Functional interactions between the estrogen receptor and the transcription activator Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogenin A1 io promoter.

Two distinct, TATA box-containing promoters regulate the transcriptional activity of the Xenopus vitellogenin A1 gene. These two promoters are of different strength and are separated by 1.8 kilobase pairs of untranslated sequence. Estrogen receptor (ER) and its ligand, 17beta-estradiol, induce the activity of both promoters. The estrogen response elements (EREs) are located proximal to the downstream i promoter while no ERE-like sequences have been identified in the vicinity of the upstream io promoter. We show here, that transcriptional activity of the upstream io promoter is Sp1-dependent. Moreover, we demonstrate that estrogen inducibility of the io promoter results from functional interactions between the io bound Sp1 and the ER bound at the proximity of i. Functional interactions between Sp1 and ER do not require the presence of a TATA box for transcriptional activation, as is demonstrated using the acyl-CoA oxidase promoter. The relative positions that ER and Sp1 occupy with respect to the initiation site determines whether these two transcription activators can synergize for transcription initiation.

Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic beta cells. Comparison with the effects of fatty acids.

GLUT2 expression is strongly decreased in glucose-unresponsive pancreatic beta cells of diabetic rodents. This decreased expression is due to circulating factors distinct from insulin or glucose. Here we evaluated the effect of palmitic acid and the synthetic glucocorticoid dexamethasone on GLUT2 expression by in vitro cultured rat pancreatic islets. Palmitic acid induced a 40% decrease in GLUT2 mRNA levels with, however, no consistent effect on protein expression. Dexamethasone, in contrast, had no effect on GLUT2 mRNA, but decreased GLUT2 protein by about 65%. The effect of dexamethasone was more pronounced at high glucose concentrations and was inhibited by the glucocorticoid antagonist RU-486. Biosynthetic labeling experiments revealed that GLUT2 translation rate was only minimally affected by dexamethasone, but that its half-life was decreased by 50%, indicating that glucocorticoids activated a posttranslational degradation mechanism. This degradation mechanism was not affecting all membrane proteins, since the alpha subunit of the Na+/K+-ATPase was unaffected. Glucose-induced insulin secretion was strongly decreased by treatment with palmitic acid and/or dexamethasone. The insulin content was decreased ( approximately 55 percent) in the presence of palmitic acid, but increased ( approximately 180%) in the presence of dexamethasone. We conclude that a combination of elevated fatty acids and glucocorticoids can induce two common features observed in diabetic beta cells, decreased GLUT2 expression, and loss of glucose-induced insulin secretion.

Fées et weise Frauen: les faiseuses de dons chez Perrault et les Grimm, du merveilleux rationalisé au merveilleux naturalisé

Dans «La Belle au bois dormant» et «Dornröschen», des personnages aux pouvoirs magiques déterminent l'avenir des héroïnes en leur accordant des dons positifs ou négatifs. La comparaison des textes montre toutefois que les fées et les weise Frauen (femmes sages), issues de traditions différentes, ne jouent pas les mêmes rôles dans les intrigues et que leurs actions ne sont pas présentées de la même manière. Si le conte de Perrault explique les motivations des fées et en fait des êtres réfléchis, le Märchen des Grimm représente les weise Frauen comme des figures énigmatiques appartenant à un univers où se déroulent des événements inexpliqués. Ainsi, le traitement de ces personnages féminins emblématiques reflète une volonté de rationaliser le merveilleux chez Perrault, contrairement aux Grimm, et témoigne ainsi de différences génériques, mais aussi historiques et culturelles plus larges. / Both in «La Belle au bois dormant» and in «Dornröschen», characters with magical powers determine the future of the heroines by endowing them with positive or negative gifts. The comparison of the two texts nonetheless shows that the fées (fairies) and the weise Frauen (wise women) -coming as they do from different cultural traditions- do not play the same role in the plot, nor are their actions presented in the same way. Whereas Perrault's conte explains the fairies' motivations and portrays them as rational beings, Grimm's Märchen depicts weise Frauen as mysterious women who belong to a universe of unexplained events. The treatment of these wondrous feminine figures thus testifies to a willingness to rationalise the marvellous in Perrault, and to present it as self-evident in Grimm, thereby reflecting generic as well as broader historical and cultural differences.

An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for Human Epidermal Growth Factor Receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer.

BACKGROUND: Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1-2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial. PATIENTS AND METHODS: Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m(2)). RESULTS: Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed. CONCLUSIONS: Our recommended dose for phase II is lapatinib 1000mg/day and docetaxel 100mg/m(2) with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.

Serra Malagueta (Santiago de Cabo Verde): Estratégias de Conservação e Valorização do Património.

Com esta dissertação, pretende – se, em primeiro lugar, dar a conhecer Serra Malagueta enquanto Parque Natural, um meio geográfico cujo área de dois mil e seiscentos hectares e uma altitude de cerca de mil metros, tendo na sua dependência 579 habitantes, sendo, 290 masculinos e 289 femininas repartidas, aproximadamente, em 74 agregados e abarcando parte de três concelhos: Santa Catarina, Tarrafal e São Miguel, sendo este último de maior abrangência. Trata-se de uma área que apresenta uma enorme biodiversidade, mas também possui um património cultural, material e imaterial, de relevo. É neste tipo de regiões que se coloca a premência e necessidade de uma relação sustentável entre o homem, o ambiente e o património. Além de observar as características patrimoniais da região, importa perceber as dificuldades que se levantam a sua preservação e conservação, pelo que se destacam os fatores ou conjunto de fatores que estão intimamente ligados aos jogos de interesses, vários, e que a preservação e conservação desse património dependem da harmonização da tríade ambiente/natureza, a sociedade e o económico. Finalmente, impõe-se a análise das questões relativas à valorização do Parque, a sua preservação e conservação numa perspetiva de integração ambiental, social e económico sustentável, estribadas num conjunto de estratégias e que poderão ajudar a gerir conflitos, garantindo, também, a valorização de Serra Malagueta enquanto Património.