INTRODUCTIONIn China ,the incidence and mortality of gastric cancer rank the second among all cancers. Recent development of cancer [1-20].The aim of this study was investigat the insight of apoptosis and bcl-2, p53 a...INTRODUCTIONIn China ,the incidence and mortality of gastric cancer rank the second among all cancers. Recent development of cancer [1-20].The aim of this study was investigat the insight of apoptosis and bcl-2, p53 and C-myc protein expression in the development of gastric cancer .展开更多
AIM:To establish a predictive algorithm which may serve for selecting optimal candidates for interferon-α(IFN-α) treatment.METHODS:A total of 474 IFN-α treated hepatitis B virus e antigen(HBeAg)-positive patients w...AIM:To establish a predictive algorithm which may serve for selecting optimal candidates for interferon-α(IFN-α) treatment.METHODS:A total of 474 IFN-α treated hepatitis B virus e antigen(HBeAg)-positive patients were enrolled in the present study.The patients' baseline characteristics,such as age,gender,blood tests,activity grading(G) of intrahepatic inflammation,score(S) of liver fibrosis,hepatitis B virus(HBV) DNA and genotype were evaluated;therapy duration and response of each patient at the 24th wk after cessation of IFN-α treatment were also recorded.A predictive algorithm and scoring system for a sustained combined response(CR) to IFN-α therapy were established.About 10% of the patients were randomly drawn as the test set.Responses to IFN-α therapy were divided into CR,partial response(PR) and non-response(NR).The mixed set of PR and NR was recorded as PR+NR.RESULTS:Stratified by therapy duration,the most significant baseline predictive factors were alanine aminotransferase(ALT),HBV DNA level,aspartate aminotransferase(AST),HBV genotype,S,G,age and gender.According to the established model,the accuracies for sustained CR and PR+NR,respectively,were 86.4% and 93.0% for the training set,81.5% and 91.0% for the test set.For the scoring system,the sensitivity and specificity were 78.8% and 80.6%,respectively.There were positive correlations between ALT and AST,and G and S,respectively.CONCLUSION:With these models,practitioners may be able to propose individualized decisions that have an integrated foundation on both evidence-based medicine and personal characteristics.展开更多
AIM. To investigate the influence of HLA-DRB1 alleles and HBV genotypes on inberferon-α therapy for chronic hepatitis B. METHODS： HLA-DRBI＊03, ＊07, ＊09,＊12, ＊15 alleles were determined using polymerase chain re...AIM. To investigate the influence of HLA-DRB1 alleles and HBV genotypes on inberferon-α therapy for chronic hepatitis B. METHODS： HLA-DRBI＊03, ＊07, ＊09,＊12, ＊15 alleles were determined using polymerase chain reaction/sequence specific primer （PCR/SSP） technique in 126 patients with chronic hepatitis B and 76 normal control subjects in Shandong Province, and HBV genotypes were determined by nested-PCR analysis using type-specific primers in 126 patients. RESULTS： The positivity of HLA-DRB1＊07 allele in chronic hepatitis B group was significantly higher than that in normal control group （X^2 = 6.33, P〈0.025, RR = 2.37）. Among the 126 patients, genotype B was found in 38 （30.2%）, genotype C in 69 （54.8%）, and mixed genotype （B＋C） in 19 （15.0%）, genotypes D-F were not found. Among the 46 DRB1＊07（＋） patients, 7 were responders and 39 were non-responders among them （X^2 = 6.71, P〈0.05）. The positivity of HLADRB1＊07 and prevalence of HBV genotype C were significantly higher in non-responders than in responders. CONCLUSION： High positivities of HLA-DRB1 ＊07 allele and HBV genotype C are closely associated with the lower response to interferon-α therapy for chronic hepatitis B.展开更多
Chronic inflammation associated with hepatitis C virus(HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effe...Chronic inflammation associated with hepatitis C virus(HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α(IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies(ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings(RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings(antiRR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2(IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.展开更多
AIM To investigate the association between interferoninduced protein with tetratricopeptide repeats 1(IFIT1) polymorphisms and interferon-α(IFNα) treatment efficiency among Chinese hepatitis B virus(HBV) infection p...AIM To investigate the association between interferoninduced protein with tetratricopeptide repeats 1(IFIT1) polymorphisms and interferon-α(IFNα) treatment efficiency among Chinese hepatitis B virus(HBV) infection patients.METHODS Two hundred and twenty five newly diagnosed chronichepatitis B(CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen(HBe Ag) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms(SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes.RESULTS At the end of the treatment, HBe Ag seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218(A > G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64(95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response(response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype(response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBe Ag seroconversion, combined response or sustained response was observed.CONCLUSION IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation.展开更多
