116 results on '"Bugatti M"'
Search Results
2. Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/Akt/mTOR pathway in mucosal melanoma fitness
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Monti, M, Benerini Gatta, L, Bugatti, M, Pezzali, I, Picinoli, S, Manfredi, M, Lavazza, A, Vanella, V, De Giorgis, V, Zanatta, L, Missale, F, Lonardi, S, Zanetti, B, Bozzoni, G, Cadei, M, Abate, A, Vergani, B, Balzarini, P, Battocchio, S, Facco, C, Turri-Zanoni, M, Castelnuovo, P, Nicolai, P, Fonsatti, E, Leone, B, Marengo, E, Sigala, S, Ronca, R, Perego, M, Lombardi, D, Vermi, W, Monti, Matilde, Benerini Gatta, Luisa, Bugatti, Mattia, Pezzali, Irene, Picinoli, Sara, Manfredi, Marcello, Lavazza, Antonio, Vanella, Virginia Vita, De Giorgis, Veronica, Zanatta, Lucia, Missale, Francesco, Lonardi, Silvia, Zanetti, Benedetta, Bozzoni, Giovanni, Cadei, Moris, Abate, Andrea, Vergani, Barbara, Balzarini, Piera, Battocchio, Simonetta, Facco, Carla, Turri-Zanoni, Mario, Castelnuovo, Paolo, Nicolai, Piero, Fonsatti, Ester, Leone, Biagio Eugenio, Marengo, Emilio, Sigala, Sandra, Ronca, Roberto, Perego, Michela, Lombardi, Davide, Vermi, William, Monti, M, Benerini Gatta, L, Bugatti, M, Pezzali, I, Picinoli, S, Manfredi, M, Lavazza, A, Vanella, V, De Giorgis, V, Zanatta, L, Missale, F, Lonardi, S, Zanetti, B, Bozzoni, G, Cadei, M, Abate, A, Vergani, B, Balzarini, P, Battocchio, S, Facco, C, Turri-Zanoni, M, Castelnuovo, P, Nicolai, P, Fonsatti, E, Leone, B, Marengo, E, Sigala, S, Ronca, R, Perego, M, Lombardi, D, Vermi, W, Monti, Matilde, Benerini Gatta, Luisa, Bugatti, Mattia, Pezzali, Irene, Picinoli, Sara, Manfredi, Marcello, Lavazza, Antonio, Vanella, Virginia Vita, De Giorgis, Veronica, Zanatta, Lucia, Missale, Francesco, Lonardi, Silvia, Zanetti, Benedetta, Bozzoni, Giovanni, Cadei, Moris, Abate, Andrea, Vergani, Barbara, Balzarini, Piera, Battocchio, Simonetta, Facco, Carla, Turri-Zanoni, Mario, Castelnuovo, Paolo, Nicolai, Piero, Fonsatti, Ester, Leone, Biagio Eugenio, Marengo, Emilio, Sigala, Sandra, Ronca, Roberto, Perego, Michela, Lombardi, Davide, and Vermi, William
- Abstract
Background: Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. Methods: Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. Results: This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Co
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- 2024
3. The RISTRETTO simulator: exoplanet reflected spectra
- Author
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Bryant, Julia J., Motohara, Kentaro, Vernet, Joël R. D., Bugatti, M., Lovis, C., Pepe, F., Blind, N., Billot, N., Chazelas, B., and Turbet, M.
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- 2024
- Full Text
- View/download PDF
4. IMMUNOGLOBULIN CLASS DICTATES TRANSFORMATION TRAJECTORY AND BCR STATUS OF MYC/BCL2 DOUBLE‐HIT LYMPHOMA: BIOLOGY AND CLINICAL IMPLICATIONS
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Casola, S., primary, Sindaco, P., additional, Lonardi, S., additional, Zanardi, F., additional, Neuman, H., additional, Lorenzi, L., additional, Balzarini, P., additional, Morello, G., additional, Varano, G., additional, Bugatti, M., additional, Chairini, M., additional, Bertolazzi, G., additional, Arima, H., additional, Ranise, C., additional, Giampaolo, S., additional, Garzon, D., additional, Capaccio, P., additional, Mainoldi, F., additional, Daffini, R., additional, Zini, S., additional, Pellegrini, V., additional, Manni, S., additional, Piazza, F., additional, Tucci, A., additional, Ferreri, A. J., additional, Pruneri, G., additional, Cabras, A., additional, Di Napoli, A., additional, Pizzi, M., additional, Ponzoni, M., additional, Mehr, R., additional, Tripodo, C., additional, and Facchetti, F., additional
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- 2023
- Full Text
- View/download PDF
5. The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease
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Dander, E, Vinci, P, Vetrano, S, Recordati, C, Piazza, R, Fazio, G, Bardelli, D, Bugatti, M, Sozio, F, Piontini, A, Bonanomi, S, Bertola, L, Tassistro, E, Valsecchi, M, Calza, S, Vermi, W, Biondi, A, Del Prete, A, Sozzani, S, D'Amico, G, Dander, Erica, Vinci, Paola, Vetrano, Stefania, Recordati, Camilla, Piazza, Rocco, Fazio, Grazia, Bardelli, Donatella, Bugatti, Mattia, Sozio, Francesca, Piontini, Andrea, Bonanomi, Sonia, Bertola, Luca, Tassistro, Elena, Valsecchi, Maria Grazia, Calza, Stefano, Vermi, William, Biondi, Andrea, Del Prete, Annalisa, Sozzani, Silvano, D'Amico, Giovanna, Dander, E, Vinci, P, Vetrano, S, Recordati, C, Piazza, R, Fazio, G, Bardelli, D, Bugatti, M, Sozio, F, Piontini, A, Bonanomi, S, Bertola, L, Tassistro, E, Valsecchi, M, Calza, S, Vermi, W, Biondi, A, Del Prete, A, Sozzani, S, D'Amico, G, Dander, Erica, Vinci, Paola, Vetrano, Stefania, Recordati, Camilla, Piazza, Rocco, Fazio, Grazia, Bardelli, Donatella, Bugatti, Mattia, Sozio, Francesca, Piontini, Andrea, Bonanomi, Sonia, Bertola, Luca, Tassistro, Elena, Valsecchi, Maria Grazia, Calza, Stefano, Vermi, William, Biondi, Andrea, Del Prete, Annalisa, Sozzani, Silvano, and D'Amico, Giovanna
- Abstract
Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1- KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium-induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD.
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- 2023
6. L1CAM expression as a predictor of platinum response in high-risk endometrial carcinoma
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Romani, C., Capoferri, D., Reijnen, C., Lonardi, S., Ravaggi, A., Ratti, M., Bugatti, M., Zanotti, L., Tognon, G., Sartori, E., Odicino, F., Calza, S., Pijnenborg, J.M.A., Bignotti, E., Romani, C., Capoferri, D., Reijnen, C., Lonardi, S., Ravaggi, A., Ratti, M., Bugatti, M., Zanotti, L., Tognon, G., Sartori, E., Odicino, F., Calza, S., Pijnenborg, J.M.A., and Bignotti, E.
- Abstract
Item does not contain fulltext, For high-risk endometrial cancer (EC) patients, adjuvant chemotherapy is recommended to improve outcome. Yet, predictive biomarkers for response to platinum-based chemotherapy (Pt-aCT) are currently lacking. We tested expression of L1 cell-adhesion molecule (L1CAM), a well-recognised marker of poor prognosis in EC, in tumour samples from high-risk EC patients, to explore its role as a predictive marker of Pt-aCT response. L1CAM expression was determined using RT-qPCR and immunohistochemistry in a cohort of high-risk EC patients treated with Pt-aCT and validated in a multicentric independent cohort. The association between L1CAM and clinicopathologic features and L1CAM additive value in predicting platinum response were determined. The effect of L1CAM gene silencing on response to carboplatin was functionally tested on primary L1CAM-expressing cells. Increased L1CAM expression at both genetic and protein level correlated with high-grade, non-endometrioid histology and poor response to platinum treatment. A predictive model adding L1CAM to prognostic clinical variables significantly improved platinum response prediction (C-index 78.1%, P = .012). In multivariate survival analysis, L1CAM expression was significantly associated with poor outcome (HR: 2.03, P = .019), potentially through an indirect effect, mediated by its influence on response to chemotherapy. In vitro, inhibition of L1CAM significantly increased cell sensitivity to carboplatin, supporting a mechanistic link between L1CAM expression and response to platinum in EC cells. In conclusion, we have demonstrated the role of L1CAM in the prediction of response to Pt-aCT in two independent cohorts of high-risk EC patients. L1CAM is a promising candidate biomarker to optimise decision making in high-risk patients who are eligible for Pt-aCT.
- Published
- 2022
7. Integrated Biomarker Analysis Reveals L1CAM as a Potential Stratification Marker for No Specific Molecular Profile High-Risk Endometrial Carcinoma
- Author
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Ravaggi, A., Capoferri, D., Ardighieri, L., Ghini, I., Ferrari, F., Romani, C., Bugatti, M., Zanotti, L., Vrede, S.W., Tognon, G., Pijnenborg, J.M.A., Sartori, E., Calza, S., Bignotti, E., Odicino, F., Ravaggi, A., Capoferri, D., Ardighieri, L., Ghini, I., Ferrari, F., Romani, C., Bugatti, M., Zanotti, L., Vrede, S.W., Tognon, G., Pijnenborg, J.M.A., Sartori, E., Calza, S., Bignotti, E., and Odicino, F.
- Abstract
Item does not contain fulltext, Histopathologic assessment of high-risk endometrial cancer (EC) suffers from intersubject variability and poor reproducibility. The pragmatic classification in four molecular subgroups helps to overcome these limits, showing a significant prognostic value. The "no specific molecular profile" (NSMP) is the most heterogeneous EC subgroup, requiring further characterization to better guide its clinical management. DNA sequencing of POLE exonuclease domain and immunohistochemistry for PMS2, MSH6, and p53 were performed in order to stratify a cohort of 94 high-risk EC patients in the four molecular subgroups. Moreover, a panel of seven additional biomarkers was tested. Patients were found to be 16% POLE-mutated, 36% mismatch repair-deficient, 27% p53-abnormal, and 21% NSMP. In the multivariable model, molecular groups confirmed their significant association with disease-specific survival and progression-free survival, with p53-abnormal and NSMP endometrial cancer characterized by poor outcomes. Among the additional evaluated biomarkers, L1CAM was the only one with a significant prognostic value within the NSMP subgroup. NSMP/L1CAM-positive patients experienced the worst outcome and were "early-relapsing" after platinum-based chemotherapy, with a significantly shorter platinum-free interval compared to L1CAM-negative patients. L1CAM appears to be a promising candidate as a prognostic and predictive biomarker in the high-risk NSMP subgroup, which is actually known to lack specific molecular markers.
