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The presence of trees along the slope and block fragmentation at impact strongly affect rockfall dynamics, and hazard as a consequence. However, these phenomena are rarely simulated explicitly in rockfall studies. We performed rockfall simulations by using the 3D rockfall simulator Hy-Stone, modelling both the presence of trees and fragmentation through specific algorithms implemented in the code. By comparing these simulations with a more classical approach that attempt to account implicitly for such phenomena in the model parameters, and by using a new probabilistic rockfall hazard analysis (PRHA) method, we were able to quantify the impact of these phenomena on the design of countermeasures and on hazard. We demonstrate that hazard changes significantly when accounting explicitly for these phenomena, and that a classical implicit approach usually overestimates both the hazard level and the 95th percentile of kinetic energy, leading to an oversizing of mitigation measures.

Supplementary Figure 3 from Phospholipase Cγ1 Is Required for Metastasis Development and Progression

Supplementary Figure 1 from Phospholipase Cγ1 Is Required for Metastasis Development and Progression

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Italy is strongly exposed to geological hazards that affect the entire national territory causing casualties and damage to buildings and infrastructures. In this contest, the planning, maintenance and management of the electric system are strongly impacted by natural hazards. This study shows a national-scale classification of the areas exposed to natural hazards as a tool for risk management related to the power network.The spatial distribution of the national electric grid elements (e.g. transmission lines, tower, and substations) was obtained by merging several regional and national databases, also accounting for the inaccuracy of the localization of the components (using positional mismatch method on regional milestones) and the voltage of each line. The vector database consists of about 72,000 kilometres of lines, 320,000 towers, and 4000 substations. The structures were overlaid with different datasets of natural hazard at national scale, including: alluvial hazard zones, landslide inventory, landslide hazard zonation, seismic hazard, earthquake-induced liquefaction hazard and avalanche map. In addition, the potential for earthquake induced landslides was obtained by combining landslide inventory and PGA (Peak Ground Acceleration) and the seismic hazard was improved by calculating the horizontal seismic coefficients for pseudostatic slope analysis, based on the national map of Vs30.Through the combination of alluvial, landslide, seismic, avalanche and liquefaction hazards a heuristic multi-hazard index (MHI) approach was developed. In order to assess the weights of the different natural hazards, a multi-criteria Analytical Hierarchy Process approach was adopted, which allows a panel of experts to analyse the degree of influence of each natural hazard by pairwise comparisons. Landslides and earthquakes resulted to be the most important natural hazards, together with liquefaction (for transmission towers) and floods (for substations). The final MHI allows to highlight the most hazardous areas in Italy, especially concentrated in the NE of the Italian Alps (Friuli Venezia Giulia Region) and along the Central and Southern Appenine range.

The aim of this paper is to achieve a quantitative assessment of rockfall protection forest efficiency at regional scale, considering site specific forest, morphological and lithological parameters. At first, a semi-automatic GIS-based method, integrated with a multi-scenario 3D-rockfall model realized by using the simulation code HY-STONE, was used to map protection forests of Regione Lombardia (central Italian Alps). For each different forest type, a rockfall protective efficiency was assessed by using empirical (energy line angle) and modelling (HY-STONE) approaches. The empirical approach shows an increase of the energy line angle value from about 36° for the bare slopes to over 40° in forested slopes, with a value ranging from 37° to 44° for different forests types. The modelling approach is based on a new efficiency index EEI ranging from 0 (minimum efficiency, equal to no forest condition) to 1 (maximum efficiency): the efficiency of different forest types ranges from 0.08 to 0.98 by using average values of the controlling parameters. To modulate the efficiency in each single forest at regional scale, a set of parametric simulations was performed to evaluate the effects of controlling parameters. The parametric simulations show that block volume, slope gradient, DBH (diameter at breast height) and forest density are the most important parameters at controlling the efficiency. These parameters were used within a multiple linear regression function to associate a protection efficiency to each specific protection forest in the regional map. This allows to discriminate quantitatively the individual forests according to their actual efficiency. Most of the protection forest area (46%) shows an efficiency greater than 0.50 and only the 24% of the total covered area shows a value lower than 0.25.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.DesignThree independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models.ResultsPI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.ConclusionLoss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.

Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.5713034. Copyright © 2021 The Authors. Amplification of the proto-oncogene MYCN is a key molecular aberration in high-risk neuroblastoma and predictive of poor outcome in this childhood malignancy. We investigated the role of MYCN in regulating the protein cargo of extracellular vesicles (EVs) secreted by tumour cells that can be internalized by recipient cells with functional consequences. Using a switchable MYCN system coupled to mass spectrometry analysis, we found that MYCN regulates distinct sets of proteins in the EVs secreted by neuroblastoma cells. EVs produced by MYCN-expressing cells or isolated from neuroblastoma patients induced the Warburg effect, proliferation and c-MYC expression in target cells. Mechanistically, we linked the cancer-promoting activity of EVs to the glycolytic kinase pyruvate kinase M2 (PKM2) that was enriched in EVs secreted by MYC-expressing neuroblastoma cells. Importantly, the glycolytic enzymes PKM2 and hexokinase II were detected in the EVs circulating in the bloodstream of neuroblastoma patients, but not in those of non-cancer children. We conclude that MYC-activated cancers might spread oncogenic signals to remote body locations through EVs. Neuroblastoma UK to AS and FAPESP SPRINT Award (50356-4); FAPESP (2014/06863-3, 2018/18257-1, 2018/15549-1, 16/50356-4); CNPq “bolsa de produtividade”; Ricerca Finalizzata GR11-172. https://doi.org/10.6084/m9.figshare.c.5713034

Pancreatic ductal adenoma carcinoma (PDAC) is considered one of the deadliest solid cancers as it is usually diagnosed in advanced stages and has a poor response to treatment. The enormous effort made in the last 2 decades in the oncology field has not led to significant progress in improving early diagnosis or therapy for PDAC. The stroma of PDAC plays an active role in tumour initiation and progression and includes immune cells and stromal cells. We previously reported that Bcl2-associated athanogene (BAG3) secreted by PDAC cells activates tumour-associated macrophages to promote tumour growth. The disruption of this tumour-stroma axis by the anti-BAG3 H2L4 therapeutic antibody is sufficient to delay tumour growth and limit metastatic spreading in different PDAC preclinical models. In the present study, we examined the role of BAG3 to activate human fibroblasts (HF) in releasing cytokines capable of supporting tumour progression. Treatment of fibroblasts with recombinant BAG3 induced important changes in the organisation of the cytoskeleton of these cells and stimulated the production of interleukin-6, monocyte chemoattractant protein-1/C-C motif chemokine ligand 2, and hepatocyte growth factor. Specifically, we observed that BAG3 triggered a depolymerisation of microtubules at the periphery of the cell while they were conserved in the perinuclear area. Conversely, the vimentin-based intermediate filaments increased and spread to the edges of the cells. Finally, the conditioned medium (CM) collected from BAG3-treated HF promoted the survival, proliferation, and migration of the PDAC cells. Blocking of the PDAC-fibroblast axis by the H2L4 therapeutic anti-BAG3 antibody, resulted in inhibition of cytokine release and, consequently, the inhibition of the migratory phenotype conferred by the CM to PDAC cells.

The lectin galactoside-binding soluble 3 binding protein (LGALS3BP) is a secreted, hyperglycosylated protein expressed by the majority of human cells. It was first identified as cancer and metastasis associated protein, while its role in innate immune response upon viral infection remains still to be clarified. Since its discovery dated in early 90 s, a large body of literature has been accumulating highlighting both a prognostic and functional role for LGALS3BP in cancer. Moreover, data from our group and other have strongly suggested that this protein is enriched in cancer-associated extracellular vesicles and may be considered a promising candidate for a targeted therapy in LGALS3BP positive cancers. Here, we extensively reviewed the literature relative to LGALS3BP role in cancer and its potential value as a therapeutic target.