AIM： To evaluate the effects of interferon-α-2b （IFN- α-2b） on expression of cyclooxygenase-2 （COX-2） and vascular endothelial growth factor （VEGF） in human hepatocellular carcinoma （HCC） inoculated in nude...AIM： To evaluate the effects of interferon-α-2b （IFN- α-2b） on expression of cyclooxygenase-2 （COX-2） and vascular endothelial growth factor （VEGF） in human hepatocellular carcinoma （HCC） inoculated in nude mice and to study the underlying mechanism of IFN-α- 2b against HCC growth. METHODS： Thirb/-two nude mice bearing human HCC were randomly divided into four groups （n = 8）. On the 10th day after implantation of HCC cells, the mice in test groups （groups A, B and C） received IFN-α- 2b at a serial dose （10000 IU for group A, 20000 IU for group B, 40000 IU for group C sc daily） for 35 d. The mice in control group received normal saline （NS）. The growth conditions of transplanted tumors were observed. Both genes and proteins of COX-2 and VEGF were detected by RT-PCR and Western blot. Apoptosis of tumor cells in nude mice was detected by TUNEL assay after treatment with IFN-α-2b. RESULTS： Tumors were significantly smaller and had a lower weight in the IFN-α-2b treatment groups than those in the control group （P 〈 0.01）, and the tumor growth inhibition rate in groups A, B and C was 27.78%, 65.22% and 49.64%, respectively. The expression levels of both genes and proteins of COX-2 and VEGF were much lower in the IFN-α-2b treatment groups than in the control group （P 〈 0.01）. The apoptosis index （AI） of tumor cells in the IFN-α-2b treatment groups was markedly higher than that in the control group （P 〈 0.01）. Group B had a higher inhibition rate of tumor growth, a lower expression level of COX-2 and VEGF and a higher AI than groups A and C （P 〈 0.05）, but there was no significant difference between groups A and C. CONCLUSION： The inhibitory effects of IFN-α-2b on implanted tumor growth and apoptosis may be associated with the down-regulation of COX-2 and VEGF expression. There is a dose-effect relationship. The medium dose of IFN-α-2b for inhibiting tumor growth is 20 000 IU/d.展开更多
Hepatitis B virus(HBV)infection is a global public health issue.Interferon-α(IFN-α)treatment has been used to treat hepatitis B for over 20 years,but fewer than 5%of Asians receiving IFN-αtreatment achieve function...Hepatitis B virus(HBV)infection is a global public health issue.Interferon-α(IFN-α)treatment has been used to treat hepatitis B for over 20 years,but fewer than 5%of Asians receiving IFN-αtreatment achieve functional cure.Thus,IFN-αretreatment has been introduced to enhance antiviral function.In recent years,immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks,including both innate and adaptive immunity,triggering immune responses that control HBV replication.However,heterogeneity of the immune system to control HBV infection,particularly HBV-specific CD8^(+)T cell heterogeneity,has consequential effects on T cell-based immunotherapy for treating HBV infection.Altogether,the host’s genetic variants,negative-feedback regulators and HBV components affecting the immune system's ability to control HBV.In this study,we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-αtreatment and retreatment.展开更多
We report a case of severe thrombocytopenia following pegylated interferon-α 2a(Peg-IFN-α 2a)treatment of hepatitis C virus infection and summarize the clinical characteristics of 16 cases of IFN-α induced severe t...We report a case of severe thrombocytopenia following pegylated interferon-α 2a(Peg-IFN-α 2a)treatment of hepatitis C virus infection and summarize the clinical characteristics of 16 cases of IFN-α induced severe thrombocytopenia and its immune-mediated mechanism.Discontinuation of IFN-α and early administration of immunosuppressants are the effective therapy for IFN-αinduced severe thrombocytopenia.展开更多
BACKGROUND: Hepatitis C virus (HCV) is a worldwide common disease. Some predictive factors influencing the response to interferon alpha (IFN-α) therapy have been identified, but the conclusions differ in various coun...BACKGROUND: Hepatitis C virus (HCV) is a worldwide common disease. Some predictive factors influencing the response to interferon alpha (IFN-α) therapy have been identified, but the conclusions differ in various counties and areas. The aim of this study was to study the associa- tions between HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin in Chinese patients with chronic hepatitis C in Northeast China. METHODS: HCV genotypes of 113 patients with HCV were investigated. Gene chips were used to analyze the fre- quency of HLA-DRB in 25 of these patients and their re- sponse to IFN-α and ribavirin. The associations of HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin were also studied. RESULTS: The response rates differed in several types of HCV, with HCV 2b being the highest (57.78% ), HCV 1a and 2a lower (46.15% and 47.62% ) and HCV 1b the low- est (11.76% ). The response rates to IFN-α and ribavirin in patients with DRB1 07 were higher than those with DRB1 04. Sex, HCV type and HLA-DRB were all related to the response. Most female patients with HCV 2b and HLA- DRB1 07 presented complete response, whereas male pa- tients with HCV 1b and HLA-DRB1 04 usually demon- strated no response. DRB1 07 allele and HCV 2b were the factors closely related to the response. CONCLUSIONS: The response rate of HCV 1b may be the lowest even IFN-α and ribavirin are combined in treat- ment. Not only virus but also the host plays an important role in anti-virus therapy. Thus, it is necessary to adjust the host's immune status to accelerate the clearance of HCV.展开更多
AIM： To evaluate the efficacy of combination chemotherapy with interferon-α （IFNα） and 5-fluorouracil （5-FU） in patients with advanced hepatocellular carcinoma （HCC）. METHODS： Twenty-eight HCC patients in ad...AIM： To evaluate the efficacy of combination chemotherapy with interferon-α （IFNα） and 5-fluorouracil （5-FU） in patients with advanced hepatocellular carcinoma （HCC）. METHODS： Twenty-eight HCC patients in advanced stage were enrolled in the study. They were treated with IFNα/ 5-FU combination chemotherapy. One cycle of therapy lasted for 4 wk. IFNα （3×10^6 units） was subcutaneously injected thrice weekly on days 1, 3, and 5 for 3 wk, and 5-FU （500 mg/d） was administered via the proper hepatic artery for 5 consecutive days per week for 3 wk. No drugs were administered during the 4th wk. The effect of combination chemotherapy was evaluated in each patient alter every cycle based on the reduction of tumor volume. RESULTS： Alter the 1^st cycle of therapy, 16 patients showed a partial response （PR, 57.1%） but none showed a complete response （CR, 0%）. At the end of therapy, the number of patients who showed a CR, PR, or no response （NR） was 1, 10, and 17, respectively. The response rate for therapy （CR＋PR） was 21.5%. Biochemical tests before therapy were compared between responsive （CR＋PR） and non-responsive （NR） patients, but no significant differences were found for any of the parameters examined, indicating that no reasonable predictors could be identified in our analysis. CONCLUSION： Attempts should be made to discriminate between responders and non-responders by evaluating tumor size alter the first cycle of IFNα/5-FU combination chemotherapy. For non-responders, therapy should not proceed to the next cycle, and instead, different combination of anticancer drugs should be explored. 2005 The WJG Press and Elsevier Inc. All rights reserved展开更多
