The influence of recipient SLCO1B1 rs2291075 polymorphism on tacrolimus dose-corrected trough concentration in the early period after liver transplantation.

PURPOSE: To explore the relationship between rs2291075 polymorphism in SLCO1B1 gene, which encodes an influx transmembrane protein transporter, and tacrolimus dose-corrected trough concentration (C/D, ng ml-1 mg-1 kg-1) in the early period after liver transplantation. METHODS: CYP3A5 rs776746 and SLCO1B1 rs2291075 polymorphisms of 210 liver transplantation patients and their corresponding donor livers were assessed by PCR amplification and DNA sequencing. The influence of gene polymorphisms on C/D values of tacrolimus was analyzed. The early postoperative period after liver transplantation was divided into the convalescence phase (1-14 days) and stationary phase (15-28 days) according to the change of liver function and tacrolimus C/D values. RESULTS: The combined analysis of donor and recipient CYP3A5 rs776746 could distinguish the metabolic phenotype of tacrolimus into three groups: fast elimination (FE), intermediate elimination (IE), and slow elimination (SE), which was entitled the FIS classification system. Tacrolimus C/D ratios of recipient SLCO1B1 rs2291075 CT and TT carriers were very close and were significantly lower than those of recipient SLCO1B1 rs2291075 CC genotype carriers in convalescence phase (p = 0.0195) and in stationary phase (p = 0.0152). There were no statistically significant differences between tacrolimus C/D ratios of patients carried with SLCO1B1 rs2291075 CT, TT genotype donors, and those carried with SLCO1B1 rs2291075 CC genotype donors. A model consisting of tacrolimus daily dose, total bilirubin, FIS classification, and recipient SLCO1B1 rs2291075 could predict tacrolimus C/D ratios in the convalescence phase by multivariate analysis. However, recipient SLCO1B1 rs2291075 genotype failed to enter forecast model for C/D ratios in stationary phase. Recipient SLCO1B1 rs2291075 genotype had significant effect on tacrolimus C/D ratios in convalescence phase (p = 0.0300) and stationary phase (p = 0.0400) in subgroup, which excluded the interference come from donor and recipient CYP3A5 rs776746. CONCLUSION: SLCO1B1 rs2291075 could be a novel genetic locus associated with tacrolimus metabolism. The combined analysis of donor and recipient CYP3A5 rs776746, recipient SLCO1B1 rs2291075 genotypes, could be helpful to guide the personalized administration of tacrolimus in early period after liver transplantation.

Postoperative serum triglyceride levels in predicting risk of new-onset diabetes mellitus in patients following liver transplantation.

To investigate the postoperative serum triglyceride (TG) levels in predicting the risk of new-onset diabetes mellitus (NODM) in patients following allogeneic liver transplantation. One hundred and forty three patients undergoing allogeneic liver transplantation in Shanghai General Hospital from July 2007 to July 2014 were enrolled in this study. The NODM developed in 33 patients after liver transplantation. The curve of dynamic TG levels in the early period after liver transplantation was generated. Independent risk factors of NODM were determined by univariate and multivariant logistic regression analyses. The clinical value of TG in predicting NODM was analyzed by area under the ROC curve (AUC). Serum TG levels were gradually rising in the first week and then reached the plateau phase (stable TG, sTG) in patients after surgery. The sTG in NODM group were significantly higher than that in non-NODM group (=-2.31, <0.05). Glucocorticoid therapy (=4.054, <0.01), FK506 drug concentration in the first week after operation (=3.482, <0.05) and sTG (=3.156, <0.05) were independent risk factors of NODM. ROC curve analysis showed that the AUC of sTG in predicting NODM was 0.72. TG shows a gradual recovery process in the early period after liver transplantation, and the higher TG level in stable phase may significantly increase the risk of NODM in patients.

Association of donor small ubiquitin-like modifier 4 rs237025 genetic variant with tacrolimus elimination in the early period after liver transplantation.

BACKGROUNDS & AIMS: Individualized tacrolimus treatment can improve drug safety and efficacy. In this study, we aimed to investigate the association of donor and recipient small ubiquitin-like modifier 4 (SUMO4) rs237025 polymorphisms with tacrolimus elimination and the potential mechanism. METHODS: A total of 297 liver transplant patients were enrolled in the study. CYP3A5 rs776746 and SUMO4 rs237025 were genotyped using TaqMan SNPs assays. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase assay. The expressions of CYP3A5 were detected by qRT-PCR and western blotting. RESULTS: Tacrolimus C/D ratios was significantly lower for donor SUMO4 rs237025 AA carriers than AG/GG carriers at weeks 1, 2, 3. In multivariate analysis, donor and recipient CYP3A5 rs776747, donor SUMO4 rs237025 and total bilirubin were independent predictors of tacrolimus C/D ratios in the early post-transplantation period both in Cohort A and Cohort B. When combined donor CYP3A5 rs776746 and donor SUMO4 rs237025 genotypes, tacrolimus C/D ratios was highly significant at all investigated time points within the four groups. CYP3A5 mRNA expression in liver tissues was significantly higher for AA carriers than AG/GG patients under inflammatory stimuli after liver transplantation (LT). Furthermore, we demonstrated that SUMO4 rs237025 G allele could increase NF-κB transcriptional activity under inflammatory condition. And activation of NF-kB suppressed the expression of pregnane X receptor (PXR)-mediated CYP3A5 gene. CONCLUSIONS: Donor SUMO4 rs237025 genetic variant was associated with higher Tac C/D ratios in the early period after LT, which might be related to the down-regulation of CYP3A5 enzyme through the NF-kB signalling pathway.

Overexpression of DBC1, correlated with poor prognosis, is a potential therapeutic target for hepatocellular carcinoma.

Deleted in Breast Cancer 1 (DBC1) is a regulatory protein involved in cell metabolism and cancer progression. Nevertheless, the expression and prognostic values of DBC1 in hepatocellular carcinoma (HCC) are still not well understood. The following study investigated the clinical significance and biological function of DBC1 in HCC. Briefly, overexpression of DBC1 at transcriptional and translational levels in human HCC tissues compared to adjacent normal tissues was observed using quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB) and immunohistochemistry (IHC) approach. Furthermore, upregulated DBC1 was significantly correlated with tumor size (p = 0.005), N stage (p = 0.016), M stage (p = 0.011), tumor differentiation (p < 0.001), and American Joint Committee on Cancer (AJCC) stage (p = 0.001). Moreover, Kaplan-Meier survival analysis revealed that DBC1 was an independent prognosis predictor for disease-free survival (DFS) (p < 0.001) and overall survival (OS) (p < 0.001). In addition, by using Cell Counting Kit-8 (CCK8) assays and colony formation assays, we found that the knockdown of DBC1 significantly suppressed the proliferation of HCC cells in vitro. To conclude, these findings demonstrated that DBC1 was essential in tumorigenesis and proliferation. Moreover, it was identified as a potential therapeutic target for HCC.

Association between donor and recipient Interleukin-18 gene polymorphisms and the risk of infection after liver transplantation.

PURPOSE: The purpose of this study was to retrospectively evaluate the association between Interleukin-18 (IL-18) gene polymorphisms of the donor and recipient in liver transplant patients with bacterial infections. METHODS: Five single nucleotide polymorphisms (SNPs) (rs7106524, rs5744247, rs1946518, rs549908 and rs187238) of the IL-18 gene from the donors were genotyped and their association with post-operative bacterial infections was evaluated in liver transplant patients (N=113). A second independent group of liver transplant patients from a different organ transplant centre was also recruited for validation purposes (N=44). RESULTS: IL-18 mRNA mean expression levels and protein levels were significantly lower in liver transplant patients with bacterial infections. For the donor SNP rs1946518, more recipients carried the A allele in the bacterial-infected group than the uninfected group (61.4% vs 39.7%; P ≤0.002). The mean IL-18 mRNA expression and protein levels were significantly lower in the transplanted livers of recipients carrying the rs1946518 AA genotype compared with those from recipients with CC genotype (3.64, 3.33 vs. 2.75, P≤0.048). The A allele of rs1946518 also resulted in lower luciferase activity than the C allele in a reporter assay. The area under ROC curve indicated that the rs1946518 SNP genotype in the donor liver predicted an increased risk of bacterial infection after liver transplantation (AUROC>0.82). CONCLUSIONS: These findings indicate that the IL-18 rs1946518 SNP in the donor liver is a risk factor for developing bacterial infection after liver transplantation.

