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2. Gut Microbiota, Inflammatory Bowel Disease, and Cancer: The Role of Guardians of Innate Immunity

Author

Giambra, V., Pagliari, D., Rio, Pierluigi, Totti, B., Di Nunzio, C., Bosi, A., Giaroni, C., Gasbarrini, Antonio, Gambassi, Giovanni, Cianci, Rossella, Rio P., Gasbarrini A. (ORCID:0000-0002-7278-4823), Gambassi G. (ORCID:0000-0002-7030-9359), Cianci R. (ORCID:0000-0001-5378-8442), Giambra, V., Pagliari, D., Rio, Pierluigi, Totti, B., Di Nunzio, C., Bosi, A., Giaroni, C., Gasbarrini, Antonio, Gambassi, Giovanni, Cianci, Rossella, Rio P., Gasbarrini A. (ORCID:0000-0002-7278-4823), Gambassi G. (ORCID:0000-0002-7030-9359), and Cianci R. (ORCID:0000-0001-5378-8442)

Abstract

Inflammatory bowel diseases (IBDs) are characterized by a persistent low-grade inflammation that leads to an increased risk of colorectal cancer (CRC) development. Several factors are implicated in this pathogenetic pathway, such as innate and adaptive immunity, gut microbiota, environment, and xenobiotics. At the gut mucosa level, a complex interplay between the immune system and gut microbiota occurs; a disequilibrium between these two factors leads to an alteration in the gut permeability, called ‘leaky gut’. Subsequently, an activation of several inflammatory pathways and an alteration of gut microbiota composition with a proliferation of pro-inflammatory bacteria, known as ‘pathobionts’, take place, leading to a further increase in inflammation. This narrative review provides an overview on the principal Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs), focusing on their recognition mechanisms, signaling pathways, and contributions to immune responses. We also report the genetic polymorphisms of TLRs and dysregulation of NLR signaling pathways that can influence immune regulation and contribute to the development and progression of inflammatory disease and cancer.

Published
2023

3. Changes in Lymphocyte Subpopulations after Remdesivir Therapy for COVID-19: A Brief Report

Author

Cianci, Rossella, Massaro, Maria Grazia, De Santis, E., Totti, B., Gasbarrini, Antonio, Gambassi, Giovanni, Giambra, V., Cianci R. (ORCID:0000-0001-5378-8442), Massaro M. G., Gasbarrini A. (ORCID:0000-0002-7278-4823), Gambassi G. (ORCID:0000-0002-7030-9359), Cianci, Rossella, Massaro, Maria Grazia, De Santis, E., Totti, B., Gasbarrini, Antonio, Gambassi, Giovanni, Giambra, V., Cianci R. (ORCID:0000-0001-5378-8442), Massaro M. G., Gasbarrini A. (ORCID:0000-0002-7278-4823), and Gambassi G. (ORCID:0000-0002-7030-9359)

Abstract

Remdesivir (RDV) has demonstrated clinical benefit in hospitalized COronaVIrus Disease (COVID)-19 patients. The objective of this brief report was to assess a possible correlation between RDV therapy and the variation in lymphocyte subpopulations. We retrospectively studied 43 hospitalized COVID-19 patients: 30 men and 13 women (mean age 69.3 ± 15 years); 9/43 had received RDV therapy. Six patients had no need for oxygen (severity group 0); 22 were on oxygen treatment with a fraction of inspired oxygen (FiO2) ≤ 50% (group 1); 7 on not-invasive ventilation (group 2); 3 on invasive mechanical ventilation (group 3); and 5 had died (group 4). Cytofluorimetric assessment of lymphocyte subpopulations showed substantial changes after RDV therapy: B lymphocytes and plasmablasts were significantly increased (p = 0.002 and p = 0.08, respectively). Cytotoxic T lymphocytes showed a robust reduction (p = 0.008). No changes were observed in CD4+-T cells and natural killers (NKs). There was a significant reduction in regulatory T cells (Tregs) (p = 0.02) and a significant increase in circulating monocytes (p = 0.03). Stratifying by disease severity, after RDV therapy, patients with severity 0–2 had significantly higher B lymphocyte and monocyte counts and lower memory and effector cytotoxic T cell counts. Instead, patients with severity 3–4 had significantly higher plasmablast and lower memory T cell counts. No significant differences for CD4+-T cells, Tregs, and NKs were observed. Our brief report showed substantial changes in the lymphocyte subpopulations analyzed between patients who did not receive RDV therapy and those after RDV treatment. Despite the small sample size, due to the retrospective nature of this brief report, the substantial changes in lymphocyte subpopulations reported could lead to speculation on the role of RDV treatment both on immune responses against the virus and on the possible downregulation of the cytokine storm observed in patients with more severe di

Published
2023

4. Covid-19 specific immune markers revealed by single cell phenotypic profiling

Author

Sansico, F, Miroballo, M, Bianco, D, Tamiro, F, Colucci, M, De Santis, E, Rossi, G, Rosati, J, Di Mauro, L, Miscio, G, Mazza, T, Vescovi, A, Mazzoccoli, G, Giambra, V, Sansico F., Miroballo M., Bianco D. S., Tamiro F., Colucci M., De Santis E., Rossi G., Rosati J., Di Mauro L., Miscio G., Mazza T., Vescovi A. L., Mazzoccoli G., Giambra V., Sansico, F, Miroballo, M, Bianco, D, Tamiro, F, Colucci, M, De Santis, E, Rossi, G, Rosati, J, Di Mauro, L, Miscio, G, Mazza, T, Vescovi, A, Mazzoccoli, G, Giambra, V, Sansico F., Miroballo M., Bianco D. S., Tamiro F., Colucci M., De Santis E., Rossi G., Rosati J., Di Mauro L., Miscio G., Mazza T., Vescovi A. L., Mazzoccoli G., and Giambra V.

