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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

Effect of the time of diagnosis on outcome in patients with acute venous thromboembolism

Fri, 31 Dec 2010 23:00:00 GMT

Title: Effect of the time of diagnosis on outcome in patients with acute venous thromboembolism Author(s) : Lecumberri, R. (Ramón); Soler, S. (Silvia); Toro, J. (Jorge) del; Barba, R. (Raquel); Rosa, V. (Vladimir); Ciammaichella, M.M. (Maurizio M.); Monreal, M. (M.); RIETE, Investigators Abstract: The influence of the day of diagnosis (weekends vs. weekdays) on outcome in patients with acute venous thromboembolism (VTE) has not been thoroughly studied. We used the RIETE database to compare the clinical characteristics, treatment details, and mortality rate at 7 and 30 days, of all patients diagnosed with acute VTE on weekends versus those diagnosed on weekdays. Up to January 2010, 30,394 patients were included in RIETE, of whom 5,479 (18%) were diagnosed on weekends. Most clinical characteristics were similar in both groups, but patients diagnosed on weekends had less often cancer (20% vs. 22%; p=0.004), and presented more likely with pulmonary embolism (PE) than those diagnosed on weekdays (52% vs. 47%; p <0.001). Most patients in both groups received initial therapy with low-molecular-weight heparin (90% and 91%, respectively; p=0.01), then switched to vitamin K antagonists (72% and 71%, respectively; p=0.007). The 7-day mortality rate in patients presenting with PE was 2.75% in those diagnosed on weekends versus 3.00% in those diagnosed on weekdays (p=0.49). At 30 days, the mortality rate was 6.51% versus 6.06%, respectively (p=0.38). In patients presenting with deep vein thrombosis alone, the 7-day mortality rate in those diagnosed on weekends was 1.04% versuss 0.66% in those diagnosed on weekdays (p=0.053). The mortality rate at 30 days was of 3.41% versus 2.88% (p=0.14), respectively. In RIETE, the clinical characteristics, treatment strategies, and 7- and 30-day mortality rates of patients diagnosed on weekends were similar to those in patients diagnosed on weekdays.

Primary plasma cell leukemia with unusual morphology and complex karyotype

Wed, 31 Dec 1997 23:00:00 GMT

Title: Primary plasma cell leukemia with unusual morphology and complex karyotype Author(s) : Panizo, C. (Carlos); Cuesta, B. (Braulila); Rocha, E. (Eduardo)

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.

Emergence of Secondary Acute Leukemia in a Patient Treated for Osteosarcoma: Implications of Germline TP53 Mutations

Wed, 31 Dec 1997 23:00:00 GMT

Title: Emergence of Secondary Acute Leukemia in a Patient Treated for Osteosarcoma: Implications of Germline TP53 Mutations Author(s) : Panizo, C. (Carlos); Patiño, A. (Ana); Calasanz, M.J. (María José); Rifon, J. (José); Sierrasesumaga, L. (Luis); Rocha, E. (Eduardo) Abstract: Secondary leukemia and myelodysplastic syndromes have been reported in patients following treatment for a wide range of neoplastic disorders. However second malignancies after chemotherapy and/or irradiation for osteosarcoma are unusual. PROCEDURE: We report the case of a 15-year-old girl who developed a myelodysplastic syndrome with evolution to acute nonlymphocytic leukemia after treatment for osteosarcoma. Therapy-related acute leukemia karyotype findings such as abnormalities of chromosomes 5, 7, and 17 were found in the cytogenetic analysis. Moreover, using denaturing gradient gel electrophoresis and DNA sequencing, we detected the presence of a double germline mutation in exon 7 of the TP53 gene. CONCLUSION: This observation supports the possibility of a causal relationship between germline TP53 mutations and the development of secondary leukemia and myelodysplasia

Linking Two Immuno-Suppressive Molecules: Indoleamine 2,3 Dioxygenase Can Modify HLA-G Cell-Surface Expression1

Fri, 31 Dec 2004 23:00:00 GMT

Title: Linking Two Immuno-Suppressive Molecules: Indoleamine 2,3 Dioxygenase Can Modify HLA-G Cell-Surface Expression1 Author(s) : Gonzalez-Hernandez, A. (Álvaro); LeMaoult, J. (Joël); Lopez, A. (Ana); Alegre, E. (Estíbaliz); Caumartin, J. (Julien); Le-Rond, S. (Solene); Daouya, M. (Mariana); Moreau, P. (Philippe); Carosella, E.D. (Edgardo D.) Abstract: Nonclassical human leukocyte antigen (HLA) class I molecule HLA-G and indoleamine 2,3 dioxygenase (INDO) in humans and mice, respectively, have been shown to play crucial immunosuppressive roles in fetal-maternal tolerance. HLA-G inhibits natural killer and T cell function by high-affinity interaction with inhibitory receptors, and INDO acts by depleting the surrounding microenvironment of the essential amino acid tryptophan, thus inhibiting T cell proliferation. We investigated whether HLA-G expression and INDO function were linked. Working with antigen-presenting cell (APC) lines and monocytes, we found that functional inhibition of INDO by 1-methyl-tryptophan induced cell surface expression of HLA-G1 by HLA-G1- negative APCs that were originally cell-surface negative, and that in reverse, the functional boost of INDO by high concentrations of tryptophan induced a complete loss of HLA-G1 cell surface expression by APCs that were originally cell-surface HLA-G1-positive. This mechanism was shown to be posttranslational because HLA-G protein cell contents remained unaffected by the treatments used. Furthermore, HLA-G cell surface expression regulation by INDO seems to relate to INDO function, but not to tryptophan catabolism itself. Potential

Do the low molecular weight heparins improve efficacy and safety of the treatment of deep venous thrombosis? A meta-analysis

Fri, 31 Dec 1999 23:00:00 GMT

Title: Do the low molecular weight heparins improve efficacy and safety of the treatment of deep venous thrombosis? A meta-analysis Author(s) : Rocha, E. (Eduardo); Martinez-Gonzalez, M.A. (Miguel Angel); Montes, R. (Ramón); Panizo, C. (Carlos) Abstract: We compared the efficacy and safety of low molecular weight heparins (LMWH) and unfractionated heparin (UFH) in the treatement of deep venous thrombosis (DVT). A comparison between two daily subcutaneous injections of LMWH against a single injection was also performed. DESIGN AND METHODS: The study was performed by a meta-analysis. Clot improvement in venography, recurrency, total mortality and major hemorrhages were assessed in 4,472 patients with DVT from 21 studies treated with subcutaneous LMWH or UFH. RESULTS: An improvement in clot reduction (odds ratio 0.73, 95% confidence interval 0.59 to 0.90, p = 0.004), a decrease in total mortality (0. 68, 0.50 to 0.91, p = 0.012) and a lower incidence of hemorrhage (0. 65, 0.43 to 0.98, p = 0.047) were observed in LMWH treated patients. There were no differences in recurrences (0.78, 0.59 to 1.04, p = 0. 10). A single dose of LMWH was better than two in reducing major bleeding (c2 = 4.99, p = 0.025); however, the two dose regimen was more effective in clot reduction (c2 = 8.56, p = 0.004). INTERPRETATION AND CONCLUSIONS: LMWH is superior to UFH in terms of safety and efficacy. A single daily dose of LMWH dose is a suitable therapeutic regimen and could facilitate the outpatient treatment of venous thromboembolism.

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.

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)