99 results on '"Francisca Ferrer-Marín"'
Search Results
2. Author Correction: Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA
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Ricardo Sánchez, Sara Dorado, Yanira Ruíz-Heredia, Alejandro Martín-Muñoz, Juan Manuel Rosa-Rosa, Jordi Ribera, Olga García, Ana Jimenez-Ubieto, Gonzalo Carreño-Tarragona, María Linares, Laura Rufián, Alexandra Juárez, Jaime Carrillo, María José Espino, Mercedes Cáceres, Sara Expósito, Beatriz Cuevas, Raúl Vanegas, Luis Felipe Casado, Anna Torrent, Lurdes Zamora, Santiago Mercadal, Rosa Coll, Marta Cervera, Mireia Morgades, José Ángel Hernández-Rivas, Pilar Bravo, Cristina Serí, Eduardo Anguita, Eva Barragán, Claudia Sargas, Francisca Ferrer-Marín, Jorge Sánchez-Calero, Julián Sevilla, Elena Ruíz, Lucía Villalón, María del Mar Herráez, Rosalía Riaza, Elena Magro, Juan Luis Steegman, Chongwu Wang, Paula de Toledo, Valentín García-Gutiérrez, Rosa Ayala, Josep-Maria Ribera, Santiago Barrio, and Joaquín Martínez-López
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Medicine ,Science - Published
- 2024
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3. S153: MECHANISMS OF TROMBOGENESIS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA UNDER TREATMENT WITH PONATINIB AND OTHER TYROSINE KINASE INHIBITORS
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Ernesto José Cuenca Zamora, Sonia Águila, María José Lis, Maria Carmen Garcia Hernandez, María Jose Fernández, María Soledad Noya Pereira, Elvira Mora Castera, Luis Palomera Bernal, Maria Alicia Senin Magan, Raúl Pérez López, Manuel Perez Encinas, Anna Angona Figueras, José Manuel Puerta, Rolando Vallansot, Venancio Conesa Garcia, Juan Carlos Hernandez-Boluda, Ana Rosell Mas, Montserrat Cortés, Guillermo Ortí, Blanca Xicoy Cirici, Gonzalo Carreño Gomez-Tarragona, Pilar Giraldo, Maria L Lozano, Valentin Garcia Gutierrez, Francisca Ferrer-Marín, and On Behalf of Spanish Group of Chronic Myeloid Leukemia (Gelmc)
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. P680: PONATINIB 15 MG AS CONSOLIDATION PRIOR TO TREATMENT FREE REMISSION IN CHRONIC MYELOID LEUKEMIA
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Valentin Garcia Gutierrez, Juan Carlos Hernandez-Boluda, Luis Felipe Casado Montero, M Teresa Gómez Casares, Rosa Ayala Diaz, Blanca Xicoy Cirici, Francisca Ferrer-Marín, Guillermo Ortí, Raquel De Paz Arias, Santiago Ossorio Prendes, Raúl Pérez López, Elvira Mora Castera, Concepcion Ruiz Nuño, Antonio Jimenez, Concepcion Boque Genovard, Magdalena Sierra, and Joaquín Martinez-Lopez
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. PB1962: INFLUENCE OF TRANSCRIPT TYPES IN SUSTAINED DEEP MOLECULAR RESPONSE (SDMR) AND TREATMENT-FREE REMISSION (TFR) IN CHRONIC PHASE-CHRONIC MYELOID LEUKEMIA (CP-CML) PATIENTS TREATED WITH TKI
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Silvia Marce Torra, Aleix Méndez, Antonella Luciana Sturla, Miriam Ratia, Anna Angona Figueras, Paula Amat, Francisca Ferrer-Marín, Silvia Escribano, Emilia Scalzulli, Montserrat Cortes Sansa, Esther Plensa, Natalia Estrada, Marta Cabezon Marco, Mireia Morgades, Maria Alicia Senin Magan, Juan Carlos Hernandez-Boluda, Eduardo Anguita, Massimo Breccia, Valentín García-Gutiérrez, Blanca Xicoy Cirici, and Lurdes Zamora
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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6. P987: IRAK1 AND JAK2 DUAL INHIBITION WITH PACRITINIB PREVENTS MYELOFIBROSIS-LIKE PHENOTYPE IN AN INFLAMMATION-DRIVEN MURINE MODEL
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Ernesto José Cuenca Zamora, Pedro Jesús Guijarro Carrillo, María José López Poveda, María Luz Morales Fernández, Maria L Lozano, Rocío González-Conejero, Constantino Martínez, Raúl Teruel Montoya, and Francisca Ferrer-Marín
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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7. P990: NF-ΚB AND JAK/STAT PATHWAYS INHIBITION REVERSES FIBROSIS IN A MURINE MODEL OF INFLAMMATION-DRIVEN MYELOFIBROSIS
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Ernesto José Cuenca Zamora, Pedro Jesús Guijarro Carrillo, María José López Poveda, María Luz Morales Fernández, Maria L Lozano, Rocío González-Conejero, Constantino Martínez, Raúl Teruel Montoya, and Francisca Ferrer-Marín
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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8. Application of IPSET-thrombosis in 1366 Patients Prospectively Followed From the Spanish Registry of Essential Thrombocythemia
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Alberto Alvarez-Larrán, Beatriz Cuevas, Patricia Velez, Soledad Noya, Gonzalo Caballero-Navarro, Francisca Ferrer-Marín, Sara Carbonell, Manuel Pérez-Encinas, María Teresa Gómez-Casares, Raúl Pérez-López, Elena Magro, Ana Moretó, Irene Pastor-Galán, Anna Angona, María Isabel Mata-Vázquez, Lucía Guerrero-Fernández, José María Guerra, Gonzalo Carreño-Tarragona, Laura Fox, Ilda Murillo, Valentín García-Gutiérrez, Elvira Mora, Ruth Stuckey, Eduardo Arellano-Rodrigo, Juan Carlos Hernández-Boluda, Arturo Pereira, and On behalf of the MPN Spanish Group (GEMFIN)
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
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.
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- 2023
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9. e14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response
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Sílvia Marcé, Aleix Méndez, Blanca Xicoy, Natalia Estrada, Marta Cabezón, Antonella Luciana Sturla, Miriam Ratia García, Anna Angona, Paula Amat, Silvia Escribano Serrat, Emilia Scalzulli, Mireia Morgades, Alicia Senín, Juan Carlos Hernández-Boluda, Francisca Ferrer-Marín, Eduardo Anguita, Montserrat Cortés, Esther Plensa, Massimo Breccia, Valentín García-Gutierrez, and Lurdes Zamora
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chronic myeloid leukemia ,BCR::ABL1 transcript type ,tyrosine kinase inhibitors ,discontinuation ,treatment free remission ,Medicine - Abstract
e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript.
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- 2024
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10. Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA
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Ricardo Sánchez, Sara Dorado, Yanira Ruíz-Heredia, Alejandro Martín-Muñoz, Juan Manuel Rosa-Rosa, Jordi Ribera, Olga García, Ana Jimenez-Ubieto, Gonzalo Carreño-Tarragona, María Linares, Laura Rufián, Alexandra Juárez, Jaime Carrillo, María José Espino, Mercedes Cáceres, Sara Expósito, Beatriz Cuevas, Raúl Vanegas, Luis Felipe Casado, Anna Torrent, Lurdes Zamora, Santiago Mercadal, Rosa Coll, Marta Cervera, Mireia Morgades, José Ángel Hernández-Rivas, Pilar Bravo, Cristina Serí, Eduardo Anguita, Eva Barragán, Claudia Sargas, Francisca Ferrer-Marín, Jorge Sánchez-Calero, Julián Sevilla, Elena Ruíz, Lucía Villalón, María del Mar Herráez, Rosalía Riaza, Elena Magro, Juan Luis Steegman, Chongwu Wang, Paula de Toledo, Valentín García-Gutiérrez, Rosa Ayala, Josep-Maria Ribera, Santiago Barrio, and Joaquín Martínez-López
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Medicine ,Science - Abstract
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
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- 2022
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11. Neonatal platelet physiology and implications for transfusion
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Francisca Ferrer-Marín and Martha Sola-Visner
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bleeding ,development ,hemostasis ,neonatal platelets ,neonates ,transfusion ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The neonatal hemostatic system is different from that of adults. The differences in levels of procoagulant and anticoagulant factors and the evolving equilibrium in secondary hemostasis during the transition from fetal/neonatal life to infancy, childhood, and adult life are known as “developmental hemostasis.” In regard to primary hemostasis, while the number (150,000–450,000/µl) and structure of platelets in healthy neonates closely resemble those of adults, there are significant functional differences between neonatal and adult platelets. Specifically, platelets derived from both cord blood and neonatal peripheral blood are less reactive than adult platelets to agonists, such as adenosine diphosphate (ADP), epinephrine, collagen, thrombin, and thromboxane (TXA2) analogs. This platelet hyporeactivity is due to differences in expression levels of key surface receptors and/or in signaling pathways, and is more pronounced in preterm neonates. Despite these differences in platelet function, bleeding times and PFA-100 closure times (an in vitro test of whole-blood primary hemostasis) are shorter in healthy full-term infants than in adults, reflecting enhanced primary hemostasis. This paradoxical finding is explained by the presence of factors in neonatal blood that increase the platelet-vessel wall interaction, such as high von Willebrand factor (vWF) levels, predominance of ultralong vWF multimers, high hematocrit, and high red cell mean corpuscular volume. Thus, the hyporeactivity of neonatal platelets should not be viewed as a developmental deficiency, but rather as an integral part of a developmentally unique, but well balanced, primary hemostatic system. In clinical practice, due to the high incidence of bleeding (especially intraventricular hemorrhage, IVH) among preterm infants, neonatologists frequently transfuse platelets to non-bleeding neonates when platelet counts fall below an arbitrary limit, typically higher than that used in older children and adults. However, recent studies have shown that prophylactic platelet transfusions not only fail to decrease bleeding in preterm neonates, but are associated with increased neonatal morbidity and mortality. In this review, we will describe the developmental differences in platelet function and primary hemostasis between neonates and adults, and will analyze the implications of these differences to platelet transfusion decisions.
