18 results on '"S. Boninsegna"'
Search Results
2. Antiviral activity of bone morphogenetic proteins and activins.
- Author
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Eddowes LA, Al-Hourani K, Ramamurthy N, Frankish J, Baddock HT, Sandor C, Ryan JD, Fusco DN, Arezes J, Giannoulatou E, Boninsegna S, Chevaliez S, Owens BMJ, Sun CC, Fabris P, Giordani MT, Martines D, Vukicevic S, Crowe J, Lin HY, Rehwinkel J, McHugh PJ, Binder M, Babitt JL, Chung RT, Lawless MW, Armitage AE, Webber C, Klenerman P, and Drakesmith H
- Subjects
- Antiviral Agents metabolism, Cells, Cultured, Endopeptidases genetics, Hepacivirus drug effects, Hepatitis C drug therapy, Hepatitis C metabolism, Hepcidins genetics, Humans, Interferon Regulatory Factors genetics, Interferon-alpha pharmacology, Interferon-alpha therapeutic use, RNA, Viral metabolism, Signal Transduction genetics, Smad1 Protein genetics, Ubiquitin Thiolesterase, Virus Replication drug effects, Zika Virus drug effects, Activins pharmacology, Antiviral Agents pharmacology, Bone Morphogenetic Protein 6 pharmacology, Gene Expression Regulation drug effects, Signal Transduction drug effects
- Abstract
Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.
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- 2019
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3. Impact of IL-27 on hepatocyte antiviral gene expression and function.
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Ramamurthy N, Boninsegna S, Adams R, Sahgal N, Lockstone H, Baban D, Marchi E, and Klenerman P
- Abstract
Background: Interleukin (IL)-27 is a member of the IL-6/IL-12 family of cytokines. It is a potent cytokine, with potential antiviral impact, and has been shown to play a role in modulating functions of diverse cell types, including Th1, Th2, and NK and B cells, demonstrating both pro- and anti-inflammatory roles. In hepatocytes, it is capable of inducing signal transducer and activator of transcription (STAT)1, STAT3 and interferon-stimulated genes. Methods: To address its role in viral hepatitis, the antiviral activity of IL-27 against hepatitis C virus (HCV) and hepatitis B virus (HBV) was tested in vitro using cell-culture-derived infectious HCV (HCVcc) cell culture system and the HepaRG HBV cell culture model. To further investigate the impact of IL-27 on hepatocytes, Huh7.5 cells were treated with IL-27 to analyse the differentially expressed genes by microarray analysis. Furthermore, by quantitative PCR, we analyzed the up-regulation of chemokine (CXCL)-10 in response to IL-27. Results: In both HCV and HBV infection models, we observed only a modest direct antiviral effect. Microarray analysis showed that the up-regulated genes mostly belonged to antigen presentation and DNA replication pathways, and involved strong up-regulation of CXCL-10 , a gene associated with liver inflammation. Overall, gene set enrichment analysis showed a striking correlation of these genes with those up-regulated in response to related cytokines in diverse cell populations. Conclusion: Our data indicate that IL-27 can have a significant pro-inflammatory impact in vitro , although the direct antiviral effect is modest. It may have a potential impact on hepatocyte function, especially chemokine expression and antigen presentation., Competing Interests: No competing interest were disclosed.
- Published
- 2016
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4. Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B.
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Lampertico P, Viganò M, Di Costanzo GG, Sagnelli E, Fasano M, Di Marco V, Boninsegna S, Farci P, Fargion S, Giuberti T, Iannacone C, Regep L, Massetto B, Facchetti F, and Colombo M
- Subjects
- Adult, Alanine Transaminase blood, Anti-HIV Agents adverse effects, Anti-HIV Agents therapeutic use, Antiviral Agents adverse effects, DNA, Viral blood, Drug Therapy, Combination, Female, Hepatitis B virus immunology, Hepatitis B, Chronic blood, Hepatitis B, Chronic genetics, Humans, Interferon-alpha adverse effects, Lamivudine adverse effects, Lamivudine therapeutic use, Male, Middle Aged, Polyethylene Glycols adverse effects, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Time Factors, Treatment Outcome, Antiviral Agents therapeutic use, Hepatitis B e Antigens blood, Hepatitis B virus genetics, Hepatitis B, Chronic drug therapy, Interferon-alpha therapeutic use, Polyethylene Glycols therapeutic use
- Abstract
Objective: Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population., Methods: 128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 μg PegIFN for 48 weeks (group A, n=51), 180 μg PegIFN for 48 weeks followed by 135 μg weekly for an additional 48 weeks (group B, n=52) or 180 μg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 μg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (primary), HBV DNA <2000 IU/ml and HBsAg clearance at 48 weeks after treatment., Results: Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA <2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg <10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events., Conclusions: In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment., Trial Registration Number: http://ClinicalTrials.gov registration number: NCT01095835.
- Published
- 2013
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5. Viral kinetics during the first weeks of pegylated interferon and ribavirin treatment can identify patients at risk of relapse after its discontinuation: new strategies for such patients?
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Milan M, Boninsegna S, Scribano L, Lobello S, Fagiuoli S, Fabris P, Buda A, and Martines D
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- Adult, Analysis of Variance, Drug Therapy, Combination, Female, Genotype, Hepacivirus physiology, Hepatitis C, Chronic genetics, Hepatitis C, Chronic virology, Humans, Interferon alpha-2, Logistic Models, Male, Middle Aged, RNA, Viral genetics, Recombinant Proteins therapeutic use, Retrospective Studies, Risk Factors, Secondary Prevention, Time Factors, Viral Load, Antiviral Agents therapeutic use, Hepacivirus isolation & purification, Hepatitis C, Chronic drug therapy, Interferon-alpha therapeutic use, Polyethylene Glycols therapeutic use, Ribavirin therapeutic use
- Abstract
Background: Pegylated interferon (PEG-IFN) and ribavirin is the most effective treatment for chronic hepatitis C virus (HCV) hepatitis, but the rate of sustained virological response (SVR) remains approximately 50%, and 15-20% of all treated patients have a virological relapse after completing the treatment. Studies on the SVR have failed to discriminate between non-responders and relapsers., Aims: To identify the risk factors for relapse among patients with an end-of-treatment response (ETR)., Methods: We retrospectively analyzed 281 patients consecutively treated with PEG-IFN and ribavirin with a follow-up period of at least 24 weeks. The baseline details collected on each patient included demographic data, histological features, and biochemical profiles., Results: Forty-six patients (16.4%) relapsed during the first 6 months of follow-up after discontinuing the therapy. Relapser patients were significantly older, had more steatosis, fibrosis, and showed significantly lower rapid virological response (RVR) rates compared with SVR patients. By logistic regression analysis, only the absence of RVR was found to be significantly associated with relapses in both subgroups of patients with genotypes 1 and 4 (p < 0.004) and those with genotypes 2 and 3 (p < 0.006). Severe fibrosis was also predictive of relapsing disease, but only for genotypes 2 and 3 patients (p < 0.003). During the treatment, serum HCV-RNA decreased more rapidly in patients with SVR compared to non-responder and relapser patients (p < 0.001). Interestingly, relapser patients exhibited an intermediate serum HCV-RNA decay during the first 4 weeks of therapy., Conclusion: Among HCV patients treated with PEG-IFN and ribavirin, the absence of RVR was the most important independent predictor of relapse, independent of the HCV genotype. In the subgroup of genotypes 2 and 3 patients, the severity of fibrosis was also an important factor associated with the relapse rate.
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- 2012
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6. Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C.
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Ferrara F, Ventura P, Vegetti A, Guido M, Abbati G, Corradini E, Fattovich G, Ferrari C, Tagliazucchi M, Carbonieri A, Orlandini A, Fagiuoli S, Boninsegna S, Minola E, Rizzo G, Belussi F, Felder M, Massari M, Pozzato G, Bonetto S, Rovere P, Sardini C, Borghi A, Zeneroli ML, Toniutto P, Rossi E, and Pietrangelo A
- Subjects
- Adult, Disease Progression, Female, Hemolysis drug effects, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic pathology, Humans, Interferon alpha-2, Interferon-alpha therapeutic use, Iron blood, Liver pathology, Male, Middle Aged, Polyethylene Glycols therapeutic use, Recombinant Proteins, Ribavirin therapeutic use, Transferrin analysis, Treatment Outcome, Antiviral Agents therapeutic use, Ferritins blood, Hepatitis C, Chronic blood
- Abstract
Objectives: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome., Methods: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome., Results: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043)., Conclusions: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.
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- 2009
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7. HCV histological recurrence and survival following liver transplantation in patients with and without hepatocellular carcinoma.
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De Martin E, Senzolo M, Boninsegna S, Guido M, Masier A, Germani G, Tomat S, Brolese A, Neri D, Cillo U, Gambato M, Russo FP, Farinati F, and Burra P
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- Adult, Aged, Carcinoma, Hepatocellular complications, Female, Follow-Up Studies, Humans, Liver Neoplasms complications, Liver Transplantation mortality, Male, Middle Aged, Recurrence, Retrospective Studies, Survival Rate, Carcinoma, Hepatocellular surgery, Hepatitis C pathology, Hepatitis C surgery, Liver Neoplasms surgery, Liver Transplantation physiology
- Abstract
Background and Aim: Hepatitis C virus (HCV)-related cirrhosis is one of the leading indication for liver transplantation (LT) and a major risk factor for the development of hepatocellular carcinoma (HCC). HCV recurrence after LT is universal. This study evaluated HCV recurrence and survival in patients transplanted for HCV and HCC., Methods: We evaluated all adults transplanted for HCV cirrhosis between January 1999 and December 2006, HCC was diagnosed on the explant and HCV recurrence confirmed on protocol liver biopsies performed at 6 months and yearly after LT. The sustained viral response (SVR) was defined as HCV-RNA undetectable at 6 months after therapy discontinuation. The patient survival rates were assessed with Kaplan-Meier curves and the chi-square test was used when appropriate., Results: Two hundred sixteen patients underwent LT for HCV including 153 men and 63 women of mean age 54 years with a mean follow-up of 35 months. There were 71 (33%) HCC(+) patients. At 1, 3, and 5 years from LT severe fibrosis (Scheuer 3-4) due to the HCV recurrence was reported in 18%, 14%, and 11% for HCC(+) and 14%, 16%, and 28% for HCC(-) patients respectively (P=NS). HCC recurred only in 3 (4%) patients at a mean follow-up of 3 years. Patients who received antiviral treatment after LT were 10% HCC(+) and 12% HCC(-) patients (P=NS). SVR was seen in 3/7 (43%) of HCC(+) and in 10/18 (55%) of HCC(-) patients (P=NS). At 1, 3, and 5 years the patient survivals was 91%, 86%, and 86% for HCC(+) and 94%, 86%, and 83% for HCC(-) patients, respectively (P=NS)., Conclusions: Severe fibrosis due to HCV recurrence, which increases over time, involves one third of transplanted patients at 5 years after LT. The long-term survival was identical among HCC(+) compared to HCC(-) recipients. The recurrence of HCC was negligible and did not affect patient survival.
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- 2008
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8. Liver transplantation for HCV cirrhosis: improved survival in recent years and increased severity of recurrent disease in female recipients: results of a long term retrospective study.
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Belli LS, Burroughs AK, Burra P, Alberti AB, Samonakis D, Cammà C, De Carlis L, Minola E, Quaglia A, Zavaglia C, Vangeli M, Patch D, Dhillon A, Cillo U, Guido M, Fagiuoli S, Giacomoni A, Slim OA, Airoldi A, Boninsegna S, Davidson BR, Rolles K, and Pinzello G
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- Adult, Age Factors, Cohort Studies, Disease Progression, Female, Hepatitis C physiopathology, Humans, Kaplan-Meier Estimate, Liver Cirrhosis physiopathology, Longitudinal Studies, Male, Middle Aged, Recurrence, Retrospective Studies, Risk Factors, Severity of Illness Index, Sex Factors, Time Factors, Tissue Donors, Hepatitis C complications, Liver Cirrhosis surgery, Liver Cirrhosis virology, Liver Transplantation
- Abstract
In recent years, a worsening outcome of hepatitis C virus (HCV)-positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre- and post-liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV-positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post-LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow-up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan-Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV-related recurrent severe fibrosis (Ishak score 4-6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence.
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- 2007
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9. Antiviral therapy for hepatitis C virus recurrence following liver transplantation: long-term results from a single center experience.
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Burra P, Targhetta S, Pevere S, Boninsegna S, Guido M, Canova D, Brolese A, Masier A, D'Aloiso C, Germani G, Tomat S, and Fagiuoli S
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- Drug Therapy, Combination, Follow-Up Studies, Humans, Interferon-alpha therapeutic use, Italy, Patient Dropouts, Recurrence, Retrospective Studies, Ribavirin therapeutic use, Time Factors, Treatment Outcome, Viral Load, Antiviral Agents therapeutic use, Hepatitis C prevention & control, Hepatitis C surgery, Liver Transplantation
- Abstract
Background: Hepatitis C virus (HCV) reinfection after liver transplantation is a virtually constant finding and leads to chronic hepatitis and cirrhosis in variable proportions. This study aimed to assess the safety and efficacy of alpha-interferon (IFN) plus ribavirin for recurrent HCV following liver transplantation., Patients and Methods: Thirty of 55 patients (54.5%) with histologically proven HCV recurrence after liver transplantation were given antiviral therapy (alpha-IFN at a dose of 6 MU x 3 x week IM associated with oral ribavirin 1 g/d for 12 months) and followed up for a further 12 months after the end of the treatment. Liver and renal function tests, hemocytometric values, and HCV-RNA were assessed every 3 months throughout the therapy and follow-up. Liver biopsy was performed before and after the treatment and after another 12 months of follow-up., Results: Eight patients (26.7%) were withdrawn from the treatment due to adverse events and another 8 (26.7%) needed a dosage reduction. Eleven patients (36.7%) had a biochemical and virological response, becoming aminotransferase and HCV-RNA negative at the end of the treatment; 6 patients (20%) still had a sustained response after 12 months of follow-up. All 6 patients are clinically stable at 6 years after completing the antiviral therapy. A low viral load before therapy was a positive predictor of sustained response. No histologically significant improvement was seen at the end of the therapy or after the follow-up., Conclusions: The combination of alpha-IFN plus ribavirin induced a sustained virologic response in 20% of liver transplant recipients with recurrent HCV, but intolerance of the therapy prompted its discontinuation or a dosage reduction in a large proportion of patients. However, we have observed a long-term efficacy of the antiviral therapy in the sustained responders.
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- 2006
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10. HLA-DRB1 donor-recipient mismatch affects the outcome of hepatitis C disease recurrence after liver transplantation.
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Belli LS, Burra P, Poli F, Battista Alberti A, Silini E, Zavaglia C, Fagiuoli S, Prando D, Espadas de Arias A, Boninsegna S, Tinelli C, Scalamogna M, de Carlis L, and Pinzello G
- Subjects
- Adult, Aged, Alleles, CD4-Positive T-Lymphocytes immunology, Female, HLA-DRB1 Chains, Humans, Liver Cirrhosis genetics, Liver Transplantation immunology, Male, Middle Aged, Recurrence, HLA-DR Antigens genetics, Hepatitis C etiology, Histocompatibility Testing, Liver Transplantation adverse effects
- Abstract
Background & Aims: This study extends our previously reported observations that various immunological factors are associated with the occurrence of histologically proven recurrent hepatitis C. The two specific issues investigated were to confirm the associations of MHC alleles and donor/recipient mismatch with the occurrence of recurrent hepatitis C in an independent cohort of newly transplanted patients and to look for immunologic and nonimmunologic variables affecting the severity of the recurrent disease., Methods: Two separate cohorts of consecutive patients were studied: a look-back cohort (LC) of 120 patients and a cohort for studying the disease progression (CSDP) of 190 patients. Protocol liver biopsies were obtained at least 1, 3, 5, 7, and 10 years after liver transplantation (LT)., Results: A fully mismatched donor/recipient pair at the DRB1 locus was confirmed to be associated with both the recurrence of histologic hepatitis in the LC (59% vs 23%, P = .0002) and its progression beyond stage 3 in the CSPD (71.4% vs 39.3%, P = .0003). Relevant immunologic and nonimmunologic variables were included into a multivariate Cox proportional model and three variables, namely, donor age, full HLA-DRB1 donor-recipient mismatch, and HLA B14, resulted in independent risk factors for the development of severe fibrosis., Conclusion: This study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and progression of recurrent hepatitis C disease. This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented.
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- 2006
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11. Fatal hepatic decompensation in a bone marrow transplant recipient with HBV-related cirrhosis following lamivudine withdrawal.
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Floreani A, Boninsegna S, Lobello S, Caroli D, and Fagiuoli S
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- Bone Marrow Transplantation, Fatal Outcome, Hepatitis B complications, Hepatitis B virus physiology, Humans, Immunocompromised Host, Liver Cirrhosis complications, Liver Cirrhosis virology, Male, Middle Aged, Multiple Myeloma therapy, Renal Insufficiency complications, Sepsis complications, Hepatitis B drug therapy, Lamivudine therapeutic use, Multiple Myeloma complications, Reverse Transcriptase Inhibitors therapeutic use, Virus Activation
- Abstract
Lamivudine is a nucleoside analogue with a potent antiviral activity used as prophylaxis against hepatitis B virus reactivation in patients with chronic HBV infection receiving chemotherapy. No standard guidelines exist, however, for the duration of lamivudine treatment. We report a clinical case of a 56-year-old patient with HBeAg-negative cirrhosis who developed a multiple myeloma. He was treated with lamivudine for 1 year while receiving chemotherapy and a subsequent bone marrow transplant. Complete remission from multiple myeloma was achieved. Four months after lamivudine was withdrawn, he experienced HBV reactivation with jaundice, though no YMDD mutations were detected. The patient rapidly developed fatal decompensation with septicemia and renal failure. In conclusion, this case shows that physicians should avoid discontinuing nucleoside therapy in patients with HBV infection who undergo immunosuppression for concomitant neoplastic conditions.
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- 2006
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12. Encapsulation of individual pancreatic islets by sol-gel SiO2: a novel procedure for perspective cellular grafts.
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Boninsegna S, Bosetti P, Carturan G, Dellagiacoma G, Dal Monte R, and Rossi M
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- Animals, Biocompatible Materials, Cell Survival, Computer Simulation, Culture Techniques, Diabetes Mellitus, Experimental metabolism, Gels, Glucose pharmacology, Insulin metabolism, Insulin Secretion, Islets of Langerhans cytology, Islets of Langerhans Transplantation methods, Microspheres, Models, Biological, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Diabetes Mellitus, Experimental surgery, Islets of Langerhans metabolism, Islets of Langerhans Transplantation instrumentation, Membranes, Artificial, Silicon Dioxide
- Abstract
Pancreatic rat islets are encapsulated by a siliceous layer deposited on the surface of single islets upon reaction with gaseous siliceous precursors. The process preserves original islet dimensions and does not suppress viability or function. The encapsulated material is homogeneously distributed on the islet surface, and layer thickness can be controlled in the 0.1-2.0 microm interval. Dynamic perfusion experiments with glucose stimulation were carried out in both encapsulated and non-encapsulated islets. Results were treated according to a kinetic model presented here for the analysis of perfusion data; the model tested by literature data, was used to substantiate the diffusion features of the siliceous layer, which does not affect mass transfer of insulin but which modifies the texture of the islet surface tissue. The clinical potential of silica encapsulation was demonstrated by in vivo experiments using encapsulated islets transplanted into diabetic rats. Transplantation was carried out in both inbred and outbred rats and indicated prolonged restoration of normal glycaemia levels and protection from immunological attack.
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- 2003
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13. SiO(2) entrapment of animal cells: liver-specific metabolic activities in silicaoOverlaid hepatocytes.
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Muraca M, Vilei MT, Zanusso GE, Ferraresso C, Boninsegna S, Dal Monte R, Carraro P, and Carturan G
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- Ammonia metabolism, Animals, Bilirubin metabolism, Diazepam metabolism, Male, Microscopy, Electron, Scanning, Rats, Rats, Inbred F344, Statistics, Nonparametric, Urea metabolism, Hepatocytes metabolism, Liver, Artificial, Silicon Dioxide metabolism
- Abstract
Rat hepatocytes in a collagen-gel sandwich configuration were exposed to silicon alkoxides in a gas phase, yielding a 0.05 to 0.15 microm porous silica layer on the gel surface. Cell viability was unaffected by the procedure. After 24 h, bilirubin conjugation, ammonia removal, urea synthesis, and diazepam metabolism were unaffected by the procedure. However, both the ammonia removal rate and diazepam metabolism were increased after 48 hr, whereas urea synthesis was unaffected. These data indicate that silica overlay allows efficient metabolic activity of collagen-gel entrapped hepatocytes. The fact that the KM of bilirubin conjugation was unaffected by the presence of the silica membrane suggests that the transport of albumin-bound substrates is not decreased. The enhancement in some metabolic activities found 48 h after the entrapment procedure may be the result of favorable changes in the hepatocyte microenvironment. These characteristics might be useful for the development of organotypical bioartificial liver devices.
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- 2002
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14. Nuclear accumulation of c-myc mRNA in phytohaemagglutinin-activated T lymphocytes treated with anti-HLA class I monoclonal antibody.
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Selvatici R, Boninsegna S, Ferrati M, and Gandini E
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- Base Sequence, Cells, Cultured, DNA Primers, Exons, Humans, Phytohemagglutinins, Polymerase Chain Reaction, Antibodies, Monoclonal pharmacology, Cell Nucleus metabolism, Genes, myc, Histocompatibility Antigens Class I immunology, Lymphocyte Activation, Proto-Oncogene Proteins c-myc biosynthesis, RNA, Messenger biosynthesis, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transcription, Genetic
- Abstract
Anti-HLA class I monoclonal antibody 01.65 inhibits the proliferative response of PHA-activated human T lymphocytes from peripheral blood mononuclear cells. The recruitment rate in the cell cycle is slack and the G1 and S phases are prolonged. Among the early events after PHA activation, only the calcium-dependent PKC activity appears to be modified: particulate PKC is completely depleted while cytosolic residual PKC is reduced by 80% after MAb 01.65 treatment. We have carried out in greater detail the study of c-myc gene regulation by MAb 01.65 and the results are as follows: (i) c-myc RNA transcription is normally initiated and finished, suggesting a post-transcriptional regulation of c-myc gene expression; (ii) no alteration in c-myc mRNA stability has been documented; (iii) steady-state levels of c-myc mRNA expression by Northern blot analysis and PCR amplification are decreased in the cytoplasmic compartment, while in the nuclear compartment they appear to be increased. Nuclear accumulation of mature mRNA after MAb 01.65 and PKC inhibitor (H7 and StSp) treatment appears to be the most probable mechanism involved. The possible implications of this are discussed.
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- 1998
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15. Identification of a novel protein kinase C inhibitor in microsomes from phytohaemagglutinin activated human peripheral blood mononuclear cells.
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Gandini E, Orlando P, Selvatici R, Balboni A, Boninsegna S, and Rubini M
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- Blood Proteins physiology, Cells, Cultured, Enzyme Inhibitors analysis, Humans, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Phytohemagglutinins pharmacology, Tetradecanoylphorbol Acetate pharmacology, Blood Proteins analysis, Leukocytes, Mononuclear chemistry, Microsomes chemistry, Protein Kinase C antagonists & inhibitors
- Abstract
A peptide inhibiting either corpuscolate or purified PKC has been identified from microsomes of PHA-activated human PBMC but it is not detectable in microsomes of resting PBMC. The peptide was obtained from a microsomal preparation in an oligomeric form that could be transformed into a monomeric form by beta-MSH. The active peptide (IN) was retained on a PC-11 chromatographic column and could be eluted with NaCl. IN is ineffective on PKC-dependent protamine phosphorylation of protamine and on Ca2+ and phospholipid-independent activity generated by mild hydrolysis with trypsin of PKC. Ca2+ binding is permissive for IN activity. IN inhibits particulate PKC in PHA-activated PBMC, but is ineffective after TPA activation. All these data indicate that IN acts at the regulatory domain of PKC.
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- 1993
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16. Anchored anti-HLA class I monoclonal antibody fails to induce inhibition of PHA-activated lymphocytes proliferation.
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Rubini M, Selvatici R, Orlando P, Balboni A, Boninsegna S, and Gandini E
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- Antibodies, Monoclonal immunology, Cell Cycle, Cells, Cultured, Humans, Kinetics, Lymphocyte Activation drug effects, Lymphocytes metabolism, Phytohemagglutinins, Protein Kinase C metabolism, Receptors, Interleukin-2 biosynthesis, Receptors, Transferrin biosynthesis, Thymidine metabolism, Antibodies, Monoclonal pharmacology, Histocompatibility Antigens Class I immunology, Lymphocyte Activation immunology, Lymphocytes immunology
- Abstract
It is known that anti-HLA Class I antibodies inhibit the proliferative response of PHA-activated T-lymphocytes. We found that plastic- or sepharose-linked anti-HLA Class I monoclonal antibody 01.65 does not inhibit either [3H]Thymidine incorporation or recruitment in the cell cycle, nor does it reduce the expression of c-myc mRNA and the membrane expression of Interleukin-2 Receptor and Transferrin Receptor. Furthermore, particulate Protein Kinase C is not affected by anchored anti-HLA Class I monoclonal antibody 01.65. We suggest that anti-HLA Class I monoclonal antibody may act through crosslinking or internalization of HLA Class I antigens.
- Published
- 1992
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17. Rapid detection of a protein C gene mutation present in the asymptomatic and not in the thrombosis-prone lineage.
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Bernardi F, Patracchini P, Gemmati D, Boninsegna S, Guerra S, Legnani C, Ballerini G, and Marchetti G
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- Adult, Base Sequence, Blotting, Southern, Electrophoresis, Polyacrylamide Gel, Exons, Humans, Male, Middle Aged, Molecular Sequence Data, Pedigree, Polymerase Chain Reaction, Serine Endopeptidases genetics, Mutation genetics, Protein C genetics, Thrombosis genetics
- Abstract
The presence of mutations in the serine protease domain of protein C was investigated by temperature gradient gel electrophoresis of PCR products in five patients with protein C deficiency and thrombosis. Molecules with an altered melting behaviour were detected in one subject with a history of venous and arterial thrombosis. Direct sequencing showed that a G deletion, present in the heterozygous state, caused a reading frame shift at Trp 300 and subsequently a premature termination at the codon 335. The resulting suppression of the protein C catalytic function explains the reduction of protease activity to half. In addition the mutation caused a reduction of the antigen level in plasma. Temperature gradient gel electrophoresis enabled the rapid detection of the gene alteration in the family of the propositus. Several members of the paternal lineage had had severe thrombotic episodes. Unexpectedly the mutation was found to be inherited from the clinically asymptomatic maternal lineage, thus suggesting that an additional unknown defect from the paternal lineage is present in the thrombosis-prone propositus.
- Published
- 1992
- Full Text
- View/download PDF
18. A recurrent missense mutation (Arg----Gln) and a partial deletion in factor VIII gene causing severe haemophilia A.
- Author
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Bernardi F, Volinia S, Patracchini P, Gemmati D, Boninsegna S, Schwienbacher C, and Marchetti G
- Subjects
- DNA Probes, Exons, Female, Humans, Male, Oligonucleotide Probes, Restriction Mapping, Chromosome Deletion, Factor VIII genetics, Hemophilia A genetics, Mutation
- Abstract
The presence of gene lesions in coagulation factor VIII (FVIII) gene was investigated in 70 Italian patients severely affected by haemophilia A. cDNA probes specific for exons 14-26 of the FVIII gene were used. In two related patients a gene deletion removes exon 26, a gene lesion similar to that described previously in a British haemophiliac. In exon 24 a C to T transition in the reverse complement strand causes a missense mutation in the coding strand (CGA----CAA, 2209 Arg----Gln). The mutation is located in a very conserved FVIII homology region and severely reduces FVIII activity. By restriction analysis and hybridizations with oligonucleotide probes this gene alteration was found in two unrelated haemophiliacs and in their relatives.
- Published
- 1989
- Full Text
- View/download PDF
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