48 results on '"Terreri, S."'
Search Results
2. The response to BTN62b2 booster doses demonstrates that serum antibodies do not predict the establishment of immune B-cell memory in common variable immune deficiencies
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Piano Mortari, E., primary, Pulvirenti, F., additional, Marcellini, V., additional, Terreri, S., additional, Fernandez Salinas, A., additional, Ferrari, S., additional, Di Napoli, G., additional, Guadagnolo, D., additional, Sculco, E., additional, Albano, C., additional, Guercio, M., additional, Di Cecca, S., additional, Milito, C., additional, Garzi, G., additional, Pesce, A.M., additional, Bonanni, L., additional, Sinibaldi, M., additional, Di Cecilia, S., additional, Agrati, C., additional, Quintarelli, C., additional, Zaffina, S., additional, Locatelli, F., additional, Carsetti, R., additional, and Quinti, I., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Impaired memory B-cell response to the Pfizer-BioNTech COVID-19 vaccine in patients with common variable immunodeficiency
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Fernandez Salinas, A., Piano Mortari, E., Terreri, S., Milito, C., Zaffina, S., Perno, C. F., Locatelli, Franco, Quinti, I., Carsetti, R., Locatelli F. (ORCID:0000-0002-7976-3654), Fernandez Salinas, A., Piano Mortari, E., Terreri, S., Milito, C., Zaffina, S., Perno, C. F., Locatelli, Franco, Quinti, I., Carsetti, R., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
no abstract
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- 2022
4. Persistent B cell memory after SARS-CoV-2 vaccination is functional during breakthrough infections
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Terreri, S., Piano Mortari, E., Vinci, M. R., Russo, C., Alteri, C., Albano, C., Colavita, F., Gramigna, G., Agrati, C., Linardos, G., Coltella, L., Colagrossi, L., Deriu, G., Ciofi Degli Atti, M., Rizzo, C., Scarsella, M., Brugaletta, R., Camisa, V., Santoro, A., Roscilli, G., Pavoni, E., Muzi, A., Magnavita, N., Scutari, R., Villani, A., Raponi, M., Locatelli, F., Perno, C. F., Zaffina, S., Carsetti, R., Piano Mortari E., Vinci M. R., Deriu G., Camisa V., Muzi A., Magnavita N. (ORCID:0000-0002-0988-7344), Villani A., Locatelli F. (ORCID:0000-0002-1268-0125), Zaffina S. (ORCID:0000-0002-8858-5423), Carsetti R., Terreri, S., Piano Mortari, E., Vinci, M. R., Russo, C., Alteri, C., Albano, C., Colavita, F., Gramigna, G., Agrati, C., Linardos, G., Coltella, L., Colagrossi, L., Deriu, G., Ciofi Degli Atti, M., Rizzo, C., Scarsella, M., Brugaletta, R., Camisa, V., Santoro, A., Roscilli, G., Pavoni, E., Muzi, A., Magnavita, N., Scutari, R., Villani, A., Raponi, M., Locatelli, F., Perno, C. F., Zaffina, S., Carsetti, R., Piano Mortari E., Vinci M. R., Deriu G., Camisa V., Muzi A., Magnavita N. (ORCID:0000-0002-0988-7344), Villani A., Locatelli F. (ORCID:0000-0002-1268-0125), Zaffina S. (ORCID:0000-0002-8858-5423), and Carsetti R.
- Abstract
Breakthrough SARS-CoV-2 infections in fully vaccinated individuals are considered a consequence of waning immunity. Serum antibodies represent the most measurable outcome of vaccine-induced B cell memory. When antibodies decline, memory B cells are expected to persist and perform their function, preventing clinical disease. We investigated whether BNT162b2 mRNA vaccine induces durable and functional B cell memory in vivo against SARS-CoV-2 3, 6, and 9 months after the second dose in a cohort of health care workers (HCWs). While we observed physiological decline of SARS-CoV-2-specific antibodies, memory B cells persist and increase until 9 months after immunization. HCWs with breakthrough infections had no signs of waning immunity. In 3–4 days, memory B cells responded to SARS-CoV-2 infection by producing high levels of specific antibodies in the serum and anti-Spike IgA in the saliva. Antibodies to the viral nucleoprotein were produced with the slow kinetics typical of the response to a novel antigen.
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- 2022
5. SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best
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Salinas, A. F., Mortari, E. P., Terreri, S., Quintarelli, C., Pulvirenti, F., Di Cecca, S., Guercio, M., Milito, C., Bonanni, L., Auria, S., Romaggioli, L., Cusano, G., Albano, C., Zaffina, S., Perno, C. F., Spadaro, G., Locatelli, Franco, Carsetti, R., Quinti, I., Locatelli F. (ORCID:0000-0002-7976-3654), Salinas, A. F., Mortari, E. P., Terreri, S., Quintarelli, C., Pulvirenti, F., Di Cecca, S., Guercio, M., Milito, C., Bonanni, L., Auria, S., Romaggioli, L., Cusano, G., Albano, C., Zaffina, S., Perno, C. F., Spadaro, G., Locatelli, Franco, Carsetti, R., Quinti, I., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. Methods: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. Results: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. Conclusion: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.
- Published
- 2021
6. B cell response induced by SARS-CoV-2 infection is boosted by the BNT162b2 vaccine in primary antibody deficiencies
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Pulvirenti, F., Salinas, A. F., Milito, C., Terreri, S., Mortari, E. P., Quintarelli, C., Di Cecca, S., Lagnese, G., Punziano, A., Guercio, M., Bonanni, L., Auria, S., Villani, F., Albano, C., Locatelli, Franco, Spadaro, G., Carsetti, R., Quinti, I., Locatelli F. (ORCID:0000-0002-7976-3654), Pulvirenti, F., Salinas, A. F., Milito, C., Terreri, S., Mortari, E. P., Quintarelli, C., Di Cecca, S., Lagnese, G., Punziano, A., Guercio, M., Bonanni, L., Auria, S., Villani, F., Albano, C., Locatelli, Franco, Spadaro, G., Carsetti, R., Quinti, I., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization. Methods: Thirty-four CVID convalescent patients after SARS-CoV-2 infection, 38 CVID patients immunized with two doses of the BNT162b2 vaccine, and 20 SARS-CoV-2 CVID convalescents later and immunized with BNT162b2 were analyzed for the anti-spike IgG production and the generation of spike-specific memory B cells and T cells. Results: Spike-specific IgG was induced more frequently after infection than after vaccination (82% vs. 34%). The antibody response was boosted in convalescents by vaccination. Although immunized patients generated atypical memory B cells possibly by extra-follicular or incomplete germinal center reactions, convalescents responded to infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Poor spike-specific T cell responses were measured independently from the immunological challenge. Conclusions: SARS-CoV-2 infection primed a more efficient classical memory B cell response, whereas the BNT162b2 vaccine induced non-canonical B cell responses in CVID. Natural infection responses were boosted by subsequent immunization, suggesting the possibility to further stimulate the immune response by additional vaccine doses in CVID.
- Published
- 2021
7. Highly specific memory b cells generation after the 2nd dose of bnt162b2 vaccine compensate for the decline of serum antibodies and absence of mucosal iga
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Mortari, E. P., Russo, C., Vinci, Maria Rosaria, Terreri, S., Salinas, A. F., Piccioni, L., Alteri, C., Colagrossi, L., Coltella, L., Ranno, S., Linardos, G., Agosta, Marilena, Albano, C., Agrati, C., Castilletti, C., Meschi, S., Romania, P., Roscilli, G., Pavoni, E., Camisa, Vincenzo, Santoro, A., Brugaletta, R., Magnavita, Nicola, Ruggiero, Antonio, Cotugno, N., Amodio, D., Atti, M. L. C. D., Giorgio, D., Russo, N., Salvatori, G., Corsetti, T., Locatelli, Federica, Perno, C. F., Zaffina, Salvatore, Carsetti, Rita, Vinci M. R., Agosta M., Camisa V., Magnavita N. (ORCID:0000-0002-0988-7344), Ruggiero A. (ORCID:0000-0002-6052-3511), Locatelli F. (ORCID:0000-0002-1268-0125), Zaffina S. (ORCID:0000-0002-8858-5423), Carsetti R., Mortari, E. P., Russo, C., Vinci, Maria Rosaria, Terreri, S., Salinas, A. F., Piccioni, L., Alteri, C., Colagrossi, L., Coltella, L., Ranno, S., Linardos, G., Agosta, Marilena, Albano, C., Agrati, C., Castilletti, C., Meschi, S., Romania, P., Roscilli, G., Pavoni, E., Camisa, Vincenzo, Santoro, A., Brugaletta, R., Magnavita, Nicola, Ruggiero, Antonio, Cotugno, N., Amodio, D., Atti, M. L. C. D., Giorgio, D., Russo, N., Salvatori, G., Corsetti, T., Locatelli, Federica, Perno, C. F., Zaffina, Salvatore, Carsetti, Rita, Vinci M. R., Agosta M., Camisa V., Magnavita N. (ORCID:0000-0002-0988-7344), Ruggiero A. (ORCID:0000-0002-6052-3511), Locatelli F. (ORCID:0000-0002-1268-0125), Zaffina S. (ORCID:0000-0002-8858-5423), and Carsetti R.
- Abstract
Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.
- Published
- 2021
8. Evolution of Human Memory B Cells From Childhood to Old Age
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Ciocca, M., Zaffina, Salvatore, Fernandez Salinas, A., Bocci, C., Palomba, P., Conti, M. G., Terreri, S., Frisullo, Giovanni, Giorda, E., Scarsella, M., Brugaletta, R., Vinci, Maria Rosaria, Magnavita, Nicola, Carsetti, Rita, Piano Mortari, E., Zaffina S. (ORCID:0000-0002-8858-5423), Frisullo G., Vinci M. R., Magnavita N. (ORCID:0000-0002-0988-7344), Carsetti R., Ciocca, M., Zaffina, Salvatore, Fernandez Salinas, A., Bocci, C., Palomba, P., Conti, M. G., Terreri, S., Frisullo, Giovanni, Giorda, E., Scarsella, M., Brugaletta, R., Vinci, Maria Rosaria, Magnavita, Nicola, Carsetti, Rita, Piano Mortari, E., Zaffina S. (ORCID:0000-0002-8858-5423), Frisullo G., Vinci M. R., Magnavita N. (ORCID:0000-0002-0988-7344), and Carsetti R.
- Abstract
High quality medical assistance and preventive strategies, including pursuing a healthy lifestyle, result in a progressively growing percentage of older people. The population and workforce is aging in all countries of the world. It is widely recognized that older individuals show an increased susceptibility to infections and a reduced response to vaccination suggesting that the aged immune system is less able to react and consequently protect the organism. The SARS-CoV-2 pandemic is dramatically showing us that the organism reacts to novel pathogens in an age-dependent manner. The decline of the immune system observed in aging remains unclear. We aimed to understand the role of B cells. We analyzed peripheral blood from children (4-18 years); young people (23-60 years) and elderly people (65-91 years) by flow cytometry. We also measured antibody secretion by ELISA following a T-independent stimulation. Here we show that the elderly have a significant reduction of CD27dull memory B cells, a population that bridges innate and adaptive immune functions. In older people, memory B cells are mostly high specialized antigen-selected CD27bright. Moreover, after in vitro stimulation with CpG, B cells from older individuals produced significantly fewer IgM and IgA antibodies compared to younger individuals. Aging is a complex process characterized by a functional decline in multiple physiological systems. The immune system of older people is well equipped to react to often encountered antigens but has a low ability to respond to new pathogens.
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- 2021
9. Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases
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Carsetti, R., Zaffina, S., Piano Mortari, E., Terreri, S., Corrente, F., Capponi, C., Palomba, P., Mirabella, M., Cascioli, S., Palange, P., Cuccaro, I., Milito, C., Zumla, A., Maeurer, M., Camisa, V., Vinci, M. R., Santoro, A., Cimini, E., Marchioni, L., Nicastri, E., Palmieri, F., Agrati, C., Ippolito, G., Porzio, O., Concato, C., Onetti Muda, A., Raponi, M., Quintarelli, C., Quinti, I., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Carsetti, R., Zaffina, S., Piano Mortari, E., Terreri, S., Corrente, F., Capponi, C., Palomba, P., Mirabella, M., Cascioli, S., Palange, P., Cuccaro, I., Milito, C., Zumla, A., Maeurer, M., Camisa, V., Vinci, M. R., Santoro, A., Cimini, E., Marchioni, L., Nicastri, E., Palmieri, F., Agrati, C., Ippolito, G., Porzio, O., Concato, C., Onetti Muda, A., Raponi, M., Quintarelli, C., Quinti, I., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; eight patients with Mild COVID-19 disease and eight cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.
- Published
- 2020
10. Are SARS‐CoV‐2 IgA antibodies in paediatric patients with chilblain‐like lesions indicative of COVID‐19 asymptomatic or paucisymptomatic infection?
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Diociaiuti, A., primary, Giancristoforo, S., additional, Terreri, S., additional, Corbeddu, M., additional, Concato, C., additional, Ciofi Degli Atti, M., additional, Zambruno, G., additional, Carsetti, R., additional, and El Hachem, M., additional
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- 2020
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11. Are SARS‐CoV‐2 IgA antibodies in paediatric patients with chilblain‐like lesions indicative of COVID‐19 asymptomatic or paucisymptomatic infection?
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Diociaiuti, A., Giancristoforo, S., Terreri, S., Corbeddu, M., Concato, C., Ciofi Degli Atti, M., Zambruno, G., Carsetti, R., and El Hachem, M.
- Subjects
CHILD patients ,COVID-19 ,SARS-CoV-2 ,IMMUNOGLOBULIN A ,IMMUNOGLOBULINS - Abstract
Are SARS-CoV-2 IgA antibodies in paediatric patients with chilblain-like lesions indicative of COVID-19 asymptomatic or paucisymptomatic infection? Dear Editor, Acral chilblain-like lesions in young patients are one of the commonest skin manifestations reported during COVID-19 pandemic.1-3 Despite the temporal and spatial correlation between the outbreak of pernio-like and the pandemic, the relationship with COVID-19 remains uncertain. Three patients of group B reported flu-like symptoms 3-4 weeks before skin lesion onset, and a single patient developed chilblain after proving positive to SARS-CoV-2. [Extracted from the article]
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- 2021
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12. FINGERPRINTING OF ULTRACONSERVED GENOMIC REGIONS(UCRS) IN BLADDER CANCER ANALYSIS REVEALS A UCR 8 AT THE TOP OF A NETWORK BETWEEN NON-CODING RNA AND MICRORNA
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Ferro, M., Matei, D. V., Bottero, D., Musi, G., Perdona, S., Terracciano, D., Olivieri, M., Durso, M., Terreri, S., Febbraio, F., Cimmino, A., Altieri, V., and OTTAVIO DE COBELLI
- Published
- 2014
13. Inflammatory conditions associated to type 2 diabetes cause Prep-1 gene overexpression by inducing epigenetic modifications on its promoter region
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Ciccarelli M, Albano L, Vastolo V, Terreri S, Desiderio A, Beguinot F, and Ungaro P.
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- 2013
14. CONDIZIONI INFIAMMATORIE ASSOCIATE AL DIABETE TIPO 2 ALTERANO LA REGOLAZIONE EPIGENETICA DEL GENE PREP1
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Ciccarelli M, Mirra P, Vastolo V, Longo M, Albano L, Terreri S, Beguinot F, and Ungaro P
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- 2012
15. Iperglicemia e acidi grassi alterano la regolazione epigenetica del gene Prep1
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Ciccarelli M, Mirra P, Vastolo V, Albano L, Terreri S, Valentino R, Begionot F, and Ungaro P.
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- 2012
16. Different reactivity to different formula in cow milk allergy: the role of Basophil Activation Test.
- Author
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Mennini, M., Terreri, S., Fierro, V., Palomba, P., Riccardi, C., Dahdah, L., Fiocchi, A. G., and Carsetti, R.
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- 2022
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17. Role of PA2G4P4 pseudogene in bladder cancer tumorigenesis
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Pasquale Barba, Giovanna L. Liguori, Amelia Cimmino, Maria Donnini, Paolo Verze, Maria Strazzullo, Vincenzo Mercadante, Alessandro Palmieri, Marianna Mastroianni, Giovanna Del Pozzo, Sara Terreri, Vincenzo Mirone, Vincenzo Altieri, Gianluigi Califano, Laura Pisapia, Pisapia, L., Terreri, S., Barba, P., Mastroianni, M., Donnini, M., Mercadante, V., Palmieri, A., Verze, P., Mirone, V., Altieri, V., Califano, G., Liguori, G. L., Strazzullo, M., Cimmino, A., and Del Pozzo, G.
- Subjects
Pseudogene ,In situ hybridization ,Biology ,Bladder cancer ,EBP1 ,Expression ,Noncoding RNA ,Oncogene ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,noncoding RNA ,03 medical and health sciences ,0302 clinical medicine ,oncogene ,Gene expression ,expression ,medicine ,lcsh:QH301-705.5 ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,General Immunology and Microbiology ,medicine.disease ,Non-coding RNA ,3. Good health ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Cancer research ,bladder cancer ,General Agricultural and Biological Sciences ,Carcinogenesis - Abstract
Background: Many pseudogenes possess biological activities and play important roles in the pathogenesis of various types of cancer including bladder cancer (BlCa), which still lacks suitable molecular biomarkers. Recently, pseudogenes were found to be significantly enriched in a pan-cancer classification based on the Cancer Genome Atlas gene expression data. Among them, the top-ranking pseudogene was the proliferation-associated 2G4 pseudogene 4 (PA2G4P4). Methods: Genomic and transcript features of PA2G4P4 were determined by GeneBank database analysis followed by 5&rsquo, RACE experiments. Therefore, we conducted a retrospective molecular study on a cohort of 45 patients of BlCa. PA2G4P4 expression was measured by RT-qPCR, whereas PA2G4P4 transcript distribution was analyzed by in situ hybridization on both normal and cancerous histological sections and compared to the immunolocalization of its parental PA2G4/EBP1 protein. Finally, we tested the effects of PA2G4P4 depletion on proliferation, migration, and death of BlCa cells. Results: We showed for the first time PA2G4P4 overexpression in BlCa tissues and in cell lines. PA2G4P4 distribution strictly overlaps PA2G4/EBP1 protein localization. Moreover, we showed that PA2G4P4 knockdown affects both proliferation and migration of BlCa cells, highlighting its potential oncogenic role. Conclusions: PA2G4P4 may play a functional role as an oncogene in BlCa development, suggesting it as a good candidate for future investigation and new clinical applications.
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18. Effects of coagulation factors on bone cells and consequences of their absence in haemophilia a patients.
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Battafarano G, Lancellotti S, Sacco M, Rossi M, Terreri S, Di Gregorio J, Di Giuseppe L, D'Agostini M, Porzio O, Di Gennaro L, Tardugno M, Pelle S, Minisola S, Toniolo RM, Luciani M, Del Fattore A, and De Cristofaro R
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- Humans, Adult, Osteoblasts metabolism, Male, Bone Resorption metabolism, Factor VIII metabolism, Factor VIII genetics, Cells, Cultured, Hemophilia A blood, Osteoclasts metabolism, Leukocytes, Mononuclear metabolism, Blood Coagulation Factors metabolism, Blood Coagulation Factors genetics, Cell Differentiation
- Abstract
Haemophilia is associated with reduced bone mass and mineral density. Due to the rarity of the disease and the heterogeneity among the studies, the pathogenesis of bone loss is still under investigation. We studied the effects of coagulation factors on bone cells and characterized in a pilot study the osteoclastogenic potential of patients' osteoclast precursors. To evaluate the effect of coagulation factors on osteoclasts, we treated Healthy Donor-Peripheral Blood Mononuclear Cells (HD-PBMC) with Factor VIII (FVIII), von Willebrand Factor (VWF), FVIII/VWF complex, activated Factor IX (FIXa), activated Factor X (FXa) and Thrombin (THB). FVIII, VWF, FVIII/VWF, FXa and THB treatments reduced osteoclast differentiation of HD-PBMC and VWF affected also bone resorption. Interestingly, PBMC isolated from patients with moderate/severe haemophilia showed an increased osteoclastogenic potential due to the alteration of osteoclast precursors. Moreover, increased expression of genes involved in osteoclast differentiation/activity was revealed in osteoclasts of an adult patient with moderate haemophilia. Control osteoblasts treated with the coagulation factors showed that FVIII and VWF reduced ALP positivity; the opposite effect was observed following THB treatment. Moreover, FVIII, VWF and FVIII/VWF reduced mineralization ability. These results could be important to understand how coagulation factors deficiency influences bone remodeling activity in haemophilia., (© 2024. The Author(s).)
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- 2024
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19. Protein Stability Regulation in Osteosarcoma: The Ubiquitin-like Modifications and Glycosylation as Mediators of Tumor Growth and as Targets for Therapy.
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Di Gregorio J, Di Giuseppe L, Terreri S, Rossi M, Battafarano G, Pagliarosi O, Flati V, and Del Fattore A
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- Humans, Glycosylation, Ubiquitin, Protein Stability, Osteosarcoma pathology, Bone Neoplasms pathology
- Abstract
The identification of new therapeutic targets and the development of innovative therapeutic approaches are the most important challenges for osteosarcoma treatment. In fact, despite being relatively rare, recurrence and metastatic potential, particularly to the lungs, make osteosarcoma a deadly form of cancer. In fact, although current treatments, including surgery and chemotherapy, have improved survival rates, the disease's recurrence and metastasis are still unresolved complications. Insights for analyzing the still unclear molecular mechanisms of osteosarcoma development, and for finding new therapeutic targets, may arise from the study of post-translational protein modifications. Indeed, they can influence and alter protein structure, stability and function, and cellular interactions. Among all the post-translational modifications, ubiquitin-like modifications (ubiquitination, deubiquitination, SUMOylation, and NEDDylation), as well as glycosylation, are the most important for regulating protein stability, which is frequently altered in cancers including osteosarcoma. This review summarizes the relevance of ubiquitin-like modifications and glycosylation in osteosarcoma progression, providing an overview of protein stability regulation, as well as highlighting the molecular mediators of these processes in the context of osteosarcoma and their possible targeting for much-needed novel therapy., Competing Interests: The authors declare no conflicts of interest.
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- 2024
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20. Functional CVIDs phenotype clusters identified by the integration of immune parameters after BNT162b2 boosters.
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Piano Mortari E, Pulvirenti F, Marcellini V, Terreri S, Salinas AF, Ferrari S, Di Napoli G, Guadagnolo D, Sculco E, Albano C, Guercio M, Di Cecca S, Milito C, Garzi G, Pesce AM, Bonanni L, Sinibaldi M, Bordoni V, Di Cecilia S, Accordini S, Castilletti C, Agrati C, Quintarelli C, Zaffina S, Locatelli F, Carsetti R, and Quinti I
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- Humans, BNT162 Vaccine, Longitudinal Studies, SARS-CoV-2, Antibodies, Neutralizing, Phenotype, COVID-19, Common Variable Immunodeficiency
- Abstract
Introduction: Assessing the response to vaccinations is one of the diagnostic criteria for Common Variable Immune Deficiencies (CVIDs). Vaccination against SARS-CoV-2 offered the unique opportunity to analyze the immune response to a novel antigen. We identify four CVIDs phenotype clusters by the integration of immune parameters after BTN162b2 boosters., Methods: We performed a longitudinal study on 47 CVIDs patients who received the 3rd and 4th vaccine dose of the BNT162b2 vaccine measuring the generation of immunological memory. We analyzed specific and neutralizing antibodies, spike-specific memory B cells, and functional T cells., Results: We found that, depending on the readout of vaccine efficacy, the frequency of responders changes. Although 63.8% of the patients have specific antibodies in the serum, only 30% have high-affinity specific memory B cells and generate recall responses., Discussion: Thanks to the integration of our data, we identified four functional groups of CVIDs patients with different B cell phenotypes, T cell functions, and clinical diseases. The presence of antibodies alone is not sufficient to demonstrate the establishment of immune memory and the measurement of the in-vivo response to vaccination distinguishes patients with different immunological defects and clinical diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Piano Mortari, Pulvirenti, Marcellini, Terreri, Salinas, Ferrari, Di Napoli, Guadagnolo, Sculco, Albano, Guercio, Di Cecca, Milito, Garzi, Pesce, Bonanni, Sinibaldi, Bordoni, Di Cecilia, Accordini, Castilletti, Agrati, Quintarelli, Zaffina, Locatelli, Carsetti and Quinti.)
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- 2023
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21. Influence of Defatting and Pasteurization on Nutrients and Oxidative Stress Markers in Human Milk.
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D'Alessandro A, Pastore A, Amadio P, D'Agostini M, Terreri S, Carsetti R, Argentieri M, Bernaschi P, Onetti Muda A, Porzio O, Dotta A, and Salvatori G
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- Infant, Female, Humans, Pasteurization methods, Cross-Sectional Studies, Prospective Studies, Breast Feeding, Nutrients analysis, Triglycerides, Oxidative Stress, Milk, Human, Milk Banks
- Abstract
Background: It is well known that the best nutritional option for infants is human milk, and that when breastfeeding is not possible, human milk banks are a possible alternative. However, in the case of infants with fat transport disorder like chylothorax, defatting of human milk is mandatory., Research Aim: The aim of the study was to reduce milk fat content without reducing other nutrients, increasing oxidative stress, or introducing harmful microorganisms., Methods: In this prospective, cross-sectional, observational study, we examined the influence of defatting and pasteurization of 50 donor samples on fat, macro- and micronutrients, as well as on oxidative stress markers., Results: Low-temperature centrifugation proved to be very efficient in defatting, reducing the concentration of triglycerides by 85% and cholesterol by 50%. The macronutrients (proteins, albumin, and Immunoglobulin A) did not undergo significant changes due to defatting and pasteurization procedures, while iron decreased by 36%. However, as the majority of iron is retained, this result does not remarkably change the milk composition. Furthermore, oxidative stress markers and antioxidant levels were unchanged, and the milk result was microbiologically safe., Conclusions: Cold milk centrifugation proved to be an effective technique that allows the reduction of human milk lipids. The determination of triglycerides and cholesterol can be used as an indicator of skimming. This procedure is not accompanied by substantial modifications of other components present in the milk.
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- 2023
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22. Anti-proliferative, pro-apototic and anti-migratory properties of HDAC inhibitor PXD-101 on osteosarcoma cell lines.
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Rossi M, De Martino V, Di Giuseppe L, Battafarano G, Di Gregorio J, Terreri S, Marampon F, Minisola S, and Del Fattore A
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- Humans, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors therapeutic use, Cell Line, Tumor, Cell Proliferation, Epigenesis, Genetic, Apoptosis, Cell Movement, Osteosarcoma drug therapy, Osteosarcoma genetics, Bone Neoplasms genetics
- Abstract
The therapeutic strategies for osteosarcoma involve both surgical approach and chemotherapy, but the identification of new therapeutic targets is particularly necessary in patients with local chemo-resistance, recurrence and lung metastases. The role of epigenetic regulation in osteosarcoma is largely unknown. Thus, in this study we disclosed the effects of histone deacetylase inhibitor drug PXD-101 on human osteosarcoma (OS) cell lines with different aggressiveness, including Saos-2, HOS and 143B cell lines. XTT assays revealed that treatment of Saos-2, HOS and 143B cells with PXD-101 decreased cell viability in a concentration-dependent manner. Fluorescence-activated cell sorting (FACS) analysis showed that PXD-101 inhibited proliferation and induced cell apoptosis. Wound healing assay indicated that PXD-101 inhibited migration of osteosarcoma cells. Real-Time RT-qPCR and protein analysis highlighted reduced expression of Runx2, Osterix and Mad2, probably due to Cyclin B1 inhibition by PXD-101 treatment. To our knowledge, this is the first study that characterized the anti-tumoral effect of PXD-101 in OS cells, suggesting a potential new therapeutic approach in osteosarcoma patients., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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23. COVID-19 Severity, Cardiological Outcome, and Immunogenicity of mRNA Vaccine on Adult Patients With 22q11.2 DS.
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Pulvirenti F, Mortari EP, Putotto C, Terreri S, Fernandez Salinas A, Cinicola BL, Cimini E, Di Napoli G, Sculco E, Milito C, Versacci P, Agrati C, Marino B, Carsetti R, and Quinti I
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- Humans, Adult, BNT162 Vaccine, COVID-19 Vaccines, SARS-CoV-2, Vaccination, mRNA Vaccines, COVID-19 epidemiology, COVID-19 prevention & control, DiGeorge Syndrome, Lymphopenia
- Abstract
Background: The contemporaneous presence of immune defects and heart diseases in patients with 22q11.2 deletion syndrome (22q11.3DS) might represent risk factors for severe coronavirus 2019 disease (COVID-19)., Objective: To analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcome in 22q11.2DS patients and immunogenicity of different doses of mRNA SARS-CoV-2 vaccine., Methods: Longitudinal observational study on SARS-CoV-2 outcome in 60 adults with 22q11.2DS (March 2020-June 2022). Anti-Spike, and anti-receptor binding domain (RBD) antibody responses, generation of Spike-specific memory B cells (MBCs) and Spike-specific T cells at different time points before and after the mRNA BNT162b2 vaccination were evaluated in 16 22q11.2DS patients., Results: We recorded a 95% rate of vaccination, with almost all patients being immunized with the booster dose. Twenty-one patients had SARS-CoV-2 infection. Three patients were infected before vaccine availability, 6 after receiving 2 doses of vaccine, and 12 after one booster dose. The SARS-CoV-2- infection had a mild course, except in one unvaccinated patient with several comorbidities who died from acute respiratory distress syndrome (fatality rate 5%). Infected patients had more frequently moderate/severe intellectual disability, lymphopenia, and lower CD4+ count. Despite major congenital heart diseases, COVID-19 did not impact cardiological conditions. The BNT162b2 vaccine induced S1-immunoglobulin G (IgG) responses, low serum S1-IgA, and slightly impaired specific MBCs response. Specific T-cell responses observed were related to lymphocytes and CD4+ T cell counts., Conclusions: The SARS-CoV-2 infection had a mild course in most patients with 22q11.2DS, even in patients with major cardiovascular diseases. Immunization induced Spike-specific IgG responses and generated specific MBCs and memory T cells. The weaker memory responses in patients with lymphopenia suggested the need for additional doses., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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24. Severe Acute Respiratory Syndrome Coronavirus 2 Infection Versus Vaccination in Pregnancy: Implications for Maternal and Infant Immunity.
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Conti MG, Terreri S, Terrin G, Natale F, Pietrasanta C, Salvatori G, Brunelli R, Midulla F, Papaevangelou V, Carsetti R, and Angelidou A
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- Antibodies, Viral, BNT162 Vaccine, COVID-19 Vaccines, Female, Humans, Immunoglobulin A, Immunoglobulin G, Infant, Infant, Newborn, Lactation, Placenta, Pregnancy, Prospective Studies, SARS-CoV-2, Vaccination, COVID-19 prevention & control, Viral Vaccines
- Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with adverse maternal and neonatal outcomes, yet uptake of SARS-CoV-2 vaccines during pregnancy and lactation has been slow. As a result, millions of pregnant and lactating women and their infants remain susceptible to the virus., Methods: We measured spike-specific immunoglobulin G (anti-S IgG) and immunoglobulin A (anti-S IgA) in serum and breastmilk (BM) samples from 3 prospective mother-infant cohorts recruited in 2 academic medical centers. The primary aim was to determine the impact of maternal SARS-CoV-2 immunization vs infection and their timing on systemic and mucosal immunity., Results: The study included 28 mothers infected with SARS-CoV-2 in late pregnancy (INF), 11 uninfected mothers who received 2 doses of the BNT162b2 vaccine in the latter half of pregnancy (VAX-P), and 12 uninfected mothers who received 2 doses of BNT162b2 during lactation. VAX dyads had significantly higher serum anti-S IgG compared to INF dyads (P < .0001), whereas INF mothers had higher BM:serum anti-S IgA ratios compared to VAX mothers (P = .0001). Median IgG placental transfer ratios were significantly higher in VAX-P compared to INF mothers (P < .0001). There was a significant positive correlation between maternal and neonatal serum anti-S IgG after vaccination (r = 0.68, P = .013), but not infection., Conclusions: BNT161b2 vaccination in late pregnancy or lactation enhances systemic immunity through serum anti-S immunoglobulin, while SARS-CoV-2 infection induces mucosal over systemic immunity more efficiently through BM immunoglobulin production. Next-generation vaccines boosting mucosal immunity could provide additional protection to the mother-infant dyad. Future studies should focus on identifying the optimal timing of primary and/or booster maternal vaccination for maximal benefit., Competing Interests: Potential conflicts of interest . V. P. participated in a lecture on coronavirus disease 2019 vaccination in children (with honorarium made to their university), and also participated in the National Greek Advisory Committee for Immunization Practices. C. P. was a steering committee member for clinical trials MN42988 and MN42989 by La Roche Ltd. A. A. received an National Institute of Allergy and Infectious Diseases (NIAID) Development of Sample Sparing Assays (DSSA) for Monitoring Immune Responses Infrastructure & Opportunity Fund (IOF) Award grant for Comprehensive Analysis of the Neonatal Immune System via High-Throughout Proteomics; and honorarium for an invited review article on neonatal vaccination. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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25. T-Cell Defects Associated to Lack of Spike-Specific Antibodies after BNT162b2 Full Immunization Followed by a Booster Dose in Patients with Common Variable Immune Deficiencies.
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Pulvirenti F, Di Cecca S, Sinibaldi M, Piano Mortari E, Terreri S, Albano C, Guercio M, Sculco E, Milito C, Ferrari S, Locatelli F, Quintarelli C, Carsetti R, and Quinti I
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- Antibodies, Viral, CD40 Ligand, Humans, Immunization, Immunoglobulin A, Immunoglobulin G, SARS-CoV-2, Tumor Necrosis Factor-alpha, Vaccines, Synthetic, mRNA Vaccines, BNT162 Vaccine, COVID-19 prevention & control
- Abstract
Following the third booster dose of the mRNA vaccine, Common Variable Immune Deficiencies (CVID) patients may not produce specific antibodies against the virus spike protein. The T-cell abnormalities associated with the absence of antibodies are still a matter of investigation. Spike-specific IgG and IgA, peripheral T cell subsets, CD40L and cytokine expression, and Spike-specific specific T-cells responses were evaluated in 47 CVID and 26 healthy donors after three doses of BNT162b2 vaccine. Testing was performed two weeks after the third vaccine dose. Thirty-six percent of the patients did not produce anti-SARS-CoV-2 IgG or IgA antibodies. Non responder patients had lower peripheral blood lymphocyte counts, circulating naïve and central memory T-cells, low CD40L expression on the CD4+CD45+RO+ and CD8+CD45+RO+ T-cells, high frequencies of TNFα and IFNγ expressing CD8+ T-cells, and defective release of IFNγ and TNFα following stimulation with Spike peptides. Non responders had a more complex disease phenotype, with higher frequencies of structural lung damage and autoimmunity, especially autoimmune cytopenia. Thirty-five percent of them developed a SARS-CoV-2 infection after immunization in comparison to twenty percent of CVID who responded to immunization with antibodies production. CVID-associated T cell abnormalities contributed to the absence of SARS-CoV-2 specific antibodies after full immunization.
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- 2022
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26. CD21 - CD27 - Atypical B Cells in a Pediatric Cohort Study: An Extensive Single Center Flow Cytometric Analysis.
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Corrente F, Terreri S, Palomba P, Capponi C, Mirabella M, Perno CF, and Carsetti R
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Atypical B cells (atBCs) are a distinct B-cell population and represent approximately 5% of B cells in peripheral blood (PB) of healthy adult individuals. However, in adults these cells are expanded in conditions of chronic infections, inflammation, primary immunodeficiencies, autoimmune diseases, and aging. Their immunophenotype is characterized by the lack of CD21 expression and the hallmark human memory B-cell marker CD27. In this study, we investigated the immunophenotype of atBCs in different pediatric pathological conditions and correlated their expansion with the children's clinical diagnosis. We were able to retrospectively evaluate 1,571 consecutive PB samples, corresponding to 1,180 pediatric patients, by using a 9-color flow-cytometric panel. The results, compared with a pediatric healthy cohort, confirmed an expansion of atBCs in patient samples with percentages greater than 5% of total B cells. Four subpopulations with different expressions of IgM and IgD were discriminated: IgM
+ IgD+ , IgM+ -only, IgD+ -only, and IgM- IgD- . IgG+ atBCs were predominant in the IgM- IgD- subpopulation. Moreover, the study highlighted some features of atBCs, such as a low CD38 expression, a heterogeneity of CD24, a high expression of CD19 and a large cell size. We also demonstrated that an increase of atBCs in a pediatric cohort is correlated with immunodeficiencies, autoimmune, inflammatory, and hematological disorders, consistent with previous studies mainly performed in adults. Furthermore, our flow cytometric clustering analysis corroborated the recent hypothesis of an alternative B origin for atBCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corrente, Terreri, Palomba, Capponi, Mirabella, Perno and Carsetti.)- Published
- 2022
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27. Persistent B cell memory after SARS-CoV-2 vaccination is functional during breakthrough infections.
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Terreri S, Piano Mortari E, Vinci MR, Russo C, Alteri C, Albano C, Colavita F, Gramigna G, Agrati C, Linardos G, Coltella L, Colagrossi L, Deriu G, Ciofi Degli Atti M, Rizzo C, Scarsella M, Brugaletta R, Camisa V, Santoro A, Roscilli G, Pavoni E, Muzi A, Magnavita N, Scutari R, Villani A, Raponi M, Locatelli F, Perno CF, Zaffina S, and Carsetti R
- Subjects
- Antibodies, Viral, BNT162 Vaccine, COVID-19 Vaccines, Humans, Vaccination, Vaccines, Synthetic, mRNA Vaccines, COVID-19 prevention & control, SARS-CoV-2
- Abstract
Breakthrough SARS-CoV-2 infections in fully vaccinated individuals are considered a consequence of waning immunity. Serum antibodies represent the most measurable outcome of vaccine-induced B cell memory. When antibodies decline, memory B cells are expected to persist and perform their function, preventing clinical disease. We investigated whether BNT162b2 mRNA vaccine induces durable and functional B cell memory in vivo against SARS-CoV-2 3, 6, and 9 months after the second dose in a cohort of health care workers (HCWs). While we observed physiological decline of SARS-CoV-2-specific antibodies, memory B cells persist and increase until 9 months after immunization. HCWs with breakthrough infections had no signs of waning immunity. In 3-4 days, memory B cells responded to SARS-CoV-2 infection by producing high levels of specific antibodies in the serum and anti-Spike IgA in the saliva. Antibodies to the viral nucleoprotein were produced with the slow kinetics typical of the response to a novel antigen., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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28. Severe Acute Respiratory Syndrome Coronavirus 2 Monoclonal Antibody Combination Therapy in Patients With Coronavirus Disease 2019 and Primary Antibody Deficiency.
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Pulvirenti F, Milito C, Cinetto F, Fernandez Salinas A, Terreri S, Piano Mortari E, Auria S, Soccodato V, Miriam L, Nicastri E, Vincenzi L, Carsetti R, D'Offizi G, and Quinti I
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- Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Antibodies, Viral immunology, Antineoplastic Agents, Immunological, Humans, Prospective Studies, Real-Time Polymerase Chain Reaction, Standard of Care, Antibodies, Viral therapeutic use, Common Variable Immunodeficiency, Primary Immunodeficiency Diseases drug therapy, SARS-CoV-2 isolation & purification, COVID-19 Drug Treatment
- Abstract
Background: Previous reports highlighted the efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs) against coronavirus disease 2019., Methods: We conducted a prospective study on the clinical outcome and antiviral effects of mAbs added to standard of care therapy in SARS-CoV-2-infected patients with primary antibody defects., Results: Median time of SARS-CoV-2 quantitative polymerase chain reaction (qPCR) positivity was shorter in 8 patients treated with mAbs (22 days) than in 10 patients treated with standard of care therapy only (37 days, P=.026). Median time of SARS-CoV-2 qPCR positivity from mAb administration was 10 days., Conclusions: The SARS-CoV-2 mAbs treatment was effective and well tolerated in patients with primary antibody defects., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2022
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29. Comprehensive phenotyping of human peripheral blood B lymphocytes in healthy conditions.
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Carsetti R, Terreri S, Conti MG, Fernandez Salinas A, Corrente F, Capponi C, Albano C, and Piano Mortari E
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- Flow Cytometry, Humans, Phenotype, B-Lymphocytes
- Abstract
The B cell compartment provides innate and adaptive immune defenses against pathogens. Different B cell subsets, reflecting the maturation stages of B cells, have noninterchangeable functions and roles in innate and adaptive immune responses. In this review, we provide an overview of the B cell subsets present in peripheral blood of healthy individuals. A specific gating strategy is also described to clearly and univocally identify B cell subsets based on the their phenotypic traits by flow cytometric analysis., (© 2021 The Authors. Cytometry Part A published by Wiley Periodicals LLC. on behalf of International Society for Advancement of Cytometry.)
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- 2022
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30. Impaired memory B-cell response to the Pfizer-BioNTech COVID-19 vaccine in patients with common variable immunodeficiency.
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Fernandez Salinas A, Piano Mortari E, Terreri S, Milito C, Zaffina S, Perno CF, Locatelli F, Quinti I, and Carsetti R
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- BNT162 Vaccine, COVID-19 Vaccines, Humans, SARS-CoV-2, COVID-19, Common Variable Immunodeficiency
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- 2022
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31. SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best.
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Salinas AF, Mortari EP, Terreri S, Quintarelli C, Pulvirenti F, Di Cecca S, Guercio M, Milito C, Bonanni L, Auria S, Romaggioli L, Cusano G, Albano C, Zaffina S, Perno CF, Spadaro G, Locatelli F, Carsetti R, and Quinti I
- Subjects
- Humans, Immunoglobulin G blood, Immunologic Memory, Lymphocytes immunology, Spike Glycoprotein, Coronavirus immunology, Antibodies, Viral blood, COVID-19 prevention & control, COVID-19 Vaccines immunology, Immunologic Deficiency Syndromes immunology, SARS-CoV-2 immunology
- Abstract
Background: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization., Methods: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine., Results: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only., Conclusion: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected., (© 2021. The Author(s).)
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- 2021
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32. Immune Response of Neonates Born to Mothers Infected With SARS-CoV-2.
