene expression of RAAS components in renal tissue., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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44. Fatal graft-versus-host disease after allogeneic stem cell transplantation in a patient recently exposed to nivolumab.
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Jiménez-Ubieto A, Rodriguez A, Martinez Sánchez P, Gómez A, Rodriguez Y, Carreño-Tarragona G, Martinez-López J, and Grande C
- Abstract
Allogeneic hematopoietic stem cell transplantation and checkpoint blockade therapy are immune-based salvage therapies for Hodgkin's lymphoma; however, the use of programmed death 1 blocking agents in the allogeneic stem cell transplantation setting could augment the incidence of steroid refractory graft-versus-host disease. Few studies suggest that that nivolumab is safe in patients previously treated with an allogeneic stem cell transplantation. Likewise, there are very limited data on the use of nivolumab before allogeneic stem cell transplantation. Here, we report a case of fatal graft-versus-host disease in a patient who underwent allogeneic stem cell transplantation 26 days after the last administration of nivolumab. Careful monitoring and close clinical assessment of atypical presentation for graft-versus-host disease in these patients, interval of time from nivolumab administration to allogeneic stem cell transplantation, drug dosage adjustments or more effective allo prophilaxys should been evaluated in prospective clinical trial.
- Published
- 2017
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45. Lupus anticoagulant-hypoprothrombinemia syndrome: A rare association in systemic lupus erythematosus.
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Carreño-Tarragona G, Morales E, Jiménez-Herrero MC, Cortés-Fornieles E, Gutierrez E, and Praga M
- Subjects
- Humans, Lupus Coagulation Inhibitor, Antiphospholipid Syndrome etiology, Hypoprothrombinemias etiology, Lupus Erythematosus, Systemic complications
- Published
- 2016
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46. Effects of age and caloric restriction on the cardiac and coronary response to endothelin-1 in rats.
- Author
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Granado M, Rubio C, Amor S, Monge L, Fernández N, Carreño-Tarragona G, Carrascosa JM, and García-Villalón ÁL
- Subjects
- Aging genetics, Animals, Coronary Circulation drug effects, Coronary Circulation genetics, Endothelin-1 administration & dosage, Endothelin-1 genetics, Gene Expression, Male, Myocardial Contraction drug effects, Myocardial Contraction genetics, Myocardium metabolism, Nitric Oxide Synthase Type II genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Wistar, Receptor, Endothelin A genetics, Receptor, Endothelin B genetics, Tumor Necrosis Factor-alpha genetics, Vasoconstriction drug effects, Vasoconstriction physiology, Aging physiology, Caloric Restriction, Coronary Circulation physiology, Endothelin-1 physiology, Myocardial Contraction physiology
- Abstract
Background and Aims: Aging is associated with alterations in the cardiovascular system such as increased vasoconstriction and decreased vasodilatation. Some of these changes are partially reversed by caloric restriction. Endothelin-1 is a potent vasoconstrictor which levels increased with age. The aim of this study is to analyze the role of endothelin-1 in the cardiac and coronary changes induced by age and whether these changes may be attenuated by a three-month caloric restriction., Methods and Results: Hearts from young (3 months old), aged (24 months old) and aged rats after 3 months of caloric restriction were perfused according to the Langendorff technique. Coronary vasoconstriction to endothelin-1 was reduced in old rats, and endothelin-1 increased myocardial contractility (dP/dt) and heart rate in old but not in young rats. These changes observed in old rats were partly reversed by caloric restriction. Also, in the myocardial tissue of old rats the gene expression of endothelin-1, inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-a) was increased, and the gene expression of endothelin ETB receptors and endothelial nitric oxide syntase (eNOS) was reduced, compared with young rats. Aging induced changes in the expression of ETB receptors and eNOS were reversed by caloric restriction., Conclusions: These results suggest that aging produces alterations in myocardial and coronary responses to endothelin-1, that may be related to changes in expression of nitric oxide synthases and/or endothelin receptor subtypes, with some of these changes being prevented by caloric restriction., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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47. Purinergic component in the coronary vasodilatation to acetylcholine after ischemia-reperfusion in perfused rat hearts.
