Matrix metalloproteinase-2 and-9 involvement in canine tumors

Matrix metalloproteinases (MMPs) are a family of enzymes implicated in the degradation and remodeling of extracellular matrix and in vascularization. They are also involved in pathologic processes such as tumor invasion and metastasis in experimental cancer models and in human malignancies. We used gelatin zymography and inummohistochemistry to determine whether MMP-2 and MMP-9 are present in canine tumors and normal tissues and whether MMP production correlates with clinicopathologic parameters of prognostic importance. High levels of pro-MMP-9, pro-MMP-2, and active MMP-2 were detected in most canine tumors. Significantly higher MMP levels were measured in canine tumors than in nontumors, malignancies had higher MMP levels than benign tumors, and sarcomas had higher active MMP-2 than carcinomas. Cartilaginous tumors produced higher MMP levels than did nonsarcomatous malignancies, benign tumors, and normal tissues, and significantly greater MMP-2 than osteosarcomas and fibrosarcomas. Pro-MMP-9 production correlated with the histologic grade of osteosarcomas. The 62-kd form of active MMP-2 was detected only in high-grade, p53-positive, metastatic malignancies. Zymography proved to be a sensitive and quantitative technique for the assessment of MMP presence but has the limitation of requiring fresh tissue; inummohistochemistry is qualitative and comparatively insensitive but could be of value in archival studies. MMP presence was shown in a range of canine tumors, and their link to tumor type and grade was demonstrated for the first time. This study will allow a substantially improved evaluation of veterinary cancer patients and provides baseline information necessary for the design of clinical trials targeting MMPs.

Large sets of large sets of Steiner triple systems of order 9

We describe a direct method of partitioning the 840 Steiner triple systems of order 9 into 120 large sets. The method produces partitions in which all of the large sets are isomorphic and we apply the method to each of the two non-isomorphic large sets of STS(9).

Synthesis and characterization of delta-atracotoxin-ar1a, the lethal neurotoxin from venom of the Sydney funnel-web spider (Atrax robustus)

delta-Atracotoxin-Ar1a (delta-ACTX-Ar1a) is the major polypeptide neurotoxin isolated from the venom of the male Sydney funnel-web spider, Atrax robustus. This neurotoxin targets both insect and mammalian voltage-gated sodium channels, where it competes with scorpion alpha-toxins for neurotoxin receptor site-3 to slow sodium-channel inactivation. Progress in characterizing the structure and mechanism of action of this toxin has been hampered by the limited supply of pure toxin from natural sources. In this paper, we describe the first successful chemical synthesis and oxidative refolding of the four-disulfide bond containing delta-ACTX-Ar1a. This synthesis involved solid-phase Boc chemistry using double coupling, followed by oxidative folding of purified peptide using a buffer of 2 M GdnHCl and glutathione/glutathiol in a 1:1 mixture of 2-propanol (pH 8.5). Successful oxidation and refolding was confirmed using both chemical and pharmacological characterization. Ion spray mass spectrometry was employed to confirm the molecular weight. H-1 NMR analysis showed identical chemical shifts for native and synthetic toxins, indicating that the synthetic toxin adopts the native fold. Pharmacological studies employing whole-cell patch clamp recordings from rat dorsal root ganglion neurons confirmed that synthetic delta-ACTX-Ar1a produced a slowing of the sodium current inactivation and hyperpolarizing shifts in the voltage-dependence of activation and inactivation similar to native toxin. Under current clamp conditions, we show for the first time that delta-ACTX-Ar1a produces spontaneous repetitive plateau potentials underlying the clinical symptoms seen during envenomation. This successful oxidative refolding of synthetic delta-ACTX-Ar1a paves the way for future structure-activity studies to determine the toxin pharmacophore.

The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells

Lipid homeostasis is controlled by the peroxisome proliferator-activated receptors (PPARalpha, -beta/delta, and -gamma) that function as fatty acid-dependent DNA-binding proteins that regulate lipid metabolism. In vitro and in vivo genetic and pharmacological studies have demonstrated PPARalpha regulates lipid catabolism. In contrast, PPARgamma regulates the conflicting process of lipid storage. However, relatively little is known about PPARbeta/delta in the context of target tissues, target genes, lipid homeostasis, and functional overlap with PPARalpha and -gamma. PPARbeta/delta, a very low-density lipoprotein sensor, is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight. Skeletal muscle is a metabolically active tissue, and a primary site of glucose metabolism, fatty acid oxidation, and cholesterol efflux. Consequently, it has a significant role in insulin sensitivity, the blood-lipid profile, and lipid homeostasis. Surprisingly, the role of PPARbeta/delta in skeletal muscle has not been investigated. We utilize selective PPARalpha, -beta/delta, -gamma, and liver X receptor agonists in skeletal muscle cells to understand the functional role of PPARbeta/delta, and the complementary and/or contrasting roles of PPARs in this major mass peripheral tissue. Activation of PPARbeta/delta by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, beta-oxidation, cholesterol efflux, and energy uncoupling. Furthermore, we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol, thus identifying this tissue as an important target of PPARbeta/delta agonists. Interestingly, fenofibrate induces genes involved in fructose uptake, and glycogen formation. In contrast, rosiglitazone-mediated activation of PPARgamma induces gene expression associated with glucose uptake, fatty acid synthesis, and lipid storage. Furthermore, we show that the PPAR-dependent reporter in the muscle carnitine palmitoyltransferase-1 promoter is directly regulated by PPARbeta/delta, and not PPARalpha in skeletal muscle cells in a PPARgamma coactivator-1-dependent manner. This study demonstrates that PPARs have distinct roles in skeletal muscle cells with respect to the regulation of lipid, carbohydrate, and energy homeostasis. Moreover, we surmise that PPARgamma/delta agonists would increase fatty acid catabolism, cholesterol efflux, and energy expenditure in muscle, and speculate selective activators of PPARbeta/delta may have therapeutic utility in the treatment of hyperlipidemia, atherosclerosis, and obesity.

Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9)

One of seven poor metabolizers of coumarin found in Thai subjects was previously genotyped as heterozygote for the CYP2A6*4 (whole deletion) and CYP2A6*9. Thus, we aimed to investigate the relationship between the genetic polymorphism in the TATA box of the CYP2A6 gene (CYP2A6*9), expression levels of CYP2A6 mRNA and coumarin 7-hydroxylase activities in human livers. Levels of CYP2A6 mRNA were quantified by real-time quantitative reverse transcriptase-polymerase chain reaction. The mean expression levels of CYP2A6 mRNA in individuals with CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 58%, 71% and 21% of the individuals genotyped as CYP2A6*1/*1, respectively. The mean in-vitro coumarin 7-hydroxylase activities in subjects carrying CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 41%, 71% and 12%, respectively, compared to those of the subjects judged as wild-type. Vmax values for coumarin 7-hydroxylation in the liver microsomes from human subjects with genotypes of CYP2A6*1/*1, CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 0.58, 0.26, 0.44 and 0.13 nmol/min/nmol total P450, respectively. CYP2A6 protein levels in human liver microsomes with the CYP2A6*4 and the CYP2A6*9 alleles were markedly decreased. These results suggest that the genetic polymorphism in the promoter region of the CYP2A6 gene (CYP2A6*9) reduced the expression levels of CYP2A6 mRNA and protein in human livers, resulting in the decrease of coumarin 7-hydroxylase activities. Individuals judged as CYP2A6*4/*9 were expected to be poor metabolizers, having extremely low activity of CYP2A6.

A????es premiadas no 9?? Concurso Inova????o na Gest??o P??blica Federal 2004

Nesta publica????o, referente ao 9?? Concurso Inova????o na Gest??o P??blica Federal, o leitor encontrar?? iniciativas inovadoras nas seguintes ??reas: Articula????o de parcerias; atendimento ao cidad??o e inclus??o digital; gerenciamento de custos; planejamento e gest??o estrat??gica; simplifica????o e agiliza????o de procedimentos

Texto para discuss??o 9: administra????o p??blica gerencial: estrat??gia e estrutura para um novo Estado

Na d??cada de 80, logo depois da eclos??o da crise de endividamento internacional, o tema que prendeu a aten????o de pol??ticos e economistas em todo o mundo foi o ajuste estrutural ou, em termos mais anal??ticos, o ajuste fiscal e as reformas orientadas para o mercado. Nos anos 90, embora o ajuste estrutural permane??a entre os principais objetivos, a ??nfase deslocou-se para a reforma do Estado, particularmente para a reforma administrativa. A quest??o central hoje ?? como reconstruir o Estado ??? como redefinir o novo Estado que est?? surgindo em um mundo globalizado

M??dulo 9 - comiss??o de licita????o: curso legisla????o aplicada ?? log??stica de suprimentos Lei 8.666/93, preg??o e registro de pre??os

Este documento trata de: aspectos conceituais da lei: finalidade, import??ncia e hierarquia da lei.; no????es gerais da lei de licita????es - Lei n?? 8.666/93; tipos de licita????o:menor pre??o, melhor t??cnica, t??cnica e pre??o e maior lance ou oferta; modalidades de licita????o: concorr??ncia, tomada de pre??os, convite, concurso e leil??o; exce????es ?? obrigatoriedade de licita????o: dispensa e inexigibilidade; regime de execu????o indireta; comiss??o de licita????o; etapas do processo licitat??rio: edital, procedimentos/documentos do certame, registro cadastral, habilita????o dos interessados, julgamento e encerramento; preg??o; registro de pre??os

Curso de especializa????o em gest??o p??blica: 9?? edi????o - 2013/2014

A especializa????o em Gest??o P??blica ?? um curso de p??s-gradua????o "lato sensu" oferecido pela ENAP desde 2002. ?? um curso que busca contribuir para a melhoria da gest??o p??blica, promovendo a forma????o profissional dos servidores p??blicos do Poder Executivo Federal. O curso foi concebido de forma a aproximar os participantes das quest??es concretas da pr??tica governamental, com estrat??gias de ensino te??rico-aplicado, por meio de instrumentos did??tico-pedag??gicos que facilitem a apropria????o daquela realidade, sua an??lise e enfrentamento dos problemas identificados

