Biomedical subjects

Ryuzo Ueda

Publications and source records attributed to Ryuzo Ueda.

At least 19 recordsLinked to original sources

PubMed2006

Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection.

BACKGROUND: Prolonged lamivudine therapy has two major problems: breakthrough hepatitis during treatment and relapse of aminotransferase (ALT) after cessation of the therapy. The aim of this study was to examine factors that could predict ALT flare after stopping lamivudine therapy. METHODS: We analyzed 22 Japanese patients with chronic hepatitis B infection, in whom lamivudine therapy was stopped after HBV DNA level had been gone undetectable (<3.7LGE/ml) during at least six consecutive months. The post-treatment followed up was carried for 28 months in median (range 9-41). HBV core-related antigen (HBcrAg) assay was assessed using newly developed assay. RESULTS: After cessation of lamivudine therapy, 11 patients (50%) had relapsed (reactivation of serum ALT >80IU/l, relapsers) and remaining 11 (50%) did not relapse (non-relapsers). In the univariate comparison of relapsers versus non-relapsers, HBcrAg level at lamivudine cessation point (4.5+/-1.0 versus 3.4+/-0.9; p=0.0145) has been shown as a significant predictive factor for non-relapse. All patients with HBcrAg <3.0logU/ml at the cessation point had no ALT flares. Multivariate analysis on effects of 10 factors (age, sex, cirrhosis, pretreatment ALT level, HBV DNA level, HBcrAg level, mean months till undetectable HBV DNA, duration of undetectable HBV DNA and HBcrAg level at lamivudine cessation point), indicated that HBcrAg level at lamivudine cessation point <3.4log U/ml was the only independent predictive factor for absence of the post-treatment relapse. CONCLUSIONS: HBcrAg level at lamivudine cessation point might be useful as a prognostic predictor of response to lamivudine therapy cessation. The measurement of HBcrAg is a useful additional test for monitoring chronic HBV infection.

Journal Article↗

PubMed2006

Spatial and chronological differences in hepatitis B virus genotypes from patients with acute hepatitis B in Japan.

Genotypes of hepatitis B virus (HBV) were determined in 485 patients with acute hepatitis B from all over Japan. They were A in 92 (19%), Ba in 26 (5%), Bj in 32 (7%), C in 330 (68%) and D in 5 (1%). Sexual contacts were the main route of transmission in them. Overall, HBV persisted in only 5 of the 464 (1%) followed patients. Genotypes C accounted for more than 68% in northern as well as southern areas, contrasting with genotype A accounting for 34% in and around the Metropolitan areas. During 24 years from 1982 to 2005, genotype A increased from 5% to 33%, while genotype B gradually decreased from 26% to 8%. Fulminant hepatitis was significantly more frequent in infection with genotype Bj (41%) than those with the other genotypes (p<0.01). The core-promoter double mutation (T1762/A1764) and precore stop-codon mutation (A1896) were more frequent in patients with fulminant than acute self-limited hepatitis (57% versus 15% and 58% versus 10%, respectively, p<0.01 for both). In conclusion, genotype A distributes unevenly over Japan, prevails in younger patients through sexual transmission and has increased with years. Furthermore, fulminant outcome was more frequent in patients with genotype Bj than those with the other genotypes.

Journal Article↗

PubMed2006

CCR4 as a novel molecular target for immunotherapy of cancer.

Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4(+) T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4(+) Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4(+) T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4(+) tumor cells, but also to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

Humans↗

PubMed2006

Variations in the viral NS5B region in Japanese patients with chronic hepatitis C virus genotype 1b infection. No specific amino acid substitution was identified as determinants of treatment response to interferon/ribavirin combination therapy.

OBJECTIVE: A recent study suggested that the substitution of amino acid 415 of HCV NS5B from phenylalanine to tyrosine in patients with HCV genotype 1a infection is induced by ribavirin and responsible for resistance to ribavirin therapy. The aim of this study was to evaluate whether specific variations in the HCV NS5B sequence in Japanese patients with HCV genotype 1b (HCV/1b) infection are associated with treatment response or selected by treatment with interferon-alpha/ribavirin combination therapy. METHODS: Eighteen Japanese patients with HCV/1b infection receiving interferon-alpha/ribavirin combination therapy for 24 weeks were studied. Five patients treated with interferon-alpha monotherapy for 24 weeks were also studied as controls. The entire HCV NS5B sequence before and after therapy was determined. RESULTS: All HCV isolates had tyrosine at position 415 of NS5B before and after therapy. Further analysis showed that no specific amino acid substitutions were identified to associate with clinical response and no specific amino acid substitutions were induced/selected by the clinical treatment. CONCLUSION: No specific HCV NS5B nucleotide/amino acid sequence variations, including amino acid 415 of NS5B, were identified as being associated with clinical treatment response or selected by the combination therapy in Japanese patients with HCV/1b infection.

