Immediate effects of dasatinib on the migration and redistribution of naïve and memory lymphocytes associated with lymphocytosis in chronic myeloid leukemia patients

Introduction: Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib. Patients, Materials and Methods: Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points. Results: We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug. Discussion: We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

Obesity is a risk factor for highly prevalent age-related neurodegenerative diseases, the pathogenesis of whichinvolves mitochondrial dysfunction and protein oxidative damage. Lipoxidation, driven by high levels of peroxidizable unsaturated fatty acids and low antioxidant protection of the brain, stands out as a significant risk factor. To gain information on the relationship between obesity and brain molecular damage, in a porcine model of obesity we evaluated (1) the level of mitochondrial respiratory chain complexes, as the main source of free radical generation, by Western blot; (2) the fatty acid profile by gas chromatography; and (3) the oxidative modification of proteins by mass spectrometry. The results demonstrate a selectively higher amount of the lipoxidation-derived biomarker malondialdehyde-lysine (MDAL) (34% increase) in the frontal cortex, and positive correlations between MDAL and LDL levels and body weight. No changes were observed in brain fatty acid profile by the high-fat diet, and the increased lipid peroxidative modification was associated with increased levels of mitochondrial complex I (NDUFS3 and NDUFA9 subunits) and complex II (flavoprotein). Interestingly, introducing n3 fatty acids and a probiotic in the high-fat diet prevented the observed changes, suggesting that dietary components can modulate protein oxidative modification at the cerebral level and opening new possibilities in neurodegenerative diseases’ prevention.This research was supported by Laboratorios Ordesa S.L., Center for Technological and Industrial Development (CDTI) through the SMARTFOODS PROJECT (IDI-20141216), Fondo Europeo de Desarrollo Regional (FEDER; Acronym: INCOMES, project number IPT-20111008), and ISCIII [PI20-000155] to M.P.O. This work was also supported by the Generalitat of Catalonia (Agency for Management of University and Research Grants [2021SGR00990]) to R.P.info:eu-repo/semantics/publishedVersio

Cambios inducidos en DKK1 en pacientes con artritis reumatoide que inician tratamiento con terapia biológica

Introduction: The aim of this study is to assess the relationship among inflammatory charge, cardiovascular risk and bone metabolism in patients with rheumatoid arthritis initiating biological therapy treatment. Patients and methods: This is a prospective cohort study conducted in patients diagnosed with active rheumatoid arthritis (RA) assessed in the Rheumatology Unit and initiating biological therapy. Patients will be selected consecutively, with preliminary data on 14 patients. We present preliminary data from 14 patients. Results: Reduced Dickkopf-1 (DKK1) concentrations after commencing biological therapy were detected (baseline: 53.12±60.43 pg/ml vs 6 months 13.5±23.2 pg/ml, p=0.307) but without statistical significance. Changes were found in markers for bone remodeling with increased osteocalcin levels and CTX which were not statistically significant either. Conclusions: We observed a nonsignificant decrease in DKK1 serum in patients with active RA treated with biologic therapy. Expanding the scope of study subjects and pending biochemical determinations will allow us, in the near future, to establish more precisely this link and the relationship of DKK1, bone remodeling, biological therapy and cardiovascular disease in RA patients.Introducción: El objetivo del estudio es evaluar la relación entre la carga inflamatoria, el riesgo cardiovascular y el metabolismo óseo en pacientes con artritis reumatoide que inician tratamiento con terapia biológica. Pacientes y métodos: Se trata de un estudio de cohortes prospectivo realizado en pacientes con diagnóstico de artritis reumatoide (AR) activa evaluados en la Unidad de Reumatología y que inician terapia biológica. Los pacientes serán seleccionados de forma consecutiva. Presentamos los datos preliminares de 14 pacientes. Resultados: Encontramos una reducción en las concentraciones de Dickkopf-1 (DKK1) tras el inicio de la terapia biológica (basal: 53,12±60,43 pg/ml vs. 6 meses 23,2±13,5 pg/ml, p=0,307) pero no se alcanzó la significación estadística. Se encontraron cambios en los marcadores de remodelado con aumento en los niveles de osteocalcina y CTX que no alcanzó la significación estadística. Conclusiones: En pacientes con AR activa tratados con terapia biológica hemos observado un descenso no significativo de las concentraciones séricas de DKK1. La ampliación tanto de los sujetos de estudio como de las determinaciones bioquímicas pendientes nos permitirán en un futuro próximo establecer de forma más precisa esta asociación, así como la relación entre DKK1, remodelado óseo, terapia biológica y enfermedad cardiovascular en pacientes con AR

Up-to-date Spanish continental Neogene synthesis and paleoclimatic interpretation

