Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease.

AIM: As it is not practical to perform regular screening for hepatocellular carcinoma (HCC) in all patients with non-alcoholic fatty liver disease (NAFLD), there is a need to identify NAFLD patients who are at high risk for HCC. Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) has been shown to be a surrogate marker for predicting HCC as well as a liver fibrosis marker in patients with chronic hepatitis B and C. The aim of this study was to investigate whether WFA+ -M2BP predicts HCC development in NAFLD patients. METHODS: Serum WFA+ -M2BP was retrospectively measured in 331 patients with histologically proven NAFLD, 51 of whom developed HCC. The association of WFA+ -M2BP and HCC development in NAFLD patients was investigated. RESULTS: The WFA+ -M2BP values were significantly greater in NAFLD patients with HCC than in those without HCC among patients with liver fibrosis ≥stage 3. Multivariate analysis identified WFA+ -M2BP as one of the predictive factors for HCC development (odds ratio, 1.57; 95% confidence interval, 1.083-2.265; P = 0.017). The optimal cut-off index of WFA+ -M2BP for predicting HCC was 1.255 with specificity of 78.4% and sensitivity of 70.4%. The area under the receiver operating characteristic curve value for the prediction of HCC development was 0.806. The cumulative incidence rate of HCC was significantly greater in patients with WFA+ -M2BP ≥ 1.255 (n = 61) than in those with WFA+ -M2BP < 1.255 (n = 137) among patients who were followed up for more than 2 years after the diagnosis of NAFLD. CONCLUSIONS: Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts HCC development and is a useful surrogate marker for identifying NAFLD patients who are at a high risk for HCC.

Compliance and problems with the surveillance program for HCC diagnosis.

We conducted a multicenter retrospective study for evaluating the background of and diagnostic opportunity for 651 patients with primary hepatocellular carcinoma (HCC). The etiologies were hepatitis B virus (HBV) in 20.0% of patients, hepatitis C virus (HCV) in 36.3%, and non-B non-C (NBNC) in 43.5%. The characteristics of non-alcoholic NBNC HCC patients included low frequency of liver cirrhosis and high frequency of life style-related diseases. The mean diameter of HCC was approximately 4cm. Most patients were diagnosed using ultrasonography and dynamic computed tomography (CT). However, 18.6% of patients were diagnosed using conventional contrast-enhanced CT. Compliance with the surveillance program for HCC diagnosis was 35.4% in HBV carriers and 49.2% in HCV carriers. The main causes of deviation from the program included undiagnosed HBV and HCV carriers, non-compliance with the surveillance program by physicians, and no medical care for HBV and HCV carriers. For an early diagnosis of HCC, it is essential to improve the diagnoses of HBV and HCV carriers, promote the follow-ups of HBV and HCV carriers in hospitals, re-educate physicians, and identify the risk factors of NBNC HCC.

Renal shear wave velocity by acoustic radiation force impulse did not reflect advanced renal impairment.

AIM: Acoustic radiation force impulse is a noninvasive method for evaluating tissue elasticity on ultrasound. Renal shear wave velocity measured by this technique has not been fully investigated in patients with renal disease. The aim of the present study was to compare renal shear wave velocity in end-stage renal disease patients and that in patients without chronic kidney disease and to investigate influencing factors. METHODS: Renal shear wave velocities were measured in 59 healthy young subjects (control group), 31 subjects without chronic kidney disease (non-CKD group), and 39 end-stage renal disease patients (ESRD group). Each measurement was performed 10 times at both kidneys, and the mean value of eight of 10 measurements, excluding the maximum and minimum values, was compared. RESULTS: Renal shear wave velocity could be measured in all subjects. Renal shear wave velocity in the control group was higher than in the non-CKD group and in the ESRD group, and no difference was found between the non-CKD group and the ESRD group. Age and depth were negatively correlated to the renal shear wave velocity. In multiple regression analysis, age and depth were independent factors for renal shear wave velocity, while renal impairment was not. There was no difference between the non-CKD group and the ESRD group, even when ages were matched and depth was adjusted. CONCLUSION: Renal shear wave velocity was not associated with advanced renal impairment. However, it reflected alteration of renal aging, and this technique may be useful to detect renal impairment in the earlier stages.

Clinical usefulness of the ablative margin assessed by magnetic resonance imaging with Gd-EOB-DTPA for radiofrequency ablation of hepatocellular carcinoma.

BACKGROUND & AIMS: The aim of this study was to investigate the feasibility of ablative margin (AM) grading by magnetic resonance imaging (MRI) with Gd-EOB-DTPA administered prior to radiofrequency ablation (RFA), and to identify factors for achieving a sufficient AM and predictors for local tumor progression. METHODS: A total of 124 hepatocellular carcinomas (HCCs) were treated by RFA after Gd-EOB-DTPA administration. MRI and enhanced CT were performed within seven hours and one month after RFA. The AM assessment was categorized using three grades: AM (+), low-intensity area with continuous high-intensity rim; AM zero, low-intensity area with discontinuous high-intensity rim; and AM (-), low-intensity area extends beyond the high-intensity rim. Patients were followed and local tumor progression was observed. RESULTS: AM (+), AM zero, AM (-), and indeterminate were found in 34, 33, 26, and 31 nodules, respectively. The overall agreement rate between MRI and enhanced CT for the diagnosis of AM was 56.8%. The κ coefficient was 0.326 (p<0.001), indicating moderate agreement. Multivariate logistic regression analysis showed that a significant factor for the achievement of AM (+) on MRI was no contiguous vessels. The cumulative local tumor progression rates (0% at 1, 2, and 3 years) in 33 AM (+) nodules were significantly lower than those (3.6%, 11.5%, and 18.3% at 1, 2, and 3 years respectively) in 32 AM zero nodules. A multivariate Cox proportional hazards model identified tumor size as an independent predictor for local tumor progression. CONCLUSION: Gd-EOB-DTPA-MRI enabled an early assessment of RFA effectiveness in the majority ofHCC nodules. Local tumor progression was not detected in AM (+) nodules during the follow-up.

Modified BEST-J Score Model Predicts Bleeding after Endoscopic Submucosal Dissection with Fewer Factors.

This study constructed a simplified post-endoscopic submucosal dissection (ESD) prediction model with a prognostic nutritional index (PNI). A total of 449 patients who underwent gastric ESD was included, divided with a ratio of 2:1, and assigned to the model or validation cohort. A prediction model of post-ESD (modified BEST-J score) was constructed using the model cohort. The modified BEST-J score was evaluated by comparing its accuracy to the BEST-J score in the validation cohort. Within 4 weeks of ESD, melena, hematemesis, or a 2 g/dL or greater decrease in hemoglobin level that required esophagogastroduodenoscopy was defined as post-ESD bleeding. In the model cohort, 299 patients were enrolled and 25 (8.4%) had post-ESD bleeding. Independent risk factors for post-ESD bleeding were use of P2Y12RA, tumor size > 30 mm, location of lesion at lower one-third of the stomach, and PNI ≤ 47.9. Constructing the modified BEST-J score based on these variables, the sensitivity, specificity, and positive likelihood ratio were 73.9%, 78.1%, and 3.37. When comparing the modified BEST-J score to the BEST-J score in the validation cohort, no significant difference was observed by ROC-AUC (0.77 vs. 0.75, p = 0.81). Modified BEST-J score can predict post-ESD bleeding more simply, with the same accuracy as the BEST-J score.

Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. METHODS: Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. RESULTS: Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. CONCLUSIONS: Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.

Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model.

BACKGROUND: The options for the treatment of nonalcoholic steatohepatitis (NASH) are limited. We examined the effects of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on the fatty liver Shionogi (FLS)-ob/ob mice, a non-alcoholic steatohepatitis mouse model. METHODS: FLS-ob/ob male mice were treated with vehicle (n = 10) and ipragliflozin (n = 8). Serum metabolic markers, histopathology of the liver, hepatic cholesterol and triglyceride levels and hepatic mRNA levels related to fibrosis, lipid metabolism and endoplasmic reticulum (ER) stress were compared between the two groups. RESULTS: The body weight and hepatic cholesterol and triglyceride levels were significantly decreased in the ipragliflozin group compared with the control group. Hepatic steatosis and fibrosis were significantly ameliorated by the treatment with ipragliflozin. Hepatic infiltration of macrophage, expression levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and hepatic mRNA levels of ER stress markers were not significantly modulated by the treatment with ipragliflozin. CONCLUSION: Ipragliflozin can be a therapeutic option for patients with NASH. The precise mechanisms of action need to be clarified in future studies.