The BAG3- and SIRPα- mediated pathways trigger distinct cellular targets and signaling mechanisms in pancreatic cancer microenvironment. To explore their functional connection, we investigated the effects of their combined blockade on cancer growth in orthotopic allografts of pancreatic cancer mt4–2D cells in immunocompetent mice. The anti-BAG3 + anti-SIRPα mAbs treatment inhibited (p = 0.007) tumor growth by about the 70%; also the number of metastatic lesions was decreased, mostly by the effect of the anti-BAG3 mAb. Fibrosis and the expression of the CAF activation marker α-SMA were reduced by about the 30% in animals treated with anti-BAG3 mAb compared to untreated animals, and appeared unaffected by treatment with the anti-SIRPα mAb alone; however, the addition of anti-SIRPα to anti-BAG3 mAb in the combined treatment resulted in a > 60% (p p p

Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal disease, lacking effective therapeutic approaches. Available therapies only marginally prolong patient survival and are frequently coupled with severe adverse events. It is therefore pivotal to investigate novel and safe pharmacological approaches. We have recently identified the ABC transporter, ABCC3, whose expression is dependent on mutation of TP53, as a novel target in PDAC. ABCC3-mediated regulation of PDAC cell proliferation and tumour growth in vivo was demonstrated and was shown to be conferred by upregulation of STAT3 signalling and regulation of apoptosis. Methods To verify the potential of ABCC3 as a pharmacological target, a small molecule inhibitor of ABCC3, referred to here as MCI-715, was designed. In vitro assays were performed to assess the effects of ABCC3 inhibition on anchorage-dependent and anchorage-independent PDAC cell growth. The impact of ABCC3 inhibition on specific signalling pathways was verified by Western blotting. The potential of targeting ABCC3 with MCI-715 to counteract PDAC progression was additionally tested in several animal models of PDAC, including xenograft mouse models and transgenic mouse model of PDAC. Results Using both mouse models and human cell lines of PDAC, we show that the pharmacological inhibition of ABCC3 significantly decreased PDAC cell proliferation and clonal expansion in vitro and in vivo, remarkably slowing tumour growth in mice xenografts and patient-derived xenografts and increasing the survival rate in a transgenic mouse model. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in PDAC progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming. Conclusions Our results indicate that ABCC3 inhibition with MCI-715 demonstrated strong antitumor activity and is well tolerated, which leads us to conclude that ABCC3 inhibition is a novel and promising therapeutic strategy for a considerable cohort of patients with pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1308-7) contains supplementary material, which is available to authorized users.

Background The very aggressive nature and low survival rate of pancreatic ductal adenocarcinoma (PDAC) dictates the necessity to find novel efficacious therapies. Recent evidence suggests that phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1) are key effectors of oncogenic KRAS in PDAC. Herein, we report the role and mechanism of action of PDK1, a protein kinase of the AGC family, in PDAC. Methods PDAC cell lines were treated with selective PDK1 inhibitors or transfected with specific PDK1-targeting siRNAs. In vitro and in vivo assays were performed to investigate the functional role of PDK1 in PDAC. Specifically, anchorage-dependent and anchorage-independent growth was assessed in PDAC cells upon inhibition or downregulation of PDK1. Detailed investigation of the effect of PDK1 inhibition/downregulation on specific signalling pathways was also performed by Western blotting analysis. A xenograft tumour mouse model was used to determine the effect of pharmacological inhibition of PDK1 on PDAC cells growth in vivo. Results Treatment with specific inhibitors of PDK1 impaired anchorage-dependent and anchorage-independent growth of pancreatic cancer cell lines, as well as pancreatic tumour growth in a xenograft model. Mechanistically, inhibition or downregulation of PDK1 resulted in reduced activation of the serum/glucocorticoid regulated kinase family member 3 and subsequent reduced phosphorylation of its target N-Myc downstream regulated 1. Additionally, we found that combination of sub-optimal concentrations of inhibitors selective for PDK1 and the class IB PI3K isoform p110γ inhibits pancreatic cancer cell growth and colonies formation more potently than each single treatment. Conclusions Our data indicate that PDK1 is a suitable target for therapeutic intervention in PDAC and support the clinical development of PDK1 inhibitors for PDAC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1191-2) contains supplementary material, which is available to authorized users.

MicroRNAs (miRs) are important posttranscriptional regulators of gene expression. Besides their well-characterized inhibitory effects on mRNA stability and translation, miRs can also activate gene expression. In this study, we identified a novel noncanonical function of miR-574-5p. We found that miR-574-5p acts as an RNA decoy to CUG RNA-binding protein 1 (CUGBP1) and antagonizes its function. MiR-574-5p induces microsomal prostaglandin E synthase-1 (mPGES-1) expression by preventing CUGBP1 binding to its 3'UTR, leading to an enhanced alternative splicing and generation of an mPGES-1 3'UTR isoform, increased mPGES-1 protein expression, PGE

