From central Atlantic continental rift to Neogene uplift - western Anti-Atlas (Morocco)

P>To put constraints on the Mesozoic to recent growth of the Anti-Atlas system, we investigated the temperature-time history of rocks by applying extensive low-temperature thermochronological analysis to three Precambrian inliers along the coast and 250 km into the interior. Bedrocks yield old U-Th/He ages on zircon (248-193 Ma) and apatite (150-50 Ma) and also fission-track ages of 173-121 Ma on apatite. These datasets are interpreted as recording passive margin upward movements from central Atlantic rifting until the Early Cretaceous. A phase of sedimentary burial was evidenced for the Cretaceous-Eocene. The extension of this thin (1.5 km) basin is loosely constrained but can be extended to the western regions of northern Africa. Effects of the existing thermal perturbation of lithospheric origin 100 km below the Atlas show that the 120-60 degrees C isotherms are not much deflected. Large-scale uplift has possibly occurred in the western Anti-Atlas since c. 30 Ma and is associated with a mean denudation rate of 0.08 km Ma-1.

Comparison of copper-67- and iodine-125-labeled anti-CEA monoclonal antibody biodistribution in patients with colorectal tumors.

Copper-67 has comparable beta-particle emissions to that of 131I, but it displays more favorable gamma emission characteristics for application in radioimmunotherapy (RIT). This study investigates the potential of 67Cu-labeled monoclonal antibody (MAb) 35 for RIT of colorectal carcinoma. METHODS: Biokinetics of simultaneously injected 67Cu- and 125I-labeled MAb35 were studied in six patients scheduled for surgery of primary colorectal cancer. RESULTS: Whole-body clearance (T 1/2) of 67Cu, estimated from sequential anterior and posterior whole-body scans and corrected for decay of 67Cu, was 41 hr. Serum clearance of 67Cu was faster (27.41 hr) than that of 125I (38.33 hr). Mean tumor uptake of the 67Cu-labeled compound (0.0133% ID/g) exceeded that of 125I (0.0095% ID/g), and tumor-to-blood ratios were higher for 67Cu than for 125I, with averages of 6.07 and 2.41, respectively. The average 67Cu/125I ratio was 1.9 for tumor uptake, 0.7 for blood and 2.6 for tumor-to-blood ratios. Nonspecific liver uptake of 67Cu as calculated from whole-body scans was high in four patients, up to 25% of residual whole-body activity at 48 hr, but did not increase with time. We also observed some nonspecific bowel activity, as well as moderate to high uptake in benign polyps. CONCLUSION: Copper-67-labeled MAb35 is more favorable than its radioiodine-labeled counterpart for RIT of colorectal carcinoma due to higher tumor-to-blood ratios, but the problem of nonspecific liver and bowel uptake must first be overcome. The absolute accumulation of activity in tumor remains low, however, so the probability of cure with this compound alone is questionable. The use of 67Cu as one component of a multimodality adjuvant treatment seems to remain the most appropriate application for RIT.

Les stratégies politiques et foncières des grands propriétaires fonciers en action : études de cas

Ce cahier présente une analyse comparée de quatre études de cas menées au sein du projet consacré aux stratégies politiques et foncières des grands propriétaires fonciers suisses à l'IDHEAP en 2007-2008. Ces études de cas concernent le complexe immobilier de « La Maladière » à Neuchâtel, le pôle de développement économique du Wankdorf à Berne, le « Centre Boujean » à Bienne ainsi que la place d'armes de Thoune. De chacun de ces cas sont présentés la chronologie des événements, les étapes et régimes du projet, les configurations et stratégies des acteurs, les impacts sur la durabilité ainsi qu'une discussion des résultats à la lumière des hypothèses du projet. L'analyse comparée fait le point des configurations et stratégies des acteurs qui sont ensuite mises en relation avec les régimes institutionnels et la durabilité des usages du sol. L'un des messages principaux est que, aujourd'hui, on ne peut plus séparer l'aménagement du territoire du foncier si l'on veut atteindre les objectifs politiques du développement du territoire. Die vorliegende Publikation enthält eine vergleichende Analyse von vier Fallstudien, die im Rahmen des Projektes zu den Strategien der grossen Grundeigentümer der Schweiz im Bereich der Ausübung ihrer Eigentumsrechte und ihrer Interventionen auf der Ebene der Raumplanung durchgeführt wurden. Sie betreffen den Immobilienkomplex ,,La Maladière" in Neuenburg, den Entwicklungsschwerpunkt Wankdorf in Bern, das ,,Centre Boujean" in Biel und den Waffenplatz Thun. Die Zusammenfassungen der Fallstudien enthalten Angaben zur Chronologie der Ereignisse, zu den verschiedenen Etappen der Projektentwicklung und der entsprechenden Regime, zu den Akteurkonfigurationen und -strategien, zu den Auswirkungen der Projekte auf die nachhaltige Entwicklung sowie eine Diskussion der empirischen Befunde im Lichte der Projekthypothesen. Die vergleichende Analyse nimmt eine Typologie der Akteurkonfigurationen vor und diskutiert deren Folgen für die institutionellen Regime und für die nachhaltige Entwicklung der Ressource Boden. Eines der Hauptergebnisse liegt in der Feststellung, dass sich heute Raumplanung mehr den je mit den Bodeneigentumsverhältnissen befassen muss, um die beabsichtigten politischen Entwicklungsziele zu erreichen.