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Conti MG, Terreri S, Piano Mortari E, Albano C, Natale F, Boscarino G, Zacco G, Palomba P, Cascioli S, Corrente F, Capponi C, Mirabella M, Salinas AF, Marciano A, De Luca F, Pangallo I, Quaranta C, Alteri C, Russo C, Galoppi P, Brunelli R, Perno CF, Terrin G, and Carsetti R
- Subjects
- Adult, COVID-19 blood, COVID-19 transmission, COVID-19 Serological Testing, Female, Humans, Immunoglobulin A isolation & purification, Immunoglobulin G immunology, Immunoglobulin G isolation & purification, Infant, Infant, Newborn, Infectious Disease Transmission, Vertical prevention & control, Male, Pregnancy, Pregnancy Complications, Infectious blood, Prospective Studies, SARS-CoV-2, Saliva immunology, Spike Glycoprotein, Coronavirus immunology, COVID-19 immunology, Immunoglobulin A immunology, Milk, Human immunology, Pregnancy Complications, Infectious immunology
- Abstract
Importance: Although several studies have provided information on short-term clinical outcomes in children with perinatal exposure to SARS-CoV-2, data on the immune response in the first months of life among newborns exposed to the virus in utero are lacking., Objective: To characterize systemic and mucosal antibody production during the first 2 months of life among infants who were born to mothers infected with SARS-CoV-2., Design, Setting, and Participants: This prospective cohort study enrolled 28 pregnant women who tested positive for SARS-CoV-2 infection and who gave birth at Policlinico Umberto I in Rome, Italy, from November 2020 to May 2021, and their newborns. Maternal and neonatal systemic immune responses were investigated by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breastmilk and infant saliva 48 hours after delivery and 2 months later., Exposures: Maternal infection with SARS-CoV-2 in late pregnancy., Main Outcomes and Measures: The systemic immune response was evaluated by the detection of SARS-CoV-2 IgG and IgA antibodies and receptor binding domain-specific IgM antibodies in maternal and neonatal serum. The mucosal immune response was assessed by measuring spike-specific antibodies in breastmilk and in infant saliva, and the presence of antigen-antibody spike IgA immune complexes was investigated in breastmilk samples. All antibodies were detected using an enzyme-linked immunosorbent assay., Results: In total, 28 mother-infant dyads (mean [SD] maternal age, 31.8 [6.4] years; mean [SD] gestational age, 38.1 [2.3] weeks; 18 [60%] male infants) were enrolled at delivery, and 21 dyads completed the study at 2 months' follow-up. Because maternal infection was recent in all cases, transplacental transfer of virus spike-specific IgG antibodies occurred in only 1 infant. One case of potential vertical transmission and 1 case of horizontal infection were observed. Virus spike protein-specific salivary IgA antibodies were significantly increased (P = .01) in infants fed breastmilk (0.99 arbitrary units [AU]; IQR, 0.39-1.68 AU) vs infants fed an exclusive formula diet (0.16 AU; IQR, 0.02-0.83 AU). Maternal milk contained IgA spike immune complexes at 48 hours (0.53 AU; IQR, 0.25-0.39 AU) and at 2 months (0.09 AU; IQR, 0.03-0.17 AU) and may have functioned as specific stimuli for the infant mucosal immune response., Conclusions and Relevance: In this cohort study, SARS-CoV-2 spike-specific IgA antibodies were detected in infant saliva, which may partly explain why newborns are resistant to SARS-CoV-2 infection. Mothers infected in the peripartum period appear to not only passively protect the newborn via breastmilk secretory IgA but also actively stimulate and train the neonatal immune system via breastmilk immune complexes.
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- 2021
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33. B Cell Response Induced by SARS-CoV-2 Infection Is Boosted by the BNT162b2 Vaccine in Primary Antibody Deficiencies.
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Pulvirenti F, Fernandez Salinas A, Milito C, Terreri S, Piano Mortari E, Quintarelli C, Di Cecca S, Lagnese G, Punziano A, Guercio M, Bonanni L, Auria S, Villani F, Albano C, Locatelli F, Spadaro G, Carsetti R, and Quinti I
- Subjects
- Adult, Antibodies, Viral immunology, COVID-19 complications, COVID-19 prevention & control, Convalescence, Female, Humans, Immunization, Immunoglobulin G immunology, Male, Middle Aged, Primary Immunodeficiency Diseases complications, Spike Glycoprotein, Coronavirus immunology, T-Lymphocytes immunology, BNT162 Vaccine immunology, COVID-19 immunology, Memory B Cells immunology, Primary Immunodeficiency Diseases immunology, SARS-CoV-2 immunology
- Abstract
Background: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization., Methods: Thirty-four CVID convalescent patients after SARS-CoV-2 infection, 38 CVID patients immunized with two doses of the BNT162b2 vaccine, and 20 SARS-CoV-2 CVID convalescents later and immunized with BNT162b2 were analyzed for the anti-spike IgG production and the generation of spike-specific memory B cells and T cells., Results: Spike-specific IgG was induced more frequently after infection than after vaccination (82% vs. 34%). The antibody response was boosted in convalescents by vaccination. Although immunized patients generated atypical memory B cells possibly by extra-follicular or incomplete germinal center reactions, convalescents responded to infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Poor spike-specific T cell responses were measured independently from the immunological challenge., Conclusions: SARS-CoV-2 infection primed a more efficient classical memory B cell response, whereas the BNT162b2 vaccine induced non-canonical B cell responses in CVID. Natural infection responses were boosted by subsequent immunization, suggesting the possibility to further stimulate the immune response by additional vaccine doses in CVID.
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- 2021
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34. Highly Specific Memory B Cells Generation after the 2nd Dose of BNT162b2 Vaccine Compensate for the Decline of Serum Antibodies and Absence of Mucosal IgA.
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Piano Mortari E, Russo C, Vinci MR, Terreri S, Fernandez Salinas A, Piccioni L, Alteri C, Colagrossi L, Coltella L, Ranno S, Linardos G, Agosta M, Albano C, Agrati C, Castilletti C, Meschi S, Romania P, Roscilli G, Pavoni E, Camisa V, Santoro A, Brugaletta R, Magnavita N, Ruggiero A, Cotugno N, Amodio D, Ciofi Degli Atti ML, Giorgio D, Russo N, Salvatori G, Corsetti T, Locatelli F, Perno CF, Zaffina S, and Carsetti R
- Subjects
- Adult, Antibodies, Neutralizing blood, Antigens, Viral immunology, B-Lymphocytes immunology, BNT162 Vaccine, Cryopreservation, Female, Health Personnel, Healthy Volunteers, Hospitals, Pediatric, Humans, Immunoglobulin G, Immunoglobulin M immunology, Lactation, Male, Middle Aged, Mucous Membrane immunology, Patient Safety, SARS-CoV-2, Vaccination, Antibodies, Viral immunology, B-Lymphocytes cytology, COVID-19 immunology, COVID-19 prevention & control, COVID-19 Vaccines therapeutic use, Immunoglobulin A immunology, Immunologic Memory
- Abstract
Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.
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- 2021
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35. Evolution of Human Memory B Cells From Childhood to Old Age.
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Ciocca M, Zaffina S, Fernandez Salinas A, Bocci C, Palomba P, Conti MG, Terreri S, Frisullo G, Giorda E, Scarsella M, Brugaletta R, Vinci MR, Magnavita N, Carsetti R, and Piano Mortari E
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- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Cytokines immunology, Female, Humans, Immunoglobulin A immunology, Immunoglobulin M immunology, Male, Middle Aged, Aging immunology, B-Lymphocytes immunology, COVID-19 epidemiology, COVID-19 immunology, Immunologic Memory, Pandemics, SARS-CoV-2 immunology
- Abstract
High quality medical assistance and preventive strategies, including pursuing a healthy lifestyle, result in a progressively growing percentage of older people. The population and workforce is aging in all countries of the world. It is widely recognized that older individuals show an increased susceptibility to infections and a reduced response to vaccination suggesting that the aged immune system is less able to react and consequently protect the organism. The SARS-CoV-2 pandemic is dramatically showing us that the organism reacts to novel pathogens in an age-dependent manner. The decline of the immune system observed in aging remains unclear. We aimed to understand the role of B cells. We analyzed peripheral blood from children (4-18 years); young people (23-60 years) and elderly people (65-91 years) by flow cytometry. We also measured antibody secretion by ELISA following a T-independent stimulation. Here we show that the elderly have a significant reduction of CD27
dull memory B cells, a population that bridges innate and adaptive immune functions. In older people, memory B cells are mostly high specialized antigen-selected CD27bright . Moreover, after in vitro stimulation with CpG, B cells from older individuals produced significantly fewer IgM and IgA antibodies compared to younger individuals. Aging is a complex process characterized by a functional decline in multiple physiological systems. The immune system of older people is well equipped to react to often encountered antigens but has a low ability to respond to new pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ciocca, Zaffina, Fernandez Salinas, Bocci, Palomba, Conti, Terreri, Frisullo, Giorda, Scarsella, Brugaletta, Vinci, Magnavita, Carsetti and Piano Mortari.)- Published
- 2021
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36. Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue.
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Terreri S, Mancinelli S, Ferro M, Vitale MC, Perdonà S, Castaldo L, Gigantino V, Mercadante V, De Cecio R, Aquino G, Montella M, Angelini C, Del Prete E, Aprile M, Ciaramella A, Liguori GL, Costa V, Calin GA, La Civita E, Terracciano D, Febbraio F, and Cimmino A
- Abstract
Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 human bladder cancer specimens. We quantified uc.8+ by in-situ hybridization and correlated its expression levels with clinical characteristics and patient survival. The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms. Moreover, analysis of uc.8+ expression and subcellular localization in tumor-surrounding stroma revealed a marked down-regulation of uc.8+ levels compared to the paired (adjacent) tumor region. Finally, deep machine-learning approaches identified nucleotide sequences associated with uc.8+ localization in nucleus and/or cytoplasm, allowing to predict possible RNA binding proteins associated with uc.8+, recognizing also sequences involved in mRNA cytoplasm-translocation. Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.
- Published
- 2021
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37. Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases.
- Author
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Carsetti R, Zaffina S, Piano Mortari E, Terreri S, Corrente F, Capponi C, Palomba P, Mirabella M, Cascioli S, Palange P, Cuccaro I, Milito C, Zumla A, Maeurer M, Camisa V, Vinci MR, Santoro A, Cimini E, Marchioni L, Nicastri E, Palmieri F, Agrati C, Ippolito G, Porzio O, Concato C, Onetti Muda A, Raponi M, Quintarelli C, Quinti I, and Locatelli F
- Subjects
- Adult, COVID-19 pathology, Female, Humans, Killer Cells, Natural pathology, Male, Severity of Illness Index, Adaptive Immunity, Antibodies, Viral immunology, COVID-19 immunology, Immunity, Innate, Immunoglobulin A immunology, Immunoglobulin M immunology, Killer Cells, Natural immunology, SARS-CoV-2 immunology
- Abstract
SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; eight patients with Mild COVID-19 disease and eight cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Carsetti, Zaffina, Piano Mortari, Terreri, Corrente, Capponi, Palomba, Mirabella, Cascioli, Palange, Cuccaro, Milito, Zumla, Maeurer, Camisa, Vinci, Santoro, Cimini, Marchioni, Nicastri, Palmieri, Agrati, Ippolito, Porzio, Concato, Onetti Muda, Raponi, Quintarelli, Quinti and Locatelli.)
- Published
- 2020
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38. Author Correction: The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia.
- Author
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Papaioannou D, Petri A, Dovey OM, Terreri S, Wang E, Collins FA, Woodward LA, Walker AE, Nicolet D, Pepe F, Kumchala P, Bill M, Walker CJ, Karunasiri M, Mrózek K, Gardner ML, Camilotto V, Zitzer N, Cooper JL, Cai X, Rong-Mullins X, Kohlschmidt J, Archer KJ, Freitas MA, Zheng Y, Lee RJ, Aifantis I, Vassiliou G, Singh G, Kauppinen S, Bloomfield CD, Dorrance AM, and Garzon R
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
- Full Text
- View/download PDF
39. Role of PA2G4P4 pseudogene in bladder cancer tumorigenesis.
- Author
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Pisapia L, Terreri S, Barba P, Mastroianni M, Donnini M, Mercadante V, Palmieri A, Verze P, Mirone V, Altieri V, Califano G, Liguori GL, Strazzullo M, Cimmino A, and Del Pozzo G
- Abstract
Background: Many pseudogenes possess biological activities and play important roles in the pathogenesis of various types of cancer including bladder cancer (BlCa), which still lacks suitable molecular biomarkers. Recently, pseudogenes were found to be significantly enriched in a pan-cancer classification based on the Cancer Genome Atlas gene expression data. Among them, the top-ranking pseudogene was the proliferation-associated 2G4 pseudogene 4 (PA2G4P4 )., Methods: Genomic and transcript features of PA2G4P4 were determined by GeneBank database analysis followed by 5' RACE experiments. Therefore, we conducted a retrospective molecular study on a cohort of 45 patients of BlCa. PA2G4P4 expression was measured by RT-qPCR, whereas PA2G4P4 transcript distribution was analyzed by in situ hybridization on both normal and cancerous histological sections and compared to the immunolocalization of its parental PA2G4/EBP1 protein. Finally, we tested the effects of PA2G4P4 depletion on proliferation, migration, and death of BlCa cells., Results: We showed for the first time PA2G4P4 overexpression in BlCa tissues and in cell lines. PA2G4P4 distribution strictly overlaps PA2G4/EBP1 protein localization. Moreover, we showed that PA2G4P4 knockdown affects both proliferation and migration of BlCa cells, highlighting its potential oncogenic role., Conclusions: PA2G4P4 may play a functional role as an oncogene in BlCa development, suggesting it as a good candidate for future investigation and new clinical applications.
- Published
- 2020
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40. Publisher Correction: The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia.
- Author
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Papaioannou D, Petri A, Dovey OM, Terreri S, Wang E, Collins FA, Woodward LA, Walker AE, Nicolet D, Pepe F, Kumchala P, Bill M, Walker CJ, Karunasiri M, Mrózek K, Gardner ML, Camilotto V, Zitzer N, Cooper JL, Cai X, Rong-Mullins X, Kohlschmidt J, Archer KJ, Freitas MA, Zheng Y, Lee RJ, Aifantis I, Vassiliou G, Singh G, Kauppinen S, Bloomfield CD, Dorrance AM, and Garzon R
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
- Full Text
- View/download PDF
41. The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia.
- Author
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Papaioannou D, Petri A, Dovey OM, Terreri S, Wang E, Collins FA, Woodward LA, Walker AE, Nicolet D, Pepe F, Kumchala P, Bill M, Walker CJ, Karunasiri M, Mrózek K, Gardner ML, Camilotto V, Zitzer N, Cooper JL, Cai X, Rong-Mullins X, Kohlschmidt J, Archer KJ, Freitas MA, Zheng Y, Lee RJ, Aifantis I, Vassiliou G, Singh G, Kauppinen S, Bloomfield CD, Dorrance AM, and Garzon R
- Subjects
- Acute Disease, Animals, Cell Line, Tumor, Cell Proliferation, HEK293 Cells, Humans, K562 Cells, Leukemia, Myeloid pathology, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Nucleophosmin, Protein Biosynthesis genetics, THP-1 Cells, Transplantation, Heterologous, Leukemia, Myeloid genetics, Mutation, Nuclear Proteins genetics, RNA, Long Noncoding genetics, RNA, Ribosomal genetics, Transcription, Genetic
- Abstract
Long non-coding RNAs (lncRNAs) are important regulatory molecules that are implicated in cellular physiology and pathology. In this work, we dissect the functional role of the HOXB-AS3 lncRNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 is shown to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.
- Published
- 2019
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42. Determination of Picomolar Concentrations of Paraoxon in Human Urine by Fluorescence-Based Enzymatic Assay.
- Author
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Cetrangolo GP, Gori C, Rusko J, Terreri S, Manco G, Cimmino A, and Febbraio F
- Subjects
- Biosensing Techniques methods, Enzyme Assays methods, Fluorescence, Humans, Insecticides urine, Nitrophenols urine, Organophosphates urine, Organophosphorus Compounds urine, Pesticides urine, Paraoxon urine
- Abstract
Organophosphate (OP) pesticides are widely used in the agricultural field and in the prevention of pest infestation in private and public areas of cities. Despite their unquestionable utility, several of these compounds demonstrate toxic effects to the environment and human health. In particular, the occurrence of some organophosphate pesticides is correlated to the incidence of nervous system disorders, especially in children. The detection of pesticide residues in the human body represents an important task to preserve human health. In our work we propose the use of esterase-based biosensors as a viable alternative to the expensive and time-consuming systems currently used for their detection in human fluids. Using the esterase-2 activity, coupled with a fluorescence inhibition assay, we are able to detect very low concentration levels of diethyl (4-nitrophenyl) phosphate (paraoxon) in the range of the femtomole (fmol). Method robustness tests indicate the stability of esterase-2 in a diluted solution of 4% human urine, and we are able to accurately determine concentration levels of paraoxon in the range from 0.1 to 2 picomoles (pmol). The system sensitivity for OP detection is calculated at 524 ± 14.15 fmol of paraoxon recognized at 10% of inhibition, with an estimated limit of quantification of 262 ± 8.12 pmol mL
-1 . These values are comparable with the most recent analysis methods based on mass spectrometry carried out on human samples for pesticide detection. This research represents a starting point to develop cheap and fast testing methods for a rapid screening of toxic substances in human samples.- Published
- 2019
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43. An Ultraconserved Element Containing lncRNA Preserves Transcriptional Dynamics and Maintains ESC Self-Renewal.
