Magma injections and destabilization of basaltic volcanoes: a numerical study. Application to La Reunion (Indian ocean, France) and Stromboli (Tyrrhenian sea, Italy)

Most basaltic volcanoes are affected by recurrent lateral instabilities during their evolution. Numerous factors have been shown to be involved in the process of flank destabilization occurring over long periods of time or by instantaneous failures. However, the role of these factors on the mechanical behaviour and stability of volcanic edifices is poorly-constrained as lateral failure usually results from the combined effects of several parameters. Our study focuses on the morphological and structural comparison of two end-member basaltic systems, La Reunion (Indian ocean, France) and Stromboli (southern Tyrrhenian sea, Italy). We showed that despite major differences on their volumes and geodynamic settings, both systems present some similarities as they are characterized by an intense intrusive activity along well-developed rift zones and recurrent phenomena of flank collapse during their evolution. Among the factors of instability, the examples of la Reunion and Stromboli evidence the major contribution of intrusive complexes to volcano growth and destruction as attested by field observations and the monitoring of these active volcanoes. Classical models consider the relationship between vertical intrusions of magma and flank movements along a preexisting sliding surface. A set of published and new field data from Piton des Neiges volcano (La Reunion) allowed us to recognize the role of subhorizontal intrusions in the process of flank instability and to characterize the geometry of both subvertical and subhorizontal intrusions within basaltic edifices. This study compares the results of numerical modelling of the displacements associated with high-angle and low-angle intrusions within basaltic volcanoes. We use a Mixed Boundary Element Method to investigate the mechanical response of an edifice to the injection of magmatic intrusions in different stress fields. Our results indicate that the anisotropy of the stress field favours the slip along the intrusions due to cointrusive shear stress, generating flank-scale displacements of the edifice, especially in the case of subhorizontal intrusions, capable of triggering large-scale flank collapses on basaltic volcanoes. Applications of our theoretical results to real cases of flank displacements on basaltic volcanoes (such as the 2007 eruptive crisis at La Reunion and Stromboli) revealed that the previous model of subvertical intrusions-related collapse is a likely mechanism affecting small-scale steeply-sloping basaltic volcanoes like Stromboli. Furthermore, our field study combined to modelling results confirms the importance of shallow-dipping intrusions in the morpho-structural evolution of large gently-sloping basaltic volcanoes like Piton de la Fournaise, Etna and Kilauea, with particular regards to flank instability, which can cause catastrophic tsunamis.

Sonic Hedgehog pathway impairment in Neural Precursor Cells of the Ts65Dn mouse, an animal model of Down syndrome

Mental retardation in Down syndrome (DS) has been imputed to the decreased brain volume, which is evident starting from the early phases of development. Recent studies in a widely used mouse model of DS, the Ts65Dn mouse, have shown that neurogenesis is severely impaired during the early phases of brain development, suggesting that this defect may be a major determinant of brain hypotrophy and mental retardation in individuals with DS. Recently, it has been found that in the cerebellum of Ts65Dn mice there is a defective responsiveness to Sonic Hedgehog (Shh), a potent mitogen that controls cell division during brain development, suggesting that failure of Shh signaling may underlie the reduced proliferation potency in DS. Based on these premises, we sought to identify the molecular mechanisms underlying derangement of the Shh pathway in neural precursor cells (NPCs) from Ts65Dn mice. We found that the expression levels of the Shh receptor Patched1 (Ptch1) were increased compared to controls both at the RNA and protein level. Partial silencing of Ptch1 expression in trisomic NPCs restored cell proliferation, indicating that proliferation impairment was due to Ptch1 overexpression. We further found that the overexpression of Ptch1 in trisomic NPCs is related to increased levels of AICD, a transcription-promoting fragment of amyloid precursor protein (APP). Increased AICD binding to the Ptch1 promoter favored its acetylated status, thus enhancing Ptch1 expression. Taken together, these data provide novel evidence that Ptch1 over expression underlies derangement of the Shh pathway in trisomic NPCs, with consequent proliferation impairment. The demonstration that Ptch1 over expression in trisomic NPCs is due to an APP fragment provides a link between this trisomic gene and the defective neuronal production that characterizes the DS brain.

SMO inhibitor specifically targets the Hedgehog Pathway and reverts the drug-resistance of Leukemic Stem Cells

Abnormal Hedgehog signaling is associated with human malignancies. Smo, a key player of that signaling, is the most suitable target to inhibit this pathway. To this aim several molecules, antagonists of Smo, have been synthesized, and some of them have started the phase I in clinical trials. Our hospital participated to one of these studies which investigated the oral administration of a new selective inhibitor of Smo (SMOi). To evaluate ex vivo SMOi efficacy and to identify new potential clinical biomarkers of responsiveness, we separated bone marrow CD34+ cells from 5 acute myeloid leukemia (AML), 1 myelofibrosis (MF), 2 blastic phases chronic myeloid leukemia (CML) patients treated with SMOi by immunomagnetic separation, and we analysed their gene expression profile using Affimetrix HG-U133 Plus 2.0 platform. This analysis, showed differential expression after 28 days start of therapy (p-value ≤ 0.05) of 1,197 genes in CML patients and 589 genes in AML patients. This differential expression is related to Hedgehog pathway with a p-value = 0.003 in CML patients and with a p-value = 0.0002 in AML patients, suggesting that SMOi targets specifically this pathway. Among the genes differentially expressed we observed strong up-regulation of Gas1 and Kif27 genes, which may work as biomarkers of responsiveness of SMOi treatment in CML CD34+ cells whereas Hedgehog target genes (such as Smo, Gli1, Gli2, Gli3), Bcl2 and Abca2 were down-regulated, in both AML and CML CD34+ cells. It has been reported that Bcl-2 expression could be correlated with cancer therapy resistance and that Hedgehog signaling modulate ATP-binding (ABC) cassette transporters, whose expression has been correlated with chemoresistance. Moreover we confirmed that in vitro SMOi treatment targets Hedgehog pathway, down-regulate ABC transporters, Abcg2 and Abcb1 genes, and in combination with tyrosine kinase inhibitors (TKIs) could revert the chemoresistance mechanism in K562 TKIs-resistant cell line.