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Biomedical subjects

George Marinos

Publications and source records attributed to George Marinos.

12 recordsLinked to original sources
PubMed2006

Circadian variation in expression of G1 phase cyclins D1 and E and cyclin-dependent kinase inhibitors p16 and p21 in human bowel mucosa.

AIM: To evaluate whether the cellular proliferation rate in the large bowel epithelial cells is characterized by circadian rhythm. METHODS: Between January 2003 and December 2004, twenty patients who were diagnosed as suffering from primary, resectable, non-metastatic adenocarcinoma of the lower rectum, infiltrating the sphincter mechanism, underwent abdominoperineal resection, total mesorectal excision and permanent left iliac colostomy. In formalin-fixed and paraffin-embedded biopsy specimens obtained from the colostomy mucosa every six hours (00:00, 06:00, 12:00, 18:00 and 24:00), we studied the expression of G(1) phase cyclins (D(1) and E) as well as the expression of the G(1) phase cyclin-dependent kinase (CDK) inhibitors p16 and p21 as indicators of cell cycle progression in colonic epithelial cells using immunohistochemical methods. RESULTS: The expression of both cyclins showed a similar circadian fashion obtaining their lowest and highest values at 00:00 and 18:00, respectively (P<0.001). A circadian rhythm in the expression of CDK inhibitor proteins p16 and p21 was also observed, with the lowest levels obtained at 12:00 and 18:00 (P<0.001), respectively. When the complexes cyclins D(1) -p21 and E-p21 were examined, the expression of the cyclins was adversely correlated to the p21 expression throughout the day. When the complexes the cyclins D(1) -p16 and E-p16 were examined, high levels of p16 expression were correlated to low levels of cyclin expression at 00:00, 06:00 and 24:00. Meanwhile, the highest expression levels of both cyclins were correlated to high levels of p16 expression at 18:00. CONCLUSION: Colonic epithelial cells seem to enter the G(1) phase of the cell cycle during afternoon (between 12:00 and 18:00) with the highest rates obtained at 18:00. From a clinical point of view, the present results suggest that G(1) -phase specific anticancer therapies in afternoon might maximize their anti-tumor effect while minimizing toxicity.

Aged↗
PubMed2005

Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.

BACKGROUND/AIMS: Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy. METHODS: Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 microg/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study. RESULTS: 67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or > or = 2 log10 decrease) at week 12 had SVRs at week 72 (HCV RNA < 50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was approximately 20% lower in those who received <80% compared with patients who received > or = 80% of the planned ribavirin dose. CONCLUSIONS: Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a > or = 2 log10 reduction in HCV RNA after 12 weeks.

Antiviral Agents↗
PubMed2004

Prevalence of production of virus-specific interferon-gamma among seronegative hepatitis C-resistant subjects reporting injection drug use.

This report describes subjects who were highly likely to have been repeatedly exposed to hepatitis C virus (HCV) through injection drug use and who remained negative for anti-HCV antibody. Production of virus-specific interferon- gamma by peripheral blood mononuclear cells was seen in the majority of subjects (72%) and was associated with higher-risk behavior. For 92% of the subjects, results of recombinant immunoblot assays demonstrated faint bands against nonstructural proteins. The immune responses described are likely to have been primed and maintained by episodes of subclinical infection without classic seroconversion and may indicate a hepatitis C-resistant phenotype. Vaccine strategies to mimic this response may provide protection against persistent HCV infection.

Adolescent↗
PubMed2004

Clearance of hepatitis C viremia associated with cellular immunity in the absence of seroconversion in the hepatitis C incidence and transmission in prisons study cohort.

Understanding the earliest virological and immunological events in acute hepatitis C virus (HCV) infection may provide insight into the determinants of protective immunity. Four cases of HCV viremia with subsequent viral clearance, but without biochemical hepatitis or anti-HCV seroconversion, are reported from a prospective cohort study of prison inmates. Two of the subjects who developed sustained viremia were assessed for production of interferon (IFN)- gamma, by use of the enzyme-linked immunospot (ELISPOT) method and by assessment of HCV cytotoxic T lymphocyte (CTL) activity, CD4 lymphocyte proliferative responses, HCV load, and genotype. After 2-6 months of viremia, all 4 subjects cleared serum HCV RNA. Specific cellular responses were detected in both of the subjects who were assessed, and production of IFN- gamma was demonstrated in one subject. All subjects had weak, but consistent, serological reactivity against HCV nonstructural proteins on immunoblot testing, despite repeatedly nonreactive HCV ELISA tests. These cases highlight the potential for cellular immune responses against HCV to facilitate viral clearance, responses that may model those required for effective HCV vaccination.

Adult↗
PubMed2004

The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C.

BACKGROUND/AIMS: Peginterferon alfa-2a plus ribavirin improves sustained virological responses compared with interferon alfa-2b and ribavirin, or peginterferon alfa-2a alone in chronic hepatitis C. We examined the impact of these treatments on health related quality of life (HRQOL). METHODS: Patients (n=1121) were randomized to peginterferon alfa-2a weekly plus ribavirin or placebo, or interferon alfa-2b thrice weekly plus ribavirin. HRQOL was assessed with the SF-36 Health Survey and Fatigue Severity Scale (FSS). RESULTS: Patients receiving peginterferon alfa-2a plus ribavirin reported better HRQOL than those receiving interferon alfa-2b plus ribavirin. These differences were statistically significant for three SF-36 domains and both FSS scores (p<=0.05). Patients receiving peginterferon alfa-2a plus placebo had the least impairment; adding ribavirin significantly decreased five domains of the SF-36 and both FSS scores. Sustained virological response was associated with improvement at follow-up on all SF-36 and FSS scores. CONCLUSIONS: The effects of combination therapy on HRQOL and fatigue are less with peginterferon alfa-2a plus ribavirin than interferon alfa-2b plus ribavirin. Each medication in combination therapy with interferon and ribavirin, affects patients' quality of life differently. Understanding the relationship of specific therapeutic options to HRQOL may help physicians minimize the impact of therapy on HRQOL.

Adult↗
PubMed2003

The presence of an intrahepatic cytotoxic T lymphocyte response is associated with low viral load in patients with chronic hepatitis C virus infection.

BACKGROUND/AIMS: The role of cytotoxic T lymphocytes (CTL) in limiting viral replication and producing hepatocellular injury in patients with chronic hepatitis C virus (HCV) infection is controversial. METHODS: Intrahepatic and peripheral blood HCV-specific CTL activity against the entire HCV polyprotein was assessed in 26 patients. CTL responses were assessed after effector lymphocytes were re-stimulated for 6 days in vitro using HCV-vaccinia virus-infected autologous cells expressing HCV antigens. Serum and hepatic viral loads were measured and immunohistochemistry for CD3 and CD8 was performed to localise and enumerate effector cells in liver. RESULTS: A positive CTL response was detected in 39/52 (75%) of assays conducted with intrahepatic mononuclear cells and 21/52 (40%) of peripheral blood assays (P<0.001). The presence of an intrahepatic CTL response was associated with low hepatic viral load (P=0.004). Hepatic lobular infiltration by CD8(+)T cells correlated weakly with serum alanine aminotransferase levels (r=0.42, P=0.04) and no relationship was demonstrated between CTL activity and histological evidence of liver damage. CONCLUSIONS: HCV-specific CTL activity is found more commonly in liver than in blood. An inverse relationship between CTL responses and viral load supports the hypothesis that HCV-specific CTL limit viral replication in patients with chronic HCV infection.

Adult↗
PubMed2003

Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon.

A dynamic equilibrium between viral production and clearance characterizes untreated chronic hepatitis C viral infection. After initiating antiviral treatment, a typical multiphasic decay of viremia can be observed and analyzed using mathematical models. To elucidate the antiviral mechanism of ribavirin when used in combination with (pegylated) interferon alfa, we investigated kinetic parameters in patients with chronic hepatitis C treated with either peginterferon alpha-2a with or without ribavirin and standard interferon alpha-2b plus ribavirin for 48 weeks. Serum HCV RNA was measured frequently before, during, and at the end-of-treatment and the follow-up period. By using an appropriate model for viral dynamics, kinetic parameters were derived from nonlinear, least square fitting of serum HCV RNA quantifications. The first phase of viral decay (day 1) and the second phase of viral decay (days 2 to 21) were similar for all treatment groups. After about 7 to 28 days, a third phase of viral decay was seen in several patients, and this phase of decay was significantly faster in patients treated with peginterferon alpha-2a plus ribavirin compared with those treated with peginterferon alpha-2a alone. The decay of this third phase was associated with the virologic end-of-treatment response and sustained virologic response. In conclusion, the third-phase decay of initial viral kinetics, which may represent a treatment-enhanced degradation of infected cells, was more pronounced in patients treated with peginterferon alpha-2a plus ribavirin. This finding suggests that combination treatment leads to a better restoration of the patient's immune response.

Adult↗
PubMed2003

Expression of the chemokine IP-10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation.

The factors influencing lymphocyte trafficking to the liver lobule during chronic hepaititis C virus (HCV) infection are currently not well defined. Interferon-gamma-inducible protein 10 (IP-10), a chemokine that recruits activated T lymphocytes, has recently been shown by in situ hybridization to be expressed in the liver during chronic HCV infection. This study sought to define the cellular source of IP-10 in the liver by immunohistochemistry, to examine the expression of its receptor, CXCR3, on T lymphocytes isolated from blood and liver tissue, and to correlate IP-10 expression with the histological markers of inflammation and fibrosis. IP-10 was expressed by hepatocytes but not by other cell types within the liver, and the most intense immunoreactivity was evident in the areas of lobular inflammation. The IP-10 receptor was expressed on a significantly higher proportion of T lymphocytes in the liver compared with blood. CD8 T lymphocytes, which predominate in the liver lobule, were almost uniformly CXCR3-positive. The expression of IP-10 mRNA correlated with lobular necroinflammatory activity but not with inflammation or fibrosis in the portal tracts. These findings suggest that IP-10 may be induced by HCV within hepatocytes and may be important in the pathogenesis of chronic HCV infection, as recruitment of inflammatory cells into the lobule is an important predictor of disease progression.

Adult↗
PubMed2003

Acute hepatitis C.

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Acute Disease↗
PubMed2002

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.

BACKGROUND: Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. METHODS: A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. RESULTS: A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin. CONCLUSIONS: In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.

Adult↗
PubMed2002

Quantification of hepatitis C virus in human liver and serum samples by using LightCycler reverse transcriptase PCR.

A highly sensitive, non-probe-based, real-time quantitative reverse transcriptase PCR was developed for viral load measurements in both serum and liver samples from patients with hepatitis C virus (HCV) infection. With synthetic RNA, the linearity of the approach was conserved over a wide range of HCV copy numbers. There was a strong correlation between hepatic and serum viral load measurements (r = 0.689, P = 0.004, n = 15), indicating that the level of viremia reflected the amount of virus present in the liver.

Hepacivirus↗