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- 2022
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12. Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis
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Adrián Mosquera-Orgueira, Manuel Pérez-Encinas, Alberto Hernández-Sánchez, Teresa González-Martínez, Eduardo Arellano-Rodrigo, Javier Martínez-Elicegui, Ángela Villaverde-Ramiro, José-María Raya, Rosa Ayala, Francisca Ferrer-Marín, María-Laura Fox, Patricia Velez, Elvira Mora, Blanca Xicoy, María-Isabel Mata-Vázquez, María García-Fortes, Anna Angona, Beatriz Cuevas, María-Alicia Senín, Angel Ramírez-Payer, María-José Ramírez, Raúl Pérez-López, Sonia González de Villambrosía, Clara Martínez-Valverde, María-Teresa Gómez-Casares, Carmen García-Hernández, Mercedes Gasior, Beatriz Bellosillo, Juan-Luis Steegmann, Alberto Álvarez-Larrán, Jesús María Hernández-Rivas, Juan Carlos Hernández-Boluda, and on behalf of the Spanish MPN Group (GEMFIN).
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.
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- 2023
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13. Deepening Our Understanding of the Factors Affecting Landscape of Myeloproliferative Neoplasms: What Do We Know about Them?
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María Luz Morales and Francisca Ferrer-Marín
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myeloproliferative neoplasms ,transcriptomics ,proteomics ,microbiota ,metabolism ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Myeloproliferative neoplasms (MPNs) arise from the uncontrolled proliferation of hematopoietic stem and progenitor cells in bone marrow. As with all tumors, the development of MPNs is a consequence of alterations in malignant cells and their interaction with other extrinsic factors that support and promote tumor progression. Since the discovery of driver mutations, much work has focused on studying and reviewing the genomic features of the disease but has neglected to delve into the important role that many other mechanisms may play. This review discusses the genetic component of MPNs but focuses mainly on some of the most relevant work investigating other non-genetic factors that may be crucial for the disease. The studies summarized here address MPN cell-intrinsic or -extrinsic factors and the interaction between them through transcriptomic, proteomic and microbiota studies, among others.
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- 2023
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14. Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients
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Natalia Estrada, Lurdes Zamora, Francisca Ferrer-Marín, Laura Palomo, Olga García, Patricia Vélez, Iris De la Fuente, Miguel Sagüés, Marta Cabezón, Montserrat Cortés, Rolando Omar Vallansot, María Alicia Senín-Magán, Concepción Boqué, and Blanca Xicoy
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chronic myeloid leukemia ,imatinib ,major molecular response ,single-nucleotide polymorphisms ,Medicine - Abstract
Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs.
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- 2022
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15. Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis
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María García-Fortes, Juan C. Hernández-Boluda, Alberto Álvarez-Larrán, José M. Raya, Anna Angona, Natalia Estrada, Laura Fox, Beatriz Cuevas, María C. García-Hernández, María Teresa Gómez-Casares, Francisca Ferrer-Marín, Silvana Saavedra, Francisco Cervantes, Regina García-Delgado, and on behalf of the Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN)
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myelofibrosis ,comorbidities ,survival ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.
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- 2022
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16. Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis
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Teresa Sevivas, José María Bastida, David S. Paul, Eva Caparros, Verónica Palma-Barqueros, Margarida Coucelo, Dalila Marques, Francisca Ferrer-Marín, José Ramón González-Porras, Vicente Vicente, Jesús María Hernández-Rivas, Steve P. Watson, María Luisa Lozano, Wolfgang Bergmeier, and José Rivera
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bleeding ,dysfunction ,platelets ,rasgrp2 ,signaling ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The RASGRP2 gene encodes the Ca2+ and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), which plays a key role in integrin activation in platelets and neutrophils. We here report two new RASGRP2 variants associated with platelet dysfunction and bleeding in patients. The homozygous patients had normal platelet and neutrophil counts and morphology. Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected; platelet secretion, clot retraction, and spreading minimally affected. Genetic analysis identified two new homozygous variants in RASGRP2: c.706C>T (p.Q236X) and c.887G>A (p.C296Y). In both patients, CalDAG-GEFI protein was not detectable in platelet lysates, and platelet αIIbβ3 activation, as assessed by fibrinogen binding, was greatly impaired in response to all agonists except PMA. Patient neutrophils showed normal integrin expression, but impaired Mn2+-induced fibrinogen binding. In summary, we have identified two new RASGRP2 mutations that can be added to this rapidly growing form of inherited platelet function disorder.
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- 2018
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17. Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib
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Sílvia Marcé, Blanca Xicoy, Olga García, Marta Cabezón, Natalia Estrada, Patricia Vélez, Concepción Boqué, Miguel Sagüés, Anna Angona, Raúl Teruel-Montoya, Francisca Ferrer-Marín, Paula Amat, Juan Carlos Hernández-Boluda, Mariana M. Ibarra, Eduardo Anguita, Montserrat Cortés, Andrés Fernández-Ruiz, Sandra Fontanals, Lurdes Zamora, and on behalf of the Grupo Español de Leucemia Mieloide Crónica (GELMC)
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chronic myeloid leukemia ,BCR-ABL1 transcripts ,response to imatinib ,survival ,discontinuation ,relapse-free survival ,Medicine - Abstract
The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine–kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate.
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- 2021
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18. Qualitative and Quantitative Comparison of Plasma Exosomes from Neonates and Adults
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Julia Peñas-Martínez, María N. Barrachina, Ernesto José Cuenca-Zamora, Ginés Luengo-Gil, Susana Belén Bravo, Eva Caparrós-Pérez, Raúl Teruel-Montoya, José Eliseo-Blanco, Vicente Vicente, Ángel García, Irene Martínez-Martínez, and Francisca Ferrer-Marín
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exosomes ,neonatal platelets ,platelet transfusion ,protein S ,proteomic ,von Willebrand factor ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Exosomes are extracellular vesicles that contain nucleic acids, lipids and metabolites, and play a critical role in health and disease as mediators of intercellular communication. The majority of extracellular vesicles in the blood are platelet-derived. Compared to adults, neonatal platelets are hyporeactive and show impaired granule release, associated with defects in Soluble N-ethylmaleimide-sensitive fusion Attachment protein REceptor (SNARE) proteins. Since these proteins participate in biogenesis of exosomes, we investigated the potential differences between newborn and adult plasma-derived exosomes. Plasma-derived exosomes were isolated by ultracentrifugation of umbilical cord blood from full-term neonates or peripheral blood from adults. Exosome characterization included size determination by transmission electron microscopy and quantitative proteomic analysis. Plasma-derived exosomes from neonates were significantly smaller and contained 65% less protein than those from adults. Remarkably, 131 proteins were found to be differentially expressed, 83 overexpressed and 48 underexpressed in neonatal (vs. adult) exosomes. Whereas the upregulated proteins in plasma exosomes from neonates are associated with platelet activation, coagulation and granule secretion, most of the underexpressed proteins are immunoglobulins. This is the first study showing that exosome size and content change with age. Our findings may contribute to elucidating the potential “developmental hemostatic mismatch risk” associated with transfusions containing plasma exosomes from adults.
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- 2021
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19. Emerging Role of Neutrophils in the Thrombosis of Chronic Myeloproliferative Neoplasms
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Francisca Ferrer-Marín, Ernesto José Cuenca-Zamora, Pedro Jesús Guijarro-Carrillo, and Raúl Teruel-Montoya
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myeloproliferative neoplasms ,neutrophils ,thrombosis ,NETs ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.
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- 2021
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20. Correction: Cuenca-Zamora, Ernesto José., et al. Tubulin in Platelets: When the Shape Matter. Int. J. Mol. Sci. 2019, 20, 3484
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Ernesto José Cuenca-Zamora, Francisca Ferrer-Marín, José Rivera, and Raúl Teruel-Montoya
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n/a ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The authors wish to make the following corrections to this paper [...]
