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Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.

Sat, 31 Dec 2011 23:00:00 GMT

Title: Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia. Author(s) : Vilas-Zornoza, A. (Amaya); Aguirre, X. (Xavier); Abizanda, G. (Gloria); Moreno, C. (Cristina); Segura, V. (Víctor); Martino-Rodriguez, A. (Alba) de; San-Jose-Eneriz, E. (Edurne); Miranda, E. (Estibaliz); Martin-Subero, J.I. (José Ignacio); Garate, L. (Leire); Blanco-Prieto, M.J. (María José); Garcia-de-Jalon, J.A. (José A.); Rio, P. (Paula); Rifon, J. (José); Cigudosa, J.C. (Juan Cruz); Martinez-Climent, J.A. (José Angel.); Roman-Gomez, J. (José); Calasanz, M.J. (María José); Ribera, J.M. (José María); Prosper, F. (Felipe) Abstract: Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.

Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.

Sat, 31 Dec 2011 23:00:00 GMT

Maintained effectiveness of an electronic alert system to prevent venous thromboembolism among hospitalized patients

Wed, 31 Dec 2008 23:00:00 GMT

Title: Maintained effectiveness of an electronic alert system to prevent venous thromboembolism among hospitalized patients Author(s) : Lecumberri, R. (Ramón); Marques, M. (Margarita); Diaz-Navarlaz, M.T. (María Teresa); Panizo, E. (Elena); Toledo, J. (Jon); Garcia-Mouriz, A. (Alberto); Paramo, J.A. (José Antonio) Abstract: Despite current guidelines, venous thromboembolism (VTE) prophylaxis is underused. Computerized programs to encourage physicians to apply thromboprophylaxis have been shown to be effective in selected populations. Our aim was to analyze the impact of the implementation of a computer-alert system for VTE risk in all hospitalized patients of a teaching hospital. A computer program linked to the clinical record database was developed to assess all hospitalized patients' VTE risk daily. The physician responsible for patients at high risk was alerted, but remained free to order or withhold prophylaxis. Over 19,000 hospitalized, medical and surgical, adult patients between January to June 2005 (pre-intervention phase), January to June 2006 and January to June 2007 (post-intervention phase), were included. During the first semesters of 2006 and 2007, an electronic alert was sent to 32.8% and 32.2% of all hospitalized patients, respectively. Appropriate prophylaxis among alerted patients was ordered in 89.7% (2006) and 88.5% (2007) of surgical patients, and in 49.2% (2006) and 64.4% (2007) of medical patients. A sustained reduction of VTE during hospitalization was achieved, Odds ratio (OR): 0.53, 95% confidence interval (CI) (0.25-1.10) and OR: 0.51, 95%CI (0.24-1.05) during the first semesters of 2006 and 2007 respectively, the impact being significant (p < 0.05) among medical patients in 2007, OR: 0.36, 95%CI (0.12-0.98). The implementation of a computer-alert program helps physicians to assess each patient's thrombotic risk, leading to a better use of thromboprophylaxis, and a reduction in the incidence of VTE among hospitalized patients. For the first time, an intervention aimed to improve VTE prophylaxis shows maintained effectiveness over time.

LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome

Fri, 31 Dec 2010 23:00:00 GMT

Title: LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome Author(s) : Malumbres, R. (Raquel); Fresquet, V. (Vicente); Roman-Gomez, J. (José); Bobadilla, M. (Míriam); Robles, E.F. (Eloy Francisco); Altobelli, G.G. (Giovanna G.); Calasanz, M.J. (María José); Smeland, E.B. (Erlend B.); Aznar, M.A. (María Angela); Agirre, X. (Xabier); Martin-Palanco, V. (Vanesa); Prosper, F. (Felipe); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Angel) Abstract: BACKGROUND: LMO2 is highly expressed at the most immature stages of lymphopoiesis. In T-lymphocytes, aberrant LMO2 expression beyond those stages leads to T-cell acute lymphoblastic leukemia, while in B cells LMO2 is also expressed in germinal center lymphocytes and diffuse large B-cell lymphomas, where it predicts better clinical outcome. The implication of LMO2 in B-cell acute lymphoblastic leukemia must still be explored. DESIGN AND METHODS: We measured LMO2 expression by real time RT-PCR in 247 acute lymphoblastic leukemia patient samples with cytogenetic data (144 of them also with survival and immunophenotypical data) and in normal hematopoietic and lymphoid cells. RESULTS: B-cell acute lymphoblastic leukemia cases expressed variable levels of LMO2 depending on immunophenotypical and cytogenetic features. Thus, the most immature subtype, pro-B cells, displayed three-fold higher LMO2 expression than pre-B cells, common-CD10+ or mature subtypes. Additionally, cases with TEL-AML1 or MLL rearrangements exhibited two-fold higher LMO2 expression compared to cases with BCR-ABL rearrangements or hyperdyploid karyotype. Clinically, high LMO2 expression correlated with better overall survival in adult patients (5-year survival rate 64.8% (42.5%-87.1%) vs. 25.8% (10.9%-40.7%), P= 0.001) and constituted a favorable independent prognostic factor in B-ALL with normal karyotype: 5-year survival rate 80.3% (66.4%-94.2%) vs. 63.0% (46.1%-79.9%) (P= 0.043). CONCLUSIONS: Our data indicate that LMO2 expression depends on the molecular features and the differentiation stage of B-cell acute lymphoblastic leukemia cells. Furthermore, assessment of LMO2 expression in adult patients with a normal karyotype, a group which lacks molecular prognostic factors, could be of clinical relevance.