Analysis on curative effects and safety of 2% liranaftate ointment in treating tinea pedis and tinea corporis & cruris.

The paper is intended to analyze and evaluate the specific curative effect and safety of 2% liranaftate ointment in treating patients with tinea pedis and tinea cruris. 1,100 cases of patients with tinea pedis and tinea corporis & cruris were selected as research objects and were divided into two groups according to the random number table method. They were treated with different methods: 550 cases of patients were treated with 2% liranaftate ointment for external use in the observation group and the rest 550 cases of patients were treated with 1% bifonazole cream in the control group. The treatment time was two weeks for patients with tinea corporis & cruris and four weeks for those with tinea pedis respectively. Meanwhile, the one-month follow-up visit was conducted among the patients to compare the curative effects of two groups. After the medication, the curative effectiveness rate was 87.65% (482/550) in the observation group, while that was 84.91% (467/550) in the control group. After the average follow-up visits of (15.5±2.4), the curative effectiveness rate 96.55% (531/550) in the observation group, while that was 91.45% (503/550) in the control group. Two groups of patients recovered well with a low incidence of adverse reactions in the treatment, and the overall curative effect was good with the inter-group difference at P>0.05, so it was without statistical significance. The curative effect of 2% liranaftate ointment is safe and obvious in treating tinea pedis and tinea corporis & cruris, so it is valuable for clinical popularization and application.

Polymorphisms in epidermal growth factor receptor (EGFR) and AKT1 as possible predictors of clinical outcome in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.

This study aimed to investigate the association of epidermal growth factor receptor (EGFR) gene polymorphism and AKT1 polymorphism with the clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). The clinical outcome and the survival of NSCLC of 230 patients after treatment with EGFR-TKIs were measured. The rs712829, rs1468727 of the EGFR gene and rs1130214 of the AKT1 gene from peripheral blood cell were detected by a multiplexed single nucleotide polymorphism (SNP) MassEXTEND assay. The relationship between genetic polymorphisms and clinical outcomes of treatment with EGFR-TKIs was analyzed. The response rates and the disease control rate of patients with genotype GG, GT, and TT in EGFR rs712829 were statistically very significant difference(19.7 vs 36.1 vs 50.0 %, P = 0.016 and 57.7 vs 77.8 vs 83.3 %, P = 0.026, respectively). Better disease control was also achieved in patients with the GG genotype of AKT1 rs1130214 than those with the GT and TT genotypes (65.6 vs. 48.7 %, P = 0.043). Patients carrying the EGFR rs712829 TT genotype had significantly longer PFS and OS than those with the GT or GG genotypes (9.0 vs. 7.0 vs. 5.0 months, P = 0.001 and 13.1 vs. 14.6 vs. 18.8 months, P = 0.008, respectively). In addition, patients carrying the AKT1 rs1130214 GG genotype also had significantly longer PFS than those with the GT and TT genotypes (5.5 vs. 4.5 months, P = 0.008). EGFR rs712829 polymorphism and AKT1 rs1130214 could influence the response to EGFR-TKIs therapy in patients with advanced NSCLC.

Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target.