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- 2020
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21. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea
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Alberto Alvarez-Larrán, Manuel Pérez-Encinas, Francisca Ferrer-Marín, Juan Carlos Hernández-Boluda, María José Ramírez, Joaquín Martínez-López, Elena Magro, Yasmina Cruz, María Isabel Mata, Pilar Aragües, María Laura Fox, Beatriz Cuevas, Sara Montesdeoca, José Angel Hernández-Rivas, Valentín García-Gutiérrez, María Teresa Gómez-Casares, Juan Luis Steegmann, María Antonia Durán, Montse Gómez, Ana Kerguelen, Abelardo Bárez, Mari Carmen García, Concepción Boqué, José María Raya, Clara Martínez, Manuel Albors, Francesc García, Carmen Burgaleta, and Carlos Besses
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0–2 phlebotomies per year (20.5% vs. 5.3% at 3 years; P
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- 2017
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22. Comprehensive comparison of neonate and adult human platelet transcriptomes.
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Eva Caparrós-Pérez, Raúl Teruel-Montoya, Mª José López-Andreo, Mª Carmen Llanos, José Rivera, Verónica Palma-Barqueros, Jose E Blanco, Vicente Vicente, Constantino Martínez, and Francisca Ferrer-Marín
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Medicine ,Science - Abstract
Understanding the underlying mechanisms of the well-substantiated platelet hyporeactivity in neonates is of interest given their implications for the clinical management of newborns, a population at higher bleeding risk than adults (especially sick and preterm infants), as well as for gaining insight into the regulatory mechanisms of platelet biology. Transcriptome analysis is useful in identifying mRNA signatures affecting platelet function. However, human fetal/neonatal platelet transcriptome analysis has never before been reported. We have used mRNA expression array for the first time to compare platelet transcriptome changes during development. Microarray analysis was performed in pure platelet RNA obtained from adult and cord blood, using the same platform in two independent laboratories. A high correlation was obtained between array results for both adult and neonate platelet samples. There was also good agreement between results in our adult samples and outcomes previously reported in three different studies. Gene enrichment analysis showed that immunity- and platelet function-related genes are highly expressed at both developmental stages. Remarkably, 201 genes were found to be differentially expressed throughout development. In particular, neonatal platelets contain higher levels of mRNA that are associated with protein synthesis and processing, while carrying significantly lower levels of genes involved in calcium transport/metabolism and cell signaling (including GNAZ). Overall, our results point to variations in platelet transcriptome as possibly underlining the hypo-functional phenotype of neonatal platelets and provide further support for the role of platelets in cellular immune response. Better characterization of the platelet transcriptome throughout development can contribute to elucidate how transcriptome changes impact different pathological conditions.
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- 2017
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23. PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase.
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Juan M Alonso-Dominguez, Luis Felipe Casado, Eduardo Anguita, Maria Teresa Gomez-Casares, Ismael Buño, Francisca Ferrer-Marín, Alicia Arenas, Rafael Del Orbe, Rosa Ayala, Pilar Llamas, Rocio N Salgado, Santiago Osorio, Pedro Sanchez-Godoy, Carmen Burgaleta, Ignacio Mahíllo-Fernández, Valentin Garcia-Gutierrez, Juan Luis Steegmann, and Joaquín Martinez-Lopez
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Medicine ,Science - Abstract
Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P
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- 2017
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24. Tubulin in Platelets: When the Shape Matters
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Ernesto José Cuenca-Zamora, Francisca Ferrer-Marín, José Rivera, and Raúl Teruel-Montoya
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Platelet ,cytoskeleton ,tubulin ,platelets activation ,post-translational modification ,neonatal ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Platelets are anuclear cells with a short lifespan that play an essential role in many pathophysiological processes, including haemostasis, inflammation, infection, vascular integrity, and metastasis. Billions of platelets are produced daily from megakaryocytes (platelet precursors). Despite this high production, the number of circulating platelets is stable and, under resting conditions, they maintain their typical discoid shape thanks to cytoskeleton proteins. The activation of platelets is associated with dynamic and rapid changes in the cytoskeleton. Two cytoskeletal polymer systems exist in megakaryocytes and platelets: actin filaments and microtubules, based on actin, and α- and β-tubulin heterodimers, respectively. Herein, we will focus on platelet-specific tubulins and their alterations and role of the microtubules skeleton in platelet formation (thrombopoiesis). During this process, microtubules mediate elongation of the megakaryocyte extensions (proplatelet) and granule trafficking from megakaryocytes to nascent platelets. In platelets, microtubules form a subcortical ring, the so-called marginal band, which confers the typical platelet discoid shape and is also responsible for changes in platelet morphology upon activation. Molecular alterations in the gene encoding β1 tubulin and microtubules post-translational modifications may result in quantitative or qualitative changes in tubulin, leading to altered cytoskeleton reorganization that may induce changes in the platelet number (thrombocytopenia), morphology or function. Consequently, β1-tubulin modifications may participate in pathological and physiological processes, such as development.
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- 2019
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25. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation
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Alberto Alvarez-Larrán, Arturo Pereira, Paola Guglielmelli, Juan Carlos Hernández-Boluda, Eduardo Arellano-Rodrigo, Francisca Ferrer-Marín, Alimam Samah, Martin Griesshammer, Ana Kerguelen, Bjorn Andreasson, Carmen Burgaleta, Jiri Schwarz, Valentín García-Gutiérrez, Rosa Ayala, Pere Barba, María Teresa Gómez-Casares, Chiara Paoli, Beatrice Drexler, Sonja Zweegman, Mary F. McMullin, Jan Samuelsson, Claire Harrison, Francisco Cervantes, Alessandro M. Vannucchi, and Carlos Besses
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2V617F mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3–42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2V617F-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.
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- 2016
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26. The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis
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Juan-Carlos Hernández-Boluda, Arturo Pereira, Montse Gómez, Concepción Boqué, Francisca Ferrer-Marín, José-María Raya, Valentín García-Gutiérrez, Ana Kerguelen, Blanca Xicoy, Pere Barba, Jesús Martínez, Elisa Luño, Alberto Alvarez-Larrán, Joaquín Martínez-López, Elisa Arbelo, and Carles Besses
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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27. CAPN1 (Calpain1)-Dependent Cleavage of STIM1 (Stromal Interaction Molecule 1) Results in an Enhanced SOCE (Store-Operated Calcium Entry) in Human Neonatal Platelets
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Alejandro Berna-Erro, Girish Ramesh, Elena Delgado, Antonio J. Corbacho, Francisca Ferrer-Marín, Raul Teruel, María P. Granados, Juan A. Rosado, and Pedro C. Redondo
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Cardiology and Cardiovascular Medicine - Abstract
Background: Altered intracellular Ca 2+ homeostasis in neonatal platelets has been previously reported. This study aims to examine the changes in the Ca 2+ entry through the store-operated calcium entry (SOCE) mechanism in neonatal platelets. Methods: Human platelets from either control women, mothers, and neonates were isolated and, following, were fixed after being treated as required. Platelet samples were analyzed by Western blotting, qRT-PCR, and MALDITOF/TOF. Ca 2+ homeostasis was also determined. Culture cells were used as surrogated of platelets to overexpress the proteins of interest to reproduce the alterations observed in platelets. Results: Altered TG (thapsigargin)-evoked SOCE, alternative molecular weight form of STIM1 (stromal interaction molecule 1; s-STIM1 [short STIM1 isoform (478 aa)], around 60 kDa) and overexpression of SARAF (SOCE-associated regulatory factor) were found in neonatal platelets as compared to maternal and control women platelets. s-STIM1 may result due to CAPN1 (calpain1)-dependent processing, as confirmed in platelets and MEG01 cells by using calpeptin and overexpressing CAPN1, respectively. In HEK293 (STIM1 and STIM2 [stromal interaction molecule 2] double knockout) cells transfected either with c-STIM1 (canonical STIM1 [685 aa]), s-STIM1 (478), STIM1B (540), and CAPN1 overexpression plasmids, we found s-STIM1 and c-STIM1, except in cells overexpressing s-STIM1 (478) that lacked CAPN1 target residues. These results and the in silico analysis, lead us to conclude that STIM1 is cleaved at Q496 by CAPN1. Ca 2+ imaging analysis and coimmunoprecipitation assay using MEG01 and HEK293 cells overexpressing SARAF together with s-STIM1 (478) reported a reduced slow Ca 2+ –dependent inactivation, so reproducing the Ca 2+ -homeostasis pattern observed in neonatal platelets. Conclusions: CAPN1 may cleave STIM1 in neonatal platelets, hence, impairing SARAF coupling after SOCE activation. s-STIM1 may avoid slow Ca 2+ –dependent inactivation and, subsequently, results in an enhanced TG-evoked SOCE as observed in neonatal platelets.