Gene Expression Analysis of the Activating Factor 3/Nuclear Protein 1 Axis in a Non-alcoholic Steatohepatitis Mouse Model.

BACKGROUND: Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a chronic liver disease related to metabolic syndrome that can progress to liver cirrhosis. The involvement of the endoplasmic reticulum (ER) stress response in NAFLD progression and the roles played by activating factor 3 (ATF3) and the downstream nuclear protein 1 (NUPR1) are poorly understood. The aim of this study was to determine the gene expression profiles around the ATF3/NUPR1 axis in relation to the development of NAFLD using novel mouse models. METHODS: Fatty liver Shionogi (FLS) mice (n = 12) as a NAFLD model and FLS-ob/ob mice (n = 28) as a NASH model were fed a standard diet. The FLS mice were sacrificed at 24 weeks of age as a control, whereas the FLS-ob/ob mice were sacrificed at 24, 36, and 48 weeks of age. Hepatic steatosis, inflammation, and fibrosis were evaluated by biochemical, histological, and gene expression analyses. The expression levels of the ER-stress related genes Jun proto-oncogene (C-jun), Atf3, Nupr1, and C/EBP homologous protein (Chop) were measured in liver tissue. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. RESULTS: Control mice demonstrated hepatic steatosis alone without apparent fibrosis. On the other hand, FLS-ob/ob mice showed severe steatohepatitis at both 24 and 36 weeks of age and severe fibrosis at both 36 and 48 weeks of age. The expression levels of Atf3, Nupr-1, and C-jun significantly increased from 24 to 48 weeks of age in FLS-ob/ob mice compared with control mice. The expression level of Chop was already high in FLS mice and maintained similar levels in FLS-ob/ob mice; the expression level was consistent with the percentage of TUNEL-positive cells. CONCLUSION: The ATF3/NUPR1 axis plays a pivotal role in NASH progression in association with C-jun and Chop and appears to induce apoptosis from early steatosis in the NASH model mice.

Two patterns of contrast-enhanced ultrasonography with Sonazoid® in spontaneous rupture of hepatocellular carcinoma: a report of four cases.

Spontaneous rupture is a life-threatening complication of hepatocellular carcinoma (HCC). Detecting active bleeding is critical. Color Doppler and contrast-enhanced ultrasonography (CEUS) with Levovist® are reported to be useful for detecting active bleeding. A few reports have described using Sonazoid® to detect bleeding in ruptured HCC. This report describes two distinctive patterns of bleeding from ruptured HCC observed in CEUS with Sonazoid®. Four patients with suspected HCC rupture were examined by gray-scale ultrasonography (US) and then CEUS with Sonazoid®. Two patterns of bleeding were observed with CEUS: jet-like extravasation (n = 2) and bubble leakage (n = 2). While contrast-enhanced computed tomography and angiography revealed active bleeding in only one patient, CEUS detected active bleeding and enabled the bleeding site to be estimated in all patients. Transcatheter arterial embolization was performed based on the findings of CEUS, and hemostasis was achieved in all patients. CEUS using Sonazoid® could demonstrate active bleeding as two patterns, and these findings enabled us to detect the rupture site of HCC more confidently than with other modalities.

Falsely Elevated Serum Vitamin B12 Levels Were Associated with the Severity and Prognosis of Chronic Viral Liver Disease.