Adult↗

PubMed2006

Specific mutations in enhancer II/core promoter of hepatitis B virus subgenotypes C1/C2 increase the risk of hepatocellular carcinoma.

BACKGROUND/AIMS: Hepatitis B virus genotype C (HBV/C) has been classified into two geographically distinct subgenotypes; HBV/C1/Cs (Southeast Asia) and HBV/C2/Ce (East Asia). METHODS: Viral differences in enhancer II/core promoter and precore regions between the subgenotypes and their association with hepatocellular carcinoma (HCC) were assessed in a matched cross-sectional control study of 118 carriers (from Hong Kong) with HBV/C1/Cs (48.0 years, 81% male, 40% HBeAg+, 44% HCC) and 210 HBV/C2/Ce (172 from Japan, 38 from Hong Kong) (50.2 years, 78% male, 30% HBeAg+, 46% HCC). RESULTS: Univariate analyses showed that mutation V1753 was predictive for HCC among HBeAg-positive-C1/Cs-carriers (P=0.0055), and T1653 among HBeAg-positive-C2/Ce-carriers (P=0.018), and T1653 or V1753 or T1762/A1764 among HBeAg-negative-C2/Ce-carriers (P<0.05). In the multivariate analysis on all HBV/C subjects, independent predictive factors for HCC were subgenotype C2/Ce (odds ratio, 4.21; 95% confidence interval, 1.07-16.23), T1653 (3.64; 1.93-6.86), V1753 (3.07; 1.66-5.65) and T1762/A1764 (2.58; 1.21-5.49) mutations, age (50 years), gender (male) and HBeAg (positive). CONCLUSIONS: Our data indicate that T1653 and/or V1753 mutations in addition to T1762/A1764 are differently associated with HCC in context of HBeAg status among HBV/C1/Cs and C2/Ce-carriers. HBV/C subgenotypes have specific mutation patterns, which is probably responsible for increased carcinogenesis of HBV/C2/Ce.

Aged↗

PubMed2006

Effect of dietary antioxidants and risk of oral, pharyngeal and laryngeal squamous cell carcinoma according to smoking and drinking habits.

Several intervention trials and prospective studies have reported that beta-carotene supplementation is not associated with a decreased risk of several cancers among smokers and drinkers, and that it may even have adverse effects in these groups. The relationship between dietary antioxidant intake and the risk of head and neck squamous cell carcinoma (HNSCC) has been examined intensively, but little is known about the effects of antioxidants on HNSCC with respect to smoking and drinking habits. Here, we conducted a case-control study of 385 histologically confirmed cases of HNSCC (193 oral, 132 pharyngeal and 60 laryngeal), excluding nasal and paranasal cancer, and 1925 age-matched and sex-matched cancer-free outpatient controls using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center, Japan. The intake of nutrients and food groups was assessed with a food frequency questionnaire, and multivariate-adjusted odds ratios for cancer were estimated for smoking and drinking habits using logistic models. The results showed an overall inverse association between the intake of dietary antioxidants, including carotene, and vitamins C and E, and risk of HNSCC. The protective effect of these antioxidants was seen in both men and women. High consumption of antioxidants was associated with a decreased risk of HNSCC among smokers, drinkers and those with both smoking and drinking habits. These findings suggest that dietary antioxidant intake prevents HNSCC in smokers and drinkers.

Adult↗

PubMed2006

Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: high interleukin-5 and -10 levels are significant unfavorable prognostic factors.

Patients with adult T-cell leukemia/lymphoma (ATLL) are in a severely immunocompromised state. Therefore, it is assumed that ATLL cells either express particular cytokines or induce their expression in host immune cells, disrupting the balanced production of cytokines and causing the host's immune system to break down. We examined the levels of serum cytokines including T helper type 1- (Th1-) associated cytokines [IFN-gamma, TNF-alpha, and interleukin (IL)-2], Th2-associated cytokines (IL-4, -5 and -6) and regulatory T cell-associated cytokines (IL-10 and TGF-beta1) in 94 ATLL patients, 39 asymptomatic human T-cell lymphotropic virus type-1 (HTLV-1) carriers and 50 healthy adult volunteers, to clarify whether elevated levels of particular cytokines are associated with the prognosis of ATLL patients. On multivariate analysis, high IL-5 and IL-10 levels were independent and significant unfavorable prognostic factors among the ATLL patients. The IL-10 level significantly increased with disease progression at each step from asymptomatic HTLV-1 carrier to ATLL of the indolent variant (chronic and smoldering subtypes) to ATLL of the aggressive variant (acute and lymphoma subtypes). Furthermore, high IL-10 was significantly associated with high lactate dehydrogenase (LDH), indicating that the IL-10 level reflects the tumor burden. The IL-5 level was not associated with disease progression nor LDH. Among ATLL patients with the aggressive variant, high IL-5, but not high IL-10, was an independent and significant unfavorable prognostic factor on multivariate analysis. Measurement of serum IL-5 and IL-10 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.

Adult↗

PubMed2006

Candesartan, an angiotensin II type-1 receptor blocker, reduces cardiovascular events in patients on chronic haemodialysis--a randomized study.

BACKGROUND: Cardiovascular events are the major determinants of the prognosis of patients on chronic haemodialysis. The present study was designed to investigate whether candesartan, an angiotensin II type-1 receptor blocker, reduces the incidence of cardiovascular events in these patients. METHODS: A total of 80 chronic haemodialysis patients (male/female, 47/33; mean age +/- SEM, 61 +/- 1 years) in stable condition and with no clinical evidence of cardiac disorders were enrolled. Patients were randomly assigned candesartan 4-8 mg/day (candesartan group; n = 43) or nothing (control group; n = 37), and followed for 19.4 +/- 1.2 months with as endpoint cardiovascular events such as fatal/nonfatal myocardial infarction, unstable angina pectoris, congestive heart failure, severe arrhythmia and sudden death. RESULTS: Both groups exhibited similar clinical characteristics at baseline. During follow-up, cardiovascular events occurred in seven patients in the candesartan group and 17 in the control group. Kaplan-Meier analysis revealed that cardiovascular events and mortality rates were significantly (P < 0.01) higher in the control group than in the candesartan group (45.9 vs 16.3% and 18.9 vs 0.0%, respectively). CONCLUSIONS: Candesartan therapy significantly reduces cardiovascular events and mortality in patients on chronic maintenance haemodialysis and therefore improves the prognosis of these patients.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Association among C-reactive protein, oxidative stress, and traditional risk factors in healthy Japanese subjects.

BACKGROUND: Inflammation and oxidative stress play a key role in the pathogenesis of atherosclerosis. This study was designed to examine the interrelationships among C-reactive protein (CRP), oxidative stress, and traditional cardiovascular risk factors. METHODS: We conducted a cross-sectional analysis among 551 apparently healthy Japanese subjects not receiving medication (mean age, 53+/-11 years; males/females, 400/151). Subject underwent laboratory assessment of cardiovascular disease risk factors, and CRP and 8-isoprostane, a marker of oxidative stress, were measured. RESULTS: In unadjusted analyses, CRP was positively correlated with age, male gender, body mass index, blood pressure, smoking habit, creatinine, uric acid, triglycerides, an index of insulin resistance, and 8-isoprostane, and inversely correlated with high-density lipoprotein-cholesterol. 8-Isoprostane was positively correlated with age, pulse pressure, smoking habit, brain natriuretic peptide, and CRP. In multiple regression analyses, body mass index (r=0.177), high-density lipoprotein-cholesterol (r=-0.162), uric acid (r=0.141), and 8-isoprostane (r=0.097) were independently correlated with CRP (P<0.001), whereas smoking (r=0.341), age (r=0.217), and pulse pressure (r=0.091) remained independently correlated with 8-isoprostane (P<0.001). CONCLUSIONS: CRP levels are associated not only with clinical cardiovascular risk factors but also with oxidative stress. There are significant interrelationships among inflammation, oxidative stress, and traditional cardiovascular risk factors.

