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

We studied clinical and immunological changes of the post-transfusional syndrome like graft versus host disease (GVDH) in six patients after open heart surgery and in one patient after hepatectomy. In the patient with hepatocellular carcinoma, transcatheter arterial embolization had been previously done. All patients received homologous blood transfusion during and after surgery and erythroderma associated hyperthermia occurred approximately 10 days after operation. Patients receiving open heart surgery died on between postoperative 17th and 21st day. One patient with hepatectomy died on the 29th day after operation. Skin biopsies in all patients showed the findings of acute GVHD. The number of CD3+ and CD4+ T lymphocytes decreased at postoperative day 1, however, the number of CD3+ T lymphocyte increased in three patients after postoperative day 14. The postoperative value of interleukin-2 production was low in patients in whom the value was measured. The immunological status in host has not been clearly resolved. However, the postoperative changes of lymphocytes subsets were abnormal and IL-2 production in two patients showed low level. Therefore, it was considered that pre and postoperative measurement of cell-modiated immunity might predict the occurrence of the post-transfusional GVHD and might be one of useful examinations to prevent the disease.
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PMID:[Post-transfusional syndrome like graft versus host disease]. 839 30

Cytokine response to viral infection can be of critical importance in the host defense against virus. Interferon (IFN)-gamma and interleukin (IL)-2 have wide ranges of activities in host defense mechanisms. Therefore, these cytokine genes in the liver were investigated in a series of patients with hepatitis C virus (HCV) infection using a reverse transcribed-polymerase chain reaction (RT-PCR). Total RNA was purified from liver biopsies, reverse transcribed to cDNA, amplified by specific primers, and the products were detected by agarose gel and slot blot hybridization. All samples from acute hepatitis (AH; n = 4) and chronic hepatitis patients (CH; n = 19) were positive for IFN-gamma at varying degrees. AH patients showed strong signals compared to CH patients, liver cirrhosis (LC; n = 12; 72% positive) patients, and hepatocellular carcinoma (HCC; n = 21; 19% positive) patients. IL-2 gene was undetectable in all patients tested. IL-2 receptor (IL-2R) was detectable in AH, CH and LC patients but not in HCC patients. We conclude that IFN-gamma has important roles in the cytokine network that indeed present in the liver of HCV patients while the presence of IL-2R gene may indicate that the signaling pathway for IL-2 is intact.
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PMID:Interferon-gamma, interleukin (IL)-2 and IL-2 receptor expressions in hepatitis C virus-infected liver. 839 42

The advanced tumours of the digestive tract are generally less responsive to conventional chemotherapies. Moreover, preliminary results with IL-2 immunotherapy also seem to show a low efficacy. On the basis of our previous studies suggesting s synergistic action between IL-2 and some neurohormones, such as the pineal indole MLT, a clinical trial was performed to investigate the clinical efficacy and tolerability of an immunotherapy with IL-2 plus MLT in patients with advanced neoplasms of the digestive tract. The study included 35 patients (colorectal cancer: 14; gastric cancer: 8; hepatocarcinoma: 6; pancreas adenocarcinoma: 7). Distant organ metastases were present in 31/35 patients. MLT was given orally at a daily dose of 50 mg at 8.00 p.m., starting 7 days before IL-2, which was given subcutaneously at a dose of 3 million IU/day at 8.00 p.m. for 6 days/week for 4 weeks, corresponding to one cycle of immunotherapy. In nonprogressed patients, a second cycle was given after a 21-day rest period. A complete response was achieved in two patients (gastric cancer: 1; hepatocarcinoma: 1). Six other patients obtained a partial response: (gastric cancer: 2; hepatocarcinoma: 2; colon cancer: 1; pancreas cancer: 1). Therefore, the overall response rate was 8/35 (23%). Stable disease was obtained in 11/35 (31%) patients, whereas the remaining 16 patients (46%) progressed. The response rate was significantly higher in untreated patients than in those previously treated with chemotherapy. Toxicity was low in all patients, who received the treatment as a home therapy. This study shows that the immunotherapy with low-dose IL-2 plus the pineal hormone MLT is a new well tolerated and effective therapy of advanced tumours of the digestive tract, mainly in gastric cancer and hepatocarcinoma.
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PMID:Immunotherapy with subcutaneous low-dose interleukin-2 and the pineal indole melatonin as a new effective therapy in advanced cancers of the digestive tract. 851 25

