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Sample records for liver cancers induced

  1. Liver (Hepatocellular) Cancer Prevention

    MedlinePlus

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Liver (Hepatocellular) Cancer Prevention (PDQ®)–Patient Version What is ... to keep cancer from starting. General Information About Liver (Hepatocellular) Cancer Key Points Liver cancer is a ...

  2. What Is Liver Cancer?

    MedlinePlus

    ... Treatment? Liver Cancer About Liver Cancer What Is Liver Cancer? Cancer starts when cells in the body ... structure and function of the liver. About the liver The liver is the largest internal organ. It ...

  3. Liver (Hepatocellular) Cancer Screening

    MedlinePlus

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Liver (Hepatocellular) Cancer Screening (PDQ®)–Patient Version What is ... These are called diagnostic tests . General Information About Liver (Hepatocellular) Cancer Key Points Liver cancer is a ...

  4. Tests for Liver Cancer

    MedlinePlus

    ... Cancer Early Detection, Diagnosis, and Staging Tests for Liver Cancer If you have some of the signs ... Health Care Team About Liver Cancer? More In Liver Cancer About Liver Cancer Causes, Risk Factors, and ...

  5. Liver cancer - hepatocellular carcinoma

    MedlinePlus

    Primary liver cell carcinoma; Tumor - liver; Cancer - liver; Hepatoma ... Hepatocellular carcinoma accounts for most liver cancers. This type of cancer occurs more often in men than women. It is usually diagnosed in people age 50 or ...

  6. Inhibition of diethylnitrosamine-induced liver cancer in rats by Rhizoma paridis saponin.

    PubMed

    Liu, Jing; Man, Shuli; Li, Jing; Zhang, Yang; Meng, Xin; Gao, Wenyuan

    2016-09-01

    Rhizoma Paridis saponin (RPS) had been regarded as the main active components responsible for the anti-tumor effects of the herb Paris polyphylla var. yunnanensis (Franch.) Hand.-Mazz. In the present research, we set up a rat model of diethylnitrosamine (DEN) induced hepatoma to evaluate antitumor effect of RPS. After 20 weeks treatment, rats were sacrificed to perform histopathological examinations, liver function tests, oxidative stress assays and so forth. As a result, DEN-induced hepatoma formation. RPS alleviated levels of liver injury through inhibiting liver tissues of malondialdehyde (MDA) and nitric oxide (NO) formation, increasing superoxide dismutases (SOD) production, and up-regulating expression of GST-α/μ/π in DEN-induced rats. All in all, RPS would be a potent agent inhibiting chemically induced liver cancer in the prospective application.

  7. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

    PubMed Central

    Zhou, Xiaorong; Comerford, Sarah A.; York, Brian; O’Donnell, Kathryn A.

    2017-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver. PMID:28273073

  8. TLR4-dependent immune response promotes radiation-induced liver disease by changing the liver tissue interstitial microenvironment during liver cancer radiotherapy.

    PubMed

    Zhi-Feng, Wu; Le-Yuan, Zhou; Xiao-Hui, Zhou; Ya-Bo, Gao; Jian-Ying, Zhang; Yong, Hu; Zhao-Chong, Zeng

    2014-12-01

    Liver tissue interstitial fluid (TIF) a special microenvironment around liver cells, which may play a vital role in cell communication during liver injury. Moreover, toll-like receptor 4 (TLR4) is an important trigger of the immune response that may also play a role in liver injuries, including radiation-induced liver disease (RILD). Therefore, the purpose of this study was to identify the roles of the TLR4-dependent immune response and TIFs in RILD after radiation therapy (RT) for liver cancer. This study consisted of two phases, and in the primary phase, the livers of TLR4 mutant (TLR4(-)) and normal (TLR4(+)) mice were irradiated with 30 Gy. TIF was then obtained from mouse livers and assessed by cytokine array analysis 20 days after irradiation, and cytokines in the TIFs, TLR4 and RILD were analyzed. In the second or validation phase, hepatocytes were isolated from TLR4(+) or TLR4(-) mice irradiated with 8 Gy and were co-cultured with TIFs from mouse livers, apoptosis of the hepatocytes was then measured using flow cytometry. We found that severe RILD was accompanied by higher expression of granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor receptor 2(VEGFR-2) in liver TIFs, from in TLR4(+) mice compared with TLR4(-) mice (P < 0.05). In both TLR4(+) and TLR4(-) hepatocytes, apoptosis after irradiaton was increased significantly after co-culture in TIFs from TLR4(+) mice that had their livers irradiated, compared with TIFs from TLR4(-) mice that had their livers irradiated or TIFs from unirradiated mice (P < 0.05). In summary, these findings indicate that the TLR4-dependent immune response may promote RILD by enhancing the expression of GM-CSF, VEGFR-2 and TRAIL in liver TIFs.

  9. Inhibition effects of Chinese cabbage powder on aflatoxin B1-induced liver cancer.

    PubMed

    Wang, Tuoyi; Li, Chunyan; Liu, Yang; Li, Tiezhu; Zhang, Jie; Sun, Yonghai

    2015-11-01

    In this study, 0.25 μg/ml aflatoxin B1 was used to establish a liver cancer model for assessing the potential anticancer ability of Chinese cabbage powder, which is a complex water-soluble extract from Chinese cabbage by spray-drying at an outlet temperature of 130 °C. We found at least 11 potential anticancer substances in Chinese cabbage powder. A 90-d animal experiment demonstrated that 10% of Chinese cabbage powder in drinking water could improve the plasma micronutrient status, inhibit the formation of aflatoxin B1-DNA adducts in liver cells, and effectively reduce the incidence of liver tumor induced by aflatoxin B1 from 6.67% to 0%. The dose effect experiment revealed that 10% may be the minimal effective dose to prevent the occurrence of early liver tumors. This study will help elucidate the basis of epidemiological observations of dietary cancer prevention in humans, as well as explore related mechanisms.

  10. Allicin induces p53-mediated autophagy in Hep G2 human liver cancer cells.

    PubMed

    Chu, Yung-Lin; Ho, Chi-Tang; Chung, Jing-Gung; Rajasekaran, Raghu; Sheen, Lee-Yan

    2012-08-29

    Garlic has been used throughout history for both culinary and medicinal purpose. Allicin is a major component of crushed garlic. Although it is sensitive to heat and light and easily metabolized into various compounds such as diallyl disulfide, diallyl trisulfide, and diallyl sulfide, allicin is still a major bioactive compound of crushed garlic. The mortality of hepatocellular carcinoma is quite high and ranks among the top 10 cancer-related deaths in Taiwan. Although numerous studies have shown the cancer-preventive properties of garlic and its components, there is no study on the effect of allicin on the growth of human liver cancer cells. In this study, we focused on allicin-induced autophagic cell death in human liver cancer Hep G2 cells. Our results indicated that allicin induced p53-mediated autophagy and inhibited the viability of human hepatocellular carcinoma cell lines. Using Western blotting, we observed that allicin decreased the level of cytoplasmic p53, the PI3K/mTOR signaling pathway, and the level of Bcl-2 and increased the expression of AMPK/TSC2 and Beclin-1 signaling pathways in Hep G2 cells. In addition, the colocalization of LC3-II with MitoTracker-Red (labeling mitochondria), resulting in allicin-induced degradation of mitochondria, could be observed by confocal laser microscopy. In conclusion, allicin of garlic shows great potential as a novel chemopreventive agent for the prevention of liver cancer.

  11. Andrographolide induces autophagic cell death in human liver cancer cells through cyclophilin D-mediated mitochondrial permeability transition pore.

    PubMed

    Chen, Wei; Feng, Lina; Nie, Hao; Zheng, Xiaodong

    2012-11-01

    Liver cancer is the third leading cause of cancer death worldwide and about half of the patients with liver cancer require adjuvant therapy after surgical resection. Therefore, development of novel agents to eradicate cancer cells may constitute a viable approach to treat patients with liver cancer. Andrographolide, a diterpenoid lactone isolated from Andrographis paniculata, is known to possess potent antioxidant, anti-inflammatory, antineoplastic and antiviral properties. In this study, we investigated the cytotoxic effect of andrographolide on human liver cancer cells and explored the cell death mechanism. Andrographolide induced a cell death distinct from apoptosis in multiple human liver cancer cells. The death was characterized by autophagy as evidenced by the accumulation of LC3 II and autophagosomes, and the formation of puncta GFP-LC3. This autophagy as well as cytotoxicity caused by andrographolide could be effectively prevented by 3-methyladenine (a chemical inhibitor of autophagy). Mechanistic study indicated that andrographolide induced autophagic cell death by disruption of mitochondrial transmembrane potential and elevation of reactive oxygen species, which were correlated with mitochondrial permeability transition pore Inhibition of cyclophilin D (a component of MPTP) by cyclosporin A or abrogation of its expression by small interfering RNA significantly suppressed the cytotoxicity of andrographolide, suggesting that cyclophilin D may play an important role in mediating andrographolide-induced cytotoxicity. Taken together, our findings unveil a novel mechanism of drug action by andrographolide in liver cancer cells and suggest that andrographolide may represent a promising novel agent in the treatment of liver cancer.