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- 2023
28. Neonatal platelet physiology and implications for transfusion
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Francisca Ferrer-Marín and Martha Sola-Visner
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Blood Platelets ,biology ,medicine.diagnostic_test ,medicine.drug_class ,Thromboxane ,business.industry ,Anticoagulant ,Physiology ,Platelet Transfusion ,Hematology ,General Medicine ,medicine.disease ,Article ,Platelet transfusion ,Intraventricular hemorrhage ,Von Willebrand factor ,Hemostasis ,medicine ,biology.protein ,Humans ,Platelet ,business ,Mean corpuscular volume - Abstract
The neonatal hemostatic system is different from that of adults. The differences in levels of procoagulant and anticoagulant factors and the evolving equilibrium in secondary hemostasis during the transition from fetal/neonatal life to infancy, childhood, and adult life are known as "developmental hemostasis." In regard to primary hemostasis, while the number (150,000-450,000/µl) and structure of platelets in healthy neonates closely resemble those of adults, there are significant functional differences between neonatal and adult platelets. Specifically, platelets derived from both cord blood and neonatal peripheral blood are less reactive than adult platelets to agonists, such as adenosine diphosphate (ADP), epinephrine, collagen, thrombin, and thromboxane (TXA2) analogs. This platelet hyporeactivity is due to differences in expression levels of key surface receptors and/or in signaling pathways, and is more pronounced in preterm neonates. Despite these differences in platelet function, bleeding times and PFA-100 closure times (an in vitro test of whole-blood primary hemostasis) are shorter in healthy full-term infants than in adults, reflecting enhanced primary hemostasis. This paradoxical finding is explained by the presence of factors in neonatal blood that increase the platelet-vessel wall interaction, such as high von Willebrand factor (vWF) levels, predominance of ultralong vWF multimers, high hematocrit, and high red cell mean corpuscular volume. Thus, the hyporeactivity of neonatal platelets should not be viewed as a developmental deficiency, but rather as an integral part of a developmentally unique, but well balanced, primary hemostatic system. In clinical practice, due to the high incidence of bleeding (especially intraventricular hemorrhage, IVH) among preterm infants, neonatologists frequently transfuse platelets to non-bleeding neonates when platelet counts fall below an arbitrary limit, typically higher than that used in older children and adults. However, recent studies have shown that prophylactic platelet transfusions not only fail to decrease bleeding in preterm neonates, but are associated with increased neonatal morbidity and mortality. In this review, we will describe the developmental differences in platelet function and primary hemostasis between neonates and adults, and will analyze the implications of these differences to platelet transfusion decisions.
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- 2021
29. Review of the risk of thrombosis or bleeding upon abrupt anagrelide discontinuation in patients with essential thrombocythemia
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Marta, Santaliestra, Francisca, Ferrer-Marín, and Alberto, Alvarez-Larrán
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Quinazolines ,Humans ,Hemorrhage ,Thrombosis ,Platelet Aggregation Inhibitors ,Thrombocythemia, Essential - Published
- 2022
30. Tyrosine kinase inhibitor dose reduction during the management of accelerated phase chronic myeloid leukemia
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Guillermo Ortí, Valentín García-Gutiérrez, Guiomar Bautista, Francisca Ferrer-Marín, Rolando Vallansot, Blanca Xicoy, Àngela Sánchez, Isabel Simon, Ana Triguero, Magdalena Sierra, and Luis Felipe Casado
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Cancer Research ,Oncology ,Drug Tapering ,Leukemia, Myeloid, Chronic-Phase ,Humans ,Leukemia, Myeloid, Accelerated Phase ,Hematology ,Protein Kinase Inhibitors - Published
- 2022
31. Características clínico-biológicas de los pacientes con mielofibrosis: un análisis de 1.000 casos del Registro Español de Mielofibrosis
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Manuel Pérez-Encinas, Alberto Alvarez-Larrán, Patricia Velez, Elena Magro, Juan Carlos Hernández-Boluda, Irene Pastor-Galán, Francisco Cervantes, José María Raya, Anna Angona, Juan-Gonzalo Correa, Elisa Arbelo, Ana Kerguelen, María José Ramírez, María Luisa Antelo, Clara Martínez-Valverde, Maria Laura Fox, Angel Ramirez Payer, Beatriz Cuevas, Natalia Estrada, Valentín García-Gutiérrez, Elvira Mora, Francisca Ferrer-Marín, Rosa Ayala, María Teresa Gómez-Casares, María Antonia Durán, Nieves Somolinos, and María Isabel Mata-Vázquez
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03 medical and health sciences ,0302 clinical medicine ,business.industry ,Medicine ,030212 general & internal medicine ,General Medicine ,business ,Humanities - Abstract
Resumen Antecedentes y objetivo La mielofibrosis es una neoplasia mieloproliferativa cronica infrecuente. Nuestro objetivo fue describir las caracteristicas clinico-biologicas, el tratamiento y el curso evolutivo de los pacientes con mielofibrosis en Espana. Material y metodos Se analizaron 1.000 pacientes del Registro Espanol de Mielofibrosis diagnosticados de mielofibrosis primaria (n = 641) o secundaria (n = 359). Resultados La mediana de edad era de 68 anos. La frecuencia de sintomatologia constitucional, anemia moderada o severa (Hb Conclusiones la mielofibrosis es una enfermedad invalidante que afecta sobre todo a personas de edad avanzada y cuyo tratamiento es fundamentalmente sintomatico. A pesar de su heterogeneidad clinica se dispone de modelos pronosticos utiles para la seleccion de candidatos a trasplante.
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- 2020
32. Clinico-biological characteristics of patients with myelofibrosis: an analysis of 1,000 cases from the Spanish Registry of Myelofibrosis
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María José Ramírez, Anna Angona, Francisco Cervantes, María Teresa Gómez-Casares, Elvira Mora, Clara Martínez-Valverde, Natalia Estrada, Juan-Gonzalo Correa, Manuel Pérez-Encinas, María Antonia Durán, Elisa Arbelo, María Isabel Mata-Vázquez, Ana Kerguelen, Nieves Somolinos, Juan Carlos Hernández-Boluda, María Luisa Antelo, Maria Laura Fox, Patricia Velez, Angel Ramirez Payer, Alberto Alvarez-Larrán, Beatriz Cuevas, Irene Pastor-Galán, Valentín García-Gutiérrez, Francisca Ferrer-Marín, Rosa Ayala, Elena Magro, en representación del Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas, and José María Raya
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Moderate to severe ,Pediatrics ,medicine.medical_specialty ,Constitutional symptoms ,business.industry ,medicine.disease ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Chronic Myeloproliferative Neoplasm ,Clinical heterogeneity ,medicine ,Elderly people ,030212 general & internal medicine ,Myelofibrosis ,business ,Prognostic models - Abstract
BACKGROUND AND OBJECTIVE MYELOFIBROSIS: is an infrequent chronic myeloproliferative neoplasm. We aimed to describe the clinico-biological characteristics, treatment, and evolutive course of myelofibrosis patients in Spain.; MATERIAL AND METHODS: A total of 1,000 patients from the Spanish Registry of Myelofibrosis diagnosed with primary (n=641) or secondary (n=359) myelofibrosis were analysed.; RESULTS: Median age was 68 years. The frequency of constitutional symptoms, moderate to severe anaemia (Hb
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- 2020
33. Platelet transfusions and mortality in necrotizing enterocolitis
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Neeta Shenvi, Kirk A. Easley, Francisca Ferrer-Marín, Akhil Maheshwari, Ravi Mangal Patel, Cassandra D. Josephson, Sean R. Stowell, and Martha Sola-Visner
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medicine.medical_specialty ,business.industry ,Immunology ,Hematology ,030204 cardiovascular system & hematology ,medicine.disease ,Rate ratio ,Neuropeptide Y receptor ,Gastroenterology ,Confidence interval ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Necrotizing enterocolitis ,Cohort ,medicine ,Immunology and Allergy ,Platelet ,Fresh frozen plasma ,business ,030215 immunology - Abstract
BACKGROUND Prior studies have suggested an association between platelet transfusions (PTXs) and worse outcomes among infants with necrotizing enterocolitis (NEC), potentially mediated by proinflammatory factors released by platelets. However, the effects of storage on platelet proinflammatory factor release and the confounding role of illness severity on NEC outcomes have not been determined. STUDY DESIGN AND METHODS First, neuropeptide Y (a potent splanchnic vasoconstrictor released by platelets) was measured by enzyme-linked immunosorbent assay in fresh frozen plasma and in the supernatant of leukoreduced apheresis-derived platelets at different times during storage. Next, we evaluated the relationship between PTX rates and death in a multicenter cohort of very-low-birth-weight infants with NEC, adjusting for illness severity. RESULTS Neuropeptide Y levels increased over time in the supernatant of leukoreduced apheresis-derived platelets and were 4.4-fold and 8.9-fold higher than in fresh frozen plasma on Days 2 and 3 of storage, respectively (p < 0.001). Among 598 very-low-birth-weight infants, 44 developed NEC. In unadjusted analysis, PTX rate was 30.3 (95% confidence interval [CI], 11.5-80.1) per 100 infant-days among infants who died, compared to 6.0 (95% CI, 3.2-11.2) among survivors (incidence rate ratio, 5.1; 95% CI, 1.6-16.2; p = 0.006). In multivariable analysis, there was no association between PTX rate and mortality (incidence rate ratio, 3.0; 95% CI, 0.6-15.0; p = 0.18), although estimation was imprecise. CONCLUSION Proinflammatory mediators accumulate in platelet suspensions during storage. Although PTX rates were not associated with increased mortality among infants with NEC in our study, our estimates suggest the potential for such an association that needs evaluation in larger studies.