Simple Summary Head and neck cancer (HNC) is a complex and extremely heterogeneous disease that includes a wide variety of cancer subtypes. Despite notable advances in understanding the molecular mechanisms involved in the disease, which allowed the increase of the therapeutic armamentarium, HNC treatment remains very challenging. In fact, to date the average 5-year survival rate for this disease is around 65%; hence, HNC continues to be one of the most aggressive solid tumors. Surgical removal is the first treatment of choice for HCN; however, in addition to this treatment modality, a broad spectrum of new therapies has been developed so far, ranging from multimodal chemotherapy to targeted and immune-therapy, mainly through the use of antibodies. In this work, we systematically reviewed the progress obtained in antibody-drug conjugate (ADC) development for the treatment of HNC. Abstract Background: Antibody-drug conjugates (ADCs) are designed to deliver potent cytotoxic agents into tumor tissues. During the last two decades, a plethora of ADCs have been successfully developed and used for several indications, including hematologic and solid tumors. In this work, we systematically reviewed the progress in ADC development for the treatment of HNC. Methods: This review was registered in PROSPERO database. A comprehensive search was conducted following PRISMA guidelines and using PubMed, Scopus and Web of Science database. Results: In total, 19 studies were included. Due to the significant heterogeneity of the outcome measures, meta-analysis was not performed, and data were summarized in tables. HNC results are poorly represented in the cohorts of completed clinical trials; published data are mostly focused on safety evaluation rather than efficacy of ADCs. Conclusions: Although several novel agents against a wide range of different antigens were investigated, showing promising results at a preclinical level, most of the targets reported in this review are not specific for HNC; hence, the development of ADCs tailored for the HNC phenotype could open up new therapeutic perspectives. Moreover, the results from the present systematic review call attention to how limited is the application of current clinical trials in HNC.

HER-3 is becoming an attractive target for antibody–drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several malignancies, and re-activation of its downstream signaling axis is known to play a critical role in modulating the sensitivity of targeted therapeutics in different tumors. In this study, we generated a novel ADC named EV20/NMS-P945 by coupling the anti-HER-3 antibody EV20 with a duocarmycin-like derivative, the thienoindole (TEI) NMS-P528, a DNA minor groove alkylating agent through a peptidic cleavable linker. This ADC showed target-dependent cytotoxic activity in vitro on several tumor cell lines and therapeutic activity in mouse xenograft tumor models, including those originating from pancreatic, prostatic, head and neck, gastric and ovarian cancer cells and melanoma. Pharmacokinetics and toxicological studies in monkeys demonstrated that this ADC possesses a favorable terminal half-life and stability and it is well tolerated. These data support further EV20/NMS-P945 clinical development as a therapeutic agent against HER-3-expressing malignancies.

Despite their centrality to rockfall risk management, two issues are frequently overlooked: the role of forests in rockfall dynamic and the fragmentation phenomenon. To investigate the importance of these issues we have developed advanced modelling case studies in two representative sites that have been recently affected by rockfall events in the Aosta Valley Region (Western Italian Alps). In the Saint Oyen case study, about 17,500 m3 of rock detached in March 2019 and reached a service road and the sport center in the lower part of the slope, passing through a mature fir forest. The presence of the forest has significantly influenced the rocks distribution along the slope, increasing the lateral dispersion of trajectories and reducing the mobility. For the design of defensive works, 3D rockfall models of three future potential risk scenarios were therefore performed by using the tree-impact algorithm of the code HY-STONE (Frattini et al., 2012). This algorithm provides the location of impacts on trees, the absorbed energy, and the deviation angle. The input parameters (i.e., the value of diameter at breast height and the forest density) were based on direct measurements of the fir forest. Compared with a traditional simulation without the protective role of forests, the results of 3D numerical modelling with tree-impact algorithm show a decrease in the number of blocks impacting the barriers (91%), no variations in the bouncing heights (for 95th percentile), and an increase in the kinetic energies due to a filter effect by the forest (85% for 95th percentile). In the Roisan case study, about 1,050 m3 of rock toppled in October 2019. While the main body of the rockfall stopped in a relatively flat area close to the failure, two blocks were exceptionally able to reach the foot of the slope causing the interruption of a municipal road. An attempt to back-calibrate this event with HY-STONE showed difficulties to describe the behaviour of these isolated blocks with respects to the main landslide body. A possible explanation for this behaviour is that the detached volume fragmented soon after impacting the slope, giving rise to flying fragments with higher mobility. To test this hypothesis we accounted for fragmentation through a specific algorithm of HY-STONE that fragments the falling blocks when their energy overcomes a certain threshold and simulate the behaviour of the resulting fragments. This approach allowed to accurately replicate the rockfall event. We therefore adopted this approach for defensive-works design, simulating all the unstable volumes overhanging the municipal road. Compared with a traditional simulation, the results of 3D numerical modelling with fragmentation algorithm show an increase in the number of blocks impacting the barriers (86%) and in the bouncing heights (96% for 95th percentile), with a decrease of the kinetic energy due to comminution (39% for 95th percentile). These two case studies demonstrate the importance of accounting for the forest or for fragmentation in the design of cost-effective defensive works. Frattini P, Crosta GB, Agliardi F (2012) Rockfall characterization and modeling. Landslides: types, mechanisms and modelling 22:267-281

