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.

Clinicopathological analysis of 114 cases of typical Kaposi's sarcoma in Xinjiang Uygur autonomous region, China.

The present study aimed to investigate the clinicopathological features of cases of classic Kaposi's sarcoma (CKS) in Xinjiang Uygur Autonomous Region, China, and analyze its etiology and treatment. A total of 114 patients, who were clinicopathologically diagnosed with CKS at the First Affiliated Hospital of Xinjiang Medical University (Urumqi, China) between 1980 and 2015 were retrospectively analyzed. The clinicopathological features of CKS were summarized, and its demographic distribution, pathogenesis, etiology and treatment were examined. The results revealed that, among the 114 patients with CKS, 100 patients were men and 14 patients were women, with a respective ratio of 7:1. The average age of these patients was 57.5 years old, and 97 of the patients were from the Uygur Autonomous Region (85.1%). Among the 114 patients, 60 patients (52.6%) were from Southern Xinjiang, 50 patients (43.9%) were from Northern Xinjiang and four patients (3.5%) were from Eastern Xinjiang. It was found that CKS in the Uygur ethnic group of Xinjiang Uygur Autonomous Region had unique clinicopathological features. The occurrence of CKS in Xinjiang may be associated with human herpes virus 8 infection, ethnicity­based susceptibility and lifestyle.

Gene Variations of Sixth Complement Component Affecting Tacrolimus Metabolism in Patients with Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Orthotopic liver transplantation (OLT) improves the prognosis of patients with hepatocellular carcinoma (HCC). Moreover, the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis. However, studies correlating the complement system with tacrolimus metabolism after OLT are scarce. In this study, the role of single nucleotide polymorphisms (SNPs) associated with the sixth complement component (C6) in tacrolimus metabolism was investigated during the early stages of liver transplantation. METHODS: The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013. Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 (CYP3A5) gene were investigated. The tacrolimus levels were monitored daily during 4 weeks after transplantation. RESULTS: Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose (C/D) ratios. Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios. Recipient CYP3A5 rs776746 allele A (yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2), C6 rs9200 allele G (exhibited median tacrolimus C/D ratios of 211.31 at week 1, 110.23 at week 2, and 99.88 at week 3), and donor CYP3A5 rs776746 allele A (exhibited median C/D ratios of 210.82 at week 1, 111.06 at week 2, 77.49 at week 3, and 85.60 at week 4) and C6 rs10052999 homozygote (exhibited median C/D ratios of 167.59 at week 2, 157.99 at week 3, and 155.36 at week 4) were associated with rapid tacrolimus metabolism. With increasing number of these alleles, patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation. In multiple linear regression analysis, recipient C6 rs9200 group (AA vs. GG/GA) was found to be related to tacrolimus metabolism at weeks 1, 2, and 3 (P = 0.005, P = 0.045, and P = 0.033, respectively), whereas donor C6 rs10052999 group (CC/TT vs. TC) was demonstrated to be correlated with tacrolimus metabolism only at week 4 (P = 0.001). CONCLUSIONS: Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.

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.

Subband Structure and Effective Mass in the Inversion Layer of a Strain Si-Based Alloy P-Type MOSFET.

In this paper, the subband structure and effective mass of an Si-based alloy inversion layer in a PMOSFET are studied theoretically. The strain condition considered in our calculations is the intrinsic strain resulting from growth of the silicon-carbon alloy on a (001) Si substrate and mechanical uniaxial stress. The quantum confinement effect resulting from the vertically effective electric field was incorporated into the k · p calculation. The distinct effective mass, such as the quantization effective mass and the density-of-states (DOS) effective mass, as well as the subband structure of the silicon-carbon alloy inversion layer for a PMOSFET under substrate strain and various effective electric field strengths, were all investigated. Ore results show that subband structure of relaxed silicon-carbon alloys with low carbon content are almost the same as silicon. We find that an external stress applied parallel to the channel direction can efficiently reduce the effective mass along the channel direction, thus producing hole mobility enhancement.

Band Structure and Effective Mass in Monolayer MoS2.

Monolayer transition-metal dichalcogenide is a very promising two-dimensional material for future transistor technology. Monolayer molybdenum disulfide (MoS2), owing to the unique electronic properties of its atomically thin two-dimensional layered structure, can be made into a high-performance metal-oxide-semiconductor field-effect transistor, or MOSFET. In this work, we focus on band structure and carrier mobility calculations for MoS2. We use the tight-binding method to calculate the band structure, including a consideration of the linear combination of different atomic orbitals, the interaction of neighboring atoms, and spin-orbit coupling for different tight-binding matrices. With information about the band structure, we can obtain the density of states, the effective mass, and other physical quantities. Carrier mobility using the Kubo-Greenwood formula is calculated based on the tight-binding band structure.