The cytoplasmic domain of the receptor for interleukin 10 (IL-10R) contains two box 3 sequence motifs that have been identified in the signal-transducing receptor subunits for IL-6-type cytokines and noted to be required for activating STAT3 and inducing transcription through IL-6-responsive elements. To determine whether the IL-10R has signaling functions similar to IL-6R in cells normally expressing these receptors, leukocytes of the B-, T-, and NK-cell lineages were treated with either cytokine. Both cytokines activated factors that bound to the sis-inducible element and included STAT1 and STAT3. The cell response to IL-10 characteristically differed from that to IL-2/IL-15, IL-4, and interferon gamma. The signaling capabilities of the IL-10R for activating specific STAT proteins and inducing gene transcription were defined by reconstitution of receptor functions in transfected tissue culture cells. COS-1 cells, co-expressing the human IL-10R and individual STAT proteins, confirmed a preference of the IL-10R for STAT3 and STAT1. Unlike many hematopoietin receptors, the IL-10R did not detectably activate STAT5. The IL-10R, together with reporter gene constructs containing different IL-6-responsive gene elements, reconstituted in hepatoma cells an induction of transcription by IL-10 that was comparable to that by IL-6. This regulation could not be appreciably modified by enhanced expression of STAT proteins. The similar actions of IL-10R and IL-6R on the induction of endogenous IL-6-responsive genes were demonstrated in hepatoma cells stably expressing the IL-10R. These receptor functions required the presence of the box 3 motifs, as shown by the analysis of the mouse IL-10R constructs containing progressively truncated cytoplasmic domains. The data demonstrate that the IL-10R, unlike other members of the interferon receptor family, is highly effective in recruiting the signaling pathways of IL-6-type cytokine receptors.
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PMID:Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements. 866 28

Previous studies showed that gammaIFN decreases metastatic hepatic tumor growth by stimulating Kupffer cells (KC). The present studies examine whether lymphocyte stimulation via cells engineered to secrete GM-CSF or IL-2 decreases hepatic tumor growth, and whether stimulation of both macrophages and lymphocytes is more effective than either individually. Rats were immunized with irradiated hepatoma cells transduced by herpes viral amplicon vectors containing the genes for GM-CSF, IL-2 or LacZ. On day 18, half of each group was treated with 5 x 10(4) U gammaIFN, or saline intraperitoneally for 3 d. On day 21, all rats received 5 x 10(5) hepatoma cells intrasplenically. On day 41, rats were killed and tumor nodules were counted. Separate rats underwent splenocyte and KC harvest for assessment of lymphocyte- and macrophage-mediated tumor cell kill in vitro. GM-CSF or IL-2 vaccines or gammaIFN decreased tumor nodules significantly (GM-CSF 13+/-4, IL-2 14+/-6 vs. control 75+/-24, P < 0.001). Combination therapy was more effective, and completely eliminated tumor in 4 of 12 IFN-GM-CSF and 8 of 11 IFN-IL-2 animals. Additional rats underwent partial hepatectomy, an immunosuppressive procedure known to accelerate the growth of hepatic tumor, following tumor challenge. Therapy was equally effective in this immunosuppressive setting. Vaccination is associated with enhancement of splenocyte-mediated tumoricidal activity, whereas the effect of gammaIFN is mediated by KC. GM-CSF and IL-2 vaccine therapy and pretreatment with gammaIFN represent effective strategies in reducing hepatic tumor. Combination therapy targets both lymphocytes and macrophages, and is more effective in reducing tumor than either therapy alone.
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PMID:Prevention of hepatic tumor metastases in rats with herpes viral vaccines and gamma-interferon. 904 85

The aim of the study was to assess the specificity of albumin-messenger RNA (mRNA)-positive cells in peripheral blood as an indicator for circulating malignant hepatocytes. Albumin-mRNA-positive cells in the peripheral blood mononuclear cell (PMNC) fraction were detected by reverse-transcription polymerase chain reaction (RT-PCR). Albumin-mRNA-positive cells in PMNC were found in 12 of 19 (63%) patients with hepatocellular carcinoma, but also in 22 of 25 (88%) patients with chronic hepatitis without evidence for hepatoma, and in 18 of 19 (94%) of patients with acute viral hepatitis. In addition, 8 of 28 (28%) of healthy control individuals had also albumin-mRNA-positive cells in peripheral blood. PMNC known to be spontaneously negative for albumin-mRNA could be induced in vitro to transcribe albumin-mRNA after activation with a variety of substances such as interleukin-1 (IL-1) plus concanavalin A (Con A), IL-2, bacterial lipopolysaccharide, platelet derived growth factor, alpha-fibroblast growth factor, or hepatocyte growth factor. These results show that the majority of patients with acute and chronic liver disease without evidence for hepatocellular carcinoma has albumin-mRNA-positive cells in their PMNC fraction indicating the nonspecificity of that parameter for the presence of circulating malignant hepatocytes. In addition, in vitro experiments suggest that PMNC are capable of transcribing mRNA for albumin at a low level after activation. In vivo-activated PMNC are likely to be the source of positivity in healthy controls, patients with nonmalignant acute and chronic liver disease, and patients with hepatocellular carcinoma.
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PMID:Lack of specificity of albumin-mRNA-positive cells as a marker of circulating hepatoma cells. 909 94

ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. We have examined the therapeutic effects of ONO-4007 on rat hepatocellular carcinoma KDH-8 cells, rat fibrosarcoma KMT-17 cells and rat mammary adenocarcinoma SST-2 cells in vivo. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after tumor implantation of KDH-8 and SST-2 cells, and on days 5, 10 and 15 after tumor implantation of KMT-17 cells. ONO-4007 showed significant therapeutic effects on KDH-8 cells; by the administration of ONO-4007 (2.5 mg/kg) 70% of rats were cured and by the administration of ONO-4007 (5 mg/kg) 50% of rats were cured. Furthermore, the ONO-4007 treatment prolonged the mean survival time of KDH-8-bearing rats. However, ONO-4007 had no effect on KMT-17 and SST-2 cells, and it had no direct effect on the growth of KDH-8 cells in vivo. Albeit the stimulation with ONO-4007 induced mRNA expressions of interleukin (IL)-1alpha, IL-6 and tumor necrosis factor (TNF)-a, those of IL-2, IL-4, IL-10 and interferon (IFN)-gamma were not induced. Using a bioassay, we found that the production of TNF-alpha in the tumor tissues was induced by ONO-4007 in a dose-dependent manner. KDH-8 cells were sensitive to human natural TNF-alpha in vitro. However, KMT-17 and SST-2 cells were resistant against TNF-alpha in vitro. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumors.
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PMID:A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells. 921 14

Involvement of the contact system of coagulation in the pathogenesis of various inflammatory diseases is suggested by reduced plasma levels of factor XII (Hageman factor) and prekallikrein generally considered to result from activation of the contact system. However, in many of these diseases patients develop an acute-phase response and, therefore, an alternative explanation for the decreased levels of factor XII could be the downregulation of factor XII gene expression in the liver as described for negative acute-phase proteins. We report here that interleukin-6 (IL-6), the principal cytokine mediating the synthesis of most acute-phase proteins in the liver, downregulates the production of factor XII by the human hepatoma cell line HepG2 by up to 75%. The decrease in protein secretion correlated with an equivalent decrease of factor XII mRNA likely indicating a pretranslational control of factor XII gene expression by IL-6. Downregulation of factor XII production by IL-6 in vitro parallelled that of transthyretin, a known negative acute-phase protein. Moreover, we show that, in patients developing an acute-phase response after immunotherapy with IL-2, plasma levels of factor XII correlate (r = .76, P < .0001) with those of transthyretin. Taken together, these results suggest that factor XII behaves as a negative acute-phase protein.
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PMID:Interleukin-6 downregulates factor XII production by human hepatoma cell line (HepG2). 926 67