- Published
- 2022
8. Immunohistochemical Detection of SARS-CoV-2 Antigens by Single and Multiple Immunohistochemistry
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Lonardi, S, Bugatti, M, Valzelli, A, and Facchetti, F
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Antibodies ,Immunohistochemistry Double/Triple immunohistochemistry ,SARS-CoV-2 ,COVID-19 Testing ,Epitopes ,Humans ,Immunohistochemistry ,COVID-19 - Published
- 2022
9. Hofbauer cells and COVID-19 in pregnancy: Molecular pathology analysis of villous macrophages, endothelial cells, and placental findings from 22 placentas infected by SARS-CoV-2 with and without fetal transmission
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Schwartz, D.A., Baldewijns, M., Benachi, A., Bugatti, M., Bulfamante, G., Cheng, K., Collins, R.R.J., Debelenko, L., Luca, D. de, Facchetti, F., Fitzgerald, B., Levitan, D., Linn, R.L., Marcelis, L., Morotti, D., Morotti, R., Patane, L., Prevot, S., Pulinx, B., Saad, A.G., Schoenmakers, S., Strybol, D., Thomas, K., Tosi, D., Toto, V., Meeren, L.E. van der, Verdijk, R.M., Vivanti, A.J., Zaigham, M., Obstetrics & Gynecology, and Pathology
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Adult ,Male ,Placenta ,Infectious Disease Transmission ,viruses ,VIRAL-INFECTION ,Research & Experimental Medicine ,PROCOAGULANT ,PHAGOCYTOSIS ,SDG 3 - Good Health and Well-being ,Pregnancy ,Pathology ,Humans ,Vertical ,Endothelium ,reproductive and urinary physiology ,Cell Proliferation ,Retrospective Studies ,Science & Technology ,Hyperplasia ,SARS-CoV-2 ,Macrophages ,fungi ,PROLIFERATION ,Infectious ,COVID-19 ,Infant ,Stillbirth ,Newborn ,Trophoblasts ,Pregnancy Complications ,body regions ,Medical Laboratory Technology ,Medicine, Research & Experimental ,embryonic structures ,Female ,Infant, Newborn ,Pregnancy Complications, Infectious ,Infectious Disease Transmission, Vertical ,Life Sciences & Biomedicine - Abstract
CONTEXT.—: SARS-CoV-2 can undergo maternal-fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARS-CoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases, including HIV and Zika virus, but their involvement in SARS-CoV-2 is unknown. OBJECTIVE.—: To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium, and other villous stromal cells in infected placentas of liveborn and stillborn infants. DESIGN.—: Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2-infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast, and other fetal-derived cells. RESULTS.—: Chronic histiocytic intervillositis and trophoblast necrosis were present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4 of 22 placentas (18.2%). Villous capillary endothelial staining was positive in 2 of 22 cases (9.1%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21 of 22 placentas (95.5%). Hofbauer cell hyperplasia was present in 3 of 22 placentas (13.6%). In the 7 cases having documented transplacental infection of the fetus, 2 (28.6%) occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2. CONCLUSIONS.—: SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement. ispartof: ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE vol:145 issue:11 pages:1328-1340 ispartof: location:United States status: published
- Published
- 2021
10. Outcome of unstable isolated fractures of the posterior acetabular wall associated with hip dislocation
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de Palma, L., Santucci, A., Verdenelli, A., Bugatti, M. G., Meco, L., and Marinelli, M.
- Published
- 2014
- Full Text
- View/download PDF
11. Formazione umana e imprenditorialità sostenibile. Responsabilità sociale e sviluppo del territorio
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Cairo, M., Speziale, S., Besana, M., Birbes, C., Bornatici, S., Vischi, A., Caporale, M., Iori, M., Ossola, P., Attolico, A., Bugatti, M., Castellazzo, S., Danesi, M., Cairo M., Vischi, Alessandra, Vischi (ORCID:0000-0002-7259-8756), Cairo, M., Speziale, S., Besana, M., Birbes, C., Bornatici, S., Vischi, A., Caporale, M., Iori, M., Ossola, P., Attolico, A., Bugatti, M., Castellazzo, S., Danesi, M., Cairo M., Vischi, Alessandra, and Vischi (ORCID:0000-0002-7259-8756)
- Abstract
La tutela del creato necessita di una solidarietà che si proietti nello spazio e nel tempo, di una governance planetaria, attraverso processi multistakeholder basati su un consenso più diffuso e convinto, che integri i diversi livelli di responsabilità - locale, nazionale e internazionale - e coinvolga le istituzioni, le imprese, la società civile. Le organizzazioni sollecitano la riflessione e la progettualità nell’ottica della formazione lifelong; in questa luce emblematico è il concetto di Responsabilità Sociale d’Impresa, che si configura come cultura condivisa per la progettazione organizzativa, ma anche come modalità di governance, indispensabile per garantire innovazione e vitalità all’organizzazione. Scegliere la responsabilità sociale può favorire lo sviluppo sociale e del territorio; la possibilità di implementare il miglioramento degli standard di sostenibilità per un’impresa è connessa con una solida base scientifica, con una cultura consapevole e specifica del territorio di origine. I benefici delle scelte green si potranno tradurre in nuove opportunità di valorizzazione dei servizi proposti, dei prodotti e dei territori connessi, producendo altresì inedite possibilità formative e di lavoro soprattutto per i giovani. Lo scopo fondamentale di una progettualità per la cura del territorio è la valorizzazione di ogni risorsa, promuovere la collaborazione e la partecipazione per costruire, insieme, un patto di fiducia, tra produzione responsabile e consumo consapevole, verso una società più sostenibile.
- Published
- 2018
12. FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients
- Author
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Tassi, Ra, Todeschini, P, Siegel, Er, Calza, S, Cappella, P, Ardighieri, L, Cadei, M, Bugatti, M, Romani, C, Bandiera, E, Zanotti, L, Tassone, L, Guarino, D, Santonocito, C, Capoluongo, Ed, Beltrame, L, Erba, E, Marchini, S, D'Incalci, M, Donzelli, C, Santin, Ad, Pecorelli, S, Sartori, E, Bignotti, E, Odicino, F, Ravaggi, A., Santonocito, C (ORCID:0000-0003-3624-1386), Capoluongo, ED (ORCID:0000-0001-9872-0572), Tassi, Ra, Todeschini, P, Siegel, Er, Calza, S, Cappella, P, Ardighieri, L, Cadei, M, Bugatti, M, Romani, C, Bandiera, E, Zanotti, L, Tassone, L, Guarino, D, Santonocito, C, Capoluongo, Ed, Beltrame, L, Erba, E, Marchini, S, D'Incalci, M, Donzelli, C, Santin, Ad, Pecorelli, S, Sartori, E, Bignotti, E, Odicino, F, Ravaggi, A., Santonocito, C (ORCID:0000-0003-3624-1386), and Capoluongo, ED (ORCID:0000-0001-9872-0572)
- Abstract
Background: Epithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. Forkhead box M1 (FOXM1) is an oncogene aberrantly expressed in many solid cancers including serous EOC, but its role in non-serous EOCs remains undefined. We examined FOXM1 expression and its correlation to prognosis across the three major EOC subtypes, and its role in tumorigenesis and chemo-resistance in vitro. Methods: Gene signatures were generated by microarray for 14 clear-cell and 26 endometrioid EOCs, and 15 normal endometrium snap-frozen biopsies. Validation of FOXM1 expression was performed by RT-qPCR and immunohistochemistry in the same samples and additionally in 50 high-grade serous EOCs and in their most adequate normal controls (10 luminal fallopian tube and 20 ovarian surface epithelial brushings). Correlations of FOXM1 expression to clinic-pathological parameters and patients' prognosis were evaluated by Kaplan-Meier and Cox proportional-hazards analyses. OVCAR-3 and two novel deeply characterized EOC cell lines (EOC-CC1 and OSPC2, with clear-cell and serous subtype, respectively) were employed for in vitro studies. Effects of FOXM1 inhibition by transient siRNA transfection were evaluated on cell-proliferation, cell-cycle, colony formation, invasion, and response to conventional first-and second-line anticancer agents, and to the PARP-inhibitor olaparib. Gene signatures of FOXM1-silenced cell lines were generated by microarray and confirmed by RT-qPCR. Results: A significant FOXM1 mRNA up-regulation was found in EOCs compared to normal controls. FOXM1 protein overexpression significantly correlated to serous histology (p = 0.001) and advanced FIGO stage (p = 0.004). Multivariate analyses confirmed FOXM1 protein overexpression as an independent indicator of worse disease specific survival in non-serous EOCs, and of shorter time to progression in platinum-resistant cases. FOXM1 downregulation in EOC cell lines inhibited cell growt
- Published
- 2017
13. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model
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Rowland, Sl, Riggs, Jm, Gilfillan, S, Bugatti, M, Vermi, William, Kolbeck, R, Unanue, Er, Sanjuan, Ma, and Colonna, M.
- Published
- 2014
14. A relay of IL-1R and CXCR2 signals in the tumour microenvironment confer tolerance to MAPK antagonism in melanoma
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Young, H., primary, Rowling, E., additional, Smith, M., additional, Bugatti, M., additional, Vermi, W., additional, Luheshi, N., additional, Wellbrock, C., additional, and Hurlstone, A., additional
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- 2016
- Full Text
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15. Outcome of unstable isolated fractures of the posterior acetabular wall associated with hip dislocation
- Author
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de Palma, L., primary, Santucci, A., additional, Verdenelli, A., additional, Bugatti, M. G., additional, Meco, L., additional, and Marinelli, M., additional
- Published
- 2013
- Full Text
- View/download PDF
16. Outcome of unstable isolated fractures of the posterior acetabular wall associated with hip dislocation.
- Author
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Palma, L., Santucci, A., Verdenelli, A., Bugatti, M., Meco, L., and Marinelli, M.
