Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which Hepatitis C virus(HCV) infection promotes the development of hepatocellular carcinoma(HCC) is not known exactly. HCV related HCC occurs frequency in the patients with cirrhosis. There have been reports indicating that Th2-type cytokines down-regulated antitumor immunity, and the activation of type 1 T cell responses produced antitumor immunity. We thought Th1/Th2 imbalance in HCV-related liver cirrhosis might be closely related to the development of HCC. In this study, therefore, we investigated the Th1/Th2 balance at the single lymphocyte level of the patients with HCV-related liver cirrhosis and compared with normal controls by using flow cytometry. Th1-type cytokines(IFN-gamma, IL-2) production was significantly decreased in patients with cirrhosis, whereas Th2-type cytokine production(IL-10) was increased. These suggest Th1/Th2 imbalance in HCV-related cirrhosis would decrease the antitumor immunity and its improvement might present the protective effect from HCC.
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PMID:[Th1/Th2 imbalance in HCV-related liver cirrhosis]. 1149 34

Patients with hepatitis C virus (HCV) related-liver cirrhosis (LC) often develop hepatoma. The type 1 helper T cell (Th1) response presents an antitumor effect. We evaluated the Th1 response in patients with HCV-related LC at the single-cell level and examined the influence of transforming growth factor (TGF)-beta, an immunosuppressive cytokine, on the Th1 response. We determined the ratios of Th1-type cytokine (IFN-gamma, IL-2)-producing cells to CD3-positive cells in 14 patients (LC group) and in 16 normal controls using flow cytometry and measured serum TGF-beta(1) and TGF-beta(2) levels by ELISA. We then incubated, peripheral blood mononuclear cells from seven healthy volunteers with recombinant TGF-beta(1) or TGF-beta(2) for 48 h, and determined the ratio of IFN-gamma producing cells to CD3-positive cells. The IFN-gamma ratio was significantly lower in the LC group (29.7+/-0.3 vs. 44.2+/-15.0%, P<0.01). The serum TGF-beta(2) level was significantly increased in the LC group (601+/-232 vs. 329+/-118 pg/ml, P<0.001). TGF-beta(2) significantly suppressed IFN-gamma production at the single-cell level (10.0+/-4.3 vs. 7.3+/-2.0%, P<0.05). These findings indicated that the enhanced down-regulation of Th1 by TGF-beta(2) in patients with HCV-related LC might be effective against hepatoma.
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PMID:Th1 down-regulation at the single-lymphocyte level in HCV-related liver cirrhosis and the effect of TGF-beta on Th1 response: possible implications for the development of hepatoma. 1239 30

We analysed the host response to hepatectomy by simultaneous measurement of various cytokines and their antagonists in the portal vein, caval vein and radial artery in 10 patients with hepatocellular carcinoma. Concentrations of tumour necrosis factor-alpha (TNF), interleukin (IL) 1 beta, IL-2, IL-6, IL-10, soluble TNF receptor type I (sTNF-R), soluble IL-2 receptor (sIL-2R), IL-1 receptor antagonist (IL-1ra), soluble CD14 (sCD14) and endotoxin were determined just before and 1 h after hepatectomy. The values of IL-6, sTNF-R and IL-1ra were significantly increased after hepatectomy at each sampling site. In contrast, the levels of sIL-2R and sCD14 after hepatectomy were significantly decreased, and the levels of IL-1 beta, IL-2 and IL-10 were below the detection limits. Differences in cytokine concentrations between sampling sites revealed that the surgical stress of hepatectomy induced significant IL-1ra production in the liver and sTNF-R and IL-6 production in the lungs. These results suggest that hepatic resection is followed by the production of cytokine antagonists, such as IL-1ra, sTNF-R and IL-6, which could represent an important regulatory mechanism against surgical stress.
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PMID:Analysis of host response to hepatectomy by simultaneous measurement of cytokines in the portal vein, caval vein and radial artery. 1244 19

