This study focused on the role of RANKL in prostate cancer EMT progression and metastasis. Activation of RANK, a receptor activator of NF-kB, by its ligand RANKL, in a paracrine manner is responsible for osteoclast differentiation and bone remodeling. RANK activation in cancer cells, however, is thought to be promoted by both autocrine and paracrine mechanisms because RANKL has been shown to be derived from either tumor or its microenvironment, such as osteoblasts, infiltrating inflammatory cells and stromal fibroblasts. In the present study, we demonstrated that autocrine and paracrine RANKL-RANK signaling could be responsible for driving prostate cancer bone metastasis by promoting epithelial to mesenchymal transition (EMT). We further characterized a novel converging RANKL-c-Met signaling network in which the activation of RANKL was found to promote the expression of both RANKL and c-Met in an autocrine manner in prostate cancer cells. The induced RANKL and c-Met in prostate cancer cells is biologically functional and contributes to increased osteoclastogenesis, epithelial to mesenchymal transition (EMT), cell motility, migration and invasion and conferred bone and soft tissue metastases. Remarkably, RANKL expression by 1,000 prostate cancer cells can provoke bone and soft tissue metastases of a “dormant” population of prostate cancer cells which by themselves failed to form tumors and colonize mouse skeleton, suggesting RANKL can serve as a factor in “reawakening” cancer dormancy to initiate the re-growth and metastasis of cancer cells. We also showed that RANKL-induced RANKL feed-forward autocrine regulation is mediated through cMyc transactivation, allowing the establishment of a “vicious cycle” further promoting prostate cancer growth and metastasis. The converging RANKL-c-Met signaling network is therefore a novel target that could be further manipulated for delaying the lethal progression of castration-resistant human prostate cancer bone metastasis.

Alzheimer’s Disease (AD) is a chronic progressive neurological condition, clinically characterized by memory deficits, cognitive and physical impairment, and personality changes. Traditionally, AD was considered a type of protein folding disorder. Here, the concept of AD as an autoimmune disease of the innate immune system was developed. After exploring evolutionary connections between the AD peptide β-amyloid (Aβ) and known antimicrobial peptides (AMPs), and elucidating the structural similarities between Aβ and AMPs, a mechanism of action for Aβ’s antimicrobial activity is proposed that is based on the compromise of bacterial membranes. Following these theoretical considerations, experimental evidence is presented for the production of Aβ by cells in response to infection, and for Aβ’s antibacterial and antiviral activity. Rooted in similarities of the cell membranes of neuronal and bacterial cells in terms of lipid composition and transmembrane potential, it is hypothesised that Aβ’s neurotoxicity is caused by its misguided attack on neurons as an AMP. In reversing the concept of Aβ as an AMP, the similarity of AMPs to Aβ is demonstrated in experiments revealing the neurotoxicity of two AMPs, LL 37, and cecropin A. To determine a mechanism for the progressive nature of AD, it was shown that, although apoptosis may be involved in AD, it is actually necrosis that is responsible for the propagation of neuronal cell death so characteristic of AD. With the Vicious Cycle of AD, a scheme was devised, integrating the results obtained here with data and research from other groups, which explains the chronic and progressive nature of AD as a result of Aβ’s physiological role as an AMP and innate immune system effector. Borne from Aβ’s activity as an AMP and its central role in the Vicious Cycle of AD, a question was investigated: do antibiotics, such as penicillin, that cause release of bacterial endotoxins due to their mechanism of action, trigger the Vicious Cycle of AD and thus lead to the development of AD? Preliminary evidence supporting this notion was presented.