- Subjects
CHI-squared test ,HIP joint dislocation ,HIP joint injuries ,HEALTH outcome assessment ,SCALE analysis (Psychology) ,TOMOGRAPHY ,DISEASE complications - Abstract
Background: Traumatic hip dislocation with fracture of the posterior acetabular wall is associated with high rates of residual invalidity. Methods: The records of patients who underwent surgical treatment of traumatic dislocation of the hip associated with an isolated fracture of the posterior acetabular wall from 1999 to 2009 were reviewed. There were 30 men and 12 women, who at the time of the trauma had a mean age of 42 years (range 21-65). Mean follow-up duration was 5 years (range 2-10). Pre-operative fracture evaluation was based on the classification of Judet et al. which divided this fractures into three types: type 1 is characterized by a single fracture line separating a single bone fragment from the remaining part of the posterior wall; type 2 fracture involves several fragments of the posterior wall and in type 3, a type 1 or type 2 fracture is associated with a sunk cancellous area in the acetabular wall medial to the fracture line but not affected by it, due to the shear impact of the femoral head at the time of dislocation. Clinical evaluation of the outcome was according to the criteria of Merle D'Aubigné and Postel as modified by Matta. Outcomes were divided into excellent/good and fair/poor. Since treatment was standard, data were further analyzed to assess the relative importance of age, sex, follow-up duration, sciatic nerve lesion on admission and mechanism of injury, using the Chi-square test. Results: Full clinical recovery without sequelae or radiographic abnormalities was achieved by 10 patients, 8 with type 1 fracture and 2 with type 2 fracture. A good outcome was seen in 13 patients, 3 with type 1 fracture, 9 with type 2 fracture and 1 with type 3 fracture. Eight patients, 3 with type 2 fracture and 5 with type 3 fracture, had a fair outcome. Only follow-up ≥6 years influenced outcome significantly ( p > 0.005). Conclusion: Our conclusions in light of our experience are that in type 1 lesions, anatomical reduction and stabilization achieve excellent outcomes, both clinical and radiographic; type 2 fractures pose greater prognostic problems because their outcome is determined by the success of the reduction and fixation of a multi-fragment fracture; finally, different considerations apply to type 3 fractures, which present varying degrees of comminution and an impacted acetabular surface: their outcome depends on the quality of the anatomical and morphological restoration of acetabular congruence. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
17. The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease
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Erica Dander, Paola Vinci, Stefania Vetrano, Camilla Recordati, Rocco Piazza, Grazia Fazio, Donatella Bardelli, Mattia Bugatti, Francesca Sozio, Andrea Piontini, Sonia Bonanomi, Luca Bertola, Elena Tassistro, Maria Grazia Valsecchi, Stefano Calza, William Vermi, Andrea Biondi, Annalisa Del Prete, Silvano Sozzani, Giovanna D’Amico, Dander, E, Vinci, P, Vetrano, S, Recordati, C, Piazza, R, Fazio, G, Bardelli, D, Bugatti, M, Sozio, F, Piontini, A, Bonanomi, S, Bertola, L, Tassistro, E, Valsecchi, M, Calza, S, Vermi, W, Biondi, A, Del Prete, A, Sozzani, S, and D'Amico, G
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immunology ,Chemokine ,Macrophage ,bone marrow transplantation ,chemokines ,General Medicine ,macrophages ,transplantation - Abstract
Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1- KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium-induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD.
- Published
- 2023
18. A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis
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Alex Pezzotta, Anna Pistocchi, Patrick Mehlen, Andrea Paradisi, Anna Di Matteo, Federico Forneris, Daniele Campolungo, Costanza Giampietro, Elisa Belloni, Gianluca Deflorian, Nina Volf, Antonella Chiapparino, Michael Rehman, William Vermi, Maria Paola Paronetto, Mattia Bugatti, Davide Pradella, Claudia Ghigna, Anne Eichmann, Matteo Campioni, Serena Zacchigna, Luigi Scietti, Paradisi, Andrea, Consiglio Nazionale delle Ricerche (CNR), Università degli Studi di Pavia = University of Pavia (UNIPV), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano = University of Milan (UNIMI), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Centre Léon Bérard [Lyon], University of Brescia, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Heidelberg University, Swiss Federal Laboratories for Materials Science and Technology [Dübendorf] (EMPA), International Centre for Genetic Engineering and Biotechnology (ICGEB) (Trieste), Yale School of Medicine [New Haven, Connecticut] (YSM), Università degli studi di Trieste = University of Trieste, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], University of Rome 'Foro Italico', Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Pradella, D., Deflorian, G., Pezzotta, A., Di Matteo, A., Belloni, E., Campolungo, D., Paradisi, A., Bugatti, M., Vermi, W., Campioni, M., Chiapparino, A., Scietti, L., Forneris, F., Giampietro, C., Volf, N., Rehman, M., Zacchigna, S., Paronetto, M. P., Pistocchi, A., Eichmann, A., Mehlen, P., Ghigna, C., University of Pavia, University of Milan, Yale University School of Medicine, University of Trieste, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
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Netrin Receptor ,Angiogenesis ,Regulator ,General Physics and Astronomy ,Apoptosis ,RNA-binding protein ,RNA-Binding Protein ,0302 clinical medicine ,Netrin ,Morphogenesis ,RNA Isoforms ,MESH: Animals ,MESH: Endothelial Cells ,MESH: Nerve Tissue Proteins ,Zebrafish ,Colonic Neoplasm ,Endothelial Cell ,0303 health sciences ,Multidisciplinary ,Neovascularization, Pathologic ,Chemistry ,MESH: Alternative Splicing ,RNA-Binding Proteins ,RNA Isoform ,Netrin-1 ,Cell biology ,MESH: Survival Analysis ,030220 oncology & carcinogenesis ,embryonic structures ,Colonic Neoplasms ,RNA splicing ,Survival Analysi ,Netrin Receptors ,Human ,Gene isoform ,animal structures ,Blood Vessel ,Science ,Nerve Tissue Proteins ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Neuro-Oncological Ventral Antigen ,Morphogenesi ,Animals ,Humans ,Alternative Splicing ,Blood Vessels ,Endothelial Cells ,Survival Analysis ,MESH: Zebrafish ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Neovascularization ,030304 developmental biology ,Pathologic ,MESH: Colonic Neoplasms ,MESH: Humans ,Animal ,MESH: Apoptosis ,fungi ,Alternative splicing ,MESH: Blood Vessels ,General Chemistry ,MESH: Netrin Receptors ,MESH: RNA Isoforms ,MESH: Morphogenesis ,Exon skipping ,MESH: RNA-Binding Proteins ,nervous system ,MESH: Netrin-1 ,Nerve Tissue Protein ,MESH: Neovascularization, Pathologic ,Tumour angiogenesis - Abstract
The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis., Nature Communications, 12, ISSN:2041-1723
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- 2021
19. TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses
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Nicoletta Caronni, Francesca Simoncello, Simone Vodret, Giulia Maria Piperno, Pierre Bourdeley, Regine J. Dress, Federica Benvenuti, Renato Ostuni, Annalisa Del Prete, Serena Zacchigna, Mattia Bugatti, Pierre Guermonprez, Yuichi Yanagihashi, Shigekatzu Nagata, Silvio Bicciato, William Vermi, Tiziana Schioppa, Emilia Maria Cristina Mazza, Charles-Antoine Dutertre, Florent Ginhoux, Licio Collavin, Oriana Romano, International Centre for Genetic Engineering and Biotechnology (ICGEB), Caronni, N., Piperno, G. M., Simoncello, F., Romano, O., Vodret, S., Yanagihashi, Y., Dress, R., Dutertre, C. -A., Bugatti, M., Bourdeley, P., Del Prete, A., Schioppa, T., Mazza, E. M. C., Collavin, L., Zacchigna, S., Ostuni, R., Guermonprez, P., Vermi, W., Ginhoux, F., Bicciato, S., Nagata, S., and Benvenuti, F.
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0301 basic medicine ,Lung Neoplasms ,Cell ,General Physics and Astronomy ,CD8-Positive T-Lymphocytes ,Mice ,0302 clinical medicine ,Receptor ,Membrane Protein ,Immunologic Surveillance ,Lung ,Adenocarcinoma ,Animals ,Antigens, Neoplasm ,Cross-Priming ,Dendritic Cells ,Humans ,Membrane Proteins ,Multidisciplinary ,3. Good health ,medicine.anatomical_structure ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,Oncology ,030220 oncology & carcinogenesis ,Tumour immunology ,Human ,Phagocytosis ,Science ,Biology ,Dendritic Cell ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Downregulation and upregulation ,Antigen ,medicine ,Antigens ,Animal ,CD8-Positive T-Lymphocyte ,General Chemistry ,medicine.disease ,Lung Neoplasm ,030104 developmental biology ,Tumor progression ,Cancer research ,Neoplasm ,CD8 - Abstract
Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8+ T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8+ T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors., Acquisition of dying tumor cell-associated antigens is an essential step for the initiation of anti-tumor immune response by conventional type 1 dendritic cells (cDC1). Here the authors show that the loss of TIM4 expression in lung tumor associated cDC1 is associated with less efficient uptake of cell associated antigens and reduction of CD8 + T cell activation in advanced lung tumors.
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- 2021
20. SARS-CoV2 vertical transmission with adverse effects on the newborn revealed through integrated immunohistochemical, electron microscopy and molecular analyses of Placenta
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Enrico Sartori, Marta Papaccio, Fabio Facchetti, Claudio Tripodo, Stefano Casola, Emma Drera, Maria Beatrice Boniotti, Antonio Lavazza, Mattia Bugatti, Valeria Cancila, Roberta Castellani, Patrizia Cavadini, Facchetti F., Bugatti M., Drera E., Tripodo C., Sartori E., Cancila V., Papaccio M., Castellani R., Casola S., Boniotti M.B., Cavadini P., and Lavazza A.
