Transfection of Thymidine Phosphorylase CDNA to Human Hepatocellular Carcinoma Cells Enhances Sensitivity to Fluoropyrimidine but Augments Endothelial Cell Migration

Journal of Cancer Research and Clinical Oncology. Aug, 2005  |  Pubmed ID: 15864645

To investigate the effects on sensitivity to fluoropyrimidine and endothelial cell (EC) migration by transfection with thymidine phosphorylase (TP) cDNA to a hepatocellular carcinoma (HCC) cell line SMMC-7721.

Liver Transplantation for Patients with Hepatocellular Carcinoma at the Liver Cancer Institute of Fudan University, China

Chinese Medical Journal. Apr, 2005  |  Pubmed ID: 15899120

Selection of patients with hepatocellular carcinoma (HCC) for orthotopic liver transplantation (OLT) remains controversial. Since there is a trend to expand the transplant criteria for HCC patients, we reviewed the data of patients with HCC who had received OLT at our institute to determine their survival and prognostic factors.

Consideration of Role of Radiotherapy for Lymph Node Metastases in Patients with HCC: Retrospective Analysis for Prognostic Factors from 125 Patients

International Journal of Radiation Oncology, Biology, Physics. Nov, 2005  |  Pubmed ID: 15913915

To evaluate the role of radiotherapy (RT) for hepatocellular carcinoma (HCC) patients with abdominal lymph node (LN) metastasis at our institution in the past 7 years.

[Changes in the Immune Function of Dendritic Cells (DC) Derived from HBV-related Hepatocellular Carcinoma (HCC) Patient's Peripheral Blood Monocytes (PBMC) Pulsed with Tumor Antigen]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. May, 2005  |  Pubmed ID: 15918966

To identify the phenotype and immune function of dendritic cells derived from HBV-related HCC patients's peripheral blood monocytes pulsed with soluble tumor antigen, and their relation to immune escape.

[Relationship Between Dendritic Cells and Memory T Lymphocytes in Tumor Site and Prognosis of Hepatocellular Carcinoma]

Zhonghua Yi Xue Za Zhi. Mar, 2005  |  Pubmed ID: 15932729

To investigate the relationship between the distribution and quantity of dendritic cells (DCs) and memory T lymphocytes in the tumor site and the prognosis of hepatocellular carcinoma (HCC).

[Study of Serum Proteome Biomarkers with Relation to the Formation of Portal Vein Tumor Thrombi in Hepatocellular Carcinoma Patients]

Zhonghua Yi Xue Za Zhi. Mar, 2005  |  Pubmed ID: 15949388

To screen serum proteome biomarkers and establish predictive model with relation to the formation of portal vein tumor thrombi (PVTT) in hepatocellular carcinoma (HCC) patients.

Risk Factors for Postoperative Complications After Liver Resection

Hepatobiliary & Pancreatic Diseases International : HBPD INT. Aug, 2005  |  Pubmed ID: 16109518

Liver resection is still a complicated operation with a high risk of postoperative morbidity. This study was undertaken to analyze the risk factors for postoperative complications after liver resection.

An Extrasynaptic GABAA Receptor Mediates Tonic Inhibition in Thalamic VB Neurons

Journal of Neurophysiology. Dec, 2005  |  Pubmed ID: 16162835

Whole cell patch-clamp recordings were obtained from thalamic ventrobasal (VB) and reticular (RTN) neurons in mouse brain slices. A bicuculline-sensitive tonic current was observed in VB, but not in RTN, neurons; this current was increased by the GABA(A) receptor agonist 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridine-3-ol (THIP; 0.1 microM) and decreased by Zn(2+) (50 microM) but was unaffected by zolpidem (0.3 microM) or midazolam (0.2 microM). The pharmacological profile of the tonic current is consistent with its generation by activation of GABA(A) receptors that do not contain the alpha(1) or gamma(2) subunits. GABA(A) receptors expressed in HEK 293 cells that contained alpha(4)beta(2)delta subunits showed higher sensitivity to THIP (gaboxadol) and GABA than did receptors made up from alpha(1)beta(2)delta, alpha(4)beta(2)gamma(2s,) or alpha(1)beta(2)gamma(2s) subunits. Western blot analysis revealed that there is little, if any, alpha(3) or alpha(5) subunit protein in VB. In addition, co-immunoprecipitation studies showed that antibodies to the delta subunit could precipitate alpha(4), but not alpha(1) subunit protein. Confocal microscopy of thalamic neurons grown in culture confirmed that alpha(4) and delta subunits are extensively co-localized with one another and are found predominantly, but not exclusively, at extrasynaptic sites. We conclude that thalamic VB neurons express extrasynaptic GABA(A) receptors that are highly sensitive to GABA and THIP and that these receptors are most likely made up of alpha(4)beta(2)delta subunits. In view of the critical role of thalamic neurons in the generation of oscillatory activity associated with sleep, these receptors may represent a principal site of action for the novel hypnotic agent gaboxadol.

[What Are the Indications of Liver Transplantion in Hepatic Cancer Patients?]

Zhonghua Yi Xue Za Zhi. Jun, 2005  |  Pubmed ID: 16251064

[Diagnosis and Management for Early Hepatic Artery Thrombosis After Liver Transplantation]

Zhonghua Yi Xue Za Zhi. Jun, 2005  |  Pubmed ID: 16251067

To explore the diagnosis and management of early hepatic artery thrombosis (HAT) after liver transplantation.

[Therapeutic Effectiveness of Liver Transplantation: a Single Center Study of 203 Consecutive Cases]

Zhonghua Yi Xue Za Zhi. Jul, 2005  |  Pubmed ID: 16253182

To investigate the measures to further improve the therapeutic efficacy of liver transplantation.

[Up-regulation of Thymidine Phosphorylase and Anti-angiogenesis by Interferon Alpha in Human Hepatocellular Carcinoma Cell Line and Xenograft]

Zhonghua Yi Xue Za Zhi. Nov, 2005  |  Pubmed ID: 16405841

To further study the impact of interferon-alpha (IFN-alpha) on thymidine phosphorylase (TP) expression and angiogenesis.

Short-term Synaptic Plasticity in the Rat Geniculo-cortical Pathway During Development in Vivo

Neuroscience Letters. May, 2006  |  Pubmed ID: 16406670

The critical period for visual system development in rats normally peaks at postnatal three weeks and ends at postnatal five weeks. However, the change of short-term synaptic plasticity during this period has rarely been investigated. In the present study, we compared the short-term plasticity of visual cortical responses to lateral geniculate nucleus stimulation in rats at different development stages (P20, P30 and adult) in vivo. The results show that paired-pulse depression (PPD) and frequency-dependent depression of evoked field potentials (FP) are present in P20 rats and increase in magnitude with development. The time course of this maturation of synaptic depression parallels that of the visual critical period. The weak synaptic depression observed in juvenile rats may be important in enhancing excitatory neurotransmission at a time when synapses are immature; this could endow immature synapses with wide integrative capabilities. In contrast, suppressive temporal interactions could provide an important substrate for neuronal processing of visual information in the mature cortex.

Dendritic Cell Infiltration and Prognosis of Human Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. May, 2006  |  Pubmed ID: 16421755

To elucidate the relationship between local immunocompetent cells and prognosis of human hepatocellular carcinoma (HCC) after resection.

Abdominal Drainage Was Unnecessary After Hepatectomy Using the Conventional Clamp Crushing Technique

Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract. Feb, 2006  |  Pubmed ID: 16455466

A prophylactic abdominal drainage catheter is routinely inserted by many surgeons in patients after hepatic resection. Between January 2002 and September 2004, 462 consecutive patients who had undergone hepatic resection using a clamp crushing method by the same surgical team were retrospectively divided into the drainage group (n = 357) and the nondrainage group (n = 105). There was no difference in hospital mortality between the two groups of patients (drainage group, 0.6% vs. nondrainage group, 0%; P = 1.0). However, there was a greater incidence of surgical complications in the drainage group (31.4% vs. 8.6%, P < 0.001), and greater incidence of wound complications and subphrenic complications in the drainage group compared to the nondrainage group (24.4% vs. 4.8%, P < 0.001). In addition, the mean (+/- SEM) postoperative hospital stay of the drainage group was 13 +/- 6.5 days, which was significantly longer than that of the nondrainage group (9.7 +/- 3.3 days, P = 0.001). On multivariate analysis, abdominal drainage and intraoperative bleeding were the independent risk factors that were significantly associated with the incidence of drainage-related complications. The results suggested that routine abdominal drainage is unnecessary after hepatic resection when the conventional clamp crushing method is used during parenchyma transection.

Solitary Fibrous Tumor of the Liver

Hepatobiliary & Pancreatic Diseases International : HBPD INT. Feb, 2006  |  Pubmed ID: 16481304

Solitary fibrous tumor of the liver is a rare neoplasm. So far, 23 cases have been described in the English literature. We reported an additional case.

Postoperative Interferon Alpha Treatment Postponed Recurrence and Improved Overall Survival in Patients After Curative Resection of HBV-related Hepatocellular Carcinoma: a Randomized Clinical Trial

Journal of Cancer Research and Clinical Oncology. Jul, 2006  |  Pubmed ID: 16557381

Recurrence after resection of hepatocellular carcinoma (HCC) is a frequent event. This study evaluated the effect of postoperative interferon alpha (IFN alpha) treatment on recurrence and survival in patients with hepatitis B virus (HBV)-related HCC.

Factors Influencing Survival in Hepatocellular Carcinoma Patients with Macroscopic Portal Vein Tumor Thrombosis After Surgery, with Special Reference to Time Dependency: a Single-center Experience of 381 Cases

Hepato-gastroenterology. Mar-Apr, 2006  |  Pubmed ID: 16608039

The prognosis ofhepatocellular carcinoma with macroscopic portal vein tumor thrombosis is extremely poor. The risk factors may differ at different postoperative intervals. This study was undertaken to clarify the surgical outcome and time dependency of factors influencing survival in these patients.

Study of Severe and Rare Complications of Transarterial Chemoembolization (TACE) for Liver Cancer

European Journal of Radiology. Sep, 2006  |  Pubmed ID: 16621394

To study severe and rare complications of transarterial chemoembolization (TACE) for liver cancer.

Consideration of the Role of Radiotherapy for Unresectable Intrahepatic Cholangiocarcinoma: a Retrospective Analysis of 75 Patients

Cancer Journal (Sudbury, Mass.). Mar-Apr, 2006  |  Pubmed ID: 16630402

The role of radiotherapy in the treatment of intrahepatic cholangiocarcinoma is controversial. We undertook this study to determine if radiotherapy is appropriate for patients with unresectable or lymph node metastatic intrahepatic cholangiocarcinoma.

Conversion to Sirolimus Immunosuppression in Liver Transplantation Recipients with Hepatocellular Carcinoma: Report of an Initial Experience

World Journal of Gastroenterology : WJG. May, 2006  |  Pubmed ID: 16718799

To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune, rapamycin) in a consecutive cohort of 248 liver allograft recipients.

[The Effects of Different Clinicopathologic Variables on Serum Protein Fingerprint in Hepatocellular Carcinoma Patients]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Apr, 2006  |  Pubmed ID: 16772076

To investigate the effects of different clinicopathologic variables on serum protein fingerprint in hepatocellular carcinoma (HCC) patients.

[Indication of Liver Transplantation for Hepatocellular Carcinoma: Shanghai Fudan Criteria]

Zhonghua Yi Xue Za Zhi. May, 2006  |  Pubmed ID: 16796876

To evaluate the effects of different selection criteria on the prognosis of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) and to explore the new criteria adapted for Chinese National Situation.

[Analysis of the Risk Factors Influencing the Prognosis of Orthotopic Liver Transplantation for Hepatocellular Carcinoma and Summary of Relevant Clinical Experience]

Zhonghua Yi Xue Za Zhi. May, 2006  |  Pubmed ID: 16796877

To analyze the risk factors influencing the prognosis of orthotopic liver transplantation for hepatocellular carcinoma (HCC) and sum up the relevant clinical experience in diagnosis and treatment of HCC.

[Inhibition of Growth and Metastasis of Hepatocellular Carcinoma by Rapamycin: Experiment with Mice]

Zhonghua Yi Xue Za Zhi. Jun, 2006  |  Pubmed ID: 16854316

To investigate the effects of rapamycin (RPM) in inhibiting the growth and metastasis of hepatocellular carcinoma (HCC).

[Indications of Liver Transplantation for Hepatocellular Carcinoma Patients]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Jul, 2006  |  Pubmed ID: 16867279

Polyethylene Glycol Fractionation Improved Detection of Low-abundant Proteins by Two-dimensional Electrophoresis Analysis of Plant Proteome

Phytochemistry. Nov, 2006  |  Pubmed ID: 16973185

Poor detection of low-abundant proteins is a common problem in two-dimensional electrophoresis (2-DE) for separation of proteins in a proteome analysis. This is attributed partially, at least, to the existence of high-abundant proteins, e.g. ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) in plants. They engage a large proportion of the whole-cell proteins and thus prevent low-abundant proteins from being up-taken by immobilized pH gradient (IPG) strip, consequently making the latter poorly detectable by 2-DE. In this work, we report a straightforward protocol for preparation of whole-cell proteins through differential polyethylene glycol (PEG) precipitation aiming at elimination of Rubisco from plant protein samples. In comparison with 2-DE analysis of protein samples prepared using a conventional TCA/acetone method, a relatively high reproducibility of proteins was achieved using a PEG fractionation protocol in terms of protein yield and protein species. As expected, the large subunit of Rubisco was precipitated predominantly in the 16% PEG fraction. This allowed proteins of the Rubisco-containing fraction to be analyzed separately from those of other PEG fractions. After taking into account the overlapping protein spots among 2-DE gels of all fractions through image and statistical analyses, we detected with this protocol a total 5077 protein spots, among which ca. 80% are proteins undetectable with the TCA/acetone method, while the rest of proteins exhibited a significant increase in their abundance. This protocol was developed using Arabidopsis as a source of protein and thus may also be applicable to protein preparations of other plants.

[Time Dependency of Factors Influencing Survival of Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis After Surgery]

Zhonghua Yi Xue Za Zhi. Nov, 2006  |  Pubmed ID: 17288818

To investigate the surgical outcome of the hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) after surgery and the time-dependency of the factors influencing survival.

Downregulation of CCR1 Inhibits Human Hepatocellular Carcinoma Cell Invasion

Biochemical and Biophysical Research Communications. Apr, 2007  |  Pubmed ID: 17336272

CC chemokine receptor 1 (CCR1) has an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 is highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we silenced CCR1 expression in the human HCC cell line HCCLM3 using artificial microRNA (miRNA)-mediated RNA interference (RNAi) and examined the invasiveness and proliferation of CCR1-silenced HCCLM3 cells and the matrix metalloproteinase (MMP) activity. The miRNA-mediated knockdown expression of CCR1 significantly inhibited the invasive ability of HCCLM3 cells, but had only a minor effect on the cellular proliferation rate. Moreover, CCR1 knockdown significantly reduced the secretion of MMP-2. Together, these findings indicate that CCR1 has an important role in HCCLM3 invasion and that CCR1 might be a new target of HCC treatment.

Incidence and Prognostic Values of Lymph Node Metastasis in Operable Hepatocellular Carcinoma and Evaluation of Routine Complete Lymphadenectomy

Journal of Surgical Oncology. Jul, 2007  |  Pubmed ID: 17345597

To study lymph node metastasis (LNM) and prognosis in patients with operable hepatocellular carcinoma (HCC) as well as the value of routine complete lymphadenectomy. Few studies have been reported on LNM in patients with operable HCC.

GABAA Receptors in the Thalamus: Alpha4 Subunit Expression and Alcohol Sensitivity

Alcohol (Fayetteville, N.Y.). May, 2007  |  Pubmed ID: 17521848

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has long been implicated in the anxiolytic, amnesic, and sedative behavioral effects of alcohol. A large number of studies have investigated the interactions of alcohol with GABA receptors. Many investigators have reported effects of "high concentrations" (50-100 mM) of alcohol on GABA-mediated synaptic inhibition, but effects of the "low concentrations" (1-30 mM) of alcohol normally associated with mild intoxication have been elusive until recently. A novel form of "tonic inhibition" has been described in the central nervous system (CNS) that is generated by the persistent activation of extrasynaptic gamma-aminobutyric acid type A receptors (GABAA-Rs). These receptors are specific GABAA-R subtypes and distinct from the synaptic subtypes. Tonic inhibition regulates the excitability of individual neurons and the activity and rhythmicity of neural networks. Interestingly, several reports show that tonic inhibition is sensitive to low concentrations of alcohol. The thalamus is a structure that is critically important in the control of sleep and wakefulness. GABAergic inhibition in the thalamus plays a crucial role in the generation of sleep waves. Among the various GABAA-R subunits, the alpha1, alpha4, beta2, and delta subunits are heavily expressed in thalamic relay nuclei. Tonic inhibition has been demonstrated in thalamocortical relay neurons, where it is mediated by alpha4beta2delta GABAA-Rs. These extrasynaptic receptors are highly sensitive to gaboxadol, a novel hypnotic, but insensitive to benzodiazepines. Tonic inhibition is absent in thalamic relay neurons from alpha4 knockout mice, as are the sedative and analgesic effects of gaboxadol. The sedative effects of alcohol can promote sleep. However, alcohol also disrupts the normal sleep pattern and reduces sleep quality. As a result, sleep disturbance caused by alcohol can play a role in the progression of alcoholism. As an important regulator of sleep cycles, inhibition in the thalamus may therefore be involved in both the sedative effects of alcohol and the development of alcoholism. Investigating the effects of alcohol on both synaptic and extrasynaptic GABAA-Rs in the thalamus should help us to understand the mechanisms underlying the interaction between alcohol and sleep.

[Survival of Patients with Liver Metastasis from Colorectal Cancer by Different Modes of Therapy: a Report of 363 Cases]

Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology]. Jan, 2007  |  Pubmed ID: 17575696

To evaluate the correlation between different therapies and survival of liver metastasis from colorectal cancer ( LMCC) , and to compare the clinical outcome of synchronous liver metastasis (SLM) with that of metachronous liver metastasis (MLM).

Intratumoral Balance of Regulatory and Cytotoxic T Cells is Associated with Prognosis of Hepatocellular Carcinoma After Resection

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jun, 2007  |  Pubmed ID: 17577038

To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection.

Atypical Hepatic Focal Nodular Hyperplasia Presenting As Acute Abdomen and Misdiagnosed As Hepatocellular Carcinoma

Hepatology Research : the Official Journal of the Japan Society of Hepatology. Dec, 2007  |  Pubmed ID: 17608671

Focal nodular hyperplasia (FNH) is a rare benign hepatic lesion, which is usually asymptomatic and solitary. Complications such as rupture and bleeding are extremely rare and only five cases have existed since 1975. We report a case of a 26-year-old woman with spontaneous rupture and hemorrhage of huge FNH presenting as acute abdomen. Different to previously recorded cases, this case was concomitant with multiple hepatic adenomas, which was misdiagnosed as rupture of hepatocellular carcinoma (HCC) with multiple intrahepatic spreading in another hospital. Our case highlights thepossible association between the size of FNH and the risk of rupture, and emphasizes the need to consider this in making treatment decisions. Although a conservative approach for asymptomatic FNH is well established, the potential for surgical intervention should always be considered, especially for large FNH. We recommend surgical resection of large FNH (>5 cm), symptomatic or not, rather than observation.