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- 2018
34. Emerging Role of Neutrophils in the Thrombosis of Chronic Myeloproliferative Neoplasms
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Pedro Jesús Guijarro-Carrillo, Francisca Ferrer-Marín, Ernesto José Cuenca-Zamora, and Raúl Teruel-Montoya
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0301 basic medicine ,Review ,030204 cardiovascular system & hematology ,Catalysis ,myeloproliferative neoplasms ,lcsh:Chemistry ,Inorganic Chemistry ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,neutrophils ,Extracellular ,Medicine ,Animals ,Humans ,In patient ,Platelet activation ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,Leukemia ,Myeloproliferative Disorders ,biology ,business.industry ,Organic Chemistry ,food and beverages ,Thrombosis ,NETs ,General Medicine ,medicine.disease ,Phenotype ,Computer Science Applications ,030104 developmental biology ,Histone ,lcsh:Biology (General) ,lcsh:QD1-999 ,Coagulation ,Immunology ,biology.protein ,business - Abstract
Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.
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- 2020
35. The risk of thrombosis in essential thrombocythemia is associated with the type of CALR mutation: A multicentre collaborative study
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Beatriz Bellosillo Paricio, Alberto Álvarez Larrán, Szukalski Łukasz, Marcio Andrade-Campos, Maria Laura Fox, Aitor Abuin Blanco, Celsa Quinteiro García, Jesús María González Martín, Alejandro Martín Martín, Anna Czyż, Manuel Mateo Pérez Encinas, K Lewandowki, Elena Magro Mazo, Juan Carlos Hernandez Boluda, Aleksandra Gołos, Mercedes Gasior Kabat, María Soledad Noya Pereira, Ruth Stuckey, María Teresa Gómez-Casares, Francisca Ferrer-Marín, José María Raya, and Marta Sobas
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medicine.medical_specialty ,Logistic regression ,Lower risk ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Odds Ratio ,Humans ,Cumulative incidence ,Genetic Predisposition to Disease ,Myeloproliferative neoplasm ,Genetic Association Studies ,Retrospective Studies ,Essential thrombocythemia ,business.industry ,Incidence ,Thrombosis ,Hematology ,General Medicine ,Janus Kinase 2 ,medicine.disease ,Prognosis ,Venous thrombosis ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Mutation ,business ,Calreticulin ,030215 immunology ,Follow-Up Studies ,Thrombocythemia, Essential - Abstract
OBJECTIVES: In patients with essential thrombocythemia (ET), after the JAK2V617F driver mutation, mutations in CALR are common (classified as type-1, 52-bp deletion, or type-2, 5-bp insertion). CALR mutations have generally been associated with a lower risk of thrombosis. This study aimed to confirm the impact of CALR mutation type on thrombotic risk. METHODS: We retrospectively investigated 983 ET patients diagnosed in Spanish and Polish hospitals. RESULTS: With 7.5 years median follow-up from diagnosis, 155 patients (15.8%) had one or more thrombotic event. The 5-year thrombosis free survival (TFS) rate was 83.8%, 91.6% and 93.9% for the JAK2V617F, CALR-type 1 and CALR-type 2 groups, respectively (p = 0.002). Comparing CALR-type 1 and CALR-type 2 groups, TFS for venous thrombosis was lower in CALR-type 1 (p = 0.046), with no difference in TFS for arterial thrombosis observed. The cumulative incidence of thrombosis was significantly different comparing JAK2V617F vs. CALR-type 2 groups but not JAK2V617F vs. CALR-type 1 groups. Moreover, CALR-type 2 mutation was a statistically significant protective factor for thrombosis with respect to JAK2V617F in multivariate logistic regression (OR: 0.45, p = 0.04) adjusted by age. CONCLUSIONS: Our results suggest that CALR mutation type has prognostic value for the stratification of thrombotic risk in ET patients.
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- 2020
36. Successful ovarian stimulation and pregnancy in an infertile woman with chronic myeloid leukemia
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Cristina Aroca, Raúl Teruel-Montoya, Francisca Ferrer-Marín, Lorena Martinez-Montesinos, and Silvina J. Rios
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0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Reproductive medicine ,Fusion Proteins, bcr-abl ,Fertilization in Vitro ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Ovulation Induction ,Pregnancy ,Internal medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Genetics ,medicine ,Humans ,Protein Kinase Inhibitors ,Genetics (clinical) ,Cryopreservation ,Fetus ,030219 obstetrics & reproductive medicine ,In vitro fertilisation ,business.industry ,Obstetrics and Gynecology ,Myeloid leukemia ,Interferon-alpha ,Fertility Preservation ,Imatinib ,General Medicine ,medicine.disease ,Embryo Transfer ,Discontinuation ,030104 developmental biology ,Blastocyst ,Pyrimidines ,Treatment Outcome ,Reproductive Medicine ,Nilotinib ,embryonic structures ,Imatinib Mesylate ,Female ,business ,Infertility, Female ,Developmental Biology ,medicine.drug - Abstract
BACKGROUND: Tyrosine kinase inhibitors (TKI) treatment has transformed chronic myeloid leukemia (CML) from a fatal neoplasm to a chronic disease with normal life expectancies. Indeed, half of CML patients are able to discontinue TKI without relapse. However, it seems clearly demonstrated that exposure to TKI may result in fetal malformations. Regarding its effects on fertility, preclinical studies and clinical case reports provide inconclusive evidence. Furthermore, due to the risk of CML relapse after TKI discontinuation, the optimal time to stop TKI represents a real dilemma. CASE REPORT: We describe a 23-year-old woman who, after more than 6 years with imatinib and 1 year in deep molecular response [(DMR), MR ≥ 4], interrupted treatment to become pregnant. After 2 failed artificial insemination cycles, she underwent one process of controlled ovarian stimulation, achieving 2 blastocyst-embryos. In the meantime, BCR-ABL1(IS) levels increased despite interferon-alpha therapy, she lost the mayor molecular response (MMR), and the 2 embryos had to be cryopreserved. A stable second MR ≥ 4.0 was again obtained with nilotinib, and after stopping it, the 2 blastocyst-embryo transfers were unsuccessfully performed. Under DMR, a second ovarian stimulation and in vitro fertilization (IVF) was performed and 1 blastocyst embryo was transferred. This time, she became pregnant and a healthy baby was born. After more than 3 years of follow-up, she remains in treatment-free remission (TFR). CONCLUSION: Compared with imatinib, nilotinib achieves earlier and deeper MR that allows safe and timely pregnancies in infertile CML women through IVF process, while patients remain in TFR after delivery.
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- 2020
37. Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis
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Gemfin, Francisca Ferrer-Marín, Francisco Cervantes, M Isabel Mata-Vázquez, Eduardo Arellano-Rodrigo, Marta Magaz, M. Teresa Gómez-Casares, Marta Garrote, Arturo Pereira, Alberto Alvarez-Larrán, Valentín García-Gutiérrez, Virginia Hernández-Gea, Beatriz Cuevas, Rehevasc groups, Juan Carlos Hernández-Boluda, Juan Carlos García-Pagán, and Fanny Turon
- Subjects
Adult ,Male ,Risk ,medicine.medical_specialty ,Hemorrhage ,Kaplan-Meier Estimate ,Lower risk ,Gastroenterology ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Polycythemia vera ,Mesenteric Veins ,Internal medicine ,medicine ,Humans ,Registries ,Splanchnic Circulation ,Myelofibrosis ,Polycythemia Vera ,Proportional Hazards Models ,Venous Thrombosis ,Acute leukemia ,Essential thrombocythemia ,business.industry ,Portal Vein ,Liver Diseases ,Neoplasms, Second Primary ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Venous thrombosis ,Splanchnic vein thrombosis ,Primary Myelofibrosis ,Spain ,Splenic Vein ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,business ,030215 immunology ,Follow-Up Studies ,Thrombocythemia, Essential - Abstract
Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5–4.01, p
- Published
- 2020
38. miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk
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Beatriz Bellosillo, E. Luño, Cristina Martínez, Carlos Besses, J.M. Hernández-Rivas, Valentín García-Gutiérrez, Juan Carlos Hernández-Boluda, Natalia Estrada, Patricia Velez, Ernesto J Cuenca, Francisca Ferrer-Marín, Rosa Ayala, C García Hernandez, Vicente Vicente, Concepción Fernández-Rodríguez, D V Fiallo-Suárez, Rosa Cifuentes, Lurdes Zamora, R. Gonzalez-Conejero, A.M. De Los Reyes-Garcia, M. T. Gomez-Casares, Ana Kerguelen, Concepción Boqué, Ana B. Arroyo, Raúl Teruel-Montoya, Beatriz Arrizabalaga, Isabel Arcas, and Alberto Alvarez-Larrán
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Genotype ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Polycythemia vera ,Internal medicine ,medicine ,Animals ,Humans ,Allele ,Myelofibrosis ,Polycythemia Vera ,Alleles ,Myeloproliferative neoplasm ,Aged ,Inflammation ,Haematological cancer ,Myeloproliferative Disorders ,business.industry ,Essential thrombocythemia ,NF-kappa B ,Hematology ,Middle Aged ,Translational research ,medicine.disease ,Phenotype ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,Primary Myelofibrosis ,030220 oncology & carcinogenesis ,Mutation ,Disease Progression ,Cytokines ,Female ,business ,Signal Transduction ,Thrombocythemia, Essential - Abstract
Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-kappa B is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-kappa B signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a(-/-) mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.
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- 2020
39. Clinico-biological characteristics of patients with myelofibrosis: an analysis of 1,000 cases from the Spanish Registry of Myelofibrosis
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Irene, Pastor-Galán, Juan Carlos, Hernández-Boluda, Juan-Gonzalo, Correa, Alberto, Alvarez-Larrán, Francisca, Ferrer-Marín, José María, Raya, Rosa, Ayala, Patricia, Velez, Manuel, Pérez-Encinas, Natalia, Estrada, Valentín, García-Gutiérrez, María Laura, Fox, Angel, Payer, Ana, Kerguelen, Beatriz, Cuevas, María Antonia, Durán, María José, Ramírez, María Teresa, Gómez-Casares, María Isabel, Mata-Vázquez, Elvira, Mora, Clara, Martínez-Valverde, Elisa, Arbelo, Anna, Angona, Elena, Magro, María Luisa, Antelo, Nieves, Somolinos, and Francisco, Cervantes
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Primary Myelofibrosis ,Spain ,Splenomegaly ,Mielofibrosis, Myelofibrosis, Myeloproliferative neoplasms, Neoplasias mieloproliferativas, Prognosis, Pronóstico, Registro Español de Mielofibrosis, Spanish Registry of Myelofibrosis, Transplantation, Trasplante, Tratamiento, Treatment ,Humans ,Registries ,respiratory system ,Prognosis ,Aged - Abstract
BACKGROUND AND OBJECTIVE MYELOFIBROSIS: is an infrequent chronic myeloproliferative neoplasm. We aimed to describe the clinico-biological characteristics, treatment, and evolutive course of myelofibrosis patients in Spain.A total of 1,000 patients from the Spanish Registry of Myelofibrosis diagnosed with primary (n=641) or secondary (n=359) myelofibrosis were analysed.Median age was 68 years. The frequency of constitutional symptoms, moderate to severe anaemia (Hb10g/dL), and symptomatic splenomegaly was 35%, 36%, and 17%, respectively. The rate of thrombosis and haemorrhage was 1.96 and 1.6 events per 100 patient-years, respectively. The cumulative incidence of leukaemia at 10 years was 15%. The most frequent therapies for the anaemia were the erythropoiesis stimulating agents and danazol. From 2010, a progressive increase in the use of ruxolitinib was noticed. A total of 7.5% of patients were transplanted. During the observation period, 42% of patients died mainly due to the clinical deterioration caused by myelofibrosis or leukaemic transformation. The median survival of the series was 5.7 years. Four different risk categories were identified by the IPSS: median survival was not reached in the low risk group and was 8.8 years, 5.3 years, and 2.8 years in the intermediate-1, intermediate-2, and high-risk groups, respectively.Myelofibrosis is a disabling condition mainly affecting elderly people. Its treatment is mostly driven by symptom control. Despite its clinical heterogeneity, several prognostic models are useful to select candidates for transplantation.
- Published
- 2020
40. Essential thrombocythaemia with mutation in MPL: clinicopathological correlation and comparison with JAK2V617F-mutated and CALR-mutated genotypes
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Francisco Cervantes, Leonor Arenillas, Luis Colomo, José María Quiroga Alonso, Soledad Noya, Natalia Papaleo, Alberto Alvarez-Larrán, Manuel Pérez-Encinas, Ariadna Rubio, Gonzalo Caballero, Eduardo Arellano-Rodrigo, Elena Magro, Gonzalo Carreño-Tarragona, María Isabel Mata, María Antonia Durán, Carlos Besses, Mónica López-Guerra, Clara Martínez, J. Alonso, María Rozman, Juan Carlos Hernandez Boluda, Raúl Sánchez Pérez, Daniel Martinez, Francisca Ferrer-Marín, and Irene Pastor-Galán
- Subjects
Pathology ,medicine.medical_specialty ,Mutation ,Essential thrombocythemia ,General Medicine ,Biology ,Hyperplasia ,medicine.disease ,medicine.disease_cause ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Genotype ,medicine ,Platelet ,Histopathology ,Bone marrow ,Myelofibrosis ,030215 immunology - Abstract
AimTo characterise the clinical and histological features of MPL-mutated essential thrombocythaemia (ET).Patients and methodsBone marrow biopsies of 175 patients with ET were centrally reviewed according to the 2016 WHO classification, including 42 cases with MPL mutation, 98 JAK2V617F-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.ResultsPatients 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 JAK2V617F genotype. In the bone marrow, the median number of megakaryocytes was higher in MPL and CALR than in JAK2V617F 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.ConclusionMPL and CALR ET genotypes share clinical and histological characteristics. In contrast to CALR genotype, features of prefibrotic myelofibrosis are uncommon in MPL-mutated ET.
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- 2018
41. Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis
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Teresa Sevivas, Jesús María Hernández-Rivas, Maria Luisa Lozano, David S. Paul, Francisca Ferrer-Marín, Dalila Marques, Verónica Palma-Barqueros, José María Bastida, José Rivera, Steve P. Watson, Eva Caparrós, José Ramón González-Porras, Wolfgang Bergmeier, Margarida Coucelo, and Vicente Vicente
- Subjects
Blood Platelets ,Male ,0301 basic medicine ,medicine.medical_specialty ,Short Communication ,Integrin ,RASGRP2 ,Platelet Glycoprotein GPIIb-IIIa Complex ,Clot retraction ,030204 cardiovascular system & hematology ,Hemorrhagic Disorders ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Guanine Nucleotide Exchange Factors ,Humans ,Platelet ,Child ,Receptor ,dysfunction ,biology ,Bleeding ,Fibrinogen binding ,Hematology ,General Medicine ,medicine.disease ,Pedigree ,Bleeding diathesis ,030104 developmental biology ,Endocrinology ,Child, Preschool ,platelets ,Mutation ,Immunology ,biology.protein ,Female ,Blood Platelet Disorders ,Guanine nucleotide exchange factor ,signaling ,Platelet factor 4 - Abstract
The RASGRP2 gene encodes the Ca2+ and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), which plays a key role in integrin activation in platelets and neutrophils. We here report two new RASGRP2 variants associated with platelet dysfunction and bleeding in patients. The homozygous patients had normal platelet and neutrophil counts and morphology. Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected; platelet secretion, clot retraction, and spreading minimally affected. Genetic analysis identified two new homozygous variants in RASGRP2: c.706C>T (p.Q236X) and c.887G>A (p.C296Y). In both patients, CalDAG-GEFI protein was not detectable in platelet lysates, and platelet αIIbβ3 activation, as assessed by fibrinogen binding, was greatly impaired in response to all agonists except PMA. Patient neutrophils showed normal integrin expression, but impaired Mn2+-induced fibrinogen binding. In summary, we have identified two new RASGRP2 mutations that can be added to this rapidly growing form of inherited platelet function disorder.
- Published
- 2017
42. Impact of genotype on leukaemic transformation in polycythaemia vera and essential thrombocythaemia
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Joaquin Martinez-Lopez, Alicia Senín, Beatriz Bellosillo, Montse Gómez, Dolors Colomer, Francisco Cervantes, Concepción Fernández-Rodríguez, Blanca Navarro, Juan Carlos Hernández-Boluda, Anna Angona, Eduardo Arellano-Rodrigo, Laura Camacho, Alberto Alvarez-Larrán, Carlos Besses, Arturo Pereira, and Francisca Ferrer-Marín
- Subjects
Male ,Clone (cell biology) ,Kaplan-Meier Estimate ,Tp53 mutation ,Gastroenterology ,0302 clinical medicine ,Risk Factors ,hemic and lymphatic diseases ,Genotype ,Medicine ,Child ,Polycythemia Vera ,Aged, 80 and over ,Leucèmia ,Polycythaemia vera ,Hematology ,Middle Aged ,Prognosis ,Cell Transformation, Neoplastic ,Leukemia, Myeloid ,030220 oncology & carcinogenesis ,Female ,Essential thrombocythaemia ,Thrombocythemia, Essential ,Adult ,medicine.medical_specialty ,Polycythaemia ,Adolescent ,Prognostic factors ,Lower risk ,Young Adult ,03 medical and health sciences ,Internal medicine ,Complex Karyotype ,Humans ,Aged ,business.industry ,Janus Kinase 2 ,medicine.disease ,Confidence interval ,Transformation (genetics) ,Spain ,Myelodysplastic Syndromes ,Mutation ,Myeloid leukaemia ,Calreticulin ,business ,Follow-Up Studies ,030215 immunology - Abstract
Summary The influence of driver mutations on leukaemic transformation was analysed in 1747 patients with polycythaemia vera or essential thrombocythaemia. With a median follow-up of 7·2 years, 349 patients died and 62 progressed to acute leukaemia or myelodysplastic syndrome. Taking death as a competing risk, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2–0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9–4·6, P = 0·09). Myelofibrotic transformation increased leukaemic risk, except in CALR-mutated patients. Next generation sequencing of 51 genes at the time of transformation showed additional mutations (median number: 3; range: 1–5) in 25 out of 29 (86%) assessable cases. Mutations (median: 1; range: 1–3) were detected in 67% of paired samples from the chronic phase. Leukaemia appeared in a JAK2 V617F negative clone in 17 (58%) cases, eleven of them being previously JAK2 V617F-positive. JAK2 V617F-mutated leukaemia was significantly associated with complex karyotype and acquisition of TP53 mutations, whereas EZH2 and RUNX1 mutations were more frequent in JAK2 V617F-negative leukaemia. Survival was longer in JAK2 V617F-unmutated leukaemia (343 days vs. 95 days, P = 0·003). In conclusion, CALR genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a JAK2 V617F-negative clone is TP53 independent and shows better survival.