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García-Villalón ÁL, Granado M, Monge L, Fernández N, Carreño-Tarragona G, and Amor S
- Subjects
- Animals, Coronary Circulation physiology, Enzyme Inhibitors pharmacology, Heart drug effects, Male, Myocardial Reperfusion Injury physiopathology, NG-Nitroarginine Methyl Ester pharmacology, Nitroprusside pharmacology, Platelet Aggregation Inhibitors pharmacology, Purinergic P2X Receptor Antagonists pharmacology, Purinergic P2Y Receptor Antagonists pharmacology, Pyridoxal Phosphate analogs & derivatives, Pyridoxal Phosphate pharmacology, Rats, Sprague-Dawley, Triazines pharmacology, Vasodilation drug effects, Vasodilation physiology, Vasodilator Agents pharmacology, Acetylcholine pharmacology, Coronary Circulation drug effects, Heart physiology, Myocardial Reperfusion Injury drug therapy, Receptors, Purinergic P2X physiology, Receptors, Purinergic P2Y physiology
- Abstract
To determine the involvement of purinergic receptors in coronary endothelium-dependent relaxation, the response to acetylcholine (1 × 10(-8) to 3 × 10(-7)M) was recorded in isolated rat hearts perfused according to the Langendorff procedure before and after 30 min of ischemia and 15 min of reperfusion and after the inhibition of nitric oxide synthesis with L-NAME (10(-4)M), in the absence and presence of the antagonist of purinergic P2X receptors, PPADS (3 × 10(-6)M), and of the antagonist of purinergic P2Y receptors, Reactive Blue 2 (3 × 10(-7)M). In control conditions, the relaxation to acetylcholine was not altered by PPADS or Reactive Blue 2. The relaxation to acetylcholine was reduced after ischemia-reperfusion, and, in this condition, it was further reduced by treatment with PPADS or Reactive Blue 2. Likewise, the relaxation to acetylcholine was reduced by L-NAME, and reduced further by Reactive Blue 2 but not by PPADS. These results suggest that the relaxation to acetylcholine may be partly mediated by purinergic receptors after ischemia-reperfusion, due to the reduction of nitric oxide release in this condition., (© 2014 S. Karger AG, Basel.)
- Published
- 2014
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48. Long-term effects of early overnutrition in the heart of male adult rats: role of the renin-angiotensin system.
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Granado M, Fernández N, Monge L, Carreño-Tarragona G, Figueras JC, Amor S, and García-Villalón AL
- Subjects
- Aging metabolism, Angiotensin II blood, Animals, Apoptosis drug effects, Apoptosis genetics, Biomarkers metabolism, Bradykinin pharmacology, Feeding Behavior drug effects, Gene Expression Regulation drug effects, Hemodynamics drug effects, In Vitro Techniques, Inflammation pathology, Leptin blood, Male, Myocardium metabolism, Myocardium pathology, Organ Size drug effects, Overnutrition blood, Overnutrition physiopathology, Perfusion, Rats, Sprague-Dawley, Time Factors, Vasoconstriction drug effects, Vasodilation drug effects, Aging pathology, Heart physiopathology, Overnutrition metabolism, Renin-Angiotensin System drug effects, Renin-Angiotensin System genetics
- Abstract
To analyze the long-term effects of early overfeeding on the heart and coronary circulation, the effect of ischemia-reperfusion (I/R) and the role of the renin-angiotensin system (RAS) was studied in isolated hearts from control and overfed rats during lactation. On the day of birth litters were adjusted to twelve pups per mother (controls) or to three pups per mother (overfed). At 5 months of age, the rats from reduced litters showed higher body weight and body fat than the controls. The hearts from these rats were perfused in a Langendorff system and subjected to 30 min of ischemia followed by 15 min of reperfusion (I/R). The myocardial contractility (dP/dt) and the coronary vasoconstriction to angiotensin II were lower, and the expression of the apoptotic marker was higher, in the hearts from overfed rats compared to controls. I/R reduced the myocardial contractily, the coronary vasoconstriction to angiotensin II and the vasodilatation to bradykinin, and increased the expression of (pro)renin receptor and of apoptotic and antiapoptotic markers, in both experimental groups. I/R also increased the expression of angiotensinogen in control but not in overfed rats. In summary, the results of this study suggest that early overnutrition induces reduced activity of the RAS and impairment of myocardial and coronary function in adult life, due to increased apoptosis. Ischemia-reperfusion produced myocardial and coronary impairment and apoptosis, which may be related to activation of RAS in control but not in overfed rats, and there may be protective mechanisms in both experimental groups.
- Published
- 2013
- Full Text
- View/download PDF
49. Effects of coronary ischemia-reperfusion in a rat model of early overnutrition. Role of angiotensin receptors.
- Author
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Granado M, Fernández N, Monge L, Figueras JC, Carreño-Tarragona G, Amor S, and García-Villalón AL
- Subjects
- Analysis of Variance, Animals, Animals, Suckling, Immunoblotting, Litter Size, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Myocardial Contraction physiology, Myocardial Reperfusion adverse effects, Overnutrition metabolism, Receptors, Angiotensin metabolism, Vasodilation physiology
- Abstract
Background: Obesity during childhood has dramatically increased worldwide in the last decades. Environmental factors acting early in life, including nutrition, play an important role in the pathogenesis of obesity and cardiovascular diseases in adulthood., Aims: To analyze the effects of early overfeeding on the heart and coronary circulation, the effect of ischemia-reperfusion (I/R) and the role of the renin-angiotensin system (RAS) were studied in isolated hearts from control and overfed rats during lactation., Methods and Results: On the day of birth litters were adjusted to twelve pups per mother (control) or to three pups per mother (overfed). At weaning (21 days) the rats were killed and the heart perfused in a Langendorff system and subjected to 30 min of ischemia followed by 15 min of reperfusion. The contractility (left developed intraventricular pressure) was lower in the hearts from overfed rats, and was reduced by I/R in hearts from control but not from overfed rats. I/R also reduced the coronary vasoconstriction to angiotensin II more in hearts from control than from overfed rats, and the vasodilatation to bradykinin similarly in both experimental groups. The expression of both angiotensin AGTRa and AGTR2 receptors was increased in the myocardium of overfed rats, and I/R increased the expression of both receptors in control rats but reduced it in overfed rats. The expression of apoptotic and antiapoptotic markers was increased in hearts of overfed rats compared with control, and further increased by I/R., Conclusions: These results suggest that both overfeeding and I/R impair cardiac and coronary function due, at least in part, to activation of the angiotensin pathway. However, overfeeding may reduce the impairment of ventricular contractility by I/R.
- Published
- 2013
- Full Text
- View/download PDF
50. Coronary response to diadenosine triphosphate after ischemia-reperfusion in the isolated rat heart.
- Author
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García-Villalón AL, Fernández N, Monge L, Granado M, Carreño-Tarragona G, Figueras JC, and Diéguez G
- Subjects
- Animals, Male, Rats, Rats, Sprague-Dawley, Vasodilation, Coronary Vessels drug effects, Dinucleoside Phosphates metabolism, Heart physiopathology, Ischemia physiopathology, Reperfusion, Vasodilator Agents metabolism
- Abstract
Diadenosine triphosphate (Ap3A) is a vasoactive mediator stored in platelet granules that may be released during coronary ischemia-reperfusion. To study its coronary effects in such circumstances, rat hearts were perfused in a Langendorff preparation and the coronary response to Ap3A (10(-7)-10(-5) mol/L) was recorded. Both at basal coronary resting tone and after precontraction with 11-dideoxy-1a,9a-epoxymethanoprostaglandin F(2)(α) (U46619), Ap3A produced concentration-dependent vasodilation in the heart, which was attenuated following ischemia-reperfusion. Ap3A-induced relaxation was also attenuated in control conditions and after ischemia-reperfusion by the purinergic P2Y antagonist reactive blue 2 (2 × 10(-6) mol/L), the P2Y(1) antagonist MRS 2179 (10(-5) mol/L), the nitric oxide synthesis inhibitor N-omega-nitro-l-arginine methyl ester (l-NAME; 10(-4) mol/L) and the ATP-dependent potassium channel blocker glibenclamide (10(-5) mol/L). These results suggest that Ap3A induces coronary vasodilation, an effect attenuated by ischemia-reperfusion due to the functional impairment of purinergic P2Y receptors and K(ATP) channels, and/or reduced nitric oxide release. This impairment of vasodilation may contribute to the coronary dysregulation that occurs during ischemia-reperfusion.
- Published
- 2012
- Full Text
- View/download PDF
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