66 results on '"Di Mitri, D"'
Search Results
2. 85P Whole-genome CRISPR screening identifies chemosensor receptors as key regulators of the cancer-macrophage crosstalk
- Author
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Marelli, G., Morina, N., Iovino, M., Puccio, S., Carvetta, M., Morosi, L., Martano, G., Paraboschi, E., Lazzeri, M., Colombo, P., Casale, P., Peano, C., Marchini, S., Lugli, E., and Di Mitri, D.
- Published
- 2023
- Full Text
- View/download PDF
3. 84P Profiling of lipid-loaded macrophages in melanoma
- Author
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Pandini, M., Iovino, M., Marelli, G., Morina, N., Carvetta, M., Portale, F., De Simone, G., Camisaschi, C., Basso, G., Giuliano, D., and Di Mitri, D.
- Published
- 2023
- Full Text
- View/download PDF
4. Facilitating self-regulated learning with personalized scaffolds on student's own regulation activities
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Graaf, J. van der, Molenaar, I., Lim, L., Fan, Y., Engelmann, K., Gasevic, D., Bannert, M., Giannakos, M., Spikol, D., Di Mitri, D., Sharma, K., Ochoa, X., Hammad, R., Giannakos, M., Spikol, D., Molenaar, I., Di Mitri, D., Sharma, K., Ochoa, X., and Hammad, R.
- Subjects
Learning and Plasticity - Abstract
Item does not contain fulltext The focus of education is increasingly set on students' ability to regulate their own learning within technology-enhanced learning environments. Scaffolds have been used to foster self-regulated learning, but scaffolds often are standardized and do not do not adapt to the individual learning process. Learning analytics and machine learning offer an approach to better understand SRL-processes during learning. Yet, current approaches lack validity or require extensive analysis after the learning process. The FLORA project aims to investigate how to advance support given to students by i) improving unobtrusive data collection and machine learning techniques to gain better measurement and understanding of SRL-processes and ii) using these new insights to facilitate student’s SRL by providing personalized scaffolds. We will reach this goal by investigating and improving trace data in exploratory studies (exploratory study 1 and study 2) and using the insight gained from these studies to develop and test personalized scaffolds based on individual learning processes in laboratory (experimental study 3 and study 4) and a subsequent field study (field study 5). At the moment study 2 is ongoing. The setup consists of a learning environment presented on a computer with a screen-based eye-tracker. Other data sources are log files and audio of students’ think aloud. The analysis will focus on detecting sequences that are indicative of micro-level self-regulated learning processes and aligning them between the different data sources. CrossMMLA 2020 (24 March 2020)
- Published
- 2020
5. The Multimodal Tutor: Adaptive Feedback from Multimodal Experiences
- Author
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Di Mitri, D., Drachsler, Hendrik, Specht, Marcus, Schneider, Dr. J., Department of Technology Enhanced Learning and Innovation, RS-Theme Trusted Learning Analytics, and RS-Theme Multimodal Learning Experiences
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multimodal data ,learning analytics ,adaptive feedback ,CPR Tutor ,sensor-based learning ,intelligent tutoring systems - Abstract
This doctoral thesis describes the journey of ideation, prototyping and empirical testing of the Multimodal Tutor, a system designed for providing digital feedback that supports psychomotor skills acquisition using learning and multimodal data capturing. The feedback is given in real-time with machine-driven assessment of the learner's task execution. The predictions are tailored by supervised machine learning models trained with human annotated samples. The main contributions of this thesis are: a literature survey on multimodal data for learning, a conceptual model (the Multimodal Learning Analytics Model), a technological framework (the Multimodal Pipeline), a data annotation tool (the Visual Inspection Tool) and a case study in Cardiopulmonary Resuscitation training (CPR Tutor). The CPR Tutor generates real-time, adaptive feedback using kinematic and myographic data and neural networks.
- Published
- 2020
6. Real-Time Multimodal Feedback with the CPR Tutor
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Di Mitri, D., Schneider Barnes, J., Trebing, Kevin, Sopka, Sasa, Specht, M.M., Drachsler, H.J., Bittencourt, Ig Ibert, Cukurova, Mutlu, Muldner, Kasia, Luckin, Rose, Millán, Eva, Bittencourt, Ig Ibert, Cukurova, Mutlu, Muldner, Kasia, Luckin, Rose, Millán, Eva, Department of Technology Enhanced Learning and Innovation, Department of Computer Science, RS-Research Line Innovation (part of LIRS program), RS-Theme Trusted Learning Analytics, RS-Theme Multimodal Learning Experiences, and RS-Theme Open Education
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Computer science ,medicine.medical_treatment ,Learning analytics ,02 engineering and technology ,Field (computer science) ,GeneralLiterature_MISCELLANEOUS ,InformationSystems_GENERAL ,real-time feedback ,Human–computer interaction ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,Cardiopulmonary resuscitation ,TUTOR ,computer.programming_language ,learning analytics ,multimodal data ,training ,05 social sciences ,050301 education ,artificial intelligence ,Test (assessment) ,Recurrent neural network ,020201 artificial intelligence & image processing ,Audio feedback ,Performance indicator ,cpr tutor ,AI in education ,0503 education ,computer - Abstract
We developed the CPR Tutor, a real-time multimodal feedback system for cardiopulmonary resuscitation (CPR) training. The CPR Tutor detects mistakes using recurrent neural networks for real-time time-series classification. From a multimodal data stream consisting of kinematic and electromyographic data, the CPR Tutor system automatically detects the chest compressions, which are then classified and assessed according to five performance indicators. Based on this assessment, the CPR Tutor provides audio feedback to correct the most critical mistakes and improve the CPR performance. To test the validity of the CPR Tutor, we first collected the data corpus from 10 experts used for model training. Hence, to test the impact of the feedback functionality, we ran a user study involving 10 participants. The CPR Tutor pushes forward the current state of the art of real-time multimodal tutors by providing: 1) an architecture design, 2) a methodological approach to design multimodal feedback and 3) a field study on real-time feedback for CPR training.
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- 2020
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7. Proceedings of CrossMMLA in practice: Collecting, annotating and analyzing multimodal data across spaces co-located with 10th International Learning and Analytics Conference (LAK 2020)
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Giannakos, M.N., Spikol, D., Molenaar, I., Di Mitri, D., Sharma, K., Ochoa, X., and Hammad, R.
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CEUR Workshop Proceedings ,Learning and Plasticity - Abstract
Item does not contain fulltext CrossMMLA in practice (24 March 2020) 63 p.
