Cristina Proietti

A quantitative approach for evaluating lava flow simulation reliability: LavaSIM code applied to the 2001 Etna eruption

An edited version of this paper was published by AGU. Copyright (2009) American Geophysical Union.

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis.

Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1

ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.

2002–2003 Lava Flow Eruption of Stromboli: A Contribution to Understanding Lava Discharge Mechanisms Using Periodic Digital Photogrammetry Surveys

Photogrammetric surveys were performed between 5 January and 26 July 2003 for monitoring the NW flank of the Sciara del Fuoco (SdF) during the eruption of Stromboli that started on 28 December 2002. The collected data were used both for controlling morphological changes after the major landslide that occurred on 30 December 2002 and lava flow field evolution until the end of the eruption (22 July 2003). The latter objective was achieved by a quantitative analysis which allowed to estimate the total lava volume (12.51 × 10 6 m 3 ) emplaced on the SdF slope corresponding to an eruption rate of about 0.69 m 3 /s. Thanks to the availability of multitemporal data set, which made this event the first well-documented and regularly surveyed Stromboli eruption, the cumulative volume and effusion rate trends were derived. A model for interpreting the behavior of the 2002―2003 Stromboli effusive eruption is also proposed: being the vents located very close to the volcano summit, a typical summit (terminal) basaltic lava flow eruption was expected; on the contrary, the observed effusion rate trend showed an initial peak followed by an exponential decline typical of flank (lateral) eruptions of basaltic volcanoes. We recognized in this trend a transition from a terminal (open conduit system) to a lateral (pressurized dike system) lava discharge followed by a longer period in which the elastic strain energy from the subvolcanic reservoir controlled the effusion rate; this effect counterbalanced the lava cooling at dike tip that tends to close the eruptive fissure causing the eruption end.

Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance.

Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.

Monitoring Active Volcanos Using Aerial Images and the Orthoview Tool

In volcanic areas, where it can be difficult to perform direct surveys, digital photogrammetry techniques are rarely adopted for routine volcano monitoring. Nevertheless, they have remarkable potentialities for observing active volcanic features (e.g., fissures, lava flows) and the connected deformation processes. The ability to obtain accurate quantitative data of definite accuracy in short time spans makes digital photogrammetry a suitable method for controlling the evolution of rapidly changing large-area volcanic phenomena. The systematic acquisition of airborne photogrammetric datasets can be adopted for implementing a more effective procedure aimed at long-term volcano monitoring and hazard assessment. In addition, during the volcanic crisis, the frequent acquisition of oblique digital images from helicopter allows for quasi-real-time monitoring to support mitigation actions by civil protection. These images are commonly used to update existing maps through a photo-interpretation approach that provide data of unknown accuracy. This work presents a scientific tool (Orthoview) that implements a straightforward photogrammetric approach to generate digital orthophotos from single-view oblique images provided that at least four Ground Control Points (GCP) and current Digital Elevation Models (DEM) are available. The influence of the view geometry, of sparse and not-signalized GCP and DEM inaccuracies is analyzed for evaluating the performance of the developed tool in comparison with other remote sensing techniques. Results obtained with datasets from Etna and Stromboli volcanoes demonstrate that 2D features measured on the produced orthophotos can reach sub-meter-level accuracy.

The Use of Surveillance Cameras for the Rapid Mapping of Lava Flows: An Application to Mount Etna Volcano

In order to improve the observation capability in one of the most active volcanic areas in the world, Mt. Etna, we developed a processing method to use the surveillance cameras for a quasi real-time mapping of syn-eruptive processes. Following an evaluation of the current performance of the Etna permanent ground NEtwork of Thermal and Visible Sensors (Etna_NETVIS), its possible implementation and optimization was investigated to determine the locations of additional observation sites to be rapidly set up during emergencies. A tool was then devised to process time series of ground-acquired images and extract a coherent multi-temporal dataset of georeferenced map. The processed datasets can be used to extract 2D features such as evolution maps of active lava flows. The tool was validated on ad-hoc test fields and then adopted to map the evolution of two recent lava flows. The achievable accuracy (about three times the original pixel size) and the short processing time makes the tool suitable for rapidly assessing lava flow evolutions, especially in the case of recurrent eruptions, such as those of the 2011–2015 Etna activity. The tool can be used both in standard monitoring activities and during emergency phases (eventually improving the present network with additional mobile stations) when it is mandatory to carry out a quasi-real-time mapping to support civil protection actions. The developed tool could be integrated in the control room of the Osservatorio Etneo, thus enabling the Etna_NETVIS for mapping purposes and not only for video surveillance.

Monitoring an active volcanic area and mapping lava flows with multisource data: The case of Mount Etna from 2011 to 2015

The ground monitoring of an active volcanic area presents many complexities. By exploiting the remote sensing techniques, we developed an analytical methodology for observing and quantifying eruptive processes and the related phenomena (lava flows, volcanic avalanche/landslides, slope stability features). This methodology integrates HR optical images and SAR interferometry, acquired in different time frames and was tested on the case study of Mount Etna. The extraction of new cartographic products allows us to define the volcanic hazards that may impact on the surrounding populated areas and infrastructures.