Positive Serum Hepatitis B E Antigen is Associated with Higher Risk of Early Recurrence and Poorer Survival in Patients After Curative Resection of Hepatitis B-related Hepatocellular Carcinoma

Journal of Hepatology. Nov, 2007  |  Pubmed ID: 17854945

To study the impact of hepatitis B e antigen on tumor recurrence and patients' survival after curative resection of hepatocellular carcinoma.

[Relation Between Changes of Dendritic Cell Function and Down-regulation of Beta-centractin in Hepatocellular Carcinoma]

Zhonghua Yi Xue Za Zhi. Aug, 2007  |  Pubmed ID: 17925177

To investigate the relation between the changes of dendritic cell (DC) function and down-regulation of beta-centractin in hepatocellular carcinoma.

[Interferon Alpha Enhances the Sensitivity of SMMC-7721 Hepatocellular Carcinoma Cells to 5'-deoxy-5-fluorouridine Related to Up-regulation of Thymidine Phosphorylase]

Zhonghua Yi Xue Za Zhi. Aug, 2007  |  Pubmed ID: 17988526

To observe changes of sensitivity to 5'-deoxy-5-fluorouridine (5'-dFUrd), and 5-fluorouracil (5-FU) in SMMC-7721 hepatocellular carcinoma cells by interferon alpha (IFN-alpha), and its relationship with the expression of thymidine phosphorylase (TP).

[Influence of Tumor Characteristics on the Outcome of Liver Transplantation Among Patients with Hepatocellular Carcinoma]

Zhonghua Yi Xue Za Zhi. Aug, 2007  |  Pubmed ID: 17988527

To identify the influence of tumor characteristics on the outcome of liver transplantation (LT) among patients with hepatocellular carcinoma (HCC).

Identification and Analysis of Alpha1,6-fucosylated Proteins in Human Normal Liver Tissues by a Target Glycoproteomic Approach

Electrophoresis. Dec, 2007  |  Pubmed ID: 18041034

alpha1,6-Fucose residues within the N-glycan core structures were commonly observed in many glycoproteins. Our previous studies showed that aberrantly alpha1,6-fucosylated glycoproteins might be associated with metastasis of hepatocellular carcinoma (HCC). Little is known about human normal liver tissues (HNLTs) in the literatures. In this study, a target glycoproteomic approach which consists of lectin-affinity chromatography, 2-DE, protein immunoprecipitation and lectin blot, and MALDI-MS/MS, was utilized to screen physiologically alpha1,6-fucosylated glycoproteins. Lens culinaris agglutinin (LCA)-affinity glycoprotein profiles of HNLT were established and analyzed, which allowed identification of 53 proteins by MS analysis, including haptoglobin precursor, alpha-enolase, etc. Gene ontology (GO) annotation proved that these proteins distribute predominately in organelle and play crucial roles in binding and catalytic reactions. The present methodology enabled the identification of all the specific subsets of glycoprotein, and the corresponding data could contribute to the finding of more aberrantly alpha1,6-fucosylated glycoproteins related to liver diseases.

[Pulmonary Infection and Its Risk Factors After Orthotopic Liver Transplantation]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Nov, 2007  |  Pubmed ID: 18073066

To investigate the characteristics of pulmonary infection and its risk factors after orthotopic liver transplantation (OLT).

Bid-independent Mitochondrial Activation in Tumor Necrosis Factor Alpha-induced Apoptosis and Liver Injury

Molecular and Cellular Biology. Jan, 2007  |  Pubmed ID: 17101783

The death receptor apoptosis pathway is intimately connected with the mitochondrial apoptosis pathway. Bid is a BH3-only pro-death Bcl-2 family protein and is the major molecule linking the two pathways. Bid-mediated mitochondrial activation occurs early and is responsible for the prompt progress of tumor necrosis factor alpha (TNF-alpha)-induced apoptosis. However, in both cultured cells and animal models of TNF-alpha-induced injury, later-phase Bid-independent mitochondrial activation could be demonstrated. Consequently, bid-deficient mice are still susceptible to endotoxin-induced liver injury and mortality. Notably, embryonic hepatocyte apoptosis and lethality caused by TNF-alpha in the absence of p65relA cannot be rescued by the simultaneous deletion of bid. Further studies indicate that multiple mechanisms including reactive oxygen species, JNK, and permeability transition are critically involved in Bid-independent mitochondrial activation. Inhibition of these events suppresses TNF-alpha-induced mitochondrial activation and apoptosis in bid-deficient cells. These findings thus indicate that there are at least two sets of mechanisms of mitochondrial activation upon TNF-alpha stimulation. While the Bid-mediated mechanism is rapid and potent, the Bid-independent mechanism progresses gradually and involves multiple players. The critical involvement of Bid-independent mitochondrial activation in TNF-alpha-induced apoptosis demands the intervention of TNF-alpha-mediated tissue injury via multiple avenues.

Utilizing Generalized Autocalibrating Partial Parallel Acquisition (GRAPPA) to Achieve High-resolution Contrast-enhanced MR Angiography of Hepatic Artery: Initial Experience in Orthotopic Liver Transplantation Candidates

European Journal of Radiology. Mar, 2007  |  Pubmed ID: 17169520

To evaluate feasibility of using GRAPPA to acquire high-resolution 3D contrast-enhanced MR angiography (CE-MRA) of hepatic artery and value of GRAPPA for displaying vessels anatomy.

Focal Nodular Hyperplasia of the Liver in 86 Patients

Hepatobiliary & Pancreatic Diseases International : HBPD INT. Feb, 2007  |  Pubmed ID: 17287167

Focal nodular hyperplasia (FNH), the second most common benign hepatic tumor after hemangioma, is characterized by a stellate central scar and hyperplastic nodules. Although some large FNH may be associated with significant symptoms, more frequently they are discovered incidentally on physical examination or the work-up of unrelated symptoms. Since its nature and pathogenesis are still controversial, accurate diagnosis of FNH based on clinical presentation and radiographic studies is difficult. The purpose of this study was to explore the diagnosis and treatment of FNH.

[Diagnosis and Treatment of Primary Hepatic Carcinoid Tumor]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Oct, 2007  |  Pubmed ID: 18241569

To discuss the diagnosis and treatment of primary hepatic carcinoid tumor (PHCT).

[The Role of FAK Expression Inhibition by RNA Interference on Liver Cancer Cells]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Oct, 2007  |  Pubmed ID: 18241574

To study the role of inhibition FAK expression by FAK siRNA in liver cancer cell (MHCC97-H) adhesion, invasion and cytoskeleton rearrangement.

[Screening Low Molecular Weight Protein Biomarkers Relevant to Portal Vein Tumor Thrombi in Serum of Patients with Hepatocellular Carcinoma]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Jul, 2007  |  Pubmed ID: 17669237

To screen low molecular weight protein biomarkers relevant to portal vein tumor thrombi (PVTT) in serum of hepatocellular carcinoma (HCC) patients.

[Focal Adhesion Kinase MRNA Overexpression in Hepatocellular Carcinoma HCC) and Correlation Thereof with Prognosis of HCC]

Zhonghua Yi Xue Za Zhi. May, 2007  |  Pubmed ID: 17686260

To investigate whether focal adhesion kinase (FAK) is involved in the progression of human hepatocellular carcinoma (HCC) and whether FAK mRNA expression has prognostic significance for HCC.

[Therapeutic Effects of Hepatic Resection in Liver Metastasis of Colorectal Cancer]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Apr, 2007  |  Pubmed ID: 17686299

To evaluate therapeutic effects of hepatic resection in liver metastasis of colorectal cancer (LMCC).

Dendritic HCN2 Channels Constrain Glutamate-driven Excitability in Reticular Thalamic Neurons

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Aug, 2007  |  Pubmed ID: 17687049

Hyperpolarization activated cyclic nucleotide (HCN) gated channels conduct a current, I(h); how I(h) influences excitability and spike firing depends primarily on channel distribution in subcellular compartments. For example, dendritic expression of HCN1 normalizes somatic voltage responses and spike output in hippocampal and cortical neurons. We reported previously that HCN2 is predominantly expressed in dendritic spines in reticular thalamic nucleus (RTN) neurons, but the functional impact of such nonsomatic HCN2 expression remains unknown. We examined the role of HCN2 expression in regulating RTN excitability and GABAergic output from RTN to thalamocortical relay neurons using wild-type and HCN2 knock-out mice. Pharmacological blockade of I(h) significantly increased spike firing in RTN neurons and large spontaneous IPSC frequency in relay neurons; conversely, pharmacological enhancement of HCN channel function decreased spontaneous IPSC frequency. HCN2 deletion abolished I(h) in RTN neurons and significantly decreased sensitivity to 8-bromo-cAMP and lamotrigine. Recapitulating the effects of I(h) block, HCN2 deletion increased both temporal summation of EPSPs in RTN neurons as well as GABAergic output to postsynaptic relay neurons. The enhanced excitability of RTN neurons after I(h) block required activation of ionotropic glutamate receptors; consistent with this was the colocalization of HCN2 and glutamate receptor 4 subunit immunoreactivities in dendritic spines of RTN neurons. The results indicate that, in mouse RTN neurons, HCN2 is the primary functional isoform underlying I(h) and expression of HCN2 constrains excitatory synaptic integration.

[An Analysis of Annexin II Related to HCC Metastatic Ability]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Aug, 2007  |  Pubmed ID: 17711622

To use a glycemic method to screen hepatocellular carcinoma (HCC) metastasis related aberrant 1-6 fucosylated glycoproteins, and to analyze the metastasis-related alterations of annexin II.

Screening and Detection of Portal Vein Tumor Thrombi-associated Serum Low Molecular Weight Protein Biomarkers in Human Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. Mar, 2008  |  Pubmed ID: 17828420

Serum low molecular weight protein biomarkers might be important in relation to portal vein tumor thrombi (PVTT) in hepatocellular carcinoma (HCC). This study aimed to screen and to detect these biomarkers.

Metastatic Hepatocellular Carcinoma in the Esophagus Following Liver Transplantation

Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Nov, 2008  |  Pubmed ID: 18975278

Osteopontin Combined with CD44, a Novel Prognostic Biomarker for Patients with Hepatocellular Carcinoma Undergoing Curative Resection

The Oncologist. Nov, 2008  |  Pubmed ID: 18997126

Osteopontin (OPN) plays important roles in tumor progression and metastasis through binding to CD44 and integrin. The goal of this study was to elucidate the prognostic significance of OPN and CD44 in hepatocellular carcinoma patients.

Association of Autophagy Defect with a Malignant Phenotype and Poor Prognosis of Hepatocellular Carcinoma

Cancer Research. Nov, 2008  |  Pubmed ID: 19010888

Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The role of autophagy and the prognostic value of autophagic genes are largely unknown in HCC. Here, we showed decreased expression of autophagic genes and their corresponding autophagic activity and increased expression of the antiapoptotic gene Bcl-xL in HCC cell lines compared with a normal hepatic cell line. We also found decreased expression of the autophagic gene Beclin 1 in 44 HCC tissue samples compared with adjacent nontumor tissues. In addition, we found that the most aggressive malignant HCC cell lines and HCC tissues with recurrent disease displayed much lower autophagic levels, especially when Bcl-xL was overexpressed. Interestingly, in a tissue microarray study consisting of 300 HCC patients who underwent curative resection, the expression of Beclin 1 was only significantly correlated with disease-free survival (DFS; P < 0.0001) and overall survival (OS; P < 0.0001) in the Bcl-xL(+) group. Multivariate and univariate analyses also revealed that Beclin 1 expression was an independent predictor for DFS and OS in Bcl-xL(+) patients. In addition, we found a significant correlation between Beclin 1 expression and tumor differentiation in Bcl-xL(+) but not in Bcl-xL(-) HCC patients. In conclusion, our data showed expression of autophagic genes and their corresponding autophagic activities were suppressed in HCC. The autophagy defects synergized with altered apoptotic activity might facilitate tumor malignant differentiation, which results in a more aggressive cancer cell phenotype and poor prognosis of HCC.

[Interferon-alpha Upregulates Thymidine Phosphorylase Expression Via JAK-STAT Transcriptional Activation and MRNA Stabilization in Human Hepatocellular Carcinoma SMMC-7721 Cells]

Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology]. Jun, 2008  |  Pubmed ID: 19024520

To examine how the thymidine phosphorylase (TP) gene expression is upregulated by interferon-alpha (IFN-alpha) in human hepatocellular carcinoma SMMC-7721 cells.

Liver Ischaemia Following Vascular Occlusion: a Century's Experience

Scandinavian Journal of Gastroenterology. 2008  |  Pubmed ID: 19031295

Prognostic Factors for Patients with Hepatocellular Carcinoma with Macroscopic Portal Vein or Inferior Vena Cava Tumor Thrombi Receiving External-beam Radiation Therapy

Cancer Science. Dec, 2008  |  Pubmed ID: 19032365

Prognostic factors in patients with hepatocellular carcinoma (HCC) with tumor thrombosis are not well established, especially for those given external-beam radiation therapy (EBRT). Patients (n = 136) with HCC who had portal vein (PV) or inferior vena cava (IVC) tumor thrombus received EBRT between January 1998 and October 2007. Demographic variables, laboratory values, tumor characteristics, and treatment modalities were determined at diagnosis and before EBRT. The total radiation dose ranged from 30 to 60 Gy (median, 50 Gy) and was focused on the tumor thrombi. Predictors of survival were identified using the univariate and multivariate analysis. Of the 136 patients, the tumor thrombus completely disappeared in 41 patients (30.1%), 36 patients (26.5%) had a partial response, 49 patients (36%) had stable disease, and 10 patients (7.4%) had progressive disease. On multivariate analysis, pretreatment unfavorable predictors were associated with lower albumin, higher gamma-glutamyltransferase and alpha-fetoprotein levels, poorer Child-Pugh classification, intrahepatic multifocality, lymph node metastases, poorer response to EBRT, and 2-dimension EBRT technique. Survival rates at 1, 2, and 3 years were 31.8%, 17.5%, and 8.8% for patients with PV tumor thrombi; 66.3%, 21.1%, and 15.8% for IVC tumor thrombi; and 25%, 8.3%, and 0% for PV plus IVC tumor thrombi, respectively. Overall median survival was 9.7 months. This study provides detailed information about the survival outcomes and prognostic factors of HCC with tumor thrombi in a relatively large cohort of patients treated with radiation, and the results will help in understanding the potential factors that influence survival for patients with HCC after EBRT.

Selection of Reference Genes for Real-time PCR in Human Hepatocellular Carcinoma Tissues

Journal of Cancer Research and Clinical Oncology. Sep, 2008  |  Pubmed ID: 18317805

To investigate the most suitable housekeeping genes for quantifying a change in mRNA expression levels due to hepatitis virus B related hepatocellular carcinoma (HCC).

[Management of Biliary Complications in Liver Transplantation]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Apr, 2008  |  Pubmed ID: 18423144

[An in Vitro Research on Interleukin-1 Beta Promoted Invasiveness of Human Hepatocellular Carcinoma MHCC97-H Cells]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Apr, 2008  |  Pubmed ID: 18423160

Identification of Side Population Cells in Human Hepatocellular Carcinoma Cell Lines with Stepwise Metastatic Potentials

Journal of Cancer Research and Clinical Oncology. Nov, 2008  |  Pubmed ID: 18470535

To identify the side population (SP) cells from four hepatocellular carcinoma (HCC) cell lines with stepwise metastatic potentials.

Ethanol Modulates Synaptic and Extrasynaptic GABAA Receptors in the Thalamus

The Journal of Pharmacology and Experimental Therapeutics. Aug, 2008  |  Pubmed ID: 18477766

Drinking alcohol is associated with the disturbance of normal sleep rhythms, and insomnia is a major factor in alcoholic relapse. The thalamus is a brain structure that plays a pivotal role in sleep regulation and rhythmicity. A number of studies have implicated GABA(A) receptors (GABA(A)-Rs) in the anxiolytic, amnestic, sedative, and anesthetic effects of ethanol. In the present study, we examined the effects of ethanol on both synaptic and extrasynaptic GABA(A)-Rs of relay neurons in the thalamus. We found that ethanol (> or =50 mM) elicits a sustained current in thalamocortical relay neurons from the mouse ventrobasal thalamus, and this current is associated with a decrease in neuronal excitability and firing rate in response to depolarization. The steady current induced by ethanol was totally abolished by gabazine and was absent in relay neurons from GABA(A)-R alpha(4) subunit knockout mice, indicating that the effect of ethanol is to enhance tonic GABA-mediated inhibition. Ethanol (50 mM) enhanced the amplitude of tonic inhibition by nearly 50%. On the other hand, ethanol had no effect on spontaneous or evoked inhibitory postsynaptic currents (IPSCs) at 50 mM but did prolong IPSCs at 100 mM. Ethanol had no effect on the paired-pulse depression ratio, suggesting that the release of GABA from presynaptic terminals is insensitive to ethanol. We conclude that ethanol, at moderate (50 mM) but not low (10 mM) concentrations, can inhibit thalamocortical relay neurons and that this occurs mainly via the actions of ethanol at extrasynaptic GABA(A)-Rs containing GABA(A)-R alpha(4) subunits.

Gold(III) Enhanced Chemiluminescence Immunoassay for Detection of Antibody Against ApxIV of Actinobacillus Pleuropneumoniae

The Analyst. Jun, 2008  |  Pubmed ID: 18493678

We report, for the first time, a chemiluminescence immunoassay (CLIA) method based on AuCl(4)(-)-enhanced luminol chemiluminescence (CL) reaction for the highly sensitive detection of ApxIV antibody of Actinobacillus pleuropneumoniae (APP). The AuCl(4)(-), which was the dissolution product of the gold nanoparticle-rabbit anti-pig IgG conjugate, served as an analyte in the CL reaction for the indirect measurement of antibody against ApxIV. The optimal condition of gold dissolution was composed of a 5.0 x 10(-2) M HCl, 1.5 x 10(-2) M NaCl, and 2.5 x 10(-4) M Br(2) solution. Under the optimal conditions, a good correlation between the relative CL photon counting and the dilution coefficient of serum was obtained in the dilution range of 1:160-1:40 000. Based on the analysis of clinical samples, the results indicated that CLIA had remarkable advantages in terms of reliability and practical use compared with indirect hemagglutination (IHA) and enzyme-linked immunosorbent assays (ELISA). The proposed method provided a new tool for the indirect determination of antibody against ApxIV in pig serum samples and showed great potential for numerous applications in immunoassays.

Hepatic Angiomyolipoma: a Retrospective Study of 25 Cases

Surgery Today. 2008  |  Pubmed ID: 18516533

We report our experience of diagnosing and treating hepatic angiomyolipoma (HAML), a rare benign mesenchymal tumor.