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0301 basic medicine ,Pathology ,COVID19 ,Placenta ,viruses ,lcsh:Medicine ,Extracellular Traps ,0302 clinical medicine ,Pregnancy ,Nasopharynx ,Pathology, Molecular ,Pregnancy Complications, Infectious ,Adult, Betacoronavirus, COVID-19, Coronavirus Infections, Coronavirus Nucleocapsid Proteins, Female, Humans, Immunohistochemistry, Infant, Newborn, Spike Glycoprotein, Coronavirus, Microscopy, Electron, Nasopharynx, Pregnancy,Spike Glycoprotein, Coronavirus,SARS-CoV-2 ,lcsh:R5-920 ,medicine.diagnostic_test ,Intervillous space ,General Medicine ,Nucleocapsid Proteins ,Immunohistochemistry ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Spike Glycoprotein, Coronavirus ,RNA, Viral ,Female ,Coronavirus Infections ,lcsh:Medicine (General) ,Adult ,medicine.medical_specialty ,Pneumonia, Viral ,In situ hybridization ,Settore MED/08 - Anatomia Patologica ,Biology ,Immunofluorescence ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Betacoronavirus ,Syncytiotrophoblast ,Immune system ,Antigen ,medicine ,Settore MED/05 - Patologia Clinica ,Coronavirus Nucleocapsid Proteins ,Humans ,Pandemics ,Fetus ,business.industry ,SARS-CoV-2 ,Macrophages ,lcsh:R ,Infant, Newborn ,COVID-19 ,medicine.disease ,Phosphoproteins ,Infectious Disease Transmission, Vertical ,Microscopy, Electron ,030104 developmental biology ,business - Abstract
Background: The occurrence of trans-placental transmission of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection remains highly debated. Placental positivity for SARS-CoV-2 has been reported in selected cases, but infection or virus-associated disease of fetal tissues or newborns remains to be demonstrated. Methods: We screened for SARS-CoV-2 spike (S) protein expression placentas from 101 women who delivered between February 7 and May 15 2020, including 15 tested positive for SARS-CoV-2 RNA, 34 tested negative, and 52 not evaluated as they did not meet testing criteria (32), or delivered before COVID-19 pandemic declaration (20). Immunostain for SARS-CoV-2 nucleocapside (N) was performed in the placentas of all COVID-19 positive women. The single placenta resulted positive for the SARS-Cov2 S and N proteins was further studied by RNA-in situ hybridization for S transcripts, RT-PCR RNA, and by electron microscopy. A detailed immunohistochemical and immunofluorescence analysis of the placental inflammatory infiltrate completed the investigations. Findings: SARS-CoV2 S and N proteins were strongly expressed in the placenta of a COVID-19 pregnant woman whose newborn tested positive for viral RNA and developed COVID-19 pneumonia soon after birth. SARS-CoV-2 antigens, RNA and/or viral particles were identified in villous syncytiotrophoblast, endothelial cells, fibroblasts, in maternal macrophages, and in Hofbauer cells and fetal intravascular mononuclear cells. The placenta intervillous inflammatory infiltrate was composed of neutrophils and monocyte-macrophages displaying activation markers. Absence of villitis was associated with an increase in the number of Hofbauer cells, which expressed PD-L1. Scattered neutrophil extracellular traps (NETs) were identified by immunofluorescence. Interpretation: We provide first-time evidence for maternal-fetal transmission of SARS-CoV-2, likely mediated by circulating virus-infected fetal mononuclear cells. Placenta infection was associated with recruitment of maternal inflammatory cells in the intervillous space, without villitis. PD-L1 expression in syncytiotrophoblast and Hofbaeur cells, together with limited production of NETs, may have prevented immune cell-driven placental damage, ensuring sufficient maternal-fetus exchanges. Funding Statement: None. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was reviewed and approved by the Institutional Ethical Board of Brescia Hospital (ASST Spedali Civili Brescia), protocol numbers: NP 4151- Study COVID-BIO (Multicentric observational prospective study on SARS-CoV-2 infection during pregnancy) and NP 4133- Study INTERCOVID (A prospective cohort study of the effects of COVID-19 in pregnancy and the neonatal period).
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- 2020
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21. FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients
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Ettore Capoluongo, Franco Odicino, Chiara Romani, Maurizio D'Incalci, Laura Zanotti, Concetta Santonocito, Paolo Cappella, Mattia Bugatti, Eugenio Erba, Sergio Pecorelli, Sergio Marchini, Enrico Sartori, Stefano Calza, Moris Cadei, Eric R. Siegel, Laura Tassone, Elisabetta Bandiera, Renata A. Tassi, Luca Beltrame, Carla Donzelli, Antonella Ravaggi, Donatella Guarino, Laura Ardighieri, Paola Todeschini, Alessandro D. Santin, Eliana Bignotti, Tassi, Ra, Todeschini, P, Siegel, Er, Calza, S, Cappella, P, Ardighieri, L, Cadei, M, Bugatti, M, Romani, C, Bandiera, E, Zanotti, L, Tassone, L, Guarino, D, Santonocito, C, Capoluongo, E, Beltrame, L, Erba, E, Marchini, S, D'Incalci, M, Donzelli, C, Santin, Ad, Pecorelli, S, Sartori, E, Bignotti, E, Odicino, F, and Ravaggi, A
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0301 basic medicine ,Cancer Research ,Microarray ,endocrine system diseases ,DNA Repair ,Subtype ,Kaplan-Meier Estimate ,Carcinoma, Ovarian Epithelial ,medicine.disease_cause ,Metastasis ,chemistry.chemical_compound ,Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,0302 clinical medicine ,Anticancer drug ,Cell line ,Chemoresistance ,Epithelial ovarian cancer ,FOXM1 ,Immunohistochemistry ,Prognosis ,Oncology ,Cell Movement ,Antineoplastic Combined Chemotherapy Protocols ,Protein Isoforms ,Neoplasms, Glandular and Epithelial ,Neoplasm Metastasis ,RNA, Small Interfering ,Aged, 80 and over ,Ovarian Neoplasms ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,female genital diseases and pregnancy complications ,3. Good health ,Gene Expression Regulation, Neoplastic ,Serous fluid ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Disease Progression ,Female ,Adult ,Prognosi ,Biology ,lcsh:RC254-282 ,Olaparib ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,Aged ,Cell Proliferation ,Neoplasm Staging ,Oncogene ,Gene Expression Profiling ,Research ,Forkhead Box Protein M1 ,medicine.disease ,Cystadenocarcinoma, Serous ,Gene expression profiling ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Cancer research ,Neoplasm Grading ,Carcinogenesis - Abstract
Background Epithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. Forkhead box M1 (FOXM1) is an oncogene aberrantly expressed in many solid cancers including serous EOC, but its role in non-serous EOCs remains undefined. We examined FOXM1 expression and its correlation to prognosis across the three major EOC subtypes, and its role in tumorigenesis and chemo-resistance in vitro. Methods Gene signatures were generated by microarray for 14 clear-cell and 26 endometrioid EOCs, and 15 normal endometrium snap-frozen biopsies. Validation of FOXM1 expression was performed by RT–qPCR and immunohistochemistry in the same samples and additionally in 50 high-grade serous EOCs and in their most adequate normal controls (10 luminal fallopian tube and 20 ovarian surface epithelial brushings). Correlations of FOXM1 expression to clinic-pathological parameters and patients’ prognosis were evaluated by Kaplan-Meier and Cox proportional-hazards analyses. OVCAR-3 and two novel deeply characterized EOC cell lines (EOC-CC1 and OSPC2, with clear-cell and serous subtype, respectively) were employed for in vitro studies. Effects of FOXM1 inhibition by transient siRNA transfection were evaluated on cell-proliferation, cell-cycle, colony formation, invasion, and response to conventional first- and second-line anticancer agents, and to the PARP-inhibitor olaparib. Gene signatures of FOXM1-silenced cell lines were generated by microarray and confirmed by RT-qPCR. Results A significant FOXM1 mRNA up-regulation was found in EOCs compared to normal controls. FOXM1 protein overexpression significantly correlated to serous histology (p = 0.001) and advanced FIGO stage (p = 0.004). Multivariate analyses confirmed FOXM1 protein overexpression as an independent indicator of worse disease specific survival in non-serous EOCs, and of shorter time to progression in platinum-resistant cases. FOXM1 downregulation in EOC cell lines inhibited cell growth and clonogenicity, and promoted the cytotoxic effects of platinum compounds, doxorubicin hydrochloride and olaparib. Upon FOXM1 knock-down in EOC-CC1 and OSPC2 cells, microarray and RT-qPCR analyses revealed the deregulation of several common and other unique subtype-specific FOXM1 putative targets involved in cell cycle, metastasis, DNA repair and drug response. Conclusions FOXM1 is up-regulated in all three major EOCs subtypes, and is a prognostic biomarker and a potential combinatorial therapeutic target in platinum resistant disease, irrespective of tumor histology. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0536-y) contains supplementary material, which is available to authorized users.
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- 2017
22. The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3ß inhibition
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Klaus Rajewsky, Fabio Facchetti, Simon Raffel, Maurilio Ponzoni, Andrea Haake, Silvia Lonardi, Laura Pasqualucci, Federica Zanardi, Stefan Kempa, Eelco van Anken, Gabriele Varano, Martina Sormani, Ulrike Paul, Laura Perucho, Mattia Bugatti, Christin Zasada, Reiner Siebert, Albert Lee, Stefano Casola, Valentina Petrocelli, Raul Rabadan, Varano, G., Raffel, S., Sormani, M., Zanardi, F., Lonardi, S., Zasada, C., Perucho, L., Petrocelli, V., Haake, A., Lee, A. K., Bugatti, M., Paul, U., Van Anken, E., Pasqualucci, L., Rabadan, R., Siebert, R., Kempa, S., Ponzoni, M., Facchetti, F., Rajewsky, K., Casola, S., and VAN ANKEN, Eelco
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0301 basic medicine ,MAPK/ERK pathway ,Male ,Lymphoma ,Lymphoma, B-cell-Receptor, MYC, Cell-competition ,Cell ,Genes, myc ,medicine.disease_cause ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Receptors ,Tumor Cells, Cultured ,B-cell lymphoma ,ras ,Mutation ,B-Lymphocytes ,Cultured ,Multidisciplinary ,breakpoint cluster region ,myc ,Burkitt Lymphoma ,Tumor Cells ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Antigen ,Female ,MAP Kinase Signaling System ,B-cell receptor ,Receptors, Antigen, B-Cell ,Biology ,NO ,03 medical and health sciences ,B-cell-Receptor ,medicine ,Animals ,Humans ,Carbon ,Genes, ras ,Glycogen Synthase Kinase 3 beta ,Genetic Fitness ,Neoplastic ,Cell-competition ,B-Cell ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Genes ,Cancer research ,Carcinogenesis - Abstract
Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival1-3, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival4-7. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies8,9. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3ß) activity to support MYC-controlled gene expression. BCR- tumour cells exhibit increased GSK3ß activity and are rescued from their competitive growth disadvantage by GSK3ß inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3ß activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumour cells.