BACKGROUND: Vitamin B12 is stored primarily in the liver, and highly elevated serum vitamin B12 levels occur in acute hepatitis and severe alcoholic liver disease. We evaluated the relationship between vitamin B12 levels and liver disease severity and long term prognosis in patients with chronic viral hepatitis and cirrhosis. METHODS: We enrolled 90 patients (57 men, 33 women) with chronic viral hepatitis and cirrhosis who admitted to our hospital as a prospective cohort study. Overall, 37 patients had chronic hepatitis and 53 had cirrhosis (Child-Pugh A 33, B 13, and C 7); 57 patients had primary liver cancer. Serum vitamin B12 concentration and holotranscobalamin (holoTC) II (active form of vitamin B12) were determined and followed prospectively for at least 5 years. RESULTS: Mean total serum vitamin B12 concentration was significantly higher in Child-Pugh C (1308 ± 599 pg/mL) compared to those with chronic hepatitis (655 ± 551 pg/mL), Child-Pugh A (784 ± 559 pg/mL), and Child-Pugh B (660 ± 464 pg/mL) (P = 0.036) Presence of primary liver cancer also influenced serum vitamin B12 levels [657 (167-2956) vs. 432 (189-2956); P = 0.015]. Patients were divided into quartiles by vitamin B12 level. Patients without primary liver cancer in quartile 4 (≥ 880 pg/mL) demonstrated significantly poorer prognosis than those in quartiles 1-3 (< 880 pg/mL) (P = 0.023). The percentage of holohaptocorrin (holoHC) [(total vitamin B12 - holoTC II) × 100] was significantly higher in Child-Pugh B and C 86 (80-87)% than chronic hepatitis and Child-Pugh A 77 (31-89)% (P = 0.006) Multivariate analysis indicated serum vitamin B12 levels (HR = 1.001, P = 0.029) as a prognostic factor. CONCLUSION: Falsely elevated serum vitamin B12 levels mainly composed of increased holoHC were associated with severity (Child-Pugh C and primary liver cancer) and prognosis in chronic viral liver disease.

Serum Procalcitonin in Patients with Acute Liver Failure.

BACKGROUND: Procalcitonin (PCT) is a known diagnostic marker of bacterial infection. There are no previous reports of PCT concerning acute liver failure (ALF). We evaluated the clinical value of serum PCT levels in patients with ALF. METHODS: Forty-four patients with acute hepatitis (19 men and 25 women; median age, 40 years; range, 20-79 years) were retrospectively enrolled from January 2001 and June 2015. PCT levels were measured by saved serum samples obtained within 3 days after admission. ALF was defined as prothrombin time (PT) < 40% regardless of hepatic encephalopathy. RESULTS: Serum PCT levels were significantly higher in the patients with ALF (n = 16) than in those with non-ALF (n = 28) [0.25 (0.13-2.66) ng/mL vs. 0.165 (0.03-1.08), P = 0.00967]. Creatinine, total bilirubin, and direct bilirubin were positively correlated, and PT was negatively correlated with PCT. Receiver operating characteristic curve analysis showed an area under the curve of 0.74 for detecting ALF. With a PCT cut-off value of 0.5 ng/mL, the presence of ALF could be demonstrated with low sensitivity (37.5%) and high specificity (96.5%) with high positive (85.7%) and negative (72.9%) predictive value. Multivariate analysis showed that PCT was an independent factor associated with the presence of ALF. The cumulative survival rate was also significantly lower in patients with PCT ≥ 0.5 ng/mL (P = 0.0314), but it was not an independent prognostic factor. CONCLUSION: Serum PCT level was significantly higher in patients with ALF.

Utility of virtual touch quantification in the diagnosis of pancreatic ductal adenocarcinoma.

This study aimed to compare the tissue stiffness of pancreatic ductal adenocarcinoma (PDAC) with that of pancreatic parenchyma using virtual touch quantification (VTQ). SWV was measured in 34 PDAC lesions and in pancreatic parenchyma of both controls and patients. SWVs in PDAC lesions were significantly higher than in pancreatic parenchyma in both healthy controls and in patients with PDAC. The area under the ROC for diagnosis of PDAC was 0.94 for pancreatic parenchyma in healthy controls, and 0.85 for pancreatic parenchyma in patients with PDAC. VTQ can provide a useful and additional information for diagnosis of PDAC.

A Series of microRNA in the Chromosome 14q32.2 Maternally Imprinted Region Related to Progression of Non-Alcoholic Fatty Liver Disease in a Mouse Model.

