Transforming growth factor-β1 gene polymorphisms are associated with progression of liver fibrosis in Caucasians with chronic hepatitis C infection

AIM: Considerable attention is focused on polymorphisms in the gene encoding transforming growth factor-β1 (TGF-β1), a multifunctional cytokine that is in turn a potent growth inhibitor involved in wound healing and differentiation. In humans, it promotes the pathogenesis of organ fibrosis, atherosclerosis, cancer, autoimmune and inflammatory diseases, keloid disease, and hypertrophic scarring. Forth is reason, much emphasis has been placed on studies elucidating the impact of TGF-131 and its gene variationsf or the susceptibility and pathogenesis of these diseases. Unfortunately, some studies have serious limitations. METHODS: We have recently described a high-throughput method for investigation the Arg25Pro polymorphism of human TGF-β1 gene and showed that the frequency of the Pro25 allele is significantly associated with hepatic fibrogenesis. In this report, we describe two novel Light Cycler (LC) techniques that facilitate the examination of the two other known alterations in the coding region of TGF-β1. We investigated whether these polymorphisms contribute to hepatitis-induced progression of fibrogenesis in Chinese and Caucasians. RESULTS: In the Chinese ancestry, the gene polymorphisms at codons 25 and 263 were not found and the genetic variant at codon 10 is unlikely to confer susceptibility to hepatic fibrosis. Contrarily, in Caucasians TGF-β1 allelic variations are more frequent and the presence of prolines     

Transforming growth factor-β and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis

AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.     

Increased hepatic expression of insulin-like growth factor-Ⅰreceptor in chronic hepatitis C

AIM: Although increased insulin-like growth factor-Ⅰreceptor (IGF-IR) gene expression has been reported in hepatocellular carcinoma, studies assessing IGF-IR in chronic hepatitis C (CHC) and cirrhosis are scarce. We therefore aimed to evaluate IGF-IR and IGF-ⅠmRNA expression in liver from patient with CHC. METHODS: IGF-IR and IGF-ⅠmRNA content were determined by semi-quantitative RT-PCR and IGF-IR protein expression was determined by immunohisto-chemistry in hepatic tissue obtained from patients with CHC before (34 patients) and after (10 patients) therapy with interferon-a and ribavirin. RESULTS: An increase of IGF-IR mRNA content was observed in hepatic tissue obtained from all CHC patients as well as from 6 cadaveric liver donors following orthopic transplantation (an attempt to evaluate normal livers) in comparison to normal liver, while no relevant modifications were detected in IGF-ⅠmRNA content. The immunohistochemical results showed that the raise in IGF-IR mRNA content was related both to ductular reaction and to increased IGF-IR expression in hepatocytes. A decrease in IGF-IR mRNA content was observed in patients who achieved sustained virological response after therapy, suggesting an improvement in hepatic damage. CONCLUSION: The up-regulation of IGF-IR expression in hepatocytes of patients with CHC could constitute an attempt to stimulate hepatocyte regeneration. Considering that liver is the organ with the highest levels of IGF-Ⅰ, our finding of increased IGF-IR expression after both acute and chronic hepatic damage highlights the need for additional studies to elucidate the role of IGF-Ⅰin liver regeneration.     

Interleukin-1β gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection

AIM: To examine the effect of interleukin-1-beta (IL-1beta) promoter region C-511T and IL-1 receptor antagonist (IL-1RN) polymorphism among the patients with chronic hepatitis B virus (HBV) infection (HCC and non-HCC). METHODS: Genomic DNA from 136 Thai patients with chronic HBV infection (HCC=46 and non-HCC=90) and 152 healthy individuals was genotyped for IL-1beta gene polymorphism (-511) using polymerase chain reaction with sequence specific primers (PCR-SSP). The variable number of tandem repeats (VNTR) of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by chi2 test. RESULTS: IL-1B-511 genotype C/C was found to be significantly different in patients with HCC when compared with healthy individuals (P=0.036, OR=2.29, 95%CI=1.05-4.97) and patients without HCC (P=0.036, OR=2.52, 95%CI=1.05-6.04). Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control (P=0.033, OR=1.72, 95%CI=1.04-2.84). However, no significant association in IL-1RN gene was found between the two groups. CONCLUSION: IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.     

