Results of a phase 4 trial of tacrobell® in liver transplantation patients: a multicenter study in South Korea

Background/Aims: This 26-week pilot study was performed in de novo liver transplant recipients to evaluate the efficacy of tacrobell capsule as an immunosuppressant drug after living donor liver transplant patients by determining the rate of acute cellular rejection after its use and evaluating its safety after transplantation. Methodology: From October 2005 to July 2007, 57 patients from four major medical centers in Seoul, South Korea were enrolled in the study. This open-label, noncomparative, multicenter pilot study lasted 26 weeks and assigned patients to receive tacrobell and corticosteroid after liver transplantation. Tacrobell (0.05mg/ kg/day, bid) and methylprednisolone were injected either on the day of the operation or on postoperative day one. A retrospective matched control group consisting of living donor liver transplant recipients at one center (Asan medical center) was used for comparison. Results: The rate of acute cellular rejection with tacrobell after 26 weeks of administration was 0.0% (95% CI, 0.0%-6.27%), which was below our hypothesized 36%. The most common drug-related adverse events included endocrine/nutritional disorders followed by gastrointestinal and hepatobiliary disorders. No patients died during the study period. The side effect profile of this drug was no different than other tacrolimus based immunosuppressants. Conclusions: Although our study was based on a low risk population and had a shortterm follow up, we conclude that tacrobell, as a generic tacrolimus, can be considered safe and effective in liver transplant patients.     

ISN/RPS 2003 class II mesangial proliferative lupus nephritis: a comparison between cases that progressed to class III or IV and cases that did not

Lupus nephritis (LN) class II has generally been considered a mild form of LN with a good response to treatment. Although the number was small, there have also been reports on later progression to class III or IV, resulting in poor renal and patient outcome. This study aims to review cases of LN class II to analyze differences between cases that progressed to class III or IV and cases that did not. We retrospectively analyzed 15 cases of LN class II among 277 cases of biopsy-proven lupus nephritis diagnosed in a tertiary medical center over about 14?years. Among the 15 patients, 5 patients progressed to class III or IV. Biopsy specimens were reviewed by a pathologist according to the ISN/RPS 2003 classification. Response to treatment was evaluated at 6?months after treatment. On fluorescence microscopy (IF), there was significantly higher degree of deposition in the glomeruli of IgM, IgA and C4 in the progression group than in the non-progression group. At 6?months after treatment, there was a trend toward higher rates of complete remission in the non-progression group (90%) compared with those in the progression group (40%, p?=?0.077). Five of the 15 cases of ISN/RPS 2003 class II glomerulonephritis progressed to class III or IV over a mean of 5?years. The degree of immune-complex deposition for IgM, IgA and C4 in the glomeruli was significantly higher in the progression group.     

Adipose-derived stem cells on the healing of ischemic colitis: a therapeutic effect by angiogenesis

Background

There has been no specific treatment for ischemic colitis. We verified the effects of adipose-derived stem cells (ASCs) on ischemia-induced colitis in a rat model.

Methods

Forty male Sprague–Dawley rats (10?weeks old; weight, 350?±?20?g) were divided into two groups: a control group (only fibrinogen and thrombin injected, n?=?20) and an ASC group (local implantation of ASCs mixed with thrombin and fibrinogen, n?=?20). An ischemic colitis model was established by modifying Nagahata's methods with double-blind randomization. ASCs (1?×?10⁶ cells) were implanted intramurally into the ischemic area using a fibrin glue mixture. The severity of adhesion, degree of ileus, the number and size of the ulcers, Wallace macroscopic and microscopic scores, and microvascular density were measured.

Results

The degree of ileus was significantly lower, and significantly fewer and smaller ulcerations were found in the ASC group than those in the control group. Wallace macroscopic and microscopic scores were lower in the ASC group than in the control group (1.90?±?1.22 versus 3.25?±?1.83, p?<?0.01 and 1.55?±?1.88 versus 2.84?±?1.89, p?<?0.05, respectively). Microvascular density was higher in the ASC group than in the control (54.45?±?19.45 versus 26.54?±?13.14, p?<?0.01, respectively).

Conclusions

Local implantation of ASCs into an ischemic-injured colonic wall reduced the grade of ischemic injury and enhanced tissue healing by promoting angiogenesis.     

Histone deacetylase 6 functions as a tumor suppressor by activating c-Jun NH2-terminal kinase-mediated beclin 1-dependent autophagic cell death in liver cancer

Ubiquitin-binding histone deacetylase 6 (HDAC6) is uniquely endowed with tubulin deacetylase activity and plays an important role in the clearance of misfolded protein by autophagy. In cancer, HDAC6 has become a target for drug development due to its major contribution to oncogenic cell transformation. In the present study we show that HDAC6 expression was down-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients, and that low expression of HDAC6 was significantly associated with poor prognosis of HCC patients in 5-year overall, disease-free, and recurrence-free survival. Notably, we observed that ectopic overexpression of HDAC6 suppressed tumor cell growth and proliferation in various liver cancer cells, and elicited increased LC3B-II conversion and autophagic vacuole formation without causing apoptotic cell death or cell cycle inhibition. In addition, the sustained overexpression of HDAC6 reduced the in vivo tumor growth rate in a mouse xenograft model. It was also found that HDAC6 mediated autophagic cell death by way of Beclin 1 and activation of the LC3-II pathway in liver cancer cells, and that HDAC6 overexpression activated c-Jun NH2-terminal kinase (JNK) and increased the phosphorylation of c-Jun. In contrast, the induction of Beclin 1 expression was blocked by SP600125 (a specific inhibitor of JNK) or by small interfering RNA directed against HDAC6. CONCLUSION: Our findings suggest that loss of HDAC6 expression in human HCCs and tumor suppression by HDAC6 occur by way of activation of caspase-independent autophagic cell death through the JNK/Beclin 1 pathway in liver cancer and, thus, that a novel tumor suppressor function mechanism involving HDAC6 may be amenable to nonepigenetic regulation.     

Sixty-five gene-based risk score classifier predicts overall survival in hepatocellular carcinoma

Clinical application of the prognostic gene expression signature has been delayed due to the large number of genes and complexity of prediction algorithms. In the current study we aimed to develop an easy-to-use risk score with a limited number of genes that can robustly predict prognosis of patients with hepatocellular carcinoma (HCC). The risk score was developed using Cox coefficient values of 65 genes in the training set (n = 139) and its robustness was validated in test sets (n = 292). The risk score was a highly significant predictor of overall survival (OS) in the first test cohort (P = 5.6 × 10(-5), n = 100) and the second test cohort (P = 5.0 × 10(-5) , n = 192). In multivariate analysis, the risk score was a significant risk factor among clinical variables examined together (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = 0.001 for OS). CONCLUSION: The risk score classifier we have developed can identify two clinically distinct HCC subtypes at early and late stages of the disease in a simple and highly reproducible manner across multiple datasets.     

Nonalcoholic fatty liver disease is associated with coronary artery calcification

Nonalcoholic fatty liver disease (NAFLD) is related to risk factors of coronary artery disease, such as dyslipidemia, diabetes, and metabolic syndrome, which are closely linked with visceral adiposity. The aim of this study was to investigate whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis independent of computed tomography (CT)-measured visceral adiposity. Out of 5,648 subjects who visited one of our health screening centers between 2003 and 2008, we enrolled 4,023 subjects (mean age, 56.9 ± 9.4 years; 60.7% males) without known liver disease or a history of ischemic heart disease. CAC score was evaluated using the Agatston method. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein cholesterol, triglycerides, and increased risk of diabetes, hypertension, smoking, and NAFLD. Increasing CAC scores (0, <10, 10-100, ≥ 100) were associated with higher prevalence of NAFLD (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.61-2.10; P<0.001). Multivariable ordinal regression analysis was adjusted for traditional risk factors, and CT-measured visceral adipose tissue area in a subgroup of subjects showed that the increased CAC scores were significantly associated with the presence of NAFLD (OR, 1.28, 95% CI, 1.04-1.59; P = 0.023) independent of visceral adiposity. CONCLUSION: Patients with NAFLD are at increased risk for coronary atherosclerosis independent of classical coronary risk factors, including visceral adiposity. These data suggest that NAFLD might be an independent risk factor for coronary artery disease.     

Factors predicting therapeutic efficacy of combination treatment with sitagliptin and metformin in type 2 diabetic patients: the COSMETIC study

Objective We assessed the predictive parameters for therapeutic efficacy of initial combination therapy with sitagliptin and metformin in drug‐naïve type 2 diabetic patients. Design, Patients, and Measurements In this 52‐week treatment study, 150 patients (mean age, 54·9 ± 12·5 years) with type 2 diabetes and HbA1c of 7·0–10% were treated with sitagliptin 100 mg once and metformin 500 mg twice daily. To assess the predictive parameters for therapeutic efficacy, a multivariate regression analysis was performed with baseline fasting glucose, insulin, C‐peptide, and glucagon levels, homoeostasis model assessment‐insulin resistance (HOMA‐IR) and β‐cell function (HOMA‐B), insulinogenic index (IGI, defined as 30–0 min insulin/30–0 min glucose), and area under the curve for glucose, insulin, and C‐peptide obtained after 75‐g oral glucose tolerance test. Results After 52 weeks, mean HbA1c levels and fasting and postload 2‐h glucose were significantly decreased from 8·7 ± 1·4% to 7·2 ± 1·3%, 9·2 ± 3·0 to 7·2 ± 1·8 mm , and 17·5 ± 5·1 to 10·9 ± 3·6 mm , respectively (P < 0·01). HOMA‐B and IGI increased significantly from 50·3 ± 33·5 to 75·1 ± 32·8 and from 11·3 ± 1·3 to 35·0 ± 6·3 at 52 weeks, respectively (P < 0·01). Multivariate regression analysis indicated that the reduction in HbA1c was significantly associated with high baseline HbA1c, low IGI, and short duration of diabetes after adjusting for age, sex, body mass index, blood pressure, triglycerides, creatinine, high‐sensitivity CRP, glucagon, C‐peptide, HOMA‐B, and HOMA‐IR. No severe adverse events were observed. Conclusion These results suggest that drug‐naïve type 2 diabetic patients with low β‐cell function would benefit the most from early initial combination therapy of sitagliptin and metformin.