We have previously reported several CTL epitopes derived from the hepatitis B viral X Ag (HBx). In this study, we evaluated whether HBx-specific CTLs can be effectively used in adoptive cancer immunotherapy. To validate the possibility, four peptides containing a HLA-A2.1-restricted binding consensus motif were identified from the HBx protein and tested for their ability to activate CTL from PBMCs isolated from chronic carriers of HBV (n = 12). We selected two highly potent epitopes, HBx 52-60 (HLSLRGLFV) and HBx 115-123 (CLFKDWEEL), that are capable of inducing Ag-specific cytotoxic T cells in patient PBMCs. For adoptive immunotherapy using HBx-specific CTLs, we generated CTL clones restricted to the HBx 52-60 or HBx 115-123 peptide using a limiting dilution technique. LC-46, an HBx 52-60-specific clone, is CD62L(-)CD69(+)CD45RO(+)CD45RA(-)CD25(dim) and is stained by IFN-gamma (approximately 92%), IL-2 (30%), and TNF-alpha (56%), but not by IL-5, IL-10, IL-12, or TNF-beta, indicating that the cells are fully activated T cytotoxic 1-type cells. When LC-46 cells were adoptively transferred into xenografted nude mice bearing human hepatomas expressing HLA-A2.1 molecules and intracellular HBx proteins, the tumors were eradicated. Taken together, our data provide solid evidence for the feasibility of adoptive immunotherapy with HBx-sensitized CTLs in hepatitis disease, including hepatocellular carcinoma (HCC).
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PMID:Tumor eradication by hepatitis B virus X antigen-specific CD8+ T cells in xenografted nude mice. 1253 74

Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infection, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Expression of the HCV core (C) protein modulates transcription of the IL-2 promoter in T lymphocytes by activating the nuclear factor of activated T lymphocyte (NFAT) pathway. Here we report on the effect of HCV C on Ca2+ signaling, which is essential for activation of NFAT. Expression of HCV C correlated with increased levels of cytosolic Ca2+ and spontaneous Ca2+ oscillations in transfected Jurkat cells. Triggering of the T-cell receptor induced a prolonged Ca2+ response characterized by vigorous high frequent oscillations in a high proportion of the responding cells. This was associated with decreased sizes and accelerated emptying of the intracellular calcium stores. The effect of HCV C on calcium mobilization was not dependent on phospholipase C-gamma 1 (PLC-gamma) activity or increased inositol 1,4,5-trisphosphate (IP3) production and did not require functional IP3 receptors, suggesting that insertion of the viral protein in the endoplasmic reticulum membrane may be sufficient to promote Ca2+ leakage with dramatic downstream consequences on the magnitude and duration of the response. Our data suggest that expression of HCV C in infected T lymphocytes may contribute to the establishment of persistent infections by inducing Ca2+ oscillations that regulate both the efficacy and information content of Ca2+ signals and are ultimately responsible for induction of gene expression and functional differentiation.
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PMID:The hepatitis C virus core protein modulates T cell responses by inducing spontaneous and altering T-cell receptor-triggered Ca2+ oscillations. 1263 62

A female patient, who was suffering major depression and advanced hepatocellular carcinoma (hepatoma), sought treatment in the Jozuka Mental Clinic. She was treated using a psycho-neuro-immunological approach. The treatments applied were psychotherapy, the antidepressant fluvoxamine, glycyrrhizinic acid and dehydroepiandrosterone (DHEA). Biochemical, endocrinological and immunological examinations were performed regularly. Improvement of liver function and reduction of alpha-fetoprotein were observed. The levels of DHEA, natural killer cell activity and cytokines (interleukines IL-2, IL-6, IL-12, interferon IFN-gamma) were normalised. Now, more than two and a half years after her admission, the patient is still well and symptom-free. While this may be a case of spontaneous regression, the results suggest that a psycho-neuro-immunological approach to treating the patient's depression and cancer was helpful for her recovery.
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PMID:Psycho-neuro-immunological treatment of hepatocellular carcinoma with major depression--a single case report. 1266 82

Chronic hepatitis B virus (HBV) infection can cause a broad spectrum diseases, including from asymptomatic HBV carriers or cryptic hepatitis, to acute hepatitis, chronic hepatitis, Liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the experimental factors. Among the human genetic factors, major candidate or identified genes involved in the process of HBV infection fall into the following categories: (1) genes that mediate the processes of viral entry into hepatocytes, including genes involved in viral binding, fusion with cellular membrane and transportation in target cells; (2) genes that modulate or control the immune response to HBV infection; (3) genes that participate in the pathological alterations in liver tissue; (4) genes involved in the development of liver cirrhosis and hepatocellular carcinoma associated with chronic HBV infection, including genes related to mother-to-infant transmission of HBV infection; and (5) those that contribute to resistance to antiviral therapies. Most of the reports of human genes associated with HBV infection have currently focused on HLA associations. For example, some investigators reported the association of the HLA class II alleles such as DRB1*1302 or HLA-DR13 or DQA1*0501-DQB1*0301-DQB1*1102 haplotypes with acute and/or chronic hepatitis B virus infection, respectively. Several pro-inflammatory cytokines such as Th1 cytokines (including IL-2 and IFN-gamma) and TNF-alpha have been identified to participate the process of viral clearance and host immune response to HBV. In contrast, the Th2 cytokine IL-10 serves as a potent inhibitor of Th1 effector cells in HBV diseases. The MBP polymorphisms in its encoding region were found to be involved in chronic infection. Thus, reports from various laboratories have shown some inconsistencies with regard to the effects of host genetic factors on HBV clearance and persistence. Since genetic interactions are complex, it is unlikely that a single allelic variant is responsible for HBV resistance or susceptibility. However, the collective influence of several single nucleotide polymorphisms (SNPs) or haplotype (s) may underlie the natural combinational or synergistic protection against HBV. The future study including the multi-cohort collaboration will be needed to clarify these preliminary associations and identify other potential candidate genes. The ongoing study of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HBV infection, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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PMID:Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection. 1267 1

