Browsing by Author "Dondossola, Eleonora"
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Item Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer(National Academy of Sciences, 2021) Bello, Thomas; Paindelli, Claudia; Diaz-Gomez, Luis A.; Melchiorri, Anthony; Mikos, Antonios G.; Nelson, Peter S.; Dondossola, Eleonora; Gujral, Taranjit S.Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.Item Deep Learning for Automated Analysis of Cellular and Extracellular Components of the Foreign Body Response in Multiphoton Microscopy Images(Frontiers Media S.A., 2022) Sarti, Mattia; Parlani, Maria; Diaz-Gomez, Luis; Mikos, Antonios G.; Cerveri, Pietro; Casarin, Stefano; Dondossola, EleonoraThe Foreign body response (FBR) is a major unresolved challenge that compromises medical implant integration and function by inflammation and fibrotic encapsulation. Mice implanted with polymeric scaffolds coupled to intravital non-linear multiphoton microscopy acquisition enable multiparametric, longitudinal investigation of the FBR evolution and interference strategies. However, follow-up analyses based on visual localization and manual segmentation are extremely time-consuming, subject to human error, and do not allow for automated parameter extraction. We developed an integrated computational pipeline based on an innovative and versatile variant of the U-Net neural network to segment and quantify cellular and extracellular structures of interest, which is maintained across different objectives without impairing accuracy. This software for automatically detecting the elements of the FBR shows promise to unravel the complexity of this pathophysiological process.Item Embargo Dissecting the Effects of Targeted Radiation on the Bone Microenvironment(2024-04-17) Barrios, Sergio; Mikos, Antonios G; Dondossola, EleonoraRadium-223 (223Ra) is a bone-targeting, alpha particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer that is currently being tested in a variety of clinical trials for a diverse set of bone-related disease. 223Ra has been shown to accumulate on mineralized bone tissue due to its calcium-mimetic properties and is highly enriched in areas with high bone turnover like the growth plates of long bones. Recent clinical studies have shown a significant fracture rate increase associated with the use of 223Ra, predominantly in tumor-free bones (68% of fractures). However, the biological mechanisms underlying this bone fragility are still unclear and generate a great concern in the clinical setting. Therefore, preclinical studies addressing the role of 223Ra-mediated modulation of the bone stromal components and the consequences on bone mechanical properties are much needed. In this thesis, we combined mechanical testing, micro-CT, and conventional endpoint analysis with fluorescent reporter mice for ex vivo 3D spatial biology microscopy analysis to clarify the effects of 223Ra on bone stromal components including osteoblasts, osteoclasts, adipocytes, and blood vessels. This approach assumes relevance when studying the response to 223Ra, which is spatially confined within 100 μm of the bone interface, due to the short penetration of alpha particles. Additionally, a novel tool for bone tissue image analysis was developed and validated. Overall, this thesis advances our understanding in bone biology and the unexplored impact of alpha-particle radiation on the bone microenvironment.Item Dissecting the recruitment and self-organization of αSMA-positive fibroblasts in the foreign body response(AAAS, 2022) Parlani, Maria; Bedell, Matthew L.; Mikos, Antonios G.; Friedl, Peter; Dondossola, EleonoraThe foreign body response (FBR) is a clinically relevant issue that can cause malfunction of implanted medical devices by fibrotic encapsulation. Whereas inflammatory aspects of the FBR have been established, underlying fibroblast-dependent mechanisms remain unclear. We here combine multiphoton microscopy with ad hoc reporter mice expressing α–smooth muscle actin (αSMA) protein to determine the locoregional fibroblast dynamics, activation, and fibrotic encapsulation of polymeric materials. Fibroblasts invaded as individual cells and established a multicellular network, which transited to a two-compartment fibrotic response displaying an αSMA cold external capsule and a long-lasting, inner αSMA hot environment. The recruitment of fibroblasts and extent of fibrosis were only incompletely inhibited after depletion of macrophages, implicating coexistence of macrophage-dependent and macrophage-independent mediators. Furthermore, neither altering material type or porosity modulated αSMA+ cell recruitment and distribution. This identifies fibroblast activation and network formation toward a two-compartment FBR as a conserved, self-organizing process partially independent of macrophages.