We previously reported that the number of TNF-alpha-producing cells was increased in the liver of patients with type C chronic liver disease. To understand further the pathophysiology of this change, we examined serum levels of two soluble TNF receptors, TNF-alphaRI (p55) and -alphaRII (p75), and IL-10, all of which act as TNF-alpha buffer, and IL-15, a novel cytokine sharing many immunological activities with IL-2, using ELISA methods. We studied control individuals and patients with type C chronic liver disease, including asymptomatic hepatitis C virus (HCV) carriers with persistently normal serum ALT values, and those with chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Both types of sTNF-alphaR closely correlated with disease progression. Patients with LC and HCC had significantly elevated levels for sTNF-alphaRII compared with the other patient groups and controls. Serum IL-10 levels were significantly greater in all chronic liver disease groups than in controls. With respect to IL-15, the values were high in CH, LC and HCC compared with those of controls. Notably, HCC patients showed highest values for both IL-10 and IL-15, with significant differences from the other patient groups. Serial determinations revealed that interferon (IFN) treatment for CH patients resulted in the suppression of circulating IL-10 and IL-15 levels along with decrease in serum aminotransferase values. Both cytokines remained at decreased levels after cessation of therapy in patients who went into clinical and virological remission. On the other hand, treatment did not affect serum levels of sTNF-alphaRs. These findings indicate that serum levels of these molecules correlated with disease progress in chronic HCV infection, and that IL-10 and IL-15 may reflect the degree of inflammation in the liver. It is also suggested that both cytokines may be related to the development of HCC.
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PMID:Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease. 932 22

There is now good evidence that cytokines contribute to the regulation of tumor growth. The cytokine-driven modulation of tumor growth was investigated during the progression of a hepatocellular carcinoma (HCC) in SV40 large T tumor antigen transgenic mice. In vivo, an increased rate of liver growth correlated with increased transforming growth factor (TGF)-beta 1 mRNA expression, while the greatest amounts of tumor necrosis factor (TNF)-alpha mRNA were detected earlier during tumor development. Conversely, no particular alteration of IL-1 alpha, IL-1 beta, IL-6, IL-2, IL-4 and IFN-gamma mRNA production could be reported. In vitro, hepatocyte-like tumor cell lines established at two stages, either before or after HCC differentiation, were characterized. The early-stage-derived cell line produced TNF-alpha mRNA, but had barely detectable expression of TGF-beta 1 mRNA, while later-stage-derived cell lines showed the reciprocal pattern. All cell lines displayed a lack of sensitivity to TNF-alpha, although some degree of sensitivity to TNF-alpha could be observed in the presence of actinomycin-D or after treatment with IFN-gamma. The early-stage-derived cell line was sensitive to the growth inhibitory effects of TGF-beta 1, but late-stage-derived tumor cell lines displayed a loss of sensitivity to TGF-beta 1 which correlated with the increased expression of TGF-beta 1 mRNA. Altogether, this suggests that tumor cells contribute to the discrete TNF-alpha and TGF-beta 1 expression patterns during HCC progression. This model of HCC could be of valuable interest to assess the impact of various immunotherapeutic strategies on modulation of tumor growth.
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PMID:Critical stages of tumor growth regulation in transgenic mice harboring a hepatocellular carcinoma revealed by distinct patterns of tumor necrosis factor-alpha and transforming growth factor-beta mRNA production. 935 45


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