A synthesis of the Spanish continental Neogene is presented by designing an integrated correlative chart of the Neo" gen-e "succes"Siuns-ofthe "lberian-PeninsuIa-. -Ninemain-sedimentary-breaks-have-been -distinguished-in-most-of-the "basins. They are considered a valuable criteria for correlation as they occur in similar time intervals from basin to basin. The determined sedimentary breaks occur in the Agenian, Ramblian, Middle Aragonian, Late Aragonian, Late Vallesian, Middle Turolian, Late Turolian, Late Ruscinian-Early Villafranchian, and Villafranchian ages. The larger interior basins (Ebro, Tajo, Duero) show a fairly complete Neogene sedimentary record in which the aboye mentioned sedimentary breaks are usually well recognized. A good correlation may be established from basin to basin. Likewise, there is a fairly good correlation among the Upper Miocene-Pliocene sedimentary record of basins spreading out in Levante and southeastern Spain. However, the correlation is not as c1ear in those basins located within the Iberian and Catalan Coastal Ranges, which usually do not show a similar sedimentary pattern. The comparison between Neogene stratigraphic logs in most of the Spanish continental basins and the pattern of global events from currentIy accepted Cenozoic Cyc1e Charts allows recognition of chronological coincidences, especially with regard to the age of seven major sedimentary ruptures (those developed at about 24.5 Ma, 22 Ma, 16 Ma, 13.5 Ma, 9.5 Ma, 5.5 Ma, 3.3 Ma). Evolutionary sedimentary trends in both offshore Mediterranean areas and inland peripheral zones of the Iberian Peninsula show also striking coincidences regarding the chronology of major sedimentary breaks observed in continental successions. Paleoc1imatic curves for the Spanish continental Neogene display four relative temperature peaks indicative of warm c1imatic conditions (Late Agenian, Early-Middle Aragonian, Vallesian-Turolian, and Late Villafranchian) as well as five relatively dry periods (Early Ramblian, Middle-Late Aragonian, Middle Turolian, Late Ruscinian, and Middle Villafranchian ages)

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

Obesity is a risk factor for highly prevalent age-related neurodegenerative diseases, the pathogenesis of whichinvolves mitochondrial dysfunction and protein oxidative damage. Lipoxidation, driven by high levels of peroxidizable unsaturated fatty acids and low antioxidant protection of the brain, stands out as a significant risk factor. To gain information on the relationship between obesity and brain molecular damage, in a porcine model of obesity we evaluated (1) the level of mitochondrial respiratory chain complexes, as the main source of free radical generation, by Western blot; (2) the fatty acid profile by gas chromatography; and (3) the oxidative modification of proteins by mass spectrometry. The results demonstrate a selectively higher amount of the lipoxidation-derived biomarker malondialdehyde-lysine (MDAL) (34% increase) in the frontal cortex, and positive correlations between MDAL and LDL levels and body weight. No changes were observed in brain fatty acid profile by the high-fat diet, and the increased lipid peroxidative modification was associated with increased levels of mitochondrial complex I (NDUFS3 and NDUFA9 subunits) and complex II (flavoprotein). Interestingly, introducing n3 fatty acids and a probiotic in the high-fat diet prevented the observed changes, suggesting that dietary components can modulate protein oxidative modification at the cerebral level and opening new possibilities in neurodegenerative diseases’ prevention

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

Altres ajuts: Laboratorios Ordesa S.L., Center for Technological and Industrial Development IDI-20141216 ; Fondo Europeo de Desarrollo Regional, IPT-20111008Obesity is a risk factor for highly prevalent age-related neurodegenerative diseases, the pathogenesis of whichinvolves mitochondrial dysfunction and protein oxidative damage. Lipoxidation, driven by high levels of peroxidizable unsaturated fatty acids and low antioxidant protection of the brain, stands out as a significant risk factor. To gain information on the relationship between obesity and brain molecular damage, in a porcine model of obesity we evaluated (1) the level of mitochondrial respiratory chain complexes, as the main source of free radical generation, by Western blot; (2) the fatty acid profile by gas chromatography; and (3) the oxidative modification of proteins by mass spectrometry. The results demonstrate a selectively higher amount of the lipoxidation-derived biomarker malondialdehyde-lysine (MDAL) (34% increase) in the frontal cortex, and positive correlations between MDAL and LDL levels and body weight. No changes were observed in brain fatty acid profile by the high-fat diet, and the increased lipid peroxidative modification was associated with increased levels of mitochondrial complex I (NDUFS3 and NDUFA9 subunits) and complex II (flavoprotein). Interestingly, introducing n3 fatty acids and a probiotic in the high-fat diet prevented the observed changes, suggesting that dietary components can modulate protein oxidative modification at the cerebral level and opening new possibilities in neurodegenerative diseases' prevention

Immediate effects of dasatinib on the migration and redistribution of naïve and memory lymphocytes associated with lymphocytosis in chronic myeloid leukemia patients

Introduction: Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib. Patients, Materials and Methods: Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points. Results: We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug. Discussion: We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells