Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis.

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive ß-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.

Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions.

PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFßTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.

Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells.

Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O2) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells.

Effects of home-based exercise and branched-chain amino acid supplementation on aerobic capacity and glycemic control in patients with cirrhosis.

AIM: The aim of the current study is to examine whether home-based step exercise at anaerobic threshold (AT) and branched-chain amino acid (BCAA) supplementation improve aerobic capacity, ectopic fat in liver and muscle, and glycemic control in patients with liver cirrhosis. METHODS: Six female patients with compensated liver cirrhosis received oral BCAA and were instructed to undertake bench step exercises at an intensity that corresponded to AT, with a goal of performing 140 min of exercise per week at home for 12 months. Fat deposition in liver (liver to spleen ratio) and intramuscular adipose tissue content were assessed at baseline and after 6 and 12 months by computed tomography. Glycemic control indices (homeostasis model assessment of insulin resistance, hemoglobin A1c [HbA1c ], glycated albumin [GA] and chronic liver disease [CLD]-HbA1c [average of HbA1c and GA/3]) were also measured. RESULTS: Twelve months of moderate training significantly increased AT, which is an index of aerobic capacity, but no changes were observed in body weight, liver to spleen ratio, or intramuscular adipose tissue content. Glycated albumin significantly decreased (P < 0.05) and there tended to be a similar decrease in CLD-HbA1c (P < 0.1) after the exercise. The baseline serum triglyceride level correlated with changes in GA (P < 0.01) and CLD-HbA1c (P < 0.1). CONCLUSION: The current results suggest that the combination of home-based step exercise at AT and BCAA supplementation enhances aerobic capacity and potentially improves glycemic control in patients with cirrhosis without changes in body weight. The baseline serum serum triglyceride may partially explain the degree of improvement in glycemic control with exercise and BCAA intervention.

Clinical course of hepatitis B surface antigen positive subjects following screening: A retrospective observational study from April 2008 to January 2013.

AIM: Determination of the percentage of hepatitis B surface antigen (HBsAg) positive participants who undergo screening and treatment may reduce the development of hepatocellular carcinoma. This study assessed the percentages of HBsAg positive participants detected by free screening at medical institutions in Saga Prefecture who underwent detailed examinations and antiviral treatment. METHODS: Participants were screened for HBsAg positivity at medical institutions in Saga Prefecture from April 2008 to January 2013, with some visiting physicians for detailed examinations and applying for reimbursement. Participants in the database of the Health Promotion Division of Saga Prefecture and results of detailed examinations were analyzed retrospectively. RESULTS: Screening revealed 193 eligible participants, 105 men (54%) and 88 women (46%), of a mean age of 55.5 ± 14.9 years. Of these 193 participants, 147 (76%) visited physicians for detailed examinations, 24 (16%) were regarded as needing treatment and seven (3.6%) were reimbursed for antiviral treatments. The 46 participants who did not undergo detailed examinations were significantly younger than the 147 examined participants (50.9 ± 13.2 vs 56.9 ± 15.2 years, P = 0.018). Of the 110 participants thought to require observation, 68 (62%) were assigned to this group without determination of alanine aminotransferase or hepatitis B virus DNA concentration, and 15 (14%) had indications for antiviral treatment according to the 2014 guidelines of the Japanese Society of Hepatology. CONCLUSION: The proportion of HBsAg positive participants receiving antiviral treatment was lower than that of participants undergoing detailed examinations.

Sarcopenia is a risk factor for the recurrence of hepatocellular carcinoma after curative treatment.

BACKGROUND AND AIM: Sarcopenia, initially proposed as decreased of muscle mass and strength, is associated with aging and malignant diseases. The aim of the present study was to determine whether there is a correlation between sarcopenia and the recurrence of hepatocellular carcinoma (HCC) after curative treatment. METHODS: We conducted a retrospective analysis of consecutive naive patients with HCC who underwent curative resection or radiofrequency ablation. To eliminate the influence of cause or the severity of liver damage, subjects were limited to those with HCC with hepatitis C-related cirrhosis and Child-Pugh class A liver function. Patients were assessed using computed tomographic measurement of muscle mass at the level of the third lumbar (L3) vertebrae, the L3 skeletal muscle index (L3 SMI). Sarcopenia was defined by using previously published, sex-specific cut-off value. RESULTS: Sarcopenia was present in 61 of 92 patients. Patients' median age was 71.5 years (range, 47-84), and the baseline characteristics of patients were comparable between patients with and without sarcopenia except for sex, serum albumin level, prothrombin time, diabetes mellitus and body mass index. Recurrence rates at 1, 3 and 5 years were 39.1%,77.1%,81.7% for patients with sarcopenia and 23.5%,59.5% and 75.7% for patients without sarcopenia, respectively (P = 0.03). Multivariate Cox analysis revealed that sarcopenia and preoperative α-fetoprotein of more than 40 ng/mL were significant independent factors for recurrence. CONCLUSION: Sarcopenia is a risk factor for recurrence in patients with HCC who were treated with curative treatment.

Pertussis outbreak in university students and evaluation of acellular pertussis vaccine effectiveness in Japan.

BACKGROUND: Recent studies worldwide have reported increasing numbers of adults diagnosed with Bordetella pertussis despite receiving childhood vaccinations. This study describes a pertussis outbreak at a university medical faculty campus and examines the effectiveness of diphtheria, tetanus, and pertussis (DTaP) vaccination completed during infancy in Japan. METHODS: After the outbreak, self-administered questionnaires and serum samples were collected from students on campus to determine the incidence of pertussis and underlying diseases. Pertussis was diagnosed on the basis of clinical criteria and serum anti-pertussis toxin antibody levels. Using data collected from 248 first and second grade students who had submitted copies of their vaccination records, we evaluated the effectiveness of DTaP vaccination in infancy against adult pertussis. RESULTS: Questionnaire responses were obtained from 636 students (of 671 registered students; 95% response rate). Of 245 students who reported a continuous cough during the outbreak period, 84 (attack rate: 13.2%) were considered "probable" pertussis cases that met clinical criteria. The outbreak occurred mainly in first and second grade students in the Faculty of Medicine. Of 248 students who provided vaccination records, 225 had received 4 DTaP doses (coverage: 90.7%); the relative risk of the complete vaccination series compared to those with fewer than 4 doses or no doses for probable cases was 0.48 (95% confidence interval: 0.24-0.97). CONCLUSIONS: Waning protection was suspected due to over time. Booster vaccination for teenagers and development of highly efficacious pertussis vaccines are needed.

Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J).

AIM: Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is associated with an increased risk of developing lifestyle-related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. No current drug therapy provides the ideal effects of decreasing hepatic inflammation while simultaneously improving liver fibrosis. Liraglutide is a glucagon-like peptide-1 receptor agonist that affects the histological findings in patients with non-alcoholic steatohepatitis (NASH). This study was conducted to evaluate the effect and action of liraglutide for biopsy-proven NASH. METHODS: After lifestyle modification intervention for 24 weeks, subjects whose hemoglobin A1c levels failed to improve to less than 6.0% and/or whose alanine aminotransferase levels were not lower than baseline, received liraglutide at 0.9 mg/body per day for 24 weeks. RESULTS: Of 27 subjects, 26 completed the lifestyle modification intervention. Nineteen subjects received liraglutide therapy for 24 weeks. Body mass index, visceral fat accumulation, aminotransferases and glucose abnormalities improved significantly. Repeated liver biopsy was performed in 10 subjects who continued liraglutide therapy for 96 weeks. Six subjects showed decreased histological inflammation as determined by NASH activity score and stage determined by Brunt classification. We saw no significant adverse events during therapy with liraglutide. CONCLUSION: Our pilot study demonstrated that treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance.

[Hepatocellular carcinoma and vitamin K2].

Despite recent progress in diagnosis and therapy, hepatocellular carcinoma(HCC)remains among the cancers with the poorest prognoses. Vitamin Ks(VKs)have been shown to suppress the growth of HCC cells. Long-term administration of VK2 has established its clinical safety, but it does not appear to exhibit marked anti-tumor effects when administered alone. For more effective use of VK2 against HCC, co-administration of VK2 with other proven anticancer agents or development of a new VK preparation with a modified side-chain should be investigated in the future.

Efficacy of ezetimibe for reducing serum low-density lipoprotein cholesterol levels resistant to lifestyle intervention in patients with non-alcoholic fatty liver disease.

