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Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signaling pathways. Furthermore, CBZ leads to the inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor κB (RANK), due to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment.

The 2011 Tohoku earthquake produced an unexpected large amount of shallow slip greatly contributing to the ensuing tsunami. How frequent are such events? How can they be efficiently modelled for tsunami hazard? Stochastic slip models, which can be computed rapidly, are used to explore the natural slip variability; however, they generally do not deal specifically with shallow slip features. We study the systematic depth-dependence of slip along a thrust fault with a number of 2D dynamic simulations using stochastic shear stress distributions and a geometry based on the cross section of the Tohoku fault. We obtain a probability density for the slip distribution, which varies both with depth, earthquake size and whether the rupture breaks the surface. We propose a method to modify stochastic slip distributions according to this dynamically-derived probability distribution. This method may be efficiently applied to produce large numbers of heterogeneous slip distributions for probabilistic tsunami hazard analysis. Using numerous M9 earthquake scenarios, we demonstrate that incorporating the dynamically-derived probability distribution does enhance the conditional probability of exceedance of maximum estimated tsunami wave heights along the Japanese coast. This technique for integrating dynamic features in stochastic models can be extended to any subduction zone and faulting style.

Assessment of volcanic hazards is necessary for risk mitigation. Typically, hazard assessment is based on one or a few, subjectively chosen representative eruptive scenarios, which use a specific combination of eruptive sizes and intensities to represent a particular size class of eruption. While such eruptive scenarios use a range of representative members to capture a range of eruptive sizes and intensities in order to reflect a wider size class, a scenario approach neglects to account for the intrinsic variability of volcanic eruptions, and implicitly assumes that inter-class size variability (i.e. size difference between different eruptive size classes) dominates over intra-class size variability (i.e. size difference within an eruptive size class), the latter of which is treated as negligible. So far, no quantitative study has been undertaken to verify such an assumption. Here, we adopt a novel Probabilistic Volcanic Hazard Analysis (PVHA) strategy, which accounts for intrinsic eruptive variabilities, to quantify the tephra fallout hazard in the Campania area. We compare the results of the new probabilistic approach with the classical scenario approach. The results allow for determining whether a simplified scenario approach can be considered valid, and for quantifying the bias which arises when full variability is not accounted for. This work was partially supported by the MED-SUV Project funded by the European Union (FP7 Grant Agreement n.308665), the “Futuro in Ricerca 2008 FIRB” ByMuR Project [RBFR0880SR] funded by MIUR (the Italian Ministry of Education, University and Research), and the DPC-INGV V1 (2013–2015) Project, funded by DPC (the Italian Department of Civil Protection) within the agreement between DPC and INGV. Background roadmap, terrain or satellite images in all the pictures were downloaded from Google Maps. The FALL3D simulations have been run at BSC using the MareNostrum supercomputer. We are very grateful to Mary Anne Thompson for providing us with helpful comments. We wish to thank the anonymous reviewers for their suggestions that significantly improved the quality of the manuscript.

In oncologic patients fever is a non-specific clinical marker of different clinical settings. Procalcitonin (PCT) seems to be the most promising infection marker. We aimed to define the potential role of PCT as an earlier diagnostic marker in patients with fever and solid tumor. This retrospective study enrolled 431 patients. All of them performed hemoculture (HE) and basal PCT assessment (reference laboratory cut-off: ≤0.5 or >0.5 ng/dL) before starting antibiotic therapy. Gram positive (G+), negative (G−) or Fungi infection were detected. A statistically significant difference in PCT levels between patients with positive and negative HE was observed (P

We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival.

Scientific Reports 5: Article number: 18670; published online: 22 December 2015; updated: 15 April 2016. The original version of this Article contained errors in the spelling of the authors Daniele Santini, Sandro Barni, Salvatore Intagliata, Alfredo Falcone, Francesco Ferraù, Domenico Galetta, LucaMoscetti, Nicla La Verde, Toni Ibrahim, Fausto Petrelli, Enrico Vasile, Laura Ginocchi, Davide Ottaviani, Flavia Longo, Cinzia Ortega, Antonio Russo, Giuseppe Badalamenti, Elena Collovà, Gaetano Lanzetta, Giovanni Mansueto, Vincenzo Adamo, Filippo De Marinis, Flavia Cantile, Andrea Mancuso, Raffaele Addeo, Marco Russano, Michelle Sterpi, Francesco Pantano, Bruno Vincenzi and Giuseppe Tonini which were incorrectly given as Santini Daniele, Barni Sandro, Intagliata Salvatore, Falcone Alfredo, Ferraù Francesco, Galetta Domenico, Moscetti Luca, La Verde Nicla, Ibrahim Toni, Petrelli Fausto, Vasile Enrico, Ginocchi Laura, Ottaviani Davide, Longo Flavia, Ortega Cinzia, Russo Antonio, Badalamenti Giuseppe, Collovà Elena, Lanzetta Gaetano, Mansueto Giovanni, Adamo Vincenzo, De Marinis Filippo, Cantile Flavia, Mancuso Andrea, Addeo Raffaele, Russano Marco, M Sterpi, Pantano Francesco, Vincenzi Bruno and Tonini Giuseppe respectively.

Cancer-associated gene expression imbalances are conventionally studied at the genomic, epigenomic and transcriptomic levels. Given the relevance of translational control in determining cell phenotypes, we evaluated the translatome, i.e., the transcriptome engaged in translation, as a descriptor of the effects of genetic instability in cancer. We performed this evaluation in high-risk neuroblastomas, which are characterized by a low frequency of point mutations or known cancer-driving genes and by the presence of several segmental chromosomal aberrations that produce gene-copy imbalances that guide aggressiveness. We thus integrated genome, transcriptome, translatome and miRome profiles in a representative panel of high-risk neuroblastoma cell lines. We identified a number of genes whose genomic imbalance was corrected by compensatory adaptations in translational efficiency. The transcriptomic level of these genes was predictive of poor prognosis in more than half of cases and the genomic imbalances found in their loci were shared by 27 other tumor types. This homeostatic process is also not limited to copy number-altered genes, as we showed the translational stoichiometric rebalance of histone genes. We suggest that the translational buffering of fluctuations in these dose-sensitive transcripts is a potential driving process of neuroblastoma evolution.