Abstract

COVID-19 is a viral infection, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and characterized by a complex inflammatory process and clinical immunophe-notypes. Nowadays, several alterations of immune response within the respiratory tracts as well as at the level of the peripheral blood have been well documented. Nonetheless, their effects on COVID-19-related cell heterogeneity and disease progression are less defined. Here, we performed a single-cell RNA sequencing of about 400 transcripts relevant to immune cell function including surface markers, in mononuclear cells (PBMCs) from the peripheral blood of 50 subjects, infected with SARS-CoV-2 at the diagnosis and 27 healthy blood donors as control. We found that patients with COVID-19 exhibited an increase in COVID-specific surface markers in different subsets of immune cell composition. Interestingly, the expression of cell receptors, such as IFNGR1 and CXCR4, was reduced in response to the viral infection and associated with the inhibition of the related signaling pathways and immune functions. These results highlight novel immunoreceptors, selectively expressed in COVID-19 patients, which affect the immune functionality and are correlated with clinical outcomes.

Published
2021

5. Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, Vescovi, A, Grandone E., Tiscia G., Pesavento R., De Laurenzo A., Ceccato D., Sartori M. T., Mirabella L., Cinnella G., Mastroianno M., Dalfino L., Colaizzo D., Vettor R., Intrieri M., Ostuni A., Margaglione M., Alboini P. E., Antonioni A., Aucella F., Bochicchio G. B., Carbonelli C., Carella M., Castori M., Centonze A., Ciliberti G., Copetti M., Corritore M., De Cosmo S., D'Aloiso L., D'Errico M. M., de Matthaeis A., Del Gaudio A., Di Giorgio A., Giambra V., Greco A., Florio L., Fontana A., Inchingolo V., Inglese M., Labonia M., La Marca A., Latiano T., Leone M., Maiello E., Mangia A., Marciano C., Massa V., Massafra S., Orciuli G., Palladino N., Perna R., Piscitelli P., Piemontese M., Prencipe M. A., Raggi P., Rodriquenz M. G., Russo R., Sancarlo D., Simeone A., Trischitta V., Zarrelli M., Vaira P., Vergara D., Vescovi A., Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, Vescovi, A, Grandone E., Tiscia G., Pesavento R., De Laurenzo A., Ceccato D., Sartori M. T., Mirabella L., Cinnella G., Mastroianno M., Dalfino L., Colaizzo D., Vettor R., Intrieri M., Ostuni A., Margaglione M., Alboini P. E., Antonioni A., Aucella F., Bochicchio G. B., Carbonelli C., Carella M., Castori M., Centonze A., Ciliberti G., Copetti M., Corritore M., De Cosmo S., D'Aloiso L., D'Errico M. M., de Matthaeis A., Del Gaudio A., Di Giorgio A., Giambra V., Greco A., Florio L., Fontana A., Inchingolo V., Inglese M., Labonia M., La Marca A., Latiano T., Leone M., Maiello E., Mangia A., Marciano C., Massa V., Massafra S., Orciuli G., Palladino N., Perna R., Piscitelli P., Piemontese M., Prencipe M. A., Raggi P., Rodriquenz M. G., Russo R., Sancarlo D., Simeone A., Trischitta V., Zarrelli M., Vaira P., Vergara D., and Vescovi A.

Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann–Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13–0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

6. Comprehensive microRNA expression profiling of the hematopoietic hierarchy

Author

Petriv, O. I., Kuchenbauer, F., Delaney, A. D., Lecault, V., White, A., Kent, D., Marmolejo, L., Heuser, M., Berg, T., Copley, M., Ruschmann, J., Sekulovic, S., Benz, C., Kuroda, E., Ho, V., Antignano, F., Halim, T., Giambra, V., Krystal, G., Takei, C. J. F., Weng, A. P., Piret, J., Eaves, C., Marra, M. A., Humphries, R. K., Hansen, C. L., and Hood, Leroy E.

Published
2010

7. Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciuli, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., Vescovi, A., Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, and Vescovi, A

Subjects
Male, Time Factors, 030204 cardiovascular system & hematology, Logistic regression, law.invention, 0302 clinical medicine, law, Risk Factors, 80 and over, 030212 general & internal medicine, Hospital Mortality, Hematology, Low-Molecular-Weight, COVID-19, Low-molecular-weight heparin, Mortality, Ventilation, Aged, Aged, 80 and over, Anticoagulants, Clinical Decision-Making, Female, Heparin, Low-Molecular-Weight, Hospitalization, Humans, Middle Aged, Protective Factors, Risk Assessment, Thromboembolism, Treatment Outcome, Blood Transfusion, Heparin, Intensive care unit, Cohort, Breathing, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Low molecular weight heparin, Article, 03 medical and health sciences, Internal medicine, medicine, low-molecular-weight heparin, mortality, ventilation, aged, aged 80 and over, anticoagulants, clinical decision-making, female, low-molecular-weight, hospital mortality, hospitalization, humans, male, middle aged, protective factors, risk assessment, risk factors, thromboembolism, time factors, treatment outcome, blood transfusion, business.industry, business
Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann–Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13–0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

8. Correction to: Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciulo, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., and Vescovi, A.

Subjects
Male, 2019-20 coronavirus outbreak, medicine.medical_specialty, Time Factors, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clinical Decision-Making, Low molecular weight heparin, Risk Assessment, Risk Factors, Internal medicine, Thromboembolism, medicine, Humans, Blood Transfusion, Hospital Mortality, Aged, Aged, 80 and over, Hematology, business.industry, Correction, Anticoagulants, COVID-19, Heparin, Low-Molecular-Weight, Middle Aged, Protective Factors, CSS COVID-19 Group, Covid-19, research groups, Hospitalization, Treatment Outcome, Emergency medicine, Breathing, Female, Cardiology and Cardiovascular Medicine, business
Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

9. Correction to: Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation (Journal of Thrombosis and Thrombolysis, (2021), 52, 3, (772-778), 10.1007/s11239-021-02429-z)

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciulo, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., and Vescovi, A.