- Published
- 2020
8. Facilitating self-regulated learning with personalized scaffolds on student's own regulation activities
- Author
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Giannakos, M., Spikol, D., Molenaar, I., Di Mitri, D., Sharma, K., Ochoa, X., Hammad, R., Graaf, J. van der, Lim, L., Fan, Y., Engelmann, K., Gasevic, D., Bannert, M., Giannakos, M., Spikol, D., Molenaar, I., Di Mitri, D., Sharma, K., Ochoa, X., Hammad, R., Graaf, J. van der, Lim, L., Fan, Y., Engelmann, K., Gasevic, D., and Bannert, M.
- Abstract
CrossMMLA 2020 (24 March 2020), Item does not contain fulltext, The focus of education is increasingly set on students' ability to regulate their own learning within technology-enhanced learning environments. Scaffolds have been used to foster self-regulated learning, but scaffolds often are standardized and do not do not adapt to the individual learning process. Learning analytics and machine learning offer an approach to better understand SRL-processes during learning. Yet, current approaches lack validity or require extensive analysis after the learning process. The FLORA project aims to investigate how to advance support given to students by i) improving unobtrusive data collection and machine learning techniques to gain better measurement and understanding of SRL-processes and ii) using these new insights to facilitate student’s SRL by providing personalized scaffolds. We will reach this goal by investigating and improving trace data in exploratory studies (exploratory study 1 and study 2) and using the insight gained from these studies to develop and test personalized scaffolds based on individual learning processes in laboratory (experimental study 3 and study 4) and a subsequent field study (field study 5). At the moment study 2 is ongoing. The setup consists of a learning environment presented on a computer with a screen-based eye-tracker. Other data sources are log files and audio of students’ think aloud. The analysis will focus on detecting sequences that are indicative of micro-level self-regulated learning processes and aligning them between the different data sources.
- Published
- 2020
9. Characterization of regulatory T cells identified as CD4+CD25highCD39+ in patients with active tuberculosis
- Author
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Chiacchio, T., Casetti, R., Butera, O., Vanini, V., Carrara, S., Girardi, E., Di Mitri, D., Battistini, L., Martini, F., Borsellino, G., and Goletti, D.
- Published
- 2009
- Full Text
- View/download PDF
10. Multimodal Pipeline: A generic approach for handling multimodal data for supporting learning
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Di Mitri, D., Schneider, Jan, Specht, M.M., Drachsler, H.J., RS-Theme Trusted Learning Analytics, RS-Theme Multimodal Learning Experiences, Department TELI, RS-Theme Open Education, and Welten Institute
- Abstract
In this demo paper, we introduce the Multimodal Pipeline, a prototypical approach for the collection, storing, annotation, processing and exploitation of multimodal data for supporting learning. At the current stage of development, the Multimodal Pipeline consists of two relevant prototypes: 1) Multimodal Learning Hub for the collection and storing of sensor data from multiple applications and 2) the Visual Inspection Tool for visualisation and annotation of the recorded sessions. The Multimodal Pipeline is designed to be a flexible system useful for supporting psychomotor skills in a variety of learning scenarios such as presentation skills, medical simulation with patient manikins or calligraphy learning. The Multimodal Pipeline can be configured to serve different support strategies, including detecting mistakes and prompting live feedback in an intelligent tutoring system or stimulating self-reflection through a learning analytics dashboard.
- Published
- 2019
11. The Multimodal Learning Analytics Pipeline
- Author
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Di Mitri, D., Schneider Barnes, J., Specht, M.M., Drachsler, H.J., Department Computer Science, RS-Theme Trusted Learning Analytics, RS-Theme Multimodal Learning Experiences, Department TELI, RS-Theme Open Education, and Welten Institute
- Abstract
We introduce the Multimodal Learning Analytics Pipeline, a generic approach for collecting and exploiting multimodal data to support learning activities across physical and digital spaces. The MMLA Pipeline facilitates researchers in setting up their multimodal experiments, reducing setup and configuration time required for collecting meaningful datasets. Using the MMLA Pipeline, researchers can decide to use a set of custom sensors to track different modalities, including behavioural cues or affective states. Hence, researchers can quickly obtain multimodal sessions consisting of synchronised sensor data and video recordings. They can analyse and annotate the sessions recorded and train machine learning algorithms to classify or predict the patterns investigated.
- Published
- 2019
12. Detecting Medical Simulation Errors with Machine learning and Multimodal Data
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Di Mitri, D., RS-Theme Trusted Learning Analytics, RS-Theme Multimodal Learning Experiences, and Department TELI
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ComputingMilieux_COMPUTERSANDEDUCATION ,GeneralLiterature_MISCELLANEOUS - Abstract
In this doctoral consortium paper, we introduce the CPR Tutor, an intelligent tutoring system for cardiopulmonary resuscitation (CPR) training based on the analysis of multimodal data. Using a multi-sensor setup, the CPR Tutor tracks the CPR execution of the trainee and generates automatic adaptive feedback to improve the trainee's performance. This research work is part of a PhD project entitled "Multimodal Tutor: adaptive feedback from multimodal experience capturing'', a project which investigates how to use multimodal and multi-sensor data to generate personalised feedback for training psycho-motor skills at the workplace or during medical simulations. In the CPR Tutor, we use Microsoft Kinect and Myo to track trainee's body position and the ResusciAnne QCPR manikin to get correct CPR performance metrics. We then use a validated approach, the Multimodal Pipeline, for the collection, storage, processing, annotation of multimodal data. This paper describes the preliminary results obtained in the first design of the CPR Tutor.
- Published
- 2019
13. Multimodal Tutor for CPR
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Di Mitri, D., Rosé, Carolyn P., Martínez-Maldonado, Roberto, Ulrich Hoppe, H., Luckin, Rose, Mavrikis, Manolis, Porayska-Pomsta, Kaska, McLaren, Bruce, du Boulay, Benedict, RS-Theme Multimodal Learning Experiences, RS-Theme Trusted Learning Analytics, Department TELI, Rosé, Carolyn P., Martínez-Maldonado, Roberto, Ulrich Hoppe, H., Luckin, Rose, Mavrikis, Manolis, Porayska-Pomsta, Kaska, McLaren, Bruce, and du Boulay, Benedict
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Psychomotor learning ,Data collection ,Computer science ,Multimodal data ,010401 analytical chemistry ,05 social sciences ,Body position ,050301 education ,01 natural sciences ,Pipeline (software) ,0104 chemical sciences ,Human–computer interaction ,Set (psychology) ,TUTOR ,0503 education ,computer ,computer.programming_language - Abstract
This paper describes the design of an intelligent Multimodal Tutor for training people to perform cardiopulmonary resuscitation using patient manikins (CPR tutor). The tutor uses a multi-sensor setup for tracking the CPR execution and generating personalised feedback, including unobtrusive vibrations and retrospective summaries. This study is the main experiment of a PhD project focusing on multimodal data support for investigating practice-based learning scenarios, such as psychomotor skills training in the classroom or at the workplace. For the CPR tutor the multimodal data considered consist of trainee’s body position (with Microsoft Kinect), electromyogram (with Myo armband) and compression rates data derived from the manikin. The CPR tutor uses a new technological framework, the Multimodal Pipeline, which motivates a set of technical approaches used for the data collection, storage, processing, annotation and exploitation of multimodal data. This paper aims at opening up the motivation, the planning and expected evaluations of this experiment to further feedback and considerations by the scientific community.