Cytokeratin 10 and Cytokeratin 19: Predictive Markers for Poor Prognosis in Hepatocellular Carcinoma Patients After Curative Resection

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jun, 2008  |  Pubmed ID: 18559605

Cytokeratin 10 (CK10) was found to be expressed differently in human hepatocellular carcinoma (HCC) cell lines with different metastatic potentials in our previous research. The aim of this study was to assess the value of CK10 alone or in combination with cytokeratin 19 (CK19) in predicting tumor recurrence after curative resection in HCC patients.

Human Catalytic Antibody Se-scFv-B3 with High Glutathione Peroxidase Activity

Journal of Molecular Recognition : JMR. Sep-Oct, 2008  |  Pubmed ID: 18574795

In order to generate catalytic antibodies with glutathione peroxidase (GPX) activity, we prepared GSH-S-2,4-dinitrophenyl t-butyl ester (GSH-S-DNPBu) as target antigen. Three clones (A11, B3, and D5) that bound specifically to the antigen were selected from the phage display antibody library (human synthetic VH + VL single-chain Fv fragment (scFv) library). Analysis of PCR products using gel electrophoresis and sequencing showed that only clone B3 beared intact scFv-encoding gene, which was cloned into the expression vector pPELB and expressed as soluble form (scFv-B3) in Escherichia coli Rosetta. The scFv-B3 was purified by Ni(2+)-immobilized metal affinity chromatography (IMAC). The yield of purified proteins was about 2.0-3.0 mg of proteins from 1 L culture. After the active site serines of scFv-B3 were converted into selenocysteines (Secs) with the chemical modification method, we obtained the human catalytic antibody (Se-scFv-B3) with GPX activity of 1288 U/micromol.

Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is Required for Interleukin (IL)-1-mediated Optimal NFkappaB and AP-1 Activation As Well As IL-6 Gene Expression

The Journal of Biological Chemistry. Sep, 2008  |  Pubmed ID: 18617512

TAK1 (transforming growth factor-beta-activated kinase 1), a mitogen-activated protein kinase kinase kinase, is activated by various cytokines, including interleukin-1 (IL-1). However, the precise regulation for TAK1 activation at the molecular level is still not fully understood. Here we report that dual phosphorylation of Thr-178 and Thr-184 residues within the kinase activation loop of TAK1 is essential for TAK1-mediated NFkappaB and AP-1 activation. Once co-overexpressed with TAB1, TAK1 mutant with alanine substitution of these two residues fails to activate IKKbeta-mediated NFkappaB and JNK-mediated AP-1, whereas TAK1 mutant with replacement of these two sites with acidic residues acts like the TAK1 wild type. Consistently, TAK1 mutant with alanine substitution of these two residues severely inhibits IL-1-induced NFkappaB and AP-1 activities, whereas TAK1 mutant with replacement of these two sites with acidic residues slightly enhances IL-1-induced NFkappaB and AP-1 activities compared with the TAK1 wild-type. IL-1 induces the phosphorylation of endogenous TAK1 at Thr-178 and Thr-184. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with wild-type TAK1 or a TAK1 mutant containing threonine 178 and 184 to alanine mutations revealed the importance of these two sites in IL-1-mediated IKK-NFkappaB and JNK-AP-1 activation as well as IL-1-induced IL-6 gene expression. Our finding is the first report that substitution of key serine/threonine residues with acidic residues mimics the phosphorylated state of TAK1 and renders TAK1 active during its induced activation.

[Research of Microenvironment of Carcinoma, Dynamics and Prospect]

Zhonghua Yi Xue Za Zhi. Feb, 2008  |  Pubmed ID: 18649761

Expression of X-linked Inhibitor-of-apoptosis Protein in Hepatocellular Carcinoma Promotes Metastasis and Tumor Recurrence

Hepatology (Baltimore, Md.). Aug, 2008  |  Pubmed ID: 18666224

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Despite significantly improved diagnosis and treatment in recent years, the long-term therapeutic effect is compromised by the frequent recurrence and metastasis, of which the molecular mechanisms are not fully understood. Our initial studies in established HCC cell lines with different metastatic capabilities indicated a correlation of metastasis with the resistance to apoptosis and therefore the ability to survive in stressed conditions. Subsequent investigation revealed that increased expression of X-linked inhibitor-of-apoptosis protein (XIAP) was correlated with the resistance to apoptosis and enhanced invasiveness in vitro, which could contribute to increased metastatic foci in vivo. Furthermore, we found that nearly 90% of clinical samples from advanced HCC patients expressed high levels of XIAP. Patients with XIAP-positive tumors had a significantly increased risk of relapse, which resulted from metastasis after total liver resection and orthotopic liver transplantation. Indeed, XIAP expression could be an independent prognostic factor for predicting disease-free survival rate and overall survival rate of these patients. XIAP expression was also highly correlated with advanced cases that exceeded the Milan criteria and could be a prognostic factor for disease-free survival in these patients as well. CONCLUSION: Our studies have shown an important molecule in controlling HCC metastasis, defined a biomarker that can be used to predict HCC recurrence and patient survival after treatment, and suggest that XIAP can be a molecular target subject to intervention to reduce metastasis and recurrence.

Effect of Rapamycin Alone and in Combination with Sorafenib in an Orthotopic Model of Human Hepatocellular Carcinoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Aug, 2008  |  Pubmed ID: 18698030

Novel therapeutic strategies are needed to prevent the tumor recurrence or metastasis after liver transplantation for hepatocellular carcinoma (HCC). This study was to investigate the effect of rapamycin, alone and in combination with sorafenib, on HCC in vivo.

[Strategy to Improve the Prognosis of Liver Transplantation for Hepatocellular Carcinoma]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Nov, 2008  |  Pubmed ID: 19094749

[Treatment of Postoperative Recurrence of Hepatocellular Carcinoma with Radiofrequency Ablation Comparing with Repeated Surgical Resection]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Nov, 2008  |  Pubmed ID: 19094752

To evaluate the efficacy of radiofrequency ablation for the treatment of postoperative recurrence of hepatocellular carcinoma and whether radiofrequency ablation can be used as first line treatment for recurrent hepatocellular carcinoma.

[Primary Experience of the Anatomical Laparoscopic Left Lateral Hepatic Lobectomy Procedure for Benign and Malignant Liver Tumors]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Nov, 2008  |  Pubmed ID: 19094754

To assess the feasibility, safety and outcome of anatomical laparoscopic left lateral hepatic lobectomy for benign and malignant liver tumors.

Isoflurane is a Potent Modulator of Extrasynaptic GABA(A) Receptors in the Thalamus

The Journal of Pharmacology and Experimental Therapeutics. Mar, 2008  |  Pubmed ID: 18094320

Volatile anesthetics are used clinically to produce analgesia, amnesia, unconsciousness, blunted autonomic responsiveness, and immobility. Previous work has shown that the volatile anesthetic isoflurane, at concentrations that produce unconsciousness (250-500 microM), enhances fast synaptic inhibition in the brain mediated by GABA(A) receptors (GABA(A)-Rs). In addition, isoflurane causes sedation at concentrations lower than those required to produce unconsciousness or analgesia. In this study, we found that isoflurane, at low concentrations (25-85 microM) associated with its sedative actions, elicits a sustained current associated with a conductance increase in thalamocortical neurons in the mouse ventrobasal (VB) nucleus. These isoflurane-evoked currents reversed polarity close to the Cl(-) equilibrium potential and were totally blocked by the GABA(A)-R antagonist gabazine. Isoflurane (25-250 microM) produced no sustained current in VB neurons from GABA(A)-R alpha(4)-subunit knockout (Gabra4(-/-)) mice, although 250 microM isoflurane enhanced synaptic inhibition in VB neurons from both wild-type and Gabra4(-/-) mice. These data indicate an obligatory requirement for alpha(4)-subunit expression in the generation of the isoflurane-activated current. In addition, isoflurane directly activated alpha(4)beta(2)delta GABA(A)-Rs expressed in human embryonic kidney 293 cells, and it was more potent at alpha(4)beta(2)delta than at alpha(1)beta(2)gamma(2) receptors (the presumptive extrasynaptic and synaptic GABA(A)-R subtypes in VB neurons). We conclude that the extrasynaptic GABA(A)-Rs of thalamocortical neurons are sensitive to low concentrations of isoflurane. In view of the crucial role of the thalamus in sensory processing, sleep, and cognition, the modulation of these extrasynaptic GABA(A)-Rs by isoflurane may contribute to the sedation and hypnosis associated with low doses of this anesthetic agent.

Taurine is a Potent Activator of Extrasynaptic GABA(A) Receptors in the Thalamus

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jan, 2008  |  Pubmed ID: 18171928

Taurine is one of the most abundant free amino acids in the brain. In a number of studies, taurine has been reported to activate glycine receptors (Gly-Rs) at moderate concentrations (> or = 100 microM), and to be a weak agonist at GABA(A) receptors (GABA(A)-Rs), which are usually activated at high concentrations (> or = 1 mM). In this study, we show that taurine reduced the excitability of thalamocortical relay neurons and activated both extrasynaptic GABA(A)-Rs and Gly-Rs in neurons in the mouse ventrobasal (VB) thalamus. Low concentrations of taurine (10-100 microM) decreased neuronal input resistance and firing frequency, and elicited a steady outward current under voltage clamp, but had no effects on fast inhibitory synaptic currents. Currents elicited by 50 microM taurine were abolished by gabazine, insensitive to midazolam, and partially blocked by 20 microM Zn2+, consistent with the pharmacological properties of extrasynaptic GABA(A)-Rs (alpha4beta2delta subtype) involved in tonic inhibition in the thalamus. Tonic inhibition was enhanced by an inhibitor of taurine transport, suggesting that taurine can act as an endogenous activator of these receptors. Taurine-evoked currents were absent in relay neurons from GABA(A)-R alpha4 subunit knock-out mice. The amplitude of the taurine current was larger in neurons from adult mice than juvenile mice. Taurine was a more potent agonist at recombinant alpha4beta2delta GABA(A)-Rs than at alpha1beta2gamma2 GABA(A)-Rs. We conclude that physiological concentrations of taurine can inhibit VB neurons via activation of extrasynaptic GABA(A)-Rs and that taurine may function as an endogenous regulator of excitability and network activity in the thalamus.

[Surgical Treatment for Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Jan, 2008  |  Pubmed ID: 18226354

Down-regulation of Beta-centractin Might Be Involved in Dendritic Cells Dysfunction and Subsequent Hepatocellular Carcinoma Immune Escape: a Proteomic Study

Journal of Cancer Research and Clinical Oncology. Feb, 2008  |  Pubmed ID: 17619203

Proteomic study was used to clarify the mechanism of hepatocellular carcinoma (HCC) immune escape concerning Dendritic cells (DCs') dysfunction and their association with HCC invasion.

Hepatectomy for Liver Metastasis of Colorectal Cancer

International Journal of Colorectal Disease. Apr, 2009  |  Pubmed ID: 19096855

The objective of this study was to investigate whether hepatic resection (HR) can increase the survival of liver metastasis of colorectal cancer (CRC).

Prognostic Significance of Beclin 1-dependent Apoptotic Activity in Hepatocellular Carcinoma

Autophagy. Apr, 2009  |  Pubmed ID: 19145109

Autophagy is believed to be important in tumorigenesis and tumor progression. However, the role of autophagy in hepatocellular carcinoma (HCC), and especially the prognostic value of autophagic proteins, has not been investigated. Our studies described here show decreased basal expression of autophagic genes and their corresponding autophagic activity under conditions of starvation in HCC cell lines, and the autophagy defect correlated well with the highly malignant phenotype of HCC. In addition, in a tissue microarray study of HCC patients who underwent resection, the expression of the autophagy-related protein Beclin 1 was extremely low in tumors, where Beclin 1 could predict the prognosis of HCC patients only in a Bcl-X(L)-positive expression background. Based on our results, we propose that autophagy defects that synergize with altered apoptotic activity might facilitate tumor progression and poor prognosis of HCC, due to the fact that autophagy may interact with apoptosis in the regulation of HCC.

Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Feb, 2009  |  Pubmed ID: 19188168

The aberrant expression of programmed cell death 1 ligands 1 and 2 (PD-Ls) on tumor cells dampens antitumor immunity, resulting in tumor immune evasion. In this study, we investigated the expression of PD-Ls in human hepatocellular carcinoma (HCC) to define their prognostic significance after curative surgery.

Peritumoral Activated Hepatic Stellate Cells Predict Poor Clinical Outcome in Hepatocellular Carcinoma After Curative Resection

American Journal of Clinical Pathology. Apr, 2009  |  Pubmed ID: 19289585

The inflammatory components of the liver remnant after hepatocellular carcinoma (HCC) resection are of prognostic importance. We evaluated prognostic potential of peritumoral activated hepatic stellate cells (HSCs) in 130 HCC cases. The messenger RNA (mRNA) levels of the functional genes in HSCs (ie, seprase, osteonectin, and tenascin-C), quantitated by real-time quantitative polymerase chain reaction, and the density of peritumoral Foxp3+ T-regulatory cells (Tregs) and CD68+ macrophages (MPhi), assessed immunohistochemically in tissue microarray sections, were positively correlated with the density of peritumoral activated HSCs. The density (P= .007 for recurrence-free survival [RFS] and P=.021 for overall survival [OS]) and functional genes (seprase, P= .001 for RFS; osteonectin, P= .007 for RFS and P=.021 for OS) of peritumoral activated HSCs independently contributed to high recurrence or death rates, as did peritumoral Tregs or MPhi. Moreover, peritumoral HSCs were related to more early recurrences. It is important to note that the density of peritumoral activated HSCs, in combination with seprase and osteonectin mRNA or density of Tregs and MPhi, might predict prognoses more effectively.

Intrahepatic Cholangiocarcinoma: Report of 272 Patients Compared with 5,829 Patients with Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. Aug, 2009  |  Pubmed ID: 19294418

To clarify clinicopathologic differences between patients with intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), and identify potential factors influencing survival after hepatectomy for ICC.

Twenty-year Survivors After Resection for Hepatocellular Carcinoma-analysis of 53 Cases

Journal of Cancer Research and Clinical Oncology. Aug, 2009  |  Pubmed ID: 19294419

To clarify the clinicopathologic features of patients surviving > or =20 years after resection for hepatocellular carcinoma (HCC).

Elevated Expression of DKK1 is Associated with Cytoplasmic/nuclear Beta-catenin Accumulation and Poor Prognosis in Hepatocellular Carcinomas

Journal of Hepatology. May, 2009  |  Pubmed ID: 19303159

To assess the value of Dickkopf-1 (DKK1) for predicting clinical outcome of human hepatocellular carcinoma (HCC) in patients with HCC.

High Expressions of Vascular Endothelial Growth Factor and Platelet-derived Endothelial Cell Growth Factor Predict Poor Prognosis in Alpha-fetoprotein-negative Hepatocellular Carcinoma Patients After Curative Resection

Journal of Cancer Research and Clinical Oncology. Oct, 2009  |  Pubmed ID: 19350273

To evaluate the prognosis value of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) patients after curative resection.

Liver Transplantation Outcomes in 1,078 Hepatocellular Carcinoma Patients: a Multi-center Experience in Shanghai, China

Journal of Cancer Research and Clinical Oncology. Oct, 2009  |  Pubmed ID: 19381688

To evaluate current selection criteria for patients undergoing liver transplantation (LT) in response to hepatocellular carcinoma (HCC), and to analyze the prognostic factors for successful transplantation.

Clinical Features and Prognostic Factors in Patients with Bone Metastases from Hepatocellular Carcinoma Receiving External Beam Radiotherapy

Cancer. Jun, 2009  |  Pubmed ID: 19382203

The current study was performed to identify clinical features and independent predictors of survival in patients with bone metastases from hepatocellular carcinoma (HCC).

Preoperative Serum Gamma-glutamyl Transferase to Alanine Aminotransferase Ratio is a Convenient Prognostic Marker for Child-Pugh A Hepatocellular Carcinoma After Operation

Journal of Gastroenterology. 2009  |  Pubmed ID: 19387533

The ratio of serum gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) is a parameter for assessing responses to antiviral therapies. The relationship between the prognosis of hepatitis B-associated hepatocellular carcinoma (HCC) and preoperative GGT/ALT is studied in hepatectomized Child-Pugh A patients.

The Antiangiogenic Effects of Tyroservatide on Animal Models of Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. Oct, 2009  |  Pubmed ID: 19399517

To investigate the tumor inhibition and antiangiogenic effects of Tyroservatide (YSV, a small polypeptide composed of 3 amino acids. The chemical structure of YSV is l-tyrosine-l-serine-l-valine, molecular structure is C(17)H(25)N(3)O(6), and molecular weight is 367.40 Da) on human hepatocarcinoma SMMC-7721 transplanted tumors in nude mice.

Tumor-infiltrating Macrophages Can Predict Favorable Prognosis in Hepatocellular Carcinoma After Resection

Journal of Cancer Research and Clinical Oncology. Mar, 2009  |  Pubmed ID: 18781326

To evaluate the prognostic value of tumor-associated macrophages (TAM), individually or synergistically with CD45RO + memory T cells (T(M)), in hepatocellular carcinoma (HCC) patients following resection.

The Modulation of Synaptic GABA(A) Receptors in the Thalamus by Eszopiclone and Zolpidem

The Journal of Pharmacology and Experimental Therapeutics. Mar, 2009  |  Pubmed ID: 19033556

Eszopiclone (Lunesta; Sepracor, Marlborough, MA) and zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)-imidazo(1,2-a)pyridine-3-acetamide] are among the most commonly prescribed hypnotics in use in the United States. The thalamus plays a pivotal role in sleep regulation and rhythmicity. Two distinct subtypes of synaptic GABA(A) receptors (GABA(A)-Rs), alpha(1)beta(2)gamma(2) and alpha(3)beta(3)gamma(2), are expressed in thalamocortical relay neurons and in interneurons of the RTN (reticular thalamic nucleus), respectively. Thalamocortical neurons also express extrasynaptic GABA(A)-Rs composed of alpha(4)beta(2)delta subunits. In this study, we compared the effects of eszopiclone and zolpidem on miniature inhibitory postsynaptic currents (IPSCs), spontaneous IPSCs, and tonic inhibition in the mouse thalamus. Eszopiclone (0.1-1 microM) slowed the decay phase of IPSCs recorded from RTN neurons, whereas zolpidem was less effective and increased the decay time constant only at > or = 0.3 microM. IPSCs of RTN neurons were more sensitive to eszopiclone than zolpidem at all concentrations tested. On the other hand, IPSCs of relay neurons in the ventrobasal nucleus (VB) were more sensitive to zolpidem than eszopiclone. Zolpidem (0.1-1 microM) prolonged the decay of IPSCs from VB neurons, whereas eszopiclone increased the decay time constant only at > or = 0.3 microM. Neither of these two hypnotics affected tonic inhibition in relay neurons. Our results demonstrate that eszopiclone has greater efficacy at synaptic GABA(A)-Rs of RTN neurons than in relay neurons, whereas zolpidem exerts bigger effects on relay neurons than RTN neurons. This distinct pattern of activity on thalamic neurons may contribute to some of the observed differences in the clinical effects of these two hypnotics.