IFN-alpha5 mediates stronger Tyk2-stat-dependent activation and higher expression of 2',5'-oligoadenylate synthetase than IFN-alpha2 in liver cells

Wed, 31 Dec 2003 23:00:00 GMT

Title: IFN-alpha5 mediates stronger Tyk2-stat-dependent activation and higher expression of 2',5'-oligoadenylate synthetase than IFN-alpha2 in liver cells Author(s) : Larrea, E. (Esther); Aldabe, R. (Rafael); Riezu-Boj, J.I. (José Ignacio); Guitart, A. (Anunciata); Civeira, M.P. (María Pilar); Prieto, J. (Jesús); Baixeras, E. (Elena) Abstract: Interferon-alpha5 (IFN-alpha5) is the main IFN-alpha subtype expressed in the liver. Hepatitis C virus (HCV) infection is associated with low IFN-alpha5 mRNA levels, possibly reflecting an escape mechanism of the virus. In this work, we sought to compare IFN-alpha2 and IFN-alpha5 with respect to activation of early cell signaling cascades and induction of antiviral genes in the human hepatoma HepG2 and Huh7 cell lines. We found that the Tyr701 phosphorylation kinetics of Stat1 mediated by IFN stimulation was higher when cells were incubated with IFN-alpha5 than when using IFN-alpha2. Similarly, Tyr(1054/1055) phosphorylation kinetics of Tyk2 were more intense after exposure to IFN-alpha5 than when using IFN-alpha2. Concomitantly, Tyr705 phosphorylation of Stat3 was higher after stimulation with IFN-alpha5 than with IFN-alpha2. In parallel to these findings, the mRNA levels of the antiviral IFN-inducible gene 2',5'-oligoadenylate synthetase were higher in cell samples treated with IFN-alpha5 than with IFN-alpha2. These findings suggest that interaction of IFN-alpha5 and IFN-alpha2 subtypes with IFN type I receptor occurs differently, and this affects the intensity of expression of antiviral genes. In conclusion, our data show that in hepatocytic cells, IFN-alpha5 induces stronger signaling and higher expression of antiviral genes than IFN-alpha2. These data warrant clinical trials to evaluate the efficacy of IFN-alpha5 in chronic viral hepatitis.

A new favourable effect of cocoa on atherosclerosis?

Mon, 31 Dec 2007 23:00:00 GMT

Title: A new favourable effect of cocoa on atherosclerosis? Author(s) : Paramo, J.A. (José Antonio)

Hemorragia, hemostasia y trombosis en cirugía

Wed, 31 Dec 2008 23:00:00 GMT

Title: Hemorragia, hemostasia y trombosis en cirugía Author(s) : Paramo, J.A. (José Antonio) Abstract: Surgery is a leading cause of major hemorrhage as well as of thrombosis unless patients are administered appropriate antithrombotic prophylaxis after their thrombo-hemorrhagic risk has been stratified. Therefore, thorough preoperative evaluation is essential to minimize surgical complications. In cases of incoercible bleeding, drugs such as desmopressin, synthetic antifibrinolytics or recombinant factor VII can be administered. To prevent postoperative thrombosis, low molecular weight heparins or pentasaccharide have been shown to significantly reduce the incidence of thromboembolism.

Atherosclerosis: Is it time for a new name?