  12. Oxaliplatin-induced sinusoidal obstruction syndrome mimicking metastatic colon cancer in the liver

    PubMed Central

    CHOI, JUNG-HYE; WON, YOUNG-WOONG; KIM, HYUN SUNG; OH, YOUNG-HA; LIM, SANGHYEOK; KIM, HAN-JOON

    2016-01-01

    Oxaliplatin is an effective chemotherapeutic agent for the treatment of colorectal cancer; however, it may cause liver injury, particularly sinusoidal obstruction syndrome (SOS). Although SOS does not usually present with focal lesions on radiological images, the present study describes the case of a 22-year-old woman with oxaliplatin-induced SOS mimicking metastatic colon cancer in the liver. An abdominal computed tomography revealed a novel 1 cm, low-density lesion in segment 1 of the liver following the administration of the fourth round of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer. Since the lesion was indistinguishable from metastasis, even with detailed imaging studies, including magnetic resonance imaging and positron emission tomography-computed tomography, an isolated caudate lobectomy was planned. The cut surface of the resected liver showed a localized reddish congested lesion measuring 1.4 cm in diameter. The adjacent hepatic parenchyma also demonstrated diffuse sinusoidal congestion with a nutmeg-like appearance. Histologically, the lesion exhibited severe sinusoidal congestion with peliosis hepatis-like features. The widened sinusoidal space was outlined by markedly attenuated hepatic cords and filled with erythrocytes. The final diagnosis was oxaliplatin-induced SOS. The patient recovered completely and was relapse-free at the time of writing. PMID:27073565

  13. Stages of Childhood Liver Cancer

    MedlinePlus

    ... Liver Cancer Prevention Liver Cancer Screening Research Childhood Liver Cancer Treatment (PDQ®)–Patient Version General Information About Childhood Liver Cancer Go to Health Professional Version Key Points ...

  14. Liver X receptor β activation induces pyroptosis of human and murine colon cancer cells

    PubMed Central

    Derangère, V; Chevriaux, A; Courtaut, F; Bruchard, M; Berger, H; Chalmin, F; Causse, S Z; Limagne, E; Végran, F; Ladoire, S; Simon, B; Boireau, W; Hichami, A; Apetoh, L; Mignot, G; Ghiringhelli, F; Rébé, C

    2014-01-01

    Liver X receptors (LXRs) have been proposed to have some anticancer properties, through molecular mechanisms that remain elusive. Here we report for the first time that LXR ligands induce caspase-1-dependent cell death of colon cancer cells. Caspase-1 activation requires Nod-like-receptor pyrin domain containing 3 (NLRP3) inflammasome and ATP-mediated P2 × 7 receptor activation. Surprisingly, LXRβ is mainly located in the cytoplasm and has a non-genomic role by interacting with pannexin 1 leading to ATP secretion. Finally, LXR ligands have an antitumoral effect in a mouse colon cancer model, dependent on the presence of LXRβ, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRβ, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis. PMID:25124554

  15. Novel piperazine core compound induces death in human liver cancer cells: possible pharmacological properties

    PubMed Central

    Samie, Nima; Muniandy, Sekaran; Kanthimathi, M. S.; Haerian, Batoul Sadat; Raja Azudin, Raja Elina

    2016-01-01

    The current study evaluates the cytotoxic mechanism of a novel piperazine derivate designated as PCC against human liver cancer cells. In this context, human liver cancer cell lines, SNU-475 and 243, human monocyte/macrophage cell line, CRL-9855, and human B lymphocyte cell line, CCL-156, were used to determine the IC50 of PCC using the standard MTT assay. PCC displayed a strong suppressive effect on SNU-475 and SNU-423 cells with an IC50 value of 6.98 ± 0.11 μg/ml and 7.76 ± 0.45 μg/ml respectively, after 24 h of treatment. Significant dipping in the mitochondrial membrane potential and elevation in the released of cytochrome c from the mitochondria indicated the induction of the intrinsic apoptosis pathway by PCC. Activation of this pathway was further evidenced by significant activation of caspase 3/7 and 9. PCC was also shown to activate the extrinsic pathways of apoptosis via activation of caspase-8 which is linked to the suppression of NF-ƙB translocation to the nucleus. Cell cycle arrest in the G1 phase was confirmed by flow cytometry and up-regulation of glutathione reductase expression was quantified by qPCR. This study suggests that PCC is a simultaneous inducer of intrinsic and extrinsic pathways of apoptosis in liver cancer cell lines. PMID:27072064

  16. Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells.

    PubMed

    Ordoñez, Raquel; Fernández, Anna; Prieto-Domínguez, Néstor; Martínez, Laura; García-Ruiz, Carmen; Fernández-Checa, José C; Mauriz, José L; González-Gallego, Javier

    2015-09-01

    Autophagy is a process that maintains homeostasis during stress, although it also contributes to cell death under specific contexts. Ceramides have emerged as important effectors in the regulation of autophagy, mediating the crosstalk with apoptosis. Melatonin induces apoptosis of cancer cells; however, its role in autophagy and ceramide metabolism has yet to be clearly elucidated. This study was aimed to evaluate the effect of melatonin administration on autophagy and ceramide metabolism and its possible link with melatonin-induced apoptotic cell death in hepatocarcinoma (HCC) cells. Melatonin (2 mm) transiently induced autophagy in HepG2 cells through JNK phosphorylation, characterized by increased Beclin-1 expression, p62 degradation, and LC3II and LAMP-2 colocalization, which translated in decreased cell viability. Moreover, ATG5 silencing sensitized HepG2 cells to melatonin-induced apoptosis, suggesting a dual role of autophagy in cell death. Melatonin enhanced ceramide levels through both de novo synthesis and acid sphingomyelinase (ASMase) stimulation. Serine palmitoyltransferase (SPT) inhibition with myriocin prevented melatonin-induced autophagy and ASMase inhibition with imipramine-impaired autophagy flux. However, ASMase inhibition partially protected HepG2 cells against melatonin, while SPT inhibition significantly enhanced cell death. Findings suggest a crosstalk between SPT-mediated ceramide generation and autophagy in protecting against melatonin, while specific ASMase-induced ceramide production participates in melatonin-mediated cell death. Thus, dual blocking of SPT and autophagy emerges as a potential strategy to potentiate the apoptotic effects of melatonin in liver cancer cells.

  17. General Information about Liver (Hepatocellular) Cancer

    MedlinePlus

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Liver (Hepatocellular) Cancer Prevention (PDQ®)–Patient Version What is ... to keep cancer from starting. General Information About Liver (Hepatocellular) Cancer Key Points Liver cancer is a ...

  18. Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling.

    PubMed

    Ma, Bo; Wheeler, Sarah E; Clark, Amanda M; Whaley, Diana L; Yang, Min; Wells, Alan

    2016-11-01

    Liver is one of the most common sites of cancer metastasis. Once disseminated, the prognosis is poor as these tumors often display generalized chemoresistance, particularly for carcinomas that derive not from the aerodigestive tract. When these cancers seed the liver, the aggressive cells usually undergo a mesenchymal to epithelial reverting transition that both aids colonization and renders the tumor cells chemoresistant. In vitro studies demonstrate that hepatocytes drive this phenotypic shift. However, the in vivo evidence and the molecular signals that protect these cells from induced death are yet to be defined. Herein, we report that membrane surface E-cadherin-expressing prostate cancer cells were resistant to cell death by chemotherapeutic drugs but E-cadherin null cells or those expressing E-cadherin only in the cytoplasm were sensitive to death signals and chemotherapies both in vitro and in vivo. While cell-cell E-cadherin ligandation reduced mitogenesis, this chemoprotection was proliferation-independent as killing of both 5-ethynyl-2'-deoxyuridine-positive (or Ki67(+) ) and 5-ethynyl-2'-deoxyuridine-negative (Ki67(-) ) cells was inversely related to membrane-bound E-cadherin. Inhibiting the canonical survival kinases extracellular signal-regulated protein kinases, protein kinase B, and Janus kinase, which are activated by chemotherapeutics in epithelial cell-transitioned prostate cancer, abrogated the chemoresistance both in cell culture and in animal models of metastatic cancer. For disseminated tumors, protein kinase B disruption in itself had no effect on tumor survival but was synergistic with chemotherapy, leading to increased killing.

  19. Liver cancer stem cells.

    PubMed

    Sell, Stewart; Leffert, Hyam L

    2008-06-10

    In an effort to review the evidence that liver cancer stem cells exist, two fundamental questions must be addressed. First, do hepatocellular carcinomas (HCC) arise from liver stem cells? Second, do HCCs contain cells that possess properties of cancer stem cells? For many years the finding of preneoplastic nodules in the liver during experimental induction of HCCs by chemicals was interpreted to support the hypothesis that HCC arose by dedifferentiation of mature liver cells. More recently, recognition of the role of small oval cells in the carcinogenic process led to a new hypothesis that HCC arises by maturation arrest of liver stem cells. Analysis of the cells in HCC supports the presence of cells with stem-cell properties (ie, immortality, transplantability, and resistance to therapy). However, definitive markers for these putative cancer stem cells have not yet been found and a liver cancer stem cell has not been isolated.

  20. Chemoprevention and cytotoxic effect of Bauhinia variegata against N-nitrosodiethylamine induced liver tumors and human cancer cell lines.

    PubMed

    Rajkapoor, B; Jayakar, B; Murugesh, N; Sakthisekaran, D

    2006-04-06

    The chemopreventive and cytotoxic effect of ethanol extract of Bauhinia variegata (EBV) was evaluated in N-nitrosodiethylamine (DEN, 200 mg/kg) induced experimental liver tumor in rats and human cancer cell lines. Oral administration of ethanol extract of Bauhinia variegata (250 mg/kg) effectively suppressed liver tumor induced by DEN as revealed by decrease in DEN induced elevated levels of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin, gamma glutamate transpeptidase (GGTP), lipid peroxidase (LPO), glutathione peroxidase (GPx) and glutathione S-transferase (GST). The extract produced an increase in enzymatic antioxidant (superoxide dismutase and catalase) levels and total proteins when compared to those in liver tumor bearing rats. The histopathological changes of liver samples were compared with respective controls. EBV was found to be cytotoxic against human epithelial larynx cancer (HEp2) and human breast cancer (HBL-100) cells. These results show a significant chemopreventive and cytotoxic effect of ethanol extract of Bauhinia variegata against DEN induced liver tumor and human cancer cell lines.

  1. Risks of Liver (Hepatocellular) Cancer Screening

    MedlinePlus

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Liver (Hepatocellular) Cancer Screening (PDQ®)–Patient Version What is ... These are called diagnostic tests . General Information About Liver (Hepatocellular) Cancer Key Points Liver cancer is a ...

  2. Do We Know What Causes Liver Cancer?

    MedlinePlus

    ... Factors, and Prevention Do We Know What Causes Liver Cancer? Although several risk factors for hepatocellular cancer ... Cancer? Can Liver Cancer Be Prevented? More In Liver Cancer About Liver Cancer Causes, Risk Factors, and ...

  3. Malnutrition, liver damage, and cancer.

    PubMed

    Grasso, P

    1981-01-01

    There is no clear indication that malnutrition, per se, is a principal cause of cancer in man, but the prevalence of liver cancer in areas where malnutrition exists supports this hypothesis. Liver damage and liver cancer have been induced in laboratory rats by diets consisting of peanut meal and proteins deficient in some essential amino acids. However, liver damage, but not cancer, was produced when the diets contained no peanut meal but consisted of a mixture of amino acids deficient in methionine and cysteine, so that it is possible that aflatoxin, a contaminant of peanut meal, may have been responsible for the malignancies seen in the earlier experiments. Liver cancer developes in a high proportion of mice allowed to feed ad libitum or given a diet containing a high proportion of fat (groundnut oil) or protein (casein). Dietary restriction reduced the incidences of this cancer. This findings lends some support to current thinking that diet may be a factor in the development of cancer in man.

  4. SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer

    PubMed Central

    Tordella, Luca; Khan, Sadaf; Hohmeyer, Anja; Banito, Ana; Klotz, Sabrina; Raguz, Selina; Martin, Nadine; Dhamarlingam, Gopuraja; Carroll, Thomas; González Meljem, José Mario; Deswal, Sumit; Martínez-Barbera, Juan Pedro; García-Escudero, Ramón; Zuber, Johannes; Zender, Lars; Gil, Jesús

    2016-01-01

    Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers. PMID:27737960

  5. Predictive Models of Liver Cancer

    EPA Science Inventory

    Predictive models of chemical-induced liver cancer face the challenge of bridging causative molecular mechanisms to adverse clinical outcomes. The latent sequence of intervening events from chemical insult to toxicity are poorly understood because they span multiple levels of bio...

  6. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer

    PubMed Central

    Asgharpour, Amon; Cazanave, Sophie C.; Pacana, Tommy; Seneshaw, Mulugeta; Vincent, Robert; Banini, Bubu A.; Kumar, Divya Prasanna; Daita, Kalyani; Min, Hae-Ki; Mirshahi, Faridoddin; Bedossa, Pierre; Sun, Xiaochen; Hoshida, Yujin; Koduru, Srinivas V.; Contaifer, Daniel; Warncke, Urszula Osinska; Wijesinghe, Dayanjan S.; Sanyal, Arun J.

    2016-01-01

    Background & Aims The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development. Methods A stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains. Results Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD. Conclusions We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH. Lay summary We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH. PMID:27261415

  7. General Information about Childhood Liver Cancer

    MedlinePlus

    ... Liver Cancer Prevention Liver Cancer Screening Research Childhood Liver Cancer Treatment (PDQ®)–Patient Version General Information About Childhood Liver Cancer Go to Health Professional Version Key Points ...

  8. The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth.

    PubMed

    Luo, Zhongguang; Yu, Guangyang; Lee, Hyuk Woo; Li, Lihui; Wang, Lingyan; Yang, Dongqin; Pan, Yongfu; Ding, Chan; Qian, Jing; Wu, Lijun; Chu, Yiwei; Yi, Jing; Wang, Xiangdong; Sun, Yi; Jeong, Lak Shin; Liu, Jie; Jia, Lijun

    2012-07-01

    Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy.

  9. Proteoglycans in liver cancer

    PubMed Central

    Baghy, Kornélia; Tátrai, Péter; Regős, Eszter; Kovalszky, Ilona

    2016-01-01

    Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects. PMID:26755884

  10. Development of a liver-specific Tet-on inducible system for AAV vectors and its application in the treatment of liver cancer.

    PubMed

    Vanrell, Lucia; Di Scala, Marianna; Blanco, Laura; Otano, Itziar; Gil-Farina, Irene; Baldim, Victor; Paneda, Astrid; Berraondo, Pedro; Beattie, Stuart G; Chtarto, Abdelwahed; Tenenbaum, Lilianne; Prieto, Jesús; Gonzalez-Aseguinolaza, Gloria

    2011-07-01

    Recombinant adeno-associated virus (rAAV) are effective gene delivery vehicles that can mediate long-lasting transgene expression. However, tight regulation and tissue-specific transgene expression is required for certain therapeutic applications. For regulatable expression from the liver we designed a hepatospecific bidirectional and autoregulatory tetracycline (Tet)-On system (Tet(bidir)Alb) flanked by AAV inverted terminal repeats (ITRs). We characterized the inducible hepatospecific system in comparison with an inducible ubiquitous expression system (Tet(bidir)CMV) using luciferase (luc). Although the ubiquitous system led to luc expression throughout the mouse, luc expression derived from the hepatospecific system was restricted to the liver. Interestingly, the induction rate of the Tet(bidir)Alb was significantly higher than that of Tet(bidir)CMV, whereas leakage of Tet(bidir)Alb was significantly lower. To evaluate the therapeutic potential of this vector, an AAV-Tet(bidir)-Alb-expressing interleukin-12 (IL-12) was tested in a murine model for hepatic colorectal metastasis. The vector induced dose-dependent levels of IL-12 and interferon-γ (IFN-γ), showing no significant toxicity. AAV-Tet(bidir)-Alb-IL-12 was highly efficient in preventing establishment of metastasis in the liver and induced an efficient T-cell memory response to tumor cells. Thus, we have demonstrated persistent, and inducible in vivo expression of a gene from a liver-specific Tet-On inducible construct delivered via an AAV vector and proved to be an efficient tool for treating liver cancer.

  11. Chrysophanol induces necrosis through the production of ROS and alteration of ATP levels in J5 human liver cancer cells

    PubMed Central

    Lu, Chi-Cheng; Yang, Jai-Sing; Huang, An-Cheng; Hsia, Te-Chun; Chou, Su-Tze; Kuo, Chao-Lin; Lu, Hsu-Feng; Lee, Tsung-Han; Wood, W. G.; Chung, Jing-Gung

    2011-01-01

    Anthraquinone compounds have been shown to induce apoptosis in different cancer cell types. Effects of chrysophanol, an anthraquinone compound, on cancer cell death have not been well-studied. The goal of this study was to examine if chrysophanol had cytotoxic effects and if such effects involved apoptosis or necrosis in J5 human liver cancer cells. Chrysophanol induced necrosis in J5 cells in a dose- and time-dependent manner. Non-apoptotic cell death was induced by chrysophanol in J5 cells and was characterized by caspase independence, delayed externalization of phosphatidylserine and plasma membrane disruption. Blockage of apoptotic induction by a general caspase inhibitor (z-VAD-fmk) failed to protect cells against chrysophanol-induced cell death. The levels of ROS production and loss of mitochondrial membrane potential (ΔΨm) were also determined to assess the effects of chrysophanol. However, reductions in ATP levels and increases in LDH activity indicated that chrysophanol stimulated necrotic cell death. In summary, human liver cancer cells treated with chrysophanol exhibited a cellular pattern associated with necrosis and not apoptosis. PMID:20169580

  12. Anticancer effect of xanthohumol induces growth inhibition and apoptosis of human liver cancer through NF-κB/p53-apoptosis signaling pathway.

