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Biomedical subjects

S C Lu

Publications and source records attributed to S C Lu.

At least 19 recordsLinked to original sources
PubMed2006

Effects of docosahexaenoic acid supplementation on blood lipids, estrogen metabolism, and in vivo oxidative stress in postmenopausal vegetarian women.

BACKGROUND: Vegetarians are generally deficient in long-chain n-3 fatty acids. Long-chain n-3 fatty acids have a beneficial effect on plasma lipid levels, and some studies showed that they had breast cancer suppression effect. One of the biomarkers of breast cancer risk is the ratio of urinary 2-hydroxyestrone (2-OHE(1)) to 16alpha-hydroxyestrone (16alpha-OHE(1)). OBJECTIVE: To investigate the effect of docosahexaenoic acid (DHA, 22:6n-3) supplementation on blood lipids, estrogen metabolism and oxidative stress in vegetarians. DESIGN: Single-blind, randomized, placebo-controlled trial. INTERVENTIONS: Twenty-seven postmenopausal vegetarian women were recruited. After a 2-week run-in period with 6 g placebo corn oil, the subjects were subsequently randomized to receive either 6 g corn oil (n=13) or 6 g DHA-rich algae oil (2.14 g of DHA/day) (n=14) for 6 weeks. Two subjects in corn oil group withdrew before completion. MAIN OUTCOME MEASURES: Plasma lipids, urinary 2-OHE(1) and 16alpha-OHE(1), urinary F(2)-isoprostanes and plasma alpha-tocopherol. RESULTS: Plasma LDL-DHA and EPA level increased significantly by DHA supplementation. DHA decreased plasma cholesterol (C) levels (P=0.04), but did not influence the levels of plasma TG, LDL-C and HDL-C, alpha-tocopherol, urinary F(2)-isoprostanes, 2-OHE(1), 16alpha-OHE(1) and ratio of 2-OHE(1) to 16alpha-OHE(1) as compared to corn oil. CONCLUSION: DHA supplementation at a dose of 2.14 g/day for 42 days decreases plasma cholesterol but neither does it show beneficial effects on estrogen metabolism, nor does it induce deleterious effects on the observed in vivo antioxidant or oxidative stress marker in postmenopausal vegetarian women. SPONSORSHIP: A grant (# DOH89-TD-1062) from Department of Health, Executive Yuan, Taiwan.

Biomarkers↗
PubMed2006

Subgingival and tongue microbiota during early periodontitis.

Periodontal infections have a microbial etiology. Association of species with early disease would be useful in determining which microbes initiate periodontitis. We hypothesized that the microbiota of subgingival and tongue samples would differ between early periodontitis and health. A cross-sectional evaluation of 141 healthy and early periodontitis adults was performed with the use of oligonucleotide probes and PCR. Most species differed in associations with sample sites; most subgingival species were associated with subgingival samples. Few species were detected more frequently in early periodontitis by DNA probes. Porphyromonas gingivalis and Tannerella forsythia (Tannerella forsythensis) were associated with early periodontitis by direct PCR. In conclusion, the microbiota of tongue samples was less sensitive than that of subgingival samples in detecting periodontal species, and there was overlap in species detected in health and early periodontitis. Detection of periodontal pathogens in early periodontitis suggests an etiology similar to that of more advanced disease.

Adult↗
PubMed2005

Increased susceptibility of glutathione peroxidase-1 transgenic mice to kainic acid-related seizure activity and hippocampal neuronal cell death.

Glutathione peroxidase (GSHPx) has been demonstrated in several in vivo studies to reduce both the risk and severity of oxidatively-induced tissue damage. The seizure-inducing neurotoxin kainic acid (KA) has been suggested to elicit its toxic effects in part via generation of oxidative stress. In this study, we report that expression of elevated levels of murine GSHPx-1 in transgenic mice surprisingly results in increased rather than decreased KA susceptibility including increased seizure activity and neuronal hippocampal damage. Isolated transgenic primary hippocampal culture neurons also display increased susceptibility to KA treatment compared with those from wildtype animals. This could be due to alterations in the redox state of the glutathione system resulting in elevated glutathione disulfide (GSSG) levels which, in turn, may directly activate NMDA receptors or enhanced response of the NMDA receptor.