Expression of interferon-alpha／beta receptor protein in liver of patients with hepatitis C virus-related chronic liver disease

ABM: To study the expression of interferon-alpha/beta (IFN-α/β) receptor protein in liver of patients with hepatitis C virus (HCV)-related chronic liver disease and its clinical significance. METHODS: A total of 181 patients with HCV-related chronic liver disease included 56 with HCV-related liver cirrhosis (LC) and 125 with chronic hepatitis C (CHC). CHC patients were treated with five megaunits of interferon-α1b six times weekly for the first 2 weeks and then every other day for 22 wk. The patients were divided into interferon (IFN) treatment-responsive and non-responsive groups, but 36 patients lost follow-up shortly after receiving the treatment. The expression of IFN-α/β receptor (IFN-α/βR) protein in liver of all patients was determined with immunofluorescence. RESULTS: In liver of patients with HCV-related chronic liver disease, the expression of IFN-α/βR protein in liver cell membrane was stronger than that in cytoplasm and more obvious in the surroundings of portal vein than in the surroundings of central vein. Moreover, it was poorly distributed in hepatic lobules. The weak positive, positive and strong positive expression of IFN-α/βR were 40% (50/125), 28% (35/125), 32% (40/125), respectively in CHC group, and 91.1% (51/56), 5.35% (3/56), and 3.56% (2/56), respectively in LC group. The positive and strong positive rates were higher in CHC group than in LC group (P<0.01). In IFN treatment responsive group, 27.8% (10/36) showed weak positive expression; 72.2% (26/36) showed positive or strong positive expression. In the non-responsive group, 71.7% (38/53) showed weak positive expression; 28.3% (15/53) showed positive or strong positive expression. The expression of IFN-α/βR protein in liver was more obvious in IFN treatment responsive group than in non-responsive group. CONCLUSION: Expression of IFN-α/βR protein in liver of patients with HCV-related chronic liver disease is likely involved in the response to IFN treatment.     

Effect of lamivudine treatment on plasma levels of transforming growth factor β1, tissue inhibitor of metalloproteinases-1 and metalloproteinase-1 in patients with chronic hepatitis B

AIM: Transforming growth factor (TGF)-β1, metalloproteinase (MMP)-1 and its tissue inhibitor (TIMP)-I are considered predictive biomarkers of chronic hepatitis activity and fibrosis.The aim of this study was to evaluate the effect of lamivudine treatment on the plasma levels of these peptides in patients with chronic hepatitis B.METHODS: TGF-β1, MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 40 patients treated with lamivudine for 48 wk. Elimination of HBV-DNA and HBV antigens was evaluated 24 wk after treatment completion.RESULTS: Baseline TGF-β1(29.6&#177;2.2 ng/mL) and TIMP-1(1 578&#177;93 ng/mL) significantly exceeded normal values(18.3&#177;1.6 ng/mL and 1 102&#177;67 ng/mL respectively). Lamivudine treatment resulted in a significant decrease of TGF-β1 and TIMP-1 during treatment with an increase after 24 wk of treatment. Pretreatment MMP-1 levels (6.7&#177;0.7 ng/mL) were significantly lower than normal values (11.9&#177;0.9 ng/mL) and increased during treatment and follow-up. A significant correlation was noted between TGF-β1 or TIMP-1 and aminotransferases as well as fibrosis scored in liver biopsy specimens. There were no statistically significant differences of TGF-β1, TIMP-1 and MMP-1 between four groups at baseline, 24 and 48 wk of treatment. TGF-β1 and TIMP-1 levels increased significantly in non-responders and normalized in responders at wk 72. MMP-1 also normalized in responders and decreased to values significantly lower than normal in non-responders.CONCLUSION: These findings support the role of TGF-β1,TIMP-1 and MMP-1 in the pathogenesis of chronic hepatitis B.Because of their association with hepatic injury and antiviral treatment efficacy, determination of these peptides may be useful in disease management.     

Efficacy and tolerability of low-dose interferon-α in hemodialysis patients with chronic hepatitis C virus infection

AIM:To evaluate the efficacy and tolerability of lowdose standard or pegylated interferon(PEG-IFN)in hepatitis C virus(HCV)-positive hemodialysis patients.METHODS:In total,19 patients were enrolled in this study,of which 12 received PEG-IFNα-2a 67.5μg 1time/wk(Group 1)and 7 received standard interferonα-2b subcutaneously 1.5×106 U 3 times/wk(Group2).The treatment durations were 48 wk for patients infected with HCV genotype 1 and 24 wk for patients infected with HCV genotype 2/3.All patients were prospectively followed after the completion of therapy.The efficacy and tolerability of the treatment were evaluated based on the sustained virological response(SVR)and treatment-related drop-out rate.RESULTS:In Group 1,11 of the 12 patients completed the treatment.Early virological response(EVR)and sustained virological response(SVR)rates were 83.3%and 91.7%,respectively.One patient withdrew from treatment due to an adverse event(leukopenia).The drop-out rate was 8.3%in this group.In Group 2,5 of the 7 patients completed the treatment with an EVR and SVR of 85.7%and 71.4%,respectively.Two patients withdrew due to treatment-related adverse events(nausea and depression).In this group,the drop-out rate was 28.6%.In total,16 of the patients attained EVR,and 15 of them completed the treatment.The SVR rate for the patients who attained EVR was93.7%.Anemia was the most frequent side effect and was observed in 10/19 patients(55.5%),but could be effectively managed with erythropoietin.CONCLUSION:Low-dose interferon monotherapy,either with PEG-IFNα-2a or standard interferonα-2b,is an effective treatment option for hemodialysis patients with chronic hepatitis C.     

Promoter polymorphism of transforming growth factor-β1 gene and ulcerative colitis

AIM： To elucidate the possible difference in two promoter polymorphisms of the transforming growth factor-β1 （TGF-β1） gene （-800G 〉 A, -509C 〉 T） between ulcerative colitis （UC） patients and normal subjects.
METHODS： A total of 155 patients with established ulcerative colitis and 139 normal subjects were selected as controls. Two single nucleotide polymorphisms within the promoter region of TGF-β1 gene （-509C 〉 T and -800G 〉 A） were genotyped using PCR-RFLP. RESULTS： There was a statistically significant difference in genotype and allele frequency distributions between UC patients and controls for the -800G 〉 A polymorphism of the TGF-β1 gene （P 〈 0.05）. The frequency of the TGF-β1 gene polymorphism at position -800 showed that the AA genotype and the allele A frequencies significantly differed between the patients and healthy controls （P 〈 0.05）. At position -509, there was no statically significant difference in genotype and allele frequency between the patients and control subjects.
CONCLUSION： The results of our study indicate that there is a significant difference in both allele and genotype frequency at position -800G 〉 A of TGF-β1 gene promoter between Iranian patients with UC and normal subjects.     

Effect of pegylated interferon alpha 2b plus ribavirin treatment on plasma transforming growth factor-β1, metalloproteinase-1, and tissue metalloproteinase inhibitor-1 in patients with chronic hepatitis C

AIM: To evaluate the effect of antiviral treatment on plasma levels of transforming growth factor-beta1 (TGF-beta1), metalloproteinase 1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with chronic hepatitis C.METHODS: TGF-beta1, MMP-1, and TIMP-1 plasma concentrations were measured by an enzyme immunoassay in 28 patients, during 48 wk of treatment with pegylated interferon-alpha 2b (PEG-IFN-alpha2b) plus ribavirin (RBV) and after 24 wk of follow-up. Patients were divided into two groups: responders (R) and non-responders (NR) related to achieved sustained virologic response. Normal values were evaluated in plasma samples of 13 healthy volunteers.RESULTS: Baseline plasma concentrations of TGF-beta1 and TIMP-1 (30.9+/-3.7 and 1 506+/-61 ng/mL respectively) measured in all subjects significantly exceeded the normal values (TGF-beta1: 18.3+/-1.6 ng/mL and TIMP-1: 1 102+/-67 ng/mL). In contrast, pretreatment MMP-1 mean level (6.5+/-0.9 ng/mL) was significantly lower than normal values (11.9+/-0.9 ng/mL). Response to the treatment was observed in 12 patients (43%). TGF-beta1 mean concentration measured during the treatment phase decreased to the control level in both groups. However at wk 72, values of NR patients increased and became significantly higher than in R group. TIMP-1 concentrations in R group decreased during the treatment to the level similar to normal. In NR group, TIMP-1 remained significantly elevated during treatment and follow-up phase and significant difference between both groups was demonstrated at wk 48 and 72. MMP-1 levels were significantly decreased in both groups at baseline. Treatment caused rise of its concentration only in the R group, whereas values in NR group remained on the level similar to baseline. Statistically significant difference between groups was noted at wk 48 and 72.CONCLUSION: These findings support the usefulness of TGF-beta1, TIMP-1, and MMP-1 in the management of chronic hepatitis C. Elevated TIMP-1 and low MMP-1 plasma concentrations during antiviral therapy may indicate medication failure.     

Effects of N-acetylcysteine on expression of transforming growth factor-β1 in diabetic nephropathy rats

Objective To investigate the effects of N-acetylcysteine (NAC) on the expression of transforming growth factor-β1 (TGF-β1) in renal cortex of diabetic nephropathy rats.Methods A rat model of DN was established.The rats were randomly divided into control group,DN group and NAC group.After 8 weeks treatment,urinary albumin excretion rate (UAER) was determined.The expression of TGF-β1 in renal cortex was detected by immunohistochemistry and RT-PCR analysis.Pathomorphological changes of renal cortex were observed.Results (1)The levels of UA ER were significantly higher in DN group and NAC group [(1268.3±297.5) μg/24 h and (315.9-±86.8) μg/24 h] than in control group [(31.2±8.9) μg/24 h,q-29.85,16.76,both P＜0.01].The groups of DN and NAC versus group of control showed the increased levels of activity of TGF-β1 in renal cortex [immune-histochemistry index of glomerular mesangial area:7.35±1.17 and 3.87 ± 0.71 vs.1.95±0.34,q= 10.75,5.82,both P＜0.01];immune-histochemistry index of renal tubulointerstitium [21.21± 3.78 and 10.67±1.86 vs.3.62±0.79,q=15.20,11.36,both P＜0.01];the expression of mRNA in renal cortex[0.72±0.06 and 0.45±0.05 vs.0.23±0.04,q=9.13,7.45,both P＜0.01].The pathomorphological changes were significant in DN group and NAC group.(2)The NAC group versus DN group showed a decreased levels of UAER (q=8.17,P＜0.01),activity of TGF-β1 in renal cortex [immune-histochemistry index of glomerular mesangial area:q= 4.97,P＜0.01]immune-histochemistry index of renal tubulointerstitium (q = 6.86,P ＜ 0.01 );the expression of mRNA in renal cortex (q= 3.69,P＜0.05) and showed improvement of pathomorphology in renal cortex.(3) There was a significantly positive correlation between expression quantity of TGF-β1 mRNA in renal cortex and UAER level in NAC group(r= 0.749,P＜0.05).Conclusions The protective effects of NAC on the kidney of DN rats may be partly related with inhibition on the expression of TGF-β1.     

Effects of N-acetylcysteine on expression of transforming growth factor-β1 in diabetic nephropathy rats