    PubMed

    Zhao, Xiangqian; Jiang, Kai; Liang, Bin; Huang, Xiaoqiang

    2016-02-01

    Xanthohumol may prevent and cure diabetes and atherosis, have oxidation resistance and antiviral function as well as anticancer effect preventing cancer cell metastasis. We investigate whether the anticancer effect of xanthohumol induces growth inhibition and apoptosis of human liver cancer through NF-κB/p53-apoptosis signaling pathway. Human liver cancer HepG2 cell were treated with 10, 20, 30 and 40 µM xanthohumol for 48 h. The present study showed that the anticancer effect of xanthohumol was effective in inhibiting proliferation and inducing apoptosis of human liver cancer HepG2 cells. Furthermore, the caspase-3 activity of human liver cancer HepG2 cells was increased by xanthohumol. In addition, 48-h treatment with xanthohumol suppressed NF-κB expression and promoted p53, cleaved PARP, AIF and cytochrome c expression and downregulated XIAP and Bcl-2/Bax expression in human liver cancer HepG2 cells. Therefore, the anticancer effect of xanthohumol induces growth inhibition and apoptosis of human liver cancer through the NF-κB/p53-apoptosis signaling pathway.

  13. Anticancer effect of xanthohumol induces growth inhibition and apoptosis of human liver cancer through NF-κB/p53-apoptosis signaling pathway

    PubMed Central

    ZHAO, XIANGQIAN; JIANG, KAI; LIANG, BIN; HUANG, XIAOQIANG

    2016-01-01

    Xanthohumol may prevent and cure diabetes and atherosis, have oxidation resistance and antiviral function as well as anticancer effect preventing cancer cell metastasis. We investigate whether the anticancer effect of xanthohumol induces growth inhibition and apoptosis of human liver cancer through NF-κB/p53-apoptosis signaling pathway. Human liver cancer HepG2 cell were treated with 10, 20, 30 and 40 µM xanthohumol for 48 h. The present study showed that the anticancer effect of xanthohumol was effective in inhibiting proliferation and inducing apoptosis of human liver cancer HepG2 cells. Furthermore, the caspase-3 activity of human liver cancer HepG2 cells was increased by xanthohumol. In addition, 48-h treatment with xanthohumol suppressed NF-κB expression and promoted p53, cleaved PARP, AIF and cytochrome c expression and downregulated XIAP and Bcl-2/Bax expression in human liver cancer HepG2 cells. Therefore, the anticancer effect of xanthohumol induces growth inhibition and apoptosis of human liver cancer through the NF-κB/p53-apoptosis signaling pathway. PMID:26718026

  14. Drugs Approved for Liver Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for liver cancer. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  15. Sorafenib Tosylate in Treating Patients With Liver Cancer Who Have Undergone a Liver Transplant

    ClinicalTrials.gov

    2015-03-25

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer

  16. Treatment Options for Adult Primary Liver Cancer

    MedlinePlus

    ... Cancer Prevention Liver Cancer Screening Research Adult Primary Liver Cancer Treatment (PDQ®)–Patient Version General Information About Adult Primary Liver Cancer Go to Health Professional Version Key Points ...

  17. Treatment Option Overview (Adult Primary Liver Cancer)

    MedlinePlus

    ... Cancer Prevention Liver Cancer Screening Research Adult Primary Liver Cancer Treatment (PDQ®)–Patient Version General Information About Adult Primary Liver Cancer Go to Health Professional Version Key Points ...

  18. Stages of Adult Primary Liver Cancer

    MedlinePlus

    ... Cancer Prevention Liver Cancer Screening Research Adult Primary Liver Cancer Treatment (PDQ®)–Patient Version General Information About Adult Primary Liver Cancer Go to Health Professional Version Key Points ...

  19. General Information about Adult Primary Liver Cancer

    MedlinePlus

    ... Cancer Prevention Liver Cancer Screening Research Adult Primary Liver Cancer Treatment (PDQ®)–Patient Version General Information About Adult Primary Liver Cancer Go to Health Professional Version Key Points ...

  20. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases.

    PubMed

    Rahbari, Nuh N; Kedrin, Dmitriy; Incio, Joao; Liu, Hao; Ho, William W; Nia, Hadi T; Edrich, Christina M; Jung, Keehoon; Daubriac, Julien; Chen, Ivy; Heishi, Takahiro; Martin, John D; Huang, Yuhui; Maimon, Nir; Reissfelder, Christoph; Weitz, Jurgen; Boucher, Yves; Clark, Jeffrey W; Grodzinsky, Alan J; Duda, Dan G; Jain, Rakesh K; Fukumura, Dai

    2016-10-12

    The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition. The density of these matrix components correlated with increased tumor stiffness after anti-VEGF therapy. Treatment-induced tumor hypoxia appeared to be the driving force for the remodeling of the extracellular matrix. In preclinical models, we show that enzymatic depletion of HA partially rescued the compromised perfusion in liver mCRCs after anti-VEGF therapy and prolonged survival in combination with anti-VEGF therapy and chemotherapy. These findings suggest that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy.

  1. L-Carnitine induces recovery of liver lipid metabolism in cancer cachexia.

    PubMed

    Silvério, Renata; Laviano, Alessandro; Rossi Fanelli, Filippo; Seelaender, Marília

    2012-05-01

    Cancer cachexia causes metabolic alterations with a marked effect on hepatic lipid metabolism. L-Carnitine modulates lipid metabolism and its supplementation has been proposed as a therapeutic strategy in many diseases. In the present study, the effects of L-carnitine supplementation on gene expression and on liver lipid metabolism-related proteins was investigated in cachectic tumour-bearing rats. Wistar rats were assigned to receive 1 g/kg of L-carnitine or saline. After 14 days, supplemented and control animals were assigned to a control (N), control supplemented with L-carnitine (CN), tumour-bearing Walker 256 carcinosarcoma (TB) and tumour-bearing supplemented with L-carnitine (CTB) group. The mRNA expression of carnitine palmitoyltransferase I and II (CPT I and II), microsomal triglyceride transfer protein (MTP), liver fatty acid-binding protein (L-FABP), fatty acid translocase (FAT/CD36), peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and organic cation transporter 2 (OCTN2) was assessed, and the maximal activity of CPT I and II in the liver measured, along with plasma and liver triacylglycerol content. The gene expression of MTP, and CPT I catalytic activity were reduced in TB, who also showed increased liver (150%) and plasma (3.3-fold) triacylglycerol content. L-Carnitine supplementation was able to restore these parameters back to control values (p<0.05). These data show that L-carnitine preserves hepatic lipid metabolism in tumour-bearing animals, suggesting its supplementation to be of potential interest in cachexia.

  2. Hepatitis B virus X induces inflammation and cancer in mice liver through dysregulation of cytoskeletal remodeling and lipid metabolism

    PubMed Central

    Xu, Zhongwei; Zhai, Linghui; Yi, Tailong; Gao, Huiying; Fan, Fengxu; Li, Yanchang; Wang, Youliang; Li, Ning; Xing, Xiaohua; Su, Na; Wu, Feilin; Chang, Lei; Chen, Xiuli; Dai, Erhei; Zhao, Chao; Yang, Xiao; Cui, Chunping; Xu, Ping

    2016-01-01

    Hepatitis B virus X protein (HBx) participates in the occurrence and development processes of hepatocellular carcinoma (HCC) as a multifunctional regulation factor. However, the underlying molecular mechanism remains obscure. Here, we describe the use of p21HBx/+ mouse and SILAM (Stable Isotope Labeling in Mammals) strategy to define the pathological mechanisms for the occurrence and development of HBx induced liver cancer. We systematically compared a series of proteome samples from regular mice, 12- and 24-month old p21HBx/+ mice representing the inflammation and HCC stages of liver disease respectively and their nontransgenic wild-type (WT) littermates. Totally we identified 22 and 97 differentially expressed proteins out of a total of 2473 quantified proteins. Bioinformatics analysis suggested that the lipid metabolism and CDC42-induced cytoskeleton remodeling pathways were strongly activated by the HBx transgene. Interestingly, the protein-protein interaction MS study revealed that HBx directly interacted with multiple proteins in these two pathways. The same effect of up-regulation of cytoskeleton and lipid metabolism related proteins, including CDC42, CFL1, PPARγ and ADFP, was also observed in the Huh-7 cells transfected with HBx. More importantly, CFL1 and ADFP were specifically accumulated in HBV-associated HCC (HBV-HCC) patient samples, and their expression levels were positively correlated with the severity of HBV-related liver disease. These results provide evidence that HBx induces the dysregulation of cytoskeleton remodeling and lipid metabolism and leads to the occurrence and development of liver cancer. The CFL1 and ADFP might be served as potential biomarkers for prognosis and diagnosis of HBV-HCC. PMID:27708241

  3. Garcinia dulcis Fruit Extract Induced Cytotoxicity and Apoptosis in HepG2 Liver Cancer Cell Line.

    PubMed

    Abu Bakar, Mohd Fadzelly; Ahmad, Nor Ezani; Suleiman, Monica; Rahmat, Asmah; Isha, Azizul

    2015-01-01

    Garcinia dulcis or locally known in Malaysia as "mundu" belongs to the family of Clusiaceae. The study was conducted to investigate the anticancer potential of different parts of G. dulcis fruit extracts and their possible mechanism of action in HepG2 liver cancer cell line. MTT assay showed that the peel, flesh, and seed extracts of G. dulcis induced cytotoxicity in HepG2 cell line with IC50 values of 46.33 ± 4.51, 38.33 ± 3.51, and 7.5 ± 2.52 µg/mL, respectively. The flesh extract of G. dulcis induced cell cycle arrest at sub-G1 (apoptosis) phase in a time-dependent manner. Staining with Annexin V-FITC and propidium iodide showed that 41.2% of the cell population underwent apoptosis after 72 hours of exposure of the HepG2 cell line to G. dulcis flesh extract. Caspase-3 has been shown to be activated which finally leads to the death of HepG2 cell (apoptosis). GC-MS analysis showed that the highest percentage of compound identified in the extract of G. dulcis flesh was hydroxymethylfurfural and 3-methyl-2,5-furandione, together with xanthones and flavonoids (based on literature), could synergistically contribute to the observed effects. This finding suggested that the flesh extract of G. dulcis has its own potential as cancer chemotherapeutic agent against liver cancer cell.