Capn4 Overexpression Underlies Tumor Invasion and Metastasis After Liver Transplantation for Hepatocellular Carcinoma

Hepatology (Baltimore, Md.). Feb, 2009  |  Pubmed ID: 19053044

Liver transplantation (LT) is one of the best therapeutic options for nonresectable hepatocellular carcinoma (HCC). Unfortunately, some HCC patients succumb to the disease after LT, which reduces long- and medium-term survival. To identify the proteins associated with HCC invasion and metastasis, HCC patients undergoing LT with complete follow-up data were included in this study and were categorized into recurrence and nonrecurrence groups. We extracted the total protein from the acquired homogeneous tumor cells and applied a cleavable isotope-coded affinity tag technology to quantitate relative changes in protein levels between the two groups. We identified a total of 149 proteins with two-dimensional liquid chromatography coupled with tandem mass spectrometry, including 52 differentially expressed proteins by at least two-fold. Among them, calpain small subunit 1 (Capn4), a protein with relevant interactions with many migration-invasion-related proteins, has attracted more attention. First, Capn4 overexpression in the recurrence group was confirmed via real-time polymerase chain reaction and western blotting in another cohort of 40 HCC patients undergoing LT. Second, Capn4 was associated with enhanced invasiveness in vitro. The small interfering RNA-mediated knockdown expression of Capn4 in HCC cell lines significantly inhibited its mobile and invasive ability. Tissue microarray in a further 192 cases revealed that Capn4 significantly correlated with invasive phenotype of HCC, and univariate and multivariate analyses indicated that Capn4 is an independent prognostic factor for recurrence and survival of HCC patients. Conclusion: Our study revealed that Capn4 overexpression underlies invasion and metastasis after LT for HCC and might be a candidate biomarker for future diagnosis and a target for therapy.

Genetic Delineation of the Pathways Mediated by Bid and JNK in Tumor Necrosis Factor-alpha-induced Liver Injury in Adult and Embryonic Mice

The Journal of Biological Chemistry. Feb, 2009  |  Pubmed ID: 19060338

Tumor necrosis factor-alpha (TNFalpha)-induced hepatocyte death and liver injury can be mediated by multiple mechanisms, which could be evaluated by different animal models. Previous studies have defined the importance of Bid in mitochondrial apoptosis activation in adult mice treated with lipopolysaccharides in the presence of galactosamine (GalN), which suppresses NF-kappaB activation, but not in embryonic mice in which NF-kappaB activation is suppressed by genetic deletion of p65RelA. JNK has also been found important in TNFalpha-induced mitochondria activation and liver injury in the lipopolysaccharide/GalN and concanavalin A (ConA)/GalN models, but not in a ConA-only model in which NF-kappaB activation was not suppressed. To determine the mechanistic relationship of pathways mediated by Bid and JNK, we investigated these two molecules in TNFalpha injury models that had not been previously examined. Most importantly, we created and studied mice deficient in both Bid and JNK. We found that, like JNK, Bid was also required for TNFalpha-induced injury induced by concanavalin A/GalN but not by ConA alone. Furthermore, our results indicate that these two molecules function in a largely overlapped manner, with Bid being downstream of JNK in the adult livers. However, JNK, but not Bid, was able to contribute to the TNFalpha-induced liver apoptosis in RelA-deficient embryos. The Bid-independent role of JNK was also observed in the adult mice, mainly in the promotion of the lethal progression of the TNFalpha injury. This work defined both linear and parallel relationships of Bid and JNK in TNFalpha-induced hepatocyte apoptosis and liver injury.

Role of Overexpression of CD151 And/or C-Met in Predicting Prognosis of Hepatocellular Carcinoma

Hepatology (Baltimore, Md.). Feb, 2009  |  Pubmed ID: 19065669

It has been reported that tetraspanin CD151 acts as a promoter of metastasis in several tumors and plays an important role in c-Met/hepatocyte growth factor signaling. However, the role of CD151 alone and coexpression of CD151/c-Met in hepatocellular carcinoma (HCC) remains unclear. We found that expression of CD151 was positively related to metastatic potential of HCC cell lines, and modified cells with CD151(high) showed higher secretion of matrix metalloproteinase 9 and aggressiveness in vitro and higher metastatic ability in vivo. Furthermore, HCC patients with vascular invasion, large tumors, multiple tumors, high tumor-node-metastasis stage, and undifferentiated tumor were prone to have higher CD151 expression. The postoperative 3-, 5-, and 7-year overall survival (OS) of patients in HCCs with CD151(high) were significantly lower than those in the CD151(low) group, and correspondingly cumulative recurrence rates in HCCs with CD151(high) were significantly higher than those in the CD151(low) group. Both CD151 and c-Met were remarkably overexpressed in HCCs, compared with adjacent nontumorous and normal liver tissues. Pearson correlation analysis showed a slight correlation between CD151 and c-Met in HCCs. Importantly, the 5- and 7-year OS rates in CD151(high)/c-Met(high) patients were 50.5% and 37.8%, respectively, significantly lower than those of CD151(low)/c-Met(low) patients (63.9% and 54.6%, respectively). Five- and 7-year cumulative recurrence rates in CD151(high)/c-Met(high) patients were 53.3% and 71.9%, respectively, markedly higher than those of CD151(low)/c-Met(low) patients (39.0% and 52.5%, respectively). Multivariate analysis revealed that CD151 and combination of CD151/c-Met were independent prognostic indicators for OS and cumulative recurrence. Conclusion: CD151 is positively associated with invasiveness of HCC, and CD151 or combination of CD151/c-Met is a novel marker in predicting the prognosis of HCC and a potential therapeutic target.

BAC Transgenesis in Human Embryonic Stem Cells As a Novel Tool to Define the Human Neural Lineage

Stem Cells (Dayton, Ohio). Mar, 2009  |  Pubmed ID: 19074416

Human embryonic stem cells (hESCs) have enormous potential for applications in basic biology and regenerative medicine. However, harnessing the potential of hESCs toward generating homogeneous populations of specialized cells remains challenging. Here we describe a novel technology for the genetic identification of defined hESC-derived neural cell types using bacterial artificial chromosome (BAC) transgenesis. We generated hESC lines stably expressing Hes5::GFP, Dll1::GFP, and HB9::GFP BACs that yield green fluorescent protein (GFP)(+) neural stem cells, neuroblasts, and motor neurons, respectively. Faithful reporter expression was confirmed by cell fate analysis and appropriate transgene regulation. Prospective isolation of HB9::GFP(+) cells yielded purified human motor neurons with proper marker expression and electrophysiological activity. Global mRNA and microRNA analyses of Hes5::GFP(+) and HB9::GFP(+) populations revealed highly specific expression signatures, suggesting that BAC transgenesis will be a powerful tool for establishing expression libraries that define the human neural lineage and for accessing defined cell types in applications of human disease.

Sirolimus Inhibits the Growth and Metastatic Progression of Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. May, 2009  |  Pubmed ID: 19002496

Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC.

Hypoxia-inducible Factor-1 Alpha, in Association with Inflammation, Angiogenesis and MYC, is a Critical Prognostic Factor in Patients with HCC After Surgery

BMC Cancer. 2009  |  Pubmed ID: 19948069

Despite well-studied tumor hypoxia in laboratory, little is known about the association with other pathophysiological events in the clinical view. We investigated the prognostic value of hypoxia-inducible factor-1 alpha (HIF-1alpha) in hepatocellular carcinoma (HCC), and its correlations with inflammation, angiogenesis and MYC oncogene.

Treatment for the Recurrence of Hepatocellular Carcinoma Following Liver Transplantation: What is the Best Strategy?

Cancer Biology & Therapy. Apr, 2009  |  Pubmed ID: 19417558

Combination of Peritumoral Mast Cells and T-regulatory Cells Predicts Prognosis of Hepatocellular Carcinoma

Cancer Science. Jul, 2009  |  Pubmed ID: 19432885

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.

Molecular Markers and Hepatocellular Carcinoma: Lending a Helping Hand in Liver Transplantation?

Expert Review of Gastroenterology & Hepatology. Jun, 2009  |  Pubmed ID: 19485802

Cre-lox Univector Acceptor Vectors for Functional Screening in Protoplasts: Analysis of Arabidopsis Donor CDNAs Encoding ABSCISIC ACID INSENSITIVE1-like Protein Phosphatases

Plant Molecular Biology. Aug, 2009  |  Pubmed ID: 19499346

The 14,200 available full length Arabidopsis thaliana cDNAs in the universal plasmid system (UPS) donor vector pUNI51 should be applied broadly and efficiently to leverage a "functional map-space" of homologous plant genes. We have engineered Cre-lox UPS host acceptor vectors (pCR701- 705) with N-terminal epitope tags in frame with the loxH site and downstream from the maize Ubiquitin promoter for use in transient protoplast expression assays and particle bombardment transformation of monocots. As an example of the utility of these vectors, we recombined them with several Arabidopsis cDNAs encoding Ser/Thr protein phosphatase type 2C (PP2Cs) known from genetic studies or predicted by hierarchical clustering meta-analysis to be involved in ABA and stress responses. Our functional results in Zea mays mesophyll protoplasts on ABA-inducible expression effects on the Late Embryogenesis Abundant promoter ProEm:GUS reporter were consistent with predictions and resulted in identification of novel activities of some PP2Cs. Deployment of these vectors can facilitate functional genomics and proteomics and identification of novel gene activities.

Chemokine Receptor CXCR4 Expression in Hepatocellular Carcinoma Patients Increases the Risk of Bone Metastases and Poor Survival

BMC Cancer. 2009  |  Pubmed ID: 19508713

The chemokine and bone marrow-homing receptor CXCR4 is implicated in metastases of various cancers. This study was conducted to analyze the association of CXCR4 expression with hepatocellular carcinoma (HCC) bone metastasis and patient survival.

[Current Advances in Molecular Targeted Therapy of Primary Hepatocellular Carcinoma]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Jun, 2009  |  Pubmed ID: 19567036

Human Leukocyte Antigen-G Protein Expression is an Unfavorable Prognostic Predictor of Hepatocellular Carcinoma Following Curative Resection

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jul, 2009  |  Pubmed ID: 19584149

Human leukocyte antigen-G (HLA-G) is a tumor-associated immunosuppressive molecule involved in tumor escape mechanisms. The aim of this study is to elucidate its prognostic significance in hepatocellular carcinoma (HCC).

[Prognostic Analysis of 669 Liver Metastasis of Colorectal Cancer Cases]

Zhonghua Wei Chang Wai Ke Za Zhi = Chinese Journal of Gastrointestinal Surgery. Jul, 2009  |  Pubmed ID: 19598013

To evaluate the relation between different therapy and survival rate of liver metastasis of colorectal cancer (LMCC).

Liver-intestine Cadherin Predicts Microvascular Invasion and Poor Prognosis of Hepatitis B Virus-positive Hepatocellular Carcinoma

Cancer. Oct, 2009  |  Pubmed ID: 19626651

Liver-intestine cadherin (LI-cadherin; CDH-17) is a new member of the cadherin superfamily with distinct structural and functional features. The study was designed to investigate the role of LI-cadherin in tumor invasion and prognosis of human hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC).

Bystin-like Protein is Upregulated in Hepatocellular Carcinoma and Required for Nucleologenesis in Cancer Cell Proliferation

Cell Research. Oct, 2009  |  Pubmed ID: 19687802

The bystin-like (BYSL) gene was previously characterized to encode an accessory protein for cell adhesion that participates in early embryo implantation. It is also involved in 40S ribosomal subunit biogenesis and is found to be expressed in rapidly growing embryo and cancer cell lines. In order to explore the role of BYSL in cancer cell proliferation and growth, we used hepatocellular carcinoma (HCC) as a model. Here, we report that BYSL is crucial for HCC cell growth both in vitro and in vivo. Expression levels of BYSL mRNA and protein in human HCC specimens were markedly increased compared with those seen in adjacent non-cancerous tissue. In vitro, inhibition of BYSL by short hairpin RNA decreased HCC cell proliferation, induced apoptosis and partially arrested the cell cycle in the G2/M phase. In vivo, HCC cells treated with BYSL siRNA failed to form tumors in nude mice after subcutaneous implantation. To determine the cellular basis for BYSL RNAi-induced cell growth arrest, BYSL subcellular localization in mitotic and interphase HepG2 cells was examined. BYSL was present at multiple stages during nucleologenesis, including in nucleolus-derived foci (NDF), perichromosomal regions and the prenucleolar body (PNB) during mitosis. BYSL depletion remarkably suppressed NDF and PNB formation, and disrupted nucleoli assembly after mitosis, resulting in increased apoptosis and reduced tolerance of HCC cells to serum starvation. Taken together, our studies indicate that upregulated BYSL expression plays a role in hepatocarcinogenesis.

CD24 is a Novel Predictor for Poor Prognosis of Hepatocellular Carcinoma After Surgery

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Sep, 2009  |  Pubmed ID: 19706825

To investigate the role of CD24 in tumor invasion and prognostic significance in hepatocellular carcinoma (HCC).

Lectin-based Glycoproteomics to Explore and Analyze Hepatocellular Carcinoma-related Glycoprotein Markers

Electrophoresis. Sep, 2009  |  Pubmed ID: 19711376

More and more new diagnostic biomarkers of hepatocellular carcinoma (HCC) have been found in association with advances in the standardization of 2-DE coupled with MS analysis. However, the diagnosis of HCC is still detected in the late stages of the disease, when treatment options are limited and prognosis is poor. The glycosylation of proteins is known to change in tumor cells during the development of HCC as the result of alterations in the levels of glycosyltransferases, such as increased fucosylation of Golgi Protein 73 and alpha-fetoprotein. These structural changes can influence the function or physiochemical properties of a protein, resulting in abnormal cancer cell behavior. Therefore, identification of HCC-related glycoprotein markers and analysis of glycan structural alterations might assist in the early detection of HCC. Here, we summarize lectin-based glycoproteomic strategies for the discovery of relevant biomarkers of HCC. The carbohydrate-binding specificities of different lectins offer a biological affinity approach that complements existing MS capabilities. These strategies involve the enrichment of glycoproteins or glycopeptides by lectins, followed by releasing carbohydrates with peptide-N-glycosidase F or reductive beta-elimination. The obtained glycopeptides are then identified by automated MS/MS and structural analysis of glycans is performed through modern methods such as quadrupole IT-TOF, MALDI-TOF/TOF and lectin microarray. These strategies will lead to faster and more clinically adaptable tests with greater sensitivity and specificity.

Oxaliplatin Induces Apoptosis in Hepatocellular Carcinoma Cells and Inhibits Tumor Growth

Expert Opinion on Investigational Drugs. Nov, 2009  |  Pubmed ID: 19780708

The platinum-based chemotherapeutic agent oxaliplatin displays a wide range of antitumor activities. To date, no detailed data are available about the effects of oxaliplatin on hepatocellular carcinoma (HCC) cells. Herein, the anti-proliferation effects of oxaliplatin on HCCLM3 and Hep3B cells in vitro and in vivo are studied.

MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer

The New England Journal of Medicine. Oct, 2009  |  Pubmed ID: 19812400

Hepatocellular carcinoma is a common and aggressive cancer that occurs mainly in men. We examined microRNA expression patterns, survival, and response to interferon alfa in both men and women with the disease.

Enriched Motor Neuron Populations Derived from Bacterial Artificial Chromosome-transgenic Human Embryonic Stem Cells

Clinical Neurosurgery. 2009  |  Pubmed ID: 20214043

[A Clinicopathologic Study of Hepatic Angiomyolipoma]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Oct, 2009  |  Pubmed ID: 20092740

To investigate the clinicopathologic features, diagnosis and treatment of hepatic angiomyolipoma (HAML).

Increased Expression of Vascular Endothelial Growth Factor-C and Nuclear CXCR4 in Hepatocellular Carcinoma is Correlated with Lymph Node Metastasis and Poor Outcome

Cancer Journal (Sudbury, Mass.). Nov-Dec, 2009  |  Pubmed ID: 20010172

Lymph node metastasis (LNM) is a chief cause of morbidity and mortality in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to investigate the relationship between the expression of CXCR4 and vascular endothelial cell growth factor (VEGF)-C and the clinicopathological features of HCC with LNM.

Delphinidin Induces Necrosis in Hepatocellular Carcinoma Cells in the Presence of 3-methyladenine, an Autophagy Inhibitor

Journal of Agricultural and Food Chemistry. Apr, 2010  |  Pubmed ID: 20025272

The present study was performed to determine whether anthocyanins could trigger different modes of cell death in different cancers. It was found that whereas cyanidin-3-rutinoside and delphinidin could induce apoptosis in leukemia cells, they caused growth retardation in hepatocellular carcinoma cells (HCC), which was accompanied with a significant cellular vacuolization. The latter was likely caused by macroautophagy and was completely suppressed by 3-methyladenine, an inhibitor of class III phosphoinositide 3-kinase that is important for autophagy activation, and by bafilomycin A1, which blocks lysosomal degradation. Delphinidin induced significant lipidation of LC3, an indication of macroautophagy, which was also suppressed by 3-methyladenine. Macroautophagy was required for the survival of delphinidin-treated HCC cells as inhibition with 3-methyladenine led to massive necrosis without caspase activation. Thus, anthocyanins could induce different modes of cell death for different cancers. Furthermore, anthocyanins could be used in combination with a macroautophagy inhibitor for treating cancers such as HCC.

[Effects of ARNT2 Gene on Invasion and Migration of Human Hepatocellular Carcinoma HCCLM6 Cell Line]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Jan, 2010  |  Pubmed ID: 20128965

To investigate the effects of ARNT2 on invasion and migration of HCCLM6 cells.

Benefit of Radiotherapy for 90 Patients with Resected Intrahepatic Cholangiocarcinoma and Concurrent Lymph Node Metastases

Journal of Cancer Research and Clinical Oncology. Sep, 2010  |  Pubmed ID: 20130909

To evaluate the role of radiotherapy for patients with resected intrahepatic cholangiocarcinoma with concurrent macroscopic abdominal lymph node metastases.

Surgical Treatment for Early Hepatocellular Carcinoma: Comparison of Resection and Liver Transplantation

Journal of Cancer Research and Clinical Oncology. Sep, 2010  |  Pubmed ID: 20148264

The optimum strategy, hepatic resection (HR) or liver transplantation (LT), for treatment of early hepatocellular carcinoma (HCC) associated with liver diseases of Child-Pugh A is far from established. The aim of this study was to compare and determine which strategy is optimal for HCC fulfilling the Milan criteria.

Expression and Prognostic Significance of Focal Adhesion Kinase in Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. Oct, 2010  |  Pubmed ID: 20151150

To examine the expressions of focal adhesion kinase (FAK) and its clinical significance in hepatocellular carcinoma (HCC).

[Cellular Signaling Pathways Involved in Hepatocellular Carcinoma Occurrence and Progression]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Dec, 2010  |  Pubmed ID: 21205491

Impact Factors for Microinvasion in Intrahepatic Cholangiocarcinoma: a Possible System for Defining Clinical Target Volume

International Journal of Radiation Oncology, Biology, Physics. Dec, 2010  |  Pubmed ID: 20378269

To quantify microscopic invasion of intrahepatic cholangiocarcinoma (IHC) into nontumor tissue and define the gross tumor volume (GTV)-to-clinical target volume (CTV) expansion necessary for radiotherapy.

