Ortiz-de-Solorzano, C. (Carlos)

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    Spheroscope: A custom-made miniaturized microscope for tracking tumour spheroids in microfluidic devices
    (Springer nature, 2020) Rodríguez-Pena, A. (Alejandro); Ortiz-de-Solorzano, C. (Carlos); Cortés-Dominguez, I. (Iván); Uranga-Solchaga, J. (J.)
    3D cell culture models consisting of self-assembled tumour cells in suspension, commonly known as tumour spheroids, are becoming mainstream for high-throughput anticancer drug screening. A usual measurable outcome of screening studies is the growth rate of the spheroids in response to treatment. This is commonly quantifed on images obtained using complex, expensive, optical microscopy systems, equipped with high-quality optics and customized electronics. Here we present a novel, portable, miniaturized microscope made of low-cost, mass-producible parts, which produces both fuorescence and phase-gradient contrast images. Since phase-gradient contrast imaging is based on oblique illumination, epi-illumination is used for both modalities, thus simplifying the design of the system. We describe the system, characterize its performance on synthetic samples and show proof-ofprinciple applications of the system consisting in imaging and monitoring the formation and growth of lung and pancreas cancer tumour spheroids within custom made microfuidic devices.
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    Evaluation of monocytes as carriers for armed oncolytic adenoviruses in murine and Syrian hamster models of cancer
    (Mary Ann Liebert, 2012) Garcia-Aragoncillo, E. (Eva); Quetglas, J.I. (José Ignacio); Ortiz-de-Solorzano, C. (Carlos); Hervas-Stubbs, S. (Sandra); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén); Benavides, C. (Carolina); Buñuales, M. (María); Raquel
    Replication-competent (oncolytic) adenoviruses (OAV) can be adapted as vectors for the delivery of therapeutic genes, with the aim of extending the antitumor effect beyond direct cytolysis. Transgene expression using these vectors is usually intense but short-lived, and repeated administrations are hampered by the rapid appearance of neutralizing antibodies (NAbs). We have studied the performance of monocytes as cell carriers to improve transgene expression in cancer models established in athymic mice and immunocompetent Syrian hamsters. Human and hamster monocytic cell lines (MonoMac6 and HM-1, respectively) were loaded with replication-competent adenovirus-expressing luciferase. Intravenous administration of these cells caused a modest increase in transgene expression in tumor xenografts, but this effect was virtually lost in hamsters. In contrast, intratumoral administration of HM-1 cells allowed repeated cycles of expression and achieved partial protection from NAbs in preimmunized hamsters bearing pancreatic tumors. To explore the therapeutic potential of this approach, HM-1 cells were loaded with a hypoxia-inducible OAV expressing the immunostimulatory cytokine interleukin-12 (IL-12). Three cycles of treatment achieved a significant antitumor effect in the hamster model, and transgene expression was detected following each administration, in contrast with the rapid neutralization of the free virus. We propose monocytes as carriers for multiple intratumoral administrations of armed OAVs.
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    Smokers with CT detected emphysema and no airway obstruction have decreased plasma levels of EGF, IL-15, IL-8 and IL-1ra
    (Public Library of Science, 2013) Seijo, L. (Luis); Campo, A. (Arantza); Pajares, M.J. (María José); Pio, R. (Rubén); Bastarrika, G. (Gorka); Ortiz-de-Solorzano, C. (Carlos); Blanco, D. (Daniel); Montes, U. (Usúa); Torres, J.P. (Juan P.) de; Montuenga-Badia, L.M. (Luis M.); Alcaide, A.B. (Ana Belén); Muñoz-Barrutia, A. (Arrate); Segura, V. (Víctor); Zulueta, J. (Javier); Pueyo, J. (Jesús)
    Current or former smokers expressing a well-defined disease characteristic such as emphysema, has a specific plasma cytokine profile. This includes a decrease of cytokines mainly implicated in activation of apoptosis or decrease of immunosurveillance. This information should be taken into account when evaluated patients with tobacco respiratory diseases.