Adult↗

PubMed2006

Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege.

Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

Adult↗

PubMed2006

Temocapril, an Angiotensin converting enzyme inhibitor, ameliorates age-related increase in carotid arterial stiffness in normotensive subjects.

BACKGROUND/AIMS: Oxidative stress plays an important role in vascular ageing. The close relationship of the renin-angiotensin system with mechanisms of oxidative stress suggests its possible involvement in the deleterious effects of ageing. The present study was designed to investigate whether inhibition of the renin-angiotensin system improves the age-related increase in arterial stiffness. METHODS: Normotensive elderly subjects in a geriatric nursing home (n = 24; male/female = 7/17; 86 +/- 9 years, mean +/- SD) were randomly assigned to receive either an angiotensin converting enzyme inhibitor, temocapril (n = 12, 1 mg daily) or nothing (n = 12). Carot id arterial stiffness parameter beta and circulating levels of malondialdehyde-modified low-density lipoprotein were measured before and 6 months after randomization. RESULTS: Temocapril decreased beta (from 7.0 +/- 1.0 to 4.9 +/- 0.9, p < 0.05) and malondialdehyde-modified low-density lipoprotein levels (from 73.2 +/- 19.9 to 61.3 +/- 18.4 U/l, p < 0.05) without changing the blood pressure. The changes in beta and malondialdehyde-modified low-density lipoprotein levels were significantly correlated (rho = 0.600, p < 0.05). CONCLUSION: These results suggest that temocapril ameliorates the age-related increase in carotid arterial stiffness in healthy, normotensive elderly subjects.

Aged↗

PubMed2006

A past history of gastric ulcers and Helicobacter pylori infection increase the risk of gastric malignant lymphoma.

Helicobacter pylori (H. pylori) is a causative agent for peptic ulcers as well as some types of gastric lymphoma; however, the relationship between a peptic ulcer history in combination with H. pylori infection and the risk of gastric lymphoma has not been fully evaluated. To examine this point, we conducted a case-control study with 645 patients histologically diagnosed as having malignant lymphomas and 3225 non-cancer controls. Plasma H. pylori IgG status was assessed for subgroups for which blood samples were available (116 cases and 114 controls). An association with a history of gastric, but not duodenal ulcers was found for gastric lymphoma [odds ratio (OR) = 5.41, 95% confidence interval (CI): 3.12-9.39]. In the examination according to histological subtype, the OR was high for both gastric mucous-associated lymphoid tissue (MALT) lymphoma (OR = 5.54, 95% CI: 2.56-12.01) and diffuse large B-cell lymphoma (DLBCL) (OR = 7.23, 95% CI: 2.62-19.90). In the analysis of H. pylori antibody, the risk of total gastric lymphoma was associated with H. pylori infection (OR = 5.34, 95% CI: 1.42-20.05). A high prevalence of H. pylori infection was also found for both gastric MALT lymphoma (8 out of 10: 80.0%) and DLBCL (8 out of 9: 88.9%). Further, in subgroup analysis of subjects with H. pylori infection, gastric ulcer history, but not duodenal ulcer history was associated with the risk of gastric lymphoma (OR = 4.15, 95% CI: 1.02-16.89). In conclusion, we found a positive association with a past history of gastric ulcer and H. pylori infection for gastric lymphoma, while duodenal ulcer history was no association. These results suggested the risk of gastric lymphoma increased by interaction between H. pylori infection and gastric ulcer history. Further studies are warranted.

Adolescent↗

PubMed2006

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection.

