Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and In vivo activity

The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, (3R,4S,5S,6R)-5-methoxy-4-(2R,3R)-2-methyl-3-(3-methylbut-2-enyl) oxiran-2-yl]-1-oxaspiro2.5]octan-6-yl] N-(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only similar to 10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ((3R, 4S, 5S, 6R)-5-methoxy-4-(2R, 3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro2.5]octan-6 -yl] N-(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.

Temas de historia argentina y americana, 2008, n° 12 (número completo)

Intelectuales y poder: la influencia de Carlos Nino en la presidencia de Alfonsín / Cristina Basombrío -- Notas sobre la influencia de las ideas políticas españolas en la Argentina. Siglo XIX / Miguel Ángel De Marco -- El significado de La rosa blindada en el ámbito intelectual argentino de la década de 1960 / María Victoria Carsen -- Una alternativa diferente. El teatro libertario (1910-1930) / María Fernanda De La Rosa -- El límite, la marca y la huella. Reflexiones acerca de la construcción de identidades socioculturales en América Latina / Valeria M. Elizalde -- Crisis política y realineamientos partidarios en los años en los años treinta. Partidos políticos en Catamarca (1928-1932) / Carlos Humberto Ibáñez, Luis Alejandro Alvero -- El doctor Dick Edgar Ibarra Grasso y el hallazgo y desciframiento de la escritura indígena andina / Julio M. Luqui Lagleyze -- El ocaso de la UCR Antipersonalista y el aporte del radicalismo a la construcción del peronismo (1943-1946) / Elena T. Piñeiro -- Leyes de Reforma de Regulares, extinción de los agustinos cuyanos y algunos modelos de secularización / Emiliano Sánchez Pérez, Osa -- Reseñas Bibliográficas

Effects of pH on Growth of Salvinia molesta Mitchell

Growth of giant salvinia ( Salvinia molesta Mitchell) under different pH regimes was examined at the Lewisville Aquatic Ecosystem Research Facility (LAERF) in Lewisville, Texas.(PDF has 5 pages.)

Regeneration of Giant Salvinia from Apical and Axillary Buds following Desiccation or Physical Damage

Can a new giant salvinia infestation occur even if most of the mat is destroyed except for the protected buds? From this study, we are able to conclude that buds can produce new growth under certain stressful conditions. They must be greater than 0.2 cm in length and they must possess greater than 30% moisture content to survive.

Electron self-injection and acceleration driven by a tightly focused intense laser beam in an underdense plasma

A scheme for electron self-injection in the laser wakefield acceleration is proposed. In this scheme, the transverse wave breaking of the wakefield and the tightly focused geometry of the laser beam play important roles. A large number of the background electrons are self-injected into the acceleration phase of the wakefield during the defocusing of the tightly focused laser beam as it propagates through an underdense plasma. Particle-in-cell simulations performed using a 2D3V code have shown generation of a collimated electron bunch with a total number of 1.4 x 109 and energies up to 8 MeV. (C) 2005 American Institute of Physics.

Sociedade de controle e medicalização na educação: cartografando as práticas de um psicólogo nas escolas de uma cidade do interior do Rio de Janeiro