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- 2018
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14. Erratum to: Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer (Nature Genetics, (2018), 50, 2, (219-228), 10.1038/s41588-017-0026-3)
- Author
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Chen, J., Guccini, I., Di Mitri, D., Brina, D., Revandkar, A., Sarti, M., Pasquini, E., Alajati, A., Pinton, S., Losa, M., Civenni, G., Catapano, C. V., Sgrignani, J., Cavalli, A., D'Antuono, R., Asara, J. M., Morandi, A., Chiarugi, P., Crotti, S., Agostini, M., Montopoli, M., Masgras, I., Rasola, A., Garcia-Escudero, R., Delaleu, N., Rinaldi, A., Bertoni, F., de Bono, J., Carracedo, A., and Alimonti, A.
- Published
- 2018
15. Profiling of the immune microenvironment in prostate cancer at single cell level
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Lazzeri, M., primary, Saita, A., additional, Casale, P., additional, Buffi, N.M., additional, Hurle, R., additional, Lughezzani, G., additional, Fasulo, V., additional, Paciotti, M., additional, Maffei, D., additional, Domanico, L., additional, Bevilacqua, G., additional, Colombo, P., additional, Elefante, G.M., additional, Peano, C., additional, Kunderfranco, P., additional, Cibella, J., additional, Guazzoni, G., additional, and Di Mitri, D., additional
- Published
- 2019
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16. Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer
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Di Mitri, D., primary, Vasilevska, J., additional, Calcinotto, A., additional, Gil, V., additional, Boysen, G., additional, Revandkar, A., additional, Waugh, D., additional, Barry, S., additional, de Bono, J., additional, and Alimonti, A., additional
- Published
- 2017
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17. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
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Chen, J., primary, Guccini, I., additional, Di Mitri, D., additional, Brina, D., additional, and Alimonti, A., additional
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- 2017
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18. 261 - Profiling of the immune microenvironment in prostate cancer at single cell level
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Lazzeri, M., Saita, A., Casale, P., Buffi, N.M., Hurle, R., Lughezzani, G., Fasulo, V., Paciotti, M., Maffei, D., Domanico, L., Bevilacqua, G., Colombo, P., Elefante, G.M., Peano, C., Kunderfranco, P., Cibella, J., Guazzoni, G., and Di Mitri, D.
- Published
- 2019
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19. Studio delle caratteristiche fenotipiche e funzionali di sottopopolazioni linfocitarie immunomodulatorie in pazienti affetti da sclerosi multipla
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DI MITRI, D
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ATP ,Th1 ,CD39 ,sclerosi multipla ,linfociti T regolatori ,Foxp3 ,Th17 ,Settore MED/26 - Neurologia - Published
- 2009
20. 1682P - Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
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Chen, J., Guccini, I., Di Mitri, D., Brina, D., and Alimonti, A.
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- 2017
- Full Text
- View/download PDF
21. 791PD - Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer
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Di Mitri, D., Vasilevska, J., Calcinotto, A., Gil, V., Boysen, G., Revandkar, A., Waugh, D., Barry, S., de Bono, J., and Alimonti, A.
- Published
- 2017
- Full Text
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22. Characterization of regulatory T cells identified as CD4+CD25highCD39+ in patients with active tuberculosis.
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Chiacchio, T., Casetti, R., Butera, O., Vanini, V., Carrara, S., Girardi, E., Di Mitri, D., Battistini, L., Martini, F., Borsellino, G., and Goletti, D.
- Subjects
T cells ,CD4 antigen ,TUBERCULOSIS ,TRANSCRIPTION factors ,INTERLEUKIN-2 ,MYCOBACTERIUM tuberculosis - Abstract
Forkhead box P3 (FoxP3) is a transcription factor whose expression characterizes regulatory T cells (T
reg ), but it is also present on activated T cells, thus hindering correct Treg identification. Using classical markers for Treg recognition, discordant results were found in terms of Treg expansion during active tuberculosis (TB) disease. Recently CD39 has been shown to be an accurate marker for Treg detection. The objectives of this study were: (i) to identify Treg expressing CD39 in patients with TB and to compare the results with those obtained by the standard phenotypic markers; (ii) to evaluate if Treg are expanded in vitro by exogenous interleukin (IL)-2 or by antigen-specific stimulation; and (iii) to characterize Treg function on the modulation of antigen-specific responses. We enrolled 13 patients with pulmonary TB and 12 healthy controls. Treg were evaluated by flow cytometry ex vivo and after antigen-specific in vitro stimulation using CD25, FoxP3, CD127 and CD39 markers. Results indicate that CD39+ cells within the CD4+ CD25high cells have Treg properties (absence of interferon-γ production and transforming growth factor-β1 release upon stimulation). Ex vivo analysis did not show significant differences between TB patients and controls of Treg by classical or novel markers. In contrast, a significantly higher percentage of Treg was found in TB patients after antigen-specific stimulation both in the presence or absence of IL-2. Depletion of CD39+ Treg increased RD1-specific responses significantly. In conclusion, CD39 is an appropriate marker for Treg identification in TB. These results can be useful for future studies to monitor Mycobacterium tuberculosis-specific response during TB. [ABSTRACT FROM AUTHOR]- Published
- 2009
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23. A0536 - Investigation of the tumor-macrophage crosstalk to identify palmitic acid as modulator of macrophage reprogramming in prostate cancer.
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Lughezzani, G., Marelli, G., Buffi, N.M., Casale, P., Saita, A., Hurle, R., Fasulo, V., Paciotti, M., Finocchiaro, A., Colombo, P., Maria, G.M., Carriero, R., Iovino, M., Kundefranco, P., Morosi, C., Di Mitri, D., and Lazzeri, M.
- Subjects
- *
PALMITIC acid , *MACROPHAGES - Published
- 2024
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24. A0428 - Single cell-based immune profiling of the tumor and its immune microenvironment revealed differences between non-muscle invasive and muscle invasive bladder cancer.