Published
2021

10. The histone variant macroh2a1 impacts circadian gene expression and cell phenotype in an in vitro model of hepatocellular carcinoma

Author

Carbone, A., De Santis, E., Cela, O., Giambra, V., Miele, Luca, Marrone, G., Grieco, Antonio, Buschbeck, M., Capitanio, N., Mazza, T., Mazzoccoli, G., Miele L. (ORCID:0000-0003-3464-0068), Grieco A. (ORCID:0000-0002-0544-8993), Carbone, A., De Santis, E., Cela, O., Giambra, V., Miele, Luca, Marrone, G., Grieco, Antonio, Buschbeck, M., Capitanio, N., Mazza, T., Mazzoccoli, G., Miele L. (ORCID:0000-0003-3464-0068), and Grieco A. (ORCID:0000-0002-0544-8993)

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. A foremost risk factor for HCC is obesity/metabolic syndrome‐related non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH), which is prompted by remarkable changes in transcription patterns of genes enriching metabolic, immune/inflammatory, and circadian pathways. Epigenetic mechanisms play a role in NAFLD‐associated HCC, and macroH2A1, a variant of histone H2A, is involved in the pathogenesis modulating the expression of oncogenes and/or tumor suppressor genes and interacting with SIRT1, which crucially impacts the circadian clock circuitry. Hence, we aimed to appraise if and how macroH2A1 regulated the expression patterns of circadian genes in the setting of NAFLD‐associated HCC. We took advantage of an in vitro model of liver cancer represented by HepG2 (human hepatocarcinoma) cells stably knocked down for macroH2A1 and conducted whole transcriptome profiling and deep phenotyping analysis. We found up‐regulation of PER1 along with several deregulated circadian genes, enriching several important pathways and functions related to cancer onset and progression, such as epithelial‐to‐mesenchymal transition, cell cycle deregulation, and DNA damage. PER1 silencing partially mitigated the malignant phenotype induced by the loss of macroH2A1 in HCC cells. In conclusion, our findings suggest a modulatory role for the core circadian protein PER1 in liver carcinogenesis in the context of a lack of the macroH2A1 epigenetic and transcriptional landscape.

Published
2021

11. Associations between allelic variants of the human IgH 3′ regulatory region 1 and the immune response to BNT162b2 mRNA vaccine

Author

Colucci, M., De Santis, E., Totti, B., Miroballo, M., Tamiro, F., Rossi, G., Piepoli, A., De Vincentis, G., Greco, A., Mangia, A., Cianci, Rossella, Di Mauro, L., Miscio, G., Giambra, V., Cianci R. (ORCID:0000-0001-5378-8442), Colucci, M., De Santis, E., Totti, B., Miroballo, M., Tamiro, F., Rossi, G., Piepoli, A., De Vincentis, G., Greco, A., Mangia, A., Cianci, Rossella, Di Mauro, L., Miscio, G., Giambra, V., and Cianci R. (ORCID:0000-0001-5378-8442)

Abstract

The escalation of Coronavirus disease 2019 (COVID-19) has required the development of safe and effective vaccines against the severe acute respiratory syndrome coronavirus 2-associated (SARS-CoV-2), which is the causative agent of the disease. Here, we determined the levels of antibodies, antigen-specific B cells, against a recombinant GFP-tagged SARS-CoV-2 spike (S) protein and total T and NK cell subsets in subjects up to 20 days after the injection of the BNT162b2 (Pfizer– BioNTech) vaccine using a combined approach of serological and flow cytometry analyses. In former COVID-19 patients and highly responsive individuals, a significant increase of antibody production was detected, simultaneous with an expansion of antigen-specific B cell response and the total number of NK-T cells. Additionally, through a genetic screening of a specific polymorphic region internal to the 3’ regulatory region 1 (3’RR1) of human immunoglobulin constant-gene (IgH) locus, we identified different single-nucleotide polymorphic (SNP) variants associated with either highly or lowly responsive subjects. Taken together, these results suggest that favorable genetic backgrounds and immune profiles support the progression of an effective response to BNT162b2 vaccination.

Published
2021

20. Polymorphism of immunoglobulin (Ig) enhancerelement HS1,2A: allele *2 associates with Systemicfrequency Sclerosis. Comparison with HLA-DR and DQ alleles frequency

Author

FREZZA, D, GIAMBRA, V, TOLUSSO, B, DE SANTIS, M, BOSELLO, S, VETTORI, S, TRIOLO, Giovanni, VALENTINI, G, FERRACCIOLI, GF, FREZZA, D, GIAMBRA, V, TOLUSSO, B, DE SANTIS, M, BOSELLO, S, VETTORI, S, TRIOLO, G, VALENTINI, G, and FERRACCIOLI, GF

Subjects
immunoglobulin (Ig), Polymorphism
Abstract

OBJECTIVE: To investigate the relationship of the polymorphic enhancer HS1,2 central to the 3' enhancer complex regulatory region (IgH3'EC) of the immunoglobulin heavy chain genes with systemic sclerosis (SSc) disease and compare it with HLA-DR and DQ associations. METHODS: A total of 116 patients with SSc were classified as diffuse (dSSc) or limited (lSSc), and as carriers of antitopoisomerase I (anti-Scl70) or anticentromere (ACA) antibodies. Allele and genotype frequencies were assessed in the population as a whole and in the two major subsets, dSSc and lSSc. The concentration of peripheral blood immunoglobulin levels was also determined and analysed according to the genotypes. RESULTS: The analysis of genotypes for the four alleles of the HS1,2A enhancer showed an increased frequency of allele *2 in the SSc cohort highly significant versus controls (57% vs. 40%, p

Published
2007

29. BALKAN ENDEMIC NEPHROPATHY RISK ASSOCIATES TO THE HS1.2 IG ENHANCER POLYMORPHISM

Author

Frezza, Domenico, Serone, E, Lolli, Serena, Cianci, Rossella, D’Addabbo, P, Mattioli, C, Giambra, V, Pavlovic, N, Vidojko, Djordjevic, Kostic, S, Pandolfi, Franco, Kostic, E., Cianci, Rossella (ORCID:0000-0001-5378-8442), Pandolfi, Franco (ORCID:0000-0001-8799-8173), Frezza, Domenico, Serone, E, Lolli, Serena, Cianci, Rossella, D’Addabbo, P, Mattioli, C, Giambra, V, Pavlovic, N, Vidojko, Djordjevic, Kostic, S, Pandolfi, Franco, Kostic, E., Cianci, Rossella (ORCID:0000-0001-5378-8442), and Pandolfi, Franco (ORCID:0000-0001-8799-8173)

