3D ultra-high resolution seismic imaging of shallow Solfatara crater in Campi Flegrei (Italy): New insights on deep hydrothermal fluid circulation processes.

Seismic tomography can be used to image the spatial variation of rock properties within complex geological media such as volcanoes. Solfatara is a volcano located within the Campi Flegrei, a still active caldera, so it is of major importance to characterize its level of activity and potential danger. In this light, a 3D tomographic high-resolution P-wave velocity image of the shallow central part of Solfatara crater is obtained using first arrival times and a multiscale approach. The retrieved images, integrated with the resistivity section and temperature and the CO2 flux measurements, define the following characteristics: 1. A depth-dependent P-wave velocity layer down to 14 m, with Vp < 700 m/s typical of poorly-consolidated tephra and affected by CO2 degassing; 2. An intermediate layer, deepening towards the mineralized liquid-saturated area (Fangaia), interpreted as permeable deposits saturated with condensed water; 3. A deep, confined high velocity anomaly associated with a CO 2 reservoir. These features are expression of an area located between the Fangaia, water saturated and replenished from deep aquifers, and the main fumaroles, superficial relief of the deep rising CO2 flux. Therefore, the changes in the outgassing rate greatly affect the shallow hydrothermal system, which can be used as a "mirror" of fluid migration processes occurring at depth.

BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity.

Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL.