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1.
J Mech Behav Biomed Mater ; 124: 104844, 2021 12.
Article in English | MEDLINE | ID: mdl-34601433

ABSTRACT

A limit analysis numerical approach oriented to predict the peak/collapse load of human proximal femur, under two different loading conditions, is presented. A yield criterion of Tsai-Hu-type, expressed in principal stress space, is used to model the orthotropic bone tissues. A simplified human femur 3D model is envisaged to carry on numerical simulation of in-vitro tests borrowed from the relevant literature and to reproduce their findings. A critical discussion, together with possible future developments, is presented.


Subject(s)
Bone and Bones , Femur , Computer Simulation , Finite Element Analysis , Humans , In Vitro Techniques , Models, Biological , Stress, Mechanical
2.
Sci Rep ; 7(1): 9563, 2017 08 25.
Article in English | MEDLINE | ID: mdl-28842599

ABSTRACT

Hypoxia-induced miR-210 displays a pro-survival, cytoprotective and pro-angiogenic role in several in vitro systems. In vivo, we previously found that miR-210 inhibition increases ischemic damage. Here we describe the generation of a versatile transgenic mouse model allowing the evaluation of miR-210 therapeutic potential in ischemic cardiovascular diseases. We generated a Tet-On miR-210 transgenic mouse strain (TG-210) by targeted transgenesis in the ROSA26 locus. To functionally validate miR-210 transgenic mice, hindlimb ischemia was induced by femoral artery dissection. Blood perfusion was evaluated by power Doppler while tissue damage and inflammation were assessed by histological evaluation. We found that miR-210 levels were rapidly increased in TG-210 mice upon doxycycline administration. miR-210 overexpression was maintained over time and remained within physiological levels in multiple tissues. When hindlimb ischemia was induced, miR-210 overexpression protected from both muscular and vascular ischemic damage, decreased inflammatory cells density and allowed to maintain a better calf perfusion. In conclusion, we generated and functionally validated a miR-210 transgenic mouse model. Albeit validated in the context of a specific cardiovascular ischemic disease, miR-210 transgenic mice may also represent a useful model to assess the function of miR-210 in other physio-pathological conditions.


Subject(s)
Gene Expression , Ischemia/etiology , MicroRNAs/genetics , Animals , Biopsy , Disease Models, Animal , Fluorescent Antibody Technique , Gene Order , Gene Targeting , Genetic Vectors/genetics , Immunohistochemistry , Ischemia/metabolism , Ischemia/pathology , Mice , Mice, Transgenic
3.
Hepatology ; 30(1): 257-64, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10385664

ABSTRACT

The aim of this study was to assess the long-term outcome in hepatitis B virus (HBV)-infected patients according to HBV, hepatitis C virus (HCV), and hepatitis D virus (HDV) replication, focusing on survival, liver failure, and hepatocellular carcinoma (HCC). A cohort of 302 hepatitis B surface antigen (HBsAg)-positive subjects (mean age, 34 +/- 15.3 years; male/female 214/88; 39 subjects under 14 years) with biopsy-proven chronic hepatitis (86 with cirrhosis) was prospectively assessed, with a median follow-up of 94 +/- 37.6 months. One hundred nine patients received interferon alfa (IFN). At baseline, 86 subjects (28.5%) were hepatitis B e antigen (HBeAg)-positive (wild-type HBV), 80 (26.5%) were HBeAg-negative, HBV-DNA-positive, 76 (25.2%) had HDV infection, 43 (14.2%) had dual HBV/HCV infection, and 17 (5.6%) were negative for HBV-DNA, anti-HCV, and anti-HDV. During follow-up, decompensation of disease occurred in 46 subjects: 8 developed HCC, 36 developed ascites, and 2 developed jaundice. Five patients underwent transplantation. Thirty-five subjects died: 33 of hepatic and 2 of nonhepatic causes. Overall mortality was 5.2-fold that of the general population (95% CI: 3.6-7.3; 35 deaths observed, 6.7 expected; P <.0001). By Cox regression analysis, survival was independently predicted by young age, absence of cirrhosis at baseline, and sustained normalization of aminotransferases during follow-up. Survival without decompensation was independently predicted by the same factors and by IFN treatment. Chronic hepatitis B infection increases mortality in comparison with the general population in our area regardless of specific virological profiles at presentation. Presence of cirrhosis and persistent necroinflammation markedly increase the risk of death.


Subject(s)
Hepatitis B, Chronic/physiopathology , Hepatitis B, Chronic/therapy , Adolescent , Adult , Aged , Alcoholism/epidemiology , Carcinoma, Hepatocellular/epidemiology , Child , Cohort Studies , DNA, Viral/blood , Disease-Free Survival , Female , Follow-Up Studies , Hepatitis B Surface Antigens/blood , Hepatitis B e Antigens/blood , Hepatitis B, Chronic/mortality , Humans , Interferons/therapeutic use , Italy , Life Expectancy , Liver Cirrhosis/epidemiology , Liver Neoplasms/epidemiology , Male , Middle Aged , Probability , Proportional Hazards Models , Risk Factors , Survival Rate , Time Factors , Treatment Outcome
4.
Dig Dis Sci ; 44(5): 1013-9, 1999 May.
Article in English | MEDLINE | ID: mdl-10235612

ABSTRACT

In chronic hepatitis C the rate of relapse after an end-of-treatment response to interferon may exceed 50%. The usefulness of retreatment of relapsers with interferon in obtaining a complete sustained response and the role of clinical, virological and immunological features in determining long-term efficacy of retreatment are unclear. We aimed to assess the efficacy of interferon retreatment in obtaining a complete sustained response, to evaluate whether increasing the dose may enhance responsiveness, and to identify possible predictors of sustained response. We enrolled 42 patients with biopsy-proven chronic hepatitis C without cirrhosis who had previously responded to a six-month course of Interferon-alpha2b (total dose: group A, 22 patients, 234 MU; group B, 20 patients, 468 MU) and then relapsed. All, except one, were HCV-RNA negative at the end of first cycle of interferon; most (31/42, 74%) were infected by HCV 1b. Subjects were randomly allocated to receive another cycle of interferon either at the original dose (group A1: 234 MU, 11 patients; group B1 468 MU, 10 patient) or twice the original dose (group A2: 468 MU, 11 patients; group B2: 936 MU, 10 patients). At the end of the second cycle of interferon, 24 subjects (57%) had normal ALT and were HCV-RNA negative, and 16 (39%) had normal ALT, but were HCV-RNA positive. A complete sustained response was obtained in eight patients (19%), at a similar rate in all treatment groups. Complete sustained responders were different from the other patients in terms of age (35.9 +/- 10.4 vs 44.1 +/- 8.8, P = 0.027), rate of infection with non-1b HCV (6/8 vs 5/34, P = 0.0005), serum HCV-RNA (74,016 vs 321,428 median copies/ml, P = 0.037) and serum levels of 90K/MAC-2 BP (5.76 +/- 3.01 vs 10.25 +/- 5.16 units/ml, P = 0.02), an N-glycoprotein implicated in cellular defense functions. Multivariate logistic analysis validated age and HCV genotype as independent predictors of CSR. Among noncirrhotic relapsers who received a total interferon dose > or = 234 MU in the first cycle, retreatment usually induced end-of-treatment response. A complete sustained response was obtained in only one of every five subjects. Increasing the dose of interferon above that of the first cycle did not enhance the rate of sustained response. In conclusion we might assert that young subjects infected by non-1b HCV and with low levels of HCV-RNA and of 90K/MAC-2 BP are the best candidates for retreatment.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/therapy , Interferon-alpha/therapeutic use , Adult , Antiviral Agents/administration & dosage , Female , Glycoproteins/blood , Hepacivirus/genetics , Humans , Immunoradiometric Assay , Interferon alpha-2 , Interferon-alpha/administration & dosage , Male , Middle Aged , RNA, Viral/analysis , ROC Curve , Recombinant Proteins , Recurrence , Sensitivity and Specificity , Treatment Outcome , Viral Load
5.
J Hepatol ; 28(4): 531-7, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9566819

ABSTRACT

BACKGROUND/AIMS: To evaluate whether sustained response to a-interferon improves clinical outcome in patients with chronic hepatitis C. METHODS: A cohort of 410 consecutive patients (65% with chronic hepatitis, 35% with cirrhosis) were treated with a-interferon in two trials (mean follow-up 62.1 months, range 7-109 months). All were serum HCV RNA positive before therapy and received first 10 then 5 million units of a-2b or a-nl interferon three times weekly for 6 to 12 months. Sustained response was defined as normal aminotransferases 12 months after stopping interferon. RESULTS: Sixty-two patients (15.1%: 54 with chronic hepatitis, eight with cirrhosis) were sustained responders. At the end of follow-up, 56 out of 62 sustained responders (90.3%) were serum HCV RNA negative. No biochemical relapse after 12 months was seen in sustained responders, regardless of initial histology, HCV genotype or persistence of HCV RNA. Although three died of non-hepatic causes, no liver-related events were observed among sustained responders. Complications of liver disease occurred in 34 relapsers/non-responders: nine hepatocellular carcinomas, 21 ascites and four portal hypertensive bleedings. Eleven relapsers/nonresponders died: eight of hepatic and three of non-hepatic causes. Event-free survival was significantly longer in sustained responders than in all the remaining patients. In a regression analysis, sustained response to interferon, low age and absence of cirrhosis were independent predictors of event-free survival. CONCLUSIONS: Hepatitis C virus is probably eradicated and progression of liver disease is prevented in most patients who remain HCV RNA negative with normal transaminases for more than 1 year after stopping treatment.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Adult , Female , Follow-Up Studies , Humans , Male , Middle Aged , Statistics as Topic , Time Factors , Treatment Outcome
6.
Gastroenterology ; 112(2): 463-72, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9024300

ABSTRACT

BACKGROUND & AIMS: Few data are available concerning the long-term prognosis of chronic liver disease associated with hepatitis C virus infection. This study examined the morbidity and survival of patients with compensated cirrhosis type C. METHODS: A cohort of 384 European cirrhotic patients was enrolled at seven tertiary referral hospitals and followed up for a mean period of 5 years. Inclusion criteria were biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of hepatitis A and B viruses and of metabolic, toxic, or autoimmune liver diseases. RESULTS: Antibodies against hepatitis C virus were positive in 98% of 361 patients tested. The 5-year risk of hepatocellular carcinoma was 7% and that of decompensation was 18%. Death occurred in 51 patients (13%), with 70% dying of liver disease. Survival probability was 91% and 79% at 5 and 10 years, respectively. Two hundred five patients (53%) were treated with interferon alfa. After adjustment for clinical and serological differences at baseline between patients treated or not treated with interferon, the 5-year estimated survival probability was 96% and 95% for treated and untreated patients, respectively. CONCLUSIONS: In this cohort of patients, life expectancy is relatively long, in agreement with the morbidity data showing a slowly progressive disease.


Subject(s)
Liver Cirrhosis/mortality , Carcinoma, Hepatocellular , Cohort Studies , Female , Follow-Up Studies , Hepatitis C Antibodies/analysis , Humans , Interferon-alpha/therapeutic use , Liver Cirrhosis/immunology , Liver Cirrhosis/therapy , Liver Neoplasms , Male , Middle Aged , Morbidity , Retrospective Studies , Risk Factors , Survival Analysis
7.
J Med Virol ; 51(1): 17-24, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8986944

ABSTRACT

In chronic hepatitis C virus (HCV) infection, the rate of sustained response to interferon is low. We evaluated, in patients responding to a 26-week course of interferon, the effect of high-dose maintenance therapy in preventing relapse. Three hundred and ten patients with chronic HCV infection (38.3% with cirrhosis, 80.6% with HCV type 1) received interferon alfa-2b for 26 weeks (10 MU tiw for 8 weeks, then 5 MU tiw for 18 weeks). One hundred and twenty-four subjects (40%) normalized aminotransferases, and were allocated randomly either to continue on 5 MU tiw for a further 26 weeks (prolonged therapy group: 60 patients) or to stop interferon (brief therapy group: 64 patients). Fifty-two weeks after stopping interferon the overall sustained biochemical response rate was 13.2% (41/310). The number of patients with normal aminotransferases was comparable between the prolonged and brief therapy groups (30% vs. 35.9%, P = n.s.), and the rate of HCV-RNA clearance was similar (48.8% vs. 42.4%, P = n.s.). The timing of posttreatment relapse was not influenced by the duration of therapy. Fifty-nine patients (19%) did not complete therapy due to adverse effects. Multivariate analysis identified four features predicting sustained biochemical response in subjects normalizing aminotransferases under therapy: negative HCV-RNA at end of therapy, normal aminotransferases at 4 weeks of therapy, high baseline aminotransferases, and high baseline platelets. Infection with HCV type 1 was not a significant predictor of response, due to its high prevalence in our population (80.6%). It is concluded that in patients with chronic hepatitis C mostly infected by HCV type 1, a prolonged high-dose interferon course (900 MU over 52 weeks) did not increase the rate of sustained biochemical response and of HCV-RNA clearance in comparison to a brief course (510 MU over 26 weeks).


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C/drug therapy , Interferon-alpha/therapeutic use , Adolescent , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Biopsy , Female , Hepacivirus/drug effects , Hepacivirus/genetics , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Liver/pathology , Liver Cirrhosis/virology , Male , Middle Aged , Multivariate Analysis , Platelet Count , RNA, Viral/analysis , RNA, Viral/drug effects , RNA, Viral/metabolism , Recombinant Proteins , Recurrence , Time Factors , Transaminases/analysis , Transaminases/metabolism
8.
Cell Growth Differ ; 6(10): 1213-24, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8845298

ABSTRACT

The mouse Htf9-a gene encodes a small hydrophilic protein, named Ran-binding protein 1 (RanBP-1), for its interaction with the Ras-related Ran protein; RanBP-1 binds the biologically active form of Ran. Ran has been implicated in a variety of nuclear events including DNA replication, RNA export and protein import, and monitoring completion of DNA synthesis before the onset of mitosis; it biological activity is thought to be regulated in S phase. We have investigated whether expression of the Htf9-a/RanBP-1 gene is linked to cell proliferation. Expression of the Htf9-a/RanBP-1 transcript appeared to be dependent on the proliferating state of the cells and peaked in S phase. We have identified a promoter region required for Htf9-a cell cycle-dependent expression and for responsiveness to cell cycle regulators. An E2F-binding site was identified within the cell cycle-regulated promoter region. Expression of the E1A oncoprotein prevented Htf9-a down-regulation in quiescent cells; in addition, both pRb and its relative p107 inhibited transcription from the Htf9-a promoter. These results link the control of Htf9-a/RanBP-1 expression to the cell cycle progression.


Subject(s)
Carrier Proteins , Cell Cycle Proteins , Cell Cycle/physiology , DNA-Binding Proteins , GTP-Binding Proteins/genetics , Gene Expression Regulation/genetics , Nuclear Proteins/genetics , Transcription, Genetic/genetics , ran GTP-Binding Protein , 3T3 Cells , Adenovirus E1A Proteins/biosynthesis , Animals , Base Sequence , Binding Sites , Cell Division , Down-Regulation , E2F Transcription Factors , Liver/chemistry , Male , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Nuclear Proteins/physiology , Promoter Regions, Genetic/genetics , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Recombinant Fusion Proteins/biosynthesis , Retinoblastoma Protein/physiology , Retinoblastoma-Binding Protein 1 , Retinoblastoma-Like Protein p107 , Transcription Factor DP1 , Transcription Factors/metabolism
9.
Exp Cell Res ; 216(2): 396-402, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7843284

ABSTRACT

As a step toward defining the signals important for the regulation of cyclin B1 expression, we cloned, sequenced, and partially characterized a 1012-bp genomic fragment encompassing the human cyclin B1 promoter. By transient expression experiments, we found that promoter activity resides within a -150/+182-bp DNA fragment. The activity of this promoter fragment was high in asynchronous NIH-3T3 cells, but dramatically decreased in quiescent cells. Time-course experiments, using stable transfectants expressing the CAT gene under the control of this fragment, were performed after releasing the cells from serum starvation. The results showed that the promoter becomes active at the end of the S phase and its activity increases during the cell cycle. Similar experiments performed with a shorter promoter region (-58/+182) showed that this 5' deletion mutant is active throughout the cell cycle. In good agreement with promoter activity, Northern analysis indicated that the endogenous gene is negatively regulated in quiescent murine NIH-3T3 cells. The data presented here demonstrate that in NIH-3T3 cells the cyclin B1 promoter is growth regulated, and important regulatory elements must exist in the region spanning -150 to -58 bp.


Subject(s)
Cyclins/genetics , Gene Expression Regulation/physiology , Promoter Regions, Genetic/genetics , 3T3 Cells/cytology , Animals , Base Sequence , Cell Cycle , Cell Division , Humans , Mice , Molecular Sequence Data , RNA, Messenger/biosynthesis , Recombinant Fusion Proteins/biosynthesis , Sequence Analysis, DNA , Sequence Deletion/physiology , Transcription, Genetic/genetics
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