- Published
- 2017
43. Developmental Stage–Specific Manifestations of Absent TPO/c-MPL Signalling in Newborn Mice
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Joseph E. Italiano, William B. Slayton, Karin M. Hoffmeister, Donald E. Mager, Sihem Bihorel, Viola Lorenz, Benjamin T. Kile, Haley E. Ramsey, Martha Sola-Visner, Zhi-Jian Liu, Zhongbo Hu, and Francisca Ferrer-Marín
- Subjects
Adult ,Blood Platelets ,0301 basic medicine ,P-selectin ,Stimulation ,Platelet Glycoprotein GPIIb-IIIa Complex ,Biology ,Article ,Andrology ,Mice ,03 medical and health sciences ,Thrombin ,medicine ,Animals ,Congenital Bone Marrow Failure Syndromes ,Humans ,Platelet ,Receptor ,Thrombopoietin ,Cell Proliferation ,Cell Size ,Mice, Knockout ,Infant, Newborn ,Gene Expression Regulation, Developmental ,Hematology ,Thrombocytopenia ,Mice, Inbred C57BL ,P-Selectin ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,Bone marrow ,Megakaryocytes ,Receptors, Thrombopoietin ,Signal Transduction ,medicine.drug - Abstract
Congenital amegakaryocytic thrombocytopaenia (CAMT) is a disorder caused by c-MPL mutations that impair thrombopoietin (TPO) signalling, resulting in a near absence of megakaryocytes (MKs). While this phenotype is consistent in adults, neonates with CAMT can present with severe thrombocytopaenia despite normal MK numbers. To investigate this, we characterized MKs and platelets in newborn c-MPL –/– mice. Liver MKs in c-MPL –/– neonates were reduced in number and size compared with wild-type (WT) age-matched MKs, and exhibited ultrastructural abnormalities not found in adult c-MPL –/– MKs. Platelet counts were lower in c-MPL –/– compared with WT mice at birth and did not increase over the first 2 weeks of life. In vivo biotinylation revealed a significant reduction in the platelet half-life of c-MPL –/– newborn mice (P2) compared with age-matched WT pups, which was not associated with ultrastructural abnormalities. Genetic deletion of the pro-apoptotic Bak did not rescue the severely reduced platelet half-life of c-MPL –/– newborn mice, suggesting that it was due to factors other than platelets entering apoptosis early. Indeed, adult GFP+ (green fluorescent protein transgenic) platelets transfused into thrombocytopenic c-MPL –/– P2 pups also had a shortened lifespan, indicating the importance of cell-extrinsic factors. In addition, neonatal platelets from WT and c-MPL –/– mice exhibited reduced P-selectin surface expression following stimulation compared with adult platelets of either genotype, and platelets from c-MPL –/– neonates exhibited reduced glycoprotein IIb/IIIa (GPIIb/IIIa) activation in response to thrombin compared with age-matched WT platelets. Taken together, our findings indicate that c-MPL deficiency is associated with abnormal maturation of neonatal MKs and developmental stage-specific defects in platelet function.
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- 2017
44. Developmental Differences in Platelet Inhibition Response to Prostaglandin E1
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Nerea Mota-Pérez, Martha Sola-Visner, José Rivera, Antonija Jurak Begonja, Raúl Teruel-Montoya, Natalia Bohdan, Verónica Palma-Barqueros, Eva Caparrós-Pérez, Jose Miguel Torregrosa, Francisca Ferrer-Marín, Vicente Vicente, and María Del Carmen Llanos
- Subjects
Adult ,Blood Platelets ,medicine.medical_specialty ,Gs alpha subunit ,Platelet Aggregation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,medicine ,Cyclic AMP ,Humans ,Platelet ,030212 general & internal medicine ,Platelet activation ,Alprostadil ,Receptor ,Prostacyclin receptor ,Chemistry ,Age Factors ,Infant, Newborn ,Adenosine ,Cyclic AMP-Dependent Protein Kinases ,Adenosine Diphosphate ,Adenosine diphosphate ,Endocrinology ,Pediatrics, Perinatology and Child Health ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,Developmental Biology ,medicine.drug ,Adenylyl Cyclases - Abstract
Background: The mechanisms underlying neonatal platelets hyporesponsiveness are not fully understood. While previous studies have demonstrated developmental impairment of agonist-induced platelet activation, differences in inhibitory signaling pathways have been scarcely investigated. Objective: To compare neonatal and adult platelets with regard to inhibition of platelet reactivity by prostaglandin E1 (PGE1). Methods: Platelet-rich plasma from umbilical cord (CB) or adult blood was incubated with PGE1 (0–1 μM). We assessed aggregation in response to adenosine diphosphate (ADP), collagen, and thrombin receptor activating peptide as well as cyclic adenosine 3′5′-monophosphate (cAMP) levels (ELISA). Gαs, Gαi2, and total- and phospho-protein kinase A (PKA) were evaluated in adult and CB ultrapure and washed platelets, respectively, by immunoblotting. Results: Neonatal (vs. adult) platelets display hypersensitivity to inhibition by PGE1 of platelet aggregation induced by ADP and collagen (PGE1 IC50: 14 and 117 nM for ADP and collagen, respectively, vs. 149 and 491 nM in adults). They also show increased basal and PGE1-induced cAMP levels. Mechanistically, PGE1 acts by binding to the prostanoid receptor IP (prostacyclin receptor), which couples to the Gαs protein-adenylate cyclase axis and increases intracellular levels of cAMP. cAMP activates PKA, which phosphorylates different target inhibitor proteins. Neonatal platelets showed higher basal and PGE1-induced cAMP levels, higher Gαs protein expression, and a trend to increased PKA-dependent protein phosphorylation compared to adult platelets. Conclusion: Neonatal platelets have a functionally increased PGE1-cAMP-PKA axis. This finding supports a downregulation of inhibitory when going from neonate to adult contributing to neonatal platelet hyporesponsiveness.
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- 2019
45. Tubulin in Platelets: When the Shape Matters
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Raúl Teruel-Montoya, Francisca Ferrer-Marín, Ernesto José Cuenca-Zamora, and José Rivera
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Blood Platelets ,0301 basic medicine ,Inflammation ,macromolecular substances ,Review ,030204 cardiovascular system & hematology ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,neonatal ,03 medical and health sciences ,0302 clinical medicine ,Megakaryocyte ,Microtubule ,medicine ,Animals ,Humans ,Platelet ,Thrombopoiesis ,Physical and Theoretical Chemistry ,Cytoskeleton ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Actin ,biology ,Chemistry ,platelets activation ,Organic Chemistry ,Genetic Variation ,Correction ,cytoskeleton ,General Medicine ,Computer Science Applications ,Cell biology ,030104 developmental biology ,Tubulin ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,tubulin ,post-translational modification ,biology.protein ,medicine.symptom ,Protein Processing, Post-Translational - Abstract
Platelets are anuclear cells with a short lifespan that play an essential role in many pathophysiological processes, including haemostasis, inflammation, infection, vascular integrity, and metastasis. Billions of platelets are produced daily from megakaryocytes (platelet precursors). Despite this high production, the number of circulating platelets is stable and, under resting conditions, they maintain their typical discoid shape thanks to cytoskeleton proteins. The activation of platelets is associated with dynamic and rapid changes in the cytoskeleton. Two cytoskeletal polymer systems exist in megakaryocytes and platelets: actin filaments and microtubules, based on actin, and α- and β-tubulin heterodimers, respectively. Herein, we will focus on platelet-specific tubulins and their alterations and role of the microtubules skeleton in platelet formation (thrombopoiesis). During this process, microtubules mediate elongation of the megakaryocyte extensions (proplatelet) and granule trafficking from megakaryocytes to nascent platelets. In platelets, microtubules form a subcortical ring, the so-called marginal band, which confers the typical platelet discoid shape and is also responsible for changes in platelet morphology upon activation. Molecular alterations in the gene encoding β1 tubulin and microtubules post-translational modifications may result in quantitative or qualitative changes in tubulin, leading to altered cytoskeleton reorganization that may induce changes in the platelet number (thrombocytopenia), morphology or function. Consequently, β1-tubulin modifications may participate in pathological and physiological processes, such as development.
