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Melka Kunture est un complexe de sites paléolithiques qui s’étend sur une centaine de km2 dans la vallée supérieure de l’Awash (Éthiopie), entre 2000 et 2200 m d’altitude. Á partir d’il y a 2 millions d’années, il y a de nombreux sites avec productions lithiques de l’Oldowayen, de l’Acheuléen inférieur (Early Acheu lean), de l’Acheuléen moyen et de l’Acheuléen final, et enfin du Middle Stone Age initial (Early Middle Stone Age) et du Middle Stone Age, suivis par le Late Stone Age. Le climat, frais et pluvieux a permis le développement d’une riche végétation de type afromontagnard. Les restes d’hippopotames sont omniprésents et dominent en termes de biomasse, mais les Alcelaphini sont bien représentés, notamment avec les genres Connochaetes et Damaliscus. Des restes fossiles d’homininés ont été découverts en association directe avec l’Oldowayen, l’Acheuléen inférieur, l’Acheuléen moyen et le Middle Stone Age initial. Des empreintes d’animaux et d’homininé s ont également été trouvés, ces dernières dans des niveaux datés entre 1,2 et 0,7 millions d’années.

Background: As the general population ages, the rising prevalence of vascular lesions of the spinal cord will become significant. Purpose: The aim of this study was to compare the neurological and functional outcomes of patients with ischemic spinal cord injury (ISCI) and traumatic spinal cord injury (TSCI). Methods: We conducted a retrospective study in a spinal cord unit of 2 rehabilitation hospitals. We studied 168 patients with a TSCI and 72 with an ISCI. At admission and discharge, patients were evaluated by American Spinal Injury Association Impairment Scale (AIS) standards and Spinal Cord Independence Measure (SCIM). Length of stay, occurrence of complications, and discharge dispositions were also recorded. Linear and logistic regression models were used to analyze the effects of the etiology of the lesion, AIS level at admission, and level of the lesion. Results: Patients with an ISCI were older and experienced fewer cervical lesions and fewer complete lesions than patients with TSCI. By linear and logistic regression, etiology was a predictor (together with lesion features) of functional (SCIM improvement and SCIM at discharge) outcome, with traumatic patients having better outcome than ischemic ones. Age, AIS level, and lesion level were the chief predictors of length of stay, occurrence of complications, and discharge dispositions. Conclusions: A diagnosis of ischemia and trauma could be a determinant of functional recovery in SCI patients.

The early gene early growth response (Egr-1), a broadly expressed member of the zing-finger family of transcription factors, is induced in many cell types by a variety of growth and differentiation stimuli, including epidermal growth factor (EGF). Here we demonstrate that Egr-1 expression is mainly regulated by integrin-mediated adhesion. Integrin-dependent adhesion plays a dual role in Egr-1 regulation, either being sufficient "per se" to induce Egr-1, or required for EGF-dependent expression of Egr-1, which occurs only in adherent cells and not in cells in suspension. To dissect the molecular basis of integrin-dependent Egr-1 regulation, we show by FLIM-based FRET that in living cells beta1-integrin associates with the EGF receptor (EGFR) and that EGF further increases the extent complex formation. Interestingly, Egr-1 induction depends on integrin-dependent PI3K/Akt activation, as indicated by the decrease in Egr-1 levels in presence of the pharmacological inhibitor LY294002, the kinase-defective Akt mutant and Akt1/2 shRNAs. Indeed, upon adhesion activated Akt translocates into the nucleus and phosphorylates FoxO1, a Forkhead transcription factors. Consistently, FoxO1silencing results in Egr-1-increased levels, indicating that FoxO1 behaves as a negative regulator of Egr-1 expression. These data demonstrate that integrin/EGFR cross-talk is required for expression of Egr-1 through a novel regulatory cascade involving the activation of the PI3K/Akt/Forkhead pathway.

Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERβ staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ERα. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERβ expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17β-estradiol led to an ERβ-mediated inhibition of malignant mesothelioma cell proliferation as well as p21CIP1 and p27KIP1 up-regulation. Consistently cell growth was suppressed by ERβ overexpression, causing a G2-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERβ acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients. [Cancer Res 2009;69(11):4598–604]

The activity of 8-prenylapigenin (8-PA) and its 3'-methoxylated analogue isocannflavin B (IsoB) was investigated in estrogen-dependent T47-D and estrogen-independent MDA-MB-231 human breast cancer cell lines. 8-PA showed a biphasic effect on T47-D cell proliferation, while no significant effect was observed on MDA-MB-231 cells. Conversely, IsoB exhibited only an inhibitory effect on T47-D cell proliferation, accompanied by the appearance of an intense intracytoplasmic vacuolization of autophagic origin. Moreover, biochemical analysis showed that IsoB reduced Akt phosphorylation and p21(Cip1) expression in T47-D cells. These data show that the prenylflavone moiety is a versatile platform for the induction and modulation of bioactivity.

