Using high-density oligonucleotide microarrays, we investigated DNA copy-number aberrations in cell lines derived from hepatocellular carcinomas (HCCs) and detected a novel amplification at 17p11. To identify the targ...
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Using high-density oligonucleotide microarrays, we investigated DNA copy-number aberrations in cell lines derived from hepatocellular carcinomas (HCCs) and detected a novel amplification at 17p11. To identify the target of amplification at 17p11, we defined the extent of the amplicon and examined HCC cell lines for expression of all seven genes in the 750-kb commonly amplified region. Mitogen-activated protein kinase (MAPK) 7, which encodes extracellular-regulated protein kinase(ERK) 5, was overexpressed in cell lines in which the gene was amplified. An increase in MAPK7 copy number was detected in 35 of 66 primary HCC tumors. Downregulation of MAPK7 by small interfering RNA suppressed the growth of SNU449 cells, the HCC cell line with the greatest amplification and overexpression of MAPK7. ERK5, phosphorylated during the G2/M phases of the cell cycle, regulated entry into mitosis in SNU449 cells. In conclusion, our results suggest that MAPK7 is likely the target of 17p11 amplification and that the ERK5 protein product of NIAPK7 promotes the growth of HCC cells by regulating mitotic entry. (c) 2008 Wiley-Liss, Inc.
The peritumoral inflammatory environment is critical for the progression of intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the relevance of peritumoral mast ...
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The peritumoral inflammatory environment is critical for the progression of intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the relevance of peritumoral mast cells (MCs) to HCC outcomes. Peritumoral tryptase(+) MCs in addition to Foxp3(+) T-regulatory cells (Tregs) were evaluated using immunohistochemistry enumeration in tissue microarrays containing 207 randomly selected HCC patients. Clinicopathological factors and postoperative outcomes were compared between high and low subgroups of MCs or Tregs. Compared to low denstiy, higher peritumoral MCs were associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence (54.1% vs 39.2%, P = 0.026). High-dense MCs were especially related to increased probability of early recurrence (within 2 years) (P = 0.004). We also found that peritumoral Tregs were positively correlated with MCs in density (r = 0.353, P < 0.001) and reversely related to HCC outcomes. Notably, MCs in combination with Tregs displayed better prognostic performances than MCs alone (area under curve [AUC](survival) = 0.629 vs 0.589, AUC(recurrence) = 0.632 vs 0.591). Moreover, MCs were positively correlated to alanine aminotransferase, a serum inflammatory marker (P = 0.014). Therefore, peritumoral MCs are promising prognostic parameters for HCC mainly through inflammation response-related mechanisms, and we propose that MCs and Tregs may cooperate with each other and result in poorer prognosis. (Cancer Sci 2009;100: 1267-1274)
In regions with a limited deceased donor pool, living donor adult liver transplantation (LDALT) has become an important treatment modality for patients with hepatocellular carcinoma (HCC) and cirrhosis. Studies have s...
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In regions with a limited deceased donor pool, living donor adult liver transplantation (LDALT) has become an important treatment modality for patients with hepatocellular carcinoma (HCC) and cirrhosis. Studies have shown higher recurrence rates of HCC after LDALT in comparison with deceased donor liver transplantation (DDLT). The aim of our study was to examine the outcome results and recurrence rates for patients with HCC who underwent LDALT at our center. During an 8-year period, 139 patients underwent LDALT, of whom 28 (20.1%) had HCC in their explanted livers. The median follow-up was 40.8 months. The mean explant tumor size was 3.3 +/- 1.2, and the mean number of tumors was 1.5 +/- 0.8. Twenty-one patients (75%) had tumors within the Milan criteria, 5 patients had tumors outside the Milan criteria but within the University of California San Francisco (UCSF) criteria, and 2 patients were beyond the UCSF criteria. The overall 1- and 5-year patient and graft survival rates were 96% and 81%, respectively. Survival following LDALT was significantly better than survival following DDLT for HCC during the same time period (P = 0.02). Eight patients (28.6%) developed tumor recurrence. Poor differentiation of tumor cells was the most significant determinant of recurrence. Despite high recurrence rates of HCC following LDALT, overall 5-year survival appears to be excellent. Liver Transpl 15:1861-1866, 2009. (C) 2009 AASLD.
Background. Tumor progression before liver transplantation (OLT) is the main cause of dropout from the waiting list (WL) of patients with hepatocellular carcinoma (HCC). The aim of this study was to show a correlation...
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Background. Tumor progression before liver transplantation (OLT) is the main cause of dropout from the waiting list (WL) of patients with hepatocellular carcinoma (HCC). The aim of this study was to show a correlation between adopted dropout criteria and dropout/intention-to-treat survival rates of WL HCC patients. Methods. The study period was 2000 to 2007. The dropout criteria were macroscopic vascular invasion, metastases, or a poorly differentiated tumor. Adult patients with benign chronic liver disease enlisted for primary OLT in the same period represented the control group. Results. Dropout probability of study (n = 128) versus control group (n = 377) subjects was similar: namely, 12% at 1 year in both groups (P = NS). Intention-to-treat survival curve of the HCC group overlapped that of the benign group (5-year survival rates were 73% and 71%, respectively;P = NS). At the time of listing, 103 study group patients were within the Milan criteria (MC): among these patients, 29 (28%) showed tumor progression beyond MC before OLT. Simulating the dropout of these 29 patients at the time of diagnosis of tumor progression, we compared the dropout probability of the 103 patients within MC with that of the control group. As a result, the 1- and 2-year dropout rates became 37% and 53%, respectively, in the study group, which were significantly higher than those in the controls (P < .01). Conclusion. HCC patients on the WL showed a significantly greater dropout rate than subjects with benign cirrhosis when too restrictive radiologic dropout criteria were used. The adoption of criteria more related to biological aggressiveness of a tumor decreased the dropout risk for HCC patients without impairing their intention-to-treat survival rates.