Esta dissertação baseia-se em uma pesquisa-intervenção realizada em cinco escolas de nível fundamental e infantil, e em uma escola de ensino especial/ atendimento educacional especializado (AEE) de uma cidade de pequeno porte do interior do Rio de Janeiro, na região sul do estado. O presente trabalho situa-se no contexto das discussões sobre as práticas de medicalização na escola-empresa e nas sociedades de controle, e tem como objetivo a investigação da medicalização e a judicialização como exigências que têm moldado um viés predominante médico-assistencialista ao trabalho do psicólogo, concentrando-se em atendimentos individualizados a alunos e famílias nas escolas públicas. O método adotado é o da cartografia (Deleuze & Guattari). Os conceitos de Medicalização (Conrad, Illitch, Szasz). Controle (Deleuze), e o conceito científico-ficcional de Pré-Crime (Dick) são a coluna vertebral do trabalho. A pesquisa de cunho qualitativo utiliza os referenciais teórico-práticos da análise institucional (AI) e dos estudos da filosofia de diferença, de autores como Michel Foucault, Gilles Deleuze e Félix Guatarri, assim como a contribuição valiosa de estudiosos mais contemporâneos, como Veiga-Neto, Gallo e Marcondes. Os analisadores dos relatórios pré-crime de medicalização do fracasso escolar, da (in)disciplina e da loucura através funcionam como pistas para as passagens dos diagnósticos para as práticas e modos coletivos de subjetivação, contexto mais amplo que nos conduz à visibilidade das questões do trabalho, da saúde no trabalho no magistério, e às plataformas de alianças coletivas entre técnicos(psicólogos) e não-técnicos (professores) para a construção dos processos de desmedicalização e desmedicalização na Educação.

Day and night abundance, distribution, and activity patterns of demersal fishes on Heceta Bank, Oregon

Most shallow-dwelling tropical marine fishes exhibit different activity patterns during the day and night but show similar transition behavior among habitat sites despite the dissimilar assemblages of the species. However, changes in species abundance, distribution, and activity patterns have only rarely been examined in temperate deepwater habitats during the day and night, where day-to-night differences in light intensity are extremely slight. Direct-observation surveys were conducted over several depths and habitat types on Heceta Bank, the largest rocky bank off the Oregon coast. Day and night fish community composition, relative density, and activity levels were compared by using videotape footage from a remotely operated vehicle (ROV) operated along paired transects. Habitat-specific abundance and activity were determined for 31 taxa or groups. General patterns observed were similar to shallow temperate day and night studies, with an overall increase in the abundance and activity of fishes during the day than at night, particularly in shallower cobble, boulder, and rock ridge habitats. Smaller schooling rockfishes (Sebastes spp.) were more abundant and active in day than in night transects, and sharpchin (S. zacentrus) and harlequin (S. variegatus) rockfish were significantly more abundant in night transects. Most taxa, however, did not exhibit distinct diurnal or nocturnal activity patterns. Rosethorn rockfish (S. helvomaculatus) and hagfishes (Eptatretus spp.) showed the clearest diurnal and nocturnal activity patterns, respectively. Because day and night distributions and activity patterns in demersal fishes are likely to influence both catchability and observability in bottom trawl and direct-count in situ surveys, the patterns observed in the current study should be considered for survey design and interpretation.

Activity in the pallial nerve of knobbed (Busycon carica) and channeled (Busycotypus canaliculatum) whelks recorded during exposure of the osphradium to odorant solutions

Adult horseshoe crabs (Limulus polyphemus) are the preferred bait in the U.S. east coast whelk pot fishery, but their harvest is being restricted because of severe population declines in the Chesapeake and Delaware bays. To identify other baits, the activity in the pallial nerve of whelks was determined during exposure of the osphradium to odorant solutions prepared from horseshoe crab eggs, horseshoe crab hemolymph, and hard clam (Mercenaria mercenaria) tissue. All three elicited significant responses; bait based on them may provide an alternative to the use of adult horseshoe crabs, although extensive behavioral testing remains to be done. Channeled whelk did not respond to molecular weight fractions (>3 kDa and <3 kDa) prepared from horseshoe crab egg odorant solutions but did respond when the molecular weight fractions were recombined. Whelks appear to have broadly tuned chemoreceptors and manufactured baits may need to mimic the complex mixture of odorants derived from natural sources.

Preliminary use of oxygen stable isotopes and the 1983 El Niño to assess the accuracy of aging black rockfish (Sebastes melanops)

Black rockfish (Sebastes melanops) range from California to Alaska and are found in both nearshore and shallow continental shelf waters (Love et al., 2002). Juveniles and subadults inhabit shallow water, moving deeper as they grow. Generally, adults are found at depths shallower than 55 meters and reportedly live up to 50 years. The species is currently managed by using information from an age-structured stock assessment model (Ralston and Dick, 2003).