  4. Garcinia dulcis Fruit Extract Induced Cytotoxicity and Apoptosis in HepG2 Liver Cancer Cell Line

    PubMed Central

    Abu Bakar, Mohd Fadzelly; Ahmad, Nor Ezani; Suleiman, Monica; Rahmat, Asmah; Isha, Azizul

    2015-01-01

    Garcinia dulcis or locally known in Malaysia as “mundu” belongs to the family of Clusiaceae. The study was conducted to investigate the anticancer potential of different parts of G. dulcis fruit extracts and their possible mechanism of action in HepG2 liver cancer cell line. MTT assay showed that the peel, flesh, and seed extracts of G. dulcis induced cytotoxicity in HepG2 cell line with IC50 values of 46.33 ± 4.51, 38.33 ± 3.51, and 7.5 ± 2.52 µg/mL, respectively. The flesh extract of G. dulcis induced cell cycle arrest at sub-G1 (apoptosis) phase in a time-dependent manner. Staining with Annexin V-FITC and propidium iodide showed that 41.2% of the cell population underwent apoptosis after 72 hours of exposure of the HepG2 cell line to G. dulcis flesh extract. Caspase-3 has been shown to be activated which finally leads to the death of HepG2 cell (apoptosis). GC-MS analysis showed that the highest percentage of compound identified in the extract of G. dulcis flesh was hydroxymethylfurfural and 3-methyl-2,5-furandione, together with xanthones and flavonoids (based on literature), could synergistically contribute to the observed effects. This finding suggested that the flesh extract of G. dulcis has its own potential as cancer chemotherapeutic agent against liver cancer cell. PMID:26557713

  5. Allicin induces anti-human liver cancer cells through the p53 gene modulating apoptosis and autophagy.

    PubMed

    Chu, Yung-Lin; Ho, Chi-Tang; Chung, Jing-Gung; Raghu, Rajasekaran; Lo, Yi-Chen; Sheen, Lee-Yan

    2013-10-16

    Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer globally and ranks first among the cancer-related mortalities in Taiwan. This study aims to understand the modes of cell death mechanism induced by allicin, a major phytochemical of crushed garlic, in human hepatoma cells. Our earlier study indicated that allicin induced autophagic cell death in human HCC Hep G2 (p53(wild type)) cells, whereas in the present study, allicin induced apoptotic cell death through caspase-dependent and caspase-independent pathways by reactive oxygen species (ROS) overproduction in human HCC Hep 3B (p53(mutation)) cells. To gain insight into the cell death mechanism in p53 knocked down Hep G2, we silenced the p53 gene using siRNA-mediated silencing. Allicin treatment induced apoptotic cell death in p53 knocked down Hep G2 cells similar to that of Hep 3B cells. These results suggest that allicin induced cell death in human hepatoma cells through either autophagy or apoptosis and might be a potential novel complementary gene therapeutic agent for the treatment of apoptosis-resistant cancer cells.

  6. Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold.

    PubMed

    Johnson, Natalie M; Egner, Patricia A; Baxter, Victoria K; Sporn, Michael B; Wible, Ryan S; Sutter, Thomas R; Groopman, John D; Kensler, Thomas W; Roebuck, Bill D

    2014-07-01

    In experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects against AFB1-induced toxicity and preneoplastic lesion formation (GST-P-positive foci). This study assessed and mechanistically characterized the chemoprotective efficacy of CDDO-Im against AFB1-induced hepatocellular carcinoma (HCC). A lifetime cancer bioassay was undertaken in F344 rats dosed with AFB1 (200 μg/kg rat/day) for four weeks and receiving either vehicle or CDDO-Im (three times weekly), one week before and throughout the exposure period. Weekly, 24-hour urine samples were collected for analysis of AFB1 metabolites. In a subset of rats, livers were analyzed for GST-P foci. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined. CDDO-Im completely protected (0/20) against AFB1-induced liver cancer compared with a 96% incidence (22/23) observed in the AFB1 group. With CDDO-Im treatment, integrated level of urinary AFB1-N(7)-guanine was significantly reduced (66%) and aflatoxin-N-acetylcysteine, a detoxication product, was consistently elevated (300%) after the first AFB1 dose. In AFB1-treated rats, the hepatic burden of GST-P-positive foci increased substantially (0%-13.8%) over the four weeks, but was largely absent with CDDO-Im intervention. The toxicogenomic RNA expression signature characteristic of AFB1 was absent in the AFB1 + CDDO-Im-treated rats. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development.

  7. What Happens After Treatment for Liver Cancer?

    MedlinePlus

    ... Support Liver Cancer After Treatment Living as a Liver Cancer Survivor Completing treatment can be both stressful ... back, this could happen. Follow-up after a liver transplant A liver transplant can be very effective ...

  8. Lipids changes in liver cancer*

    PubMed Central

    Jiang, Jing-ting; Xu, Ning; Zhang, Xiao-ying; Wu, Chang-ping

    2007-01-01

    Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer. PMID:17565510

  9. 3-Tesla MRI Response to TACE in HCC (Liver Cancer)

    ClinicalTrials.gov

    2016-08-22

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Stage A Adult Primary Liver Cancer (BCLC); Stage B Adult Primary Liver Cancer (BCLC)

  10. Acetaldehyde targets superoxide dismutase 2 in liver cancer cells inducing transient enzyme impairment and a rapid transcriptional recovery.

    PubMed

    Clavijo-Cornejo, Denise; Gutiérrez-Carrera, Mario; Palestino-Domínguez, Mayrel; Dominguez-Perez, Mayra; Nuño, Natalia; Souza, Veronica; Miranda, Roxana U; Kershenobich, David; Gutiérrez-Ruiz, Ma Concepción; Bucio, Leticia; Gómez-Quiroz, Luis E

    2014-07-01

    Alcohol is undoubtedly, the main toxic agent that people consume by recreation and the abuse is associated with liver damage, mainly by the overproduction of reactive oxygen species and the toxic effects of its first metabolite acetaldehyde. It is known that acetaldehyde targets mitochondria inducing redox imbalance and oxidative stress. Mitochondrial superoxide dismutase transforms superoxide radical into hydrogen peroxide, which in addition, is transformed in water by other enzymes. In the present study we demonstrate that acetaldehyde transiently impairs SOD2 activity in HepG2 cells, the decrease in the enzyme activity was associated to a reduction in the protein content, which was rapidly recovered, to basal values, by synthesis de novo in a mechanism mediated by NF-κB and PKC. The SOD2 impairment was not associated with adduct formation. The recovery on SOD2 activity in HepG2 cells can represent survival advantage for cancer cells, the results shown that SOD2 could be considered a therapeutic target in liver cancer.

  11. Antioxidant activity of ethanolic extract of Tinospora cordifolia on N-nitrosodiethylamine (diethylnitrosamine) induced liver cancer in male Wister albino rats

    PubMed Central

    Jayaprakash, R.; Ramesh, V.; Sridhar, M. P.; Sasikala, C.

    2015-01-01

    Background: Cancer is a disease that evokes wide spread fear among people and is one of the leading causes of deaths in the world. Diethylnitrosamine (DEN) is a known carcinogen in rodent liver. DENs reported to undergo metabolic activation by cytochrome P450 enzymes to form reactive electrophiles that cause oxidative stress leading to cytotoxicity, mutagenicity and carcinogenicity. Objective: The present study was carried out to evaluate the antioxidant activity of ethanolic extract of Tinospora cordifolia (EETC) in N-nitrosodiethylamine (DEN) induced liver cancer in male Wister albino rats. Materials and Methods: The antioxidant activity was assessed by the levels of lipid peroxidation (LPO), enzymic and nonenzymic antioxidants. Result: A significant levels of LPO was increased as the enzymic and nonenzymic antioxidants values were decreased in liver cancer bearing animals. Conclusions: The administration of EETC to cancer bearing animals reverted the LPO levels, enzymic and nonenzymic antioxidants to near normal PMID:26015745

  12. Radiofrequency Ablation for Liver Cancer.

    PubMed

    Jacobs, Amy

    2015-01-01

    Interventional ablative technologies aided by imaging techniques such as ultrasonography, computed tomography, and magnetic resonance imaging have been crucial in managing patients with primary liver cancer and liver metastases over the past 20 years. Several ablative technologies have been used to treat liver cancer; however, radiofrequency ablation (RFA) has emerged as the most common ablative therapy for hepatic lesions, both in the United States and globally. RFA is the treatment of choice for patients who cannot have surgical resection of the liver. This article focuses on the role of imaging in RFA treatment of primary and metastatic hepatic lesions.