Abstract

Balkan Endemic Nephropathy (BEN) is a kidney degenerative disease with a high incidence in the valleys of the Danube and tributary rivers. Many evidences describe it as a multifactorial disease. Environmental as well immuno-inflammatory and genetic cofactors have been suggested to trigger the onset of the disease. Recently, high levels of C-reactive protein were demonstrated in BEN patients. We performed this study to evaluate the possible correlation of BEN with the polymorphism of the Ig heavy chain 3’Regulatory Region enhancer hs1.2 that is related to changes of consensus for trans activators binding within the DNA sequence and probably consequently autoimmune and inflammatory diseases. Therefore, we studied three cohorts: 1) 111 control subjects, 2) 95 BEN patients in dialysis therapy and 3) 133 components of a large family “J” the same geographical area. The allelic frequencies of hs1.2 of BEN patients and family “J” components had the similar decrease frequency of allele *1 and increase of allele *2 respect to the controls. This trend suggests the association of allele *1 as a protective and allele *2 as a risk component for the disease. The presence of a consensus sequence for NF-kb in the allele *2 may link the polymorphism to the inflammatory activity of BEN. This study supports the presence of an inflammatory pathway in BEN through the involvement of polymorphic enhancer hs1.2 influencing differently binding complexes and consequently the 3D structure of 3’ Regulatory Region of IgH. Our work is the first study that clearly links BEN to a gene involved in the regulation of immune response.

Published
2012

30. Allele *1 of HS1.2 enhancer associates with selective IgA deficiency and IgM concentration

Author

Giambra, V, Cianci, Rossella, Lolli, Serena, Mattioli, C, Tampella, G, Cattalini, M, Kilic, S, Pandolfi, Franco, Plebani, A, Frezza, D., Cianci, Rossella (ORCID:0000-0001-5378-8442), Kilic, Ss, Pandolfi, Franco (ORCID:0000-0001-8799-8173), Giambra, V, Cianci, Rossella, Lolli, Serena, Mattioli, C, Tampella, G, Cattalini, M, Kilic, S, Pandolfi, Franco, Plebani, A, Frezza, D., Cianci, Rossella (ORCID:0000-0001-5378-8442), Kilic, Ss, and Pandolfi, Franco (ORCID:0000-0001-8799-8173)

Abstract

Selective IgA deficiency (IGAD) is the most common primary immunodeficiency, yet its pathogenesis is elusive. The IG (heavy) H chain human 3' Regulatory Region harbors three enhancers and has an important role in Ig synthesis. HS1.2 is the only polymorphic enhancer of the 3' RRs. We therefore evaluated HS1.2 allelic frequencies in 88 IGAD patients and 101 controls. Our data show that IGAD patients have a highly significant increase of homozygousity of the allele *1 (39% in the IGAD patients and 15% in controls), with an increase of 2.6-fold. Allele *4 has a similar trend of allele *2, both showing a significant decrease of frequency in IGAD. No relationship was observed between allele *1 frequencies and serum levels of IgG. However, allele *1 was associated in IGAD patients with relatively low IgM levels (within the 30th lowest percentile of patients). The HS1.2 polymorphism influences Ig seric production, but not IgG switch, in fact 30th lowest or highest percentile of IgG in patients did not associate to different frequencies of HS1.2 alleles. The control on normal healthy subjects did not correlate high or low levels of IgM or IgG with HS1.2 allelic frequence variation. Overall our candidate gene approach confirms that the study of polymorphisms in human diseases is a valid tool to investigate the function of these Regulatory Regions that confers multiple immune features.

Published
2009

31. Allele*1 of HS1,2 enhancer associates with selective IgA deficiency and IgM concentration

Author

Giambra, V, Cianci, Rossella, Lolli, Serena, Mattioli, C, Tampella, M, Cattalini, M, Kilic, S, Pandolfi, Franco, Plebani, A, Frezza, Domenico, Cianci, Rossella (ORCID:0000-0001-5378-8442), Pandolfi, Franco (ORCID:0000-0001-8799-8173), Giambra, V, Cianci, Rossella, Lolli, Serena, Mattioli, C, Tampella, M, Cattalini, M, Kilic, S, Pandolfi, Franco, Plebani, A, Frezza, Domenico, Cianci, Rossella (ORCID:0000-0001-5378-8442), and Pandolfi, Franco (ORCID:0000-0001-8799-8173)

Abstract

Selective IgA deficiency (IGAD) is the most common primary immunodeficiency, yet its pathogenesis is elusive. The IG (heavy) H chain human 3' Regulatory Region harbors three enhancers and has an important role in Ig synthesis. HS1.2 is the only polymorphic enhancer of the 3' RRs. We therefore evaluated HS1.2 allelic frequencies in 88 IGAD patients and 101 controls. Our data show that IGAD patients have a highly significant increase of homozygousity of the allele *1 (39% in the IGAD patients and 15% in controls), with an increase of 2.6-fold. Allele *4 has a similar trend of allele *2, both showing a significant decrease of frequency in IGAD. No relationship was observed between allele *1 frequencies and serum levels of IgG. However, allele *1 was associated in IGAD patients with relatively low IgM levels (within the 30th lowest percentile of patients). The HS1.2 polymorphism influences Ig seric production, but not IgG switch, in fact 30th lowest or highest percentile of IgG in patients did not associate to different frequencies of HS1.2 alleles. The control on normal healthy subjects did not correlate high or low levels of IgM or IgG with HS1.2 allelic frequence variation. Overall our candidate gene approach confirms that the study of polymorphisms in human diseases is a valid tool to investigate the function of these Regulatory Regions that confers multiple immune features.

Published
2008

38. Position and sequence conservation in Amniota of polymorphic enhancer HS1.2 within the palindrome of IgH 3'Regulatory Region

Author

Rocchi Mariano, Giambra Vincenzo, Scascitelli Moira, D'Addabbo Pietro, and Frezza Domenico

Subjects
Evolution, QH359-425
Abstract

Abstract Background The Immunoglobulin heavy chain (IgH) 3' Regulatory Region (3'RR), located at the 3' of the constant alpha gene, plays a crucial role in immunoglobulin production. In humans, there are 2 copies of the 3'RR, each composed of 4 main elements: 3 enhancers and a 20 bp tandem repeat. The single mouse 3'RR differs from the two human ones for the presence of 4 more regulative elements with the double copy of one enhancer at the border of a palindromic region. Results We compared the 3'RR organization in genomes of vertebrates to depict the evolutionary history of the region and highlight its shared features. We found that in the 8 species in which the whole region was included in a fully assembled contig (mouse, rat, dog, rabbit, panda, orangutan, chimpanzee, and human), the shared elements showed synteny and a highly conserved sequence, thus suggesting a strong evolutionary constraint. In these species, the wide 3'RR (~30 kb in human) bears a large palindromic sequence, consisting in two ~3 kb complementary branches spaced by a ~3 kb sequence always including the HS1.2 enhancer. In mouse and rat, HS3 is involved by the palindrome so that one copy of the enhancer is present on each side. A second relevant feature of our present work concerns human polymorphism of the HS1.2 enhancer, associated to immune diseases in our species. We detected a similar polymorphism in all the studied Catarrhini (a primate parvorder). The polymorphism consists of multiple copies of a 40 bp element up to 12 in chimpanzees, 8 in baboons, 6 in macaque, 5 in gibbons, 4 in humans and orangutan, separated by stretches of Cytosine. We show specific binding of this element to nuclear factors. Conclusions The nucleotide sequence of the palindrome is not conserved among evolutionary distant species, suggesting pressures for the maintenance of two self-matching regions driving a three-dimensional structure despite of the inter-specific divergence at sequence level. The information about the conservation of the palindromic structure and the settling in primates of the polymorphic feature of HS1.2 show the relevance of these structures in the control and modulation of the Ig production through the formation of possible three-dimensional structures.

Published
2011
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39. COVID-19 Specific Immune Markers Revealed by Single Cell Phenotypic Profiling

Author

Francesca, Sansico, Mattia, Miroballo, Daniele Salvatore, Bianco, Francesco, Tamiro, Mattia, Colucci, Elisabetta De, Santis, Giovanni, Rossi, Jessica, Rosati, Lazzaro, Di Mauro, Giuseppe, Miscio, Tommaso, Mazza, Angelo Luigi, Vescovi, Gianluigi, Mazzoccoli, Vincenzo, Giambra, On Behalf Of Css-Covid Group, Sansico, F, Miroballo, M, Bianco, D, Tamiro, F, Colucci, M, De Santis, E, Rossi, G, Rosati, J, Di Mauro, L, Miscio, G, Mazza, T, Vescovi, A, Mazzoccoli, G, and Giambra, V

Subjects
QH301-705.5, Cell, Medicine (miscellaneous), Biology, COVID-19, flow cytometry, immune cells, SARS-CoV-2, single-cell RNA sequencing, Peripheral blood mononuclear cell, CXCR4, General Biochemistry, Genetics and Molecular Biology, Article, Flow cytometry, Immune system, medicine, Biology (General), Receptor, Immune cell, medicine.diagnostic_test, Phenotype, medicine.anatomical_structure, Immunology, Signal transduction
Abstract

COVID-19 is a viral infection, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and characterized by a complex inflammatory process and clinical immunophenotypes. Nowadays, several alterations of immune response within the respiratory tracts as well as at the level of the peripheral blood have been well documented. Nonetheless, their effects on COVID-19-related cell heterogeneity and disease progression are less defined. Here, we performed a single-cell RNA sequencing of about 400 transcripts relevant to immune cell function including surface markers, in mononuclear cells (PBMCs) from the peripheral blood of 50 subjects, infected with SARS-CoV-2 at the diagnosis and 27 healthy blood donors as control. We found that patients with COVID-19 exhibited an increase in COVID-specific surface markers in different subsets of immune cell composition. Interestingly, the expression of cell receptors, such as IFNGR1 and CXCR4, was reduced in response to the viral infection and associated with the inhibition of the related signaling pathways and immune functions. These results highlight novel immunoreceptors, selectively expressed in COVID-19 patients, which affect the immune functionality and are correlated with clinical outcomes.

Published
2021

40. TRIM8 interacts with KIF11 and KIFC1 and controls bipolar spindle formation and chromosomal stability

Author

Anna Irma Croce, Vincenzo Giambra, Pietro Pucci, Maria Chiara Monti, Giuseppe Merla, Lucia Micale, Flora Cozzolino, Tommaso Mazza, Santina Venuto, Carmela Fusco, Diana Canetti, Paolo Malatesta, Patrizio Panelli, Gabriella Maria Squeo, Silvia Soddu, Laura Monteonofrio, Irene Appolloni, Venuto, S., Monteonofrio, L., Cozzolino, F., Monti, M., Appolloni, I., Mazza, T., Canetti, D., Giambra, V., Panelli, P., Fusco, C., Squeo, G. M., Croce, A. I., Pucci, P., Malatesta, P., Soddu, S., Merla, G., and Micale, L.