Animals↗
PubMed2005

Distribution of human chemokine (C-X3-C) receptor 1 (CX3CR1) gene polymorphisms and haplotypes of the CC chemokine receptor 5 (CCR5) promoter in Chinese people, and the effects of CCR5 haplotypes on CCR5 expression.

Two chemokine (C-X3-C) receptor 1 (CX3CR1) gene polymorphisms, V249I and T280M, and 10 CC chemokine receptor 5 (CCR5) promoter haplotypes, P1-P10, have recently been reported to influence the progression of acquired immune-deficiency syndrome (AIDS). As these studies were performed mainly with Caucasian and African-American subjects, we determined the distribution of these alleles in Chinese people for the purpose of predicting possible clinical responses to the human immunodeficiency virus type 1 (HIV) epidemics in countries with significant Chinese populations, as well as to establish their effects on the expression of surface CCR5. Ninety-six HIV-negative Chinese individuals in Taiwan were subjected to genotyping, and we thus determined that the allelic frequencies of CX3CR1V249I and T280M changes were 2.6% and 2.1%, respectively, which were lower than found in Caucasians (25.5% and 14.0%, respectively). Unlike the previous reports, we only detected CCR5P1 and P4 haplotypes in Taiwanese people, and the P1/P1, P1/P4 and P4/P4 genotype frequencies were 21.0%, 41.1% and 37.9%, respectively. The sequencing data confirmed the results of previous studies, showing that CCR5P1 exhibited a complete linkage disequilibrium with a polymorphic allele 59029A present in the CCR5 promoter. Furthermore, fluorescence-activated cell sorter analysis revealed that, in the absence of the CCR2-64I mutation, individuals carrying CCR5P1 tended to express more surface CCR5 on monocytes and CD4+ cells. Therefore, this study not only reports the frequencies for the CX3CR1 and CCR5 promoter haplotypes in a Chinese population living in Taiwan, but also identifies a statistical link between the P1/P1 haplotype and the elevated CCR5 expression levels in the study group.

Adult↗
PubMed2001

Oxidized low-density lipoprotein downregulates endothelial basic fibroblast growth factor through a pertussis toxin-sensitive G-protein pathway: mediator role of platelet-activating factor-like phospholipids.

BACKGROUND: Oxidized LDL (oxLDL) inhibits angiogenesis in part by downregulating endothelial basic fibroblast growth factor (bFGF). To determine the mechanism of the downregulation, we investigated the signal transduction pathway involving potential phospholipid mediators. METHODS AND RESULTS: Cultured bovine aortic endothelial cells were incubated with PBS (lipoprotein-free control), LDL, or copper oxLDL under serum-free conditions. At 24 hours, oxLDL (50 microg/mL) decreased bFGF mRNA (Northern blot), bFGF protein (Western blot and ELISA), and concomitant DNA synthesis, all by 40% to 50% compared with PBS. LDL had no effect. Pretreating the cells with 100 ng/mL pertussis toxin (PTX) for 18 hours before oxLDL exposure almost completely blocked the inhibitory effects of oxLDL. In contrast, inhibiting other major cellular signal transduction pathways with PD-98059 (mitogen-activated protein kinase kinase inhibitor), HA-1004 (inhibitor of cGMP- and cAMP-dependent protein kinase), or Ro-31-8220 (protein kinase C inhibitor) or chelating intracellular Ca(2+) with BAPTA-AM failed to attenuate any of the oxLDL effects assayed. Addition to the cultures of WEB 2086, a specific antagonist of the PTX-sensitive G protein-coupled platelet-activating factor (PAF) receptor, blocked the action of oxLDL. Whereas PAF dispersed in the culture medium failed to produce oxLDL-like effects, degradation of PAF and PAF-like phospholipids accumulated in oxLDL with a recombinant human PAF acetylhydrolase eliminated the inhibitory effects of oxLDL on bFGF expression and DNA synthesis. CONCLUSIONS: OxLDL suppresses endothelial bFGF expression and DNA synthesis through a PTX-sensitive heterotrimeric G-protein pathway involving mediator phospholipids similar, but not identical, to PAF.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2001

Cloning and characterization of the 5'-flanking region of the rat glutamate-cysteine ligase catalytic subunit.

Glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis, is made up of two subunits, a catalytic (heavy) subunit (GCLC) and a modifier (light) subunit (GCLM), which are differentially regulated. Increased hepatic GCLC expression occurs during rapid growth, oxidative stress and after ethanol treatment. To facilitate studies of GCLC transcriptional regulation, we have cloned and characterized a 1.8 kb 5'-flanking region of the rat GCLC (GenBank accession number AF218362). A consensus TATA box and one transcriptional start site are located at 302 and 197 nucleotides upstream of the translational start site, respectively. The promoter contains consensus binding sites for many transcription factors including nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1). The rat GCLC promoter was able to efficiently drive luciferase expression in H4IIE cells. Sequential deletion analysis revealed that three DNA regions, -595 to -111, -1108 to -705 and -705 to -595, are involved in positive (the first two regions) and negative (the latter region) gene regulation. Specific protein binding to these regions was confirmed by DNase I footprinting and electrophoretic mobility-shift assays (EMSAs). Ethanol-fed livers exhibit increased protein binding to region -416 to -336 on DNase I footprinting analysis, which was found to be NF-kappaB and AP-1 on EMSA and supershift analysis. Acetaldehyde treatment of H4IIE cells led to a time- and dose-dependent increase in GCLC mRNA levels, binding of NF-kappaB and AP-1 to the GCLC promoter, and luciferase activity driven by the GCLC promoter fragment containing these binding sites.

5' Untranslated Regions↗
PubMed2001

Cloning and analysis of the rat glutamate-cysteine ligase modifier subunit promoter.

Glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione (GSH) synthesis, is made up of two subunits, a catalytic (GCLC) and a modifier (GCLM) subunit, which are differentially regulated. Increased GCLM expression occurs under certain oxidative stress conditions. To facilitate studies of GCLM transcriptional regulation, we have cloned and characterized a 1.86-kb 5'-flanking region of the rat GCLM (GenBank Accession No. AF311745). A TATA-like element and one transcriptional start sites are located at 364 and 93 nucleotides upstream of the translational start site, respectively. The promoter contains consensus binding sites for many transcription factors including activator protein 1 (AP-1), transcription factor 11 (TCF11), heat shock transcription factor (HSF), and nuclear factor kappa B (NFkappaB). The rat GCLM promoter was able to drive efficiently luciferase expression in H4IIE cells. Sequential deletion analysis revealed DNA regions, -649 to -154 and -1251 to -649, are involved in positive and negative gene regulation, respectively. Candidate transcription factors were identified by DNase I footprinting.

Animals↗
PubMed2001

Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation.

Liver-specific and nonliver-specific methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (AdoMet), the principal biological methyl donor. Mature liver expresses MAT1A, whereas MAT2A is expressed in extrahepatic tissues and is induced during liver growth and dedifferentiation. To examine the influence of MAT1A on hepatic growth, we studied the effects of a targeted disruption of the murine MAT1A gene. MAT1A mRNA and protein levels were absent in homozygous knockout mice. At 3 months, plasma methionine level increased 776% in knockouts. Hepatic AdoMet and glutathione levels were reduced by 74 and 40%, respectively, whereas S-adenosylhomocysteine, methylthioadenosine, and global DNA methylation were unchanged. The body weight of 3-month-old knockout mice was unchanged from wild-type littermates, but the liver weight was increased 40%. The Affymetrix genechip system and Northern and Western blot analyses were used to analyze differential expression of genes. The expression of many acute phase-response and inflammatory markers, including orosomucoid, amyloid, metallothionein, Fas antigen, and growth-related genes, including early growth response 1 and proliferating cell nuclear antigen, is increased in the knockout animal. At 3 months, knockout mice are more susceptible to choline-deficient diet-induced fatty liver. At 8 months, knockout mice developed spontaneous macrovesicular steatosis and predominantly periportal mononuclear cell infiltration. Thus, absence of MAT1A resulted in a liver that is more susceptible to injury, expresses markers of an acute phase response, and displays increased proliferation.