  13. Liver Cancer and Hepatitis B

    MedlinePlus

    ... Our Accomplishments Annual Reports Our Videos What Is Hepatitis B? What Is Hepatitis B? The ABCs of Viral Hepatitis Liver Cancer and Hepatitis B Hepatitis Delta Coinfection Hepatitis C Coinfection HIV/AIDS ...

  14. An alternatively spliced variant of CXCR3 mediates the metastasis of CD133+ liver cancer cells induced by CXCL9.

    PubMed

    Ding, Qiang; Xia, Yujia; Ding, Shuping; Lu, Panpan; Sun, Liang; Liu, Mei

    2016-03-22

    Metastasis of liver cancer is closely linked to tumor microenvironment, in which chemokines and their receptors act in an important role. The CXCR3, the receptor of chemokine CXCL9, belongs to a superfamily of rhodopsin-like seven transmembrane GPCRs and CXCR subfamily. In HCC tissues, CXCR3 was frequently upregulated and correlated with tumor size, tumor differentiation, portal invasion and metastasis. In the study, CXCR3-A isoform that was bound by CXCL9 was found to cause significant change of ERK1/2 phosphorylation level in the MAPK signaling pathway, consequently upregulating the MMP2 and MMP9 expression and promoting invasion and metastasis of CD133+ liver cancer cells. Also, CXCR3-A suppressed the adhesion ability of CD133+ liver cancer cells that stimulated by CXCL9 for 24h. These findings suggest that CXCR3 and its ligand CXCL9 could promote the metastasis of liver cancer cells and might be a potential target for the intervention of liver cancer metastasis.

  15. The C/EBPbeta isoform, liver-inhibitory protein (LIP), induces autophagy in breast cancer cell lines.

    PubMed

    Abreu, Maria M; Sealy, Linda

    2010-11-15

    Autophagy is a process involving the bulk degradation of cellular components in the cytoplasm via the lysosomal degradation pathway. Autophagy manifests a protective role in stressful conditions such as nutrient or growth factor depletion; however, extensive degradation of regulatory molecules or organelles essential for survival can lead to the demise of the cell, or autophagy-mediated cell death. The role of autophagy in cancer is complex with roles in both tumor suppression and tumor promotion proposed. Here we report that an isoform of the C/EBPbeta transcription factor, liver-enriched inhibitory protein (LIP), induces cell death in human breast cancer cells and stimulates autophagy. Overexpression of LIP is incompatible with cell growth and when cell cycle analysis was performed, a DNA profile of cells undergoing apoptosis was not observed. Instead, LIP expressing cells appeared to have large autophagic vesicles when examined via electron microscopy. Autophagy was further assessed in LIP expressing cells by monitoring the development of acidic vesicular organelles and conversion of LC3 from the cytoplasmic form to the membrane-bound form. Our work shows that C/EBPbeta isoform, LIP, is another member of the group of transcription factors, including E2F1 and p53, which are capable of playing a role in autophagy.

  16. The C/EBPbeta isoform, liver-inhibitory protein (LIP), induces autophagy in breast cancer cell lines

    SciTech Connect

    Abreu, Maria M.; Sealy, Linda

    2010-11-15

    Autophagy is a process involving the bulk degradation of cellular components in the cytoplasm via the lysosomal degradation pathway. Autophagy manifests a protective role in stressful conditions such as nutrient or growth factor depletion; however, extensive degradation of regulatory molecules or organelles essential for survival can lead to the demise of the cell, or autophagy-mediated cell death. The role of autophagy in cancer is complex with roles in both tumor suppression and tumor promotion proposed. Here we report that an isoform of the C/EBPbeta transcription factor, liver-enriched inhibitory protein (LIP), induces cell death in human breast cancer cells and stimulates autophagy. Overexpression of LIP is incompatible with cell growth and when cell cycle analysis was performed, a DNA profile of cells undergoing apoptosis was not observed. Instead, LIP expressing cells appeared to have large autophagic vesicles when examined via electron microscopy. Autophagy was further assessed in LIP expressing cells by monitoring the development of acidic vesicular organelles and conversion of LC3 from the cytoplasmic form to the membrane-bound form. Our work shows that C/EBPbeta isoform, LIP, is another member of the group of transcription factors, including E2F1 and p53, which are capable of playing a role in autophagy.

  17. Liver Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing liver cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  18. Mechanisms of HCV-induced liver cancer: What did we learn from in vitro and animal studies?

    PubMed Central

    Rusyn, Ivan; Lemon, Stanley M.

    2013-01-01

    Hepatitis C virus (HCV) is a cause of liver diseases that range from steatohepatitis, to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The challenge of understanding the pathogenesis of HCV-associated liver cancer is difficult as most standard animal models used in biomedical research are not permissive to HCV infection. Herein, we provide an overview of a number of creative in vivo, mostly in the mouse, and in vitro models that have been developed to advance our understanding of the molecular and cellular effects of HCV on the liver, specifically with their relevance to HCC. PMID:23871966

  19. Drug-induced Liver Injury

    PubMed Central

    David, Stefan; Hamilton, James P

    2011-01-01

    Drug-induced liver injury (DILI) is common and nearly all classes of medications can cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or acute liver failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Treatment of drug and herbal-induced liver injury consists of rapid drug discontinuation and supportive care targeted to alleviate unwanted symptoms. PMID:21874146

  20. BMS-247550 in Treating Patients With Liver or Gallbladder Cancer

    ClinicalTrials.gov

    2014-05-13

    Adult Primary Cholangiocellular Carcinoma; Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  1. Chemoprotective properties of rooibos (Aspalathus linearis), honeybush (Cyclopia intermedia) herbal and green and black (Camellia sinensis) teas against cancer promotion induced by fumonisin B1 in rat liver.

    PubMed

    Marnewick, Jeanine L; van der Westhuizen, Francois H; Joubert, Elizabeth; Swanevelder, Sonja; Swart, Pieter; Gelderblom, Wentzel C A

    2009-01-01

    The chemoprotective properties of unfermented and fermented rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) herbal teas, and green and black teas (Camellia sinensis) were investigated against fumonisin B1 (FB1) promotion in rat liver utilizing diethylnitrosamine (DEN) as cancer initiator. The various teas differently affected the clinical chemical parameters associated with liver and kidney damage associated with FB1 suggesting specific FB1/iron/polyphenolic interactions. Green tea enhanced (P<0.05) the FB1-induced reduction of the oxygen radical absorbance capacity, while fermented herbal teas and unfermented honeybush significantly (P<0.05) decreased FB1-induced lipid peroxidation in the liver. The teas exhibited varying effects on FB1-induced changes in the activities of catalase, glutathione peroxidase (GPx) glutathione reductase (GR) as well as the glutathione (GSH) status. Unfermented rooibos and honeybush significantly (P<0.05) to marginally (P<0.1) reduced the total number of foci (>10microm), respectively, while all the teas reduced the relative amount of the larger foci. Fermentation seems to reduce the protective effect of the herbal teas. Differences in the major polyphenolic components and certain FB1/polyphenolic/tissue interactions may explain the varying effects of the different teas on the oxidative parameters, hepatotoxic effects and cancer promotion in rat liver.

  2. Abacavir-induced liver toxicity.

    PubMed

    Pezzani, Maria Diletta; Resnati, Chiara; Di Cristo, Valentina; Riva, Agostino; Gervasoni, Cristina

    2016-01-01

    Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

  3. Mechanism Involved in Trichloroethylene-Induced Liver Cancer: Importance to Environmental Cleanup

    SciTech Connect

    Bull, Richard J.; Thrall, Brian D.

    1999-06-01

    The objective of this project is to develop critical data for improving risk-based cleanup standards for trichloroethylene (TCE). Importance to DOE. Cleanup costs for chlorinated solvents found on DOE sites are most frequently driven by TCE because it is the most widespread contaminant and is generally present at the highest concentrations. Data that would permit increases in risk-based standards for TCE would reduce complex wide cleanup costs by hundreds of millions of dollars. Current Regulatory Actions that Research will Impact. EPA is currently reviewing its risk assessment for TCE. Richard J. Bull has worked with EPA on this review by writing the mode of action section of their determination. A presentation by James Cogliano of EPA at the 1999 Annual Society of Toxicology Meeting indicates that they have accepted the concept of nonlinear extrapolation for liver tumor induction by TCE. This project will end in FY 1999 with its major technical and policy objectives satisfied.

