Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.

Effect of specific exercise training on bone mineral density in women with postmenopausal osteopenia or osteoporosis.

AIM: To analyse the effect of a specific program of weight training exercise with closed kinetic chain in bone mineral density in postmenopausal women with osteopenia or osteoporosis. METHODS: A total of 59 postmenopausal women with osteoporosis or osteopenia were included in this prospective study. Subjects were divided into two groups: the study group (SG, n = 30; 57.5 + or - 5.1 years) and the control group (CG, n = 29; 56.6 + or - 4.6 years). In the study group was applied a weight exercise protocol (longitudinal forces in closed kinetic chain) during 12 months, whereas in the control group no weight exercise protocol was applied. Bone mineral density at the lumbar spine and hip was assessed at baseline and at the end of follow-up by dual energy X-ray absorptiometry. RESULTS. Although no significant intragroup differences were found, patients in SG showed a 1.17% increase in the lumbar spine whereas in CG a 2.26% decrease in bone density was detected. CONCLUSION: This protocol of weight training exercise did not significantly improve bone mineral density in postmenopausal women with osteopenia or osteoporosis, but in comparison to the control group, the results showed the importance of practising the specific exercise program for maintenance of bone health in postmenopausal women.

A flexibilidade em adolescentes - um contributo para a avaliação global / Flexibility among adolescents - a contribution to global evaluation

O presente estudo pretendeu avaliar a flexibilidade de adolescentes de ambos os sexos, envolvendo diversosgrupos articulares e regiões corporais, comparar meninos com meninas, estabelecer, por intermédio da análisefactorial, correlações inter-provas de flexibilidade, de modo a obter explicações do resultado nas variáveis originais, e verificar quais as componentes principais que, pela redução do número de variáveis correlacionadas, são susceptíveisde explicar uma maior variabilidade total. A amostra é constituída por 52 sujeitos, dos quais 28 são do sexo feminino e 24 do sexo masculino, com idades compreendidas entre os 15 e os 18 anos. A bateria utilizada para avaliação da flexibilidade é formada por oito testes: sentar e alcançar (SA), sentar e alcançar em V (V-SA), flexão do tronco à frente em pé (FTFP), extensão do tronco (ET), extensão do tronco e braços (ETB), flexão lateral do tronco (FLT-D e FLT-E), alcançaras mãos atrás das costas (AMAC-D e AMAC-E) e agachar e alcançar atrás (AAA). Os principais resultados apontam, de um modo geral, para um equilíbrio entre os dois sexos quanto à capacidade de realizar movimentos amplos. Existe uma forte associação: 1) entre as provas com características técnicas similares, o que parece indiciar a não necessidade de uso cumulativo destas provas, e 2) entre aquelas que apresentam efeitos directos sobre a lateralidade, AMAC-D/AMAC-E (excepto meninos) e FLT-D/FLT-E. A prova AAA não se associa com nenhuma prova realizada, particularmente no grupo dos meninos. A análise factorial de componentes principais (CP) mostrou que nas meninas 3 componentes, com valor próprio superior a 1, explicam 83,2% da variância total, ao passo que nos meninos são necessárias quatrocomponentes para explicarem 88,8% da variabilidade total. As provas que mais fortemente se correlacionam com cadauma das componentes principais são: 1) meninos: SA, FTFP, V-SA (CP1), FLT-D, FLT-E (CP2), AMAC-D, AAA (CP3) e ETB,ET (CP4);...

The present study intended to assess flexibility of adolescents of both sexes, involving several body regions andarticular groups; to compare males with females, to establish, by factor analyses, inter-tests correlations, in order toobtain explanations of the result in original variables and, to verify which principal components, by reduction of thenumber of correlated variables, are susceptible to better explain variability. The sample is constituted by 52 subjects (28 females and 24 males), aged between 15 and 18 years. Flexibility assessment battery was formed by eight tests: sit and reach (SA), v-sit and reach (V-SA), stand and reach (FTFP), trunk lift (ET), arm-trunk lift (ETB), side bending (FLT-D e FLTE), shoulder stretch (AMAC-D e AMAC-E) and, bend and reach (AAA). The main results showed, in general, a balance inboth sexes as far as the ability to perform wide movements is concerned. There is a strong association: 1) among similar technical characteristic tests, which seems there is no need for cumulative use among these tests, and 2) among those tests that have direct effects on laterality, AMAC-D/AMAC-E (except males) and FLT-D/FLT-E. The AAA test did not correlate with any of the performed tests, particularly in males. Factor analyses of principal components (CP) showed the existenceof three components in the female group, with eigenvalues higher than 1, explaining 83,2% of total variance, while in the male group four components were necessary to explain 88,8% of total variability. The tests that were more strongly correlated with each one of principal components were: 1) for males: SA, FTFP, V-SA (CP1), FLT-D, FLT-E (CP2), AMAC-D,AAA (CP3), and ETB, ET (CP4); 2) for females: AAA, FLT-E, AMAC-D, AMAC-E, FTFP (CP1), V-SA, SA, FTFP (CP2), and ETB,ET (CP3)...