Jeon-Han Park

Allelotype analysis of hepatocellular carcinoma

To elucidate the genetic events which may play important roles in hepatocarcinogenesis, we examined every non‐acrocentric chromosome arm of 22 hepatocellular carcinomas (HCCs) for loss of heterozygosity (LOH) using 68 highly polymorphic microsatellite markers. Thirty‐six (92%) of 39 chromosome arms showed LOH in at least one patient, however 3 chromosome arms, 2p, 2q, and 20q, did not show any LOH. High to moderate frequency of LOH (>30% of informative cases) was observed at chromosomes 1q (68.1%), 4q (72.7%), 8p (63.6%), 8q (77.3%), 10q (33.3%), 13q (40%), 14q (46.1%), 16q (59.1%), and 17p (46.2%). Among these, LOH on chromosomes 1q and 8q have not been previously identified in HCC. Our results suggest that novel tumor suppressor genes may be involved in the development and progression of HCC. Int. J. Cancer 75:29–33, 1998.© 1998 Wiley‐Liss, Inc.

Expression of fas ligand in human hepatoma cell lines: role of hepatitis-B virus X (HBX) in induction of Fas ligand.

It has been postulated that tumor cells expressing Fas ligand (FasL) can evade immune surveillance by inducing apoptosis in T cells expressing Fas. In this study, we investigated FasL expression in 13 human hepatoma cell lines. Strong FasL expression was detected by reverse transcription‐polymerase chain reaction or immunofluorescence in Hep G2.2.15, in which the hepatitis‐B‐virus (HBV) genome was transfected, and in SNU‐354, which showed HBx transcripts. To determine the biological activity of FasL, Hep G2.2.15 was co‐cultured with MOLT‐4, T‐cell‐leukemia cells. Hep G2.2.15 induced apoptosis in MOLT‐4 and this was inhibited by the antagonistic anti‐Fas antibody, ZB4. For further analysis of the role of HBx in the induction of FasL, PLC/PRF/5 cells were transfected transiently with the HBV genome, or HBx, or the frameshift mutant of HBx. In PLC/PRF/5 cells transfected with the HBV genome or HBx but not in cells transfected with the frameshift mutant of HBx, FasL expression was detected. Our data suggest that HBx plays a role in the induction of FasL in hepatoma cells and in the escape from immune surveillance. Int. J. Cancer 82:587–591, 1999.

Deletion mapping of chromosome 4q in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) frequently shows a loss of heterozygosity (LOH) on chromosome 4q. In order to define the commonly affected region on chromosome 4q for further positional cloning of the putative tumor suppressor gene, we carried out allelic imbalance (AI) studies in 41 HCCs using a panel of 43 microsatellite markers. Thirty‐four cases (82.9%) showed AI at one or more loci. Detailed deletion mapping identified 7 independent, frequently deleted regions on this chromosome arm. These were the (1) D4S1615 locus, (2) D4S1598 locus, (3) D4S620 locus, (4) D4S1566 and D4S2979 loci, (5) D4S1617 and D4S1545 loci, (6)D4S1537 locus; and (7) from the D4S2920 to D4S2954 locus. Among these 7 frequently deleted regions, 5 were associated with tumor differentiation. Our results suggest that several putative tumor suppressor genes may be present on chromosome 4q and that the AI of chromosome 4q may play a role in the aggressive progression of HCC. Int. J. Cancer (Pred. Oncol.) 79:356–360, 1998.

Deletion of the M6P/IGF2r gene in primary hepatocellular carcinoma

To evaluate the different alteration patterns of the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r) gene in hepatocellular carcinoma (HCC), 41 HCCs were screened for homozygous deletion and loss of heterozygosity (LOH) at the M6P/IGF2r gene with a dinucleotide repeat polymorphic marker. Of these, three (8.8%) were heterozygous and LOH was observed in two (66.7%) of these informative cases. Five (14.7%) out of 34 informative cases showed homozygous deletions for the dinucleotide repeat polymorphic marker. The frequent allelic loss and homozygous deletion of the M6P/ IGF2r gene suggest that the M6P/IGF2r gene functions as a tumor suppressor gene in the development of HCC.

Expression of hMSH2 and hMLH1 in Colorectal Carcinomas with Microsatellite Instability

Microsatellite instability (MIN) due to defective mismatch repair (MMR) genes has been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Among the known MMR genes, hMSH2 and hMLH1 genes are known to be predominantly altered in HNPCC patients and MIN-positive tumors. In this study, we examined MIN and the protein expression pattern of the hMSH2 and hMLH1 by Western blot and immunohistochemistry from 32 sporadic colorectal carcinomas. MIN was observed in 6 (18%) colorectal carcinomas. Of the 6 MIN-positive tumors, one case showed no expression of either protein, 3 cases showed an absence of hMSH2 protein expression, one case showed an absence of hMLH1 protein expression and one case showed no altered expression of either protein by immunohistochemistry. The decreased expression of the hMSH2 protein in a tumor compared to the normal mucosa was also observed in 5 of the 6 MIN-positive cases by Western blot analysis. All of the MIN-negative tumors showed expression of both proteins by immunohistochemistry. Thus most of the MIN-positive tumors appear to be directly related to the altered expression of these two genes and can be diagnosed by the examination of protein expression.

Photoinactivation of vesicular stomatitis virus by a photodynamic agent, chlorophyll derivatives from silkworm excreta.