In order to investigate the antitumor effect and molecular mechanism of interferon-α （IFN-α） on human acute myeloid leukemia cell line U937 cells in vitro, the proliferation of U937 cells was determined by MTT ass...In order to investigate the antitumor effect and molecular mechanism of interferon-α （IFN-α） on human acute myeloid leukemia cell line U937 cells in vitro, the proliferation of U937 cells was determined by MTT assay, the apoptosis rate was analyzed by flow cytometry （FCM）, and the mRNA expression of cell cycle regulatory protein cyclin E was detected by RT-PCR. The results showed that IFN-α could inhibit the proliferation of U937 cells significantly in a dose- and time-dependent way （P〈0.01）, and induce the apoptosis of U937 cells also in a dose- and time-dependent manner at the concentration of 1000--4000 U/L （P〈0.01）. The apoptosis rate of U937 cells was even over 50% when cultured with IFN-α for 36--48 h at the concentration of 2000 -4000 U/L. Moreover, the expression of cyclin E mRNA was markedly inhibited by the addition of IFN-α, and the inhibition was time-dependent （P〈0.01）. It was concluded that the anti-leukemia mechanism of IFN-α might be correlated with its antiproliferative and apoptotic inducing effects, and the down-regulation of the cyclin E expression might be one of its molecular mechanisms.展开更多
Pure red cell aplasia (PRCA) is a rare hematological disorder which is characterized by severe anemia,reticulocytopenia and almost complete absence of erythroid precursors in bone marrow.The pathophysiology of PRCA ma...Pure red cell aplasia (PRCA) is a rare hematological disorder which is characterized by severe anemia,reticulocytopenia and almost complete absence of erythroid precursors in bone marrow.The pathophysiology of PRCA may be congenital or acquired.To our knowledge,there is only one case report in the English literature of PRCA after pegylated interferon combination therapy for chronic hepatitis C.We report a second case of PRCA after pegylated interferon combination treatment for chronic hepatitis C.The diagnosis of PRCA was confirmed by the typical findings of bone marrow biopsy.The possible etiologies of our case are also discussed in this paper.展开更多
Hepatocarcinoma is one of the malignant cancers with significant morbidity and mortality.Immunotherapy has emerged in clinical treatment,owing to the limitation and severe side effects of chemotherapy.In the immune sy...Hepatocarcinoma is one of the malignant cancers with significant morbidity and mortality.Immunotherapy has emerged in clinical treatment,owing to the limitation and severe side effects of chemotherapy.In the immune system,natural killer（NK）cells are important effectors required to eliminate malignant tumor cells without the limitation of major histocompatibility complex（MHC）molecule issues.Hence,treatment which could stimulate NK cells is of great interest.Here,we investigated the efficacy of the combined therapy of TT-1（a mutant of melittin）and interferon-α（IFN-α）on NK cells and human liver cancer HepG-2/Huh7 cells in vitro and in vivo,as well as the mechanism involved.The combination therapy significantly inhibited the growth of HepG-2/Huh7 cells in vivo,but this effect was impaired after depleting NK cells.TT-1 not only up-regulated MHC class I-related chain molecules A（MICA）expression,but also prevented the secretion of soluble MICA（sM ICA）.Both the mR NA and protein of a disintegrin and metallopeptidase 10（ADAM 10）in HepG-2/Huh7 cells were decreased after TT-1 treatment.The combined therapy of TT-1 and IFN-αcould suppress the growth of HepG-2/Huh7 xenografted tumor effectively via promoting the interaction of NK group 2,member D（NKG2D）and MICA,indicating that TT-1＋IFN-αwould be a potential approach in treating liver cancer.展开更多
Objective: To study the effect of intracerebroventricular administration of interferon (IFN-α) on the splenic sympathetic nerve activity. Methods: IFN-α (3×104 U/rat ) was microinjected into the third cerebrove...Objective: To study the effect of intracerebroventricular administration of interferon (IFN-α) on the splenic sympathetic nerve activity. Methods: IFN-α (3×104 U/rat ) was microinjected into the third cerebroven-tricle of urethane and α-chloralose anesthetized rats. Electrical activity of the splenic nerve. body temperature and blood pressure were determined simultaneously. Results: Intracerebroventricular administration of IFN-α caused amarked and long term (>120 min) increase in the splenic nerve activity, which could be reversed by naloxonetreatment. No changes in blood pressure and body temperature. which could alter the sympathetic nerve actlvity by reflex. were observed during IFN-α and naloxone treatment. Naloxone intravenous injection alone had no effecton the splenic nerve activity. Conclusion: IFN-α in the brain can activate the splenic sympathetic nerve, and thisaction is, in some way, mediated by the opioid receptor.展开更多