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- 2017
23. 337 - A relay of IL-1R and CXCR2 signals in the tumour microenvironment confer tolerance to MAPK antagonism in melanoma.
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Young, H., Rowling, E., Smith, M., Bugatti, M., Vermi, W., Luheshi, N., Wellbrock, C., and Hurlstone, A.
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- 2016
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24. Progesterone receptor is constitutively expressed in induced Pluripotent Stem Cells (iPSCs).
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Manganelli M, Mazzoldi EL, Ferraro RM, Pinelli M, Parigi M, Aghel SAM, Bugatti M, Collo G, Stocco G, Vermi W, Masneri S, Almici C, Mori L, and Giliani S
- Abstract
Induced Pluripotent Stem Cells (iPSCs) are nowadays a common starting point for wide-ranging applications including 3D disease modeling (i.e. organoids) and in future regenerative medicine. Physiological processes like homeostasis, cell differentiation, development and reproduction are tightly regulated by hormones through binding to their transmembrane or nuclear receptors of target cells. Considering their pleiotropic effect, take into account also their expression in an iPSCs-based disease modeling would better recapitulate the molecular events leading to 3D organoid development and disease study. Here we reported the expression pattern of estrogen receptor (ERα) and progesterone receptor (PR) in four different iPSCs, obtained from CD34 + progenitor cells and skin fibroblasts with four different methods. Expression of ERα and PR mRNA were significantly downregulated in iPSCs as well as fibroblasts compared to MCF7 positive control. Immunofluorescence (IF) staining detected only the expression of PR protein in all the different iPSCs cell lines, while ERα was not detectable. By flow cytometry analysis we observed that the ~ 65% of the total population of iPSCs cells expressed only PR, with 100% fold increase compared to HSPCs and fibroblasts, while ERα was not expressed. Our results collectively demonstrated for the first time that the reprogramming of somatic cells into iPSCs leads to the expression of PR receptor., (© 2024. The Author(s).)
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- 2024
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25. Claudin-2: A marker for a better evaluation of histological mucosal healing in inflammatory bowel diseases.
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Villanacci V, Del Sordo R, Lanzarotto F, Ricci C, Sidoni A, Manenti S, Mino S, Bugatti M, and Bassotti G
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Background: Histological mucosal healing has become a paramount target goal to achieve in the treatment of inflammatory bowel diseases. However, there is still a lack of agreement on the best way to reach this goal, since numerous histological scores are available worldwide., Aims: We investigated whether claudin-2, a member of claudin family involved in the regulation of intestinal tight junctions, might be useful to assess the presence of active disease in patients with inflammatory bowel diseases., Methods: Biopsies from 123 patients with ulcerative colitis, Crohn's disease, infectious colitides and irritable bowel syndrome patients where tested with immunohistochemistry for claudin-2., Results: Claudin-2 appeared to be a very sensitive marker of disease activity in inflammatory bowel diseases, but was negative in the other kinds of patients. In addition, immunohistochemistry for claudin-2 showed good reproducibility by different pathologists., Conclusions: Should these findings be confirmed in more numerous cohorts of patients, and especially in those with minimal or focal residual disease activity, this simple assessment could be useful in the routine daily practice to facilitate the task of pathologists and clinicians in the diagnosis and management of patients with inflammatory bowel diseases., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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26. Correction to: Immunoglobulin light chain transcript detection by ultrasensitive RNA in situ hybridization for B-cell lymphoma diagnosis.
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Lorenzi L, Lonardi S, Bonezzi M, Zini S, Bugatti M, Valzelli A, Melotti F, Facchetti M, Ghini I, Villanacci V, Balzarini P, Pizzi M, Giustini V, Galvagni A, Chiarini M, Dei Tos AP, Vermi W, Casola S, and Facchetti F
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- 2024
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27. Plasmacytoid dendritic cells at the forefront of anti-cancer immunity: rewiring strategies for tumor microenvironment remodeling.
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Monti M, Ferrari G, Gazzurelli L, Bugatti M, Facchetti F, and Vermi W
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- Humans, Animals, Tumor Microenvironment immunology, Dendritic Cells immunology, Neoplasms immunology, Neoplasms pathology
- Abstract
Plasmacytoid dendritic cells (pDCs) are multifaceted immune cells executing various innate immunological functions. Their first line of defence consists in type I interferons (I-IFN) production upon nucleic acids sensing through endosomal Toll-like receptor (TLR) 7- and 9-dependent signalling pathways. Type I IFNs are a class of proinflammatory cytokines that have context-dependent functions on cancer immunosurveillance and immunoediting. In the last few years, different studies have reported that pDCs are also able to sense cytosolic DNA through cGAS-STING (stimulator of interferon genes) pathway eliciting a potent I-IFN production independently of TLR7/9. Human pDCs are also endowed with direct effector functions via the upregulation of TRAIL and production of granzyme B, the latter modulated by cytokines abundant in cancer tissues. pDCs have been detected in a wide variety of human malignant neoplasms, including virus-associated cancers, recruited by chemotactic stimuli. Although the role of pDCs in cancer immune surveillance is still uncompletely understood, their spontaneous activation has been rarely documented; moreover, their presence in the tumor microenvironment (TME) has been associated with a tolerogenic phenotype induced by immunosuppressive cytokines or oncometabolites. Currently tested treatment options can lead to pDCs activation and disruption of the immunosuppressive TME, providing a relevant clinical benefit. On the contrary, the antibody-drug conjugates targeting BDCA-2 on immunosuppressive tumor-associated pDCs (TA-pDCs) could be proposed as novel immunomodulatory therapies to achieve disease control in patients with advance stage hematologic malignancies or solid tumors. This Review integrate recent evidence on the biology of pDCs and their pharmacological modulation, suggesting their relevant role at the forefront of cancer immunity., (© 2024. The Author(s).)
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- 2024
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28. Immunoglobulin light chain transcript detection by ultrasensitive RNA in situ hybridization for B-cell lymphoma diagnosis.
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Lorenzi L, Lonardi S, Bonezzi M, Zini S, Bugatti M, Valzelli A, Melotti F, Facchetti M, Ghini I, Villanacci V, Balzarini P, Pizzi M, Giustini V, Galvagni A, Chiarini M, Dei Tos AP, Vermi W, Casola S, and Facchetti F
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- Humans, Immunohistochemistry, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, In Situ Hybridization methods, Lymphoma, B-Cell genetics, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell pathology, Immunoglobulin Light Chains genetics
- Abstract
Evaluation of B-cell clonality can be challenging in the interpretation of lymphoid infiltrates on tissue sections. Clonality testing based on IG gene rearrangements analysis by PCR (IG-PCR) is the gold standard. Alternatively, B-cell clonality can be assessed by the recognition of immunoglobulin light chain (IgLC) restriction, by immunohistochemistry (IHC), chromogenic in situ hybridization (ISH) or flow cytometry (FC). IG-PCR requires molecular facilities, and FC requires cell suspensions, both not widely available in routine pathology units. This study evaluates the performance of B-cell clonality detection by IgLC-RNAscope® (RNAsc) in a group of 216 formalin-fixed, paraffin-embedded samples including 185 non-Hodgkin B-cell lymphomas, 11 Hodgkin lymphomas (HL) and 20 reactive samples. IgLC-RNAsc, performed in parallel with FC in 53 cases, demonstrated better performances (93% vs 83%), particularly in diffuse large B-cell lymphoma (98% vs 71%) and follicular lymphoma (93% vs 83%) diagnosis. IgLC-RNAsc was also superior to IHC and ISH especially in samples with limited tumor cell content, where IG-PCR was not informative. Performed for the first time on mediastinal lymphomas, IgLC-RNAsc identified monotypic IgLC transcripts in 69% of primary mediastinal large B-cell lymphoma (PMBCL) and 67% of mediastinal gray zone lymphomas (MGZL). IGK/L double-negative cells were detected in 1 PMBCL, 2 MGZL, and all classical HL, while monotypic IgLC expression appeared to be a hallmark in nodular lymphocyte-predominant HL. IgLC-RNAsc demonstrates to be a powerful tool in B-cell lymphoma diagnosis, above all in challenging cases with limited tumor cell content, ensuring in situ investigations on mechanisms of Ig regulation across lymphoma entities., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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29. Massive parallel sequencing unveils homologous recombination deficiency in follicular dendritic cell sarcoma.
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Lorenzi L, Haferlach T, Mori L, Simbeni M, Walter W, Balzarini P, Meggendorfer M, Döring C, Lonardi S, Bugatti M, Agostinelli C, Mehta J, Borges A, Agaimy A, Simonitsch-Klupp I, Cabeçadas J, Campo E, Pileri SA, Facchetti F, Leo Hansmann M, and Hartmann S
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- Humans, Male, Middle Aged, Female, Aged, Exome Sequencing, Homologous Recombination, Adult, Whole Genome Sequencing, Biomarkers, Tumor genetics, Dendritic Cell Sarcoma, Follicular genetics, Dendritic Cell Sarcoma, Follicular pathology, Dendritic Cell Sarcoma, Follicular diagnosis, Mutation, High-Throughput Nucleotide Sequencing
- Abstract
Standardized treatment options are lacking for patients with unresectable or multifocal follicular dendritic cell sarcoma (FDCS) and disease-related mortality is as high as 20%. Applying whole-genome sequencing (WGS) in one case and whole-exome sequencing (WES) in additional twelve cases, this study adds information on the molecular landscape of FDCS, expanding knowledge on pathobiological mechanisms and identifying novel markers of potential theragnostic significance. Massive parallel sequencing showed high frequency of mutations on oncosuppressor genes, particularly in RB1, CARS and BRCA2 and unveiled alterations on homologous recombination DNA damage repair-related genes in 70% (9/13) of cases. This indicates that patients with high-stage FDCS may be eligible for poly ADP ribose polymerase inhibition protocols. Low tumor mutational burden was confirmed in this study despite common PDL1 expression in FDCS arguing on the efficacy of immune checkpoint inhibitors. CDKN2A deletion, detected by WGS and confirmed by fluorescence in situ hybridization in 41% of cases (9/22) indicates that impairment of cell cycle regulation may sustain oncogenesis in FDCS. Absence of mutations in the RAS/RAF/MAPK pathway and lack of clonal hematopoiesis-related mutations in FDCS sanction its differences from dendritic cell-derived neoplasms of hematopoietic derivation. WGS and WES in FDCS provides additional information on the molecular landscape of this rare tumor, proposing novel candidate genes for innovative therapeutical approaches to improve survival of patients with multifocal disease.