Sun, 31 Dec 2000 23:00:00 GMT

Title: Atherosclerosis: Is it time for a new name? Author(s) : Paramo, J.A. (José Antonio); Beloqui, O. (Óscar); Diez, J. (Javier)

The hemostatic system as a modulator of atherosclerosis

Fri, 31 Dec 2010 23:00:00 GMT

Title: The hemostatic system as a modulator of atherosclerosis Author(s) : Paramo, J.A. (José Antonio)

Inherited haemorrhagic disease with abnormal prothrombin consumption

Mon, 31 Dec 1984 23:00:00 GMT

Title: Inherited haemorrhagic disease with abnormal prothrombin consumption Author(s) : Rocha, E. (Eduardo); Paramo, J.A. (José Antonio); Cuesta, B. (Braulia); Fernandez, J. (Javier) Abstract: The propositus is a 4-year-old boy who presented with a history of excessive bleeding after surgical procedures as well as haematomas and epistaxis. The defect in haemostasis consisted in an anomaly of the prothrombin consumption tests as the only abnormality while all the other conventional coagulation and fibrinolysis tests as well as platelet function tests were normal. The father of the propositus had no previous history of excessive bleeding but was found to have an abnormal prothrombin consumption index. The reaction to prothrombin conversion, normal at onset, slowed down to less than normal and did not reach completion until 24 h. The in vivo studies suggest that the effect does not act on the interaction between platelet phospholipid and plasma. The factor II dosage and the electrophoretic mobility of prothrombin of the plasma were normal; nevertheless when studying the purified prothrombin by means of crossed immunoelectrofocusing there appeared an anomaly of pI. This result suggests the possible existence of an abnormal prothrombin molecule responsible for a slow prothrombin conversion.

Influence of the fast-acting inhibitor of plasminogen activator on in vivo thrombolysis induced by tissue-type plasminogen activator in rabbits. Interference of tissue-derived components

Tue, 31 Dec 1985 23:00:00 GMT

Title: Influence of the fast-acting inhibitor of plasminogen activator on in vivo thrombolysis induced by tissue-type plasminogen activator in rabbits. Interference of tissue-derived components Author(s) : Colucci, M. (M.); Paramo, J.A. (José Antonio); Stassen, J.M. (J.M.); Collen, D. (D.) Abstract: The influence of endotoxin-induced elevated plasma levels of the fast-acting inhibitor of plasminogen activator (PA-inhibitor) on thrombolysis was investigated in rabbits with a jugular vein thrombus. Infusion of human tissue-type plasminogen activator (t-PA) produced similar degrees of thrombolysis in control and endotoxin-treated rabbits, although no free t-PA could be demonstrated in plasma of endotoxin-treated animals. Infusion of t-PA in an extracorporeal arteriovenous shunt resulted in loss of thrombolytic activity in endotoxin-treated animals but not in control animals. Blood clots superfused in vitro with mixtures of t-PA and normal plasma lysed in contrast to clots superfused with t-PA and PA-inhibitor-rich plasma. However, addition of rabbit lung slices to the plasma surrounding the blood clot, reversed the inhibition of thrombolysis by PA-inhibitor-rich plasma. This indicates that tissue-derived factor(s) are involved in the regulation of in vivo thrombolysis. These hypothetical factor(s) are, however, very unstable in plasma, which has thus far precluded their further characterization.

Inhibition of one-chain and two-chain forms of human tissue-type plasminogen activator by the fast-acting inhibitor of plasminogen activator in vitro and in vivo

Tue, 31 Dec 1985 23:00:00 GMT

Title: Inhibition of one-chain and two-chain forms of human tissue-type plasminogen activator by the fast-acting inhibitor of plasminogen activator in vitro and in vivo Author(s) : Colucci, M. (M.); Paramo, J.A. (José Antonio); Collen, D. (D.) Abstract: The inhibition of one-chain and two-chain molecular forms of human tissue-type plasminogen activator (t-PA) by the fast-acting inhibitor of plasminogen activator (PA-inhibitor) present in plasma was studied in vitro and in vivo in rabbits. In vitro, both one-chain and two-chain forms of t-PA were neutralized very rapidly in rabbit plasma with high levels of PA-inhibitor. The rate constant of the interaction between two-chain t-PA and PA-inhibitor was estimated to be 3.10(7) L/mol/sec. The presence of CNBr-digested fibrinogen, which mimics the effect of fibrin on the activation of plasminogen by t-PA, did not influence the rate constant. Moreover, PA-inhibitor-rich plasma inhibited in a very similar way in vitro thrombolysis by one-chain or two-chain t-PA incorporated into the clot. Injection of one-chain or two-chain t-PA into rabbits with increased levels of PA-inhibitor, induced by endotoxin, resulted in very rapid inhibition of t-PA activity. Within 30 seconds after injection, no residual free t-PA could be demonstrated. Gel filtration analysis showed that the disappearance of t-PA activity was associated with the generation of t-PA-PA-inhibitor complex with an apparent Mr of 100,000. This enzyme-inhibitor complex, like free t-PA, was cleared from the circulation with a half-life of approximately 2 minutes, mainly via the liver. It is concluded that PA-inhibitor neutralizes one-chain and two-chain molecular forms of t-PA in plasma at very similar rates, both in vitro and in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Trombosis arterial y polimorfismos genéticos: demasiados actores, escenario complejo