The outcome of acute hepatitis B virus (HBV) infection is variable, influenced by host and viral factors. From 1982 through 2004, 301 patients with acute HBV infection entered a multi-center cross-sectional study in Japan. Patients with fulminant hepatitis (n = 40) were older (44.7 +/- 16.3 vs. 36.0 +/- 14.3 years, P < .0017), less predominantly male (43% vs. 71%, P = .0005), less positive for hepatitis B e antigen (HBeAg) (23% vs. 60%, P < .0001), less infected with subgenotype Ae (0% vs. 13%, P < .05), and more frequently with Bj (30% vs. 4%, P < .0001) than those with acute self-limited hepatitis (n = 261). Precore (G1896A) and core-promoter (A1762T/G1764A) mutations were more frequent in patients with fulminant than acute self-limited hepatitis (53% vs. 9% and 50% vs. 17%, P < .0001 for both). HBV infection persisted in only three (1%) patients, and they represented 2 of the 23 infected with Ae and 1 of the 187 with the other subgenotypes (9% vs. 0.5%, P = .032); none of them received antiviral therapy. In multivariate analysis, age 34 years or older, Bj, HBeAg-negative, total bilirubin 10.0 mg/dL or greater, and G1896A mutation were independently associated with the fulminant outcome. In in vitro transfection experiments, the replication of Bj clone was markedly enhanced by introducing either G1896A or A1762T/G1764A mutation. In conclusion, persistence of HBV was rare (1%) and associated with Ae, whereas fulminant hepatitis was frequent (13%) and associated with Bj and lack of HBeAg as well as high replication due to precore mutation in patients with acute HBV infection.

Acute Disease↗

PubMed2006

Molecular epidemiology of hepatitis B virus in the United Republic of Tanzania.

In the United Republic of Tanzania, 457 voluntary blood donors were enrolled in hepatitis B virus (HBV) serological screening; 4.8% (22/457) carried HBsAg, 13.6% (3/22) of whom were HBeAg-positive. The mean age among HBeAg-negative carriers was 31 years. HBV DNA was detectable in 81.8% (18/22), the mean level was 3.67 (+/-1.77) log copies/ml. Genotype A was determined in 90.9% (20/22) and 18/20 were classified into subgenotype Aa (Asia/Africa). The basal core promoter, precore and partial core nucleotide sequences were analyzed in the 18 strains; T1809/T1812 ("Kozak" sequence) and A/T1888 (encapsidation signal) variants were identified in 100% and 78%, respectively. The complete genome sequencing for one of the Tanzanian strains revealed no recombination. In conclusion, HBV seroprevalence is high among general population in Tanzania, and the HBV/Aa-infection is predominant. The indicated tendency to early HBeAg seroconversion and declining of the viral load should be confirmed further in case-control studies.

Adult↗

PubMed2006

Immunoglobulin VH genes in thymic MALT lymphoma are biased toward a restricted repertoire and are frequently unmutated.

Thymic MALT lymphoma shows certain distinctive features among MALT lymphomas, such as expression of IgA isotype, consistent lack of API2-MALT1 gene fusion, and very strong association with autoimmune disease, especially Sjogren's syndrome. To help clarify the nature of the clonal lymphoid infiltrates, we analysed the usage and somatic hypermutation of the Ig heavy chain variable region (V(H)) genes in nine different cases. The V(H) rearrangement was potentially functional in all cases and was restricted to the V(H)3 family. V(H) usage was biased toward V(H)3-30 (five cases) and V(H)3-23 (three cases) segments, which have both been frequently expressed by autoimmune B cells. Somatic hypermutation was absent in five cases. Fewer than the expected replacement mutations were found in the framework regions in two cases, indicating a negative antigen selection pressure. Ongoing mutation was absent in all cases. D segment usage was varied, whereas J(H) segment usage was restricted to J(H)4. The observed patterns of V(H) usage and mutations suggested that specific antigens may play a pathologically relevant role in the genesis or progression of thymic MALT lymphoma.

Aged↗

PubMed2006

Smoking increases the treatment failure for Helicobacter pylori eradication.

PURPOSE: Treatment failure for Helicobacter pylori (H. pylori) eradication is encountered in approximately 10-20% of patients, and many studies have pointed to a link with smoking. To investigate the effects of smoking on eradication outcome, we performed a meta-analysis. METHODS: A PubMed search was performed to retrieve articles published up to August 2005. Pooled odds ratio (OR) and differences rate for H. pylori eradication failure in smokers compared with nonsmokers were used as summary statistics. Meta-regression was used for examining the source of heterogeneity. RESULTS: Twenty-two published studies (5538 patients), which provided information on eradication failure according to smoking status, were included in the analysis. The summary OR for eradication failure among smokers relative to nonsmokers was 1.95 (95% confidence interval [CI]: 1.55-2.45; P <.01). It corresponds with the differences in eradication rates between smokers and nonsmokers (8.4% [95% CI: 3.3-13.5%, P <.01]). Meta-regression analysis demonstrated that a high proportion of nonulcer dyspepsia patients in studies revealed a higher failure rate among smokers, compared with a low proportion of nonulcer dyspepsia. CONCLUSIONS: Our meta-analysis demonstrated that smoking increases the treatment failure rate for H. pylori eradication.