[Hepatectomy for Hepatocellular Carcinoma]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Feb, 2010  |  Pubmed ID: 20388411

High Expression Levels of Putative Hepatic Stem/progenitor Cell Biomarkers Related to Tumour Angiogenesis and Poor Prognosis of Hepatocellular Carcinoma

Gut. Jul, 2010  |  Pubmed ID: 20442200

To investigate the prognostic values of putative hepatic stem/progenitor cell (HSC/HPC) biomarkers in patients with hepatocellular carcinoma (HCC).

[Effect of Postoperative Adjuvant Transarterial Chemoembolization Upon Early Recurrence After Radical Resection of Hepatocellular Carcinoma]

Zhonghua Yi Xue Za Zhi. Mar, 2010  |  Pubmed ID: 20450622

To explore the effect of postoperative adjuvant transarterial chemoembolization (TACE) upon early recurrence of hepatocellular carcinoma (HCC) patients after radical resection.

Identification of Palmatine As an Inhibitor of West Nile Virus

Archives of Virology. Aug, 2010  |  Pubmed ID: 20496087

In this study, we investigated the specific inhibition of West Nile virus (WNV) NS2B-NS3 protease and viral propagation by palmatine, a chemical compound from Coptis chinensis Franch. It was demonstrated that palmatine could inhibit WNV NS2B-NS3 protease activity in an uncompetitive manner, with a 50% inhibitory concentration (IC(50)) of 96 microM. Palmatine suppressed WNV without detectable cytotoxicity (a 50% effective concentration [EC(50)] of 3.6 microM and a 50% cytotoxicity concentration [CC(50)] of 1,031 microM). Furthermore, palmatine could also suppress dengue virus and yellow fever virus in a dose-dependent manner. This compound could potentially be developed for the treatment of flavivirus infections.

Transcriptional and Post-transcriptional Control of DNA Methyltransferase 3B is Regulated by Phosphatidylinositol 3 Kinase/Akt Pathway in Human Hepatocellular Carcinoma Cell Lines

Journal of Cellular Biochemistry. Sep, 2010  |  Pubmed ID: 20506537

DNA methyltransferases (DNMTs) are essential for maintenance of aberrant methylation in cancer cells and play important roles in the development of cancers. Unregulated activation of PI3K/Akt pathway is a prominent feature of many human cancers including human hepatocellular carcinoma (HCC). In present study, we found that DNMT3B mRNA and protein levels were decreased in a dose- and time-dependent manner in HCC cell lines with LY294002 treatment. However, we detected that LY294002 treatment did not induce increase of the degradation of DNMT3B protein using protein decay assay. Moreover we found that Akt induced alteration of the expression of DNMT3B in cells transfected with myristylated variants of Akt2 or cells transfected with small interfering RNA respectively. Based on DNMT3B promoter dual-luciferase reporter assay, we found PI3K pathway regulates DNMT3B expression at transcriptional level. And DNMT3B mRNA decay analysis suggested that down-regulation of DNMT3B by LY294002 is also post-transcriptional control. Furthermore, we demonstrated that LY294002 down-regulated HuR expression in a time-dependent manner in BEL-7404. In summary, we have, for the first time, demonstrate that PI3K/Akt pathway regulates the expression of DNMT3B at transcriptional and post-transcriptional levels, which is particularly important to understand the effects of PI3K/Akt and DNMT3B on hepatocarcinogenesis.

The Current Status of Pediatric Liver Transplantation in Mainland China

Pediatric Transplantation. Aug, 2010  |  Pubmed ID: 20557474

The aim of this article is to study the current status of pediatric liver transplantation in Mainland China. A total of 337 cases of pediatric liver transplantation enrolled in CLTR between 1993 and May 2009 were analyzed retrospectively. The median transplant age was 8.7 yr (64 day-17.8 yr), and Wilson's disease was the most common indication (35.4%). Liver transplantation for biliary atresia accounted for 49.3% and 54.2% in 2008 and 2009 and had become the most common indication nowadays. One- and three-yr survival rates of children transplanted at age<1 yr were 69.2% and 59.3%, respectively, and were significantly worse than those transplanted at age > or =1 yr (83.9% and 76.6%, p < 0.05).In 63.8% (208/326) of the patients, LDLT was used with an overall one- and three-yr survival rates of 87.5% and 84.4%, respectively. The one- and three-yr survival for DDLT was significantly lower (66.7% and 52.2%, p < 0.05). The one- and three-yr survival rates for those transplanted in era 1993-2000 were 63.6% and 36.4%, respectively, and the one- and two-yr survival rates in the latest era (2007-2009) were markedly improved (81.9% and 79.0%, p < 0.05). Cox's analysis identified DDLT (HR = 2.90, CI 95% 1.5-5.6), being transplanted in era 1993-2000(HR = 3.4, CI 95% 1.1-10.2), fulminant liver failure (HR = 6.0, CI 95% 2.0-17.5), and malignancy (HR = 3.8, CI 95% 1.4-10.3) as predictors of increased mortality, and children transplanted at age 8-17 yr have an better survival (HR = 0.2, CI 95% 0.1-0.6). We concluded that pediatric liver transplantation is gradually developing and would probably be a promising therapy for pediatric end-stage liver diseases in Mainland China.

CD151 Modulates Expression of Matrix Metalloproteinase 9 and Promotes Neoangiogenesis and Progression of Hepatocellular Carcinoma

Hepatology (Baltimore, Md.). Jul, 2010  |  Pubmed ID: 20578262

Tetraspanin CD151 is involved in several pathological activities associated with tumor progression, including neoangiogenesis. However, the role and molecular mechanism of CD151 in the neoangiogenesis of hepatocellular carcinoma (HCC) remain enigmatic. We found that the level of expression of matrix metalloproteinase 9 (MMP9) was positively associated with CD151 expression in HCC cells. We developed a zone-by-zone blockade and demonstrated that overexpression of CD151 in HCC cells facilitated MMP9 expression through a phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3beta (GSK-3beta)/Snail signaling pathway. In contrast, down-regulation of CD151 expression impaired the ability of HCC cells to form microvessels in vitro and reduced their in vivo metastatic potential. In a clinical setting, a significant correlation of the expression of CD151 with MMP9 expression and with microvessel density (MVD) was revealed by Pearson correlation analysis of HCC patients. The postoperative 3-, 5-, and 7-year overall survival rates of HCC patients with CD151(high)/MMP9(high)/MVD(high) were significantly lower than those of the CD151(low)/MMP9(low)/MVD(low) group or groups in which only one or two of CD151, MMP9, and MVD were highly expressed. Cumulative recurrence rates were also highest in HCC patients with CD151(high)/MMP9(high)/MVD(high) in comparison with the other groups. Multivariate Cox proportional hazards analysis showed that the concomitant overexpression of CD151, MMP9, and MVD was an independent marker for predicting poor prognosis of HCC. CONCLUSION: Overexpression of CD151 up-regulated the expression of MMP9 through the PI3K/Akt/GSK-3beta/Snail pathway. CD151-dependent neoangiogenesis appeared to promote the progression of HCC, and this suggests that CD151 may be useful as a high-priority therapeutic target for antiangiogenesis in HCC.

[A Clinicopathologic Study of Biliary Intraductal Papillary Neoplasm]

Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. Apr, 2010  |  Pubmed ID: 20646655

To investigate the clinicopathologic features, diagnosis and treatment of biliary intraductal papillary neoplasm (IPN-B).

The Effect of Epidermal Growth Factor Receptor Variant III on Glioma Cell Migration by Stimulating ERK Phosphorylation Through the Focal Adhesion Kinase Signaling Pathway

Archives of Biochemistry and Biophysics. Oct, 2010  |  Pubmed ID: 20650261

Epidermal growth factor receptor variant III (EGFRvIII), the most common EGFR mutation, is associated with cell migration of glioblastoma multiforme (GBM) cases; however, the mechanism has not been elucidated. In this study, we found that the EGFRvIII-promoted glioma cell migration was closely linked to high levels of tyrosine phosphorylation in focal adhesion kinase (FAK) Y397. We also demonstrated that EGFRvIII formed a complex with FAK, resulting in enhanced tyrosine phosphorylation levels of FAK Y397 and EGFR Y1068. After knockdown of FAK expression via anti-FAK shRNA, the U87ΔEGFR cell migration was significantly inhibited, accompanying with the reduced phosphorylation levels of extracellular signal-regulated kinase (ERK1/2). Furthermore, the role of ERK1/2 in FAK-regulated cell migration was confirmed. Taken together, our results suggest that FAK and its downstream molecule ERK were involved in EGFRvIII-promoted glioma cell migration in U87ΔEGFR cells.

Fibroblast Growth Factor 21 Levels Are Increased in Nonalcoholic Fatty Liver Disease Patients and Are Correlated with Hepatic Triglyceride

Journal of Hepatology. Nov, 2010  |  Pubmed ID: 20675007

Fibroblast growth factor 21 (FGF21), a hormone primarily secreted by the liver in response to peroxisome proliferator-activated receptor-α (PPARα) activation, has recently been shown to possess beneficial effects on lipid metabolism and hepatic steatosis in animal models. This study investigated the association of FGF21 with nonalcoholic fatty liver disease (NAFLD) in Chinese patients.

Overexpression of CD151 As an Adverse Marker for Intrahepatic Cholangiocarcinoma Patients

Cancer. Dec, 2010  |  Pubmed ID: 20715158

Previous studies have indicated that CD151, a hydrophobic protein, forms a functional complex with the proto-oncogene that encodes an N-methyl-N'-nitro-N-nitroso-guanidine (MET) protein (c-Met), and CD151 overexpression reportedly is involved in metastasis/invasion of several tumors. The objective of the current study was to investigate the expression and role of CD151 and/or c-Met in intrahepatic cholangiocarcinoma (ICC).

[Nuclear Accumulation of CXCR4 and Overexpressions of VEGF-C and CK19 Are Associated with a Higher Risk of Lymph Node Metastasis in Hepatocellular Carcinoma]

Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology]. May, 2010  |  Pubmed ID: 20723431

The aim of this study was to evaluate the correlation of protein expressions of CXC chemokine receptor 4 (CXCR4), vascular endothelial growth factor-C (VEGF-C) and cytokeratin 19 (CK-19) with lymph node metastasis (LNM) in patients with hepatocellular carcinoma (HCC), and their survival.

Up-regulation of Krüppel-like Factor 8 Promotes Tumor Invasion and Indicates Poor Prognosis for Hepatocellular Carcinoma

Gastroenterology. Dec, 2010  |  Pubmed ID: 20728449

The transcription factor Krüppel-like factor 8 (KLF8) has a role in tumor development, growth, and metastasis, but its role in hepatocellular carcinoma (HCC) is not clear.

PEBP1 Downregulation is Associated to Poor Prognosis in HCC Related to Hepatitis B Infection

Journal of Hepatology. Nov, 2010  |  Pubmed ID: 20739083

Phosphatidylethanolamine-binding protein 1 (PEBP1, also RKIP) plays a pivotal role in cancer by regulating multiple cellular signaling processes and suppressing metastasis in animal models. We examined whether PEBP1 expression in hepatocellular carcinoma (HCC) correlated with the risk of recurrence and survival after resection.

[Effect of Postoperative Adjuvant Transarterial Chemoembolization on Late Recurrence of Hepatocellular Carcinoma After Radical Resection]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Aug, 2010  |  Pubmed ID: 20825715

To identify the effect of postoperative adjuvant transarterial chemoembolization (TACE) on late recurrence of hepatocellular carcinoma (HCC) patients after radical resection.

Determining the Role of External Beam Radiotherapy in Unresectable Intrahepatic Cholangiocarcinoma: a Retrospective Analysis of 84 Patients

BMC Cancer. 2010  |  Pubmed ID: 20840777

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary liver cancer. Only few studies have focused on palliative radiotherapy used for patients who weren't suitable for resection by surgery. This study was conducted to investigate the effect of external beam radiotherapy (EBRT) for patients with unresectable ICC.

The Effect of Receptor Protein Tyrosine Phosphatase Kappa on the Change of Cell Adhesion and Proliferation Induced by N-acetylglucosaminyltransferase V

Journal of Cellular Biochemistry. Jan, 2010  |  Pubmed ID: 19911372

N-acetylglucosaminyltransferase V (GnT-V) has been reported to be positively associated with tumor progression, but its mechanism still remains unknown. In the present study, we found that GnT-V overexpression not only changed the glycosylation of receptor protein tyrosine phosphatase kappa (RPTPkappa) but also decreased its protein level. Moreover, GnT-V overexpression decreased cell calcium-independent adhesion and increased the tyrosine phosphorylation level of beta-catenin, in which RPTPkappa played an important role. Since RPTPkappa has an RXKR motif, which is a favored cleavage site for furin, we used furin inhibitor to further explore the effect of RPTPkappa on the change of cell adhesion and beta-catenin signaling induced by GnT-V. Our results showed that preventing RPTPkappa cleavage rescued the above effects of GnT-V, suggesting that furin cleavage could be one of the factors for RPTPkappa to regulate cell adhesion and beta-catenin signaling in GnT-V overexpression cell lines. In addition, the increased tyrosine phosphorylation level of beta-catenin was associated with the increased nuclear level of beta-catenin and downstream signaling molecules such as c-myc and cyclin D1 that were associated with cell proliferation. Our results suggest that GnT-V could decrease human hepatoma SMMC-7721 cell adhesion and promote cell proliferation partially through RPTPkappa.

The Dynamic Changes of T-bet(+)/GATA-3(+) and RORgammat(+)/FOXP3(+) Cells in Recipient Spleens and Grafts After Rat Orthotopic Liver Transplantation

Transplant Immunology. Feb, 2010  |  Pubmed ID: 19922796

Rejection of transplanted liver occurs when the host generates alloantigen-reactive T cells, and CD4(+) T-cell subsets, including Th1, Th2, T17 and iTreg, could be involved in changing the dynamics of graft rejection onset. In the current immunosuppressive strategies, rejection is treated as an undifferentiated process that is uniform, which results in the failure of tolerance induction. Here, we established a rejection model to observe the reciprocal interaction of CD4(+) T-cell subsets in the complex networks of the immune system.

Increased Integrin Alpha5beta1 Heterodimer Formation and Reduced C-Jun Expression Are Involved in Integrin Beta1 Overexpression-mediated Cell Growth Arrest

Journal of Cellular Biochemistry. Feb, 2010  |  Pubmed ID: 19960514

Integrins, heterodimers of alpha and beta subunits, are a family of cell surface molecules mediating cell-cell and cell-extracellular matrix interaction. The largest subgroup is formed by the beta(1) subunit containing integrins which consist of 12 members with different ligand-binding properties. We previously reported that overexpressed integrin beta(1) subunit in the hepatocellular carcinoma cell line SMMC-7721 imposed a growth inhibitory effect through the upregulation of p21(cip1) and p27(kip1). In this study, we confirmed the growth inhibitory effect of beta(1) subunit overexpression in different cancer cell lines. The upregulated CDK inhibitors induced by beta(1) integrin overexpression were essential for this integrin-mediated growth arrest. Reduced c-Jun level after integrin beta(1) overexpression plays an important role in the transcriptional activation of p21 through the Sp1 sites. Solely overexpressed beta(1) subunit could induce the expression of diverse alpha subunit in different cell lines, among which alpha(5) subunit was found to be correlated with integrin beta(1)-mediated growth arrest. Relative lack of ECM-integrin interaction might be a reason for integrin beta(1) overexpression-mediated growth arrest. These results helped us understand more about the mechanisms that integrins regulate cell growth.

Impact Factors for Microinvasion in Patients with Hepatocellular Carcinoma: Possible Application to the Definition of Clinical Tumor Volume

International Journal of Radiation Oncology, Biology, Physics. Feb, 2010  |  Pubmed ID: 19406586

To evaluate the degree of invasion of hepatocellular carcinoma (HCC) microscopically that will provide a potential application for gross tumor volume to clinical tumor volume (GTV-to-CTV) expansion.

Expression of Cytokeratin 19 and Matrix Metalloproteinase 2 Predicts Lymph Node Metastasis in Hepatocellular Carcinoma

Molecular Biology Reports. Jun, 2011  |  Pubmed ID: 21104440

The purpose of this study was to assess the value of cytokeratin 19 (CK19) and matrix metalloproteinase 2 (MMP-2) in predicting lymph node metastasis (LNM) and survival after curative resection in hepatocellular carcinoma (HCC) patients. Expression of CK19 and MMP-2 in tumor tissue was assessed through immunohistochemical staining of tissue microarrays (TMAs), which were constructed using samples from HCC patients with (n = 123) and without (n = 145) LNM. Positive CK19 expression was correlated with LNM (P < 0.001), satellite lesions (P = 0.016), and lymph node location (P = 0.039). High MMP-2 expression correlated with LNM (P < 0.001), UICC T stage (P = 0.023), and Edmondson grade (P = 0.022). Moreover, CK19 expression correlated with MMP-2 expression (P = 0.033). CK19 and MMP-2 expression were predictive of HCC LNM (AUC: 0.640; 95% CI: 0.572-0.707; P < 0.001 and AUC: 0.611; 95% CI: 0.544-0.679; P = 0.002, respectively). CK19 and MMP-2 expression were independent prognostic factors for disease-free survival (P = 0.031 and P = 0.012, respectively) and overall survival (P = 0.013 and P = 0.018, respectively) in HCC patients with LNM. CK19 expression (P < 0.001), MMP-2 expression (P = 0.006), and UICC T stage (P < 0.001) were independent risk factors for developing LNM in HCC. These findings show that CK19 and MMP-2 expression may be beneficial in predicting HCC LNM and survival.

Direct Evidence for Catalase and Peroxidase Activities of Ferritin-platinum Nanoparticles

Biomaterials. Feb, 2011  |  Pubmed ID: 21112084

Using apoferritin (apoFt) as a nucleation substrate, we have successfully synthesized 1-2 nm platinum nanoparticles (Pt-Ft) which are highly stable. By directly measuring the products of Pt-Ft-catalyzed reactions, we showed, with no doubt, Pt-Ft possesses both catalase and peroxidase activities. With hydrogen peroxide as substrate, we observed oxygen gas bubbles were generated from hydrogen peroxide decomposed by Pt-Ft; the generation of oxygen gas strongly supports Pt-Ft reacts as catalase, other than peroxidase. While with organic dyes and hydrogen peroxide as substrates, distinctive color products were formed catalyzed by Pt-Ft, which indicates a peroxidase-like activity. Interestingly, these biomimetic properties showed differential response to pH and temperature for different reaction substrates. Pt-Ft showed a significant increase in catalase activity with increasing pH and temperature. The HRP-like activity of Pt-Ft was optimal at physiological temperature and slightly acidic conditions. Our current study demonstrates that Pt-Ft possesses both catalase and peroxidase activities for different substrates under different conditions.

Intratumoral Neutrophils: a Poor Prognostic Factor for Hepatocellular Carcinoma Following Resection

Journal of Hepatology. Mar, 2011  |  Pubmed ID: 21112656

Neutrophil infiltration has been linked to clinical outcome of various cancer types. However, its role in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated prognostic values for intratumoral and peritumoral neutrophils in HCC patients undergoing curative resection.