In patients with hepatocellular carcinoma (HCC), natural killer (NK) cell activity decreases significantly, and the reduced activity may be associated with the progression of HCC. In this study we evaluated the effects of pulsing with interleukin (IL)-2 and/or IL-12 on the activation of freshly isolated peripheral blood lymphocytes (PBL) derived from patients with HCC. PBL obtained from 9 HCC patients, 4 liver cirrhosis patients, and 9 normal subjects were cultured in the presence of IL-2 and/or IL-12. After 24 h of incubation, the levels of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha presented in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The IFN-gamma and TNF-alpha production of PBL pulsed by a combination of IL-2 and IL-12 was significantly higher than those of PBL stimulated by either IL-2 or IL-12 alone. The mRNA encoding perforin, granzyme B, as well as IFN-gamma and TNF-alpha, were markedly enhanced in PBL stimulated with a combination of IL-12 and IL-2. The pulsing procedure of IL-12 in combination with IL-2 resulted in the increase of IFN-gamma and TNF-alpha, and the expression of perforin and granzyme B mRNA in PBL obtained from HCC patients, as well as in those obtained from normal subjects. These results indicate that adoptive immunotherapy based on PBL pulsed with a combination of IL-2 and IL-12 may be a promising adjunctive strategy for HCC treatment.
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PMID:Effects of pulsing procedure of interleukin-12 in combination with interleukin-2 on the activation of peripheral blood lymphocytes derived from patients with hepatocellular carcinoma. 1472 65

Hepatocellular carcinoma is an important health problem in Asia. A blend of herbal extracts containing radix bupleuri (KY88) was tested for its effects on liver cancer cells. A hepatocellular carcinoma cell line (HB8064) was cultured with methanol extract of KY88. We were able to produce a dose-dependent inhibition of cancer cell proliferation. At IC50 and IC100, KY88 induces a DNA ladder pattern, indicating the presence of apoptosis. We also checked the changes of the levels of interleukin (IL)-2, -4 and -6, interferon (INF)-gamma and tumor necrosis factor (TNF)-alpha by ELISA kits. After 24 hours of culture, there was activation of IL-2 and -4 and TNF-alpha. However, significant changes were observed only for IL-4 and TNF-alpha. Therefore, we concluded that KY88 is able to induce apoptosis, which may be regulated through changes in IL-4 and TNF-alpha.
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PMID:Radix bupleuri containing compound (KY88 liver-livo) induces apoptosis and production of interleukin-4 and tumor necrosis factor-alpha in liver cancer cells in vitro. 1531 57

The purpose of this study is to compare transarterial chemoembolization (TACE) alone and in combination with other therapies in an animal model. Subcapsular implantation of a solid Morris hepatoma 3924A in the liver was carried out in 50 male ACI rats (day 0). Tumor volume (V1) was measured by MRI (day 13). After laparotomy and retrograde placement of a catheter into the gastroduodenal artery (day 14), the following protocols of the interventional procedure were applied: TACE (mitomycin C + lipiodol) + immunotherapy (group A: TNFalpha + IL-2, group B: OK-432 + IL-2); TACE + antiangiogenesis therapy (group C: TNP-470, group D: endostatin); TACE alone in group E (control group). Tumor volume (V2) was assessed by MRI and the mean ratio of x (V2/V1) was calculated. Data were analyzed using Dunnett's t test (comparing therapeutic groups with the control group) and the Student-Newman-Keuls test (comparing significant therapeutic groups). Multivariate analysis showed a significant reduction in the tumor growth rate (P<0.05) in groups B (x=6.53) and C (x=4.01) compared to the mean ratio of the control group E (x=9.14). Significant results were observed in group C (P<0.05) in comparison with the other therapeutic groups. TACE combined with immunotherapy (OK-432) and antiangiogenesis therapy (TNP-470) retards tumor growth compared with TACE alone in an HCC animal model.
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PMID:Transarterial chemoembolization alone and in combination with other therapies: a comparative study in an animal HCC model. 1558 May 7


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