The risk management of rainfall-induced landslides requires reliable rainfall thresholds to issue early warning alerts. The practical application of these thresholds often leads to misclassifications, either false negative or false positive, which induce costs for the society. Since missed-alarm (false negative) and false-alarm (false positive) cost may be significantly different, it is necessary to find an optimal threshold that accounts for and minimises such costs, tuning the false-alarm and missed-alarm rates. In this paper, we propose a new methodology to develop cost-sensitive rainfall thresholds, and we also analyse several factors that produce uncertainty, such as the accuracy of rainfall intensity values at landslide location, the time of occurrence, the minimum rainfall amount to define the non-triggering event, and the variability of cost scenarios. Starting from a detailed mapping of landslides that occurred during five large-scale rainfall events in the Italian Central Alps, we first developed rainfall threshold curves with a ROC-based approach by using both rain gauge and bias-adjusted weather radar data. Then, based on a reference cost scenario in which we quantified several cost items for both missed alarms and false alarms, we developed cost-sensitive rainfall threshold curves by using cost-curve approach (Drummond and Holte 2000). Finally, we studied the sensitivity of cost items. The study confirms how important is the information regarding rainfall intensity at the landslide site for the development of rainfall thresholds. Although the use of bias-corrected radar strongly improves these values, a large uncertainty related to the exact time of landslide occurrence still remains, negatively affecting the analysis. Accounting for the different missed-alarm and false-alarm misclassification costs is important because different combinations of these costs make an increase or decrease of the rainfall thresholds convenient. In our reference cost scenario, the most convenient threshold is lower than ROC-based thresholds because it seeks to minimise the number of missed alarms, whereas the missed-alarm costs are almost seven times greater than false-alarm costs. However, for different cost scenarios, threshold may vary significantly, as much as half an order of magnitude.

Gastrointestinal tumors, including pancreatic and colorectal cancers, represent one of the greatest public health issues worldwide, leading to a million global deaths. Recent research demonstrated that the human heavy chain ferritin (HFt) can encapsulate different types of drugs in its cavity and can bind to its receptor, CD71, in several solid and hematological tumors, thus highlighting the potential use of ferritin for tumor-targeting therapies. Here, we describe the development and characterization of a novel nanomedicine based on the HFt that is named The-0504. In particular, this novel system is a nano-assembly comprising an engineered version of HFt that entraps about 80 molecules of a potent, wide-spectrum, non-camptothecin topoisomerase I inhibitor (Genz-644282). The-0504 can be produced by a standardized pre-industrial process as a pure and homogeneously formulated product with favourable lyophilization properties. The preliminary anticancer activity was evaluated in cultured cancer cells and in a mouse model of pancreatic cancer. Overall results reported here make The-0504 a candidate for further preclinical development against CD-71 expressing deadly tumors.

Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer., Facultad de Ciencias Médicas, Centro de Investigaciones Inmunológicas Básicas y Aplicadas

In mountainous areas, rockfall phenomena cause damages and safety problems in residential areas and along transportation facilities. Forests that lay upslope the elements at risk can mitigate rockfall hazard by reducing the kinetic energy of blocks and the probability of impact. Nevertheless, the effects of rockfall protection forests is usually quantified only at local scale.In order to assess the forest efficiency for different combinations of forest (tree size, forest density, forest position, forest length), morphological (slope gradient) and lithological (expected block volume) conditions, we performed a large set of parametric simulations by using the HY-STONE rockfall simulator (Crosta et al, 2004) with a tree impact algorithm that allows calculating the probability of impact, the loss of energy and the lateral deviation of the trajectories based on forest density, tree size and block volume. For each simulation, we therefore quantified the forest efficiency by using a new energy-based efficiency index (EEI) that measure the reduction of rockfall kinetic energy along the forest.The results of the parametric simulations show that the block volume, the slope inclination, the tree size, and the forest density are, in decreasing order of relevance, the most sensitive parameters for rockfall efficiency. Due to its importance, the volume of blocks associated to different lithologies found in Central Italian Alps have been analysed through a statistical analysis of talus deposits. This allowed to obtain volume frequency distributions for the different lithologies, and the associated percentiles of expected block volume.Starting from the parametric simulations, we developed a multiple linear regression that allows to predict an EEI index value (efficiency of protection forest) as a function of forest, morphological and lithological parameters. This regression function has been eventually applied to all the protection forest of Central Italian Alps, providing regional scale maps of rockfall-protection forest efficiency for different block volume percentiles. Crosta, G. B., and F. Agliardi. (2004) Parametric evaluation of 3D dispersion of rockfall trajectories.” Natural Hazards and Earth System Science 4.4: 583-598.

The MYC family of transcription factors is a major driver of human cancer and potential therapeutic target. However, no clinically viable drugs have been yet developed that are able to directly tackle MYC oncoproteins. In our laboratory, we are exploring alternative approaches aiming to disturb signalling downstream of MYC. MYCN is frequently activated in neuroblastoma, a paediatric solid malignancy that, in its metastatic form, has a very poor prognosis. An important pathway regulated by MYC is the CKS1/SKP2/p27kip1 axis. In this study, we have repurposed the anti-psychotic drug Prozac to disrupt CKS1/SKP2/p27Kip1 signalling and assess its potential as an anti-neuroblastoma agent in vitro and in vivo. Using DNA editing technology, we show that stabilisation of p27Kip1 operated by Prozac in MYC-activated cells is essential for the anti-neuroblastoma activity of the drug. Furthermore, dosing mice with a concentration of Prozac equivalent to that used in long-term clinical trials in children with psychiatric disorders caused a significant reduction of metastatic disease in two models of high-risk neuroblastoma. The favourable toxicity profile of Prozac suggests that long-term treatments might be implemented in children with MYC/CKS1high neuroblastomas.

Liver cancer (LC) is an aggressive disease with a markedly poor prognosis. Therapeutic options are limited, and, until recently the only FDA‑approved agent for first‑line treatment of patients with LC was the multi‑kinase inhibitor sorafenib, which exhibits limited activity and an increased overall survival (OS) of only 3 months over placebo. Therefore, the development of alternative therapeutic molecules for the treatment of LC is an urgent medical need. Antibody‑drug conjugates (ADCs) are an emerging class of novel anticancer agents, which have been developed recently for the treatment of malignant conditions, including LC, and are being studied in preclinical and clinical settings. Our group has recently generated an ADC [EV20/monomethyl auristatin F (MMAF)] by coupling the HER3 targeting antibody (EV20) to MMAF via a non‑cleavable maleimidocaproyl linker. This ADC was revealed to possess potent therapeutic activity in melanoma and breast carcinoma. In the present study, using western blot and flow cytometric analysis, it was reported that HER‑3 receptor was highly expressed in LC and activated by its ligand NRG‑1β in a panel of LC cell lines, thus indicating that this receptor may serve as a suitable target for ADC therapy. A novel ADC [EV20‑sss‑valine‑citrulline (vc)/MMAF] was generated, in which the cytotoxic payload MMAF was site‑specifically coupled to an engineered variant of EV20 via a vc cleavable linker. Cytotoxicity assays were performed to investigate in vitro antitumor activity of EV20‑sss‑vc/MMAF and it was compared to EV20/MMAF, which revealed only modest activity in LC.EV20‑sss‑vc/MMAF exhibited a significant cell killing activity in several LC cell lines. Additionally, in vivo xenograft experiments revealed that EV20‑sss‑vc/MMAF inhibited growth of LC tumors. The present data indicated that EV20‑sss‑vc/MMAF is a worthy candidate for the treatment of HER‑3 positive LC.