AIM: To investigate the efficacy of ezetimibe and lifestyle intervention for treating patients with non-alcoholic fatty liver disease (NAFLD) and residual dyslipidemia via a combination of ezetimibe and lifestyle intervention. METHODS: Patients with NAFLD with residual dyslipidemia after a 6-month lifestyle intervention program were included. After completion of the 6-month program, the patients received p.o. administration of ezetimibe at 10 mg/day, in addition to lifestyle intervention, for 6 months. RESULTS: Of the 59 patients with NAFLD who had participated in the 6-month lifestyle intervention program between 2007 and 2012, 21 with residual dyslipidemia (10 males and 11 females) were enrolled. Median age was 58 years (range, 27-75), median bodyweight was 63.0 kg (range, 39.4-109.0), median body mass index was 25.4 kg/m2 (range, 18.2-37.1), median alanine aminotransferase was 23 IU/L (14-73), median high-density lipoprotein (HDL) was 58 mg/dL (range, 37-93), median triglycerides (TG) was 105 mg/dL (range, 42-216) and median low-density lipoprotein (LDL) was 153 (66-209) mg/dL. After 6 months of treatment with ezetimibe, serum LDL levels were improved in 15 of 20 (75%) patients (P = 0.0015), while no improvements were observed in the remaining five patient (25%). Ezetimibe was discontinued in one patient who developed skin rash. CONCLUSION: Ezetimibe is effective for treating residual dyslipidemia after lifestyle intervention in patients with NAFLD.

Mumps vaccination and immune status among Japanese university students: A multicenter cross-sectional study.

Background: During the mumps outbreak in Japan in 2016, 159,031 cases were reported. In a survey conducted in 2015, mumps vaccination rates for the first dose were 30%-40%. However, the rates for two or more doses were not determined. We assessed the mumps vaccination rates and mumps infection prevalence according to vaccine doses received. Design and methods: This was a multicenter cross-sectional study. Students from three universities participated in 2019. Informed consent was obtained from the students and their guardians. The primary outcome was the prevalence of breakthrough mumps infection according to the number of doses of vaccine received. We collected data on past illnesses of vaccine-preventable diseases and vaccination history using a questionnaire, photocopies of the Maternal and Child Health Handbook from the guardians, and virus antibody titers from the universities' health centers. Results: This study assessed 2004 eligible students and included 593 (29.6%); of these, 250 (42.7%) had a mumps infection history. Furthermore, 264 (44.6%), 31 (5.2%), and 2 (0.3%) students received the first, second, and third doses of mumps vaccine, respectively. The mumps seropositivity prevalence was 43.2% (n = 127), 36.7% (n = 97), 26.7% (n = 8), and 100% (n = 2) for the no-, first-, second-, and third-dose groups, respectively (p for trend = 0.09). The mumps infection prevalence rates were 69.8% (n = 203), 11.3% (n = 28), 3.9% (n = 1), and 0% for the no-, first-, second-, and third-dose groups, respectively. Conclusions: Approximately 1 in 10 students who had received only one dose of mumps-containing vaccine had a breakthrough infection history.

Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation.

The role that transforming growth factor-α (TGF-α) has in chronic pancreatitis and pancreatic cancer has not been fully elucidated. We evaluated the effects of TGF-α on the human pancreatic stellate cell (PSC) line RLT-PSC and primary human PSCs, and the expression levels of TGF-α and metalloproteinase-1 (MMP-1) in human chronic pancreatitis and pancreatic cancer tissues. TGF-α stimulated the proliferation and migration of PSCs. Although the mRNA expression levels of tissue inhibitor of metalloproteinase-1 and α1(I) collagen were unchanged, the mRNA expression levels of MMP-1 increased concomitant with increases in MMP-1 protein levels and collagenase activity. TGF-α-stimulated migration of RLT-PSC cells was partially blocked by tissue inhibitor of metalloproteinase-1 protein and MMP-1 small interfering RNA. MMP-1 was also observed to stimulate the migration of PSCs. TGF-α-induced MMP-1 expression was completely blocked by gefitinib in PSCs. The Ras-ERK and PI3/Akt pathways appear to be involved in the activation of MMP-1 in PSCs. Immunohistochemical analyses showed that MMP-1 expression was significantly increased in the pancreatic interstitial tissues in case of chronic pancreatitis or pancreatic cancer compared with those in case of normal pancreas. In conclusion, TGF-α increased proliferation and migration of PSCs. TGF-α-induced migration of cells may be partly due to upregulation of MMP-1. TGF-α and MMP-1 upregulation may contribute to the pathogenesis of chronic pancreatitis and pancreatic cancer.

Downregulation of programmed cell death 4 (PDCD4) in tumorigenesis and progression of human digestive tract cancers.