Anti-Bacterial Agents↗

PubMed2006

Novel subtypes (subgenotypes) of hepatitis B virus genotypes B and C among chronic liver disease patients in the Philippines.

Several hepatitis B virus (HBV) subtypes (subgenotypes), HBV/Aa (A1 : Asia/Africa), Ae (A2 : Europe), Bj (B1 : Japan) and Ba (B2 : Asia), have been reported with respect to clinical differences between patients infected with these subtypes (subgenotypes). HBV genotype distribution among patients with chronic liver diseases was investigated in the Philippines, where such studies have not been carried out previously. One hundred sera were obtained from such patients, consisting of 32 chronic hepatitis (CH), 37 cirrhosis and 31 hepatocellular carcinoma (HCC) patients. Nine complete genomes and 100 core promoter/precore genes of HBV were sequenced directly. Phylogenetic analyses revealed 51 HBV/A (Aa/A1), 22 HBV/B and 27 HBV/C strains. Interestingly, most HBV/C strains in the Philippines formed a specific cluster distinct from previous HBV/C strains (C1-4), indicating a novel subtype (subgenotype), HBV/C5. Moreover, most HBV/B strains fell within the specific cluster of the HBV/B subtype (subgenotype) B5, with viral characteristics of HBV/Ba (B2) carrying a recombination with HBV/C over the precore and core genes. Of the three genotypes, HBV/B and HBV/C were significantly more prevalent than HBV/A in cirrhosis and HCC patients (P<0.02). The prevalence of the core promoter mutations T1762/A1764 was higher in HCC patients with HBV/B and HBV/C. Multivariate analysis indicated that age [odds ratio (OR) 3.43; 95 % confidence interval (CI) 1.04-11.36; P=0.044] and the core promoter mutation (OR 14.08; 95% CI 3.62-4.74; P<0.001) were significant factors for HCC development. In conclusion, novel HBV subtypes (subgenotypes) C5 and B5 are prevalent in the Philippines, as well as HBV/Aa (A1).

Carcinoma, Hepatocellular↗

PubMed2006

Role of ABCG2 as a biomarker for predicting resistance to CPT-11/SN-38 in lung cancer.

To examine the mechanism of resistance to 7-ethyl-10-hydroxycamptothecin (SN-38) in lung cancer, we continuously exposed the non-small-cell lung cancer (NSCLC) cell line NCI-H23 to SN-38 and selected the SN-38-resistant clone H23/SN-38. After 2 months of culturing in SN-38-free conditions, H23/SN-38 cells recovered their sensitivity to SN-38 and were subsequently established as the revertant H23/SN-38REV cell line. Because H23/SN-38 cells show cross resistance to certain anticancer drugs, such as topotecan, etoposide, doxorubicin and mitoxantrone, we examined the gene and protein expression levels of drug efflux transporters of the ATP-binding cassette (ABC) family. We found that both gene and protein expression of ABCG2/BCRP (ABCG2) in H23/SN-38 cells was increased compared with that in NCI-H23 cells and H23/SN-38REV cells. The cellular accumulation of topotecan in H23/SN-38 cells was decreased compared with that in NCI-H23 and H23/SN-38REV cells, and treatment with reserpine (an inhibitor of ABCG2) increased the cellular accumulation of topotecan in H23/SN-38 cells. Furthermore, treatment with reserpine also altered the sensitivity of H23/SN-38 cells to SN-38. These results indicate that the upregulation of ABCG2 was functional, and related to the resistance of H23/SN-38 cells to SN-38. Moreover, we found that gene expression levels of ABCG2 were significantly correlated with the concentration of SN-38 for 50% cell survival in 13 NSCLC cells (r=0.592, P<0.05). The present results indicate that the induction of ABCG2 by SN-38 does confer acquired resistance to CPT-11/SN-38, but the induction of ABCG2 and subsequent drug resistance are reversible. However, the expression level of ABCG2 may be a useful indicator of CPT-11/SN-38 activity in lung cancer.

ATP Binding Cassette Transporter, Subfamily G, Mem↗