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.

[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.

Prevalence and risk factor for MDR-GNB infection in liver transplantation.

Liver transplantation (LT) has emerged as a viable therapy for various end-stage liver diseases. Multi-drug resistant Gram-negative bacilli (MDR-GNB) have emerged as predominant pathogens. The prevalence of MDR-GNB infection has been increasing in LT recipients, especially in early post-LT stages. MDR-GNB infection has become a main cause of death following LT. Since key elements of MDR-GNB infection after LT mainly include the pre-LT severity of underlying disease, technical problems, acute rejection, and so on, appropriate measures, such as improvement of LT technology and management, restriction of antibiotic use and immunosuppressive therapy advancement, should be commenced to prevent and control the occurrence of MDR-GNB infection. A better understanding of the prevalence of and risk factors for MDR-GNB infection complications is needed to improve quality of life and survival rate after LT.

Identification of recurrence-related microRNAs in hepatocellular carcinoma following liver transplantation.

Tumor recurrence-related microRNAs (miRNAs) in hepatocellular carcinoma (HCC) following orthotopic liver transplantation (OLT) are not clear yet. This study was designed to determine whether altered miRNA expression is associated with HCC recurrence and prognosis following OLT. 18 miRNAs, including 6 up-regulated and 12 down-regulated miRNAs were identified by microarray in primary HCC samples of patients who had developed HCC recurrence (n = 5) compared to those with non-recurrence (n = 5) following OLT by using p < 0.05 as cutoff value. The six most significantly altered miRNAs (fold change ≥ 2: miR-19a, miR-886-5p, miR-126, miR-223, miR-24 and miR-147) were further confirmed by qRT-PCR in the remaining 105 HCC samples. In receiver-operating characteristic curve analysis, this six miRNAs were of high sensitivity and specificity in predicting HCC recurrence. Using Cox regression and risk score analysis, we built a six-miRNA signature based on their qRT-PCR readings for the prediction of outcome of HCC following OLT. Kaplan-Meier and Cox proportional regression revealed this six-miRNA signature was a significant independent predictor of overall survival (log-rank p = 0.020) and recurrence-free survival (log-rank p < 0.001). Finally, the data were further reconfirmed in an independent cohort of 50 patients from another transplant center. In addition, bioinformatics Gene Ontology and pathway analysis were also performed to better understand the critical roles of these miRNAs in HCC recurrence. Our study, in addition to suggesting a different miRNA expression pattern between HCC samples of patients with recurrence and those with non-recurrence, proposes that this six-miRNA signature may serve as biomarker for prognosis of HCC patients following OLT.

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.

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.

miR-203 expression predicts outcome after liver transplantation for hepatocellular carcinoma in cirrhotic liver.

Many recent studies have shown the utility of microRNAs (miRs) as cancer-related biomarkers. The aim of the present study was to evaluate the correlation between miR-203 expression and prognosis of patients with hepatocellular carcinoma (HCC) and cirrhosis after liver transplantation (LT). Sixty-six HCC samples from patients who had undergone LT were examined for miR-203 expression using quantitative reverse transcription-polymerase chain reaction. The data were correlated with clinicopathological parameters and prognosis. Patient survival was analyzed by the Kaplan-Meier method and log-rank test. Cox regression was used for multivariate analysis of prognostic factors. We found that miR-203 expression was low in tumor tissues of patients (n = 16) with post-LT HCC recurrence in comparison with those in patients with non-recurrence (n = 50) (P = 0.003). Patients with higher miR-203 expression had significantly better recurrence-free survival (RFS) and overall survival (OS) (P = 0.016 for RFS; P = 0.014 for OS). Multivariate analysis revealed that high-miR-203 expression was an independent predictor of good prognosis (HR 0.202, P = 0.006 for RFS; HR 0.332, P = 0.013 for OS). Our results suggest that miR-203 could be a novel prognostic marker in HCC patients who have undergone LT and might also be a potential therapeutic target.

Multidrug-resistant gram-negative bacterial infections after liver transplantation - spectrum and risk factors.

OBJECTIVES: Gram-negative bacilli infections, especially multidrug-resistant gram-negative bacilli infections, are the leading cause of high mortality after liver transplantation. This study sought to investigate the type of infection, infection rate, pathogenic spectrum, antibiotic-resistance profile, risk factors, and epidemiology of multidrug-resistant gram-negative bacterial infection. METHODS: A retrospective cohort study was conducted and data of 217 liver transplant patients receiving cadaveric livers between January 2007 and April 2010 were analyzed. Antibiotic susceptibility was determined by minimum inhibitory concentration test. Extended-spectrum and metallo-ß-lactamase assays were used to analyze ß-lactamase-produced isolates, and repetitive-sequence polymerase chain reaction was used to differentiate bacterium subspecies. RESULTS: Sixty-seven isolates of multidrug-resistant gram-negative bacteria were isolated from 66 infected liver transplant patients. Stenotrophomonas maltophilia (100%, 8/8), Klebsiella pneumoniae (61.5%, 8/13), Enterobacter cloacae (75%, 3/4) and Escherichia coli (81.3%, 13/16) were the most common extended-spectrum ß-lactamase-producing bacilli. Metallo-ß-lactamase expressing isolates were identified as S. maltophilia (100%, 8/8), Pseudomonas aeruginosa (83.3%, 5/6), Acinetobacter baumannii (95%, 19/20). Significant independent risk factors for multidrug-resistant gram-negative infection were extended use of pre-transplant broad-spectrum antibiotics (OR 9.027, P=0.001) and prolonged (≧72h) endotracheal intubation (OR 3.537, P=0.033). CONCLUSIONS: To reduce the risk of acquiring MDR gram-negative bacillus infections after liver transplant, control measures are required to limit the use of prophylactic antibiotic in preventing infection during liver transplant and to shorten endotracheal intubation time.

Up-regulation of microRNA-155 promotes cancer cell invasion and predicts poor survival of hepatocellular carcinoma following liver transplantation.

PURPOSE: MicroRNAs play important roles in cancer development, progression, and metastasis. The aim of this study was to determine whether altered microRNA-155 expression is associated with hepatocellular carcinoma (HCC) recurrence and prognosis following orthotopic liver transplantation (OLT). METHODS: Tissue specimens from 100 HCC patients following OLT were recruited. MicroRNA-155 expression levels were detected using 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 survival of patients. MicroRNA-155 expression levels of two HCC cell lines (HepG2 and SMMC-7721) and normal liver tissue were quantified using qRT-PCR. The potential function of miR-155 on invasiveness was evaluated in the above HCC cell lines. RESULTS: We found that microRNA-155 expression levels were high in tumor tissues in patients with post-OLT HCC recurrence (n = 45) compared with those in patients with non-recurrence (n = 55) (P = 0.001) and correlated with micro-vascular invasion of HCC tissue samples (P = 0.001). Patients with higher miR-155 expression had significantly poorer recurrence-free survival (RFS, log rank P < 0.001) and overall survival (OS, log rank P < 0.001). Multivariate analysis revealed that high miR-155 expression was an independent predictor of poor prognosis (HR 2.748, P = 0.001 for RFS; HR 5.752, P < 0.001 for OS). In addition, the invasiveness of HCC cells was significantly increased by higher microRNA-155 expression. CONCLUSIONS: MicroRNA-155 is a candidate oncogenic microRNA and plays an important role in promoting HCC cells invasion. Our findings suggest that microRNA-155 may serve as a novel biomarker for tumor recurrence and survival of HCC patients following OLT.

Biglycan expression correlates with aggressiveness and poor prognosis of gastric cancer.

Biglycan, a member of the small leucine-rich proteoglycan family, has been implicated in the development and progression of human cancers. However, the clinical significance of biglycan expression in gastric cancer has not been determined. In the present study, biglycan mRNA and protein concentrations were analyzed using quantitative realtime reverse transcription polymerase chain reaction and Western blot in 69 gastric cancer and adjacent non-tumorous tissues, respectively. Biglycan expression was further assessed using immunohistochemistry in tissue microarrays that contained 264 cases of gastric cancer, and others containing normal or metastasized lymph node tumor tissues. Biglycan was upregulated at the transcriptional and translational levels and there was a correlation between the expression of biglycan mRNA and protein (P = 0.000, κ = 0.769). Over-expression of biglycan was strongly associated with lymph node metastasis, tumor (T) classification, metastasis (M) classification, vascular invasion and Union for International Cancer Control (UICC) stage. Patients with biglycan-positive tumors had a significantly higher disease recurrence rate and poorer survival than patients with biglycan-negative tumors after the radical surgery. Multivariate analysis revealed that biglycan expression is an independent prognostic indicator for survival of patients with gastric cancer. The data from the current study demonstrate that elevated expression of biglycan may play an important role in the development and progression of gastric cancer, and could be further evaluated as a biomarker for predication of a poor clinical outcome.

Overexpression of Forkhead box M1 protein associates with aggressive tumor features and poor prognosis of hepatocellular carcinoma.

The aim of this study was to detect the expression of the Forkhead box M1 (FOXM1) protein in human hepatocellular carcinoma (HCC) and to associate FOXM1 expression with clinicopathological features of the patients, and predict the prognosis of patients with FOXM1 expression. Surgical tissue specimens from 151 HCC patients were subjected to a tissue microarray construction and immunohistochemistry analysis of FOXM1 and the proliferation marker proliferating cell nuclear antigen (PCNA). The data showed that the FOXM1 protein was expressed in 59.3% of the HCC tissues, which was significantly higher compared to that of the surrounding non-tumorous tissues (23.8%; P<0.001). Moreover, FOXM1 expression was positively correlated with the labeling index of PCNA (P<0.001) in HCC and with aggressive tumor phenotypes, such as larger tumor size, multiple tumors, bilobar involvement, poor tumor cell differentiation, advanced stage and macrovascular invasion (P<0.05). In addition, HCC patients with FOXM1-positive tumors had a poorer recurrence-free and overall survival after hepatectomy than those with FOXM1-negative tumors. Multivariate Cox regression analysis demonstrated that FOXM1 expression was an independent predictor of unfavorable outcome (P<0.05). The data from the current study suggest that FOXM1 may play an important role in HCC progression and could be further evaluated as a prognostic biomarker and potential therapeutic target.

Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer.

PURPOSE: To investigate the clinicopathologic significance and predictive value of Bmi-1 expression in patients with colon cancer. METHODS: Bmi-1 expression was assessed by immunohistochemistry, PCR, and western blotting in specimens from 203 patients and by immunohistochemistry in 66 specimens of lymph node metastasis (LNM). RESULTS: Positive staining of Bmi-1 occurred in 7.9% (16/203), 66.5% (135/203), and 86.4% (57/66) of specimens from normal tissue, colon cancer, and LNM, respectively. Staining was significantly correlated with clinical stage, depth of invasion, nodal involvement, distant metastasis, and Ki67 level. Bmi-1 was upregulated at the transcriptional and translational levels. Patients with Bmi-1-positive localized tumors had a much lower 5-year disease-free survival (relative risk 2.919, P < 0.0001) and overall survival (relative risk 5.056, P < 0.0001). Bmi-1 immunoreactivity emerged as an independent prognostic factor in the multivariate analysis. CONCLUSIONS: We have shown that expression of Bmi-1 was elevated in colon cancer and might serve as an independent prognostic marker.

Refined mapping of loss of heterozygosity on 1q31.1-32.1 in sporadic colorectal carcinoma.

AIM: To explore precise deleted regions and screen the candidate tumor suppressor genes related to sporadic colorectal carcinoma. METHODS: Six markers on 1q31.1-32.1 were chosen. These polymorphic microsatellite markers in 83 colorectal cancer patients tumor and normal DNA were analyzed via PCR. PCR products were electrophoresed on an ABI 377 DNA sequencer. Genescan 3.1 and Genotype 2.1 software were used for Loss of heterozygosity (LOH) scanning and analysis. Comparison between LOH frequency and clinicopathological factors was performed by c2 test. RESULTS: 1q31.1-32.1 exhibited higher LOH frequency in colorectal carcinoma. The average LOH frequency of 1q31.1-32.1 was 23.0%, with the highest frequency of 36.7% (18/49) at D1S2622, and the lowest of 16.4% (11/67) at D1S412, respectively. A minimal region of frequent deletion was located within a 2 cM genomic segment at D1S413-D1S2622 (1q31.3-32.1). There was no significant association between LOH of each marker on 1q31.1-32.1 and the clinicopathological data (patient sex, age, tumor size, growth pattern or Dukes stage), which indicated that on 1q31.1-32.1, LOH was a common phenomenon in all kinds of sporadic colorectal carcinoma. CONCLUSION: Through our refined deletion mapping, the critical and precise deleted region was located within 2 cM chromosomal segment encompassing 2 loci (D1S413, D1S2622). No significant association was found between LOH and clinicopathologic features in 1q31.1-32.1.