HBx-induced Androgen Receptor Expression in HBV-associated Hepatocarcinoma is Independent of the Methylation Status of Its Promoter

Histology and Histopathology. Jan, 2011  |  Pubmed ID: 21117024

A remarkable feature of HBV-associated HCC is male predominance. The cooperation of hepatitis B virus X protein (HBx) with androgen receptor (AR) signaling pathway has been documented to contribute to this dominance. HBx, a multifunctional viral regulator, has been documented to induce promoter hypermethylation and low expression of tumor suppressor genes via activation of DNA methyl-transferase (DNMT) in hepatocarcinogenesis. In prostate cancer, hypermethylation of AR promoter is associated with loss of AR expression. However, the relationship among HBx, DNMTs, the methylation status of AR and AR expression in HBV-associated HCC is still unknown. In this report, we found that HBx correlated with high levels of AR in HCC cases and induced AR expression by stimulating its transcription in liver cell lines. HBx correlated with high expression of DNMTs in HCC cases too. Both in vivo and in vitro, however, the expression of AR was not associated with its promoter methylation status, and the methylation status of AR was not regulated by DNMTs. AR expression is higher in peritumoral tissues than in tumors, as well as being higher in HBV-associated HCC than in HBV-negative cases. Therefore, HBx-induced high expression of AR plays a role during hepatocarcinogenesis, but is not involved with its promoter methylation or DNMTs. HBx-mediated DNMT deregulation is gene-specific, and the expression and methylated regulation of AR is tissue-specific.

Expression and Prognostic Significance of Placental Growth Factor in Hepatocellular Carcinoma and Peritumoral Liver Tissue

International Journal of Cancer. Journal International Du Cancer. Apr, 2011  |  Pubmed ID: 20521248

Vascular endothelial growth factor-targeted therapy is a promising treatment for hepatocellular carcinoma (HCC), but its clinical benefit is often accompanied by acquired resistance. In animal studies, antiplacental growth factor therapy is effective with less resistance. The role of placental growth factor (PlGF) in the progression of HCC is not clear. In our study, we used immunohistochemistry in tissue microarrays to investigate PlGF expression in tumor and peritumoral liver tissues from 105 patients with HCC. Intratumoral and peritumoral PlGF mRNA expression was analyzed in another cohort of 37 patients. Peritumoral PlGF expression was significantly higher than intratumoral PlGF expression (p < 0.001). Intratumoral PlGF expression was not associated with patients' overall survival (OS) or time to recurrence (TTR). However, peritumoral PlGF expression, which was associated with tumor size, presence of intrahepatic metastasis, TNM stage and Barcelona Clinic Liver Cancer stage, was an independent risk factor for OS (p = 0.026) and TTR (p = 0.041). The prognostic value of peritumoral PlGF expression was further validated in a validation cohort (n = 394). We inferred that the elevation of PlGF in peritumoral liver might be induced by hypoxia. We found that peritumoral PlGF expression was associated with hypoxia-inducible factor-1α (p = 0.017). PlGF expression was elevated in L02, a hepatic cell line, under hypoxic conditions in vitro. These findings indicate that high peritumoral PlGF expression is associated with tumor recurrence and survival after resection of HCC. PlGF could be a target of adjuvant therapy and deserves further investigations.

Preoperative Serum Retinol-binding Protein 4 is Associated with the Prognosis of Patients with Hepatocellular Carcinoma After Curative Resection

Journal of Cancer Research and Clinical Oncology. Apr, 2011  |  Pubmed ID: 20549233

Metabolic syndrome and insulin resistance have been linked to increased risk of occurrence and mortality of hepatocellular carcinoma (HCC). Recently, retinol-binding protein 4 (RBP4) was clarified as a specific serological marker of insulin resistance. The aim of this study was to determine whether serum RBP4 could be used as a potential marker for predicting prognosis in patients with HCC after curative resection.

Activated Hepatic Stellate Cells Promote Hepatocellular Carcinoma Development in Immunocompetent Mice

International Journal of Cancer. Journal International Du Cancer. Dec, 2011  |  Pubmed ID: 21213212

Activated hepatic stellate cells (HSCs) play a central role in the hepatic fibrosis and cirrhosis. Recently, HSCs were reported to have strong immune modulatory activities. However, the role of HSCs in hepatocellular carcinoma (HCC) remains unclear. In this study, we showed that HSCs could promote HCC growth both in vitro and in vivo. We examined the HSC-mediated inhibition of T-cell proliferation and the ability of conditioned medium from activated HSCs to promote the growth of murine HCC cell lines in vitro. We also assessed the immune suppression by HSCs during the development of HCC in immunocompetent mice. Cotransplantation of HSCs promoted HCC growth and progression by enhancing tumor angiogenesis and tumor cell proliferation and by creating an immunosuppressed microenvironment. Cotransplanted HSCs inhibited the lymphocyte infiltration in tumors and the spleens of mice bearing tumors, induced apoptosis of infiltrating mononuclear cells, and enhanced the expression of B7H1 and CD4(+) CD25(+) Treg cells. The immune modulation by HSCs seemed to be systemic. In conclusion, our data provide new information to support an integral role for HSCs in promoting HCC progression in part via their immune regulatory activities, and suggest that HSCs may serve as a therapeutic target in HCC.

Validity of Plasma Macrophage Migration Inhibitory Factor for Diagnosis and Prognosis of Hepatocellular Carcinoma

International Journal of Cancer. Journal International Du Cancer. Nov, 2011  |  Pubmed ID: 21213214

We performed our study to determine whether plasma macrophage migration inhibitory factor (MIF) levels have diagnostic and prognostic value in hepatocellular carcinoma (HCC) patients. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to measure the expression of MIF in plasma and tissues, respectively. Plasma MIF levels were compared to HCC occurrence, clinicopathological features and outcomes. Cutpoints of plasma MIF levels for diagnosis and prognosis were, respectively, determined by receiver operating characteristic analysis and X-tile in corresponding training cohort, and then were confirmed in the validation cohort. The postoperative plasma MIF levels of HCC patients were detected in an independent cohort (80 HCC patients). As a result, MIF expression in situ was mainly observed in the cytoplasm of HCC cells. Intratumoral MIF expression was positively correlated with plasma MIF levels (r = 0.759, p < 0.001). Compared to serum α-fetoprotein (AFP), plasma MIF had a higher diagnostic value for discrimination of HCC from controls at 35.3 ng/ml. With determined cutpoints, plasma MIF levels demonstrated a significant association with overall survival (OS) and disease-free survival (DFS) of HCC patients even in patients with normal serum AFP levels and Tumor Node Metastasis (TNM) stage I. In addition, the plasma MIF levels were identified as an independent factor for OS [hazard ratio (HR) = 1.754; p = 0.012] and DFS (HR = 2.121; p < 0.001). Plasma MIF levels decreased markedly within 30 days after tumor resection (p < 0.001). Therefore, plasma MIF levels have potential as a diagnostic and prognostic factor for HCC.

Risk Factors, Prognosis, and Management of Early and Late Intrahepatic Recurrence After Resection of Primary Clear Cell Carcinoma of the Liver

Annals of Surgical Oncology. Jul, 2011  |  Pubmed ID: 21240562

Primary clear cell carcinoma of the liver (PCCCL) is an uncommon variant of hepatocellular carcinoma (HCC). The prognostic factors influencing its recurrence and survival are not clarified. This study is to evaluate the predictive factors, the therapy, and prognosis of intrahepatic recurrences after resection of PCCCL.

The PI3K-Akt Pathway Regulates Calpain 6 Expression, Proliferation, and Apoptosis

Cellular Signalling. May, 2011  |  Pubmed ID: 21255642

The calpains are a family of cysteine proteases involved in some biological processes whose activities are highly dependent on Ca(2+). Calpain 6 (CAPN6), one member of the family, is unique in that it lacks the active-site cysteine residues for protease activity. According to the data that CAPN6 was up-regulated in the Akt transformed mouse embryonic fibroblast cells by cDNA chip, the mechanisms underlying elevated CAPN6 expression by PI3K-Akt signaling pathway and its biological functions were studied. The results showed that CAPN6 was down-regulated on transcriptional and post-transcriptional levels by the PI3K inhibitor or Akt deletion. CAPN6 protein was stabilized by PI3K-GSK-3β pathway. Deleted CAPN6 promoters activity were assessed by dual-luciferase reporter system, and the founding indicated that -93/+200 DNA fragment was the core promoter of it. Transcription factor binding sites in the CAPN6 promoter were mutated and the results showed that AP1, Oct-1, and FoxD3 were the critical transcription factors in regulation of CAPN6 expression. In addition, CAPN6 promoted cancer cell proliferation and inhibited its apoptosis. The finding demonstrates that CAPN6 is regulated by the PI3K-Akt signaling pathway and provides evidence that it may be a therapeutic target of cancer.

Acetylcholinesterase, a Key Prognostic Predictor for Hepatocellular Carcinoma, Suppresses Cell Growth and Induces Chemosensitization

Hepatology (Baltimore, Md.). Feb, 2011  |  Pubmed ID: 21274871

Acetylcholinesterase (ACHE) plays important roles in the cholinergic system, and its dysregulation is involved in a variety of human diseases. However, the roles and implications of ACHE in hepatocellular carcinoma (HCC) remain elusive. Here we demonstrate that ACHE was significantly down-regulated in the cancerous tissues of 69.2% of HCC patients, and the low ACHE expression in HCC was correlated with tumor aggressiveness, an elevated risk of postoperative recurrence, and a low survival rate. Both the recombinant ACHE protein and the enhanced expression of ACHE significantly inhibited HCC cell growth in vitro and tumorigenicity in vivo. Further study showed that ACHE suppressed cell proliferation via its enzymatic activity of acetylcholine catalysis and degradation. Moreover, ACHE could inactivate mitogen-activated protein kinase and phosphatidyl inositol-3'-phosphate kinase/protein kinase B pathways in HCC cells and thereby increase the activation of glycogen synthase kinase 3β and lead to β-catenin degradation and cyclin D1 suppression. In addition, increased ACHE expression could remarkably sensitize HCC cells to chemotherapeutic drugs (i.e., adriamycin and etoposide). Conclusion: For the first time, we describe the function of ACHE as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways, and the drug sensitivity of HCC cells. ACHE is a promising independent prognostic predictor for HCC recurrence and the survival of HCC patients. These findings provide new insights into potential strategies for drug discovery and improved HCC treatment.

CD151 Amplifies Signaling by Integrin α6β1 to PI3K and Induces the Epithelial-mesenchymal Transition in HCC Cells

Gastroenterology. May, 2011  |  Pubmed ID: 21320503

Overexpression of CD151 is associated with poor prognosis for hepatocellular carcinoma (HCC), yet its role in pathogenesis is not known.

[The Establishment of a Systematic Site-specific Metastasis Model of Human Hepatocellular Carcinoma in Nude Mouse.]

Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chinese Journal of Hepatology. Feb, 2011  |  Pubmed ID: 21492513

To establish a systematic site-specific metastatsis model of human hepatocellular carcinoma (HCC) in nude mouse. HCCLM3-R cells were seeded into mice liver to establish xenograft mouse models. With the help of RFP, metastasis foci in lungs and lymph nodes in mice were detected using fluorescent stereomicroscopy and were removed. Cells derived from the metastasis foci were named HCCLM3-R-LM1 and HCCLM3-R-LnM1 respectively. HCCLM3-R-LM1 and HCCLM3-R-LnM1 cells were seeded into mice livers to analyze the lung and lymph node metastasis. Lungs of all tested mice were collected, examined by pathological evaluation and counted lung metastasis. Both lung and lymph node metastasis were found in HCCLM3-R-LM1, HCCLM3-R and HCCLM3-R-LnM1 cells and a significant difference was found between the lung and the lymph node metastasis levels in the three cells. The fluorescent areas (pixels) of lung and lymph node metastasis were 8687.00+/-1844.63 versus 2570.00+/-318.20 (P = 0.0031) in HCCLM3-R-LM1 cells, 6457.67+/-832.62 versus 10 994.33+/-2 212.31 (P = 0.0036) in HCCLM3-R cells, and 2968.67+/-2571.00 versus 24 416.00+/-7 186.13 (P = 0.0094) in HCCLM3-R-LnM1 cells, respectively. The middle numbers of microscopic lung metastatic foci were 775, 430 and 310 in HCCLM3-R-LM1, HCCLM3-R and HCCLM3-R-LnM1 cells (P less than 0.001), respectively, consist with the results quantified by RFP. We established the systematic site-specific metastasis models which demonstrates lung- and lymph node-specific metastasis potential in nude mice and can be used as a model for researches on site-specific metastasis of HCC.

Isomalto Oligosaccharide Sulfate Inhibits Tumor Growth and Metastasis of Hepatocellular Carcinoma in Nude Mice

BMC Cancer. 2011  |  Pubmed ID: 21513518

Hepatocellular carcinoma (HCC) usually has a dismal prognosis because of its limited response to current pharmacotherapy and high metastatic rate. Sulfated oligosaccharide has been confirmed as having potent antitumor activities against solid tumors. Here, we explored the preclinical effects and molecular mechanisms of isomalto oligosaccharide sulfate (IMOS), another novel sulfated oligosaccharide, in HCC cell lines and a xenograft model.

Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Molecular & Cellular Proteomics : MCP. Jul, 2011  |  Pubmed ID: 21518826

Hepatocellular carcinoma (HCC) is a common malignancy in the world with high morbidity and mortality rate. Identification of novel biomarkers in HCC remains impeded primarily because of the heterogeneity of the disease in clinical presentations as well as the pathophysiological variations derived from underlying conditions such as cirrhosis and steatohepatitis. The aim of this study is to search for potential metabolite biomarkers of human HCC using serum and urine metabolomics approach. Sera and urine samples were collected from patients with HCC (n = 82), benign liver tumor patients (n = 24), and healthy controls (n = 71). Metabolite profiling was performed by gas chromatography time-of-flight mass spectrometry and ultra performance liquid chromatography-quadrupole time of flight mass spectrometry in conjunction with univariate and multivariate statistical analyses. Forty three serum metabolites and 31 urinary metabolites were identified in HCC patients involving several key metabolic pathways such as bile acids, free fatty acids, glycolysis, urea cycle, and methionine metabolism. Differentially expressed metabolites in HCC subjects, such as bile acids, histidine, and inosine are of great statistical significance and high fold changes, which warrant further validation as potential biomarkers for HCC. However, alterations of several bile acids seem to be affected by the condition of liver cirrhosis and hepatitis. Quantitative measurement and comparison of seven bile acids among benign liver tumor patients with liver cirrhosis and hepatitis, HCC patients with liver cirrhosis and hepatitis, HCC patients without liver cirrhosis and hepatitis, and healthy controls revealed that the abnormal levels of glycochenodeoxycholic acid, glycocholic acid, taurocholic acid, and chenodeoxycholic acid are associated with liver cirrhosis and hepatitis. HCC patients with alpha fetoprotein values lower than 20 ng/ml was successfully differentiated from healthy controls with an accuracy of 100% using a panel of metabolite markers. Our work shows that metabolomic profiling approach is a promising screening tool for the diagnosis and stratification of HCC patients.

Risk Factors for Residual Tumor After Resection of Hepatocellular Carcinoma

World Journal of Gastroenterology : WJG. Apr, 2011  |  Pubmed ID: 21528064

To identify the clinicopathological risk factors correlated with residual tumor in hepatocellular carcinoma (HCC) patients after resection.

An Autoregulatory Feedback Loop Involving PAP1 and TAS4 in Response to Sugars in Arabidopsis

Plant Molecular Biology. May, 2011  |  Pubmed ID: 21533841

miR828 in Arabidopsis triggers the cleavage of Trans-Acting SiRNA Gene 4 (TAS4) transcripts and production of small interfering RNAs (ta-siRNAs). One siRNA, TAS4-siRNA81(-), targets a set of MYB transcription factors including PAP1, PAP2, and MYB113 which regulate the anthocyanin biosynthesis pathway. Interestingly, miR828 also targets MYB113, suggesting a close relationship between these MYBs, miR828, and TAS4, but their evolutionary origins are unknown. We found that PAP1, PAP2, and TAS4 expression is induced specifically by exogenous treatment with sucrose and glucose in seedlings. The induction is attenuated in abscisic acid (ABA) pathway mutants, especially in abi3-1 and abi5-1 for PAP1 or PAP2, while no such effect is observed for TAS4. PAP1 is under regulation by TAS4, demonstrated by the accumulation of PAP1 transcripts and anthocyanin in ta-siRNA biogenesis pathway mutants. TAS4-siR81(-) expression is induced by physiological concentrations of Suc and Glc and in pap1-D, an activation-tagged line, indicating a feedback regulatory loop exists between PAP1 and TAS4. Bioinformatic analysis revealed MIR828 homologues in dicots and gymnosperms, but only in one basal monocot, whereas TAS4 is only found in dicots. Consistent with this observation, PAP1, PAP2, and MYB113 dicot paralogs show peptide and nucleotide footprints for the TAS4-siR81(-) binding site, providing evidence for purifying selection in contrast to monocots. Extended sequence similarities between MIR828, MYBs, and TAS4 support an inverted duplication model for the evolution of MIR828 from an ancestral gymnosperm MYB gene and subsequent formation of TAS4 by duplication of the miR828* arm. We obtained evidence by modified 5'-RACE for a MYB mRNA cleavage product guided by miR828 in Pinus resinosa. Taken together, our results suggest that regulation of anthocyanin biosynthesis by TAS4 and miR828 in higher plants is evolutionarily significant and consistent with the evolution of TAS4 since the dicot-monocot divergence.

Tumor Stroma Reaction-related Gene Signature Predicts Clinical Outcome in Human Hepatocellular Carcinoma

Cancer Science. Aug, 2011  |  Pubmed ID: 21564420

The tumor stroma is a source of many potential new tumor biomarkers, in which the immune response is of major importance. Little is known regarding how changes in stromal gene expression affect hepatocellular carcinoma (HCC) progression. We analyzed the expression of 28 stroma-related genes using quantitative RT-PCR in 122 HCC samples, and related the results to patient prognosis. Hierarchical clustering based on expression of the 28 genes, or the 6-Th1 cell markers, can classify HCC patients into prognostically different subgroups. We further identified a five-gene classifier (protective genes IRF1 and GZMB and risk genes CRTH2, VEGF, and MMP7) as a significant independent prognosticator for recurrence (hazard ratio [HR], 4.80; 95% confidence interval [CI], 2.31-9.96; P = 2.6 × 10(-5) ) by multivariate analyses. Importantly, the classifier was further validated in an independent set of 172 HCC samples (HR, 2.21; 95% CI, 1.20-3.00; P = 0.002). The predictive ability of the classifier, as measured by area under the curve (0.713 and 0.613 for original and validation cohorts, respectively), was comparable to those of vascular invasion, Barcelona Clinic Liver Cancer stage, and TNM stage. The densities of various tumor stromal cells were analyzed by immunostaining. Comparing the immunostaining and gene expression data showed significant association of the gene classifier with the amount of reactive stroma in both cohorts. Thus, the signature reveals the strong prognostic capacity of immune responses, angiogenic activity, and ECM remodeling, highlighting the importance of stromal biology in HCC progression. Contained in this novel predictor may be targets suitable for new therapeutic interventions, or for use as independent prognosticators.