The occurrence of de novo hepatocellular carcinoma (HCC) after liver transplantation (LT) for advanced HCCs has been extremely limited. In this article, a case of de novo HCC in a liver graft with sustained hepatitis ...
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The occurrence of de novo hepatocellular carcinoma (HCC) after liver transplantation (LT) for advanced HCCs has been extremely limited. In this article, a case of de novo HCC in a liver graft with sustained hepatitis C virus clearance after living donor liver transplantation (LDLT) for multiple HCCs and hepatitis C cirrhosis is reported. The recipient was a 58-year-old female, and the left lobe living donor was the 30-year-old healthy daughter of the recipient. Three years after LDLT, the patient received 48 weeks of interferon treatment for recurrent hepatitis C with advanced fibrosis. The patient has shown successful viral clearance since then. However, an HCC was recognized in the liver graft during a follow-up computed tomography scan performed 6 years after LDLT, and it was surgically resected. To analyze its origin [either from the patient (metastatic) or from the living donor (de novo)], genotyping by microsatellite analysis of tissue and blood samples from the donor and recipient was performed, and it revealed that the HCC originated from the donor. To the best of our knowledge, this is the first report of de novo HCC in a liver graft with sustained hepatitis C virus clearance after LT for advanced HCCs and hepatitis C cirrhosis. Liver Transpl 15:1412-1416, 2009. (C) 2009 AASLD.
Chronic hepatitis C virus (HCV) infection often results in hepatocellular carcinoma (HCC). Previous studies have shown that there might be some characteristic mutations in the core region of HCV related to HCC. Thus, ...
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Chronic hepatitis C virus (HCV) infection often results in hepatocellular carcinoma (HCC). Previous studies have shown that there might be some characteristic mutations in the core region of HCV related to HCC. Thus, we downloaded and analyzed HCV genotype 1b core gene sequences from HCV databases online to identify them. Based on the information of the sequences, 63 from patients with HCC and 188 from non-HCC were enrolled into our analysis. Then, the nucleotides at each position were compared by KH2-test between the two groups, and 24 polymorphisms were found to be associated with HCC. Further analysis of these 24 polymorphisms by logistic regression indicated that eight were significantly related to the increased HCC risk: A028C, G209A, C219U/A, U264C, A271C/U, C378U/A, G435A/C, and G481A. Moreover, U303C/A was associated with the decreased HCC risk. These mutations could bring about four amino acid substitutions: K10Q, R70Q, M91L, and G161S. In conclusion, eight characteristic mutations in the HCV-1b core gene related to the occurrence of HCC were identified. The structural and functional alterations of core protein due to these mutations and the relationship with the occurrence of HCC need to be further studied. (Cancer Sci 2009;100: 2465-2468).
Mst1 and Mst2 are key components of the Hippo tumor suppressor pathway. In this issue, Zhou et al. (2009) reported that Mst1/2 ablation leads to hepatocellular carcinomas. Unexpectedly, Mst1/2 may activate another kin...
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Mst1 and Mst2 are key components of the Hippo tumor suppressor pathway. In this issue, Zhou et al. (2009) reported that Mst1/2 ablation leads to hepatocellular carcinomas. Unexpectedly, Mst1/2 may activate another kinase besides Lats1 and Lats2 to phosphorylate YAP, and the role of Mst1/2 in YAP regulation is cell type dependent.
The efficacy of sorafenib for the treatment of hepatocellular carcinoma (HCC) has triggered major interest in molecular therapy in this setting and the search for agents or a combination of agents that exceed the bene...
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The efficacy of sorafenib for the treatment of hepatocellular carcinoma (HCC) has triggered major interest in molecular therapy in this setting and the search for agents or a combination of agents that exceed the benefits of sorafenib. An understanding of a new drug's mechanism of action is essential in determining whether the new agent has a unique therapeutic profile worth further testing, either alone or in combination. Additionally, proper description of patients and treatment effects in terms of response to therapy and of safety is essential. Cirrhosis underlies HCC in most patients and impairment of liver function-leading to life-threatening complications-is of major concern. It is important to note that molecular targeted agents do not induce a large number of objective tumour responses.3 Accordingly, capturing potential efficacy is based on time to tumour progression (TTP) data rather than in a reduction in tumour burden. New tools will be developed using imaging techniques to measure tumour perfusion and metabolic activity. However, until these are available, we must stick to definitions that can be used across studies.
Currently, applications that focus on providing conversations with virtual humans require extensive work to create robust conversational models. We present a new approach called human-centered Distributed Conversation...
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ISBN:
(纸本)9783642043796
Currently, applications that focus on providing conversations with virtual humans require extensive work to create robust conversational models. We present a new approach called human-centered Distributed Conversational Modeling. Using this approach, users create conversational models in a distributed manner. To do this, end-users interact with virtual humans to provide new stimuli (questions and statements), and domain-specific experts (e.g. medical/psychology educators) provide new virtual human responses. Using this process, users become the primary developers of conversational models. We tested our approach by creating an example application, Virtual People Factory. Using Virtual People Factory, a pharmacy instructor and 186 pharmacy students were able to create a robust conversational model in 15 hours. This is approximately 10% of the time typical in current approaches and results in more comprehensive coverage of the conversational space. In addition, surveys demonstrate the acceptability of this approach by both educators and students.
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