Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways

Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. We demonstrated that GPC3 inhibits canonical Wnt signaling, as well as it activates non canonical pathway. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one. We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival.

Mass Spectrometric Analysis of a Cyclic 7,8-Butanoguanine Adduct of N-Nitrosopyrrolidine: Comparison to Other N-Nitrosopyrrolidine Adducts in Rat Hepatic DNA

The well established rat hepatocarcinogen N-nitrosopytrolidine (NPYR, 1) requires metabolic activation to DNA adducts to express its carcinogenic activity. Among the NPYR-DNA adducts that have been identified, the cyclic 7,8-butanoguanine adduct 2-amino-6,7,8,9-tetrahydro-9-hydroxypyrido[2,1-f]purine-4(3H)-one (6) has been quantified using moderately sensitive methods, but its levels have never been compared to those of other DNA adducts of NPYR in rat hepatic DNA. Therefore, in this study, we developed a sensitive new LC-ESI-MS/MS-SRM method for the quantitation of adduct 6 and compared its levels to those of several other NPYR-DNA adducts formed by different mechanisms. The new method was shown to be accurate and precise, with good recoveries and low fmol detection limits. Rats were treated with NPYR by gavage at doses of 46, 92, or 184 mg/kg body weight and sacrificed 16 h later. Hepatic DNA was isolated and analyzed for NPYR-DNA adducts. Adduct 6 was by far the most prevalent, with levels ranging from about 900-3000 mu mol/mol Gua and responsive to dose. Levels of adducts formed from crotonaldehyde, a metabolite of NPYR, were about 0.2-0.9 mu mol/mol dGuo, while those of adducts resulting from reaction with DNA of tetrahydrofuranyl-like intermediates were in the range of 0.01-4 mu mol/mol deoxyribonucleoside. The results of this study demonstrate that, among typical NPYR-DNA adducts, adduct 6 is easily the most abundant in hepatic DNA. Since previous studies have shown that it can be detected in the urine of NPYR-treated rats, the results suggest that it is a potential candidate as a biomarker for assessing human exposure to and metabolic activation of NPYR.

Quantum-chemical, NMR and X-ray diffraction studies on (+/-)-1-[3,4-(methylenedioxy)phenyl]-2-methylaminopropane

Time-averaged conformations of (+/-)-1-[3,4-(methylenedioxy)phenyl]-2-methylaminopropane hydrochloride (MDMA, ""ecstasy"") in D(2)O, and of its free base and trifluoroacetate in CDCl(3), were deduced from their (1)H NMR spectra and used to calculate their conformer distribution. Their rotational potential energy surface (PES) was calculated at the RHF/6-31G(d,p), 133LYP/6-31G(d,p), B3LYP/cc-pVDZ and AM1 levels. Solvent effects were evaluated using the polarizable continuum model. The NMR and theoretical studies showed that, in the free base, the N-methyl group and the ring are preferentially trans. This preference is stronger in the salts and corresponds to the X-ray structure of the hydrochloride. However, the energy barriers separating these forms are very low. The X-ray diffraction crystal structures of the anhydrous salt and its monohydrate differed mainly in the trans or cis relationship of the N-methyl group to the a-methyl, although these two forms interconvert freely in solution. (C) 2007 Elsevier Inc. All rights reserved.

Population pharmacokinetics and pharmacodynamics: An underutilized resource

A meeting was convened in Canberra, Australia, at the request of the Australian Drug Evaluation Committee (ADEC), on December 3-4, 1997 to discuss the role of population pharmacokinetics and pharmacodynamics in drug evaluation and development. The ADEC was particularly concerned about registration of drugs in the pediatric age group. The population approach could be used more often than is currently the case in pharmacokinetic and pharmacodynamic studies to provide valuable information for the safe and effective use of drugs in neonates, infants, and children. The meeting ultimately broadened to include discussion about other subgroups. The main conclusions of the meeting were: 1. The population approach, pharmacokinetic and pharmacodynamic analysis, is a valuable tool both for drug registration purposes and for optimal dosing of drugs in specific groups of patients, 2. Population pharmacokinetic and pharmacodynamic studies are able to fill in the gaps' in registration of drugs, for example, to provide information on optimal pediatric dosing. Such studies provide a basis for enhancing product information to improve rational prescribing, 3. Expertise is required to perform the population studies and expertise, with a clinical perspective, is also required to evaluate such studies if they are to be submitted as part of a drug registration dossier Such expertise is available in the Australasian region and is increasing. Centers of excellence with the appropriate expertise to advise and assist should be encouraged to develop and grow in the region, 4. The use of the population approach by the pharmaceutical industry needs to be encouraged to provide valuable information not obtainable by other techniques. The acceptance of population pharmacokinetic and pharmacodynamic analyses by regulatory agencies also needs to be encouraged, and 5. Development of the population approach to pharmacokinetics and pharmacodynamics is needed from a public health perspective to ensure that all available information is collected and used to improve the way drugs are used. This important endeavor needs funding and support at the local and international levels.