Nowadays, digestive tract cancers become the commonest neoplasia and one of the leading causes of cancer deaths worldwide. The development of diagnosis and therapy is urgently required. Programmed cell death 4 (PDCD4), a new tumor suppressor, has been documented to be a potential diagnostic tool and treatment target for neoplasia due to the inhabitation of tumor promotion/progression and metastasis. However, its role in human digestive tract cancers is few available up to now. In this study, we examined the expression of PDCD4 in human digestive tract cancers (61 gastric cancer, 65 colorectal cancer, and 69 pancreatic cancer patients) by Western blot analysis, reverse transcription (RT)-PCR, and immunohistochemistry. Western blot, RT-PCR, and immunohistochemistry examination showed that expressions of PDCD4 were significantly lower in cancers specimens than in noncancerous tissues. Among the different differentiated cancer tissues, PDCD4 expression was significantly lower in moderately or poorly differentiated cancers than in well-differentiated cancers (p < 0.05). Our findings suggested that PDCD4 might be a potentially valuable molecular target in diagnosis and therapy for human digestive tract cancers.

Severity of non-alcoholic steatohepatitis is associated with substitution of adipose tissue in skeletal muscle.

BACKGROUND AND AIMS: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is now focusing on its organ cross-talk with not only adipose tissue but also systemic skeletal muscle. Cross-sectional and longitudinal studies were conducted to determine the role of intramuscular adipose tissue content (IMAC) measured by computed tomography on the severity of NAFLD/non-alcoholic steatohepatitis (NASH). METHODS: Two hundred eight Japanese patients with NAFLD/NASH diagnosed by liver biopsy were enrolled into a cross-sectional study. Twenty-one patients were enrolled in a longitudinal study and received a programmed diet and exercise intervention, in some cases the combination of pharmacotherapy. We measured IMAC in the multifidus muscle and biochemical parameters, and conducted liver histology to assess NAFLD/NASH status. RESULTS: Histopathological stage in terms of simple steatosis and Brunt's classification was significantly correlated with IMAC (P < 0.01). Multivariate logistic regression analysis indicated that risk factors associated with the severity of NASH were IMAC and aging (IMAC: odds ratio = 2.444, P < 0.05; Age: odds ratio = 2.355, P < 0.05). The interventions improved histopathological changes in 11 patients with NASH as well as IMAC. CONCLUSION: These results suggest that skeletal muscle fat accumulation may have been linked to the pathogenesis and severity of NASH.

Survival advantage of radiofrequency ablation for hepatocellular carcinoma: comparison with ethanol injection.

BACKGROUND/AIMS: The aims of this study were to compare long-term prognosis of patients with hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI). METHODOLOGY: Two hundred and thirteen patients with HCC were initially treated with PEI or RFA at Saga University Hospital between 1990 and 2004. The present study included 190 patients: 98 treated with PEI from 1990 to 1999, and 92 with RFA from 2000 to 2004. The association of treatment method with survival prognosis was evaluated by multivariate analysis. RESULTS: There were no significant differences in gender, etiology, and tumor stage between the two groups. Five-year survival rate in the PEI group was 40% and 51% in the RFA group. According to tumor stage, there were no differences in 5-year survival rate between the two groups for tumor stage I and III. For stage II patients, RFA had better survival than PEI (48% vs. 28%, p = 0.03). Multivariate analysis indicated that RFA was more effective for long-term survival than PEI in patients with tumor stage II (p = 0.04). CONCLUSIONS: Compared to PEI, RFA improved survival in patients with stage II HCC, indicating a therapeutic advantage of RFA.

Induction of premature senescence and a less-fibrogenic phenotype by programmed cell death 4 knockdown in the human hepatic stellate cell line Lieming Xu-2.

Although programmed cell death 4 (PDCD4) was initially reported as a tumor suppressor and has been shown to inhibit cancer cell growth and metastasis, recent studies have demonstrated that loss of PDCD4 expression also induces growth inhibition by inducing apoptosis and/or cellular senescence. At present, the roles of PDCD4 in the activation and profibrogenic properties of myofibroblasts, which are critically involved in organ fibrosis, such as that in the liver, are unclear. We, therefore, investigated the roles of PDCD4 in myofibroblasts using human hepatic stellate cell line Lieming Xu-2 (LX-2). PDCD4 knockdown inhibited LX-2 proliferation and induced a senescent phenotype with increased ß-galactosidase staining and p21 expression in a p53-independent manner together with downregulation of the notch signaling mediator RBJ-κ/CSL. During PDCD4 knockdown, alpha smooth muscle actin (α-SMA; an activation marker of myofibroblasts), matrix metalloproteinases MMP-1 and MMP-9, and collagen IV were upregulated, but the expression of collagen1α1 and collagen III was markedly downregulated without any marked change in the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). These results demonstrated that knockdown of PDCD4 induced the cellular senescence phenotype and activated myofibroblasts while suppressing the profibrogenic phenotype, suggesting roles of PDCD4 in cellular senescence and fibrogenesis in the liver.

HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease.

There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima-media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.

Regulation of tumor suppressor PDCD4 by novel protein kinase C isoforms.

Transforming growth factor-beta1 (TGF-beta1) induces apoptosis in normal hepatocytes and hepatoma cells. PDCD4 is involved in TGF-beta1-induced apoptosis via the Smad pathway. The tumor promoter 12-O-tetradecanoylphorbor-13-acetate (TPA), a protein kinase C stimulator, inhibits TGF-beta1-induced apoptosis. However, the mechanisms of TPA action on PDCD4 expression remain to be elucidated. Therefore. the regulatory mechanism of PDCD4 expression by PKC was investigated. The treatment of the human hepatoma cell line, Huh7 with TPA suppressed PDCD4 protein expression and TGF-beta1 failed to increase the PDCD4 protein expression. PKC inhibitors Ro-31-8425 or bisindolylmaleimide-1-hydrocholoride (pan-PKC inhibitors) and rottlerin (PKCdelta inhibitor), but not Go6976 (PKCalpha inhibitor), enhanced the induction of PDCD4 protein by TGF-beta1. Furthermore, siRNA-mediated knockdown of PKCdelta and epsilon, but not PKCalpha, augmented the TGF-beta1-stimulated PDCD4 protein expression. However, TPA or pan-PKC inhibitor did not alter the PDCD4 mRNA expression either under basal- and TGF-beta1-treated conditions. The down-regulation of PDCD4 by TPA was restored by treatment with the proteasome inhibitor MG132. These data suggest that two isoforms of PKCs are involved in the regulation of the PDCD4 protein expression related to the proteasomal degradation pathway.

Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study.

BACKGROUND: Acoustic radiation force impulse (ARFI) is a new technology integrated into conventional B-mode ultrasonography. ARFI is used to evaluate tissue stiffness in several organs, but this method has not been applied for liver fibrosis. AIM: The aim of this study was to determine whether ARFI elastography is useful for the evaluation of liver fibrosis. METHODS: This study enrolled 55 consecutive patients with chronic liver disease who underwent a liver biopsy for histological assessment of liver fibrosis by the Metavir scoring system. Liver stiffness of the 55 patients and 25 healthy volunteers was evaluated by ARFI elastography and was expressed as the shear wave velocity. Cut-off values were determined using receiver-operating characteristic (ROC) curves. RESULTS: Histological liver fibrosis was evaluated by Metavir scoring; F0: six cases, F1: 14 cases, F2: nine cases, F3: nine cases and F4: 17 cases. Liver stiffness determined by ARFI elastography was correlated with histological liver fibrosis (P<0.0001). The areas under the ROC curves were 0.94 (95% confidence intervals, 0.87-0.99) for F2-F4, 0.94 (0.88-0.99) for F3-F4 and 0.96 (0.91-1.01) for F4. The cut-off values of the shear wave velocity were as follows: >1.34 m/s for F2-F4 (sensitivity 91.4%, specificity 80%); >1.44 m/s for F3-F4 (sensitivity 96.2%, specificity 79.3%); and >1.80 m/s for F4 (sensitivity 94.1%, specificity 86.8%). CONCLUSIONS: Ultrasonic ARFI elastography is a novel, non-invasive and reliable method for the assessment of liver fibrosis in patients with chronic liver disease.

Whole-body insulin sensitivity index is a highly specific predictive marker for virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients with genotype 1b and high viral load.

Insulin resistance is a candidate predictive factor for virological response to peginterferon plus ribavirin (PEG/RBV) therapy in chronic hepatitis C patients. We examined whether indices of insulin resistance could serve as a predictor of sustained virological response (SVR). Fifty-one patients with genotype 1b and high viral load who received PEG/RBV therapy for 48 weeks were included. Homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI) calculated from the 75-g oral glucose tolerance test and serum levels of soluble tumor necrosis factor receptor 2 (sTFNR2) were evaluated before therapy. Patients who achieved SVR had significantly lower HOMA-IR and sTNFR2 levels and a higher WBISI compared with non-SVR patients. The positive predictive value for SVR was 0.653 for a HOMA-IR of <2 and 0.846 for a WBISI of 6 or higher. WBISI may serve as a highly specific predictor for SVR in PEG/RBV therapy.