- Author
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Pandini, M., Carriero, R., Buffi, N., Carvetta, M., Iovino, M., Casale, P., Lughezzani, G., Hurle, R., Alberto, S., Fasulo, V., Guazzoni, G., Elefante, G., Colombo, P., Basso, G., Marchini, S., Kunderfranco, P., Di Mitri, D., and Lazzeri, M.
- Subjects
- *
NON-muscle invasive bladder cancer , *CANCER invasiveness , *TUMOR microenvironment , *UROTHELIUM - Published
- 2023
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25. T regulatory cells are markers of disease activity in multiple sclerosis patients
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Diletta Di Mitri, Luca Battistini, Giovanna Borsellino, Gianvito Martino, Carlo Avolio, Giancarlo Comi, Federica Sallusto, Roberto Furlan, Vittorio Martinelli, Maria Grazia Grasso, Dacia Dalla Libera, Diego Centonze, Alessandra Bergami, Claudio Gasperini, Simona Galgani, Libera, Dd, Di Mitri, D, Bergami, A, Centonze, D, Gasperini, C, Grasso, Mg, Galgani, S, Martinelli, V, Comi, Giancarlo, Avolio, C, Martino, Gianvito, Borsellino, G, Sallusto, F, Battistini, L, and Furlan, R.
- Subjects
Adult ,Multiple Sclerosis ,Adolescent ,Immune Cells ,Science ,T-Lymphocytes ,Inflammation ,chemical and pharmacologic phenomena ,Relapsing-Remitting ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Peripheral blood mononuclear cell ,Autoimmune Diseases ,Autoimmunity ,Multiple Sclerosis, Relapsing-Remitting ,Antigen ,Antigens, CD ,medicine ,Humans ,IL-2 receptor ,Longitudinal Studies ,Antigens ,Autoimmune disease ,Multidisciplinary ,T Cells ,business.industry ,Multiple sclerosis ,FOXP3 ,hemic and immune systems ,Forkhead Transcription Factors ,Middle Aged ,medicine.disease ,Demyelinating Disorders ,Regulatory ,Acute Disease ,Biological Markers ,CD ,Neurology ,Immunology ,Medicine ,Clinical Immunology ,Settore MED/26 - Neurologia ,medicine.symptom ,business ,Biomarkers ,Research Article - Abstract
FoxP3+ Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS), an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis.
- Published
- 2011
26. C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer.
- Author
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Portale F, Carriero R, Iovino M, Kunderfranco P, Pandini M, Marelli G, Morina N, Lazzeri M, Casale P, Colombo P, De Simone G, Camisaschi C, Lugli E, Basso G, Cibella J, Marchini S, Bordi M, Meregalli G, Garbin A, Dambra M, Magrini E, Rackwitz W, Cecconi F, Corbelli A, Fiordaliso F, Eitler J, Tonn T, and Di Mitri D
- Subjects
- Animals, Humans, Mice, Male, Cell Line, Tumor, Receptors, CXCR4 metabolism, Receptors, CXCR4 genetics, Neoplasms immunology, Neoplasms genetics, Neoplasms pathology, Neoplasms metabolism, Prostatic Neoplasms immunology, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism, Mice, Inbred C57BL, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Autophagy immunology, CCAAT-Enhancer-Binding Protein-beta metabolism, CCAAT-Enhancer-Binding Protein-beta genetics
- Abstract
NK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagy as an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies., Competing Interests: Competing interests: T. Tonn is named as an inventor on patents in the field of cancer immunotherapy. The remaining authors declare no competing interests. Ethics statement: This study adheres to the principles outlined in the Declaration of Helsinki and the ethical standards set by our Institution. All human participants provided informed consent, and animal experiments were conducted with approval from the Institutional Animal Care. We promote diversity, equity, and inclusion in research, and we have disclosed any potential conflicts of interest., (© 2024. The Author(s).)
- Published
- 2024
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27. Macrophage diversity in cancer dissemination and metastasis.
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Mantovani A, Marchesi F, Di Mitri D, and Garlanda C
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- Humans, Animals, Macrophages immunology, Macrophages pathology, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism, Tumor-Associated Macrophages pathology, Neoplasm Metastasis, Neoplasms pathology, Neoplasms immunology, Tumor Microenvironment
- Abstract
Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous and lymphatic pathways of metastasis, cancer cell dissemination can occur via the transcoelomic and perineural routes, which are typical of ovarian and pancreatic cancer, respectively. Macrophages are a universal major component of the tumor microenvironment and, in established tumors, promote growth and dissemination to secondary sites. Here, we review the role of tumor-associated macrophages (TAMs) in cancer cell dissemination and metastasis, emphasizing the diversity of myeloid cells in different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models of lung metastasis fail to capture the diversity of pathways and tissue microenvironments. A better understanding of TAM diversity in different tissue contexts may pave the way for tailored diagnostic and therapeutic approaches., (© 2024. The Author(s).)
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- 2024
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28. NaCl enhances CD8 + T cell effector functions in cancer immunotherapy.
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Scirgolea C, Sottile R, De Luca M, Susana A, Carnevale S, Puccio S, Ferrari V, Lise V, Contarini G, Scarpa A, Scamardella E, Feno S, Camisaschi C, De Simone G, Basso G, Giuliano D, Mazza EMC, Gattinoni L, Roychoudhuri R, Voulaz E, Di Mitri D, Simonelli M, Losurdo A, Pozzi D, Tsui C, Kallies A, Timo S, Martano G, Barberis E, Manfredi M, Rescigno M, Jaillon S, and Lugli E
- Subjects
- Animals, Mice, Humans, Cell Differentiation, Tumor Microenvironment immunology, Neoplasms immunology, Neoplasms therapy, Neoplasms drug therapy, Cell Line, Tumor, Interferon-gamma metabolism, Glutamine metabolism, Mice, Inbred C57BL, Immunotherapy, Adoptive methods, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Sodium Chloride, Immunotherapy methods
- Abstract
CD8
+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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- View/download PDF
29. NK Cells in Cancer: Mechanisms of Dysfunction and Therapeutic Potential.
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Portale F and Di Mitri D
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- Humans, Killer Cells, Natural pathology, Immunotherapy, Adoptive methods, Immunotherapy methods, Adoptive Transfer, Tumor Microenvironment, Neoplasms therapy, Neoplasms pathology
- Abstract
Natural killer cells (NK) are innate lymphocytes endowed with the ability to recognize and kill cancer cells. Consequently, adoptive transfer of autologous or allogeneic NK cells represents a novel opportunity in cancer treatment that is currently under clinical investigation. However, cancer renders NK cells dysfunctional, thus restraining the efficacy of cell therapies. Importantly, extensive effort has been employed to investigate the mechanisms that restrain NK cell anti-tumor function, and the results have offered forthcoming solutions to improve the efficiency of NK cell-based therapies. The present review will introduce the origin and features of NK cells, summarize the mechanisms of action and causes of dysfunction of NK cells in cancer, and frame NK cells in the tumoral microenvironment and in the context of immunotherapies. Finally, we will discuss therapeutic potential and current limitations of NK cell adoptive transfer in tumors.