BACKGROUND & AIMS: Simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) are subtypes of non-alcoholic fatty liver disease (NAFLD), and the pathogenic differences between SS and NASH remain unclear. MicroRNAs (miRNAs) are endogenous, non-coding, short RNAs that regulate gene expression. The aim of this study was to use animal models and human samples to examine the relationship between miRNA expression profiles and each type of NAFLD (SS and NASH). METHODS: DD Shionogi, Fatty Liver Shionogi (FLS) and FLS ob/ob mice were used as models for normal control, SS and NASH, respectively. Microarray analysis and real-time PCR were used to identify candidate NAFLD-related miRNAs. Human serum samples were used to examine the expression profiles of these candidate miRNAs in control subjects and patients with SS or NASH. RESULTS: Fourteen miRNAs showed clear expression differences among liver tissues from SS, NASH, and control mice with good reproducibility. Among these NAFLD candidate miRNAs, seven showed similar expression patterns and were upregulated in both SS and NASH tissues; these seven candidate miRNAs mapped to an miRNA cluster in the 14q32.2 maternally imprinted region delineated by delta-like homolog 1 and type III iodothyronine deiodinase (Dlk1-Dio3 mat). Software-based predictions indicated that the transforming growth factor-ß pathway, insulin like growth factor-1 and 5' adenosine monophosphate activated protein kinase were potential targets of theses Dlk1-Dio3 mat NAFLD candidate miRNAs. In addition, serum samples from patients with SS or NASH differed markedly with regard to expression of the putative Dlk1-Dio3 mat miRNAs, and these differences accurately corresponded with NAFLD diagnosis. CONCLUSION: The expression profiles of seven miRNAs in 14q32.2 mat have high potential as biomarkers for NAFLD and for improving future research on the pathogenesis and treatment of NASH.

Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model.

AIM: To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model. METHODS: Fatty liver shionogi (FLS) FLS-ob/ob mice (male, 12 wk old) received ambrisentan (2.5 mg/kg orally per day; n = 8) or water as a control (n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver. RESULTS: In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group (18.0 µg/g ± 6.1 µg/g vs 33.9 µg/g ± 13.5 µg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group (0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related mRNA expression in the liver were not significantly different between the groups. CONCLUSION: Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.

Left Renal Cortical Thickness Measured by Ultrasound Can Predict Early Progression of Chronic Kidney Disease.

AIMS: The kidney becomes atrophic in advanced chronic kidney disease, and renal size and parenchymal volume correlate with renal function. However, alterations in renal parenchymal volume have not been adequately studied in terms of the renal cortex and medulla. We investigated the relationship between the changes in the renal cortex and medulla and renal function. METHODS: Renal ultrasound (US) parameters including renal length, parenchymal thickness, cortical thickness and medullary thickness were assessed in 176 subjects, who were categorized into 4 groups based on the estimated glomerular filtration rate (ml/min/1.73 m2): group 1, ≥ 90; group 2, ≥ 60 but < 90; group 3, ≥ 30 but < 60; and group 4, < 30. Renal US parameters in both kidneys were compared among the 4 groups. RESULTS: We found stepwise associations in renal length, cortical thickness and parenchymal thickness with decreased renal function. Medullary thickness showed no changes among groups 1-3. Multiple linear regression analysis including sex, age and renal US parameters showed that only renal length was an independent predictor of renal function. When analyzed in groups 1-3, cortical thickness was the strongest associated parameter. Lower cortical left/right ratio (left cortical thickness/right cortical thickness) showed a stepwise association with a decrease in renal function. CONCLUSION: Renal length and cortical thickness measured by US were correlated with renal function. In particular, left cortical thickness could help to detect early changes in renal function.

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice.

