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Sökning: WFRF:(Sgarzi M)

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  • Mazzeschi, M., et al. (författare)
  • The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer
  • 2022
  • Ingår i: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 41:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). Methods In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. Results ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Conclusions Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.
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3.
  • Bazzicalupi, Carla, et al. (författare)
  • Multimodal Use of New Coumarin-Based Fluorescent Chemosensors: Towards Highly Selective Optical Sensors for Hg2+ Probing
  • 2013
  • Ingår i: Chemistry - A European Journal. - : Wiley-VCH Verlag. - 0947-6539 .- 1521-3765. ; 19:43, s. 14639-14653
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite several types of fluorescent sensing molecules have been proposed and examined to signal Hg2+ ion binding, the development of fluorescence-based devices for in-field Hg2+ detection and screening in environmental and industrial samples is still a challenging task. Herein, we report the synthesis and characterization of three new coumarin-based fluorescent chemosensors featuring mixed thia/aza macrocyclic framework as receptors units, that is, ligands L1-L3. These probes revealed an OFF-ON selective response to the presence of Hg2+ ions in MeCN/H2O 4:1 (v/v), which allowed imaging of this metal ion in Cos-7 cells in vitro. Once included in silica core-polyethylene glycol (PEG) shell nanoparticles or supported on polyvinyl chloride (PVC)-based polymeric membranes, ligands L1-L3 can also selectively sense Hg2+ ions in pure water. In particular we have developed an optical sensing array tacking advantage of the fluorescent properties of ligand L3 and based on the computer screen photo assisted technique (CSPT). In the device ligand L3 is dispersed into PVC membranes and it quantitatively responds to Hg2+ ions in natural water samples.
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