Objective To investigate the effects of N-acetylcysteine (NAC) on the expression of transforming growth factor-β1 (TGF-β1) in renal cortex of diabetic nephropathy rats.Methods A rat model of DN was established.The rats were randomly divided into control group,DN group and NAC group.After 8 weeks treatment,urinary albumin excretion rate (UAER) was determined.The expression of TGF-β1 in renal cortex was detected by immunohistochemistry and RT-PCR analysis.Pathomorphological changes of renal cortex were observed.Results (1)The levels of UA ER were significantly higher in DN group and NAC group [(1268.3±297.5) μg/24 h and (315.9-±86.8) μg/24 h] than in control group [(31.2±8.9) μg/24 h,q-29.85,16.76,both P＜0.01].The groups of DN and NAC versus group of control showed the increased levels of activity of TGF-β1 in renal cortex [immune-histochemistry index of glomerular mesangial area:7.35±1.17 and 3.87 ± 0.71 vs.1.95±0.34,q= 10.75,5.82,both P＜0.01];immune-histochemistry index of renal tubulointerstitium [21.21± 3.78 and 10.67±1.86 vs.3.62±0.79,q=15.20,11.36,both P＜0.01];the expression of mRNA in renal cortex[0.72±0.06 and 0.45±0.05 vs.0.23±0.04,q=9.13,7.45,both P＜0.01].The pathomorphological changes were significant in DN group and NAC group.(2)The NAC group versus DN group showed a decreased levels of UAER (q=8.17,P＜0.01),activity of TGF-β1 in renal cortex [immune-histochemistry index of glomerular mesangial area:q= 4.97,P＜0.01]immune-histochemistry index of renal tubulointerstitium (q = 6.86,P ＜ 0.01 );the expression of mRNA in renal cortex (q= 3.69,P＜0.05) and showed improvement of pathomorphology in renal cortex.(3) There was a significantly positive correlation between expression quantity of TGF-β1 mRNA in renal cortex and UAER level in NAC group(r= 0.749,P＜0.05).Conclusions The protective effects of NAC on the kidney of DN rats may be partly related with inhibition on the expression of TGF-β1.     

Effects of six months Iosartan administration on liver fibrosis in chronic hepatitis C patients： A pilot study

AIM: To evaluate the safety and efficacy of chronic administration of losartan on hepatic fibrosis in chronic hepatitis C patients. METHODS: Fourteen patients with chronic hepatitis C non-responders (n = 10), with contraindications (n = 2) or lack of compliance (n = 2) to interferon plus ribavirin therapy and liver fibrosis were enrolled. Liver and renal function test, clinical evaluation, and liver biopsies were performed at baseline and after losartan administration at a dose of 50 mg/d during the 6 mo. The control group composed of nine patients with the same inclusion criteria and paired liver biopsies (interval 6-14 mo). Histological activity index (HAI) with fibrosis stage was assessed under blind conditions by means of Ishak's score. Subendothelial fibrosis was evaluated by digital image analyses. RESULTS: The changes in the fibrosis stage were significantly different between losartan group (decrease of 0.5±1.3) and controls (increase of 0.89±1.27; P<0.03). In the treated patients, a decrease in fibrosis stage was observed in 7/14 patients vs 1/9 control patients (P<0.04). A decrease in sub-endothelial fibrosis was observed in the losartan group. No differences were found in HAI after losartan administration. Acute and chronic decreases in systolic arterial pressures (P<0.05) were observed after the losartan administration, without changes in mean arterial pressure or renal function. CONCLUSION: Chronic AT-Ⅱ type 1 receptor (AT1R) blockade may reduce liver fibrosis in patients with chronic hepatitis C.     

Effects of N-acetylcysteine on expression of transforming growth factor-β1 in diabetic nephropathy rats

Objective To investigate the effects of N-acetylcysteine (NAC) on the expression of transforming growth factor-β1 (TGF-β1) in renal cortex of diabetic nephropathy rats.Methods A rat model of DN was established.The rats were randomly divided into control group,DN group and NAC group.After 8 weeks treatment,urinary albumin excretion rate (UAER) was determined.The expression of TGF-β1 in renal cortex was detected by immunohistochemistry and RT-PCR analysis.Pathomorphological changes of renal cortex were observed.Results (1)The levels of UA ER were significantly higher in DN group and NAC group [(1268.3±297.5) μg/24 h and (315.9-±86.8) μg/24 h] than in control group [(31.2±8.9) μg/24 h,q-29.85,16.76,both P＜0.01].The groups of DN and NAC versus group of control showed the increased levels of activity of TGF-β1 in renal cortex [immune-histochemistry index of glomerular mesangial area:7.35±1.17 and 3.87 ± 0.71 vs.1.95±0.34,q= 10.75,5.82,both P＜0.01];immune-histochemistry index of renal tubulointerstitium [21.21± 3.78 and 10.67±1.86 vs.3.62±0.79,q=15.20,11.36,both P＜0.01];the expression of mRNA in renal cortex[0.72±0.06 and 0.45±0.05 vs.0.23±0.04,q=9.13,7.45,both P＜0.01].The pathomorphological changes were significant in DN group and NAC group.(2)The NAC group versus DN group showed a decreased levels of UAER (q=8.17,P＜0.01),activity of TGF-β1 in renal cortex [immune-histochemistry index of glomerular mesangial area:q= 4.97,P＜0.01]immune-histochemistry index of renal tubulointerstitium (q = 6.86,P ＜ 0.01 );the expression of mRNA in renal cortex (q= 3.69,P＜0.05) and showed improvement of pathomorphology in renal cortex.(3) There was a significantly positive correlation between expression quantity of TGF-β1 mRNA in renal cortex and UAER level in NAC group(r= 0.749,P＜0.05).Conclusions The protective effects of NAC on the kidney of DN rats may be partly related with inhibition on the expression of TGF-β1.     

