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The first part of the experiment identifies and validates MRI biomarkers distinctive of the disease progression in the transgenic superoxide dismutase gene (SOD1(G93A)) animal model. The second part assesses the efficacy of a mesenchymal stem cell-based therapy through the MRI biomarkers previously defined.The first part identifies MRI differences between SOD1(G93A) and healthy mice. The second part of the experiment follows the disease evolution of stem cell-treated and non-stem-cell treated SOD1(G93A) mice. The analysis focused on voxel-based morphometry and T2 mapping on the brain tissues, and T2-weighted imaging and diffusion tensor imaging (DTI) on the hind limbs.Comparing diseased mice to healthy control revealed gray matter alterations in the brainstem area, accompanied by increased T2 relaxation time. Differences in muscle volume, muscle signal intensity, fractional anisotropy, axial diffusivity, and radial diffusivity were measured in the hind limbs. In the comparison between stem cell-treated mice and nontreated ones, differences in muscle volume, muscle signal intensity, and DTI-derived maps were found.MRI-derived biomarkers can be used to identify differences between stem cell-treated and nontreated SOD1(G93A) mice. Magn Reson Med 79:459-469, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Among the wide range of nanoparticles (NPs) studied for diagnostic and therapeutic applications lanthanide-doped nanosystems have raised special interest [1]. Their very small dimension (10 nm) and upconversion emission property have increased the range of their applications from contrast agent probes in bioimaging to drug delivery systems [2,3]. Here, the cytotoxicity of rare earth (Yb and Er)-doped CaF2 and SrF2 NPs has been investigated both in vitro and in vivo. In vitro studies have been conducted in a motoneuron cell line as model of neuronal interaction, and in a line of human dendritic cells which play a key role in the immune response. In the motoneuron cell line, a weak response was observed at early time points while the cell viability showed an increment, except for the highest concentration of lanthanide- doped NPs. The levels of cytokines released from human dendritic cells were low and dose-dependent. The NP biodistribution was investigated after a single peripheral administration in mice. Aggregates of NPs were shown, with different techniques, mostly in peripheral organs (spleen and liver) after one day. A limited penetration of both CaF2 and SrF2 NPs was seen in the brain parenchyma, associated with a mild astrocytic activation. Since the present in vitro findings indicate that lanthanide- doped NPs are safe, and the in vivo data show that they can enter the brain parenchyma crossing the blood-brain barrier, these NPs may represent promising tools for diagnostic and therapeutical applications., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets. Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)–educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography. Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients. Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients. Clin Cancer Res; 23(14); 3721–33. ©2017 AACR.