The efficacy of chlorophyll derivatives from silkworm excreta (CpD) in photodynamic antimicrobial chemotherapy (PACT) was studied. An enveloped animal virus, vesicular stomatitis virus (VSV), was used as a target organism. For CpD mediated PACT, the viruses in suspensions were treated with various doses of CpD (15-60 microg/ml) and visible red light was fixed at 120 mJ/cm(2). The antiviral effect of the CpD-PACT was measured 1 h after light irradiation by the extent of suppression of plaque forming units (pfu). In cultures inoculated with PACT-treated VSV, suppression of pfu was prominent and the results were demonstrated in a dose-dependent manner. In assays of RT-PCR, a single dose of 30 microg/ml CpD and light caused complete inhibition of viral RNA synthesis in the host cells, which agreed with the complete loss of plaque forming activity observed in pfu assays. An in vitro transcription assay for viral RNA using [3H]UTP and gel electrophoresis for the level of M protein was conducted. A gradual decrease in viral RNA transcription and an immediate decrease in M protein levels were observed in cells inoculated with the CpD-PACT-treated virus. These results demonstrated that CpD is a potential photodynamic antiviral agent, which causes inactivation of the matrix protein as well as transcription mechanisms involved in VSV replication.

The predictors for continuous renal replacement therapy in liver transplant recipients.

BACKGROUND Acute renal failure (ARF) after liver transplantation requiring continuous renal replacement therapy (CRRT) adversely affects patient survival. We suggested that postoperative renal failure can be predicted if a clinically simple nomogram can be developed, thus selecting potential risk factors for preventive strategy. METHODS We retrospectively reviewed the medical records of 153 liver transplant recipients from January 2008 to December 2011 at Severance Hospital, Yonsei University Health System, in Seoul, Korea. There were 42 patients treated with CRRT (20 and 22 patients received transplants from living and deceased donors, respectively) and 115 were not. Univariate and stepwise logistic multivariate analyses were performed. A clinical nomogram to predict postoperative CRRT application was constructed and validated internally. RESULTS Hepatic encephalopathy (HEP; odds ratio OR, 5.47), deceased donor liver donations (OR, 3.47), Model for End-Stage Liver Disease (MELD) score (OR, 1.09), intraoperative blood loss (L; OR, 1.16), and tumor (hepatocellular carcinoma) as the indication for liver transplantation (OR, 0.11) were identified as independent predictive factors for postoperative CRRT on multivariate analysis. A clinical prediction model constructed for calculating the probability of CRRT post-transplantation was 1.7000 × HEP + [-4.5427 + 1.2440 × (deceased donor) + 0.0830 × (MELD score) + 0.000149 × the amount of intraoperative bleeding (L) - 2.1785 × tumor]. The validation set discriminated well with an area under the curve (AUC) of 0.90 (95% confidence interval, 0.85-0.95). The predicted and the actual probabilities were calibrated with the clinical nomogram. CONCLUSIONS We developed a predictive model of postoperative CRRT in liver transplantation patients. Perioperative strategies to modify these factors are needed.

Mixed finite element domain decomposition for nonlinear parabolic problems

Abstract Fully discrete mixed finite element method is considered to approximate the solution of a nonlinear second-order parabolic problem. A massively parallel iterative procedure based on domain decomposition technique is presented to solve resulting nonlinear algebraic equations. Robin type boundary conditions are used to transmit information between subdomains. The convergence of the iteration for each time step is demonstrated. Optimal-order error estimates are also derived. Numerical examples are given.

Abstract 5110: Activation of Wnt/β-catenin, hedgehog and androgen receptor signaling pathways in solid pseudopapillary neoplasm of pancreas.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Solid pseudopapillary neoplasm (SPN), is an uncommon pancreatic tumor with distinct clinicopathologic features. Mutations in the exon 3 of β-catenin are characteristically identified in SPNs, however little is known about gene and microRNA expression characteristics. To investigate the molecular characteristics of SPNs, we analyzed mRNA and microRNA expression profiles of 14 SPNs and compared their expressions to that of 6 pancreatic ductal adenocarcinomas, 6 endocrine tumors of pancreas, and 5 non-neoplastic pancreas tissues. We demonstrated both mRNA and microRNA expression profiles completely distinguish SPNs to the other pancreatic tumors and non-neoplastic pancreas tissues. We found that Wnt/β-catenin, Hedgehog and androgen receptor signaling pathways are activated in SPNs by analyzing 1,686 genes that showed specific expression changes in SPN. We also found that 7 microRNAs were specifically down-regulated in SPNs, and miR-30a was most closely associated with the up-regulation of the genes belong to the three distinct activated pathways of SPN. We also demonstrated that genes involved in epithelial to mesenchymal transition (EMT) are up-regulated in SPNs than the other type of pancreatic tumors. SPN is characterized by increased expression of mesenchymal markers (N-cadherin, MMP9, Vercican, TIMP1) and decreased expression of epithelial markers (E-cadherin, Desmoplakin, Mucin1, Caveolin). Considering that activated Wnt/β-catenin and Hedgehog pathways are related to the activation of the genes involved in EMT, these activated signaling pathways of SPNs can explain lack of epithelial cell differentiation, and the molecular mechanism of SPN tumorigenesis. Citation Format: Minhee Park, Minhyung Kim, Daehee Hwang, SangKyum Kim, Eunsung Park, Youngki Paik, Jeonhan Park, Hogeun Kim. Activation of Wnt/β-catenin, hedgehog and androgen receptor signaling pathways in solid pseudopapillary neoplasm of pancreas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5110. doi:10.1158/1538-7445.AM2013-5110