Disciplina 4.9: sistema de or??amento federal

O Sistema de Or??amento Federal: ??rg??o central (SOF), ??rg??os setoriais e seccionais; processo e sistema or??ament??rio. As fun????es do or??amento. Aspectos institucionais e legais da fun????o or??ament??ria. Contexto legal e normativo do processo or??ament??rio. Modelos or??ament??rios. A reforma gerencial do or??amento (nova concep????o de programa). Classifica????es or??ament??rias e a transpar??ncia das opera????es or??ament??rias. Classifica????o funcional e estrutura program??tica, tipos de opera????es or??ament??rias (atividades, projetos e opera????es especiais). Classifica????o da despesa. A Lei de Responsabilidade Fiscal: princ??pios de responsabilidade na gest??o das finan??as p??blicas nacionais; a LRF como mecanismo de controle das contas p??blicas; as inova????es or??ament??rias; novas atribui????es da Lei de Diretrizes Or??ament??rias; a Receita P??blica ap??s a LRF; as Novas Exig??ncias para a Gera????o de Despesas P??blicas; a D??vida P??blica; a transpar??ncia na elabora????o e execu????o dos instrumentos de planejamento, execu????o e presta????o de contas; a responsabilidade civil, penal e administrativa dos gestores p??blicos.

9?? Encontro Nacional de Escolas de Governo

Este relat??rio apresenta uma s??ntese dos resultados do IX Encontro Nacional de Escolas de Governo, realizado na Escola Nacional de Administra????o P??blica, ENAP, nos dias 24 e 25 de maio de 2012, Em Bras??lia.

9?? concurso inova????o na gest??o p??blica federal: id??ias que fazem diferen??a

Para premiar e incentivar a gera????o e incorpora????o de novas pr??ticas e conhecimentos na gest??o p??blica, a ENAP e o Minist??rio do Planejamento, Or??amento e Gest??o promovem, desde 1996, o Concurso Inova????o na Gest??o P??blica Federal. Em 2004, os tr??s primeiros colocados foram o Sistema Radar Comercial, do Minist??rio do Desenvolvimento, Ind??stria e Com??rcio Exterior (MDIC), o Sistema de Custos e Informa????es Gerenciais, do Banco Central (Bacen), e o Centro de Pesquisas do HCPA: Inovando a gest??o da pesquisa, por meio de laborat??rios compartilhados, do Hospital de Cl??nicas de Porto Alegre (HCPA). A RSP conversou com as equipes vencedoras do 9?? Concurso Inova????o na Gest??o P??blica Federal para relatar um pouco de suas experi??ncias.

O administrador p??blico tipo delta para o s??culo 21

O artigo estuda um aspecto da reforma do Estado que, segundo o autor, tem sido sistematicamente negligenciado pelas atuais propostas que focalizam o modelo da administra????o gerencial. Trata-se das fun????es vitais do governo de tomar decis??es cr??ticas e adotar pol??ticas diante das mudan??as provocadas pela revolu????o global. Segundo Dror, as tarefas de alto comando (high-order tasks) de definir trajet??rias e as novas formas de governan??a exigem um ajuste significativo do governo central. Este ajuste refere-se, principalmente, ?? concep????o e ao desenvolvimento de um novo padr??o de funcion??rios do primeiro escal??o p??blico, o qual contribuiria com conhecimento e perspectivas para enfrentar as tarefas de alto comando. O autor estabelece uma tipologia para caraterizar a evolu????o do perfil do servi??o p??blico, marcando suas fases hist??ricas: a) tipo alpha (status atribu??do, fus??o de pap??is pol??ticos e administrativos); b) tipo beta (compra de cargos governamentais) e c) tipo gamma (quase profissionalismo). O novo funcion??rio s??nior, do tipo delta, se concentraria nas quest??es de ordem estrat??gica, deixando as fun????es gerenciais para servidores do tipo gamma e para os servi??os t??cnicos. Ap??s uma breve an??lise, Dror conclui que o funcionalismo p??blico de primeiro escal??o, na maioria dos pa??ses (com exce????o de alguns pa??ses do Sudeste Asi??tico), encontra-se obsoleto, com base profissional inadequada e capacidade insuficiente para lidar com escolhas cr??ticas.

Como não se perder com 9 milhões de endereços

Na adoção de novas tecnologias, o problema nem sempre é a disponibilidade de recursos, mas sim a possibilidade de acesso à informação adequada e à capacidade de utilizar novos quadros de referência analíticos. Quando se empregam Sistemas Geográficos de Informação no tratamento de endereços para o Database Marketing, é preciso passar a enxergar os endereços como as entidades autônomas que realmente são, em vez de considerá-los como meros atributos dos clientes. Essaestratégia reduz, consideravelmente, o esforço de geodecodificação.