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- 2024
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30. Session Reactions Scale-3: Initial psychometric evidence.
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Řiháček T, Elliott R, Owen J, Ladmanová M, Coleman JJ, and Bugatti M
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- Humans, Psychometrics, Surveys and Questionnaires, Self Report, Professional-Patient Relations, Psychotherapy methods
- Abstract
Objective: This study aimed to develop an updated brief self-report post-session measure, suitable for collecting systematic feedback on clients' session reactions in the context of measurement-based care (MBC). Method: The Session Reactions Scale-3 (SRS-3; 33 items) was developed by extending and adjusting the Revised Session Reactions Scale. In Study 1, the psychometric properties of the SRS-3 were tested on N = 242 clients. In Study 2, a brief version of the SRS-3 (SRS-3-B; 15 items) was developed using a combination of conceptual, empirical, and pragmatic criteria. In Study 3, the psychometric properties of the SRS-3-B were tested on a new sample of N = 265 clients. Results: Exploratory factor analysis supported the use of the SRS-3-B as a two-factor (helpful reactions, hindering reactions) or unidimensional (overall session evaluation) instrument. The SRS-3-B was meaningfully related to another process measure (Individual Therapy Process Questionnaire) both on the item and factor levels. Conclusions: The SRS-3-B is a reliable process measure to elicit rich and clinically meaningful feedback from clients within the MBC context and as a research instrument to assess the helpful and hindering aspects of therapy sessions.
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- 2024
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31. Cutting Edge: PDGF-DD Binding to NKp44 Costimulates TLR9 Signaling and Proinflammatory Cytokine Secretion in Human Plasmacytoid Dendritic Cells.
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Barrow AD, Cella M, Edeling MA, Khan MA, Cervantes-Barragan L, Bugatti M, Schmedt C, Vermi W, and Colonna M
- Subjects
- Animals, Mice, Humans, Interferon-alpha metabolism, Dendritic Cells, Killer Cells, Natural, Immunity, Innate, Toll-Like Receptor 9 metabolism
- Abstract
NKp44 is a human receptor originally found on activated NK cells, group 1 and group 3 innate lymphoid cells that binds dimers of platelet-derived growth factor D (PDGF-DD). NKp44 is also expressed on tissue plasmacytoid dendritic cells (PDCs), but NKp44-PDGF-DD interaction on PDCs remains unstudied. Engagement of NKp44 with PDGF-DD in vitro enhanced PDC secretion of IFN-α, TNF, and IL-6 in response to the TLR9 ligand CpG-ODN, but not TLR7/8 ligands. In tissues, PDCs were found in close contact with PDGF-DD-expressing cells in the high endothelial venules and epithelium of tonsils, melanomas, and skin lesions infected with Molluscum contagiosum. Recombinant PDGF-DD enhanced the serum IFN-α response to systemic HSV-1 infection in a humanized mouse model. We conclude that NKp44 integrates with TLR9 signaling to enhance PDC cytokine production. These findings may have bearings for immune responses to TLR9-based adjuvants, therapy for tumors expressing PDGF-DD, and infections with DNA viruses that induce PDGF-DD expression to enhance viral spread., (Copyright © 2024 by The American Association of Immunologists, Inc.)
- Published
- 2024
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32. Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/Akt/mTOR pathway in mucosal melanoma fitness.
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Monti M, Benerini Gatta L, Bugatti M, Pezzali I, Picinoli S, Manfredi M, Lavazza A, Vanella VV, De Giorgis V, Zanatta L, Missale F, Lonardi S, Zanetti B, Bozzoni G, Cadei M, Abate A, Vergani B, Balzarini P, Battocchio S, Facco C, Turri-Zanoni M, Castelnuovo P, Nicolai P, Fonsatti E, Leone BE, Marengo E, Sigala S, Ronca R, Perego M, Lombardi D, and Vermi W
- Subjects
- Mice, Animals, Humans, Mice, Inbred NOD, Mice, SCID, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Proteomics, TOR Serine-Threonine Kinases, Melanoma
- Abstract
Background: Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology., Methods: Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay., Results: This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines., Conclusions: Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites., (© 2023. The Author(s).)
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- 2024
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33. Impaired activation of plasmacytoid dendritic cells via toll-like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift.
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Monti M, Ferrari G, Grosso V, Missale F, Bugatti M, Cancila V, Zini S, Segala A, La Via L, Consoli F, Orlandi M, Valerio A, Tripodo C, Rossato M, and Vermi W
- Subjects
- Humans, Cytokines metabolism, Toll-Like Receptor 7 metabolism, Toll-Like Receptor 9 metabolism, Interferon-alpha, Immunosuppressive Agents metabolism, Dendritic Cells, Nucleotidyltransferases metabolism, Melanoma metabolism, Skin Neoplasms metabolism
- Abstract
Introduction: Plasmacytoid dendritic cells (pDCs) infiltrate a large set of human cancers. Interferon alpha (IFN-α) produced by pDCs induces growth arrest and apoptosis in tumor cells and modulates innate and adaptive immune cells involved in anti-cancer immunity. Moreover, effector molecules exert tumor cell killing. However, the activation state and clinical relevance of pDCs infiltration in cancer is still largely controversial. In Primary Cutaneous Melanoma (PCM), pDCs density decreases over disease progression and collapses in metastatic melanoma (MM). Moreover, the residual circulating pDC compartment is defective in IFN-α production., Methods: The activation of tumor-associated pDCs was evaluated by in silico and microscopic analysis. The expression of human myxovirus resistant protein 1 (MxA), as surrogate of IFN-α production, and proximity ligation assay (PLA) to test dsDNA-cGAS activation were performed on human melanoma biopsies. Moreover, IFN-α and CXCL10 production by in vitro stimulated (i.e. with R848, CpG-A, ADU-S100) pDCs exposed to melanoma cell lines supernatants (SN-mel) was tested by intracellular flow cytometry and ELISA. We also performed a bulk RNA-sequencing on SN-mel-exposed pDCs, resting or stimulated with R848. Glycolytic rate assay was performed on SN-mel-exposed pDCs using the Seahorse XFe24 Extracellular Flux Analyzer., Results: Based on a set of microscopic, functional and in silico analyses, we demonstrated that the melanoma milieu directly impairs IFN-α and CXCL10 production by pDCs via TLR-7/9 and cGAS-STING signaling pathways. Melanoma-derived immunosuppressive cytokines and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape., Discussion: These findings propose a new window of intervention for novel immunotherapy approaches to amplify the antitumor innate immune response in cutaneous melanoma (CM)., 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. The reviewer CM declared a shared affiliation with the authors VG, MO and MR to the handling editor at time of review., (Copyright © 2024 Monti, Ferrari, Grosso, Missale, Bugatti, Cancila, Zini, Segala, La Via, Consoli, Orlandi, Valerio, Tripodo, Rossato and Vermi.)
- Published
- 2024
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34. A distinct human cell type expressing MHCII and RORγt with dual characteristics of dendritic cells and type 3 innate lymphoid cells.
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Ulezko Antonova A, Lonardi S, Monti M, Missale F, Fan C, Coates ML, Bugatti M, Jaeger N, Fernandes Rodrigues P, Brioschi S, Trsan T, Fachi JL, Nguyen KM, Nunley RM, Moratto D, Zini S, Kong L, Deguine J, Peeples ME, Xavier RJ, Clatworthy MR, Wang T, Cella M, Vermi W, and Colonna M
- Subjects
- Humans, Mice, Animals, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Inflammation metabolism, Dendritic Cells, Lymphocytes, Immunity, Innate
- Abstract
Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt
+ MHCII+ type 3 innate lymphoid cells (ILC3) have also been implicated in the instruction of microbiota-specific Tregs. While RORγt+ APCs have been actively investigated in mice, the identity and function of these cell subsets in humans remain elusive. Herein, we identify a rare subset of RORγt+ cells with dendritic cell (DC) features through integrated single-cell RNA sequencing and single-cell ATAC sequencing. These cells, which we term RORγt+ DC-like cells (R-DC-like), exhibit DC morphology, express the MHC class II machinery, and are distinct from all previously reported DC and ILC3 subsets, but share transcriptional and epigenetic similarities with DC2 and ILC3. We have developed procedures to isolate and expand them in vitro, enabling their functional characterization. R-DC-like cells proliferate in vitro, continue to express RORγt, and differentiate into CD1c+ DC2-like cells. They stimulate the proliferation of allogeneic T cells. The identification of human R-DC-like cells with proliferative potential and plasticity toward CD1c+ DC2-like cells will prompt further investigation into their impact on immune homeostasis, inflammation, and autoimmunity., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2023
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35. Therapist engagement in measurement-based care: The association between client outcomes and therapist viewing frequency.
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Bugatti M, Owen J, Richardson Z, Rasmussen W, and Newton D
- Abstract
Engagement in measurement-based care (MBC) has been shown to be an effective practice for optimizing psychotherapy outcomes. Best practices for MBC suggest that it is crucial for therapists to consistently review scores. However, the exact impact of this practice on MBC's effectiveness has yet to be fully elucidated. The current study examined the association between the frequency of therapists reviewing clients' depression scores and client psychotherapy outcomes. The sample consisted of 6182 clients diagnosed with depression who sought treatment from 2248 therapists through a practice research group. Patient Health Questionnaire-9 (PHQ-9) was administered prior to sessions, and therapists could access the scores via their therapist portal. The results based on multilevel modelling revealed that how often therapists view their clients' PHQ-9 results was not a significant predictor of therapy outcomes. However, therapists who, across their caseloads, viewed client PHQ-9 scores more frequently facilitated better treatment outcomes. These results suggest that therapists who routinely engage in MBC facilitate better therapy outcomes. Implications for practice and research are provided., (© 2023 John Wiley & Sons, Ltd.)
- Published
- 2023
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36. Clinical and transcriptomic characteristics of a novel SMARCD2 mutation that disrupts neutrophil maturation and function.
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Dotta L, Baresi G, Tamassia N, Calzetti F, Bianchetto-Aguilera F, Gasperini S, Gardiman E, Chiarini M, Moratto D, Martellosio G, Serana F, Micheletti M, Tregambe D, Pintabona V, Soncini E, Meini A, Girelli MF, Beghin A, Lanfranchi A, Bugatti M, Brugnoni D, Soresina A, Plebani A, Cassatella M, Vermi W, Porta F, and Badolato R
- Abstract
We report a novel case of SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) mutation successfully treated with hematopoietic stem cell transplantation. The female patient presented delayed cord separation, chronic diarrhea, skin abscesses, skeletal dysmorphisms, and neutropenia with specific granule deficiency. Analysis of the transcriptomic profile of peripheral blood sorted mature and immature SMARCD2 neutrophils showed defective maturation process that associated with altered expression of genes related to specific, azurophilic, and gelatinase granules, such as LTF, CRISP3, PTX3, and CHI3L1. These abnormalities account for the prevalence of immature neutrophils in the peripheral blood, impaired function, and deregulated inflammatory responses., (© 2023 Wiley Periodicals LLC.)
- Published
- 2023
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37. Letter: The importance of histological assessment-a further stride in STRIDE.
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Villanacci V, Bugatti M, Zini S, Del Sordo R, and Bassotti G
- Published
- 2023
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38. The modulation of iron metabolism affects the Rhabdomyosarcoma tumor growth in vitro and in vivo.
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Asperti M, Cantamessa L, Gryzik M, Bugatti M, Codenotti S, Denardo A, Vermi W, Fanzani A, and Poli M
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- Humans, Cell Line, Tumor, Apoptosis, Iron, Iron Chelating Agents pharmacology, Iron Chelating Agents therapeutic use, Rhabdomyosarcoma drug therapy, Rhabdomyosarcoma metabolism, Rhabdomyosarcoma pathology
- Abstract
Rhabdomyosarcoma (RMS) is an aggressive rare neoplasm that derives from mesenchymal cells, which frequently develops resistance to the current therapies and the formation of metastases. Thus, new therapies are needed. The alteration of iron metabolism in cancer cells was effective in reducing the progression of many tumors but not yet investigated in RMS. Here we investigated the effect of iron modulation in RMS both in vitro and in vivo. We first characterized the most used RMS cell lines representing the most common subtypes, embryonal (ERMS, RD cells) and alveolar (ARMS, RH30 cells), for their iron metabolism, in basal condition and in response to its modulation. Then we investigated the effects of both iron overload and chelation strategies in vitro and in vivo. RMS cell lines expressed iron-related proteins, even if at lower levels compared to hepatic cell lines and they are correctly modulated in response to iron increase and deprivation. Interestingly, the treatment with different doses of ferric ammonium citrate (FAC, as iron source) and with deferiprone (DFP, as iron chelator), significantly affected the cell viability of RD and RH30. Moreover, iron supplementation (in the form of iron dextran) or iron chelation (in the form of DFP) were also effective in vivo in inhibiting the tumor mass growth both derived from RD and RH30 with iron chelation treatment the most effective one. All the data suggest that the iron modulation could be a promising approach to overcome the RMS tumor growth. The mechanism of action seems to involve the apoptotic cell death for both iron supplementation and chelation with the concomitant induction of ferroptosis in the case of iron supplementation., (© 2023. The Author(s).)
- Published
- 2023
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39. Immuno-Contexture and Immune Checkpoint Molecule Expression in Mismatch Repair Proficient Colorectal Carcinoma.
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Giacomelli M, Monti M, Pezzola DC, Lonardi S, Bugatti M, Missale F, Cioncada R, Melocchi L, Giustini V, Villanacci V, Baronchelli C, Manenti S, Imberti L, Giurisato E, and Vermi W
- Abstract
Colorectal carcinoma (CRC) represents a lethal disease with heterogeneous outcomes. Only patients with mismatch repair (MMR) deficient CRC showing microsatellite instability and hyper-mutated tumors can obtain clinical benefits from current immune checkpoint blockades; on the other hand, immune- or target-based therapeutic strategies are very limited for subjects with mismatch repair proficient CRC (CRC
pMMR ). Here, we report a comprehensive typing of immune infiltrating cells in CRCpMMR . We also tested the expression and interferon-γ-modulation of PD-L1/CD274. Relevant findings were subsequently validated by immunohistochemistry on fixed materials. CRCpMMR contain a significantly increased fraction of CD163+ macrophages (TAMs) expressing TREM2 and CD66+ neutrophils (TANs) together with decrease in CD4- CD8- CD3+ double negative T lymphocytes (DNTs); no differences were revealed by the analysis of conventional and plasmacytoid dendritic cell populations. A fraction of tumor-infiltrating T-cells displays an exhausted phenotype, co-expressing PD-1 and TIM-3. Remarkably, expression of PD-L1 on fresh tumor cells and TAMs was undetectable even after in vitro stimulation with interferon-γ. These findings confirm the immune suppressive microenvironment of CRCpMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion, and interferon-γ unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCpMMR .- Published
- 2023
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40. Alternative Splicing Changes Promoted by NOVA2 Upregulation in Endothelial Cells and Relevance for Gastric Cancer.
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Di Matteo A, Belloni E, Pradella D, Chiaravalli AM, Pini GM, Bugatti M, Alfieri R, Barzan C, Franganillo Tena E, Bione S, Terenzani E, Sessa F, Wyatt CDR, Vermi W, and Ghigna C
- Subjects
- Neovascularization, Pathologic genetics, Humans, Male, Female, Adult, Middle Aged, Aged, Aged, 80 and over, Biomarkers, Prognosis, Cells, Cultured, Animals, Mice, Alternative Splicing, Up-Regulation, Endothelial Cells pathology, Stomach Neoplasms physiopathology
- Abstract
Angiogenesis is crucial for cancer progression. While several anti-angiogenic drugs are in use for cancer treatment, their clinical benefits are unsatisfactory. Thus, a deeper understanding of the mechanisms sustaining cancer vessel growth is fundamental to identify novel biomarkers and therapeutic targets. Alternative splicing (AS) is an essential modifier of human proteome diversity. Nevertheless, AS contribution to tumor vasculature development is poorly known. The Neuro-Oncological Ventral Antigen 2 (NOVA2) is a critical AS regulator of angiogenesis and vascular development. NOVA2 is upregulated in tumor endothelial cells (ECs) of different cancers, thus representing a potential driver of tumor blood vessel aberrancies. Here, we identified novel AS transcripts generated upon NOVA2 upregulation in ECs, suggesting a pervasive role of NOVA2 in vascular biology. In addition, we report that NOVA2 is also upregulated in ECs of gastric cancer (GC), and its expression correlates with poor overall survival of GC patients. Finally, we found that the AS of the Rap Guanine Nucleotide Exchange Factor 6 ( RapGEF6 ), a newly identified NOVA2 target, is altered in GC patients and associated with NOVA2 expression, tumor angiogenesis, and poor patient outcome. Our findings provide a better understanding of GC biology and suggest that AS might be exploited to identify novel biomarkers and therapeutics for anti-angiogenic GC treatments.
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- 2023
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41. The prometastatic relevance of tumor-infiltrating B lymphocytes in laryngeal squamous cell carcinoma.
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Missale F, Bugatti M, Marchi F, Mandelli GE, Bruni M, Palmerini G, Monti M, Bozzola AM, Arena G, Guastini L, Boggio M, Parrinello G, Peretti G, and Vermi W
- Abstract
Objectives: Laryngeal squamous cell carcinomas (LSCCs) typically have an excellent prognosis for stage I tumors but a significant risk of locoregional and distant recurrence for intermediate to advanced disease. This study will investigate the clinical relevance of the tumor microenvironment in a large cohort of treatment-naïve patients affected by stage II-IV LSCC., Methods: Whole slide-based digital pathology analysis was applied to measure six immune cell populations identified by immunohistochemistry (IHC) staining for CD3, CD8, CD20, CD66b, CD163 and CD38. Survival analysis was performed by Cox proportional hazards models and unsupervised hierarchical clustering using the k-means method. Double IHC staining and in-situ hybridisation by RNAscope allowed further analysis of a protumoral B cell population., Results: A cohort of 98 patients was enrolled and analysed. The cluster of immune-infiltrated LSCCs demonstrated a significantly worse disease-specific survival rate. We also discovered a new association between high CD20
+ B cells and a greater risk of distant recurrence. The phenotypic analysis of infiltrating CD20+ B cells showed a naïve (BCL6- CD27- Mum1- ) regulatory phenotype, producing TGFβ but not IL10, according to an active TGFβ pathway, as proved by positive pSMAD2 staining., Conclusion: The identification of regulatory B cells in the context of LSCC, along with the activation of the TGFβ pathway, could provide the basis for new trials investigating the efficacy of already available molecules targeting the TGFβ pathway in the treatment of LSCC., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
- 2023
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42. The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease.
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Dander E, Vinci P, Vetrano S, Recordati C, Piazza R, Fazio G, Bardelli D, Bugatti M, Sozio F, Piontini A, Bonanomi S, Bertola L, Tassistro E, Valsecchi MG, Calza S, Vermi W, Biondi A, Del Prete A, Sozzani S, and D'Amico G
- Subjects
- Animals, Mice, Adoptive Transfer methods, Bacterial Translocation genetics, Bacterial Translocation immunology, Chemokines blood, Chemokines genetics, Chemokines immunology, Inflammation blood, Inflammation genetics, Inflammation immunology, Inflammation pathology, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins immunology, Monocytes immunology, Monocytes transplantation, Neutrophil Infiltration genetics, Neutrophil Infiltration immunology, Receptors, Chemokine blood, Receptors, Chemokine genetics, Receptors, Chemokine immunology, Transplantation, Homologous adverse effects, Bone Marrow Transplantation adverse effects, Colitis blood, Colitis genetics, Colitis immunology, Colitis pathology, Colitis therapy, Graft vs Host Disease blood, Graft vs Host Disease genetics, Graft vs Host Disease immunology, Graft vs Host Disease pathology, Graft vs Host Disease therapy
- Abstract
Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1-KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium-induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD.
- Published
- 2023
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43. Iron supplementation enhances RSL3-induced ferroptosis to treat naïve and prevent castration-resistant prostate cancer.
- Author
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Maccarinelli F, Coltrini D, Mussi S, Bugatti M, Turati M, Chiodelli P, Giacomini A, De Cillis F, Cattane N, Cattaneo A, Ligresti A, Asperti M, Poli M, Vermi W, Presta M, and Ronca R
- Abstract
Prostate cancer (PCa) is a leading cause of death in the male population commonly treated with androgen deprivation therapy that often relapses as androgen-independent and aggressive castration-resistant prostate cancer (CRPC). Ferroptosis is a recently described form of cell death that requires abundant cytosolic labile iron to promote membrane lipid peroxidation and which can be induced by agents that inhibit the glutathione peroxidase-4 activity such as RSL3. Exploiting in vitro and in vivo human and murine PCa models and the multistage transgenic TRAMP model of PCa we show that RSL3 induces ferroptosis in PCa cells and demonstrate for the first time that iron supplementation significantly increases the effect of RSL3 triggering lipid peroxidation, enhanced intracellular stress and leading to cancer cell death. Moreover, the combination with the second generation anti-androgen drug enzalutamide potentiates the effect of the RSL3 + iron combination leading to superior inhibition of PCa and preventing the onset of CRPC in the TRAMP mouse model. These data open new perspectives in the use of pro-ferroptotic approaches alone or in combination with enzalutamide for the treatment of PCa., (© 2023. The Author(s).)
- Published
- 2023
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44. Measurement-based care professional practice guideline: Don't forget the therapists!
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Bugatti M, Richardson Z, Rasmussen W, Newton D, and Owen J
- Subjects
- Humans, Practice Guidelines as Topic, Psychotherapy, Standard of Care
- Abstract
Boswell et al. (2022) professional practice guideline builds an excellent, evidence-driven argument in favor of the routine implementation of measurement-based care (MBC). Nonetheless, as learned from the attempted implementation of evidence-based psychotherapies, presenting empirical evidence does not affect therapist behavior. As such, we argue for an actionable and practical professional practice guideline. We review some of the most hindering barriers to the implementation of MBC, and we offer guidance introducing some of the efforts needed to overcome them. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
- Published
- 2023
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45. Functional profiles of curatively treated adenoid cystic carcinoma unveil prognostic features and potentially targetable pathways.
- Author
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Romani C, Lorini L, Bozzola A, Bignotti E, Tomasoni M, Ardighieri L, Bugatti M, Battocchio S, Ravaggi A, Tomasini D, Ravanelli M, Gurizzan C, Lombardi D, Mattavelli D, Calza S, Piazza C, and Bossi P
- Subjects
- Humans, Prognosis, Proteostasis, G2 Phase Cell Cycle Checkpoints, Carcinoma, Adenoid Cystic genetics
- Abstract
Adenoid cystic carcinoma (ACC) of salivary gland is a slowly growing tumor showing a propensity for delayed recurrence, with decreased survival rates. The identification of poor prognosis patients may help in defining molecular-based targeted strategies in this rare disease orphan of new treatments. Through a gene expression microarray-based approach followed by GSE functional analysis the expression profile of 46 primary untreated ACC samples and of ACC (h-TERT) tumor cells was analyzed. Patients who experienced early relapse showed enrichment in proliferation-related gene sets, including the G2-M checkpoint, E2F and myc targets, and in gene sets related to IFN signaling and aberrant proteostasis (FDR < 0.1), indicating increased mitotic and transcriptional activity in aggressive ACC. Similar functions were enriched in ACC samples classified by immunohistochemical staining as p63-negative, which exhibited increased protein burden and activation of pro-survival stress response pathways compared to p63-positive tumors. Compared to ACC tissues, ACC (h-TERT) cells share transcriptional features of aggressive p63-negative tumors. These data suggest association of specific pathway alterations with histopathological features of ACC, as recapitulated by p63 testing in patient prognostic stratification, anticipating new avenues for therapeutic intervention., (© 2023. The Author(s).)
- Published
- 2023
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46. Integrated Biomarker Analysis Reveals L1CAM as a Potential Stratification Marker for No Specific Molecular Profile High-Risk Endometrial Carcinoma.
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Ravaggi A, Capoferri D, Ardighieri L, Ghini I, Ferrari F, Romani C, Bugatti M, Zanotti L, Vrede S, Tognon G, Pijnenborg JMA, Sartori E, Calza S, Bignotti E, and Odicino F
- Abstract
Histopathologic assessment of high-risk endometrial cancer (EC) suffers from intersubject variability and poor reproducibility. The pragmatic classification in four molecular subgroups helps to overcome these limits, showing a significant prognostic value. The "no specific molecular profile" (NSMP) is the most heterogeneous EC subgroup, requiring further characterization to better guide its clinical management. DNA sequencing of POLE exonuclease domain and immunohistochemistry for PMS2, MSH6, and p53 were performed in order to stratify a cohort of 94 high-risk EC patients in the four molecular subgroups. Moreover, a panel of seven additional biomarkers was tested. Patients were found to be 16% POLE-mutated, 36% mismatch repair-deficient, 27% p53-abnormal, and 21% NSMP. In the multivariable model, molecular groups confirmed their significant association with disease-specific survival and progression-free survival, with p53-abnormal and NSMP endometrial cancer characterized by poor outcomes. Among the additional evaluated biomarkers, L1CAM was the only one with a significant prognostic value within the NSMP subgroup. NSMP/L1CAM-positive patients experienced the worst outcome and were "early-relapsing" after platinum-based chemotherapy, with a significantly shorter platinum-free interval compared to L1CAM-negative patients. L1CAM appears to be a promising candidate as a prognostic and predictive biomarker in the high-risk NSMP subgroup, which is actually known to lack specific molecular markers.
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- 2022
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47. A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types.
- Author
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Bugatti M, Bergamini M, Missale F, Monti M, Ardighieri L, Pezzali I, Picinoli S, Caronni N, Missolo-Koussou Y, Helft J, Benvenuti F, and Vermi W
- Subjects
- Humans, Macrophages, CD8-Positive T-Lymphocytes, Chemokines metabolism, Tertiary Lymphoid Structures, Carcinoma metabolism, Folate Receptor 2 metabolism
- Abstract
TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remain poorly explored. Here we combined extensive immunolabeling of human tissues with in silico analysis of pan-cancer transcriptomic data sets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In silico analysis of a pan-cancer data set revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells, and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had a higher expression of the immunosuppressive molecules TREM2, IL10, and TGFβ as compared with TLSTIM4+MΦ. By analyzing a scRNA sequence data set of tumor-associated myeloid cells, we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene signature positively correlates with a better prognosis. Together, these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotypes and tissue localization and that may have opposing roles in tumor immunity., (©2022 American Association for Cancer Research.)
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- 2022
- Full Text
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48. Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways.
- Author
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Filiberti S, Russo M, Lonardi S, Bugatti M, Vermi W, Tournier C, and Giurisato E
- Abstract
Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal.
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- 2022
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49. Clinician perceptions of nomothetic and individualized patient-reported outcome measures in measurement-based care.
- Author
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Bugatti M and Boswell JF
- Subjects
- Feedback, Humans, Evidence-Based Practice, Patient Reported Outcome Measures
- Abstract
Objective : Measurement-based care (MBC), which encompasses routine outcome monitoring (ROM) and measurement feedback systems (MFSs), is an evidence-based practice (EBP) supporting treatment personalization and clinical responsiveness. Despite MBC's effectiveness, clinicians report reservations regarding its utility, which may be a function of overreliance on nomothetic (i.e., standardized) measures. Although research suggests that individualized (i.e., idiographic) patient-reported outcome measures (I-PROMs) may have the potential to overcome these obstacles, little is known regarding clinicians' perceptions of different measurement approaches to MBC. Methods : This study examined clinicians' perceptions of the clinical utility, relevance to treatment planning, and practicality of nomothetic, individualized, and combined clinical feedback provided by a simulated MFS. Three hundred and twenty-nine clinicians were randomized to one of three conditions that presented a clinical vignette comprising: (a) nomothetic, (b) individualized, or (c) combined clinical feedback. Results : Participants' perceptions of the clinical feedback were not affected by the measurement approach. However, cognitive behavioral participants reported more positive perceptions of all aspects associated with the clinical feedback. Conclusion : These results were consistent with previous findings, suggesting that clinicians' theoretical orientation may have a significant impact on their perceptions of MBC, and should be considered when designing and implementing these systems.
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- 2022
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50. L1CAM expression as a predictor of platinum response in high-risk endometrial carcinoma.
- Author
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Romani C, Capoferri D, Reijnen C, Lonardi S, Ravaggi A, Ratti M, Bugatti M, Zanotti L, Tognon G, Sartori E, Odicino F, Calza S, Pijnenborg JMA, and Bignotti E
- Subjects
- Biomarkers, Tumor analysis, Carboplatin pharmacology, Female, Humans, Neoplasm Staging, Platinum, Prognosis, Carcinoma, Endometrioid pathology, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics, Endometrial Neoplasms metabolism, Neural Cell Adhesion Molecule L1 genetics
- Abstract
For high-risk endometrial cancer (EC) patients, adjuvant chemotherapy is recommended to improve outcome. Yet, predictive biomarkers for response to platinum-based chemotherapy (Pt-aCT) are currently lacking. We tested expression of L1 cell-adhesion molecule (L1CAM), a well-recognised marker of poor prognosis in EC, in tumour samples from high-risk EC patients, to explore its role as a predictive marker of Pt-aCT response. L1CAM expression was determined using RT-qPCR and immunohistochemistry in a cohort of high-risk EC patients treated with Pt-aCT and validated in a multicentric independent cohort. The association between L1CAM and clinicopathologic features and L1CAM additive value in predicting platinum response were determined. The effect of L1CAM gene silencing on response to carboplatin was functionally tested on primary L1CAM-expressing cells. Increased L1CAM expression at both genetic and protein level correlated with high-grade, non-endometrioid histology and poor response to platinum treatment. A predictive model adding L1CAM to prognostic clinical variables significantly improved platinum response prediction (C-index 78.1%, P = .012). In multivariate survival analysis, L1CAM expression was significantly associated with poor outcome (HR: 2.03, P = .019), potentially through an indirect effect, mediated by its influence on response to chemotherapy. In vitro, inhibition of L1CAM significantly increased cell sensitivity to carboplatin, supporting a mechanistic link between L1CAM expression and response to platinum in EC cells. In conclusion, we have demonstrated the role of L1CAM in the prediction of response to Pt-aCT in two independent cohorts of high-risk EC patients. L1CAM is a promising candidate biomarker to optimise decision making in high-risk patients who are eligible for Pt-aCT., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Published
- 2022
- Full Text
- View/download PDF
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