1,721,172 research outputs found
KIR/HLA immunogenetic background influences the evolution of hepatocellular carcinoma
No full textNatural killer (NK) cells play a major role in antitumor immune responses. Recent results from our laboratory demonstrate the impact of the immunogenetic background on the activity of NK cells and hence on the outcome of hepatocellular carcinoma, disclosing perspectives for the development of NK-cell based therapies
Cytokines in acute liver inflammation and in chronic evolution of viral hepatitis
No full textCytokines constitute a complex network of molecules involved in the regulation of the inflammatory response and the homeostasis of organ functions. Cytokines coordinate physiologic and pathologic processes going on in the liver, such as liver growth and regeneration, inflammatory processes including viral liver disease, liver fibrosis and cirrhosis. Liver growth and regeneration are regulated by several cytokines. The platelet-derived hepatocyte growth factor, in particular, delivers a strong mitogenic stimulus for hepatocyte regeneration. The cell-mediated immune response plays a central role in hepatocellular necrosis and in the immunopathogenetic mechanisms involved in viral clearance and persistence in liver disease of viral etiology. In this context, cytokines modulate the immune system and exert direct antiviral activity by cytopathic and non-cytopathic mechanisms,as demonstrated in a transgenic mouse model. IL-6, TNF-α, IL-1 and IL-2 increase in acute fulminant viral hepatitis; in fact, they have pro-inflammatory and cytotoxic effects. Reduced IL-2 and IFN-α synthesis and increased serum levels of IL-1 and IL-2 soluble receptor (IL-2R) have been observed in HBV chronic liver disease. In HCV chronic hepatitis, IL-2R increases as well, while IFN-γ and IL-2 decrease. In personal experimental observations, intrahepatic messenger RNA expression of several cytokines was measured in liver specimens of patients with chronic HBV and HCV infections: patients with HCV chronic liver disease had higher levels of IL-2, IL-6, IL-10, and IFN-γ. These data are in accordance with immunological studies showing a vigorous cell-mediated immune response in HCV chronic liver disease and a deficient immune response in HBV chronic hepatitis. The main cytokines involved in the mechanisms of liver fibrosis and cirrhosis are also discussed
Natural killer cells in hepatocellular carcinoma: Anti-tumor effect and therapeutic potential
No full textNatural killer (NK) cells are key players in the anti-tumor immune response in hematologic malignancy and solid tumors. NK-cells represent a relevant fraction of lymphocytes infiltrating the human liver and they are expected to control hepatocellular carcinoma (HCC) growth at least in the initial phases of tumorigenesis. This has been shown by preclinical data and clinical studies demonstrating association of NK-cell number, cytotoxic phenotype and function with outcome. For these reasons NK-cells represent anti-tumor immune cells with possible positive implications for immunotherapeutic approaches in patients with HCC. In order to understand functional properties and defects of this innate cell response in controlling HCC, several aspects have to be considered: the possible deregulation induced by chronic hepatitis B and C viral infections that represent the main causes of liver disease associated with HCC, the effect of tumor microenvironment by soluble mediators and the inhibitory effect of other immune elements involved in tumor-associated inflammatory response. High mortality of patients with primary liver tumors suggests tumor evasion mechanisms. Several mechanisms have been proposed to explain NK-cell dysfunction and different immunotherapeutic approaches can be envisaged to overcome HCC growth and spread. Autologous or allogeneic NK-cells have been adoptively transferred after in-vitro stimulation with promising clinical results. Soluble mediators and monoclonal antibodies activating NK-cell response are in the clinic for hematologic and solid malignancies and initial results are also available for HCC patients. Combined approaches based on increasing tumor sensitivity and potentiating NK-cell response are also under study
Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications
No full textThe development of immunotherapy for solid tumours has boosted interest in the contexture of tumour immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumour cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high-resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response and possibly new therapeutic targets. Here, we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies
Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial
No full textPreliminary data suggest that rifaximin a new non-absorbable rifamycin-derivate, has beneficial effects on chronic portal systemic encephalopathy (PSE). To compare the efficacy and safety of rifaximin vs neomycin in the treatment of the hyperammoniemic state of PSE, 30 cirrhotic patients with grade I to III of PSE were randomly allocated to one of two groups: group A (15 patients) receiving rifaximin (400 mg/8h) and group B (15 patients) neomycin (1gr/8h). The duration of treatment was 21 consecutive days. Age, sex, hepatic and renal function, level of PSE, EEG and number connection test were similar in both groups. A significant decrease in blood ammonia levels was observed at the end of the treatment period in both groups; moreover rifaximin produced an earlier reduction of blood ammonia levels. The neuropsychic syndrome related to the PSE improved in both groups without significant difference. No side effects attributable to therapy were observed in the rifaximin group. These results indicate that, rifaximin is at least as effective as neomycin in the achievement and maintenance of low blood ammonia levels in cirrhotics with chronic PSE
The role of anti-core antibody response in the detection of occult hepatitis B virus infection
No full textOccult hepatitis B virus (HBV) infection is characterized by the presence of HBV DNA in serum and/or in the liver of patients negative for hepatitis B surface antigen (HBsAg). Occult infection may impact in several different clinical contexts including the risk of HBV transmission with transfusion or transplantation, and endogenous viral reactivation. The gold standard test for detection of occult infection is the amplification of HBV DNA. However, the serological assay for the long-lasting antibody response to the highly immunogenic HBV core antigen (anti-HBc) represents a qualified candidate as a surrogate for DNA amplification, or for increasing overall sensitivity when assessing the risk of occult hepatitis in peripheral blood. The risk of occult hepatitis associated with anti-HBc seropositivity has been demonstrated extensively, and the presence of antibody response to HBc can be considered a sentinel marker of occult HBV infection. Clin Chem Lab Med 2010; 48: 23-9
Hepatitis C virus and alcohol: Same mitotic targets but different signaling pathways
No full textBackground & Aims: Chromosomal aberrations are frequently observed in hepatitis C virus (HCV)- and alcohol-related hepatocellular carcinomas (HCCs). The mechanisms by which chromosomal aberrations occur during hepatocarcinogenesis are still unknown. However, these aberrations are considered to be the result of deregulation of some mitotic proteins, including the alteration of Cyclin B1 and Aurora kinase A expression, and the phosphorylation of gamma-tubulin. Our study aims at investigating changes in expression of the above mentioned proteins and related intracellular pathways, in in vitro and in vivo models of both HCV- and alcohol- dependent HCCs.Methods: In this study, the molecular defects and the mechanisms involved in deregulation of the mitotic machinery were analyzed in human hepatoma cells, expressing HCV proteins treated or not with ethanol, and in liver tissues from control subjects (n = 10) and patients with HCV- (n = 10) or alcohol-related (n = 10) HCCs.Results: Expression of Cyclin B1, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin was analyzed in models reproducing HCV infection and ethanol treatment in HCC cells. Interestingly, HCV and alcohol increased the expression of Cyclin B, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin also in tissues from patients with HCV- or alcohol-related HCCs. In vitro models suggest that HCV requires the expression of PKR (RNA-activated protein kinase), as well as JNK (c-Jun N-terminal kinase) and p38MAPK (p38 mitogen-activated protein kinase) proteins; while, ethanol bypasses all these pathways.Conclusions: Our results support the idea that HCV and alcohol may promote oncogenesis by acting through the same mitotic proteins, but via different signaling pathways. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver
Hepatocellular cancer therapy in patients with HIV infection: Disparities in cancer care, trials enrolment, and cancer-related research
Full text linkIn the highly active antiretroviral therapy (HAART) era, hepatocellular carcinoma (HCC) is arising as a common late complication of human immunodeficiency virus (HIV) infection, with a great impact on morbidity and mortality. Though HIV infection alone may not be sufficient to promote hepatocarcinogenesis, the complex interaction of HIV with hepatitis is a main aspect influencing HCC morbidity and mortality. Data about sorafenib effectiveness and safety in HIV-infected patients are limited, particularly for patients who are on HAART. However, in properly selected subgroups, outcomes may be comparable to those of HIV-uninfected patients. Scarce data are available for those other systemic treatments, either tyrosine kinase inhibitors, as well as immune checkpoint inhibitors (ICIs), which have been added to our therapeutic armamentarium. This review examines the influence of HIV infection on HCC development and natural history, summarizes main data on systemic therapies, offers some insight into possible mechanisms of T cell exhaustion and reversal of HIV latency with ICIs and issues about clinical trials enrollment. Nowadays, routine exclusion of HIV-infected patients from clinical trial participation is totally inappropriate, since it leaves a number of patients deprived of life-prolonging therapies
Etanercept in the treatment of psoriasis and psoriatic arthritis with concomitant hepatitis C virus infection: Clinical and virological study in three patients
No full textTreatment of patients with psoriasis and concomitant hepatitis-C virus (HCV) infection poses a therapeutic challenge because most systemic drugs are associated with potential hepatotoxicity, either due to direct liver damage or to immunosuppression. Among newly available drugs for the treatment of psoriasis and psoriatic arthritis, studies investigating the effect of anti-tumour necrosis factor-alpha in such patients are still limited. We describe three psoriatic patients with HCV, one with concomitant alcoholic hepatitis, who were treated with etanercept monotherapy for six months. We obtained good clinical responses for both psoriasis and arthritis in all three patients. While no significant changes in viral load and transaminases were observed in two patients, alanine aminotrasferase and gamma-glutamyltransferase levels were raised during treatment in the patient with concomitant alcoholic hepatitis. At baseline, one patient was negative and two were positive for mixed-type cryoglobulins. During treatment, none of the patients developed cryoglobulinemia-related clinical symptoms, and one of the two patients positive at baseline was negative for cryoglobulins at the end of follow-up. Our results add to accumulating data suggesting that etanercept represents a valuable therapeutic option for treatment of HCV-positive psoriatic patients, with an acceptable safety profile in the short-term. However, etanercept treatment of HCV cases with concomitant alcoholic hepatitis must be undertaken with caution
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