Subjects
0301 basic medicine, Proteomics, Cancer Research, Kinesins, Micronuclei, Mice, 0302 clinical medicine, Neural Stem Cells, TRIM8, Cytoskeleton, Cells, Cultured, Cultured, Kinesin, Mitosi, beta Karyopherins, Chromosomal stability, Ubiquitin ligase, Cell biology, Oncology, Embryo, Mitosis, Aneuploidy, Animals, Carrier Proteins, Embryo, Mammalian, Fibroblasts, HEK293 Cells, Humans, Micronuclei, Chromosome-Defective, Nerve Tissue Proteins, Primary Cell Culture, Prometaphase, Protein Binding, Spindle Apparatus, Ubiquitin-Protein Ligases, Chromosomal Instability, 030220 oncology & carcinogenesis, KIFC1, Centrosome separation, Cells, Biology, 03 medical and health sciences, Mammalian, Embryonic stem cell, Spindle apparatus, 030104 developmental biology, biology.protein, Chromosome-Defective
Abstract

The faithful inheritance of chromosomes is essential for the propagation of organisms. In eukaryotes, central to this process is the mitotic spindle. Recently, we have identified TRIM8 as a gene aberrantly expressed in gliomas whose expression reduces the clonogenic potential in the patients' glioma cells. TRIM8 encodes an E3 ubiquitin ligase involved in various pathological processes, including hypertrophy, antiviral defense, encephalopathy, and cancer development. To gain insights into the TRIM8 functions, we characterized the TRIM8 interactome in primary mouse embryonic neural stem cells using proteomics. We found that TRIM8 interacts with KIFC1, and KIF11/Eg5, two master regulators of mitotic spindle assembly and cytoskeleton reorganization. By exploring the TRIM8 role in the mitotic spindle machinery, we showed that TRIM8 localizes at the mitotic spindle during mitosis and plays a role in centrosome separation at the beginning of mitosis with a subsequent delay of the mitotic progression and impact on chromosomal stability.

Published
2019

41. Polymorphism of immunoglobulin enhancer element HS1,2A: allele *2 associates with systemic sclerosis. Comparison with HLA‐DR and DQ allele frequency

Author

Vincenzo Giambra, Gianfranco Ferraccioli, M. De Santis, Barbara Tolusso, Gabriele Valentini, Domenico Frezza, Silvia Laura Bosello, Giovanni Triolo, Serena Vettori, Frezza, D, Giambra, V, Tolusso, B, DE SANTIS, M, Bosello, S, Vettori, Serena, Triolo, G, Valentini, Gabriele, and Ferraccioli, G.

Subjects
Male, Settore MED/16 - REUMATOLOGIA, systemic sclerosis, clinical evaluation, genotype phenotype correlation, HLA DR antigen, Scleroderma, Gene Frequency, Genotype, Immunology and Allergy, centromere antibody, immunoglobulin enhancer binding protein, scl 70 antibody, adult, aged, article, controlled study, DNA polymorphism, female, gene frequency, human, major clinical study, male, priority journal, risk factor, Adult, Aged, Autoantibodies, Enhancer Elements (Genetics), Esophagus, Female, Genetic Predisposition to Disease, HLA-DQ Antigens, HLA-DR Antigens, Humans, Immunoglobulin Heavy Chains, Middle Aged, Phenotype, Polymorphism, Genetic, Scleroderma, Systemic, Statistics, Nonparametric, Stomach, education.field_of_study, Statistics, Extended Report, Enhancer Elements, Genetic, Immunology, Population, Biology, General Biochemistry, Genetics and Molecular Biology, Genetic, Rheumatology, HLA-DR, Nonparametric, Polymorphism, Allele, education, Enhancer, Allele frequency, Systemic, Genotype frequency, Settore BIO/18 - Genetica, Immunoglobulin heavy chain
Abstract

OBJECTIVE: To investigate the relationship of the polymorphic enhancer HS1,2 central to the 3' enhancer complex regulatory region (IgH3'EC) of the immunoglobulin heavy chain genes with systemic sclerosis (SSc) disease and compare it with HLA-DR and DQ associations. METHODS: A total of 116 patients with SSc were classified as diffuse (dSSc) or limited (lSSc), and as carriers of antitopoisomerase I (anti-Scl70) or anticentromere (ACA) antibodies. Allele and genotype frequencies were assessed in the population as a whole and in the two major subsets, dSSc and lSSc. The concentration of peripheral blood immunoglobulin levels was also determined and analysed according to the genotypes. RESULTS: The analysis of genotypes for the four alleles of the HS1,2A enhancer showed an increased frequency of allele *2 in the SSc cohort highly significant versus controls (57% vs. 40%, p

Published
2007

42. ASIA Syndrome: State-of-the-Art and Future Perspectives.

Author

Caldarelli M, Rio P, Giambra V, Gasbarrini A, Gambassi G, and Cianci R

Abstract

The expression "Autoimmune/inflammatory syndrome induced by adjuvants (ASIA)" was coined by Shoenfeld and colleagues in 2011. It defines a group of immune-mediated disorders that arise in people, with a genetic predisposition, following exposure to adjuvant agents. This syndrome has been reported after contact with silicone implants, medications, infections, metals, vaccines, and other substances. It typically occurs in individuals with a genetic predisposition, particularly involving genes, such as HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) and PTPN22 (protein tyrosine phosphatase non-receptor type 22). Some stimuli lead to an overactivation of the immune system, prompt the production of autoantibodies, and finally cause autoimmune disorders. This narrative review aims to provide an overview of the ASIA syndrome with a special focus on the role of adjuvants in different vaccines, especially after the COVID-19 pandemic, and insights into development of new treatments.

Published
2024
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43. Inflammaging: The Next Challenge-Exploring the Role of Gut Microbiota, Environmental Factors, and Sex Differences.

Author

Caldarelli M, Rio P, Marrone A, Giambra V, Gasbarrini A, Gambassi G, and Cianci R

Abstract

The term 'inflammaging' has been coined to describe the chronic state of inflammation derived from ongoing cycles of tissue damage and the subsequent immune responses. This inflammatory status contributes to the decline of organs and physiological functions, accelerates the aging process, and increases the risk of age-related illnesses and death. During aging, the gut microbiota (GM) undergoes significant changes, including a decreased diversity of species, a decline in beneficial bacteria, and a rise in proinflammatory ones, resulting in persistent low-grade inflammation. Moreover, environmental factors, such as diet and medications, contribute to age-related changes in GM and immune function, preventing or promoting inflammaging. This narrative review aims to clarify the underlying mechanisms of inflammaging and to specifically investigate the influence of GM and several environmental factors on these mechanisms, while also exploring potential differences related to sex. Moreover, lifestyle and pharmacological interventions will be suggested to promote healthy aging.

Published
2024
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44. Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle.

