Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

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.

Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury.

Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.

Effects of Tocilizumab on Experimental Severe Acute Pancreatitis and Associated Acute Lung Injury.

OBJECTIVE: To examine the therapeutic effects of tocilizumab, an antibody against interleukin-6 receptor, on experimental severe acute pancreatitis and associated acute lung injury. The optimal dose of tocilizumab and the activation of interleukin-6 inflammatory signaling were also investigated. DESIGN: Randomized experiment. SETTING: Research laboratory at a university hospital. SUBJECT: Experimental severe acute pancreatitis in rats. INTERVENTIONS: Severe acute pancreatitis was induced by retrograde injection of sodium taurocholate (50 mg/kg) into the biliopancreatic duct. In dose-study, rats were administered with different doses of tocilizumab (1, 2, 4, 8, and 16 mg/kg) through the tail vein after severe acute pancreatitis induction. In safety-study, rats without severe acute pancreatitis induction were treated with high doses of tocilizumab (8, 16, 32, and 64 mg/kg). Serum and tissue samples of rats in time-study were collected for biomolecular and histologic evaluations at different time points (2, 6, 12, 18, and 24 hr). MEASUREMENTS AND MAIN RESULTS: 1) Under the administration of tocilizumab, histopathological scores of pancreas and lung were decreased, and severity parameters related to severe acute pancreatitis and associated lung injury, including serum amylase, C-reactive protein, lung surfactant protein level, and myeloperoxidase activity, were all significant alleviated in rat models. 2) Dose-study demonstrated that 2 mg/kg tocilizumab was the optimal treatment dose. 3) Basing on multi-organ pathologic evaluation, physiological and biochemical data, no adverse effect and toxicity of tocilizumab were observed in safety-study. 4) Pancreatic nuclear factor-κB and signal transducer and activator of transcription 3 were deactivated, and the serum chemokine (C-X-C motif) ligand 1 was down-regulated after tocilizumab administration. CONCLUSIONS: Our study demonstrated tocilizumab, as a marketed drug commonly used for immune-mediated diseases, was safe and effective for the treatment of experimental severe acute pancreatitis and associated acute lung injury. Our findings provide experimental evidences for potential clinical application of tocilizumab in severe acute pancreatitis and associated complications.

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.

Elevated OCT1 participates in colon tumorigenesis and independently predicts poor prognoses of colorectal cancer patients.

Octamer transcription factor 1 (OCT1) was found to influence the genesis and progression of numerous cancers except for colorectal cancer (CRC). This study tried to explore the role of OCT1 in CRC and clarify the association between its expression and patients' clinical outcome. Transcriptional and post-transcriptional expression of OCT1 was detected in CRC cancerous tissues and paired normal mucosae by real-time PCR as well as immunohistochemistry. Moreover, the effect of OCT1 knockdown on CRC cell proliferation was investigated both in vitro and in vivo using Cell Counting Kit-8 assay, colony-forming assay, and mouse tumorigenicity assay. Expression of OCT1 was found to be elevated in CRC. Suppression of OCT1 significantly inhibited CRC cell proliferation both in vitro and in vivo. Furthermore, upregulated level of OCT1 was significantly associated with N stage, M stage, and American Joint Committee on Cancer (AJCC) stage (P = 0.027, 0.014, and 0.002, respectively) as well as differential degree (P = 0.022). By using multivariate Cox hazard model, OCT1 was also shown to be a factor independently predicting overall survival (OS; P = 0.013, hazard ratio = 2.747, 95 % confidence interval 1.125 to 3.715) and disease-free survival (DFS; P = 0.004, hazard ratio = 2.756, 95 % confidence interval 1.191 to 4.589) for CRC patients. Our data indicate that OCT1 carries weight in colorectal carcinogenesis and functions as a novel prognostic indicator and a promising target of anti-cancer therapy for CRC.

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.

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.

Enhanced photocatalytic U(VI) reduction via double internal electric field in CoWO4/covalent organic frameworks p-n heterojunction.

Photoreduction of highly toxic U(VI) to less toxic U(IV) is crucial for mitigating radioactive contamination. Herein, a CoWO4/TpDD p-n heterojunction is synthesized, with TpDD serving as the n-type semiconductor substrate and CoWO4 as the p-type semiconductor grown in situ on its surface. The Fermi energy difference between TpDD and CoWO4 provides the electrochemical potential for charge-hole separation. Moreover, the Coulombic forces from the distinct carrier types between the two materials synergistically facilitate the transfer of electrons and holes. Hence, an internal electric field directed from TpDD to CoWO4 is established. Under photoexcitation conditions, charges and holes migrate efficiently along the curved band and internal electric field, further enhancing charge-hole separation. As a result, the removal capacity of CoWO4/TpDD increases from 515.2 mg/g in the dark to 1754.6 mg/g under light conditions. Thus, constructing a p-n heterojunction proves to be an effective strategy for remediating uranium-contaminated environments.