8-Prenylnaringenin (8PN), one of the strongest plant-derived oestrogen receptors (ERs) ligand, has been suggested to have potential cancer chemo-preventive activities and anti-angiogenic properties. Because published data suggest that ERs serve as nodal point that allows interactions between hormones and growth factors mediated pathways, we decided to investigate the effects exerted by 8PN on Epidermal growth factor (EGF)-elicited pathways in breast cancer cells. Here we show that in ER positive MCF-7 cells, 8PN interferes with EGF induced cell proliferation by strongly inhibiting activation of PI(3)K/Akt pathway, without affecting EGFR expression or tyrosine phosphorylation, and exerting a synergistic activation of Erk1/2 phosphorylation. Moreover, we demonstrate that 8PN is a direct inhibitor of PI(3)K activity as it is shown by in vitro experiments with the purified enzyme and by its inability to impair serine phosphorylation of a constitutive active form of Akt. These findings suggest that inhibition of PI(3)K is a novel mechanism which contributes to 8PN activity to inhibit cancer cell survival and EGF induced proliferation.

The estrogen receptors, responsible for the effects of this hormone, are known to be able to recognize nonsteroidogenic molecules, and this has led to the development of molecules with therapeutic potential. The phenomenon of nonsteroidal ligands of the estrogen receptors is also thought to play a major role in food and environmental sciences, with the winepolyphenol resveratrol and the insecticide DDT thought to act as estrogenic substances. It is therefore evident that it is of great interest to develop specific nonsteroidal substances that interfere with the estrogen receptors in a receptor-specific and/or tissue-specific manner and that display agonistic, antagonistic, or partial agonistic properties. Indeed, a number of strategies have been or could be employed to generate new structures, namely the screening of existing chemical libraries, the screening of natural compound libraries, novel modifications of known compounds with estrogenic potential, or the de novo generation of chemical libraries using rapid synthetic methods. Click chemistry is an increasingly common method for rapid synthesis of novel biologically active compounds. This term, coined by Barry K. Sharpless, now refers to reactions yielding the product in high yield without the need for further purification, without generating offensive byproducts, and operating in a benign solvent, usually water. In this way, it is possible to generate a plethora of new compounds reliably and thereby accelerate the process of drug discovery. Briefly, the paradigmatic “click” reaction is the [3+2] cycloaddition between an azide and an alkyne in the presence of copper (I) salts which generate the 1,4 disubstituted 1H-1,2,3-triazole ring in excellent yield. Three distinct observations have drawn our attention to the possibility of applying click chemistry to the synthesis of ER ligands: 1) reports that a pyrazole core can be used to build compounds that are ER ligands, 2) the successful bioisosteric replacement of pyrazole with a triazole in fibronil, an insecticide acting as a GABA receptor antagonist, and 3) our report that several resveratrol analogues synthesized by click chemistry retain estrogen-like activity. We have therefore used the archetypical [3+2] azide-alkyne cycloaddition to link two phenol rings, bearing the hydroxyl moieties in different positions, with a distance comparable to estradiol or diethylstilbestrol. Azides (1–3, Figure 1) were obtained by reacting commercially available amine phenols, via diazonium salt, with sodium azide. The desired ethynyl phenols (4–6, Figure 1) were ob

The discovery that the hop constituent 8-prenylnaringenin (8PN) shows potent estrogenic activity, higher than that of the known phytoestrogens coumestrol, genistein and daidzein, has spurred an intense activity aimed at elucidating its biological profile and its dietary relevance connected with the consumption of beer. We have investigated if 8PN can induce signal transduction pathways via rapid estrogen receptor (ER) activation. Under conditions of estrogen-dependent growth, treatment of MCF-7 human breast cancer cells with 8PN induced a rapid and transient activation of the MAP kinase Erk-1 and Erk-2, with kinetics similar to those induced by 17beta-estradiol (E2). 8PN could trigger the MAP kinase pathway via dual c-Src kinase activation and association with ERalpha. Co-treatment with the ER antagonist ICI 182,780 blocked each step of this transduction pathway, confirming its ER dependence. However, and in striking contrast with E2, 8PN could not induce the PI3K/Akt pathway, resulting in altered kinetics and levels of cyclin D1 expression. In accordance with these observations, flow cytometric and biochemical analysis showed that 8PN inhibited cell cycle progression and induced apoptosis in MCF-7 cells. Interference with an ER associated PI3K pathway is proposed as a possible mechanism underlying the inhibition of survival and proliferation of estrogen responsive cells by 8PN. Taken together, our finding show that 8PN is an interesting new chemotype to explore the biology of ERs.