- Published
- 2019
46. Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice: results from a nationwide series of 236 patients
- Author
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Valentín García-Gutiérrez, Francisco Cervantes, Grupo Español de Leucemia Mieloide Crónica, Jose Manuel Puerta, Juan Luis Steegmann, Luis Felipe Casado, Santiago Osorio, Juan Carlos Hernández-Boluda, Arturo Pereira, José María Sánchez-Pina, Manuel Pérez-Encinas, Arantxa Mendizábal, Rolando Vallansot, Fermín Sánchez-Guijo, Natalia de las Heras, Luis Palomera, Rosa Collado, Carmen González García, Concepción Boqué, Miguel Sagüés, José Luis López-Lorenzo, Irene Pastor-Galán, Alberto Alvarez-Larrán, Anna Angona, Raúl Pérez-López, Alvaro Díaz-González, Alisa Savchuk, and Francisca Ferrer-Marín
- Subjects
Male ,medicine.medical_specialty ,Fusion Proteins, bcr-abl ,lcsh:RC254-282 ,Article ,Leucèmia -- Tractament ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Anticarcinogenic Agents ,Humans ,Cumulative incidence ,Protein Kinase Inhibitors ,Aged ,Proportional Hazards Models ,Proportional hazards model ,business.industry ,Incidence (epidemiology) ,Myeloid leukemia ,Imatinib ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Discontinuation ,Clinical trial ,Leukemia ,Treatment Outcome ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,business ,Biomarkers ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
Over half of chronic myeloid leukemia (CML) patients in deep molecular response do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in clinical trials, but its applicability in the real-life setting remains unsettled. We describe the outcomes after TKI discontinuation in a nationwide series of 236 CML patients. Median follow-up from treatment discontinuation was 21.5 months and 5 patients died from CML-unrelated causes. TKI therapy was reinitiated due to MMR loss (n = 52), increase ≥ 1 log in BCR-ABL transcript level without losing MMR (n = 12), patient preference (n = 2), and withdrawal syndrome (n = 1). Treatment-free remission rate at 4 years was 64% (95% confidence interval, CI: 55%–72%). Cumulative incidence of molecular recurrence at 3 years was 33% (95% CI: 26%–38%). TKI treatment for n = 196), MR4 (n = 15), MMR (n = 14), complete cytogenetic response (n = 10), and other (n = 1). A significant increase in Hb and cholesterol levels was observed after imatinib withdrawal. Our results demonstrate that TKI treatment discontinuation is feasible in real-life clinical practice.
- Published
- 2018
47. Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response
- Author
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Arturo Pereira, Sara Redondo, Fermín Sánchez-Guijo, Isabel Pérez, Santiago Osorio, Francisca Ferrer-Marín, Dolors Colomer, J.L. Steegmann, Juan-Gonzalo Correa, Valentín García-Gutiérrez, Francisco Cervantes, and Antonio Jiménez-Velasco
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Antineoplastic Agents ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Hematology ,Dose-Response Relationship, Drug ,business.industry ,Myeloid leukemia ,Imatinib ,General Medicine ,Middle Aged ,Surgery ,Treatment Outcome ,Tolerability ,030220 oncology & carcinogenesis ,Molecular Response ,Leukemia, Myeloid, Chronic-Phase ,Toxicity ,Imatinib Mesylate ,Female ,Dose reduction ,business ,030215 immunology ,medicine.drug - Abstract
To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2–5.9) years; molecular response was MR4, MR4.5, and MR5 of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7–3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR3. At the last follow-up, response was MR3, MR4, MR4.5, and MR5 in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.
- Published
- 2016
48. Correction: Cuenca-Zamora, Ernesto José., et al. Tubulin in Platelets: When the Shape Matter. Int. J. Mol. Sci. 2019, 20, 3484
- Author
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José Rivera, Ernesto José Cuenca-Zamora, Francisca Ferrer-Marín, and Raúl Teruel-Montoya
- Subjects
biology ,Chemistry ,Organic Chemistry ,INT ,General Medicine ,Molecular biology ,Catalysis ,Computer Science Applications ,lcsh:Chemistry ,Inorganic Chemistry ,n/a ,Tubulin ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,Platelet ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy - Abstract
The authors wish to make the following corrections to this paper [...]
- Published
- 2020
49. Significant Hypo-Responsiveness to GPVI and CLEC-2 Agonists in Pre-Term and Full-Term Neonatal Platelets and following Immune Thrombocytopenia
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Alexander T, Hardy, Verónica, Palma-Barqueros, Stephanie K, Watson, Jean-Daniel, Malcor, Johannes A, Eble, Elizabeth E, Gardiner, José E, Blanco, Rafael, Guijarro-Campillo, Juan L, Delgado, María L, Lozano, Raúl, Teruel-Montoya, Vicente, Vicente, Steve P, Watson, José, Rivera, and Francisca, Ferrer-Marín
- Subjects
Blood Platelets ,full-term neonates ,Platelet Membrane Glycoproteins ,premature ,Mice ,Pregnancy ,Cellular Haemostasis and Platelets ,Animals ,Humans ,Syk Kinase ,Lectins, C-Type ,development ,Cells, Cultured ,Purpura, Thrombocytopenic, Idiopathic ,Membrane Glycoproteins ,Phospholipase C gamma ,Infant, Newborn ,Platelet Activation ,platelet hypo-responsiveness ,P-Selectin ,immune-induced thrombocytopenia ,ITAM-containing receptors ,Premature Birth ,Female ,Receptors, Thrombin ,Integrin alpha2beta1 ,Signal Transduction - Abstract
Neonatal platelets are hypo-reactive to the tyrosine kinase-linked receptor agonist collagen. Here, we have investigated whether the hypo-responsiveness is related to altered levels of glycoprotein VI (GPVI) and integrin α2β1, or to defects in downstream signalling events by comparison to platelet activation by C-type lectin-like receptor 2 (CLEC-2). GPVI and CLEC-2 activate a Src- and Syk-dependent signalling pathway upstream of phospholipase C (PLC) γ2. Phosphorylation of a conserved YxxL sequence known as a (hemi) immunotyrosine-based-activation-motif (ITAM) in both receptors is critical for Syk activation. Platelets from human pre-term and full-term neonates display mildly reduced expression of GPVI and CLEC-2, as well as integrin αIIbβ3, accounted for at the transcriptional level. They are also hypo-responsive to the two ITAM receptors, as shown by measurement of integrin αIIbβ3 activation, P-selectin expression and Syk and PLCγ2 phosphorylation. Mouse platelets are also hypo-responsive to GPVI and CLEC-2 from late gestation to 2 weeks of age, as determined by measurement of integrin αIIbβ3 activation. In contrast, the response to G protein-coupled receptor agonists was only mildly reduced and in some cases not altered in neonatal platelets of both species. A reduction in response to GPVI and CLEC-2, but not protease-activated receptor 4 (PAR-4) peptide, was also observed in adult mouse platelets following immune thrombocytopenia, whereas receptor expression was not impaired. Our results demonstrate developmental differences in platelet responsiveness to GPVI and CLEC-2, and also following immune platelet depletion leading to reduced Syk activation. The rapid generation of platelets during development or following platelet depletion is achieved at the expense of signalling by ITAM-coupled receptors.
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- 2018
50. Essential thrombocythaemia with mutation in
- Author
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Alberto, Alvarez-Larran, Daniel, Martínez, Leonor, Arenillas, Ariadna, Rubio, Eduardo, Arellano-Rodrigo, Juan Carlos, Hernández Boluda, Natalia, Papaleo, Gonzalo, Caballero, Clara, Martínez, Francisca, Ferrer-Marín, María Isabel, Mata, Manuel, Pérez-Encinas, María Antonia, Durán, José María, Alonso, Gonzalo, Carreño-Tarragona, Juan Manuel, Alonso, Soledad, Noya, Elena, Magro, Raúl, Pérez, Mónica, López-Guerra, Irene, Pastor-Galán, Francisco, Cervantes, Carlos, Besses, Luis, Colomo, and María, Rozman
- Subjects
Adult ,Genetic Markers ,Male ,Adolescent ,Biopsy ,DNA Mutational Analysis ,Hemoglobins ,Young Adult ,Humans ,Genetic Predisposition to Disease ,Child ,Aged ,Cell Proliferation ,Aged, 80 and over ,Platelet Count ,Bone Marrow Examination ,Janus Kinase 2 ,Middle Aged ,Prognosis ,Phenotype ,Primary Myelofibrosis ,Mutation ,Female ,Calreticulin ,Megakaryocytes ,Receptors, Thrombopoietin ,Thrombocythemia, Essential - Abstract
To characterise the clinical and histological features ofBone marrow biopsies of 175 patients with ET were centrally reviewed according to the 2016 WHO classification, including 42 cases withPatients with
- Published
- 2018
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