Christian Thomasius and the desacralization of philosophy

Despite his significance in early modern Germany, where he was well-known as a political and moral philosopher, jurist, lay-theologian, social and educational reformer, Christian Thomasius (1655-1728) is little known in the world of Anglophone scholarship. 1 Unlike those of his mentor, Samuel Pufendorf, none of Thomasius's works was translated into English, when, at the end of the seventeenth century, English thinkers were searching for a final settlement to the religious question. None has been translated since. Moreover, while Thomasius has been subject to increasing scholarly attention in Germany since the 1970s, where he has been treated largely as a representative of the "early Enlightenment," there is very little secondary literature on him in English. 2 Things are however beginning to change in this regard, with recent research already giving rise to important new Anglophone books and essays. 3 Knud Haakonssen's article on [End Page 595] Thomasius for the new Routledge Encyclopedia of Philosophy might well be a straw in the wind

Management of Uncommon Hernias in Cirrhotic Patients

Background. Abdominal hernias are a common disease among cirrhotic patients, because of malnutrition and persistently high intra-abdominal pressure due to ascites. When tense ascites is present, life-threatening complications are likely to occur. In such cases, the morbidity and mortality rates are high. Objective. We describe 3 cirrhotic patients with rare complicated hernias that needed surgical repair. We discuss optimal timing for surgical approaches and the necessity of ascites control before surgery, as well as the technical details of the procedures. Method. Review of hospital charts of selected rare cases of herniae in cirrhotic patients. Conclusion. Elective surgical approaches can treat even uncommon hernias in cirrhotic patients with good results.

Interferon and Alternative Activation of Monocyte/Macrophages in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Objective. To explore the relationship between biomarkers of pulmonary arterial hypertension (PAH), interferon (IFN)-regulated gene expression, and the alternative activation pathway in systemic sclerosis (SSc). Methods. Peripheral blood mononuclear cells (PBMCs) were purified from healthy controls, patients with idiopathic PAH, and SSc patients (classified as having diffuse cutaneous SSc, limited cutaneous SSc [lcSSc] without PAH, and lcSSc with PAH). IFN-regulated and ""PAH biomarker"" genes were compared after supervised hierarchical clustering. Messenger RNA levels of selected IFN-regulated genes (Siglec1 and MX1), biomarker genes (IL13RA1, CCR1, and JAK2), and the alternative activation marker gene (MRC1) were analyzed on PBMCs and on CD14- and CD14+ cell populations. Interleukin-13 (IL-13) and IL-4 concentrations were measured in plasma by immunoassay. CD14, MRC1, and IL13RA1 surface expression was analyzed by flow cytometry. Results. Increased PBMC expression of both IFN-regulated and biomarker genes distinguished SSc patients from healthy controls. Expression of genes in the biomarker cluster, but not in the IFN-regulated cluster, distinguished lcSSc with PAH from lcSSc without PAH. The genes CCR1 (P < 0.001) and JAK2 (P < 0.001) were expressed more highly in lcSSc patients with PAH compared with controls and mainly by CD14+ cells. MRC1 expression was increased exclusively in lcSSc patients with PAH (P < 0.001) and correlated strongly with pulmonary artery pressure (r = 0.52, P = 0.03) and higher mortality (P = 0.02). MRC1 expression was higher in CD14+ cells and was greatly increased by stimulation with IL-13. IL-13 concentrations in plasma were most highly increased in lcSSc patients with PAH (P < 0.001). Conclusion. IFN-regulated and biomarker genes represent distinct, although related, clusters in lcSSc patients with PAH. MRC1, a marker for the effect of IL-13 on alternative monocyte/macrophage activation, is associated with this severe complication and is related to mortality.