AIM： To evaluate the daily high-dose induction therapy with interferon-α2b （IFN-α2b） in combination with ribavirin for the treatment of patients who failed with interferon monotherapy and had a relapse, based on ...AIM： To evaluate the daily high-dose induction therapy with interferon-α2b （IFN-α2b） in combination with ribavirin for the treatment of patients who failed with interferon monotherapy and had a relapse, based on the assumption that the viral burden would decline faster, thus increasing the likelihood of higher response rates in this difficult-totreat patient group. METHODS： Seventy patients were enrolled in this study. Treatment was started with 10 NU IFN-α2b daily for 3 wk, followed by IFN-α2b 5 NU/TIW in combination with ribavirin （1 000-1 200 mg/d） for 21 wk. In case of a negative HCV RNA PCR, treatment was continued until wk 48 （IFN-α2b 3MU/TIW＋1000-1200 mg ribavirin/daily）. RESULTS： The dose of IFN-α2b or ribavirin was reduced in 16% of patients because of hematologic side effects, and treatment was discontinued in 7% of patients. An early viral response （EVR） was achieved in 60% of patients. Fifty percent of all patients achieved an end-oftreatment response （EOT） and d0% obtained a sustained viral response （SVR）. Patients with no response had a significantly lower response rate than those with a former relapse （SVR 30% vs 53%; P=0.049）. Furthermore, lower response rates were observed in patients infected with genotype la/b than in patients with non-1-genotype （SVR 28% vs7d%; P=0.001）. As a significant predictive factor for a sustained response, a rapid initial decline of HCV RNA could be identified. No patient achieving a negative HCV-RNA PCR at wk 18 or later eventually eliminated the virus. CONCLUSION： Daily high-dose induction therapy with interferon-α2b is well tolerated and effective for the treatment of non-responders and relapsers, when interferon monotherapy fails. A fast decline of viral load during the first 12 wk is strongly associated with a sustained viral response.展开更多
AIM: To evaluate interferon-λ3(IFNL3) polymorphisms in response-guided pegylated interferon-α plus ribavirin(Peg-IFNα/RBV) therapy for genotype 2(G2) chronic hepatitis C.METHODS: Between January 2006 and June 2012,...AIM: To evaluate interferon-λ3(IFNL3) polymorphisms in response-guided pegylated interferon-α plus ribavirin(Peg-IFNα/RBV) therapy for genotype 2(G2) chronic hepatitis C.METHODS: Between January 2006 and June 2012, a total of 180 patients with chronic infections of G2 hepatitis C virus(HCV) were treated with responseguided Peg-IFNα/RBV therapy. The treatment duration was 24 wk for patients who achieved rapid virologic response(RVR), and 36 or 48 wk for patients who did not. Then, the impact of the IFNL3 single nucleotide polymorphism genotype(TT/non-TT at rs8099917) on treatment outcomes was evaluated in the 180 patients, and between patients infected with either HCV subgenotype 2a or 2b.RESULTS: Of the 180 patients evaluated, 111 achieved RVR, while the remaining 69 patients did not. In RVR patients, the sustained virologic response(SVR) rate was 96.4%, and the IFNL3 genotype did not influence the SVR rate(96.6% vs 95.8% in IFNL3 genotype TT vs non-TT). However, in non-RVR patients, the SVR rate decreased to 72.5%(P < 0.0001), and this rate was significantly different between the IFNL3 genotype TT and non-TT groups(80.0% vs 42.9%, P = 0.0146). Multivariate regression analysis in non-RVR patients identified the IFNL3 genotype TT as the only baseline-significant factor associated with SVR(OR = 5.39, 95%CI: 1.29-22.62; P = 0.0189). In analysis according to HCV sub-genotype, no significant difference in the SVR rate was found between HCV sub-genotypes 2a and 2b.CONCLUSION: In response-guided Peg-IFNα/RBV combination therapy for chronically HCV G2-infected patients, the impact of the IFNL3 genotype on SVR was limited to non-RVR patients.展开更多
AIM:To investigate the pathological features of ocular surface squamous neoplasia(OSSN)and evaluate the synergistic therapeutic effects of interferon-α2b(IFNα2b)and 5-fluorouracil(5-FU)on cellular proliferation,migr...AIM:To investigate the pathological features of ocular surface squamous neoplasia(OSSN)and evaluate the synergistic therapeutic effects of interferon-α2b(IFNα2b)and 5-fluorouracil(5-FU)on cellular proliferation,migration,apoptosis,and cell cycle of human oral squamous carcinoma cell line Cal27.METHODS:Tissue specimens from OSSN were processed with hematoxylin-eosin(HE)and immunofluorescence(IF)staining to characterize pathological changes.We analyzed the expression levels of four pivotal proteins involved in 5-FU metabolism:interferon alpha receptor(IFNAR),thymidylate synthase(TS),thymidine phosphorylase(TP),and dihydropyrimidine dehydrogenase(DPD).Cal27 cell lines were treated with a spectrum of concentrations of IFNα2b and 5-FU,either in isolation or in combination.Then,cell activity was measured utilizing CCK-8 assay and dose-effect curves were calculated,while tumor cell migration was detected by cell scratch experiments.Cal27 cells were added with IFNα2b and 5-FU in a non-constant ratio drug combination design and the corresponding combination index(CI)and fraction affected(Fa)were calculated with CompuSyn software.Western blot assay was conducted to quantify the expression of TP,TS,and DPD.Cell cycle and apoptosis were measured with flow cytometry and terminal deoxynucleotidyl transferasemediated dUTP nick and labeling(TUNEL)assay.RESULTS:Treatment with both IFNα2b and 5-FU inhibited cell proliferation.Except for the lowest and highest doses of 5-FU,CI values for all other groups were below 1,suggesting a synergistic interaction.Low concentrations of IFNα2b and 5-FU both diminished the relative mobility of Cal27 cells,instead,a stronger inhibitory effect was observed when the two drugs were co-applied.The expression levels of TP and DPD in Cal27 cells were dose-dependently increased at a low concentration of IFNα2b.Low-dose IFNα2b combined with 5-FU significantly inhibited cell proliferation in G0/G1 phase compared to 5-FU monotherapy.Medium and high doses of IFNα2b and all concentrations of 5-FU could induce apoptosis in a concentration-dependent manner.The susceptibility to 5-FU treatment and apoptosis rates of tumor cells were elevated with low doses of IFNα2b.CONCLUSION:Both IFNα2b and 5-FU,when administered individually or in combination,effectively suppress the proliferation and migration of Cal27 tumor cells,induce cell apoptosis and arrest cell cycle.Low doses of IFNα2b increase the antitumor effects of 5-FU on Cal27 potentially through up-regulating the expression of TP,demonstrating a synergistic effect between IFNα2b and 5-FU.展开更多
文摘INTRODUCTIONIn China ,the incidence and mortality of gastric cancer rank the second among all cancers. Recent development of cancer [1-20].The aim of this study was investigat the insight of apoptosis and bcl-2, p53 and C-myc protein expression in the development of gastric cancer .
文摘AIM:To establish a predictive algorithm which may serve for selecting optimal candidates for interferon-α(IFN-α) treatment.METHODS:A total of 474 IFN-α treated hepatitis B virus e antigen(HBeAg)-positive patients were enrolled in the present study.The patients' baseline characteristics,such as age,gender,blood tests,activity grading(G) of intrahepatic inflammation,score(S) of liver fibrosis,hepatitis B virus(HBV) DNA and genotype were evaluated;therapy duration and response of each patient at the 24th wk after cessation of IFN-α treatment were also recorded.A predictive algorithm and scoring system for a sustained combined response(CR) to IFN-α therapy were established.About 10% of the patients were randomly drawn as the test set.Responses to IFN-α therapy were divided into CR,partial response(PR) and non-response(NR).The mixed set of PR and NR was recorded as PR+NR.RESULTS:Stratified by therapy duration,the most significant baseline predictive factors were alanine aminotransferase(ALT),HBV DNA level,aspartate aminotransferase(AST),HBV genotype,S,G,age and gender.According to the established model,the accuracies for sustained CR and PR+NR,respectively,were 86.4% and 93.0% for the training set,81.5% and 91.0% for the test set.For the scoring system,the sensitivity and specificity were 78.8% and 80.6%,respectively.There were positive correlations between ALT and AST,and G and S,respectively.CONCLUSION:With these models,practitioners may be able to propose individualized decisions that have an integrated foundation on both evidence-based medicine and personal characteristics.
文摘AIM. To investigate the influence of HLA-DRB1 alleles and HBV genotypes on inberferon-α therapy for chronic hepatitis B. METHODS： HLA-DRBI＊03, ＊07, ＊09,＊12, ＊15 alleles were determined using polymerase chain reaction/sequence specific primer （PCR/SSP） technique in 126 patients with chronic hepatitis B and 76 normal control subjects in Shandong Province, and HBV genotypes were determined by nested-PCR analysis using type-specific primers in 126 patients. RESULTS： The positivity of HLA-DRB1＊07 allele in chronic hepatitis B group was significantly higher than that in normal control group （X^2 = 6.33, P〈0.025, RR = 2.37）. Among the 126 patients, genotype B was found in 38 （30.2%）, genotype C in 69 （54.8%）, and mixed genotype （B＋C） in 19 （15.0%）, genotypes D-F were not found. Among the 46 DRB1＊07（＋） patients, 7 were responders and 39 were non-responders among them （X^2 = 6.71, P〈0.05）. The positivity of HLADRB1＊07 and prevalence of HBV genotype C were significantly higher in non-responders than in responders. CONCLUSION： High positivities of HLA-DRB1 ＊07 allele and HBV genotype C are closely associated with the lower response to interferon-α therapy for chronic hepatitis B.
基金Supported by Brazilian government research foundations National Council for Research and Technology and Coordination for the Improvement of Higher Education Personnel with research grant and scholarships processNo.9028-11-0+2 种基金No.305064/2011-8 and No.232711/2014-3Sao Paulo Government agency Sao Paulo State Research Foundation withprocess No.2011/12448-0both granted to Andrade LEC and Keppeke GD
文摘Chronic inflammation associated with hepatitis C virus(HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α(IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies(ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings(RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings(antiRR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2(IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.
文摘AIM To investigate the association between interferoninduced protein with tetratricopeptide repeats 1(IFIT1) polymorphisms and interferon-α(IFNα) treatment efficiency among Chinese hepatitis B virus(HBV) infection patients.METHODS Two hundred and twenty five newly diagnosed chronichepatitis B(CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen(HBe Ag) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms(SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes.RESULTS At the end of the treatment, HBe Ag seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218(A > G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64(95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response(response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype(response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBe Ag seroconversion, combined response or sustained response was observed.CONCLUSION IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation.
基金Supported by Clinical Key Program Point Subject Foundation of Ministry of Public Health, No. 20012434
文摘AIM： To evaluate the effects of interferon-α-2b （IFN- α-2b） on expression of cyclooxygenase-2 （COX-2） and vascular endothelial growth factor （VEGF） in human hepatocellular carcinoma （HCC） inoculated in nude mice and to study the underlying mechanism of IFN-α- 2b against HCC growth. METHODS： Thirb/-two nude mice bearing human HCC were randomly divided into four groups （n = 8）. On the 10th day after implantation of HCC cells, the mice in test groups （groups A, B and C） received IFN-α- 2b at a serial dose （10000 IU for group A, 20000 IU for group B, 40000 IU for group C sc daily） for 35 d. The mice in control group received normal saline （NS）. The growth conditions of transplanted tumors were observed. Both genes and proteins of COX-2 and VEGF were detected by RT-PCR and Western blot. Apoptosis of tumor cells in nude mice was detected by TUNEL assay after treatment with IFN-α-2b. RESULTS： Tumors were significantly smaller and had a lower weight in the IFN-α-2b treatment groups than those in the control group （P 〈 0.01）, and the tumor growth inhibition rate in groups A, B and C was 27.78%, 65.22% and 49.64%, respectively. The expression levels of both genes and proteins of COX-2 and VEGF were much lower in the IFN-α-2b treatment groups than in the control group （P 〈 0.01）. The apoptosis index （AI） of tumor cells in the IFN-α-2b treatment groups was markedly higher than that in the control group （P 〈 0.01）. Group B had a higher inhibition rate of tumor growth, a lower expression level of COX-2 and VEGF and a higher AI than groups A and C （P 〈 0.05）, but there was no significant difference between groups A and C. CONCLUSION： The inhibitory effects of IFN-α-2b on implanted tumor growth and apoptosis may be associated with the down-regulation of COX-2 and VEGF expression. There is a dose-effect relationship. The medium dose of IFN-α-2b for inhibiting tumor growth is 20 000 IU/d.
文摘Hepatitis B virus(HBV)infection is a global public health issue.Interferon-α(IFN-α)treatment has been used to treat hepatitis B for over 20 years,but fewer than 5%of Asians receiving IFN-αtreatment achieve functional cure.Thus,IFN-αretreatment has been introduced to enhance antiviral function.In recent years,immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks,including both innate and adaptive immunity,triggering immune responses that control HBV replication.However,heterogeneity of the immune system to control HBV infection,particularly HBV-specific CD8^(+)T cell heterogeneity,has consequential effects on T cell-based immunotherapy for treating HBV infection.Altogether,the host’s genetic variants,negative-feedback regulators and HBV components affecting the immune system's ability to control HBV.In this study,we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-αtreatment and retreatment.
基金Supported by National High Technology Research and Development Program of China,No.2007AA02Z151 to Lu J
文摘We report a case of severe thrombocytopenia following pegylated interferon-α 2a(Peg-IFN-α 2a)treatment of hepatitis C virus infection and summarize the clinical characteristics of 16 cases of IFN-α induced severe thrombocytopenia and its immune-mediated mechanism.Discontinuation of IFN-α and early administration of immunosuppressants are the effective therapy for IFN-αinduced severe thrombocytopenia.
文摘BACKGROUND: Hepatitis C virus (HCV) is a worldwide common disease. Some predictive factors influencing the response to interferon alpha (IFN-α) therapy have been identified, but the conclusions differ in various counties and areas. The aim of this study was to study the associa- tions between HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin in Chinese patients with chronic hepatitis C in Northeast China. METHODS: HCV genotypes of 113 patients with HCV were investigated. Gene chips were used to analyze the fre- quency of HLA-DRB in 25 of these patients and their re- sponse to IFN-α and ribavirin. The associations of HCV genotypes, HLA-DRB alleles and their response to IFN-α and ribavirin were also studied. RESULTS: The response rates differed in several types of HCV, with HCV 2b being the highest (57.78% ), HCV 1a and 2a lower (46.15% and 47.62% ) and HCV 1b the low- est (11.76% ). The response rates to IFN-α and ribavirin in patients with DRB1 07 were higher than those with DRB1 04. Sex, HCV type and HLA-DRB were all related to the response. Most female patients with HCV 2b and HLA- DRB1 07 presented complete response, whereas male pa- tients with HCV 1b and HLA-DRB1 04 usually demon- strated no response. DRB1 07 allele and HCV 2b were the factors closely related to the response. CONCLUSIONS: The response rate of HCV 1b may be the lowest even IFN-α and ribavirin are combined in treat- ment. Not only virus but also the host plays an important role in anti-virus therapy. Thus, it is necessary to adjust the host's immune status to accelerate the clearance of HCV.
文摘AIM： To evaluate the efficacy of combination chemotherapy with interferon-α （IFNα） and 5-fluorouracil （5-FU） in patients with advanced hepatocellular carcinoma （HCC）. METHODS： Twenty-eight HCC patients in advanced stage were enrolled in the study. They were treated with IFNα/ 5-FU combination chemotherapy. One cycle of therapy lasted for 4 wk. IFNα （3×10^6 units） was subcutaneously injected thrice weekly on days 1, 3, and 5 for 3 wk, and 5-FU （500 mg/d） was administered via the proper hepatic artery for 5 consecutive days per week for 3 wk. No drugs were administered during the 4th wk. The effect of combination chemotherapy was evaluated in each patient alter every cycle based on the reduction of tumor volume. RESULTS： Alter the 1^st cycle of therapy, 16 patients showed a partial response （PR, 57.1%） but none showed a complete response （CR, 0%）. At the end of therapy, the number of patients who showed a CR, PR, or no response （NR） was 1, 10, and 17, respectively. The response rate for therapy （CR＋PR） was 21.5%. Biochemical tests before therapy were compared between responsive （CR＋PR） and non-responsive （NR） patients, but no significant differences were found for any of the parameters examined, indicating that no reasonable predictors could be identified in our analysis. CONCLUSION： Attempts should be made to discriminate between responders and non-responders by evaluating tumor size alter the first cycle of IFNα/5-FU combination chemotherapy. For non-responders, therapy should not proceed to the next cycle, and instead, different combination of anticancer drugs should be explored. 2005 The WJG Press and Elsevier Inc. All rights reserved
基金This project was supported by a grant from National Natural Sciences Foundation of China (No 30472267)
文摘In order to investigate the antitumor effect and molecular mechanism of interferon-α （IFN-α） on human acute myeloid leukemia cell line U937 cells in vitro, the proliferation of U937 cells was determined by MTT assay, the apoptosis rate was analyzed by flow cytometry （FCM）, and the mRNA expression of cell cycle regulatory protein cyclin E was detected by RT-PCR. The results showed that IFN-α could inhibit the proliferation of U937 cells significantly in a dose- and time-dependent way （P〈0.01）, and induce the apoptosis of U937 cells also in a dose- and time-dependent manner at the concentration of 1000--4000 U/L （P〈0.01）. The apoptosis rate of U937 cells was even over 50% when cultured with IFN-α for 36--48 h at the concentration of 2000 -4000 U/L. Moreover, the expression of cyclin E mRNA was markedly inhibited by the addition of IFN-α, and the inhibition was time-dependent （P〈0.01）. It was concluded that the anti-leukemia mechanism of IFN-α might be correlated with its antiproliferative and apoptotic inducing effects, and the down-regulation of the cyclin E expression might be one of its molecular mechanisms.
文摘Pure red cell aplasia (PRCA) is a rare hematological disorder which is characterized by severe anemia,reticulocytopenia and almost complete absence of erythroid precursors in bone marrow.The pathophysiology of PRCA may be congenital or acquired.To our knowledge,there is only one case report in the English literature of PRCA after pegylated interferon combination therapy for chronic hepatitis C.We report a second case of PRCA after pegylated interferon combination treatment for chronic hepatitis C.The diagnosis of PRCA was confirmed by the typical findings of bone marrow biopsy.The possible etiologies of our case are also discussed in this paper.
基金supported by the Outstanding Young Talent Foundation Project of Science and Technology Department in Jilin Province(No.20170520018JH),China
文摘Hepatocarcinoma is one of the malignant cancers with significant morbidity and mortality.Immunotherapy has emerged in clinical treatment,owing to the limitation and severe side effects of chemotherapy.In the immune system,natural killer（NK）cells are important effectors required to eliminate malignant tumor cells without the limitation of major histocompatibility complex（MHC）molecule issues.Hence,treatment which could stimulate NK cells is of great interest.Here,we investigated the efficacy of the combined therapy of TT-1（a mutant of melittin）and interferon-α（IFN-α）on NK cells and human liver cancer HepG-2/Huh7 cells in vitro and in vivo,as well as the mechanism involved.The combination therapy significantly inhibited the growth of HepG-2/Huh7 cells in vivo,but this effect was impaired after depleting NK cells.TT-1 not only up-regulated MHC class I-related chain molecules A（MICA）expression,but also prevented the secretion of soluble MICA（sM ICA）.Both the mR NA and protein of a disintegrin and metallopeptidase 10（ADAM 10）in HepG-2/Huh7 cells were decreased after TT-1 treatment.The combined therapy of TT-1 and IFN-αcould suppress the growth of HepG-2/Huh7 xenografted tumor effectively via promoting the interaction of NK group 2,member D（NKG2D）and MICA,indicating that TT-1＋IFN-αwould be a potential approach in treating liver cancer.
文摘Objective: To study the effect of intracerebroventricular administration of interferon (IFN-α) on the splenic sympathetic nerve activity. Methods: IFN-α (3×104 U/rat ) was microinjected into the third cerebroven-tricle of urethane and α-chloralose anesthetized rats. Electrical activity of the splenic nerve. body temperature and blood pressure were determined simultaneously. Results: Intracerebroventricular administration of IFN-α caused amarked and long term (>120 min) increase in the splenic nerve activity, which could be reversed by naloxonetreatment. No changes in blood pressure and body temperature. which could alter the sympathetic nerve actlvity by reflex. were observed during IFN-α and naloxone treatment. Naloxone intravenous injection alone had no effecton the splenic nerve activity. Conclusion: IFN-α in the brain can activate the splenic sympathetic nerve, and thisaction is, in some way, mediated by the opioid receptor.