  4. Role of metabolism and viruses in aflatoxin-induced liver cancer

    SciTech Connect

    Groopman, John D. . E-mail: jgroopma@jhsph.edu; Kensler, Thomas W.

    2005-08-07

    The use of biomarkers in molecular epidemiology studies for identifying stages in the progression of development of the health effects of environmental agents has the potential for providing important information for critical regulatory, clinical and public health problems. Investigations of aflatoxins probably represent one of the most extensive data sets in the field and this work may serve as a template for future studies of other environmental agents. The aflatoxins are naturally occurring mycotoxins found on foods such as corn, peanuts, various other nuts and cottonseed and they have been demonstrated to be carcinogenic in many experimental models. As a result of nearly 30 years of study, experimental data and epidemiological studies in human populations, aflatoxin B{sub 1} was classified as carcinogenic to humans by the International Agency for Research on Cancer. The long-term goal of the research described herein is the application of biomarkers to the development of preventative interventions for use in human populations at high-risk for cancer. Several of the aflatoxin-specific biomarkers have been validated in epidemiological studies and are now being used as intermediate biomarkers in prevention studies. The development of these aflatoxin biomarkers has been based upon the knowledge of the biochemistry and toxicology of aflatoxins gleaned from both experimental and human studies. These biomarkers have subsequently been utilized in experimental models to provide data on the modulation of these markers under different situations of disease risk. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development, validation and application of other chemical-specific biomarkers to cancer or other chronic diseases.

  5. PET-CT in Determining the Radioembolization Dose Delivered to Patients With Liver Metastasis, Primary Liver Cancer, or Biliary Cancer

    ClinicalTrials.gov

    2017-01-24

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage D Adult Primary Liver Cancer (BCLC); Unspecified Adult Solid Tumor, Protocol Specific

  6. Mutual inhibition between YAP and SRSF1 maintains long non-coding RNA, Malat1-induced tumourigenesis in liver cancer.

    PubMed

    Wang, Jiayi; Wang, Hongmei; Zhang, Yue; Zhen, Ni; Zhang, Li; Qiao, Yongxia; Weng, Wenhao; Liu, Xiangfan; Ma, Lifang; Xiao, Weifan; Yu, Wenjun; Chu, Qinghua; Pan, Qiuhui; Sun, Fenyong

    2014-05-01

    Emerging studies have revealed that Malat1 is overexpressed in many malignant diseases, including liver cancer, and contributes to enhancing cell migration or facilitating proliferation. However, the mechanism underlying its regulation has largely remained elusive. Here, we characterised the oncoprotein Yes-associated protein (YAP), which up-regulated metastasis-associated lung adenocarcinoma transcript 1 (Malat1) expression at both transcriptional and post-transcriptional levels, whereas serine/arginine-rich splicing factor 1 (SRSF1) played an opposing role. SRSF1 inhibited YAP activity by preventing its co-occupation with TCF/β-catenin on the Malat1 promoter. In contrast, overexpression of YAP impaired the nuclear retention of both SRSF1 and itself via an interaction with Angiomotin (AMOT). This effect removed the inhibitory role of SRSF1 on Malat1 in the nucleus. Furthermore, higher expression of YAP was consistent with a lower SRSF1 nuclear accumulation in human liver cancer tissues. We also revealed that overexpression of YAP combined with a knockdown of SRSF1 resulted in conspicuously enhanced transwell cell mobility, accelerated tumour growth rate, and loss of body weight in a tail vein-injected mouse models. Taken together, these data provided a novel mechanism underlying the balance between SRSF1, YAP and Malat1 and uncovered a new role of YAP in regulating long non-coding RNA (lncRNA). Thus, disrupting the interaction between YAP and SRSF1 may serve as a crucial therapeutic method in liver cancer.

  7. What's New in Liver Cancer Research and Treatment?

    MedlinePlus

    ... Liver Cancer About Liver Cancer What's New in Liver Cancer Research and Treatment? Because there are only ... other larger studies before it is widely used. Liver transplant Only a small portion of patients with ...

  8. A Novel Tetraenoic Fatty Acid Isolated from Amaranthus spinosus Inhibits Proliferation and Induces Apoptosis of Human Liver Cancer Cells

    PubMed Central

    Mondal, Arijit; Guria, Tanmoy; Maity, Tapan Kumar; Bishayee, Anupam

    2016-01-01

    Amaranthus spinosus Linn. (Family: Amaranthaceae) has been shown to be useful in preventing and mitigating adverse pathophysiological conditions and complex diseases. However, only limited information is available on the anticancer potential of this plant. In this study, we examined the antiproliferative and pro-apoptotic effects of a novel fatty acid isolated from A. spinosus—(14E,18E,22E,26E)-methyl nonacosa-14,18,22,26 tetraenoate—against HepG2 human liver cancer cells. We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to determine cell viability, flow cytometry assay for cell cycle analysis, and Western blot analysis to measure protein expression of Cdc2), cyclin B1, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). The MTT assay showed that the fatty acid markedly inhibited the proliferation of HepG2 cells in a dosage-dependent fashion, with a half maximal inhibitory concentration (IC50) value of 25.52 µmol/L. This antiproliferative result was superior to that of another known fatty acid, linoleic acid (IC50 38.65 µmol/L), but comparable to that of standard anticancer drug doxorubicin (IC50 24.68 µmol/L). The novel fatty acid also induced apoptosis mediated by downregulation of cyclin B1, upregulation of Bax, and downregulation of Bcl-2, resulting in the G2/M transition arrest. Our results provide the first experimental evidence that a novel fatty acid isolated from A. spinosus exhibits significant antiproliferative activity mediated through the induction of apoptosis in HepG2 cells. These encouraging results may facilitate the development of A. spinosus fatty acid for the prevention and intervention of hepatocellular carcinoma. PMID:27669220

  9. Liquid biopsy in liver cancer.

    PubMed

    Labgaa, Ismail; Villanueva, Augusto

    2015-04-01

    Liver cancer has become the second cause of cancer-related death worldwide. Most patients are still diagnosed at intermediate or advanced stage, where potentially curative treatment options are not recommended. Unlike other solid tumors, there are no validated oncogenic addiction loops and the only systemic agent to improve survival in advanced disease is sorafenib. All phase 3 clinical trials testing molecular therapies after sorafenib have been negative, none of which selected patients based on predictive biomarkers of response. Theoretically, analysis of circulating cancer byproducts (e.g., circulating tumor cells, cell-free nucleic acids), namely "liquid biopsy," could provide easy access to molecular tumor information, improve patients' stratification and allow to assess tumor dynamics over time. Recent technical developments and preliminary data from other malignancies indicate that liquid biopsy might have a role in the future management of cancer patients.

  10. Liver cancer mortality rate model in Thailand

    NASA Astrophysics Data System (ADS)

    Sriwattanapongse, Wattanavadee; Prasitwattanaseree, Sukon

    2013-09-01

    Liver Cancer has been a leading cause of death in Thailand. The purpose of this study was to model and forecast liver cancer mortality rate in Thailand using death certificate reports. A retrospective analysis of the liver cancer mortality rate was conducted. Numbering of 123,280 liver cancer causes of death cases were obtained from the national vital registration database for the 10-year period from 2000 to 2009, provided by the Ministry of Interior and coded as cause-of-death using ICD-10 by the Ministry of Public Health. Multivariate regression model was used for modeling and forecasting age-specific liver cancer mortality rates in Thailand. Liver cancer mortality increased with increasing age for each sex and was also higher in the North East provinces. The trends of liver cancer mortality remained stable in most age groups with increases during ten-year period (2000 to 2009) in the Northern and Southern. Liver cancer mortality was higher in males and increase with increasing age. There is need of liver cancer control measures to remain on a sustained and long-term basis for the high liver cancer burden rate of Thailand.

  11. Sedanolide induces autophagy through the PI3K, p53 and NF-κB signaling pathways in human liver cancer cells.

    PubMed

    Hsieh, Shu-Ling; Chen, Chi-Tsai; Wang, Jyh-Jye; Kuo, Yu-Hao; Li, Chien-Chun; Hsieh, Lan-Chi; Wu, Chih-Chung

    2015-12-01

    Sedanolide (SN), a phthalide-like compound from celery seed oil, possesses antioxidant effects. However, the effect of SN on cell death in human liver cancer cells has yet to be determined. In this study, cell viability determination, monodansylcadaverine (MDC) fluorescent staining and immunoblot analysis were performed to determine autophagy induction and autophagy-induced protein expression changes via molecular examination after human liver cancer (J5) cells were treated with SN. Our studies demonstrate that SN suppressed J5 cell viability by inducing autophagy. Phosphoinositide 3-kinase (PI3K)-I, mammalian target of rapamycin (mTOR) and Akt protein levels decreased, whereas PI3K-III, LC3-II and Beclin-1 protein levels increased following SN treatment in J5 cells. In addition, SN treatment upregulated nuclear p53 and damage-regulated autophagy modulator (DRAM) and downregulated cytosolic p53 and Tp53-induced glycolysis and apoptosis regulator (TIGAR) expression in J5 cells. Furthermore, the cytosolic phosphorylation of inhibitor of kappa B (IκB) and nuclear p65 and the DNA-binding activity of NF-κB increased after SN treatment. These results suggest that SN induces J5 cell autophagy by regulating PI3K, p53 and NF-κB autophagy-associated signaling pathways in J5 cells.