Author

Fusco C, Nardella G, Morlino S, Micale L, Tragni V, Agolini E, Novelli A, Massuras S, Giambra V, Pierri CL, and Castori M

Subjects
Humans, DNA-Binding Proteins metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Cell Cycle genetics, Transforming Growth Factor beta, Molecular Dynamics Simulation, Marfan Syndrome
Abstract

Heterozygous deleterious variants in SKI cause Shprintzen-Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming growth factor beta signaling. Paucity of reported studies exploring the SGS molecular pathogenesis hampers disease recognition and clinical interpretation of private variants. Here, the unpublished c.349G>A, p.[Gly117Ser] and the recurrent c.539C>T, p.[Thr180Met] SKI variants were studied combining in silico and in vitro approach. 3D comparative modeling and calculation of the interaction energy predicted that both variants alter the SKI tertiary protein structure and its interactions. Computational data were functionally corroborated by the demonstration of an increase of MAPK phosphorylation levels and alteration of cell cycle in cells expressing the mutant SKI. Our findings confirmed the effects of SKI variants on MAPK and opened the path to study the role of perturbations of the cell cycle in SGS., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Published
2024
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45. The Notch1 signaling pathway directly modulates the human RANKL-induced osteoclastogenesis.

Author

Padovano C, Bianco SD, Sansico F, De Santis E, Tamiro F, Colucci M, Totti B, Di Iasio S, Bruno G, Panelli P, Miscio G, Mazza T, and Giambra V

Subjects
Humans, Cell Differentiation, Osteoclasts metabolism, RANK Ligand pharmacology, RANK Ligand metabolism, Signal Transduction, Leukocytes, Mononuclear, Osteogenesis
Abstract

Notch signaling is an evolutionary conserved pathway with a key role in tissue homeostasis, differentiation and proliferation. It was reported that Notch1 receptor negatively regulates mouse osteoclast development and formation by inhibiting the expression of macrophage colony-stimulating factor in mesenchymal cells. Nonetheless, the involvement of Notch1 pathway in the generation of human osteoclasts is still controversial. Here, we report that the constitutive activation of Notch1 signaling induced a differentiation block in human mononuclear CD14 + cells directly isolated from peripheral blood mononuclear cells (PBMCs) upon in vitro stimulation to osteoclasts. Additionally, using a combined approach of single-cell RNA sequencing (scRNA-Seq) simultaneously with a panel of 31 oligo-conjugated antibodies against cell surface markers (AbSeq assay) as well as unsupervised learning methods, we detected four different cell stages of human RANKL-induced osteoclastogenesis after 5 days in which Notch1 signaling enforces the cell expansion of specific subsets. These cell populations were characterized by distinct gene expression and immunophenotypic profiles and active Notch1, JAK/STAT and WNT signaling pathways. Furthermore, cell-cell communication analyses revealed extrinsic modulators of osteoclast progenitors including the IL7/IL7R and WNT5a/RYK axes. Interestingly, we also report that Interleukin-7 receptor (IL7R) was a downstream effector of Notch1 pathway and that Notch1 and IL7R interplay promoted cell expansion of human RANKL-induced osteoclast progenitors. Taken together, these findings underline a novel cell pattern of human osteoclastogenesis, outlining the key role of Notch1 and IL-7R signaling pathways., (© 2023. The Author(s).)

Published
2023
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46. Gut Microbiota, Inflammatory Bowel Disease, and Cancer: The Role of Guardians of Innate Immunity.

Author

Giambra V, Pagliari D, Rio P, Totti B, Di Nunzio C, Bosi A, Giaroni C, Gasbarrini A, Gambassi G, and Cianci R

Subjects
Humans, Immunity, Innate, Inflammation, Toll-Like Receptors metabolism, Gastrointestinal Microbiome, Inflammatory Bowel Diseases, Neoplasms
Abstract

Inflammatory bowel diseases (IBDs) are characterized by a persistent low-grade inflammation that leads to an increased risk of colorectal cancer (CRC) development. Several factors are implicated in this pathogenetic pathway, such as innate and adaptive immunity, gut microbiota, environment, and xenobiotics. At the gut mucosa level, a complex interplay between the immune system and gut microbiota occurs; a disequilibrium between these two factors leads to an alteration in the gut permeability, called 'leaky gut'. Subsequently, an activation of several inflammatory pathways and an alteration of gut microbiota composition with a proliferation of pro-inflammatory bacteria, known as 'pathobionts', take place, leading to a further increase in inflammation. This narrative review provides an overview on the principal Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs), focusing on their recognition mechanisms, signaling pathways, and contributions to immune responses. We also report the genetic polymorphisms of TLRs and dysregulation of NLR signaling pathways that can influence immune regulation and contribute to the development and progression of inflammatory disease and cancer.

Published
2023
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47. A functional role of Ephrin type-B receptor 6 (EPHB6) in T-cell acute lymphoblastic leukemia.

Author

Colucci M, Trivieri N, Mencarelli G, De Santis E, Sansico F, Tamiro F, Visioli A, Barile C, Pracella R, Rossi G, Binda E, and Giambra V

Abstract

T-cell lymphoblastic acute leukemia (T-ALL) is an aggressive blood cancer, characterized by restricted cellular subsets with enriched leukemia initiating cells (LICs). Recently, Ephrin receptors (Eph) were described to be highly expressed in cancer stem cells. Here, using public RNA-Seq datasets of human T-ALL, we reported that EphB6 was the only member within the Eph family overexpressed in over 260 samples. We also found the highest level of EphB6 in a minor cell subpopulation within bulk tumors of patient-derived xenografts, obtained through the injection of primary patient biopsy material into immunocompromised NOD-Scid/IL2Rγc -/- (NSG) mice. Interestingly, this EphB6 positive (EphB6+) subset showed an enriched LIC activity after in vivo transplantation into NSG mice. Additionally, gene expression data at the single-cell level of primary patients' leukemic cells revealed that EphB6 + cells were significantly selected in minimal residual disease up to 30 days from the standard treatments and characterized by high levels of markers related to cell proliferation and poor clinical outcome, such as CCNB1 and KIF20A. Taken together, our data suggest that EphB6 supports LICs' maintenance and progression in T-ALL and, thus, targeting EphB6 + cells could be therapeutically relevant for the treatment of T-ALL patients., (© 2023. Yumed Inc. and BioMed Central Ltd., part of Springer Nature.)