- Published
- 2023
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30. Macrophages and bone metastasis.
- Author
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Di Mitri D, Conforti F, and Mantovani A
- Subjects
- Male, Humans, Tumor Microenvironment, Macrophages, Bone Neoplasms
- Abstract
In the prostate bone metastasis microenvironment, macrophages activate a cascade that involves Activin A, the extracellular matrix, and SRC kinase and drives resistance to anti-androgen therapy. These findings (Li et al., 2023. J. Exp. Med.https://doi.org/10.1084/jem.20221007) have broad implications, including metastasis diversity in different tissue milieus and the interplay between hormones and immunity., (© 2023 Di Mitri et al.)
- Published
- 2023
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31. Editorial: Profiling the tumour microenvironment to unveil biomarkers and develop novel therapeutics for cancer therapy.
- Author
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Jaillon S and Di Mitri D
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
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32. From Sensor Data to Educational Insights.
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Ruipérez-Valiente JA, Martínez-Maldonado R, Di Mitri D, and Schneider J
- Subjects
- Learning
- Abstract
Technology is gradually becoming an integral part of learning at all levels of educational [...].
- Published
- 2022
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33. Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target.
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Alvisi G, Termanini A, Soldani C, Portale F, Carriero R, Pilipow K, Costa G, Polidoro M, Franceschini B, Malenica I, Puccio S, Lise V, Galletti G, Zanon V, Colombo FS, De Simone G, Tufano M, Aghemo A, Di Tommaso L, Peano C, Cibella J, Iannacone M, Roychoudhuri R, Manzo T, Donadon M, Torzilli G, Kunderfranco P, Di Mitri D, Lugli E, and Lleo A
- Subjects
- Humans, Bile Ducts, Intrahepatic pathology, RNA metabolism, T-Lymphocytes, Regulatory, Transcription Factors metabolism, Tumor Microenvironment, Single-Cell Analysis, Bile Duct Neoplasms pathology, Cholangiocarcinoma pathology
- Abstract
Background & Aims: The landscape and function of the immune infiltrate of intrahepatic cholangiocarcinoma (iCCA), a rare, yet aggressive tumor of the biliary tract, remains poorly characterized, limiting development of successful immunotherapies. Herein, we aimed to define the molecular characteristics of tumor-infiltrating leukocytes with a special focus on CD4+ regulatory T cells (Tregs)., Methods: We used high-dimensional single-cell technologies to characterize the T-cell and myeloid compartments of iCCA tissues, comparing these with their tumor-free peritumoral and circulating counterparts. We further used genomics and cellular assays to define the iCCA-specific role of a novel transcription factor, mesenchyme homeobox 1 (MEOX1), in Treg biology., Results: We found poor infiltration of putative tumor-specific CD39+ CD8+ T cells accompanied by abundant infiltration of hyperactivated CD4+ Tregs. Single-cell RNA-sequencing identified an altered network of transcription factors in iCCA-infiltrating compared to peritumoral T cells, suggesting reduced effector functions by tumor-infiltrating CD8+ T cells and enhanced immunosuppression by CD4+ Tregs. Specifically, we found that expression of MEOX1 was highly enriched in tumor-infiltrating Tregs, and demonstrated that MEOX1 overexpression is sufficient to reprogram circulating Tregs to acquire the transcriptional and epigenetic landscape of tumor-infiltrating Tregs. Accordingly, enrichment of the MEOX1-dependent gene program in Tregs was strongly associated with poor prognosis in a large cohort of patients with iCCA., Conclusions: We observed abundant infiltration of hyperactivated CD4+ Tregs in iCCA tumors along with reduced CD8+ T-cell effector functions. Interfering with hyperactivated Tregs should be explored as an approach to enhance antitumor immunity in iCCA., Lay Summary: Immune cells have the potential to slow or halt the progression of tumors. However, some tumors, such as intrahepatic cholangiocarcinoma, are associated with very limited immune responses (and infiltration of cancer-targeting immune cells). Herein, we show that a specific population of regulatory T cells (a type of immune cell that actually suppresses the immune response) are hyperactivated in intrahepatic cholangiocarcinoma. Targeting these cells could enable cancer-targeting immune cells to act more effectively and should be looked at as a potential therapeutic approach to this aggressive cancer type., Competing Interests: Conflict of interest E.L. receives research grants from Bristol Myers Squibb and consulting fees from BD Biosciences. A.L. reports receiving consulting fees from Intercept Pharma, AlfaSigma, Takeda, AbbVie, Gilead, and MSD and travel expenses from Intercept Pharma, AlfaSigma and AbbVie. M.I. participates in advisory boards/consultancies for Gilead Sciences, Roche, Third Rock Ventures, Antios Therapeutics, Amgen, Asher Bio, Allovir, ENYO Pharma. The other authors have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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34. Lipid-loaded macrophages as new therapeutic target in cancer.
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Marelli G, Morina N, Portale F, Pandini M, Iovino M, Di Conza G, Ho PC, and Di Mitri D
- Subjects
- Humans, Lipids, Macrophages, Neoplasms, Tumor Microenvironment
- Abstract
Macrophages are main players of the innate immune system. They show great heterogeneity and play diverse functions that include support to development, sustenance of tissue homeostasis and defense against infections. Dysfunctional macrophages have been described in multiple pathologies including cancer. Indeed tumor-associated macrophages (TAMs) are abundant in most tumors and sustain cancer growth, promote invasion and mediate immune evasion. Importantly, lipid metabolism influences macrophage activation and lipid accumulation confers pathogenic features on macrophages. Notably, a subset of lipid-loaded macrophages has been recently identified in many tumor types. Lipid-loaded TAMs support tumor growth and progression and exert immune-suppressive activities. In this review, we describe the role of lipid metabolism in macrophage activation in physiology and pathology and we discuss the impact of lipid accumulation in macrophages in the context of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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35. Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer.
