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61.
Sanchez RM Erhard K Hardwicke MA Lin H McSurdy-Freed J Plant R Raha K Rominger CM Schaber MD Spengler MD Moore ML Yu H Luengo JI Tedesco R Rivero RA 《Bioorganic & medicinal chemistry letters》2012,22(9):3198-3202
A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (~ 0.100 μM IC(50)) growth inhibition in a PTEN deficient cancer cell line. 相似文献
62.
Martínez González S Hernández AI Varela C Rodríguez-Arístegui S Lorenzo M Rodríguez A Rivero V Martín JI Saluste CG Ramos-Lima F Cendón E Cebrián D Aguirre E Gomez-Casero E Albarrán M Alfonso P García-Serelde B Oyarzabal J Rabal O Mulero F Gonzalez-Granda T Link W Fominaya J Barbacid M Bischoff JR Pizcueta P Pastor J 《Bioorganic & medicinal chemistry letters》2012,22(10):3460-3466
Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition. 相似文献
63.
López-Cortés LF Ruiz-Valderas R Jimenez-Jimenez L González-Escribano MF Torres-Cornejo A Mata R Rivero A Pineda JA Marquez-Solero M Viciana P;Grupo para el Estudio de las Hepatitis Víricas 《PloS one》2012,7(1):e28115
Background
Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients.Methods and Findings
Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed.Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype.Conclusions
Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses.Trial Registration:
ClinicalTrials.gov NCT00553930相似文献64.
A Rivero-Juárez J Morgaz A Camacho P Muñoz-Rascón JM Dominguez R Sánchez-Céspedes J Torre-Cisneros A Rivero 《PloS one》2012,7(7):e41557
Background
The objectives of this study were to evaluate the best position and best exploration probe for determining liver stiffness (LS) in dogs using transient liver elastography (TE). Thirteen dogs were used in the study.Methodology/Principal Findings
Morphometric measurements taken were thoracic circumference, weight and height. Elastographic measurements were taken in 4 anatomical positions using two different probes: medium (M) and small (S). The exploration was considered correct when the success rate was above 60% and the interquartile range of the measurements did not exceed 30%. The best measurements were obtained in the middle of the 6th–9th intercostal spaces, with the dog in the left lateral position and using probe M for preference in adults and probe S mandatory for animals <2 years. The correlation between probes was 99%. Intra-observer variability showed an intra-class correlation of 97.6%.Conclusions/Significance
TE is a technique that is reproducible in dogs. 相似文献65.
CD63 is not required for production of infectious human immunodeficiency virus type 1 in human macrophages
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During the assembly of human immunodeficiency virus type 1 (HIV-1) particles, the tetraspanin CD63 can be incorporated into the viral membrane. Indeed, cell surface tetraspanin microdomains that include CD63 have been proposed as sites for virus release. In addition, antibodies against CD63 can inhibit HIV infection of macrophages. In this cell type, HIV assembles into intracellularly sequestered plasma membrane domains that contain several other tetraspanins, including CD81, CD9, and CD53. CD63 is recruited to this domain following HIV infection. Together, these observations suggest that CD63 may have some function in the assembly of infectious virus particles and/or the infectivity of assembled virions. Here we have used RNA interference to knock down CD63 expression in monocyte-derived primary macrophages. We show that in the absence of CD63, HIV assembly is quantitatively comparable to that seen in CD63-expressing macrophages and that virus assembly occurs on compartments positive for CD81, CD9, and CD53. Moreover, the infectivity of macrophage-derived virus is unaffected by the loss of CD63. Together, our results indicate that at least in tissue culture, CD63 expression is not required for either the production or the infectivity of HIV-1. 相似文献
66.
67.
Kátia Gisele Oliveira Rancura Michelli Rivero Montaño Robson Francisco Carvalho Cesar Martins Adriane Pinto Wasko Luciana Casaletti Alexandre Azevedo 《Acta zoologica》2008,89(1):29-36
This study presents data on myosin Va localization in the central nervous system of rainbow trout. We demonstrate, via immunoblots and immunocytochemistry, the expression of myosin Va in several neuronal populations of forebrain, midbrain, hindbrain and spinal cord. The neuronal populations that express myosin Va in trout constitute a very diverse group that do not seem to have many specific similarities such as neurotransmitters used, cellular size or length of their processes. The intensity of the immunoreactivity and the number of immunoreactive cells differ from region to region. Although there is a broad distribution of myosin Va, it is not present in all neuronal populations. This result is in agreement with a previous report, which indicated that myosin Va is approximately as abundant as conventional myosin II and kinesin, and it is broadly involved in neuronal motility events such as axoplasmatic transport. Furthermore, this distribution pattern is in accordance with what was shown in rats and mice; it indicates phylogenetic maintenance of the myosin Va main functions. 相似文献
68.
The role of fungicides in the physiology of higher plants: Implications for defense responses 总被引:1,自引:0,他引:1
Plants react to pathogen attack through a variety of active and passive defense mechanisms primarily related to the metabolism
of phenolic compounds and oxidative metabolism. Thus the activation of defensive reactions is associated with the increased
expression of a great number of genes that encode enzymes involved in the biosynthetic pathway of phenolic compounds. Similarly,
the activation of oxidative metabolism precedes the expression of defense genes during plant-pathogen interactions, so both
metabolic processes must exert a major function in directing the mechanisms to resist disease. Similarly, it has been suggested
that certain fungicides used to mitigate or prevent pathogen attack may be involved in activating certain defensive responses
of plants. However, the fact that such substances may influence the key steps of the phenolic and oxidative processes has
scarcely been studied. Our work confirms the results proposed by other authors, who suggest that certain wide-spectrum fungicides,
in addition to their antibiotic action against pathogens, may be involved in the activation of some defensive responses of
plants. 相似文献
69.
Juan M. Ruiz Rosa M. Rivero Inmaculada López-Cantarero Luis Romero 《Plant Growth Regulation》2003,41(2):173-177
Given the essential role played by phenol metabolism in many resistance responses to different types of stress, the aim of the present work was to determine how different application rates of calcium may influence this metabolic process. Increased calcium in the nutrient solution in which tobacco plants were grown considerably reduced the foliar concentration of phenolic compounds. Calcium clearly exerted a positive influence on the activities of enzymes (phenylalanine ammonia-lyase, polyphenol oxidase and peroxidase) involved in the metabolism of the phenolics. High dosages of calcium (5 mM) promoted more oxidation than synthesis of these compounds, thus explaining the lower concentration of the phenolics. 相似文献
70.
Esteban Sánchez Pablo C. Garcia Luis R. López-Lefebre Rosa M. Rivero Juan Manuel Ruiz Luis Romero 《Plant Growth Regulation》2002,36(3):261-265
The objective of the present work was to determine the impact ofnitrogen deficiency on proline metabolism in French Bean plants(Phaseolus vulgaris L. cv. Strike). The nitrogen wasapplied to the nutrient solution in the form of NH4NO3 at1.45 mM (N1), 2.90mM (N2) and 5.80mM (N3, optimal level). Our results indicateNdeficiency is characterised by a decline in proline accumulation both in theroot and leaves, fundamentally because proline degradation is encouraged by thestimulation of the enzyme proline dehydrogenase. By contrast, under conditionsof adequate N (N3), proline levels rise due to the action of ornithine,suggesting predominance of the ornithine pathway over the glutamine pathway, inaddition to the inhibition of proline dehydrogenase activity. 相似文献