An Immune Function Assay Predicts Post-transplant Recurrence in Patients with Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. Oct, 2011  |  Pubmed ID: 21809031

An immune function assay has been proposed as a new strategy to monitor immunosuppression after organ transplantation. However, there are limited data regarding its role in liver transplant recipients with hepatocellular carcinoma (HCC). In this study, we sought to determine the utility of this functional assay in assessing the risk of infection, rejection, and tumor recurrence in liver transplant recipients.

Prognostic Role of Diabetes Mellitus in Hepatocellular Carcinoma Patients After Curative Treatments: a Meta-analysis

Hepatobiliary & Pancreatic Diseases International : HBPD INT. Aug, 2011  |  Pubmed ID: 21813381

The prognostic role of diabetes mellitus (DM) coexisting with hepatocellular carcinoma (HCC) remains controversial. To clarify its impact on survival in HCC patients after curative treatments, a meta-analysis was performed.

Autophagy Activation in Hepatocellular Carcinoma Contributes to the Tolerance of Oxaliplatin Via Reactive Oxygen Species Modulation

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Oct, 2011  |  Pubmed ID: 21825039

Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC.

A Polymeric Nanoparticle Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Aug, 2011  |  Pubmed ID: 21868763

PURPOSE: To illustrate the prognostic significance of hedgehog (Hh) signaling in hepatocellular carcinoma (HCC) patients, and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor, Gli-1 ("NanoHHI") using in vitro and in vivo models of human HCC.EXPERIMENTAL DESIGN: Patched1 (Ptch) expression was detected in tumor tissue microarrays of 396 HCC patients who underwent curative surgical resection during 2/2000 to 12/2002. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. The effects of NanoHHI alone and in combination with sorafenib were investigated on HCC cell lines. Primary HCC tumor growth and metastasis were examined in vivo using subcutaneous and orthotopic HCC xenografts in nude mice. RESULTS: Elevated expression of Ptch in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in HCC patients. In vitro, NanoHHI significantly inhibited the proliferation and invasion of HCC cell lines. NanoHHI potently suppressed in vivo tumor growth of HCC xenografts in both subcutaneous and orthotopic milieus, and in contrast to sorafenib, resulted in significant attenuation of systemic metastases in the orthotopic setting. Further, NanoHHI significantly decreased the population of CD133-expressing HCC cells, which have been implicated in tumor initiation and metastases.CONCLUSIONS: Downstream Hh signaling has prognostic significance in HCC patients as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and anti-metastatic effects in HCC models, which may provide a new strategy in the treatment of HCC patients and prevention post-operative recurrence.

A Clinicopathological Model to Predict Bone Metastasis in Hepatocellular Carcinoma

Journal of Cancer Research and Clinical Oncology. Dec, 2011  |  Pubmed ID: 21915751

We aimed to develop a clinicopathological model that would predict the risk of bone metastasis (BM) in hepatocellular carcinoma (HCC).

Profiling of the Tetraspanin CD151 Web and Conspiracy of CD151/integrin β1 Complex in the Progression of Hepatocellular Carcinoma

PloS One. 2011  |  Pubmed ID: 21961047

Tetraspanin CD151 has been implicated in metastasis through forming complexes with different molecular partners. In this study, we mapped tetraspanin web proteins centered on CD151, in order to explore the role of CD151 complexes in the progression of hepatocellular carcinoma (HCC). Immunoprecipitation was used to isolate tetraspanin complexes from HCCLM3 cells using a CD151 antibody, and associated proteins were identified by mass spectrometry. The interaction of CD151 and its molecular partners, and their roles in invasiveness and metastasis of HCC cells were assayed through disruption of the CD151 network. Finally, the clinical implication of CD151 complexes in HCC patients was also examined. In this study, we identified 58 proteins, characterized the tetraspanin CD151 web, and chose integrin β1 as a main partner to further investigate. When the CD151/integrin β1 complex in HCC cells was disrupted, migration, invasiveness, secretion of matrix metalloproteinase 9, and metastasis were markedly influenced. However, both CD151 and integrin β1 expression were untouched. HCC patients with high expression of CD151/integrin β1 complex had the poorest prognosis of the whole cohort of patients. Together, our data show that CD151 acts as an important player in the progression of HCC in an integrin β1-dependent manner.

Metadherin Promotes Hepatocellular Carcinoma Metastasis Through Induction of Epithelial-mesenchymal Transition

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Dec, 2011  |  Pubmed ID: 21976539

To investigate the expression of metadherin (MTDH) for its prognostic value in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis.

HIWI is Associated with Prognosis in Patients with Hepatocellular Carcinoma After Curative Resection

Cancer. Oct, 2011  |  Pubmed ID: 21989785

BACKGROUND: PIWI protein family was found to play an important role in stem cell self-renewal. Overexpression of HIWI, the human homolog of PIWI family proteins, was found in several solid tumors, although the role of HIWI in hepatocellular carcinoma (HCC) and its prognostic value remain unclear. METHODS: HIWI expression was measured in stepwise metastatic HCC cell lines (HCCLM3, MHCC97H, MHCC97L, SMMC7721, and HepG2), the normal liver cell line (L02), and HCC tissue samples (n = 20). Proliferation and invasion were investigated in HCC cell lines undergoing HIWI target small interfering RNA transfection. Also explored was HIWI expression in HCC tissue microarrays (n = 168) for survival analysis. RESULTS: Levels of HIWI protein and mRNA were up-regulated in highly metastatic HCC cell lines (HCCLM3, MHCC97H, and MHCC97L), whereas their proliferation and invasion significantly decreased after depletion of HIWI. Intratumoral HIWI expression was higher than that of peritumoral tissue (P < .001) and positively associated with proliferating cell nuclear antigen expression (P < .001). Positive expression of intratumoral HIWI was associated with larger tumor size (P = .047) and intrahepatic metastasis (P = .027) and was an independent risk factor for overall survival (P = .007) and recurrence-free survival (P = .036), particularly in patients with low serum α-fetoprotein and low Edmondson-Steiner grade. CONCLUSIONS: HIWI may play a key role in HCC proliferation and metastasis and can be a potential prognostic factor for HCC after curative resection, particularly with well-differentiated HCC. Cancer 2011. © 2011 American Cancer Society.

Genetic Variations in Plasma Circulating DNA of HBV-related Hepatocellular Carcinoma Patients Predict Recurrence After Liver Transplantation

PloS One. 2011  |  Pubmed ID: 21998744

Recurrence prediction of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) present a great challenge because of a lack of biomarkers. Genetic variations play an important role in tumor development and metastasis.

The Role of Polymeric Immunoglobulin Receptor in Inflammation-induced Tumor Metastasis of Human Hepatocellular Carcinoma

Journal of the National Cancer Institute. Nov, 2011  |  Pubmed ID: 22025622

Expression of the polymeric immunoglobulin receptor (pIgR), a transporter of polymeric IgA and IgM, is commonly increased in response to viral or bacterial infections, linking innate and adaptive immunity. Abnormal expression of pIgR in cancer was also observed, but its clinical relevance remains uncertain.

Sorafenib Inhibits Growth and Metastasis of Hepatocellular Carcinoma by Blocking STAT3

World Journal of Gastroenterology : WJG. Sep, 2011  |  Pubmed ID: 22025881

To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC).

Plasma MicroRNA Panel to Diagnose Hepatitis B Virus-related Hepatocellular Carcinoma

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Dec, 2011  |  Pubmed ID: 22105822

More than 60% of patients with hepatocellular carcinoma (HCC) do not receive curative therapy as a result of late clinical presentation and diagnosis. We aimed to identify plasma microRNAs for diagnosing hepatitis B virus (HBV) -related HCC.

Clinical Features and Prognostic Factors in Patients with Bone Metastases from Hepatocellular Carcinoma After Liver Transplantation

BMC Cancer. 2011  |  Pubmed ID: 22107882

Little is known about the clinical features and prognostic factors of bone metastases of hepatocellular carcinoma (HCC) following liver transplantation (LT).

IL-17 Induces AKT-dependent IL-6/JAK2/STAT3 Activation and Tumor Progression in Hepatocellular Carcinoma

Molecular Cancer. 2011  |  Pubmed ID: 22171994

ABSTRACT:

Cell Line Misidentification: the Case of the Chang Liver Cell Line

Hepatology (Baltimore, Md.). Nov, 2011  |  Pubmed ID: 21656536

Potential Prognostic Biomarkers for Bone Metastasis from Hepatocellular Carcinoma

The Oncologist. 2011  |  Pubmed ID: 21665914

Hepatocellular carcinoma (HCC) most commonly develops in patients who have a viral infection, especially in the case of hepatitis B virus (HBV), and in patients with a chronic liver disease. HCC patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. Identification of patients who are at high risk for BM after undergoing potentially curative treatment for HCC remains challenging. Here, we aimed to identify HCC BM-related genes and proteins to establish prediction biomarkers.

An Investigation of the Effect of Sorafenib on Tumour Growth and Recurrence After Liver Cancer Resection in Nude Mice Independent of Phosphorylated Extracellular Signal-regulated Kinase Levels

Expert Opinion on Investigational Drugs. Aug, 2011  |  Pubmed ID: 21671804

Objective: The goal of this study is to investigate the effects of sorafenib on tumor growth, recurrence and metastasis after curative resection of liver cancer. Research methods: SMMC-7721 and HCCLM3 liver tumors, each with different metastatic potential and basal phosphorylated extracellular signal-regulated kinase (pERK) levels, were orthotopically implanted into 56 nude mice. Mice were divided into a treatment sub study and a prevention sub study. Results: In the treatment sub study, tumor volumes in the high pERK-expressing HCCLM3 model were 2.58 ? 0.83 and 0.38 ? 0.09 cm(3) without and with sorafenib, respectively (p < 0.001). The corresponding volumes in the low pERK-expressing SMMC-7721 model were 1.36 ? 0.24 and 0.24 ? 0.14 cm(3) (p < 0.001), respectively. Sorafenib inhibited HCCLM3 cell proliferation and decreased tumor angiogenesis, but did not inhibit proliferation in the SMMC-7721 model. In the prevention sub study, intrahepatic recurrent tumor volumes were 1.96 ? 0.45 and 0.18 ? 0.24 cm(3) (p < 0.001); lung metastasis frequencies were 100 and 0% (p = 0.005); and lifespans were 36 ? 3 and 46 ? 5 days (p = 0.002) in the control and sorafenib subgroups, respectively. Conclusions: Sorafenib inhibits tumor growth and prevents metastatic recurrence after resection of hepatocellular carcinoma in nude mice. The effect of sorafenib does not exclusively depend on high levels of pERK in tumors.

An Unusual Cause of Cerebral Venous Sinus Thrombosis. Paroxysmal Nocturnal Hemoglobinuria

Neurosciences (Riyadh, Saudi Arabia). Jul, 2011  |  Pubmed ID: 21677620

Cerebral venous sinus thrombosis caused by paroxysmal nocturnal hemoglobinuria is uncommon. Our case is a 44-year-old woman who presented with a 2 day history of headaches, nausea, and seizures followed by a Todd`s paresis; she had been diagnosed as paroxysmal nocturnal hemoglobinuria for 4 years. A magnetic resonance venography revealed extensive thrombosis of the cerebral venous sinus. She received antithrombotic treatment with a good outcome. We highlight paroxysmal nocturnal hemoglobinuria as the reason for the cerebral venous sinus thrombosis. The treatment of cerebral venous sinus thrombosis caused by paroxysmal nocturnal hemoglobinuria should be individualized.

Circulating Tumor Cells: Advances in Detection Methods, Biological Issues, and Clinical Relevance

Journal of Cancer Research and Clinical Oncology. Aug, 2011  |  Pubmed ID: 21681690

Circulating tumor cells (CTCs) have long been considered a reflection of tumor aggressiveness. Hematogenous spreading of CTCs from a primary tumor is a crucial step in the metastasis cascade, which leads ultimately to the formation of overt metastases. However, owing to the rarity of CTCs in peripheral blood, detecting these cells requires methods combined with high sensitivity and specificity, which sets tremendous challenges for the implementation of these assays into clinical routine.

Targeting Autophagy Enhances Sorafenib Lethality for Hepatocellular Carcinoma Via ER Stress-related Apoptosis

Autophagy. Oct, 2011  |  Pubmed ID: 21691147

Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.

Gene Expression Profiling of Fixed Tissues Identified Hypoxia-inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 As Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Aug, 2011  |  Pubmed ID: 21712445

Hepatocellular carcinoma (HCC) most often develops in patients infected with hepatitis B or hepatitis C virus. Differential gene expression profiling is useful for investigating genes associated with lymph node metastasis (LNM). We screened genes to identify potential biomarkers for LNM in HCC.

Prognostic Indicators for Tumor Recurrence After Liver Transplantation in Hepatocellular Carcinoma and Related Molecular Targeted Therapy

Oncology. 2011  |  Pubmed ID: 22212945

Liver transplantation (LT) is a viable therapeutic option for hepatocellular carcinoma (HCC). Many criteria, such as the Milan criteria and the University of California at San Francisco (UCSF) criteria, have been established to select a subset of HCC patients who stand to benefit from LT. However, they are still insufficient for predicting HCC patients at high risk for recurrence and selecting those at low risk. Many molecules which are probable candidates for recognizing HCC patients at high or low risk for recurrence give a wider perspective to consider for LT indication. Besides working as biomarkers, most of them are also functionally involved in some important pathways which contribute to HCC metastasis. The complex network constituted by them shows a multichannel, multistep HCC metastatic process which indicates difficulty in tumor therapy. Given the efficacy of some molecular targeted drugs in the treatment of HCC or prevention of tumor recurrence after LT, the emerging molecular targeted therapy is also discussed in this review.

Use of Multiphoton Microscopy to Diagnose Liver Cancer and Lung Metastasis in an Orthotopic Rat Model

Scanning. Feb, 2012  |  Pubmed ID: 22331704

Liver or lung biopsy for suspicious lesions has several disadvantages such as bleeding, bile leak or pneumothorax, needle track seeding, and time-consuming histopathological procedure. The ability to directly observe cellular and subcellular details and then perform "optical biopsy" is a major goal in the development of new interventional techniques. Multiphoton microscopy (MPM) enables real-time noninvasive visualization of tissue architecture and cell morphology in live tissue. We performed a study to evaluate whether MPMcan make real-time optical diagnosis for liver cancer and lung metastasis using an orthotopic rat model with Morris hepatoma. We found that real-time high-resolution MPMimaging could clearly show tissue architecture and cell morphology. In the normal liver tissue, MPMimaging clearly revealed the blood-filled sinusoids and cords of hepatocytes. In the cancerous tissue, MPMimaging clearly illustrated that cancer cells displayed marked cellular and nuclear pleomorphism. MPMimages were comparable to golden standard hematoxylin-eosin staining images. Moreover, MPMimaging had deep penetration with the capability of optical sectioning. In short, MPMcan make real-time optical diagnosis for liver cancer and lung metastasis. This study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive "optical biopsy" for liver cancer and lung metastasis in the near future.

Sp1 is Involved in Regulation of Cystathionine γ-lyase Gene Expression and Biological Function by PI3K/Akt Pathway in Human Hepatocellular Carcinoma Cell Lines

Cellular Signalling. Jun, 2012  |  Pubmed ID: 22360859

Hydrogen sulfide (H(2)S) has been found to play an important role as a novel gasotransmitter involved in many biological processes. The regulatory role of endogenous H(2)S-producing enzyme on cancer cell survival is complex and unclear. According to the data that cystathionine γ-lyase (CSE) gene, catalyzed H(2)S production in trans-sulfuration pathway, was upregulated in Akt stably transformed mouse embryonic fibroblast cells, the mechanisms that elevated CSE expression by PI3K/Akt signaling pathway and its biological functions in cell survival were studied. In the present study, firstly, the results showed that PI3K/Akt positively correlated with CSE expression levels in human hepatocellular carcinoma cell lines. CSE expression was decreased by the PI3K inhibitor or Akt deletion, while upregulated with the activating of Akt. Based on dual-luciferase reporter assay, the -592/+139 gene fragment represented the CSE core promoter, and the PI3K/Akt pathway regulated CSE expression on transcriptional level. Sp1 was the critical transcription factor in regulation of CSE expression via the mutation of transcription factor binding sites on the promoter. Furthermore, we proved that Sp1 could directly bind to CSE promoter by ChIP assay. In addition, we explored that the endogenous H(2)S production was connected with the regulated CSE expression, and CSE/H(2)S promoted human hepatocellular carcinoma cell proliferation via cell cycle progression regulation. In summary, we have, for the first time, demonstrated that PI3K/Akt pathway regulates the CSE expression via Sp1, which is particularly important to understand the effect of PI3K/Akt and CSE on the tumorigenesis.

Rapid In-process Measurement of Surface Roughness Using Adaptive Optics

Optics Letters. Mar, 2012  |  Pubmed ID: 22378414

We present an in-process measurement of surface roughness by combining an optical probe of laser-scattering phenomena and adaptive optics for aberration correction. Measurement results of five steel samples with a roughness ranging from 0.2 to 3.125 μm demonstrate excellent correlation between the peak power and average roughness with a correlation coefficient (R(2)) of 0.9967. The proposed adaptive-optics-assisted system is in good agreement with the stylus method, and error values of less than 8.7% are obtained for average sample roughness in the range of 0.265 to 1.119 μm. The proposed system can be used as a rapid in-process roughness monitor/estimator to further increase the precision and stability of manufacturing processes in situ.

Influence of Tumor Thrombus Location on the Outcome of External-beam Radiation Therapy in Advanced Hepatocellular Carcinoma with Macrovascular Invasion

International Journal of Radiation Oncology, Biology, Physics. Feb, 2012  |  Pubmed ID: 22381903

PURPOSE: The present study evaluates the influence of portal vein (PV) vs. inferior vena cava (IVC) tumor thrombosis sites on the effectiveness of external-beam radiation therapy (EBRT) in advanced hepatocellular carcinoma (HCC) with macrovascular invasion. METHODS AND MATERIALS: We retrospectively reviewed 181 HCC patients with PV and/or IVC tumor thrombi who were referred for EBRT at our institution between 2000 and 2009. EBRT was designed to focus on the tumor thrombi with or without primary intrahepatic tumors to deliver a median total conventional dose of 50 Gy (range, 30-60 Gy). Predictors of survival were identified using univariate and multivariate analyses. RESULTS: The median survival was 10.2, 7.4, 17.4, and 8.5 months for patients with PV branch, PV trunk, IVC, and PV plus IVC tumor thrombosis, respectively. Unfavorable pretreatment predictors were associated by multivariate analysis with lower albumin and higher α-fetoprotein levels, poorer Child-Pugh liver function classification, multiple intrahepatic foci, lymph node metastases, thrombus location, less chance to receive post-EBRT transarterial chemoembolization (TACE) and the two-dimensional EBRT technique. In comparison to patients with PV tumor thrombosis, patients with IVC thrombi had a higher occurrence of solitary intrahepatic lesions (p = 0.027), well-controlled intrahepatic tumors (p < 0.001), and a better response to EBRT (p < 0.001), and they were more likely to receive post-EBRT TACE (p = 0.033). CONCLUSIONS: In HCC, patients with IVC thrombus treated with EBRT had a better response rate and longer survival than those with PV thrombus.