Animals↗
PubMed2001

The role of c-Myb in the up-regulation of methionine adenosyltransferase 2A expression in activated Jurkat cells.

Methionine adenosyltransferase (MAT) is a critical cellular enzyme which catalyses the formation of S-adenosylmethionine (SAM), the principal methyl donor. In mammals, two different genes, MAT1A and MAT2A, encode liver-specific and non-liver-specific MATs, respectively. SAM level increases during T-lymphocyte activation and is required for proliferation. A major mechanism for the increase in SAM level is increased MAT2A transcription. In the current work we examined the molecular mechanism of increased MAT2A expression in activated Jurkat cells. Treatment of Jurkat cells with interleukin-2 (IL-2), PMA or PMA plus phytohaemagglutinin (PHA) resulted in a 2-fold increase in MAT2A mRNA levels and a 2-fold increase in luciferase activity driven by the transfected human MAT2A promoter construct -571/+60 but not -270/+60. The region -571 to -270 of the human MAT2A contains a c-Myb consensus binding site. c-Myb is known to be induced during T-lymphocyte activation and its mRNA level was increased after treatment of Jurkat cells with IL-2, PMA or PMA plus PHA. Increased nuclear binding to the MAT2A c-Myb site was confirmed on electrophoretic mobility-shift and supershift analyses. Mutation of the MAT2A c-Myb site abolished the stimulatory effect of these agents on c-Myb nuclear binding and MAT2A promoter activities. Overexpression of c-Myb increased MAT2A promoter activity by 2-fold. Dexamethasone, a known inhibitor of lymphocyte activation, blocked the effect of these agents on MAT2A expression by preventing the increase in c-Myb expression.

Cell Extracts↗
PubMed2001

Seroprevalence and demographic characteristics of HTLV-I among blood donors in Taiwan: 1996-1999.

Screening for the human T-cell lymphotropic virus type I (HTLV-I) and-II in blood donors was implemented in Taiwan beginning in February 1996. The purpose of the present study was to investigate the changes in HTLV-I seroprevalence in all unpaid blood donors in Taiwan during the period from February 1996 to December 1999 and to determine the influence of age and sex on the HTLV-I seropositivity of donors. HTLV-I and HTLV-II screening was performed using combined HTLV-I/II immunoassay. Repeated reactive samples were confirmed by Western blot analysis. Of a total of 3,701,087 donors in all 6 blood centers in Taiwan, 2,311 (0.058%) were seropositive for HTLV-I. The HTLV-I seropositivity was 0.130%, 0.063%, 0.044%, and 0.032% in the years 1996, 1997,1998, and 1999, respectively. There was a linear increase of HTLV-I seropositivity with advancing age. The HTLV-I carrier rate for female donors was twice that for the male donors. Ninty-seven percent of HTLV-I seropositive results came from first-time donors. Our findings suggest that Taiwan is a low-prevalence nonendemic area for HTLV-I infection. The large-scale HTLV-I screening program has decreased HTLV-I seropositivity among blood donors and is useful for preventing HTLV-I transmission via blood transfusion.

Adolescent↗
PubMed2001

Current concepts in the pathogenesis of alcoholic liver injury.

Alcoholic liver disease (ALD) develops as a consequence of priming and sensitizing mechanisms rendered by cross-interactions of primary mechanistic factors and secondary risk factors. This concept, albeit not novel, is becoming widely accepted by the field, and more research is directed toward identifying and characterizing the interfaces of the cross-interactions to help understand individual predisposition to the disease. Another pivotal development is the beginning of cell type-specific research to elucidate specific contributions not only of hepatocytes, but also of hepatic macrophages, liver-associated lymphocytes, sinusoidal endothelial cells, and hepatic stellate cells to sensitizing and priming mechanisms. In particular, the critical role of hepatic macrophages has been highlighted and the priming mechanisms concerning this paracrine effect have been proposed. Glutathione depletion in hepatocyte mitochondria is considered the most important sensitizing mechanism. One of the contributing factors is decreased methionine metabolism. Remaining key questions include how altered methionine metabolism contribute to the pathogenesis of ALD; how cross-talk among nonparenchymal liver cells or between nonparenchymal cells and hepatocytes leads to ALD; how dysfunctional mitochondria determine the type of cell death in ALD; and what secondary factors are critical for the development of advanced ALD such as alcoholic hepatitis and cirrhosis.