Interferon β-1a alone or in combination with ribavirin: A randomized trial to compare efficacy and safety in chronic hepatitis C

AIM: To compare the efficacy and safety of recombinant human IFN β-1a alone or in combination with ribavirin in treatment-naive subjects with chronic hepatitis C. METHODS: Open, randomized trial was performed in 6 Italian tertiary centers: 102 of the 108 patients screened were randomized to receive 6 MIU of recombinant human IFN β-1a subcutaneously daily for 24 wk, alone (Group 1, n = 51) or in combination with ribavirin 1000 to 1200 mg/d (Group 2, n = 51). RESULTS: The end-of-treatment virologic response rate was 29.4% in Group 1 and 41.2% in Group 2 (nonsignificant). Twenty-four weeks after stopping therapy, sustained virologic response rate was 21.6% in Group 1 and 27.4% in Group 2 (non-significant). All subjects in Group 1 completed treatment, while two subjects in Group 2 stopped therapy due to treatment-related adverse events. CONCLUSION: Recombinant human IFN β-1a, alone or in combination with ribavirin, has an excellent safety profile and, may represent an alternative for chronic hepatitis C patients who are unable to tolerate pegylated α-interferon.     

Effect of interferon and ribavirin combined with amantadine in interferon and ribavirin non-responder patients with chronic hepatitis C （genotype 1）

AIM: To evaluate the efficacy of amantadine plus interferon-alpha and ribavirin in non-responder patients with chronic hepatitis C. METHODS: Twenty-six non-responder patients received the regimen of IFN-α-2a at a dose of 6 million units three times a week, 1 000-1 200 mg of ribavirin daily, and 200 mg of amantadine daily in divided doses over 48 wk. After the end of treatment, at the 72nd wk, a sustained viral response rate was determined. RESULTS: An early (after 12 wk of therapy) response was seen in 34.6% (9/26) of patients. Response rate at the 24th wk was 42.3% (11/26). End of treatment response (ETR) was 53.8% (14/26). Sustained viral response (SVR) was 42.3% (11/26). There was a statistically significant difference between 0 and 12 wk (P= 0.04), 0 and 24 wk (P= 0.01), 0 and 48 wk (P= 0.00), and 0 and 72 wk (P= 0.001). No patient had severe adverse effects during the treatment. CONCLUSION: Combination regimen of interferon-α, ribavirin and amantadine can enhance sustained viral response on IFN-α and ribavirin non-responder patients with HCV. Triple therapy with amantadine should be evaluated in further studies.     

Effects of interferon-alpha on expression of hepatic stellate cell and transforming growth factor-β1 and α-smooth muscle actin in rats with hepatic fibrosis