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    Treatment of pancreatic cancer with an oncolytic adenovirus expressing Interleukin-12 in syrian hamsters
    (Nature Publishing Group, 2009) González-Aseguinolaza, G. (Gloria); Ortiz-de-Solorzano, C. (Carlos); Otano, I. (Itziar); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén); Buñuales, M. (María); Perez-Martin, D. (Daniel)
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    NMF-RI: blind spectral unmixing of highly mixed multispectral flow and image cytometry data
    (Oxford University Press, 2020) Ortiz-de-Solorzano, C. (Carlos); Cortés-Dominguez, I. (Iván); Morgado, J.M. (José Mário); Jiménez-Sanchez, D. (Daniel); Ariz, M. (Mikel)
    Motivation Recent advances in multiplex immunostaining and multispectral cytometry have opened the door to simultaneously visualizing an unprecedented number of biomarkers both in liquid and solid samples. Properly unmixing fluorescent emissions is a challenging task, which normally requires the characterization of the individual fluorochromes from control samples. As the number of fluorochromes increases, the cost in time and use of reagents becomes prohibitively high. Here, we present a fully unsupervised blind spectral unmixing method for the separation of fluorescent emissions in highly mixed spectral data, without the need for control samples. To this end, we extend an existing method based on non-negative Matrix Factorization, and introduce several critical improvements: initialization based on the theoretical spectra, automated selection of ‘sparse’ data and use of a re-initialized multilayer optimizer. Results Our algorithm is exhaustively tested using synthetic data to study its robustness against different levels of colocalization, signal to noise ratio, spectral resolution and the effect of errors in the initialization of the algorithm. Then, we compare the performance of our method to that of traditional spectral unmixing algorithms using novel multispectral flow and image cytometry systems. In all cases, we show that our blind unmixing algorithm performs robust unmixing of highly spatially and spectrally mixed data with an unprecedently low computational cost. In summary, we present the first use of a blind unmixing method in multispectral flow and image cytometry, opening the door to the widespread use of our method to efficiently pre-process multiplex immunostaining samples without the need of experimental controls.
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    Modulation of Haemophilus influenzae interaction with hydrophobic molecules by the VacJ/MlaA lipoprotein impacts strongly on its interplay with the airways
    (Nature, 2018) Garmendia, J. (Junkal); Bengoechea, J.A. (José A.); Fernández-Calvet, A. (Ariadna); Ortiz-de-Solorzano, C. (Carlos); Euba, B. (Begoña); Ramos-Vivas, J. (Jose); Moleres, J. (Javier); Caballero, L. (Lucía); Martí, S. (Sara); Almagro, G. (Goizeder); Yuste, J.E. (José Enrique); Leigh-Bartholomew, T. (Toby); Morales-Urteaga, X. (Xabier); Rodríguez-Arce, I. (Irene); Conde-Alvarez, R. (Raquel)
    Airway infection by nontypeable Haemophilus influenzae (NTHi) associates to chronic obstructive pulmonary disease (COPD) exacerbation and asthma neutrophilic airway inflammation. Lipids are key inflammatory mediators in these disease conditions and consequently, NTHi may encounter free fatty acids during airway persistence. However, molecular information on the interplay NTHi-free fatty acids is limited, and we lack evidence on the importance of such interaction to infection. Maintenance of the outer membrane lipid asymmetry may play an essential role in NTHi barrier function and interaction with hydrophobic molecules. VacJ/MlaA-MlaBCDEF prevents phospholipid accumulation at the bacterial surface, being the only system involved in maintaining membrane asymmetry identified in NTHi. We assessed the relationship among the NTHi VacJ/MlaA outer membrane lipoprotein, bacterial and exogenous fatty acids, and respiratory infection. The vacJ/mlaA gene inactivation increased NTHi fatty acid and phospholipid global content and fatty acyl specific species, which in turn increased bacterial susceptibility to hydrophobic antimicrobials, decreased NTHi epithelial infection, and increased clearance during pulmonary infection in mice with both normal lung function and emphysema, maybe related to their shared lung fatty acid profiles. Altogether, we provide evidence for VacJ/MlaA as a key bacterial factor modulating NTHi survival at the human airway upon exposure to hydrophobic molecules.
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    Evaluation of bioluminescent imaging for noninvasive monitoring of colorectal cancer progression in the liver and its response to immunogene therapy
    (BioMed Central, 2009) González-Aseguinolaza, G. (Gloria); Zabala, M. (Maider); Ortiz-de-Solorzano, C. (Carlos); Alzuguren, P. (Pilar); Crettaz, J. (Julien); Kramer, M.G. (María Gabriela); Prieto, J. (Jesús); Hernandez-Alcoceba, R. (Rubén); Benavides, C. (Carolina); Gonzalez-Aparicio, M. (Manuela)
    BACKGROUND: Bioluminescent imaging (BLI) is based on the detection of light emitted by living cells expressing a luciferase gene. Stable transfection of luciferase in cancer cells and their inoculation into permissive animals allows the noninvasive monitorization of tumor progression inside internal organs. We have applied this technology for the development of a murine model of colorectal cancer involving the liver, with the aim of improving the pre-clinical evaluation of new anticancer therapies. RESULTS: A murine colon cancer cell line stably transfected with the luciferase gene (MC38Luc1) retains tumorigenicity in immunocompetent C57BL/6 animals. Intrahepatic inoculation of MC38Luc1 causes progressive liver infiltration that can be monitored by BLI. Compared with ultrasonography (US), BLI is more sensitive, but accurate estimation of tumor mass is impaired in advanced stages. We applied BLI to evaluate the efficacy of an immunogene therapy approach based on the liver-specific expression of the proinflammatory cytokine interleukin-12 (IL-12). Individualized quantification of light emission was able to determine the extent and duration of antitumor responses and to predict long-term disease-free survival. CONCLUSION: We show that BLI is a rapid, convenient and safe technique for the individual monitorization of tumor progression in the liver. Evaluation of experimental treatments with complex mechanisms of action such as immunotherapy is possible using this technology.