Cytochrome P-450 CYP2E1↗
PubMed2001

The role of c-Myb and Sp1 in the up-regulation of methionine adenosyltransferase 2A gene expression in human hepatocellular carcinoma.

Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine. We showed a switch from MAT1A to MAT2A expression at the transcriptional level in human hepatocellular carcinoma (HCC) that facilitates cancer cell growth. The purpose of the present study was to better understand the molecular mechanism of increased MAT2A expression in HCC. In vitro DNase I footprinting analysis revealed two protected sites (-354 to -312 and -73 to -28) using nuclear proteins from HCC and HepG2 cells, but not normal liver. These sites are also protected in HepG2 cells on in vivo DNase I footprinting analysis. These protected sites contain consensus binding sites for c-Myb and Sp1. In HCC, the mRNA levels of c-myb and Sp1 and binding to their respective sites increased. Mutation of the c-Myb or Sp1 site reduced MAT2A promoter activity by 67% and 50%, respectively. The importance of these cis-acting elements and trans-activating factors was confirmed using heterologous promoter and expression vectors. Increased expression of c-Myb and Sp1 and binding to the MAT2A promoter contribute to transcriptional up-regulation of MAT2A in HCC.-Yang, H., Huang, Z.-Z., Wang, J., Lu, S. C. The role of c-Myb and Sp1 in the up-regulation of methionine adenosyltransferase 2A gene expression in human hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed2001

Role of promoter methylation in increased methionine adenosyltransferase 2A expression in human liver cancer.

Methionine adenosyltransferase (MAT), an essential enzyme that catalyzes the formation of S-adenosylmethionine (SAM), is encoded by two genes, MAT1A (liver-specific) and MAT2A (non-liver-specific). We showed a switch from MAT1A to MAT2A expression in human liver cancer, which facilitates cancer cell growth. The present work examined the role of methylation in MAT2A transcriptional regulation. We found that the human MAT2A promoter is hypomethylated in hepatocellular carcinoma, in which the gene is upregulated transcriptionally, but hypermethylated in normal liver, in which the gene is minimally expressed. Luciferase activities driven by in vitro methylated MAT2A promoter constructs were 75-95% lower than activities driven by unmethylated constructs. SAM treatment of Hep G2 cells reduced MAT2A endogenous expression by 75%, hypermethylated the MAT2A promoter, and reduced luciferase activities driven by MAT2A promoter constructs by 65-75% while not affecting MAT1A's promoter activity. Treatment of adult rat and human hepatocytes with trichostatin A, an inhibitor of histone deacetylase, upregulated MAT2A expression by more than fourfold. Collectively, these results suggest that MAT2A expression is regulated by promoter methylation and histone acetylation.

Animals↗
PubMed2001

Intrafamilial transmission and risk assessment of HTLV-I among blood donors in southern Taiwan.

The human T-lymphotropic virus type I (HTLV-I) is one of the important etiological agents of adult T-cell leukemia/lymphoma and of HTLV-I associated myelopathy or tropical spastic paraparesis. There is still a lack of data concerning HTLV-I transmission by seropositive carriers in Taiwan. We investigated the patterns of HTLV-I intrafamilial transmission in HTLV-I seropositive blood donors and assessed the risk factors of HTLV-I transmission in relatives of HTLV-I carriers in Taiwan. A total of twenty HTLV-I seropositive donors and their 103 relatives were enrolled. Among those 103 relatives, 40 (38.8%) were seropositive for HTLV-I. Their ages ranged from one to 70 years old with a mean age of 31.0 +/- 1.65 year-old. Three of the ten wives of male carriers were HTLV-I seropositive. However, none of the six husbands of female carriers were HTLV-I seropositive. Mother-to-child vertical transmission was found in nine of 48 (18.8%) tested. Significant risk factors of HTLV-I transmission among relatives of HTLV-I carriers were hospital admission, previous transfusion, breast feeding, anti-HCV seropositivity and female relatives of age >/= 30 with odds ratio (OR) of 9.73, 8.64, 4.36, 8.86 and 4.91, respectively (all p < 0.05). Nonsignificant risk factors of HTLV-I transmission were sharing needles, operation history, HBsAg seropositivity and male relatives of age >/= 30. Our findings suggest that mother-to-child and husband-to-wife transmissions are the important forms of intrafamilial transmission of HTLV-I in Taiwan. Screening for HTLV-I in family members of HTLV-I seropositive blood donors may be warranted.