- Author
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Masetti M, Carriero R, Portale F, Marelli G, Morina N, Pandini M, Iovino M, Partini B, Erreni M, Ponzetta A, Magrini E, Colombo P, Elefante G, Colombo FS, den Haan JMM, Peano C, Cibella J, Termanini A, Kunderfranco P, Brummelman J, Chung MWH, Lazzeri M, Hurle R, Casale P, Lugli E, DePinho RA, Mukhopadhyay S, Gordon S, and Di Mitri D
- Subjects
- Animals, Cell Plasticity genetics, Cell Plasticity immunology, Cytokines metabolism, Disease Models, Animal, Disease Progression, Gene Expression Profiling, Gene Knockdown Techniques, Heterografts, Humans, Lipid Metabolism, Male, Metabolic Networks and Pathways, Mice, Prostatic Neoplasms pathology, Single-Cell Analysis, Lipids chemistry, Prostatic Neoplasms immunology, Prostatic Neoplasms metabolism, Tumor Microenvironment, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism
- Abstract
Tumor-associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa). The mechanistic basis of this correlation and therapeutic strategies to target TAMs in PCa remain poorly defined. Here, single-cell RNA sequencing was used to profile the transcriptional landscape of TAMs in human PCa, leading to identification of a subset of macrophages characterized by dysregulation in transcriptional pathways associated with lipid metabolism. This subset of TAMs correlates positively with PCa progression and shorter disease-free survival and is characterized by an accumulation of lipids that is dependent on Marco. Mechanistically, cancer cell-derived IL-1β enhances Marco expression on macrophages, and reciprocally, cancer cell migration is promoted by CCL6 released by lipid-loaded TAMs. Moreover, administration of a high-fat diet to tumor-bearing mice raises the abundance of lipid-loaded TAMs. Finally, targeting lipid accumulation by Marco blockade hinders tumor growth and invasiveness and improves the efficacy of chemotherapy in models of PCa, pointing to combinatorial strategies that may influence patient outcomes., Competing Interests: Disclosures: R.A. DePinho reported being a Founder and Advisor for Tvardi Therapeutics, Asylia Therapeutics, Nirogy Therapeutics, Stellanova Therapeutics, and Sporos Bioventures. The focus of these companies is not directly related to the content of this manuscript. S. Gordon reported personal fees from Verseau, Myeloid Therapeutics, and Alnylam outside the submitted work. No other disclosures were reported., (© 2021 Masetti et al.)
- Published
- 2022
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36. Mobile Sensing with Smart Wearables of the Physical Context of Distance Learning Students to Consider Its Effects on Learning.
- Author
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Ciordas-Hertel GP, Rödling S, Schneider J, Di Mitri D, Weidlich J, and Drachsler H
- Subjects
- Humans, Smartphone, Software, Students, Education, Distance, Wearable Electronic Devices
- Abstract
Research shows that various contextual factors can have an impact on learning. Some of these factors can originate from the physical learning environment (PLE) in this regard. When learning from home, learners have to organize their PLE by themselves. This paper is concerned with identifying, measuring, and collecting factors from the PLE that may affect learning using mobile sensing. More specifically, this paper first investigates which factors from the PLE can affect distance learning. The results identify nine types of factors from the PLE associated with cognitive, physiological, and affective effects on learning. Subsequently, this paper examines which instruments can be used to measure the investigated factors. The results highlight several methods involving smart wearables (SWs) to measure these factors from PLEs successfully. Third, this paper explores how software infrastructure can be designed to measure, collect, and process the identified multimodal data from and about the PLE by utilizing mobile sensing. The design and implementation of the Edutex software infrastructure described in this paper will enable learning analytics stakeholders to use data from and about the learners' physical contexts. Edutex achieves this by utilizing sensor data from smartphones and smartwatches, in addition to response data from experience samples and questionnaires from learners' smartwatches. Finally, this paper evaluates to what extent the developed infrastructure can provide relevant information about the learning context in a field study with 10 participants. The evaluation demonstrates how the software infrastructure can contextualize multimodal sensor data, such as lighting, ambient noise, and location, with user responses in a reliable, efficient, and protected manner.
- Published
- 2021
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37. Are We There Yet? - A Systematic Literature Review on Chatbots in Education.
- Author
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Wollny S, Schneider J, Di Mitri D, Weidlich J, Rittberger M, and Drachsler H
- Abstract
Chatbots are a promising technology with the potential to enhance workplaces and everyday life. In terms of scalability and accessibility, they also offer unique possibilities as communication and information tools for digital learning. In this paper, we present a systematic literature review investigating the areas of education where chatbots have already been applied, explore the pedagogical roles of chatbots, the use of chatbots for mentoring purposes, and their potential to personalize education. We conducted a preliminary analysis of 2,678 publications to perform this literature review, which allowed us to identify 74 relevant publications for chatbots' application in education. Through this, we address five research questions that, together, allow us to explore the current state-of-the-art of this educational technology. We conclude our systematic review by pointing to three main research challenges: 1) Aligning chatbot evaluations with implementation objectives, 2) Exploring the potential of chatbots for mentoring students, and 3) Exploring and leveraging adaptation capabilities of chatbots. For all three challenges, we discuss opportunities for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wollny, Schneider, Di Mitri, Weidlich, Rittberger and Drachsler.)
- Published
- 2021
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38. Neutrophil diversity and plasticity in tumour progression and therapy.
- Author
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Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, and Mantovani A
- Subjects
- Animals, Humans, Immunotherapy, Neoplastic Processes, Tumor Microenvironment immunology, Neoplasms immunology, Neoplasms therapy, Neutrophils immunology
- Abstract
Neutrophils play a key role in defence against infection and in the activation and regulation of innate and adaptive immunity. In cancer, tumour-associated neutrophils (TANs) have emerged as an important component of the tumour microenvironment. Here, they can exert dual functions. TANs can be part of tumour-promoting inflammation by driving angiogenesis, extracellular matrix remodelling, metastasis and immunosuppression. Conversely, neutrophils can also mediate antitumour responses by direct killing of tumour cells and by participating in cellular networks that mediate antitumour resistance. Neutrophil diversity and plasticity underlie the dual potential of TANs in the tumour microenvironment. Myeloid checkpoints as well as the tumour and tissue contexture shape neutrophil function in response to conventional therapies and immunotherapy. We surmise that neutrophils can provide tools to tailor current immunotherapy strategies and pave the way to myeloid cell-centred therapeutic strategies, which would be complementary to current approaches.
- Published
- 2020
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39. Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer.
- Author
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Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, Gil V, Boysen G, Losa M, Mosole S, Pasquini E, D'Antuono R, Masetti M, Zagato E, Chiorino G, Ostano P, Rinaldi A, Gnetti L, Graupera M, Martins Figueiredo Fonseca AR, Pereira Mestre R, Waugh D, Barry S, De Bono J, and Alimonti A
- Subjects
- Animals, Carcinogenesis metabolism, Carcinogenesis pathology, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Polarity, Chemokine CXCL2 administration & dosage, Chemokine CXCL2 pharmacology, Humans, Inflammation pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Staging, Neutralization Tests, PTEN Phosphohydrolase metabolism, Receptors, Interleukin-8B metabolism, Signal Transduction drug effects, Tumor Necrosis Factor-alpha metabolism, Tumor Suppressor Protein p53 metabolism, Cellular Senescence, Macrophages pathology, Prostatic Neoplasms pathology, Receptors, Interleukin-8B antagonists & inhibitors
- Abstract
Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Pten
pc-/- ; Trp53pc-/- mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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40. Detecting Mistakes in CPR Training with Multimodal Data and Neural Networks.
- Author
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Di Mitri D, Schneider J, Specht M, and Drachsler H
- Subjects
- Body Weight, Cardiopulmonary Resuscitation methods, Computer-Assisted Instruction instrumentation, Data Curation, Databases, Factual, Education, Medical methods, Equipment Design, Humans, Information Storage and Retrieval, Manikins, Posture, Surveys and Questionnaires, Thorax, Cardiopulmonary Resuscitation education, Computer-Assisted Instruction methods, Neural Networks, Computer
- Abstract
This study investigated to what extent multimodal data can be used to detect mistakes during Cardiopulmonary Resuscitation (CPR) training. We complemented the Laerdal QCPR ResusciAnne manikin with the Multimodal Tutor for CPR, a multi-sensor system consisting of a Microsoft Kinect for tracking body position and a Myo armband for collecting electromyogram information. We collected multimodal data from 11 medical students, each of them performing two sessions of two-minute chest compressions (CCs). We gathered in total 5254 CCs that were all labelled according to five performance indicators, corresponding to common CPR training mistakes. Three out of five indicators, CC rate, CC depth and CC release, were assessed automatically by the ReusciAnne manikin. The remaining two, related to arms and body position, were annotated manually by the research team. We trained five neural networks for classifying each of the five indicators. The results of the experiment show that multimodal data can provide accurate mistake detection as compared to the ResusciAnne manikin baseline. We also show that the Multimodal Tutor for CPR can detect additional CPR training mistakes such as the correct use of arms and body weight. Thus far, these mistakes were identified only by human instructors. Finally, to investigate user feedback in the future implementations of the Multimodal Tutor for CPR, we conducted a questionnaire to collect valuable feedback aspects of CPR training.
- Published
- 2019
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41. Publisher Correction: Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.
- Author
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Chen J, Guccini I, Di Mitri D, Brina D, Revandkar A, Sarti M, Pasquini E, Alajati A, Pinton S, Losa M, Civenni G, Catapano CV, Sgrignani J, Cavalli A, D'Antuono R, Asara JM, Morandi A, Chiarugi P, Crotti S, Agostini M, Montopoli M, Masgras I, Rasola A, Garcia-Escudero R, Delaleu N, Rinaldi A, Bertoni F, de Bono J, Carracedo A, and Alimonti A
- Abstract
In the HTML version of this article initially published, the name of author Diletta Di Mitri was miscoded in the XML such that Di was included as part of the given name instead of the family name. The error has been corrected in the HTML version of the article.
- Published
- 2018
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42. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.
- Author
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Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M, De Bernardis G, Losa M, Mirenda M, Pasquini E, Rinaldi A, Sumanasuriya S, Lambros MB, Neeb A, Lucianò R, Bravi CA, Nava-Rodrigues D, Dolling D, Prayer-Galetti T, Ferreira A, Briganti A, Esposito A, Barry S, Yuan W, Sharp A, de Bono J, and Alimonti A
- Subjects
- Androgen Receptor Antagonists pharmacology, Androgen Receptor Antagonists therapeutic use, Androgens deficiency, Animals, Benzamides, Cell Proliferation, Cell Survival, Humans, Interleukin-23 blood, Interleukin-23 immunology, Male, Mice, Myeloid-Derived Suppressor Cells cytology, Myeloid-Derived Suppressor Cells immunology, Nitriles, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Phenylthiohydantoin therapeutic use, Prostatic Neoplasms, Castration-Resistant blood, Prostatic Neoplasms, Castration-Resistant metabolism, Receptors, Androgen metabolism, Receptors, Interleukin metabolism, Signal Transduction, Interleukin-23 antagonists & inhibitors, Interleukin-23 metabolism, Myeloid-Derived Suppressor Cells metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant therapy
- Abstract
Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.
- Published
- 2018
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43. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.
- Author
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Chen J, Guccini I, Di Mitri D, Brina D, Revandkar A, Sarti M, Pasquini E, Alajati A, Pinton S, Losa M, Civenni G, Catapano CV, Sgrignani J, Cavalli A, D'Antuono R, Asara JM, Morandi A, Chiarugi P, Crotti S, Agostini M, Montopoli M, Masgras I, Rasola A, Garcia-Escudero R, Delaleu N, Rinaldi A, Bertoni F, Bono J, Carracedo A, and Alimonti A
- Subjects
- Animals, Cell Line, Tumor, Cell Nucleus genetics, Cell Nucleus metabolism, Cell Nucleus pathology, Cells, Cultured, Cytoplasm genetics, Cytoplasm metabolism, Cytoplasm pathology, Humans, Male, Mice, Mice, Knockout, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Protein Processing, Post-Translational genetics, Pyruvate Dehydrogenase (Lipoamide) metabolism, Pyruvate Dehydrogenase Complex metabolism, Cell Compartmentation physiology, Lipogenesis genetics, Prostatic Neoplasms metabolism, Pyruvate Dehydrogenase (Lipoamide) genetics, Pyruvate Dehydrogenase Complex physiology
- Abstract
The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy.
- Published
- 2018
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44. Non-Cell-Autonomous Regulation of Cellular Senescence in Cancer.
- Author
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Di Mitri D and Alimonti A
- Subjects
- Animals, Cell Transformation, Neoplastic immunology, Cytokines physiology, Humans, Inflammation pathology, Neoplasms genetics, Neoplasms immunology, Oncogenes, Tumor Microenvironment immunology, Cellular Senescence, Neoplasms pathology
- Abstract
Cellular senescence is a permanent growth arrest that is broadly recognized to act as a barrier against tumorigenesis. Senescence is predominant in premalignant tumors, and senescence escape is thought to be required for tumor progression. Importantly, evidences indicate that cell-autonomous mechanisms, such as genetic alterations or therapeutic interventions targeting specific genetic pathways, can affect the senescence response in cancer. Nevertheless, new findings have emerged in the last few years that indicate a fundamental role for the tumor microenvironment in the regulation of cellular senescence. Indeed, cytokines belonging to the senescent secretome, as well as tumor-infiltrating immune subsets, have been described to modulate the senescence response in tumors. Such evidence demonstrates that senescence initiation also relies on non-cell-autonomous mechanisms, which are discussed in the present review., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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45. The p38 mitogen-activated protein kinase cascade modulates T helper type 17 differentiation and functionality in multiple sclerosis.