文摘AIM： To evaluate the daily high-dose induction therapy with interferon-α2b （IFN-α2b） in combination with ribavirin for the treatment of patients who failed with interferon monotherapy and had a relapse, based on the assumption that the viral burden would decline faster, thus increasing the likelihood of higher response rates in this difficult-totreat patient group. METHODS： Seventy patients were enrolled in this study. Treatment was started with 10 NU IFN-α2b daily for 3 wk, followed by IFN-α2b 5 NU/TIW in combination with ribavirin （1 000-1 200 mg/d） for 21 wk. In case of a negative HCV RNA PCR, treatment was continued until wk 48 （IFN-α2b 3MU/TIW＋1000-1200 mg ribavirin/daily）. RESULTS： The dose of IFN-α2b or ribavirin was reduced in 16% of patients because of hematologic side effects, and treatment was discontinued in 7% of patients. An early viral response （EVR） was achieved in 60% of patients. Fifty percent of all patients achieved an end-oftreatment response （EOT） and d0% obtained a sustained viral response （SVR）. Patients with no response had a significantly lower response rate than those with a former relapse （SVR 30% vs 53%; P=0.049）. Furthermore, lower response rates were observed in patients infected with genotype la/b than in patients with non-1-genotype （SVR 28% vs7d%; P=0.001）. As a significant predictive factor for a sustained response, a rapid initial decline of HCV RNA could be identified. No patient achieving a negative HCV-RNA PCR at wk 18 or later eventually eliminated the virus. CONCLUSION： Daily high-dose induction therapy with interferon-α2b is well tolerated and effective for the treatment of non-responders and relapsers, when interferon monotherapy fails. A fast decline of viral load during the first 12 wk is strongly associated with a sustained viral response.
文摘AIM: To evaluate interferon-λ3(IFNL3) polymorphisms in response-guided pegylated interferon-α plus ribavirin(Peg-IFNα/RBV) therapy for genotype 2(G2) chronic hepatitis C.METHODS: Between January 2006 and June 2012, a total of 180 patients with chronic infections of G2 hepatitis C virus(HCV) were treated with responseguided Peg-IFNα/RBV therapy. The treatment duration was 24 wk for patients who achieved rapid virologic response(RVR), and 36 or 48 wk for patients who did not. Then, the impact of the IFNL3 single nucleotide polymorphism genotype(TT/non-TT at rs8099917) on treatment outcomes was evaluated in the 180 patients, and between patients infected with either HCV subgenotype 2a or 2b.RESULTS: Of the 180 patients evaluated, 111 achieved RVR, while the remaining 69 patients did not. In RVR patients, the sustained virologic response(SVR) rate was 96.4%, and the IFNL3 genotype did not influence the SVR rate(96.6% vs 95.8% in IFNL3 genotype TT vs non-TT). However, in non-RVR patients, the SVR rate decreased to 72.5%(P < 0.0001), and this rate was significantly different between the IFNL3 genotype TT and non-TT groups(80.0% vs 42.9%, P = 0.0146). Multivariate regression analysis in non-RVR patients identified the IFNL3 genotype TT as the only baseline-significant factor associated with SVR(OR = 5.39, 95%CI: 1.29-22.62; P = 0.0189). In analysis according to HCV sub-genotype, no significant difference in the SVR rate was found between HCV sub-genotypes 2a and 2b.CONCLUSION: In response-guided Peg-IFNα/RBV combination therapy for chronically HCV G2-infected patients, the impact of the IFNL3 genotype on SVR was limited to non-RVR patients.
基金Supported by the National Natural Science Foundation of China(No.82070934,No.82171025).
文摘AIM:To investigate the pathological features of ocular surface squamous neoplasia(OSSN)and evaluate the synergistic therapeutic effects of interferon-α2b(IFNα2b)and 5-fluorouracil(5-FU)on cellular proliferation,migration,apoptosis,and cell cycle of human oral squamous carcinoma cell line Cal27.METHODS:Tissue specimens from OSSN were processed with hematoxylin-eosin(HE)and immunofluorescence(IF)staining to characterize pathological changes.We analyzed the expression levels of four pivotal proteins involved in 5-FU metabolism:interferon alpha receptor(IFNAR),thymidylate synthase(TS),thymidine phosphorylase(TP),and dihydropyrimidine dehydrogenase(DPD).Cal27 cell lines were treated with a spectrum of concentrations of IFNα2b and 5-FU,either in isolation or in combination.Then,cell activity was measured utilizing CCK-8 assay and dose-effect curves were calculated,while tumor cell migration was detected by cell scratch experiments.Cal27 cells were added with IFNα2b and 5-FU in a non-constant ratio drug combination design and the corresponding combination index(CI)and fraction affected(Fa)were calculated with CompuSyn software.Western blot assay was conducted to quantify the expression of TP,TS,and DPD.Cell cycle and apoptosis were measured with flow cytometry and terminal deoxynucleotidyl transferasemediated dUTP nick and labeling(TUNEL)assay.RESULTS:Treatment with both IFNα2b and 5-FU inhibited cell proliferation.Except for the lowest and highest doses of 5-FU,CI values for all other groups were below 1,suggesting a synergistic interaction.Low concentrations of IFNα2b and 5-FU both diminished the relative mobility of Cal27 cells,instead,a stronger inhibitory effect was observed when the two drugs were co-applied.The expression levels of TP and DPD in Cal27 cells were dose-dependently increased at a low concentration of IFNα2b.Low-dose IFNα2b combined with 5-FU significantly inhibited cell proliferation in G0/G1 phase compared to 5-FU monotherapy.Medium and high doses of IFNα2b and all concentrations of 5-FU could induce apoptosis in a concentration-dependent manner.The susceptibility to 5-FU treatment and apoptosis rates of tumor cells were elevated with low doses of IFNα2b.CONCLUSION:Both IFNα2b and 5-FU,when administered individually or in combination,effectively suppress the proliferation and migration of Cal27 tumor cells,induce cell apoptosis and arrest cell cycle.Low doses of IFNα2b increase the antitumor effects of 5-FU on Cal27 potentially through up-regulating the expression of TP,demonstrating a synergistic effect between IFNα2b and 5-FU.