Adult↗
PubMed2000

Mechanism and significance of increased glutathione level in human hepatocellular carcinoma and liver regeneration.

Increased glutathione (GSH) level occurs early during liver regeneration and in many drug and/or radiation-resistant tumors. Whether GSH level is elevated in liver cancer is unknown. GSH levels and expression of GSH synthetic enzymes were measured in hepatocellular carcinoma (HCC) and normal liver. GSH levels doubled in HCC. The mRNA levels of g-glutamylcysteine synthetase heavy subunit (GCS-HS) and GSH synthetase (GS) doubled, whereas the expression of GCS light subunit was unchanged. Nuclear run-on assay showed that the rate of gene transcription doubled for both GCS-HS and GS. In HCC, there is increased binding to anti-oxidant response, AP-1 and NF-kB, three cis-acting elements in the 5'-flanking region of the human GCS-HS important for its transcriptional regulation. The role of GSH in cell growth was examined by using HepG2 cells. Cell GSH level was varied by treating cells with cystine (0 to 0.2 mM) with or without GSH ester or buthionine sulfoximine. Cell GSH level correlated directly with growth rate. Finally, preventing the increase in GSH after two-thirds partial hepatectomy blunted liver regeneration. Thus, GSH level is increased during liver growth as a result of up-regulation of GCS-HS and GS. This increase, in turn, facilitates growth.

Antioxidants↗
PubMed2000

Inducers of gamma-glutamylcysteine synthetase and their effects on glutathione synthetase expression.

Synthesis of GSH occurs via two enzymatic steps, the first is catalyzed by gamma-glutamylcysteine synthetase (GCS) and the second is catalyzed by GSH synthetase (GS). A heavy (HS) and light subunit (LS) make up GCS; regulation of both subunits have been well characterized, whereas regulation of GS is largely unknown. In this study, we examined the effects of treatments known to influence the gene expression of GCS subunits on GS expression. Insulin and hydrocortisone treatment of rat hepatocytes or ethanol-feeding of rats for 9 weeks, which increased the expression of GCS-HS only, had no influence on GS expression. However, two-thirds partial hepatectomy in rats which increased the expression of GCS-HS only, also increased GS expression. Treatment of hepatocytes or rats with diethyl maleate, buthionine sulfoximine, tert-butylhydroquinone, or thioacetamide, which increased the expression of both GCS subunits, increased the expression of GS. The GSH synthesis capacity increased 50-100% by treatments that increased only the GCS-HS expression, whereas it increased 161-200% by treatments that increased both GCS-HS and GS expression. Thioacetamide treatment of Chang cells increased cell GSH and GS expression by 50%, but had minimal influence on GCS subunits. Thus, GS induction can further increase the cell's GSH synthetic capacity and in some cells may be as important as GCS in determining the rate of GSH synthesis.

Animals↗
PubMed2000

Aberrant transcripts of the cyclin-dependent kinase-associated protein phosphatase in hepatocellular carcinoma.

The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a human dual specificity protein phosphatase that dephosphorylates Cdk2 on threonine 160 in a cyclin-dependent manner. To investigate whether mutations of this enzyme occur in hepatocellular carcinoma (HCC), KAP mRNA was analyzed by reverse transcription-PCR (RT-PCR), followed by cloning and sequencing. Eight of 14 biopsy tissues obtained from advanced HCC, 6 of 13 surgically removed HCC tissues, and 2 of the adjacent noncancerous tissues contained aberrant KAP transcripts. Using the yeast two-hybrid system, five of seven representative KAP mutants were shown to be defective in interacting with Cdk2. These data suggest a possible role of KAP mutations in multiple-step hepatocarcinogenesis.

Amino Acid Sequence↗