- Author
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Di Mitri D, Sambucci M, Loiarro M, De Bardi M, Volpe E, Cencioni MT, Gasperini C, Centonze D, Sette C, Akbar AN, Borsellino G, and Battistini L
- Subjects
- Adenosine Triphosphatases metabolism, Adult, Case-Control Studies, Cation Transport Proteins metabolism, Cells, Cultured, Copper-Transporting ATPases, Enzyme Activation, Eukaryotic Initiation Factor-4E metabolism, Female, Humans, Interleukin-17 metabolism, Interleukins metabolism, Middle Aged, Multiple Sclerosis, Relapsing-Remitting immunology, Phenotype, Phosphorylation, Th17 Cells immunology, Cell Differentiation, Lymphocyte Activation, MAP Kinase Signaling System, Multiple Sclerosis, Relapsing-Remitting enzymology, Th17 Cells enzymology, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
The p38 mitogen-activated protein kinase cascade is required for the induction of a T helper type 17 (Th17) -mediated autoimmune response, which underlies the development and progression of several autoimmune diseases, such as experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis (MS). However, the contribution of p38 phosphorylation to human Th cell differentiation has not been clarified. Here we demonstrate that the p38 signalling pathway is implicated in the generation of Th17 lymphocytes from human CD4(+) CD27(+) CD45RA(+) naive T cells, both in healthy donors and in patients affected by the relapsing-remitting form of MS. Our data also indicate that p38 activation is essential for interleukin-17 release from central memory lymphocytes and committed Th17 cell clones. Furthermore, CD4(+) T cells isolated from individuals with relapsing-remitting MS display an altered responsiveness of the p38 cascade, resulting in increased p38 phosphorylation upon stimulation. These findings suggest that the p38 signalling pathway, by modulating the Th17 differentiation and response, is involved in the pathogenesis of MS, and open new perspectives for the use of p38 inhibitors in the treatment of Th17-mediated autoimmune diseases., (© 2015 John Wiley & Sons Ltd.)
- Published
- 2015
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46. Molecular Pathways: Targeting Tumor-Infiltrating Myeloid-Derived Suppressor Cells for Cancer Therapy.
- Author
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Di Mitri D, Toso A, and Alimonti A
- Subjects
- Animals, Humans, Immune Tolerance immunology, Myeloid Cells immunology, Neoplasms immunology, Tumor Microenvironment immunology
- Abstract
Tumor-infiltrating myeloid-derived suppressor cells (MDSC) are a heterogeneous and immunosuppressive cell subset that blocks the proliferation and the activity of both T and natural killer (NK) cells and promotes tumor vasculogenesis and progression. Recent evidences demonstrate that the recruitment of MDSCs in tumors also blocks senescence induced by chemotherapy promoting chemoresistance. Hence, the need of novel therapeutic approaches that can efficiently target MDSC recruitment and function in cancer. Among them, novel combinatorial treatments of chemotherapy and immunotherapy or treatments that induce depletion of MDSCs in peripheral sites should be taken in consideration., (©2015 American Association for Cancer Research.)
- Published
- 2015
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47. A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours.
- Author
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Kalathur M, Toso A, Chen J, Revandkar A, Danzer-Baltzer C, Guccini I, Alajati A, Sarti M, Pinton S, Brambilla L, Di Mitri D, Carbone G, Garcia-Escudero R, Padova A, Magnoni L, Tarditi A, Maccari L, Malusa F, Kalathur RK, A Pinna L, Cozza G, Ruzzene M, Delaleu N, Catapano CV, Frew IJ, and Alimonti A
- Subjects
- Animals, Casein Kinase II metabolism, Drug Evaluation, Preclinical, Female, HCT116 Cells, Humans, Male, Mice, Transgenic, Naphthyridines pharmacology, Nuclear Proteins metabolism, Phenazines, Promyelocytic Leukemia Protein, RNA, Small Interfering, STAT3 Transcription Factor metabolism, Transcription Factors metabolism, Tumor Suppressor Proteins metabolism, Casein Kinase II antagonists & inhibitors, Cellular Senescence drug effects, Molecular Targeted Therapy, Naphthyridines therapeutic use, PTEN Phosphohydrolase deficiency, Prostatic Neoplasms drug therapy
- Abstract
Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.
- Published
- 2015
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48. Tumor-infiltrating myeloid cells drive senescence evasion and chemoresistance in tumors.
- Author
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Di Mitri D, Toso A, and Alimonti A
- Abstract
The present study supports a model in which Pten loss-induced senescence is hindered in prostate tumor cells by non cell-autonomous mechanisms. Indeed, paracrine signaling by tumor-infiltrating CD11b
+ Gr-1+ myeloid cells triggers senescence evasion in prostate lesions of Pten -null mice, eventually promoting tumor progression.- Published
- 2015
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- View/download PDF
49. Enhancing chemotherapy efficacy by reprogramming the senescence-associated secretory phenotype of prostate tumors: A way to reactivate the antitumor immunity.
- Author
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Toso A, Di Mitri D, and Alimonti A
- Published
- 2015
- Full Text
- View/download PDF
50. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.
- Author
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Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, D'Antuono R, Montani E, Garcia-Escudero R, Guccini I, Da Silva-Alvarez S, Collado M, Eisenberger M, Zhang Z, Catapano C, Grassi F, and Alimonti A
- Subjects
- Animals, Disease Progression, Docetaxel, Drug Resistance, Neoplasm, Humans, Immunity, Innate, Interleukin 1 Receptor Antagonist Protein deficiency, Interleukin 1 Receptor Antagonist Protein metabolism, Interleukin-1alpha immunology, Interleukin-1alpha metabolism, Male, Mice, Myeloid Cells transplantation, PTEN Phosphohydrolase deficiency, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, Prostatic Neoplasms drug therapy, Prostatic Neoplasms immunology, Prostatic Neoplasms metabolism, Receptors, Interleukin-8B antagonists & inhibitors, Taxoids pharmacology, Tumor Escape, Tumor Microenvironment, Cell Movement, Cellular Senescence drug effects, Myeloid Cells cytology, Myeloid Cells metabolism, Prostatic Neoplasms pathology, Receptors, Chemokine metabolism
- Abstract
Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.
- Published
- 2014
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