Administrando o estado: a experi??ncia dos gestores governamentais

A implanta????o da carreira de Especialistas em Pol??ticas P??blicas e Gest??o Governamental destinou-se a prover o Estado brasileiro de um corpo de funcion??rios com perfil generalista, ampla mobilidade funcional, e alta qualifica????o, para ocupa????o de cargos nos escal??es superiores da administra????o p??blica federal. Este artigo recupera a hist??ria do recrutamento, forma????o e inser????o na m??quina administrativa da primeira turma de Gestores Governamentais. O perfil profissional delineado no recrutamento e no curso de forma????o encontrou ampla receptividade na administra????o federal, mas o ??xito da experi??ncia n??o asegurou a sua consolida????o, constatando-se a debilita????o da carreira e a evas??o de seus quadros, motivada pela interrup????o do projeto, que at?? o presente realizou apenas um concurso recrutamento.

A ilustração e o Skate

Este projecto de investigação tem como objectivo o estudo da relação entre a Cultura Urbana do Skate e a Ilustração. A partir desta premissa, é proposto um trabalho teórico-prático que reflecte sobre a aplicação da Ilustração no universo do Skate. Através da vertente teórica, procura-se fundamentar e explicar a prática, constituindo uma recolha de estudos de caso adequados aos objectivos práticos do projecto. Na vertente prática, é proposto um sistema de trabalho em rede entre os dois autores, são delineadas várias etapas de implementação repartidas entre ambos, onde cada autor desempenha o seu cargo de forma autónoma com valores e objectivos compartilhados. Posteriormente, é apresentado um relatório com os resultados práticos deste projecto que envolvem a criação de um blogue gráfico experimental, uma marca que o identifica e um evento que reúne a Cultura Urbana do Skate, a Ilustração e a Música. O presente documento é composto por dois volumes distintos. O primeiro volume destina-se à redação escrita da dissertação sobre a investigação realizada. O segundo volume destina-se à documentação de todas as etapas de implementação prática do projecto, através de um dossier de campo.

Quantificação da difusão na ressonância magnética da mama: ADC e Kurtosis

Mestrado em Radiações Aplicadas às Tecnologias da Saúde. Área de especialização: Ressonância Magnética

Accounting logic and new professional in healthcare: a case study

The central place hospitals occupy in health systems transforms them into prime target of healthcare reforms. This study aims to identify current trends in organizational structure change in public hospitals and explore the role of accounting in attempts to develop controls over professionals within public hospitals. The analytical framework we proposed crosses the concept of “new professionalism” (Evetts, 2010), with the concept of “accounting logic” for controlling professionals (Broadbent and Laughlin, 1995). Looking for a more holistic overview, we developed a qualitative and exploratory study. The data were collected trough semi-structured interviews with doctors of a clinical hospital unit. Content analysis suggests that, although we cannot say that there is a complete and generalized integration of accounting information in the clinical decisions, important improvement has been made in that area. Despite the extensive literature developed on this topic, there is any empirical studies of authors are aware that allow us to realize how real doctors in reals day-to-day work integrated these trends of change in theirs clinical decisions.

Redes (des)conexas de intervenção local na violência infanto-juvenil

O objectivo deste estudo é apresentar os resultados de uma análise diagnóstica da atuação institucional relativamente às situações de violência infanto-juvenil em três territórios de um concelho da períferia de Lisboa(Portugal)

Relação entre o Conceito de Poder e o de Acção

A ordenação social é um dos temas centrais estudados pela sociologia desde há muito tempo. As teorias de acção social e de estrutura social são duas tradições teóricas usadas para explicar a forma como o mundo social se organiza e como funciona sem necessitar de uma imposição contínua de regras e normas. O poder e a acção social são dois conceitos centrais no mundo social, com uma forte ligação e influência mútua. O poder permite ou limita a acção, dá aos actores a possibilidade de ter mais e melhores oportunidades e posições sociais. A vida social é uma negociação constante, onde o poder e a acção estão sempre presentes, e é esta relação complexa que determina a natureza das relações sociais e o comportamento de cada indivíduo. Partindo de uma exposição teórica, o relatório irá apresentar alguns exemplos relacionados com o mercado de trabalho e comportamento organizacional para realçar a interacção entre os dois conceitos e a sua importância na vida social.

Alumbramentos: investigação e escrita de argumento para documentário: trabalho de projeto

Trabalho de Projeto submetida(o) à Escola Superior de Teatro e Cinema para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Desenvolvimento de Projecto Cinematográfico - especialização em Narrativas Cinematográficas.