Methods for detection and confirmation of Hematide?/peginesatide in anti-doping samples.

Since the 1990's, cheating athletes have abused substances to increase their oxygen transport capabilities; among these substances, recombinant EPO is the most well known. Currently, other investigational pharmaceutical products are able to produce an effect similar to EPO but without having chemical structures related to EPO; these are the synthetic erythropoiesis stimulating agents (ESAs). Peginesatide (also known as Hematide?) is being developed by Affymax and Takeda and, if approved by regulatory authorities, could soon be released on the international market. To detect potential athletic abuse of this product and deter athletes who consider cheating, we initiated a collaboration to implement a detection test for anti-doping purposes. Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. It is undetectable using current anti-doping tests due to its lack of sequence homology to EPO. To detect and deter potential abuse of peginesatide, we initiated an industry/antidoping laboratory collaboration to develop and validate screening and confirmation assays so that they would be available before peginesatide reaches the market. We describe a screening ELISA and a confirmation assay consisting of immune-purification followed by separation with SDS-PAGE and revelation with Western double blotting. Both assays can detect 0.5 ng/mL concentrations of peginesatide in blood samples, enabling detection for several days after administration of a physiologically relevant dose. This initial report describes experimental characterization of these assays, including testing with a blinded set of samples from a clinical study conducted in healthy volunteers.

Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4.

PURPOSE: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. EXPERIMENTAL DESIGN: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. RESULTS: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells. CONCLUSIONS: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.

Caspase-induced inactivation of the anti-apoptotic TRAF1 during Fas ligand-mediated apoptosis.

The activation of the transcription factor NF-kappaB often results in protection against apoptosis. In particular, pro-apoptotic tumor necrosis factor (TNF) signals are blocked by proteins that are induced by NF-kappaB such as TNFR-associated factor 1 (TRAF1). Here we show that TRAF1 is cleaved after Asp-163 when cells are induced to undergo apoptosis by Fas ligand (FasL). The C-terminal cleavage product blocks the induction of NF-kappaB by TNF and therefore functions as a dominant negative (DN) form of TRAF1. Our results suggest that the generation of DN-TRAF1 is part of a pro-apoptotic amplification system to assure rapid cell death.

Imaging of inflammatory and infectious lesions after injection of radioiodinated monoclonal anti-granulocytes antibodies.

Successful detection of inflammatory lesions by planar scintigraphy and SPECT after injection of iodine-123 labelled monoclonal antibodies directed against human granulocytes (123I-Mabgc) is demonstrated. This new tracer has been compared with indium-111 labelled white blood cells (111In-WBC) in selected patients with proven infectious lesions. Scans were equally positive in all cases, but the methodical advantages of the new marker were obvious, namely, there is no need for cell separation and the images of inflammatory lesions were better defined. In addition, SPECT could be performed with 123I-Mabgc and allowed a better anatomic localization and a three-dimensional description of the lesions. No adverse reactions have been seen. It is concluded, therefore, that 123I-Mabgc is a promising agent for the detection of acute focal inflammatory lesions which may, with advantages, replace 111In-WBC.

Anti-leishmania effector functions of CD4+ Th1 cells and early events instructing Th2 cell development and susceptibility to Leishmania major in BALB/c mice.

Resistance and susceptibility to infection with the intracellular parasite, Leishmania major, are mediated by parasite-specific CD4+ Th1 and Th2 cells, respectively. It is well established that the protective effect of parasite-specific CD4+ Th1 cells is largely dependent upon the IFN-gamma produced. However, recent results indicate that the effect of Th1 cells on resolution of lesions induced by L. major in genetically resistant mice also requires a functional Fas-FasL pathway of cytotoxicity. In contrast to resistant mice, susceptible BALB/c mice develop aberrant Th2 responses following infection with L. major and consequently suffer progressive disease. These outcomes clearly depends upon the production of interleukin 4 (IL-4) early after infection. We have shown that a burst of IL-4 mRNA, peaking in draining lymph nodes of BALB/c mice 16 hrs after infection, occurs within CD4+ T cells that express V beta 4-V alpha 8 T cell receptors. In contrast to control and V beta 6-deficient mice, V beta 4-deficient BALB/c mice were resistant to infection, demonstrating the role of these cells in Th2 development. The early IL-4 response was absent in these mice, and Th1 responses occurred following infection. The LACK antigen of L. major induced comparable IL-4 production in V beta 4-V alpha 8 CD4+ T cells. Thus, the IL-4 required for Th2 development and susceptibility to L. major is produced by a restricted population of V beta 4-V alpha 8 CD4+ T cells after cognate interaction with a single antigen from this complex parasite. The IL-4 produced rapidly by these CD4+ T cells induces within 48 hours a state of unresponsiveness to IL-12 among parasite-specific CD4+ T cell precursors by downregulating the IL-12 receptor beta 2 chain expression.