Non-alcoholic steatohepatitis is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The dipeptidyl peptidase­IV enzyme is important in glucose metabolism, as well as lipid accumulation, extracellular matrix metabolism and immune stimulation. Furthermore, the enzyme activity of dipeptidyl peptidase­IV is known to be increased in non­alcoholic steatohepatitis. Therefore, dipeptidyl peptidase­IV inhibitors are potential therapeutic agents for non­alcoholic steatohepatitis. The present study assessed the therapeutic effects of sitagliptin, a dipeptidyl peptidase­IV inhibitor, on non­alcoholic steatohepatitis using fatty liver Shionogi­ob/ob male mice. Sitagliptin (2 mg/kg/day; n=10) or placebo (control; n=10) was orally administered to fatty liver Shionogi­ob/ob mice for 12 weeks, and hepatic steatosis, fibrosis, inflammation and oxidative stress were assessed in comparison with the controls. Sitagliptin administration reduced body weight and blood glucose levels, and improved hepatic fibrosis. It also inhibited the gene expression levels of fatty acid synthase, transforming growth factor­ß1, tissue inhibitor of metalloproteinases­1, procollagen­type 1, tumor necrosis factor­α, monocyte chemoattractant protein­1 and enhanced peroxisome proliferator activated receptor­α. Furthermore, a marked attenuation of hepatic stellate cell activation and Kupffer cells was observed in the sitagliptin group. A decrease in oxidative stress and apoptosis was also observed. Sitagliptin attenuated the progression of hepatic fibrosis by improving lipid metabolism, inflammation and oxidative stress in non-alcoholic steatohepatitis.

Rapid and early α-fetoprotein and des-γ-carboxy prothrombin responses to initial arterial infusion chemotherapy predict treatment outcomes of advanced hepatocellular carcinoma.

The aim of the present study was to predict the effects of transarterial infusion (TAI) chemotherapy based on early changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) in patients with advanced hepatocellular carcinoma (HCC). Seventy-four patients who underwent TAI with cisplatin, 5-fluorouracil, mitomycin C and epirubicin for advanced HCC were enrolled. Antitumor responses were evaluated 6 months after TAI. Rapid and early responses were defined as the ratio of AFP or DCP after 1 week and 1 month compared to baseline. A total of 5, 10, 17 and 42 patients had complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), respectively. Early AFP response was significantly lower in the CR+PR compared to the SD+PD groups (P<0.01). The early DCP response was significantly lower in the CR+PR compared to the SD+PD. The sensitivity and specificity of rapid and early AFP responses in the CR+PR were 0.78 and 0.72, and 0.80 and 0.73, respectively, and those of rapid and early DCP responses were 0.67 and 0.65, and 0.77 and 0.71, respectively. The combination of AFP and DCP responses had higher specificity compared to AFP or DCP alone responses. Patients were divided into responder and non-responder groups to evaluate the prediction of survival outcome. Early responders of AFP, DCP and AFP+DCP, who were divided based on the cut-off values of CR+PR survived significantly longer than the non-responders (P<0.05). In conclusion, rapid or early responses of AFP and/or DCP levels 1 and 4 weeks after TAI chemotherapy helped to predict the treatment effects.

Tonometric biosensor with a differential pressure sensor for chemo-mechanical measurement of glucose.

A tonometric biosensor for glucose was constructed using a chemo-mechanical reaction unit and a differential pressure sensor. The reaction unit was fabricated by using both liquid and gas cells separated by an enzyme diaphragm membrane, in which glucose oxidase was immobilized onto the single (gas cell) side of the dialysis membrane. By applying glucose solution (0, 25.0, 50.0, 100, 150 and 200 mmol/l) into the liquid cell of the chemo-mechanical reaction unit, the pressure in the gas cell decreased continuously with a steady de-pressure slope because the oxygen consumption in the gas cell was induced by the glucose oxidase (GOD) enzyme reaction at the enzyme side of the porous diaphragm membrane. The steady de-pressure slope in the gas cell showed the linear relationship with the glucose concentration in the liquid cell between 25.0 and 200.0 mmol/l (correlation coefficient of 0.998). A substrate regeneration cycle coupling GOD with l-ascorbic acid (AsA: 0, 1.0, 3.0, 10.0 and 50.0 mmol/l; as reducing reagent system) was applied to the chemo-mechanical reaction unit in order to amplify the output signal of the tonometric biosensor. 3.0 mmol/l concentration of AsA could optimally amplify the sensor signal more than 2.5 times in comparison with that of non-AsA reagent.