- Author
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Fiorenzano A, Pascale E, Gagliardi M, Terreri S, Papa M, Andolfi G, Galasso M, Tagliazucchi GM, Taccioli C, Patriarca EJ, Cimmino A, Matarazzo MR, Minchiotti G, and Fico A
- Subjects
- Animals, Cell Proliferation genetics, Cytoplasm physiology, Humans, Mice, MicroRNAs genetics, Polycomb Repressive Complex 2 genetics, Rats, Transcription, Genetic genetics, Conserved Sequence genetics, Embryonic Stem Cells physiology, RNA, Long Noncoding genetics
- Abstract
Ultraconserved elements (UCEs) show the peculiar feature to retain extended perfect sequence identity among human, mouse, and rat genomes. Most of them are transcribed and represent a new family of long non-coding RNAs (lncRNAs), the transcribed UCEs (T-UCEs). Despite their involvement in human cancer, the physiological role of T-UCEs is still unknown. Here, we identify a lncRNA containing the uc.170+, named T-UCstem1, and provide in vitro and in vivo evidence that it plays essential roles in embryonic stem cells (ESCs) by modulating cytoplasmic miRNA levels and preserving transcriptional dynamics. Specifically, while T-UCstem1::miR-9 cytoplasmic interplay regulates ESC proliferation by reducing miR-9 levels, nuclear T-UCstem1 maintains ESC self-renewal and transcriptional identity by stabilizing polycomb repressive complex 2 on bivalent domains. Altogether, our findings provide unprecedented evidence that T-UCEs regulate physiological cellular functions and point to an essential role of T-UCstem1 in preserving ESC identity., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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44. The role of a new class of long noncoding RNAs transcribed from ultraconserved regions in cancer.
- Author
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Terracciano D, Terreri S, de Nigris F, Costa V, Calin GA, and Cimmino A
- Subjects
- Animals, Carcinogenesis, CpG Islands, DNA Methylation, Genetic Variation, Humans, MicroRNAs physiology, Neoplasms etiology, Polymorphism, Single Nucleotide, Conserved Sequence genetics, Neoplasms genetics, RNA, Long Noncoding physiology
- Abstract
Ultraconserved regions (UCRs) represent a relatively new class of non-coding genomic sequences highly conserved between human, rat and mouse genomes. These regions can reside within exons of protein-coding genes, despite the vast majority of them localizes within introns or intergenic regions. Several studies have undoubtedly demonstrated that most of these regions are actively transcribed in normal cells/tissues, where they contribute to regulate many cellular processes. Interestingly, these non-coding RNAs exhibit aberrant expression levels in human cancer cells and their expression profiles have been used as prognostic factors in human malignancies, as well as to unambiguously distinguish among distinct cancer types. In this review, we first describe their identification, then we provide some updated information about their genomic localization and classification. More importantly, we discuss about the available literature describing an overview of the mechanisms through which some transcribed UCRs (T-UCR) contribute to cancer progression or to the metastatic spread. To date, the interplay between T-UCRs and microRNAs is the most convincing evidence linking T-UCRs and tumorigenesis. The limitations of these studies and the future challenges to be addressed in order to understand the biological role of T-UCRs are also discussed herein. We envision that future efforts are needed to convincingly include this class of ncRNAs in the growing area of cancer therapeutics., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
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45. Urinary long noncoding RNAs in nonmuscle-invasive bladder cancer: new architects in cancer prognostic biomarkers.
- Author
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Terracciano D, Ferro M, Terreri S, Lucarelli G, D'Elia C, Musi G, de Cobelli O, Mirone V, and Cimmino A
- Subjects
- Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, Oncogenes, RNA, Long Noncoding physiology, Urinary Bladder Neoplasms urine, Biomarkers, Tumor genetics, RNA, Long Noncoding urine, Urinary Bladder Neoplasms genetics
- Abstract
Several reports over the last 10 years provided evidence that long noncoding RNAs (lncRNAs) are often altered in bladder cancers. lncRNAs are longer than 200 nucleotides and function as important regulators of gene expression, interacting with the major pathways of cell growth, proliferation, differentiation, and survival. A large number of lncRNAs has oncogenic function and is more expressed in tumor compared with normal tissues. Their overexpression may be associated with tumor formation, progression, and metastasis in a variety of tumors including bladder cancer. Although lncRNAs have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle-invasive bladder cancer remain largely unknown. Nevertheless, a growing body of evidence suggests that several lncRNAs expression profiles in bladder malignancies are associated with poor prognosis, and they can be detected in biological fluids, such as urines. Here, we review current progress in the biology and the implication of lncRNAs associated with bladder cancer, and we discuss their potential use as diagnosis and prognosis biomarkers in bladder malignancies with a focus on their role in high-risk nonmuscle-invasive tumors., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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46. New Cross-Talk Layer between Ultraconserved Non-Coding RNAs, MicroRNAs and Polycomb Protein YY1 in Bladder Cancer.
- Author
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Terreri S, Durso M, Colonna V, Romanelli A, Terracciano D, Ferro M, Perdonà S, Castaldo L, Febbraio F, de Nigris F, and Cimmino A
- Abstract
MicroRNAs (miRNAs) are highly conserved elements in mammals, and exert key regulatory functions. Growing evidence shows that miRNAs can interact with another class of non-coding RNAs, so-called transcribed ultraconserved regions (T-UCRs), which take part in transcriptional, post-transcriptional and epigenetic regulation processes. We report here the interaction of miRNAs and T-UCRs as a network modulating the availability of these non-coding RNAs in bladder cancer cells. In our cell system, antagomiR-596 increased the expression of T-UCR 201+. Moreover, T-UCR 8+ silencing increased miR-596 expression, which in turn reduced total T-UCR 283+, showing that the perturbation of one element in this network changes the expression of other interactors. In addition, we identify the polycomb protein Yin Yang 1 (YY1) as mediator of binding between miR-596 and T-UCR 8+. These new findings describe for the first time a network between T-UCRs, miRNAs and YY1 protein, highlighting the existence of an additional layer of gene expression regulation., Competing Interests: The authors have no conflict of interest.
- Published
- 2016
- Full Text
- View/download PDF
47. Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis.
- Author
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Olivieri M, Ferro M, Terreri S, Durso M, Romanelli A, Avitabile C, De Cobelli O, Messere A, Bruzzese D, Vannini I, Marinelli L, Novellino E, Zhang W, Incoronato M, Ilardi G, Staibano S, Marra L, Franco R, Perdonà S, Terracciano D, Czerniak B, Liguori GL, Colonna V, Fabbri M, Febbraio F, Calin GA, and Cimmino A
- Subjects
- Aged, Apoptosis, Base Sequence, Biomarkers, Tumor genetics, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic pathology, Female, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Staging, Tumor Cells, Cultured, Urinary Bladder Neoplasms pathology, Cell Transformation, Neoplastic genetics, Conserved Sequence genetics, Gene Expression Regulation, Neoplastic, RNA, Untranslated genetics, Urinary Bladder Neoplasms genetics
- Abstract
Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies.
- Published
- 2016
- Full Text
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48. Chemical modifications in the seed region of miRNAs 221/222 increase the silencing performances in gastrointestinal stromal tumor cells.
- Author
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Durso M, Gaglione M, Piras L, Mercurio ME, Terreri S, Olivieri M, Marinelli L, Novellino E, Incoronato M, Grieco P, Orsini G, Tonon G, Messere A, and Cimmino A
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, MicroRNAs genetics, Rats, Gastrointestinal Stromal Tumors genetics, Gastrointestinal Stromal Tumors pathology, Gene Silencing drug effects, MicroRNAs chemistry, MicroRNAs pharmacology, Phosphates pharmacology
- Abstract
Most GastroIntestinal Stromal Tumors (GISTs) are characterized by KIT gene overexpression, which in turn is regulated by levels of microRNA 221 and microRNA 222. GISTs can also be distinguished by their miRNAs expression profile in which miRNAs 221/222 result reduced in comparison with GI normal tissues. In this paper, to restore normal miRNAs levels and to improve the silencing performances of miRNAs 221/222, new miRNA mimics in which guide strands are modified by Phosphorothioate (PS) and/or 2'-O-methyl RNA (2'-OMe) inside and outside the seed region, were synthesized and tested in GIST48 cells. We evaluated the positional effect of the chemical modifications on the miRNAs silencing activity, compared to natural and several commercial miRNA mimics. Our results show that chemically modified miRNAs 221/222 with alternating 2'-OMe-PS and natural nucleotides in the seed region are effective inhibitors of KIT gene expression and exhibit increased stability in rat plasma. Besides, their transfection in GIST 48 cells showed significant effects on different cellular processes in which KIT plays a functional role for tumor development (such as migration, cell proliferation, and apoptosis). Therefore, modified miRNAs 221/222 may provide an alternative therapeutic option for GIST treatment also aimed to overcome drug resistance concerns., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
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