Fri, 31 Dec 2004 23:00:00 GMT

Title: Trombosis arterial y polimorfismos genéticos: demasiados actores, escenario complejo Author(s) : Paramo, J.A. (José Antonio); Lecumberri, R. (Ramón); Orbe, J. (Josune) Abstract: La trombosis arterial es una enfermedad compleja y multifactorial, resultado de interacciones entre factores genéticos y ambientales. La tríada de Virchow, clásicamente empleada para definir la trombosis venosa, también se aplica a la trombosis arterial: alteraciones reológicas, disfunción endotelial y alteraciones hemostáticas que producen hipercoagulabilidad sanguínea. Algunos estudios llevados a cabo en la última década han identificado numerosos polimorfismos en genes involucrados en diversos componentes de esta tríada, entre los que destacan polimorfismos en factores de coagulación, fibrinólisis y receptors plaquetarios, en el metabolismo de la homocisteína, en la enzima óxido nítrico sintetasa, polimorfismos asociados con alteraciones reológicas y, finalmente, los relacionados con el estrés oxidativo.En conjunto, la contribución individual de estos polimorfismos a la trombosis arterial es modesta, mientras que interacciones gen-gen y gen-factores de riesgo parecen ser más relevantes en el desarrollo de la trombosis arterial.

Randomized study of aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass surgery

Fri, 31 Dec 1993 23:00:00 GMT

Title: Randomized study of aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass surgery Author(s) : Rocha, E. (Eduardo); Hidalgo, F. (Francisco); Llorens, R. (Rafael); Melero, J.M. (José María); Arroyo, J.L. (José L.); Paramo, J.A. (José Antonio) Abstract: BACKGROUND: Patients on cardiopulmonary bypass (CPB) have an increased susceptibility to postoperative bleeding. Previous reports using desmopressin acetate (DDAVP) for the prevention of postoperative bleeding have given contradictory results, whereas the protease inhibitor aprotinin has been shown to reduce blood loss after this type of surgery. This randomized study was performed to assess the efficacy of DDAVP versus aprotinin in the prevention of bleeding after CPB. METHODS AND RESULTS: One hundred nine of 122 eligible patients were randomized to four different groups: Group A (n = 28) received aprotinin starting with a bolus of 2 x 10(6) KIU followed by a continuous infusion of 0.5 x 10(6) KIU/h until the end of surgery; group B (n = 25) received of DDAVP 0.3 micrograms/kg i.v. on completion of CPB; group C (n = 28) received two doses of DDAVP, the first as in group B and an additional dose 6 hours after surgery; group D (n = 28) received no treatment. There was a marked reduction of postoperative blood loss either at 12 hours (P < .01) or 72 hours (P < .02) in the aprotinin group compared with all other groups, whereas no significant effect was observed in either of the two DDAVP regimens. A significant reduction in the amount of blood used was observed only in the aprotinin group (P < .01). Of the plasma fibrinolytic components assayed, there was a significant reduction of the fibrin degradation product generation in the aprotinin group (P < .001), whereas a significant systemic hyperfibrinolysis was observed in both DDAVP-treated groups and the control group. No side effects related to the study drugs were observed in any patient. CONCLUSIONS: Aprotinin inhibited fibrinolysis; this correlated with a significant reduction of postoperative blood loss and need for blood replacement after CPB. Neither one nor two doses of DDAVP had a beneficial effect. Aprotinin offers a better alternative than DDAVP in the prevention of bleeding after CPB.

Enfermedad tromboembólica y modificaciones de la coagulación tras artroplastia total de cadera. Acción de la profilaxis con ácido acetilsalicílico o heparina-dihidroergotamina

Tue, 31 Dec 1985 23:00:00 GMT

Title: Enfermedad tromboembólica y modificaciones de la coagulación tras artroplastia total de cadera. Acción de la profilaxis con ácido acetilsalicílico o heparina-dihidroergotamina Author(s) : Alfaro, M.J. (M.J.); Paramo, J.A. (José Antonio); Pablos, J. (Julio) de; Cañadell, J.M. (J. M.); Rocha, E. (Eduardo)