The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Melhoria da Atenção ao Pré-Natal e Puerpério na UBS Mazagão Velho, Mazagão/AP

PÉREZ, Akelis Texidó. Melhoria da Atenção ao Pré-natal e Puerpério na UBS Mazagão Velho, Mazagão/AP. 2015. 76f Trabalho de Conclusão de Curso (Curso de Especialização em Saúde da Família) - Departamento de Medicina Social, Faculdade de Medicina, Universidade Federal de Pelotas, Pelotas, 2015. A intervenção teve como foco a atenção ao pré-natal e puerpério, que foi escolhido por ser uma ação programática de extrema importância para melhorar os indicadores de saúde deste grupo populacional e com isso diminuir a ocorrência de doenças que podem afetar tanto à mãe como ao futuro bebé. O objetivo foi melhorar a atenção ao pré-natal e puerpério na UBS Mazagão Velho, do município Mazagão, Estado Amapá, a qual está situada numa zona rural e atende também áreas ribeirinhas onde o acesso é difícil já que só pode ser feito pela água. Para a realização desta intervenção usamos como instrumento de trabalho as fichas espelho e as planilhas de coleta de dados de pré-natal e puerpério, onde todas as semanas eram registrados todos os dados permitindo ao final de 16 semanas avaliar o comportamento dos indicadores previstos. Participaram da intervenção 29 gestantes de modo que a cobertura alcançada foi 58%. Dentre alguns indicadores de qualidade, 100% das gestantes tiveram suas mamas examinadas, foram solicitados todos os exames laboratoriais e prescritos ácido fólico e sulfato ferroso como preconiza o Ministério da Saúde. Por meio da intervenção formamos um grupo de gestantes que foi de grande aceitação por parte das usuárias. Com relação às consultas de puerpério de 50% realizadas no primeiro mês de implementação do projeto conseguimos que 100% das puérperas que tiverem filhos desse período realizaram sua consulta após os 42 dias do parto. Esta intervenção teve um impacto muito grande na comunidade, pois permitiu ampliar a cobertura da atenção de gestantes e puérperas da área de abrangência, aumentando a qualidade dos serviços prestados mediante o monitoramento e avaliação da cobertura do pré-natal e puerpério, para nosso serviço e para a equipe também, pois propiciou uma melhora nos registros já existentes alcançando maior organização e controle delas, além da capacitação de todos nós sobre o Manual de Atenção ao Pré-natal e Puerpério para conseguir atingir as metas propostas. Palavras-chave: Saúde da família; Atenção Primária à Saúde; Saúde da Mulher; Pré-natal, Puerpério; Saúde Bucal

Hacia la utopía concreta: crítica y prospección para la Ciudad Puerto de Antofagasta, Chile

El Puerto de Antofagasta es una infraestructura urbana ha sido foco de diversos problemas socio-espaciales históricos en la ciudad, generando una constante fricción entre sus funciones productivas (asociadas al acopio de material tóxico para la salud humana) y la creciente vida urbana en la llamada capital mundial del cobre. A partir de un conjunto de antecedentes y experiencias que antes han intentado transformar la relación del puerto con la ciudad, el presente artículo explora cómo dichas ideas pueden ser reaplicadas al contexto actual. La investigación posee una virtud procedimental al introducir el método de la utopía concreta (Lefebvre, 1970) para para organizar y sistematizar propuestas de diseño urbano, junto a abrir el debate sobre el rol del puerto de Antofagasta y como resolver sus conflictos desde las disciplinas urbanísticas, necesitando para ello, de transformaciones institucionales que empoderen el accionar de nivel local

The Toll-like Receptor Protein Rp105 Regulates Lipopolysaccharide Signaling in B Cells

The susceptibility to infections induced by Gram-negative bacteria is largely determined by innate immune responses to bacteria cell wall lipopolysaccharide (LPS). The stimulation of B cells by LPS enhances their antigen-presenting capacity and is accompanied by B cell proliferation and secretion of large quantities of LPS-neutralizing antibodies. Similar to macrophages and neutrophils, the LPS-induced activation of B cells is dependent on Toll-like receptor (TLR)4. Here, we demonstrate that the responses of B cells to LPS are also regulated by another TLR protein, RP105, which is predominantly expressed on mature B cells in mice and humans. The analysis of mice homozygous for the null mutation in the RP105 gene revealed impaired proliferative and humoral immune responses of RP105-deficient B cells to LPS. Using originally LPS-unresponsive Ba/F3 cells expressing exogenous TLR4 and RP105, we demonstrate the functional cooperation between TLR4 and RP105 in LPS-induced nuclear factor κB activation. These data suggest the existence of the TLR4–RP105 signaling module in the LPS-induced B cell activation

The Molecular Mechanism of B Cell Activation by toll-like Receptor Protein RP-105

The B cell–specific transmembrane protein RP-105 belongs to the family of Drosophila toll-like proteins which are likely to trigger innate immune responses in mice and man. Here we demonstrate that the Src-family protein tyrosine kinase Lyn, protein kinase C β I/II (PKCβI/II), and Erk2-specific mitogen-activated protein (MAP) kinase kinase (MEK) are essential and probably functionally connected elements of the RP-105–mediated signaling cascade in B cells. We also find that negative regulation of RP-105–mediated activation of MAP kinases by membrane immunoglobulin may account for the phenomenon of antigen receptor–mediated arrest of RP-105–mediated B cell proliferation

Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells

In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development to the pre-B stage. A subsequent functional light chain (LC) rearrangement then results in the surface expression of IgM at the immature B cell stage. Here we show that interruption of basal IgM signaling in immature B cells, either by the inducible deletion of surface Ig via Cre-mediated excision or by incubating cells with the tyrosine kinase inhibitor herbimycin A or the phosphatidylinositol 3-kinase inhibitor wortmannin, led to a striking “back-differentiation” of cells to an earlier stage in B cell development, characterized by the expression of pro-B cell genes. Cells undergoing this reversal in development also showed evidence of new LC gene rearrangements, suggesting an important role for basal Ig signaling in the maintenance of LC allelic exclusion. These studies identify a previously unappreciated level of plasticity in the B cell developmental program, and have important implications for our understanding of central tolerance mechanisms

NMDA receptors and BAX are essential for Aβ impairment of LTP

Accumulation of amyloid-β (Aβ) is a hallmark of Alzheimer’s disease, a neurodegenerative disorder in which synapse loss and dysfunction are early features. Acute exposure of hippocampal slices to Aβ leads to changes in synaptic plasticity, specifically reduced long-term potentiation (LTP) and enhanced long-term depression (LTD), with no change in basal synaptic transmission. We also report here that D-AP5, a non-selective NMDA receptor antagonist, completely prevented Aβ-mediated inhibition of LTP in area CA1 of the hippocampus. Ro25-6981, an antagonist selective for GluN2B (NR2B) NMDA receptors, only partially prevented this Aβ action, suggesting that GluN2A and GluN2B receptors may both contribute to Aβ suppression of LTP. The effect of Aβ on LTP was also examined in hippocampal slices from BAX −/− mice and wild-type littermates. Aβ failed to block LTP in hippocampal slices from BAX −/− mice, indicating that BAX is essential for Aβ inhibition of LTP