Submitted by ALISSON CARVALHO DE ALENCAR (alissoncalencar@hotmail.com) on 2016-02-17T15:01:24Z No. of bitstreams: 1 AS IMPLICAÇÕES DOS RESTOS A PAGAR NA GESTÃO DA SAÚDE PÚBLICA- O CASO DE MATO GROSSO versão 15.02.16.pdf: 1690575 bytes, checksum: c4ee06f1a76420d9490170d637b2443c (MD5) / Approved for entry into archive by BRUNA BARROS (bruna.barros@fgv.br) on 2016-02-23T13:42:12Z (GMT) No. of bitstreams: 1 AS IMPLICAÇÕES DOS RESTOS A PAGAR NA GESTÃO DA SAÚDE PÚBLICA- O CASO DE MATO GROSSO versão 15.02.16.pdf: 1690575 bytes, checksum: c4ee06f1a76420d9490170d637b2443c (MD5) / Approved for entry into archive by Maria Almeida (maria.socorro@fgv.br) on 2016-02-24T19:39:49Z (GMT) No. of bitstreams: 1 AS IMPLICAÇÕES DOS RESTOS A PAGAR NA GESTÃO DA SAÚDE PÚBLICA- O CASO DE MATO GROSSO versão 15.02.16.pdf: 1690575 bytes, checksum: c4ee06f1a76420d9490170d637b2443c (MD5) / Made available in DSpace on 2016-02-24T19:40:27Z (GMT). No. of bitstreams: 1 AS IMPLICAÇÕES DOS RESTOS A PAGAR NA GESTÃO DA SAÚDE PÚBLICA- O CASO DE MATO GROSSO versão 15.02.16.pdf: 1690575 bytes, checksum: c4ee06f1a76420d9490170d637b2443c (MD5) Previous issue date: 2015-11-05 / The health issue is the center of national and international discussion about the need for development of public policies to be adopted by public agencies. Therefore, the State has an obligation to implement public policies that provide at all, concrete actions aimed at safeguarding the right to health. From this perspective, the objective of the research is to evaluate the implications of remains to pay in the management of public health of Mato Grosso, in the years 2008 to 2014. In that intent, from documentary research, literature and field it was observed that the state is inserted into a vicious cycle of remains to pay. Expenses dammed in the period maintained a dynamic evolution, damaging the financial implementation of the priority programs of Mato Grosso health. The programmatic financial realization is no longer considered optimal in 2008, with 92% of performance, to be characterized as a regular in 2014, with 66% of execution. Through the case study, it was identified that there isn't way to Mato Grosso get excellent results in the implementation of the interests of their society if the state meets the credibility shaken as against creditors, by excessively delaying its financial commitments without respect, or have the ability to perform the approved budget, by purchasing goods and contracting services through emergency mechanisms that increase the cost of buying public and enhance the power of the companies, in the implementation of the budget. In addition to damage the budget and financial programming, creating real parallel budgets, it is concluded that the excess costs passed on the year in which should occur for subsequent, damaged the quality of public services run on state health, hindering the realization of this right fundamental, essential to life. / O tema saúde é o centro do debate nacional e internacional acerca da necessidade de evolução das políticas públicas a serem adotadas pelos órgãos públicos. Portanto, o Estado tem obrigação de executar programas que forneçam, a todos, ações concretas voltadas ao resguardo do direito à saúde. Nessa perspectiva, o objetivo da pesquisa é avaliar as implicações dos restos a pagar na gestão da saúde pública de Mato Grosso, nos anos de 2008 a 2014. Nesse intento, a partir de pesquisa documental, bibliográfica e de campo, observou-se que o Estado está inserido em um ciclo vicioso de inscrição de restos a pagar. As despesas represadas no período mantiveram uma dinâmica de evolução, prejudicando a execução financeira dos programas prioritários da saúde mato-grossense. Segundo os dados, a realização financeira programática deixou de ser considerada ótima em 2008, com 92% de realização, para caracterizar-se como regular em 2014, com 66% de execução. Por meio do estudo de caso, identificou-se que não há como Mato Grosso obter resultados excelentes na implementação dos interesses de sua sociedade se o Estado encontra-se com a credibilidade abalada em relação aos credores, por postergar seus compromissos financeiros, sem respeitar, ou ter a capacidade de executar o orçamento aprovado, adquirindo bens e contratando serviços lançando mão de mecanismos emergenciais que elevam o custo da compra pública e potencializam o poder das empresas na execução do orçamento. Além de deteriorar a programação orçamentária e financeira, criando verdadeiros orçamentos paralelos, conclui-se que o excesso de despesas repassadas do exercício em que deveriam ocorrer para os subsequentes, prejudicou a qualidade dos serviços públicos executados na saúde do Estado, dificultando a realização deste direito fundamental, imprescindível à vida.