AIM: To investigate the effect of interferon-α(IFN-α) on preventing or reversing hepatic fibrosis in rat experimental model induced by CCl4.METHODS: One hundred and ten Sprague-Dawley rats were divided into five groups: group A (normal controls,n=18), group B (fibrotic model controls, n=22), group C (IFN-α prevention, n=22) initially treated with intra-muscular injection of IFN-α in saline daily at the doses of 1&#215;105U for 6wk, group D (IFN-α treatment, n=24) treated with intra-muscular injection of IFN-α in saline daily at the doses of 1&#215;105U for 6wk after the first 6wk, group E (0.9% sodium chloride treatment control, n=24) treated with intra-muscular injection of 0.01mL/kg daily for 6wk after the first 6wk. At the end of the experiment, all rats of each group were killed. Samples of the liver obtained by biopsy were subjected to histological, immunohistochemical and electron microscopic studies for the expressions of transforming growth factor-β1(TGF-β1) and α-smooth muscle actin (α-SMA).RESULTS: The expressions of TGF-β1, the number of activated hepatic stellate cells and α-SMA in hepatic tissue of group C were significantly less than those of group B(P&lt;0.01). The degree of fibrosis score in group B was also significantly less than that of group C under light microscope (P&lt;0.01).CONCLUSION: IFN-α can inhibit the production of TGF-β1, decrease HSC activation and stimulate its apoptosis.     

Serum transforming growth factor-β1 level reflects disease status in patients with esophageal carcinoma after radiotherapy

AIM To evaluate the relationship between changes in serum transforming growth factor β1 (TGFβ1) level and curative effect of radiotherapy (RT) in patients with esophageal carcinoma.METHODS Ninety patients with histologically confirmed esophageal carcinoma were enrolled. Serum samples for TGFβ1 analysis were obtained before and at the end of RT. An enzyme-linked immunosorbent assay was used to measure serum TGFβ1 level. Multivariate analysis was performed to investigate the relationship between disease status and changes in serum TGFβ1 level.RESULTS Serum TGFβ1 level in patients with esophageal carcinoma before RT was significantly higher than that in healthy controls (P ＜ 0.001). At the end of RT, serum TGFβ1 level was decreased in 67.82% (59/87) of the patients. The overall survival rate at 1,3 and 5 years was 48.28% (42/87), 19.54% (17/87)and 12.64% (11/87), respectively. Main causes of death were local failure and regional lymph node metastasis.In patients whose serum TGFβ1 level decreased after RT,the survival rate at 1, 3 and 5 years was 61.02% (36/59),28.81% (17/59) and 18.64% (11/59), respectively. The survival rate at 1 year was 17.86% (5/28) in patients whose serum TGFβ1 level increased after RT, and all died within 18 mo (P ＜ 0.01).CONCLUSION Serum TGFβ1 level may be a useful marker for monitoring disease status after RT in patients with esophageal carcinoma.     

Expression and significance of E-cadherin,N-cadherin,transforming growth factor-β1 and Twist in prostate cancer

Objective:To study the expression of E-cadherin,N-cadherin,TGF-|3 1 and Twist protein and investigate its significance in the occurrence and development of prostate cancer.Methods:The expression of E-cadherin,N-cadherin,TGF-β1 and Twist protein in 59 prostate cancer tissues and 21 adjacent tissues were detected by immunohistochemical SABC staining,and the correlation with clinicopathological features was analyzed.Results:Positive rates of E-cadherin,N-cadherin,TGF-β1 and Twist were 32.2%,54.2%,71.2%and 74.6%,respectively,in prostate cancer tissues and 85.7%,9.52%,19.0%and 9.52%,respectively,in cancer—adjacent tissues,with significant differences between the two groups(P0.05).The reduced expression of E-cadherin was related to the differentiation of prostate cancer tissues and PSA level,but was not associated with clinical stage,lymph node metastasis,bony metastasis and age.The increased expression of N-cadherin,TGF-β1 and Twist was related to the differentiation of prostate cancer tissues,clinical stage,lymph node metastasis,bony metastasis,but not to age.The difference in positive expression of N-cadherin and TGF-β1 was significant between PSA≤20μg/L group and PSA20μg/L group,but the positive expression of Twist was not significant between groups.The expression of E-cadherin was highly negatively correlated with that of N-cadherin and also highly negatively correlated with that of Twist The expression of TGF-β1 was correlated with those of E-cadherin,N-cadherin and Twist.Conclusions:The reduced expression of E-cadherin,abnormal expression of N-cadherin,transformation form E-cadherin to N-cadherin and the increased expression of TGF-β1 and Twist play an important role in the occurrence and development of prostate cancer.