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    Longitudinal study of a mouse model of chronic pulmonary inflammation using breath hold gated micro-CT.
    (Springer, 2010-05-24) Bastarrika, G. (Gorka); Ortiz-de-Solorzano, C. (Carlos); Blanco, D. (Daniel); Torres, J.P. (Juan P.) de; Montuenga-Badia, L.M. (Luis M.); Biurrun, G. (Gabriel) de; Artaechevarria-Artieda, X. (Xabier); Muñoz-Barrutia, A. (Arrate); Perez-Martin, D. (Daniel); Zulueta, J. (Javier)
    Abstract Objectives To evaluate the feasibility of using automatic quantitative analysis of breath hold gated micro-CT images to detect and monitor disease in a mouse model of chronic pulmonary inflammation, and to compare image-based measurements with pulmonary function tests and histomorphometry. Material and methods Forty-nine A/J mice were used, divided into control and inflammation groups. Chronic inflammation was induced by silica aspiration. Fourteen animals were imaged at baseline, and 4, 14, and 34 weeks after silica aspiration, using micro-CT synchronized with ventilator-induced breath holds. Lung input impedance was measured as well using forced oscillation techniques. Five additional animals from each group were killed after micro-CT for comparison with histomorphometry. Results At all time points, micro-CT measurements show statistically significant differences between the two groups, while first differences in functional test parameters appear at 14 weeks. Micro-CT measurements correlate well with histomorphometry and discriminate diseased and healthy groups better than functional tests. Conclusion Longitudinal studies using breath hold gated micro-CT are feasible on the silica-induced model of chronic pulmonary inflammation, and automatic measurements from micro-CT images correlate well with histomorphometry, being more sensitive than functional tests to detect lung damage in this model.
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    NaroNet: Discovery of tumor microenvironment elements from highly multiplexed images
    (Elsevier, 2022) Ortiz-de-Solorzano, C. (Carlos); Andrea, C.E. (Carlos Eduardo) de; Matías-Guiu, X. (Xavier); Chang, H. (Hang); Jiménez-Sanchez, D. (Daniel); Ariz, M. (Mikel)
    Understanding the spatial interactions between the elements of the tumor microenvironment -i.e. tumor cells. fibroblasts, immune cells- and how these interactions relate to the diagnosis or prognosis of a tu- mor is one of the goals of computational pathology. We present NaroNet, a deep learning framework that models the multi-scale tumor microenvironment from multiplex-stained cancer tissue images and pro- vides patient-level interpretable predictions using a seamless end-to-end learning pipeline. Trained only with multiplex-stained tissue images and their corresponding patient-level clinical labels, NaroNet un- supervisedly learns which cell phenotypes, cell neighborhoods, and neighborhood interactions have the highest influence to predict the correct label. To this end, NaroNet incorporates several novel and state-of- the-art deep learning techniques, such as patch-level contrastive learning, multi-level graph embeddings, a novel max-sum pooling operation, or a metric that quantifies the relevance that each microenvironment element has in the individual predictions. We validate NaroNet using synthetic data simulating multiplex- immunostained images where a patient label is artificially associated to the -adjustable- probabilistic inci- dence of different microenvironment elements. We then apply our model to two sets of images of human cancer tissues: 336 seven-color multiplex-immunostained images from 12 high-grade endometrial cancer patients; and 382 35-plex mass cytometry images from 215 breast cancer patients. In both synthetic and real datasets, NaroNet provides outstanding predictions of relevant clinical information while associating those predictions to the presence of specific microenvironment elements.
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    Design and validation of a tunable inertial microfluidic system for the efficient enrichment of circulating tumor cells in blood
    (2022) Armendáriz, E. (Estibaliz); Pio, R. (Rubén); D'Avola, D. (Delia); Cochonneau, D. (Denis); Rodríguez-Pena, A. (Alejandro); Ruiz-Fernandez-de-Cordoba, B. (Borja); Ortiz-de-Solorzano, C. (Carlos); Cortés-Dominguez, I. (Iván); Sangro, B. (Bruno); Cornago, I. (Iñaki); Oyarbide, A. (Alvaro); Heymann, D. (Dominique); Morales-Urteaga, X. (Xabier); Ortiz-Espinosa, S. (Sergio); Lecanda, F. (Fernando); Argemí, J. (Josepmaria)
    The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial-based separation is a promising high-throughput, marker-free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine-tunable cut-off value of 9 mu m and a separation range of 2 mu m. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirm highly efficient CTC isolation with a stringent cut-off value and better separation results than the state of the art.