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.

[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.

Synergistic effect of double Schottky potential well and oxygen vacancy for enhanced plasmonic photocatalytic U(VI) reduction.

Plasmonic photocatalysis is an effective strategy to solve radioactive uranium hazards in wastewater. A plasmonic photocatalyst Bi/Bi2O3-x@COFs was synthesized by in-situ growth of covalent organic frameworks (COFs) on Bi/Bi2O3-x surface for the U(VI) adsorption and plasmonic photoreduction in rare earth tailings wastewater. The presence of oxygen vacancy in Bi/Bi2O3-x and Schottky potential well formed by Bi and Bi2O3-x interface increased the number of free electrons, which induced localized surface plasmon resonance (LSPR) and enhanced the light absorption performance of composites. In addition, oxygen vacancy improved the Fermi level of Bi/Bi2O3-x, leading to another potential well between Bi2O3-x and COFs interface. The electron transport direction was reversed, thus increasing the electron density of COFs layer. COFs was an N-type semiconductor with specific binding U(VI) groups and suitable band structure, which could be used as an active reaction site. Bi/Bi2O3-x@COFs had 1411.5 mg g-1 removal capacity and high separation coefficient for U(VI) due to the synergistic action of photogenerated electrons and hot electrons. Moreover, the removal rate of uranium from rare earth tailings wastewater by regenerated Bi/Bi2O3-x@COFs was over 93.9%. The scheme of introducing LSPR and Schottky potential well provides another way to improve the photocatalytic effect.

IDO-competent-DCs induced by IFN-γ attenuate acute rejection in rat liver transplantation.

PURPOSE: We established a stable rat model of liver transplantation using Sprague-Dawley rats and Wistar rats in order to investigate the role of the IDO gene in acute rejection after rat liver transplantation. METHODS: IDO gene expression and IDO enzyme activity were quantified in liver syngeneic grafts and allografts using microdialysis-HPLC. Liver allografts were evaluated for IDO expression by histopathology. We measured liver function-related biomarkers in liver allografts which were re-infused with untreated or IFN-γ-treated dendritic cells (DCs). RESULTS: We found a significant increase in IDO gene expression and IDO enzyme activity in liver allografts compared the sham and syngeneic graft groups. There was a significant correlation between the number of IDO-positive cells and severity of acute rejection. IDO gene expression and enzyme activity was upregulated in the IFN-γ-treated DC group within 7 days after transplantation compared to the untreated DC group and survival rates were significantly improved. CONCLUSIONS: Our results suggested that IDO gene expression correlates with the severity of acute rejection and that IFN-γ-induced IDO-positive DCs may attenuate acute rejection and catalyze local tryptophan metabolism via IDO enzyme expression, leading to immune tolerance after liver transplantation.

The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in Chinese adult liver-transplant patients.

AIMS: The aims of this study were to determine the population pharmacokinetics of tacrolimus in Chinese adult liver-transplant recipients and to identify factors that may account for this variability. METHODS: Tacrolimus dose and blood concentrations, along with clinical data, were collected retrospectively from 262 liver-transplant recipients. Data were analyzed using a nonlinear mixed-effects modeling method. A 1-compartment model with first-order absorption and elimination was selected as the base model. The influence of the following parameters were explored: (1) demographic characteristics, (2) biochemical and hematological laboratory test results, (3) surgery parameters, and (4) commonly used comedications. RESULTS: The typical values (interindividual variability percent coefficient of variation) for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 20.9 L h (23.8%) and 808 l (70.4%), respectively. The residual variability was 33.6%. Finally, the 4 covariates that showed a strong correlation with CL/F in this study were daily dose, hematocrit, total plasma protein, and the coadministration of sulfonylureas. CL/F was reduced significantly with sulfonylureas cotherapy, higher hematocrit levels, and elevated total protein. Moreover, CL/F increased nonlinearly with larger daily doses of tacrolimus. CONCLUSIONS: Concurrent therapy with sulfonylureas influenced tacrolimus CL/F in liver transplantation patients. These results and model will help clinicians to optimize tacrolimus regimens in Chinese liver transplantation patients.

Effect of ursodeoxycholic acid administration after liver transplantation on serum liver tests and biliary complications: a randomized clinical trial.

BACKGROUND/AIMS: Endogenous hydrophobic bile acids are suspected to be one of the pathogenetic factors of biliary complications after orthotopic liver transplantation (OLT). This study was designed to investigate the effects of hydrophilic ursodeoxycholic acid (UDCA) administration early after OLT on serum liver tests and the incidence of biliary complications. METHODS: 112 adult patients undergoing OLT from donation after cardiac death (DCD) were randomized to UDCA (13-15 mg/kg/day for 4 weeks; 56 patients) or placebo (56 patients). Serum liver tests and serum bile acids of all patients and biliary bile acids in patients with T-tube drainage were determined during the 4 weeks after OLT. Biliary complications as well as patient and graft survival were analyzed during a mean follow-up of 41.6 months. RESULTS: UDCA treatment decreased ALT, AST and GGT (p < 0.05) during the 4 weeks after OLT and the incidence of biliary sludge and casts within the 1st year (p < 0.05). However, no differences in the incidence of other biliary complications as well as 1-, 3- and 5-year graft and patient survival were observed. CONCLUSIONS: UDCA administration early after DCD-OLT improves serum liver tests and decreases the incidence of biliary sludge and casts within the 1st postoperative year but does not affect overall outcome up to 5 years after OLT.

Identification and validation of Kallikrein-ralated peptidase 11 as a novel prognostic marker of gastric cancer based on immunohistochemistry.

BACKGROUND AND OBJECTIVES: It is important to identify and validate the differentially expressed genes in gastric cancer to screen diagnostic and/or prognostic tumor markers. METHODS: cDNA expression microarray, gene set enrichment analysis, and bioinformatics approaches were used to screen the differentially expressed genes between gastric cancer tissues and adjacent non-cancerous mucosa. A novel candidate prognostic marker, Kallikrein-related peptidase 11 (KLK11), was validated in 400 Chinese gastric cancer patients. KLK11 expression in gastric cancer tissues was detected using real-time PCR and Western blot. KLK11 protein expression was further analyzed by immunostaining on tissue microarray, followed with clinicopathological significance and survival analysis. RESULTS: KLK11 expression was significantly decreased in gastric cancer compared with that in normal gastric mucosa (P<0.001). Furthermore, KLK11 expression was much lower in poorly differentiated cancer samples than that in well-differentiated group (P<0.01). Survival analysis showed that negative KLK11 expression was associated with nearly fivefold increased risk of distant metastasis after curative gastrectomy (HR 4.65, P<0.01). Multivariate Cox regression analysis showed that KLK11 expression emerged as a significant independent prognostic factor for disease-free survival and overall survival (P<0.05). CONCLUSIONS: The results indicated that KLK11 expression was decreased in gastric cancer and might serve as a novel independent prognostic marker.

[Effects of non-bioartificial liver support system on Gc-globulin in patients with liver failure].

OBJECTIVE: To investigate the effects of artificial liver support system(plasma exchange combined with continuous veno - venous hemodiafiltration, PE + CVVHDF) on Gc globulin in patients with liver failure. METHODS: 81 patients with liver failure were divided into 4 groups according to the treatment protocols and indicators such as liver function and clinical symptoms. Totally 29 effective cases and 14 ineffective cases in the ALSS group versus 15 effective cases and 23 ineffective cases in the medical group were included. Finally the changes of Gc globulin were observed in four subgroups before and after treatment. The correlation between Gc globulin and IL-10, IL-4, IL-18, TNFa, endotoxin, NO, sVCAM-1and sICAM-1were analyzed by Pearson correlation analysis. RESULTS: The effectiveness rate was 67.44% in ALSS group and 34.21% in the medical treatment (P less than 0.01). Gc globulin, one of liver cell protection proteins was notably increased following the artificial liver treatment as compared with the increase in the medical treatment (P less than 0.01). The time-response curve of Gc globulin level had a significant upward trend in the effective group as compared to no significant rise in the ineffective group. Moreover, the Gc globulin was negatively correlated with IL-4, IL-18, TNFa, SVCAM-1, SICAM-1 and NO. In contrast, no correlation existed between Gc globulin and IL-10. The treatment with artificial liver can improve the outcome of the patients with liver failure. The level of Gc globulin was correlated with the curative effect and thus may be used as a potential indicator for curative effect forcast in the patients with liver failure.

Population pharmacokinetic study of cyclosporine based on NONMEM in Chinese liver transplant recipients.

A population pharmacokinetic study of cyclosporine (CsA) was performed in liver transplant recipients. A total of 3731 retrospective drug monitoring data points at predose (C0) and 2 hours postdose (C2) were collected from 124 liver transplant recipients receiving CsA microemulsion. Population pharmacokinetic analysis was performed using the program NONMEM (nonlinear mixed-effect modeling). Various covariates potentially related to CsA pharmacokinetics were explored, and the final model was validated by a bootstrap method and by assessing the predictive performance using empiric Bayesian estimates. A one-compartment model with first-order absorption was considered. Population parameters of apparent clearance (CL/F) and volume of distribution were estimated as 23.1 L/h and 105 L, respectively. CL/F was influenced by four covariates: duration of CsA therapy (DT), hematocrit (HCT), and concurrent prednisone dose (PR). The final model for CL/F was fitted as follows: CL/F = 23.1 + 0.5 × (DT/200) - 0.07 × HCT + 0.04 × PR. The interindividual variability in CL/F, volume of distribution, and Ka calculated as coefficient of variation were 15.1%, 9.3%, and 66.0%, respectively. The intraindividual variability was 18.6%. The model fitted well with the observed data, and the bootstrap method guaranteed robustness of the population pharmacokinetic study model. Model validation was performed by a visual predictive check. Moreover, simulation was conducted to facilitate the individualized treatment based on patient information and the final model. The model to characterize population pharmacokinetic study of CsA provided better clinical individualization of CsA dosing in liver transplant recipients based on patient information and to assess patients' suitability for CsA therapy.

Post-transplant infection improves outcome of hepatocellular carcinoma patients after orthotopic liver transplantation.

BACKGROUND: Tumor recurrence after orthotopic liver transplantation (OLT) remains a serious threat for long-term survival of the recipients with hepatocellular carcinoma (HCC), since very few factors or measures have shown impact on overcoming HCC recurrence after OLT. Postoperative infection suppresses tumor recurrence and improves patient survival in lung cancer and malignant glioma probably via stimulating the immune system. Post-transplant infection (PTI), a common complication, is deemed to be harmful for the liver transplant recipients from a short-term perspective. Nevertheless, whether PTI inhibits HCC recurrence after OLT and prolongs the long-term survival of HCC patients needs to be clarified. AIM: To investigate the potential influence of PTI on the survival and tumor recurrence of patients with HCC after OLT. METHODS: A total of 238 patients with HCC who underwent OLT between August 2002 and July 2016 at our center were retrospectively included and accordingly subdivided into a PTI group (53 patients) and a non-PTI group (185 patients). Univariate analyses, including the differences of overall survival (OS), recurrence-free survival (RFS), and post-recurrence survival (PRS), between the PTI and non-PTI subgroups as well as survival curve analysis were performed by the Kaplan-Meier method, and the differences were compared using the log rank test. The variables with a P-value < 0.1 in univariate analyses were included in the multivariate survival analysis by using a Cox proportional-hazards model. RESULTS: The 1-, 3-, and 5-year OS and RFS rates of the whole cohort were 86.6%, 69.0%, and 63.6%, and 75.7%, 60.0%, and 57.3%, respectively. The 1-, 3-, and 5-year OS rates for the PTI patient group (96.0%, 89.3%, and 74.0%) were significantly higher than those for the non-PTI group (84.0%, 63.4%, and 60.2%) (P = 0.033). The absence of PTI was an independent risk factor for dismal OS (relative risk [RR] = 2.584, 95%CI: 1.226-5.449) and unfavorable RFS (RR = 2.683, 95%CI: 1.335-5.390). Subgroup analyses revealed that PTI remarkably improved OS (P = 0.003) and RFS (P = 0.003) rates of HCC patients with vascular invasion (IV), but did not impact on OS (P = 0.404) and RFS (P = 0.304) of patients without VI. Among the patients who suffered post-transplant tumor recurrence, patients with PTI showed significantly better OS (P = 0.026) and PRS (P = 0.042) rates than those without PTI. CONCLUSION: PTI improves OS and RFS of the transplant HCC patients at a high risk for post-transplant death and tumor recurrence, which is attributed to suppressive effect of PTI on HCC recurrence.

USP10 regulates Musashi-2 stability via deubiquitination and promotes tumour proliferation in colon cancer.

Recent studies have demonstrated that ubiquitin-specific protease 10 (USP10) plays a catalytic role in tumour suppression mainly by deubiquitinating its target proteins to enhance their stabilities. However, we found that USP10 could interact with and regulate the expression of oncogenic factor Musashi-2 (MSI2). We investigated whether USP10 positively regulates the expression of MSI2 by deubiquitination and confirmed the type of polyubiquitin chain that is linked to MSI2. We also explored the role of USP10 in regulating the proliferation of colon cancer through different experiments. This study provides a completely new perspective in understanding the role of USP10 in deubiquitination. In the future, USP10 may serve as a target for colon cancer treatment.