This study investigated the significance of La-related protein 1 (LARP1) in the development and progression of colorectal cancer (CRC). Quantitative real-time polymerase chain reaction and Western blot analyses were carried out to determine the mRNA and protein expression of LARP1 in CRC tumor tissues and paired adjacent normal mucosa. The expression of LARP1 was upregulated in CRC. Immunohistochemical analysis using tissue microarray was performed. A positive correlation between LARP1 and proliferating cell nuclear antigen (PCNA) in the area of proliferation was observed using the Spearman's correlation coefficient test (r = 0.332, P < 0.01). The elevated expression of LARP1 significantly correlated with T stage (P = 0.02), N stage (P = 0.006), M stage (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P = 0.04), differentiation rank (P < 0.001), and PCNA level (P < 0.001). In addition, the inhibitory effect of LARP1 knockdown on CRC cell proliferation was demonstrated using Cell Counting Kit-8 (CCK8) and colony-forming cell (CFC) assays. Multivariate analysis showed that LARP1 was an independent prognostic factor for overall survival (OS; hazard rate (HR) = 0.244; 95 % confidence interval (CI), 0.078-0.769; P = 0.016) and disease-free survival (DFS; HR = 0.281; 95 % CI, 0.086-0.917; P = 0.035) in CRC patients. LARP1 plays an important role in the proliferation of colorectal cancer and represents a new prognostic indicator.

Long-Term Outcomes of Simultaneous Liver-Kidney Transplant Patients with Hepatitis B Compared to with Liver Transplant Alone.

BACKGROUND: The number and survival rate of simultaneous liver-kidney transplant (SLKT) recipients have increased dramatically since 2002. However, the long-term effectiveness of SLKT in patients with hepatitis B is unknown. MATERIAL/METHODS: Forty-six patients who visited the Organ Transplant Center of the Shanghai First People's Hospital between January 2001 and May 2005 had hepatitis B virus infection and renal failure (any degree), and underwent organ transplantation: 21 patients underwent SLKT and 25 patients underwent liver transplant (LT) alone. RESULTS: The 1-, 3-, and 5-year survival rates of SLKT recipients were 90.5%, 81.0%, and 81.0%, respectively. Incidence of acute hepatic allograft rejection between SLKT recipients and LT recipients (33% vs. 16%) did not reach significance (P=0.170). Despite higher infection rate, more prevalent hepatitis B relapse, and longer stay in the intensive care unit, SLKT recipients experienced significantly higher 1-year survival rate (90.5%) compared with LT recipients (60%, P=0.019). Multivariate regression analysis revealed that postoperative renal failure (odds ratio (OR)=48, P=0.003) and Risk/Injury/Failure/Loss/End-stage (RIFLE) stage (OR=8, P=0.012) were independent risk factors for postoperative death after LT. CONCLUSIONS: SLKT in patients with hepatitis B had higher early-stage infection rate, but had a higher long-term survival rate compared with the LT group. Although the incidence of postoperative hepatitis B relapse in SLKT recipients was higher, timely and reasonable treatment can ensure long-term survival of patients. Worsening RIFLE stage of recipients can predict high mortality when only given LT. SLKT might be a better choice for RIFLE stage 2 or 3 patients than LT alone.

Donor interleukin 6 gene polymorphisms predict the recurrence of hepatocellular carcinoma after liver transplantation.

BACKGROUND: Application of the Milan criteria is an effective strategy to select patients with hepatocellular carcinoma (HCC) for liver transplantation, but HCC recurrence is still a major concern. The aim of this study was to determine whether interleukin 6 (IL6) polymorphisms and clinical variables are potential predictors for HCC recurrence and prognosis after transplantation. METHODS: A total of 110 consecutive patients with HCC undergoing liver transplantation were enrolled in the study. Six tag single nucleotide polymorphisms in IL6 were genotyped in both the donors and recipients. Demographic characteristics, HCC features, and IL6 polymorphisms were assessed against HCC recurrence. RESULTS: Pretransplant hepatitis B virus DNA (P = 0.014), pretransplant serum alpha-fetoprotein (P = 0.035), number of nodules (P = 0.011), diameter of main nodule (P = 0.001), macrovascular invasion (P = 0.001), microvascular invasion (P = 0.001), HCC exceeding the Milan criteria (P < 0.001), and donor rs2069852 AA genotype (P = 0.010) were associated with HCC recurrence. Recurrence-free survival rate and overall survival rate were significantly lower (P = 0.011 and P = 0.026, respectively) in patients whose donor had the rs2069852 AA genotype than in those whose donor had the AG and GG genotypes. Independent risk factors for recurrence-free survival and overall survival were microvascular invasion (P = 0.003; P = 0.002), HCC exceeding the Milan criteria (P < 0.001; P = 0.001), and donor rs2069852 AA genotype (P = 0.002; P = 0.010). CONCLUSIONS: Our data suggest that donor IL6 rs2069852 polymorphisms may be a potential genetic marker for HCC recurrence after liver transplantation in the Han Chinese population.

Variants Fok1 and Bsm1 on VDR are associated with the melanoma risk: evidence from the published epidemiological studies.

BACKGROUND: The vitamin D receptor (VDR) mediates the major cellular activities of vitamin D and regulates various signaling pathways implicated in cancer development and progression. VDR variants have been found associated with the risk of developing melanoma; however, previous epidemiological studies are inconsistent. We have systematically reviewed the published epidemiological literature and conducted a meta-analysis to assess associations between common VDR variants and melanoma risk. RESULTS: We identified 10 eligible studies that evaluated six VDR variants (Apa1, Bsm1, Cdx2, EcoRV, Fok1, and Taq1) in a total of 4,961 melanoma patients and 4,605 controls. The pooled estimates identified two variants-Fok1 and Bsm1-as significantly associated with melanoma risk, but not for the other four variants Apa1, Cdx2, EcorV and Taq1. For Fok1, the pooled OR was 1.18 (95% CI = 1.06-1.30; I(2) = 22%) for Ff vs. FF and 1.19 (95% CI = 1.01-1.41; I(2) = 0%) for ff vs. FF. The dominant genetic model suggested the allele f carriers showed an 18% (pooled OR = 1.18, 95% CI = 1.07-1.29; I(2) = 0%) increased risk for melanoma compared to homozygote FF. In contrast, the Bsm1 was found to be associated with a decreased risk for melanoma with the pooled OR was 0.85 (95% CI = 0.76-0.95; I(2) = 0%) for Bb vs. bb and 0.83 (95% CI = 0.68-1.00; I(2) = 28%) for BB vs. bb. Under the dominant genetic model, a 15% (pooled OR = 0.85, 95% CI = 0.76-0.94; I(2) = 0%) decrease of melanoma risk was found for those with BB or Bb genotype compared to those of bb genotype. CONCLUSIONS: The VDR variants Fok1 and Bsm1 may influence the susceptibility to developing melanoma, though further studies are needed to verify these conclusions.

Association between interleukin-18 promoter variants and tacrolimus pharmacokinetics in Chinese renal transplant patients.

PURPOSE: Interleukin 18 (IL-18) is a potent proinflammatory cytokine thought to down-regulate cytochrome P450 (CYP) enzyme activities. This study aimed to assess the potential influence of two functional single nucleotide polymorphisms (SNPs) in the IL-18 promoter region on the tacrolimus pharmacokinetics in Chinese renal transplant patients. METHODS: We enrolled 96 renal allograft recipients receiving tacrolimus-based immunosuppressive regiments. Two functional SNPs in the IL-18 gene promoter region at the positions -137G/C (rs187283) and -607A/C (rs1946518) and one SNP (rs776746) of CYP3A5 were genotyped using a Mass ARRAY platform. Tacrolimus daily doses (mg/day) and trough tacrolimus concentration (ng/ml) were continuously recorded for 1 month after transplantation. RESULTS: The tacrolimus C/D ratio was significantly associated with the IL-18 rs1946518 gene polymorphism in the first month after transplantation (P = 0.0225). We studied the influence of its polymorphism on tacrolimus C/D ratios in subjects with different CYP3A5 genotype backgrounds, and among patients with CYP3A5 expressers, the difference among the three genotypes was even more striking (P < 0.001). We did not find significant differences in tacrolimus C/D ratios between the IL-18 rs187238 genotypes, either nominally or according to the CYP3A5 genotype. In a simple linear regression model, age, hemoglobin (Hb), CYP3A5 gene polymorphisms, and IL-18 A-607C gene polymorphisms were associated with log-transformed tacrolimus C/D ratios (P < 0.05). In the final multiple linear regression model, CYP3A5 polymorphisms were the most important variant, accounting for 19.5 % of total variation involved in tacrolimus pharmacokinetics. CONCLUSION: Our findings suggest that a combined analysis of CYP3A5 and IL-18 promoter polymorphisms may help clinicians develop individualized tacrolimus treatment, which is based on determining CYP3A5 genotype.

Mapping of hepatic expression quantitative trait loci (eQTLs) in a Han Chinese population.

BACKGROUND: Elucidating the genetic basis underlying hepatic gene expression variability is of importance to understand the aetiology of the disease and variation in drug metabolism. To date, no genome-wide expression quantitative trait loci (eQTLs) analysis has been conducted in the Han Chinese population, the largest ethnic group in the world. METHODS: We performed a genome-wide eQTL mapping in a set of Han Chinese liver tissue samples (n=64). The data were then compared with published eQTL data from a Caucasian population. We then performed correlations between these eQTLs with important pharmacogenes, and genome-wide association study (GWAS) identified single nucleotide polymorphisms (SNPs), in particular those identified in the Asian population. RESULTS: Our analyses identified 1669 significant eQTLs (false discovery rate (FDR) < 0.05). We found that 41% of Asian eQTLs were also eQTLs in Caucasians at the genome-wide significance level (p=10⁻8). Both cis- and trans-eQTLs in the Asian population were also more likely to be eQTLs in Caucasians (p<10⁻4). Enrichment analyses revealed that trait-associated GWAS-SNPs were enriched within the eQTLs identified in our data, so were the GWAS-SNPs specifically identified in Asian populations in a separate analysis (p<0.001 for both). We also found that hepatic expression of very important pharmacogenetic (VIP) genes (n=44) and a manually curated list of major genes involved in pharmacokinetics (n=341) were both more likely to be controlled by eQTLs (p<0.002 for both). CONCLUSIONS: Our study provided, for the first time, a comprehensive hepatic eQTL analysis in a non-European population, further generating valuable data for characterising the genetic basis of human diseases and pharmacogenetic traits.

A novel model for orthotopic liver transplantation in rats using hepatic rearterialization and biliary extradrainage system.

BACKGROUND: Although the rat orthotopic liver transplantation (OLT) model has existed for many years, only a few models can be applied for dynamic bile collection. The aim of this study was to introduce a dependent rat OLT model with hepatic rearterialization and an expediently dynamic bile collection system. METHODS: Forty-five male Sprague-Dawley rats were divided into the following three groups (n = 15 each): group A, OLT without hepatic rearterialization; group B, OLT with hepatic rearterialization; group C, OLT with hepatic rearterialization and a biliary extradrainage system. In groups B and C, a modified sleeve anastomosis between the donor common hepatic artery and the recipient proper hepatic artery was performed to restore the hepatic artery blood flow. In group C, after hepatic rearterialization, biliary extradrainage and jejunum stoma were performed to reestablish the bile flow, and a waistcoat-like external fixator was introduced to protect this system. RESULTS: The surgical success rates in groups A, B, and C were 100% (15/15), 93% (14/15), and 93% (14/15), respectively. In groups B and C, the hepatic artery patency rates were 93% and 86% on postoperative day 3 and postoperative day 21, respectively. Also, the liver function and bile duct integrity were preserved better than that in group A. In group C, the biliary extradrainage system was well preserved and bile collection was easily performed. CONCLUSIONS: The rat OLT model with hepatic rearterialization and a convenient biliary extradrainage system was satisfactory in maintaining the survival rate, hepatic artery patency rate, and recovery of graft function, so it can be applied in various studies after transplantation.

Influence of TLR4 rs1927907 locus polymorphisms on tacrolimus pharmacokinetics in the early stage after liver transplantation.

PURPOSE: The aim of this study was to assess the potential influence of single nucleotide polymorphisms (SNPs) in the TLR4 gene on tacrolimus pharmacokinetics in the early stage after liver transplantation. METHODS: A total of 96 liver transplant patients receiving tacrolimus-based immunosuppressive regimens were enrolled in this study. The SNPs of CYP3A5 rs776746 and TLR4 rs1927907 were genotyped in both donors and recipients. Trough tacrolimus concentration (ng/mL) and tacrolimus daily doses (mg/day) were recorded for the first 4 weeks post-transplantation. The tacrolimus dose-adjusted trough concentrations (C/D ratio) required to achieve target concentrations were compared among patients according to allele status for CYP3A5 rs776746 and TLR4 rs1927907 during the first 4 weeks post-transplantation. RESULTS: Both donor and recipient CYP3A5 rs776746 allele A and donor TLR4 rs1927907 allele A were associated with a lower C/D ratio during the early stage after transplantation. The difference was even more striking in patients with both the CYP3A5 and TLR4 genotypes. With increasing numbers of genotype AA/AG, patients were found to have increasingly lower tacrolimus C/D ratios at all time points between post-transplantation weeks 1 and 4. CONCLUSIONS: Collectively, donor TLR4 rs1927907 SNPs were closely associated with tacrolimus elimination in our Chinese Han patient population. The combination of the donor TLR4 rs1927907 SNP and both donor and recipient CYP3A5 rs776746 SNP might have a greater effect on tacrolimus elimination than each SNP separately. Screening for these SNPs prior to liver transplantation might be useful for determining adequate initial daily doses of immunosuppressive agents and achieving the desired immunosuppressive effect.

Case report: living donor liver transplantation for giant hepatic hemangioma using a right lobe graft without the middle hepatic vein.

Hepatic hemangioma patients with Kasabach-Merritt syndrome have reportedly been cured by liver transplantation. However, liver transplantation as a potential cure for a stable patient without Kasabach-Merritt syndrome remains debatable. We report the case of a 27-year-old female patient with a giant hepatic hemangioma. The hemangioma measured 50×40×25 cm in size and weighed 15 kg, which is the largest and heaviest hemangioma reported in the literature. The patient showed jaundice, ascites, anemia, and appetite loss; but no disseminated intravascular coagulation was observed through laboratory findings. We successfully operated using a right lobe graft without the middle hepatic vein from a 55-year-old donor. At the long-term follow-up, the patient experienced two acute rejections, which were confirmed by biopsy. However, the patient still survives with good graft function after 50 months.

Stability assessment of surrounding rock in downward mining route supported by slab-wall backfill structure.

Characteristic of ground pressure in surrounding rock is generally considered as the theoretical basis of parameter optimization for stope structure and technology. To explore the feasibility of efficient method for the second-step downward route backfill stopes in Shanjin gold mine, various numerical simulation methods were used to investigate the effect of slab-wall backfill structure on stability of surrounding rock in downward route mining system. The maximum principal stress, artificial false roof stress, and displacement were analyzed to evaluate the level of ground pressure in different mining areas. These results indicate the optimized structural parameters for backfill stopes, which may also provide a low-cost way to achieve a high safety for downward route mining system.

Downregulation of metallothionein 1F, a putative oncosuppressor, by loss of heterozygosity in colon cancer tissue.

PURPOSE: Downregulation of metallothionein (MT) genes has been reported in several tumors with discrepant results. This study is to investigate molecular mechanism of MT gene regulation in colon cancer which is characterized by tumor suppressor gene alterations. EXPERIMENTAL DESIGN: Integral analysis of microarray data with loss of heterozygosity (LOH) information was employed. Quantitative real-time PCR and immunohistochemistry were used to validate MT isoform expression in colon cancer tissues and cell lines. The effects of MT1F expression on RKO cell survival and tumorigenesis was analyzed. Bisulphite sequencing PCR (BSP) and methylation-specific PCR were employed to detect the methylation status of the MT1F gene in colon cancer tissues and cell lines. DNA sequencing was used to examine the LOH at the MT1F locus. RESULTS: MT1F, MT1G, MT1X, and MT2A gene expression was significantly downregulated in colon cancer tissue (p<0.05). Exogenous MT1F expression increased RKO cell apoptosis and inhibited RKO cell migration, invasion and adhesion as well as in vivo tumorigenicity. Downregulation of MT1F gene in majority of human colon tumor tissues is mainly through mechanism by loss of heterozygosity (p=0.001) while CpG island methylation of MT1F gene promoter region was only observed in poorly differentiated, MSI-positive RKO and LoVo colon cancer cell lines. CONCLUSIONS: MT1F is a putative tumor suppressor gene in colon carcinogenesis that is downregulated mainly by LOH in colon cancer tissue. Further studies are required to elucidate a possible role for MT1F downregulation in colon cancer initiation and/or progression.

Establishment of a novel volume-loaded heterotopic heart transplantation model in rats.

BACKGROUND: Non-volume-loaded (NL) donor hearts in the heterotopic heart transplantation model in rats undergo atrophy and thrombus formation in graft cavities after transplantation. The present study aimed to establish a novel model with volume-loaded donor hearts. METHODS: We used Sprague-Dawley rats as donors and recipients. We established an NL model by anastomosing the donor ascending aorta and pulmonary artery end-to-side to the recipient abdominal aorta and inferior vena cava, respectively, and ligating the superior and inferior vena cava on the donor right atrium. The method of the volume-loaded (VL) model was the same as described above, except we performed an anastomosis of the donor left atrium to the recipient abdominal aorta to allow volume loading of the donor's left ventricle. We assessed the characteristics of the grafts by the surgical success rate, echocardiography, and histologic evaluation between the two models. RESULTS: Echocardiography showed that donor left ventricle in VL models was volume loaded and had normal systolic and diastolic function compared with the NL models. The mean weight of NL hearts was significantly less than that of VL hearts. Morphologic observation revealed that thrombus formation in donor heart cavities in NL model was significantly higher than that in the VL model. The area of cardiomyocytes per high-power field in the NL model was significantly lower than that in the VL model. CONCLUSIONS: We provide a novel VL heterotopic heart transplantation model in rats, in which hemodynamic performance of grafts is close to the normal cardiac physiologic situation; thus, the novel model will be more suitable for clinical research.

[Expression and survival prediction of microRNA-155 in hepatocellular carcinoma after liver transplantation].

OBJECTIVE: To explore the expression of microRNA-155 in hepatocellular carcinoma (HCC) and its contribution to recurrence and prognosis of HCC after liver transplantation (LT). METHODS: The expression levels of microRNA-155 in 100 HCC samples were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Kaplan-Meier and Cox proportional regression analyses were utilized to determine the association of microRNA-155 expression with patient survivals. RESULTS: The expression levels of microRNA-155 were higher in primary HCC patients with post-LT recurrence (n = 45, mean relative level = 14.94) than those with non-recurrence (n = 55, mean relative level = 4.70) (P = 0.001) and correlated with micro-vascular invasion of HCC tissue samples (P = 0.001). The patients with a higher expression of microRNA-155 had significantly worse recurrence-free survival (RFS: (21.5 ± 3.2) months, log rank P < 0.001) and overall survival (OS: (29.3 ± 3.2) months, log rank P < 0.001) than those with a lower expression of microRNA-155 (RFS: (50.8 ± 3.2) months; OS: (54.6 ± 3.5) months). Multivariate analysis revealed that a high expression of miR-155 was an independent prognostic predictor. CONCLUSION: MicroRNA-155 is over-expressed in primary HCC with tumor recurrence and may serve as a novel biomarker for tumor recurrence and survival of HCC patients after LT. The detection of microRNA-155 is of clinical significance in HCC.