Intratumoral IL-17(+) Cells and Neutrophils Show Strong Prognostic Significance in Intrahepatic Cholangiocarcinoma

Annals of Surgical Oncology. Mar, 2012  |  Pubmed ID: 22411204

BACKGROUND: Inflammatory reactions at a tumor site have both detrimental and beneficial effects on tumor progression. This study was designed to assess the clinical significance of tumor-infiltrating inflammatory cells in patients with intrahepatic cholangiocarcinoma (ICC). METHODS: A total of 123 consecutive ICC patients who underwent curative resection were enrolled. Tissue microarray and immunohistochemistry were used to analyze the distribution and clinical relevance of IL-17(+), FOXP3(+), CD8(+), CD66b(+) cells, and microvessel density (CD34) in different microanatomical areas. RESULTS: IL-17(+) cells, FOXP3(+) lymphocytes, CD66b(+) neutrophils, and microvessels were enriched predominantly in intratumor (IT) area, whereas CD8(+) lymphocytes were most abundant in tumor invasive front. On univariate analyses, increasing IL-17 (IT) (+) and neutrophils(IT) were significantly associated with worse patient survival. Multivariate analyses revealed that IL-17 (IT) (+) (hazard ratio [HR] = 1.59; 95% confidence interval [CI], 1.05-2.41; P = 0.028), neutrophils(IT) (HR = 1.76; 95% CI, 1.16-2.65; P = 0.007), and their combination (HR 2.8; 95% CI 1.72-4.57; P < 0.001) were independent prognostic factors, which were superior to conventional clinicopathologic features, such as intrahepatic metastasis and TNM stage. IL-17 (IT) (+) significantly correlated with the presence of lymph node metastasis, intrahepatic metastasis, and advanced stages, whereas neutrophils(IT) correlated with the presence of vascular invasion. In addition, significant positive correlations were detected among densities of IL-17(+) cells, neutrophils, and microvessel density. CONCLUSIONS: Our data suggested that intratumor IL-17(+) cells, neutrophils are novel, powerful predictors of prognosis in patients with ICC.

TREM-1 Expression in Hepatic Stellate Cells and Prognostic Value in Hepatitis B-related Hepatocellular Carcinoma

Cancer Science. Mar, 2012  |  Pubmed ID: 22417086

Hepatocellular carcinoma (HCC) is a typical inflammation-related malignancy characterized by high postoperative recurrence and metastasis. Although several inflammatory cells and inflammatory signatures have been linked to poor prognosis, the inflammation-associated molecular mechanisms of HCC development and progression are largely unknown. Here we showed that triggering receptor expressed in myeloid cells (TREM)-1, a transmembrane receptor expressing in myeloid cells, was also expressed in tumor activated hepatic stellate cells (HSCs) and associated with the aggressive behavior of HCC cells. Enzyme-linked immunosorbent assay was used to measure the expression levels of soluble TREM-1 (sTREM-1) in activated hepatic stellate cells supernatant and 92 preoperative and postoperative plasmas of patients with malignancy and/or benign liver tumor/disease, respectively. Expression levels of TREM-1 were assessed by immunohistochemistry in tissue microarray from 240 patients with HCC. As a result, increased secretion of sTREM-1 from activated HSCs was observed after co-culture with HCC cell lines (P<0.001), and conditioned medium collected from activated HSCs/CAMFs with or without agonist/inhibitor of TREM-1 significantly changed migratory ability of HCC cells. The levels of sTREM-1 were significantly higher in patients with HCC than those with benign liver tumors (P<0.005). Peritumoral density of TREM-1 was demonstrated to be an independent prognosis predictor according to univariate (P<0.001 for both overall survival [OS] and time to recurrence [TTR]) and multivariate analysis (P=0.008 for OS; P=0.005 for TTR). Thus, these observations suggest that TREM-1 is related to the tumor aggressive behavior and has potential value as a prognostic factor for HCC. © 2012 Japanese Cancer Association.

Low Level of Low-density Lipoprotein Receptor-related Protein 1 Predicts an Unfavorable Prognosis of Hepatocellular Carcinoma After Curative Resection

PloS One. 2012  |  Pubmed ID: 22427881

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC).

Activation of PI3K/AKT and MAPK Pathway Through a PDGFRβ-Dependent Feedback Loop Is Involved in Rapamycin Resistance in Hepatocellular Carcinoma

PloS One. 2012  |  Pubmed ID: 22428038

Rapamycin is an attractive approach for the treatment and prevention of HCC recurrence after liver transplantation. However, the objective response rates of rapamycin achieved with single-agent therapy were modest, supporting that rapamycin resistance is a frequently observed characteristic of many cancers. Some studies have been devoted to understanding the mechanisms of rapamycin resistance, however, the mechanisms are cell-type-dependent and studies on rapamycin resistance in HCC are extremely limited.

Overexpression of Galectin-1 Associates with Poor Prognosis in Human Hepatocellular Carcinoma Following Resection

Journal of Gastroenterology and Hepatology. Mar, 2012  |  Pubmed ID: 22432916

Background and Aim:  High expression of the galectin-1 predicted poor patient outcome in several tumors. The aim of this study was to investigate its prognostic value in patients with hepatocellular carcinoma (HCC) after resection. Methods:  Galectin-1 and tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) were validated by tissue microarrays from HCC patients (n=386) and statistically assessed for correlations with the clinical profiles and the prognosis of the patients. Results:  We found that galectin-1, prevalently up-regulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, incomplete encapsulation, poor differentiation, multiple number and large tumor size). Patients with high galectin-1 expression had a significantly poorer tumor recurrence (p=0.025) and overall survival (p=0.021) than those with low galectin-1 expression. Even in early-stage disease, high galectin-1 expression also independently associated with shortened survival (p<0.001) and increased tumor recurrence (p=0.005). Multivariate Cox proportional hazards analysis showed that galectin-1 was an independent marker for predicting poor prognosis of HCC. Galectin-1level was positively related to number of tumor-infiltrating FoxP3(+) Tregs (r=0.416, p<0.001) and their combination served as a better prognosticator. The postoperative tumor recurrence and survival of HCC patients with galectin-1(high) and FoxP3(high) were significantly poorer than the other groups (both p<0.001). Conclusions:   Galectin-1 may be a new prognostic factor for HCC after resection and potentially be a high-priority therapeutic target. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Combined Hepatocellular Carcinoma and Cholangiocarcinoma: Clinical Features, Treatment Modalities, and Prognosis

Annals of Surgical Oncology. Mar, 2012  |  Pubmed ID: 22451237

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary liver cancer that has rarely been reported in large-scale clinical studies. The aim of this study was to clarify the clinical features, treatment modalities, and prognosis of cHCC-CC. METHODS: Included in this study were 113 patients who were histologically diagnosed as having Allen type C cHCC-CC, 103 of whom received liver resection, 6 transarterial chemoembolization treatment, 3 radiofrequency ablation, and 1 palliative supportive treatment. Clinicopathologic features and prognosis of 103 cHCC-CC patients after liver resection were compared with those of 6,679 patients with hepatocellular carcinoma (HCC) and 386 patients with intrahepatic cholangiocarcinoma (ICC) who underwent liver resection during the same period. RESULTS: The proportion of cHCC-CC in primary liver cancers was 1.5 %. The 103 cases of cHCC-CC were characterized by male predominance, infection with hepatitis virus or presence of liver cirrhosis, and elevated alfa-fetoprotein-findings similar to HCC. However, serum CA19-9 elevation, incomplete capsules, and lymph node involvement were similar to ICC. The 1-, 3-, and 5-year overall survival rates after liver resection were 73.9, 41.4, and 36.4 %, respectively, for patients with cHCC-CC versus 77.5, 53.3, and 41.4 % for HCC patients, and 58.0, 29.1, and 22.3 % for ICC patients (χ(2) = 137.5, P < 0.001). Tumor, node, metastasis system stage (hazard ratio 1.27, 95 % confidence interval 1.08-1.49, P = 0.003) and radical liver resection (hazard ratio 0.31, 95 % confidence interval 0.14-0.68, P = 0.004) were independent prognostic factors for overall survival. CONCLUSIONS: cHCC-CC has biological behavior and prognosis that are intermediate between HCC and ICC. Radical liver resection can provide a better outcome for this uncommon malignancy.

Coexpression of Stemness Factors Oct4 and Nanog Predict Liver Resection

Annals of Surgical Oncology. Mar, 2012  |  Pubmed ID: 22461131

BACKGROUND: Oct4 and Nanog are two major transcription factors related to the stem cell self-renewal and differentiation. The aim of this study was to evaluate the correlation between these two stemness markers with recurrence, metastasis, and prognosis of hepatocellular carcinoma (HCC). METHODS: Expression of Oct4 and Nanog was evaluated by immunohistochemistry in a random cohort of 228 HCC patients (cohort A), predominantly hepatitis B related, and validated in another independent cohort of 95 patients (cohort B). Survival analysis was performed by univariate and multivariate analyses. Oct4 and Nanog expression levels in 5 HCC cell lines with different metastatic potential were detected by Western blot assay and quantitative real-time PCR assay. RESULTS: In tissue microarrays, coexpression of Oct4 and Nanog was dramatically associated with big tumor size (P = .001) and vascular invasion (P = .02) and was an independent predictor of postoperative recurrence (hazard ratio [HR] = 1.57, 95 % confidence interval [95 % CI] 1.21-2.04, P = .01) and poor prognosis (HR = 2.20, 95 % CI 1.71-2.88, P < .001). This association was further validated in patients in cohort B. Importantly, this correlation remained significant in patients with early-stage HCC or alpha-fetoprotein (AFP) negative HCC. In addition, expression of Oct4 and Nanog increased in a concordant manner with the increase of metastatic potential in human HCC cell lines. CONCLUSIONS: Coexpression of stemness markers Oct4 and Nanog in HCC indicated the aggressive tumor behaviors and predicted a worse clinical outcome, which may be a useful biomarker to identify patients at high risk of postoperative recurrence.

Preclinical Study of Using Multiphoton Microscopy to Diagnose Liver Cancer and Differentiate Benign and Malignant Liver Lesions

Journal of Biomedical Optics. Feb, 2012  |  Pubmed ID: 22463036

Recently, the miniaturized multiphoton microscopy (MPM) and multiphoton probe allow the clinical use of multiphoton endoscopy for diagnosing cancer via "optical biopsy". The purpose of this study was to establish MPM optical diagnostic features for liver cancer and evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis. Firstly, we performed a pilot study to establish the MPM diagnostic features by investigating 60 surgical specimens, and found that high-resolution MPM images clearly demonstrated apparent differences between benign and malignant liver lesions in terms of their tissue architecture and cell morphology. Cancer cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, were identified by MPM images, which were comparable to hematoxylin-eosin staining images. Secondly, we performed a blinded study to evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis by investigating another 164 specimens, and found that the sensitivity, specificity, and accuracy of MPM diagnosis was 96.32%, 96.43%, and 96.34%, respectively. In conclusion, it is feasible to use MPM to diagnose liver cancer and differentiate benign and malignant liver lesions. This preclinical study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive "optical biopsy" for liver lesions in the near future.

Prognostic Significance and Clinical Relevance of Sprouty 2 Protein Expression in Human Hepatocellular Carcinoma

Hepatobiliary & Pancreatic Diseases International : HBPD INT. Apr, 2012  |  Pubmed ID: 22484587

In vitro experiments and mice models have confirmed the importance of Sprouty 2 (Spry2) in inhibiting tumorigenesis and the progression of human cancer. However, the prognostic value of Spry2 in cancer patients remains unknown. This study is aimed to investigate the clinical relevance and prognostic significance of Spry2 expression in patients with hepatocellular carcinoma (HCC).

HDGF-related Protein-3 is Required for Anchorage-independent Survival and Chemoresistance in Hepatocellular Carcinomas

Gut. Apr, 2012  |  Pubmed ID: 22490522

ObjectiveHepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of six members and are characterised by a conserved HATH domain. Among the family members, HDGF was the first to be identified as a mitogenic factor and shown to play an important role in hepatocellular carcinoma pathogenesis. The aim of the present study is to examine the relevance of HDGF-related protein-3 (HRP-3), another member of the HRP family in hepatocellular carcinoma (HCC).DesignHRP-3 expression in HCC tissues was measured by quantitative reverse transcriptase PCR, western blot and immunohistochemistry analysis. The biological consequences of overexpression and knockdown of HRP-3 in HCC cell lines were studied in vitro and in vivo.ResultsExpression of HRP-3 mRNA and protein was shown to be highly upregulated in HCC tissues. While knockdown of HRP-3 by small interference RNAs failed to affect anchorage-dependent growth of HCC cells, it inhibited anchorage-independent growth of HCC cells in vitro and xenograft tumour growth in vivo. Further, knockdown of HRP-3 was shown to sensitise HCC cells to anoikis. Moreover, HRP-3 specifically activated the extracellular-signal-regulated kinase (ERK) pathway without affecting c-Jun N-terminal kinase (JNK), p38, AKT and signal transducer and activator of transcription 3 (STAT3). Importantly, inhibition of the ERK pathway diminished HRP-3-mediated protection of HCC cells from anoikis. Finally, knockdown of HRP-3 was shown to enhance apoptosis of HCC cells induced by multiple chemotherapeutic drugs.ConclusionThese findings indicate that HRP-3 plays an essential role in HCC pathogenesis and suggest that it may serve as a novel prognostic marker and molecular target for development of drugs for treatment of HCC.

Infiltrating Memory/senescent T Cell Ratio Predicts Extrahepatic Metastasis of Hepatocellular Carcinoma

Annals of Surgical Oncology. Feb, 2012  |  Pubmed ID: 21792513

The density of tumor-infiltrating immunocytes (TICs) has been proposed as an independent predictor of intrahepatic recurrence in patients with hepatocellular carcinoma (HCC). However, the relative roles of TIC density in predicting tumor extrahepatic metastasis remain to be elucidated.

Palliative Radiation Therapy for Pulmonary Metastases from Hepatocellular Carcinoma

Clinical & Experimental Metastasis. Mar, 2012  |  Pubmed ID: 22173728

Although the lung is the most common site of extrahepatic metastases from hepatocellular carcinoma (HCC), the optimal treatment for such metastases has'nt been established. External beam radiotherapy (EBRT) is becoming a useful local control therapy for lung cancer. To evaluated the efficacy of EBRT treatment for such metastases, we retrospectively studied 13 patients (11 men and 2 women; mean age, 52.6 years) with symptomatic pulmonary metastases from HCC who had been treated with EBRT in our institution. The palliative radiation dose delivered to the lung lesions ranged from 47 to 60 Gy (median 50) in conventional fractions, while the intrahepatic lesions were treated with surgery or transarterial chemoembolization, and/or EBRT. Follow-up period from radiotherapy ranged from 3.7 to 49.1 months (median, 16.7). Among the 13 patients, 23 out of a total of 31 pulmonary metastatic lesions received EBRT. In 12/13(92.3%) patients, significant symptoms were completely or partially relieved. An objective response was observed in 10/13(76.9%) of the subjects by computed tomography imaging. The median progression-free survival for all patients was 13.4 months. The 2-year survival rate from pulmonary metastasis was 70.7%. Adverse effects were mild and consisted of bone marrow suppression in three patients and pleural effusion in one patient (all CTCAE Grade II). In conclusion, EBRT with ≤60 Gy appears to be a good palliative therapy with reasonable safety for patients with pulmonary metastases from HCC. However, large-scale randomized clinical trials will be necessary to confirm the therapeutic role of this method.

Expression of Connective Tissue Growth Factor and Interleukin-11 in Intratumoral Tissue is Associated with Poor Survival After Curative Resection of Hepatocellular Carcinoma

Molecular Biology Reports. May, 2012  |  Pubmed ID: 22205539

In the present study, we evaluated the prognostic value of intratumoral and peritumoral expression of connective tissue growth factor (CTGF), transforming growth factor-beta 1 (TGF-β1), and interleukin-11 (IL-11) in patients with hepatocellular carcinoma (HCC) after curative resection. Expression of CTGF, TGF-β1, and IL-11 was assessed by immunohistochemical staining of tissue microarrays containing paired tumor and peritumoral liver tissue from 290 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of these and other clinicopathologic factors were evaluated. The median follow-up time was 54.3 months (range, 4.3-118.3 months). High intratumoral CTGF expression was associated with vascular invasion (P = 0.015), intratumoral IL-11 expression correlated with higher tumor node metastasis (TNM) stage (P = 0.009), and peritumoral CTGF overexpression correlated with lack of tumor encapsulation (P = 0.031). Correlation analysis of these proteins revealed that intratumoral CTGF and IL-11 correlated with high intratumoral TGF-β1 expression (r = 0.325, P < 0.001; and r = 0.273, P < 0.001, respectively). TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.010), and intratumoral IL-11 expression (P = 0.015) were independent prognostic factors for progression-free survival (PFS). Vascular invasion (P = 0.032), TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.036), and intratumoral IL-11 expression (P = 0.013) were independent prognostic factors for overall survival (OS). High intratumoral CTGF and intratumoral IL-11 expression were associated with PFS and OS after hepatectomy, and the combination of intratumoral CTGF with IL-11 may be predictive of survival.

The Expression of HIF-1α in Primary Hepatocellular Carcinoma and Its Correlation with Radiotherapy Response and Clinical Outcome

Molecular Biology Reports. Feb, 2012  |  Pubmed ID: 21647551

The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic LN EBRT response. Kaplan-Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = -0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence interval (CI): 0.499-0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509-0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531-0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis.

Aryl Hydrocarbon Receptor Nuclear Translocator is Associated with Tumor Growth and Progression of Hepatocellular Carcinoma

International Journal of Cancer. Journal International Du Cancer. Apr, 2012  |  Pubmed ID: 21544813

bHLH/PAS proteins play important roles in tumor progression. Lost or reduced expression of single-minded homolog 2 (SIM) as well as aryl hydrocarbon receptor repressor (AHRR) has been observed in cancerous human tissues. Here, we investigated the role of aryl hydrocarbon receptor nuclear translocator (ARNT), another bHLH/PAS protein, in hepatocellular carcinoma (HCC). Using tissue microarray and immunohistochemistry, we found that intratumoral ARNT was inversely correlated with time to recurrence and overall survival of HCC patients after resection. Knockdown of ARNT in HepG2, HCCLM3 and HCCLM6 cells significantly shortened cell doubling time, increased S-phase cell populations and accelerated in vivo HCCLM6 growth and metastasis. After ARNT expression was rescued, prolonged cell doubling time and decreased S-phase cell populations were observed in HepG2, HCCLM3 and HCCLM6 cells. And, HCCLM6 growth and metastasis in vivo were remarkably inhibited. Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC. According to the results of immunoprecipitation assay, both ARNT/ARNT and ARNT/AHRR complexes were clearly formed in HCCLM6 xenograft with increased ARNT expression. In summary, ARNT is an important regulator of HCC growth and metastasis and could be a promising prognostic candidate in HCC patients.