Published
2023
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48. Changes in Lymphocyte Subpopulations after Remdesivir Therapy for COVID-19: A Brief Report.

Author

Cianci R, Massaro MG, De Santis E, Totti B, Gasbarrini A, Gambassi G, and Giambra V

Subjects
Male, Humans, Female, Middle Aged, Aged, Aged, 80 and over, Retrospective Studies, COVID-19 Drug Treatment, Lymphocyte Subsets, Oxygen, COVID-19
Abstract

Remdesivir (RDV) has demonstrated clinical benefit in hospitalized COronaVIrus Disease (COVID)-19 patients. The objective of this brief report was to assess a possible correlation between RDV therapy and the variation in lymphocyte subpopulations. We retrospectively studied 43 hospitalized COVID-19 patients: 30 men and 13 women (mean age 69.3 ± 15 years); 9/43 had received RDV therapy. Six patients had no need for oxygen (severity group 0); 22 were on oxygen treatment with a fraction of inspired oxygen (FiO 2 ) ≤ 50% (group 1); 7 on not-invasive ventilation (group 2); 3 on invasive mechanical ventilation (group 3); and 5 had died (group 4). Cytofluorimetric assessment of lymphocyte subpopulations showed substantial changes after RDV therapy: B lymphocytes and plasmablasts were significantly increased ( p = 0.002 and p = 0.08, respectively). Cytotoxic T lymphocytes showed a robust reduction ( p = 0.008). No changes were observed in CD4 + -T cells and natural killers (NKs). There was a significant reduction in regulatory T cells (Tregs) ( p = 0.02) and a significant increase in circulating monocytes ( p = 0.03). Stratifying by disease severity, after RDV therapy, patients with severity 0-2 had significantly higher B lymphocyte and monocyte counts and lower memory and effector cytotoxic T cell counts. Instead, patients with severity 3-4 had significantly higher plasmablast and lower memory T cell counts. No significant differences for CD4 + -T cells, Tregs, and NKs were observed. Our brief report showed substantial changes in the lymphocyte subpopulations analyzed between patients who did not receive RDV therapy and those after RDV treatment. Despite the small sample size, due to the retrospective nature of this brief report, the substantial changes in lymphocyte subpopulations reported could lead to speculation on the role of RDV treatment both on immune responses against the virus and on the possible downregulation of the cytokine storm observed in patients with more severe disease.

Published
2023
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49. The circadian clock circuitry modulates leukemia initiating cell activity in T-cell acute lymphoblastic leukemia.

Author

Murgo E, De Santis E, Sansico F, Melocchi V, Colangelo T, Padovano C, Colucci M, Carbone A, Totti B, Basti A, Gottschlich L, Relogio A, Capitanio N, Bianchi F, Mazzoccoli G, and Giambra V

Subjects
Humans, Animals, Mice, Signal Transduction, Disease Models, Animal, RNA, Small Interfering, T-Lymphocytes, Circadian Clocks, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
Abstract

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, characterized by restricted cellular subsets with asymmetrically enriched leukemia initiating cell (LIC) activity. Nonetheless, it is still unclear which signaling programs promote LIC maintenance and progression., Methods: Here, we evaluated the role of the biological clock in the regulation of the molecular mechanisms and signaling pathways impacting the cellular dynamics in T-ALL through an integrated experimental approach including gene expression profiling of shRNA-modified T-ALL cell lines and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) of leukemic cells. Patient-derived xenograft (PDXs) cell subsets were also genetically manipulated in order to assess the LIC activity modulated by the loss of biological clock in human T-ALL., Results: We report that the disruption of the circadian clock circuitry obtained through shRNA-mediated knockdown of CLOCK and BMAL1 genes negatively impacted the growth in vitro as well as the activity in vivo of LIC derived from PDXs after transplantation into immunodeficient recipient mice. Additionally, gene expression data integrated with ChIP-Seq profiles of leukemic cells revealed that the circadian clock directly promotes the expression of genes, such as IL20RB, crucially involved in JAK/STAT signaling, making the T-ALL cells more responsive to Interleukin 20 (IL20)., Conclusion: Taken together, our data support the concept that the biological clock drives the expression of IL20R prompting JAK/STAT signaling and promoting LIC activity in T-ALL and suggest that the selective targeting of circadian components could be therapeutically relevant for the treatment of T-ALL patients., (© 2023. Italian National Cancer Institute ‘Regina Elena’.)

Published
2023
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50. Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia.

Author

Panelli P, De Santis E, Colucci M, Tamiro F, Sansico F, Miroballo M, Murgo E, Padovano C, Gusscott S, Ciavarella M, Chavez EA, Bianchi F, Rossi G, Carella AM, Steidl C, Weng AP, and Giambra V

Subjects
Humans, beta Catenin metabolism, Leukemia, Myeloid, Acute pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy characterized by cell subsets and enriched with leukemia-initiating cells (LICs). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown. To identify functionally relevant protein interactions of β-catenin in T-ALL, we performed coimmunoprecipitation followed by liquid chromatography-mass spectrometry. Here, we report that a noncanonical functional interaction of β-catenin with the Forkhead box O3 (FOXO3) transcription factor positively regulates LIC-related genes, including the cyclin-dependent kinase 4, which is a crucial modulator of cell cycle and tumor maintenance. We also confirm the relevance of these findings using stably integrated fluorescent reporters of β-catenin and FOXO3 activity in patient-derived xenografts, which identify minor subpopulations with enriched LIC activity. In addition, gene expression data at the single-cell level of leukemic cells of primary patients at the time of diagnosis and minimal residual disease (MRD) up to 30 days after the standard treatments reveal that the expression of β-catenin- and FOXO3-dependent genes is present in the CD82+CD117+ cell fraction, which is substantially enriched with LICs in MRD as well as in early T-cell precursor ALL. These findings highlight key functional roles for β-catenin and FOXO3 and suggest novel therapeutic strategies to eradicate aggressive cell subsets in T-ALL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2023
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