  12. Hypoxia-inducible factors as molecular targets for liver diseases.

    PubMed

    Ju, Cynthia; Colgan, Sean P; Eltzschig, Holger K

    2016-06-01

    Liver disease is a growing global health problem, as deaths from end-stage liver cirrhosis and cancer are rising across the world. At present, pharmacologic approaches to effectively treat or prevent liver disease are extremely limited. Hypoxia-inducible factor (HIF) is a transcription factor that regulates diverse signaling pathways enabling adaptive cellular responses to perturbations of the tissue microenvironment. HIF activation through hypoxia-dependent and hypoxia-independent signals have been reported in liver disease of diverse etiologies, from ischemia-reperfusion-induced acute liver injury to chronic liver diseases caused by viral infection, excessive alcohol consumption, or metabolic disorders. This review summarizes the evidence for HIF stabilization in liver disease, discusses the mechanistic involvement of HIFs in disease development, and explores the potential of pharmacological HIF modifiers in the treatment of liver disease.

  13. Hydroxycut-induced Liver Toxicity

    PubMed Central

    Kaswala, DH; Shah, S; Patel, N; Raisoni, S; Swaminathan, S

    2014-01-01

    In the recent era, use of various nutritional supplements is highly encouraged amongst the people of United States. Weight loss supplements are major part of the nutritional supplements and their usage is unregulated in the US. Obesity is a major health concern in the US and Americans spend around $30 billion a year for weight loss supplements. At times, these supplements can be responsible for documented or undocumented adverse drug effects. The health consequences related to these supplements are often overlooked by the general public, even though FDA issues advisories regarding them. One common supplement used for weight loss was Hydroxycut (Iovate Health Sciences Research, Oakville, Ontario, Canada). Hydroxycut was recalled from the market after a FDA warning in May 2009 because of 23 reports of serious health problems ranging from jaundice and elevated liver enzymes to liver damage. 1 This case report adds evidence for Hydroxycut - induced hepatotoxicity. A 27 year old man with right upper quadrant pain and jaundice was found to have elevated liver enzymes and was taking Hydroxycut along with other supplements. Liver biopsy showed drug induced hepatotoxicity. Discontinuation of Hydroxycut dramatically improved liver functions and related symptoms. PMID:24669349

  14. Flavonoid-enriched apple fraction AF4 induces cell cycle arrest, DNA topoisomerase II inhibition, and apoptosis in human liver cancer HepG2 cells.

    PubMed

    Sudan, Sudhanshu; Rupasinghe, H P Vasantha

    2014-01-01

    Apples are a major source of dietary phytochemicals such as flavonoids in the Western diet. Here we report anticancer properties and possible mechanism of action of apple flavonoid-enriched fraction (AF4) isolated from the peels of Northern Spy apples in human hepatocellular carcinoma cells, HepG2. Treatment with AF4 induced cell growth inhibition in HepG2 cells in time- and dose-dependent manner. Concentration of 50 μg/ml (50 μg total monomeric polyphenols/ml) AF4 was sufficient to induce a significant reduction in cell viability within 6 h of treatment (92%, P < 0.05) but had very low toxicity (minimum 4% to maximum 16%) on primary liver and lung cells, which was significantly lower than currently prescribed chemotherapy drug Sorafenib (minimum 29% to maximum 49%, P < 0.05). AF4 induced apoptosis in HepG2 cells within 6 h of treatment via activation of caspase-3. Cell cycle analysis via flow-cytometer showed that AF4 induced G2/M phase arrest. Further, results showed that AF4 acts as a strong DNA topoisomerase II catalytic inhibitor, which may be a plausible reason to drive the cells to apoptosis. Overall, our data suggests that AF4 possesses a significantly stronger antiproliferative and specific action than Sorafenib in vitro and is a potential natural chemotherapy agent for treatment of liver cancer.

  15. The Virtual Liver: Modeling Chemical-Induced Liver Toxicity

    EPA Science Inventory

    The US EPA Virtual Liver (v-Liver) project is aimed at modeling chemical-induced processes in hepatotoxicity and simulating their dose-dependent perturbations. The v-Liver embodies an emerging field of research in computational tissue modeling that integrates molecular and cellul...

  16. Liver cell cancer--intervention studies.

    PubMed

    Linsell, C A

    1981-01-01

    The field studies leading to possible intervention procedures are reviewed. Currently the most promising form of intervention is the prevention of aflatoxin contamination of foodstuffs. It is essential that these are monitored and their efficacy in lowering the incidence of liver cancer measured. The association of liver cancer with hepatitis B infection may be a confounding factor and the impact of this on the study population must also be considered. The imminent production of vaccines for hepatitis B infection may provide an alternative or additional mode of intervention. The possibilities for intervention in liver cell cancer appear one of the brighter prospects for primary prevention of a cancer.

  17. A study of structural differences between liver cancer cells and normal liver cells using FTIR spectroscopy

    NASA Astrophysics Data System (ADS)

    Sheng, Daping; Xu, Fangcheng; Yu, Qiang; Fang, Tingting; Xia, Junjun; Li, Seruo; Wang, Xin

    2015-11-01

    Since liver cancer seriously threatens human health, it is very urgent to explore an effective method for diagnosing liver cancer early. In this study, we investigated the structure differences of IR spectra between neoplastic liver cells and normal liver cells. The major differences of absorption bands were observed between liver cancer cells and normal liver cells, the values of A2955/A2921, A1744/A1082, A1640/A1535, H1121/H1020 might be potentially useful factors for distinguishing liver cancer cells from normal liver cells. Curve fitting also provided some important information on structural differences between malignant and normal liver cancer cells. Furthermore, IR spectra combined with hierarchical cluster analysis could make a distinction between liver cancer cells and normal liver cells. The present results provided enough cell basis for diagnosis of liver cancer by FTIR spectroscopy, suggesting FTIR spectroscopy may be a potentially useful tool for liver cancer diagnosis.

  18. Drug-induced liver injury.

    PubMed

    Katarey, Dev; Verma, Sumita

    2016-12-01

    Drug-induced liver injury (DILI) remains the most common cause of acute liver failure (ALF) in the western world. Excluding paracetamol overdose, nearly all DILI encountered in the clinical setting is idiosyncratic in nature because affected individuals represent only a small proportion of those treated with such drugs. In many cases, the mechanism for idiosyncrasy is immune-mediation and is often identified by genetic risk determined by human leukocyte antigen variants. In the absence of diagnostic tests and/or biomarkers, the diagnosis of DILI requires a high index of suspicion after diligently excluding other causes of abnormal liver tests. Antibiotics are the class of drugs most frequently associated with idiosyncratic DILI, although recent studies indicate that herbal and dietary supplements are an increasingly recognised cause. It is imperative that upon development of DILI the culprit drug be discontinued, especially in the presence of elevated transaminases (aspartate aminotransferase/alanine aminotransferase ratio ≥5 times the upper limit of normal) and/or jaundice. Risk factors for the development ALF include hepatocellular DILI and female gender, the treatment being supportive with some benefit of N-acetylcysteine in the early stages. In view of the poor transplant-free survival in idiosyncratic DILI, early consideration for liver transplant is mandatory.

  19. Detection of liver cancer and abnormal liver tissue by Raman spectroscopy and fluorescence

    NASA Astrophysics Data System (ADS)

    Li, Xiaozhou; Ding, Jianhua; Zhang, Xiujun; Lin, Junxiu; Wang, Deli

    2005-01-01

    In this paper, laser induced human serum Raman spectra of liver cancer are measured. The spectra differences in serum from normal people and liver disease patients are analyzed. For the typical spectrum of normal serum, there are three sharp Raman peaks and relative intensity of Raman peaks excited by 514.5nm is higher than that excited by 488.0nm. For the Raman spectrum of liver cancer serum there are no peaks or very weak Raman peaks at the same positions. Results from more than two hundred case measurements show that clinical diagnostic accuracy is 92.86%. And then, the liver fibrosis and liver cirrhosis are studied applying the technology of LIF. To liver cirrhosis, the shape of Raman peak is similar to normal and fluorescence spectrum is similar to that of liver cancer from statistic data. The experiment indicates that there is notable fluorescence difference between the abnormal and normal liver tissue and have blue shift in fluorescence peak. Except for human serum, we use rats serum for researching either. Compared with results of path al examination, we analyze the spectra of normal cases, hepatic fibrosis and hepatocirrhosis respectively in an attempt to find some difference between them. Red shift of fluorescence peak is observed with disease evolution using 514.5nm excitation of an Ar-ion laser. However, no distinct changes happen with 488.0nm excitation. These results have important reference values to explore the method of laser spectrum diagnosis.

  20. Drug-Induced Liver Injury.

    PubMed

    Hamilton, Leslie A; Collins-Yoder, Angela; Collins, Rachel E

    2016-10-01

    Drug-induced liver injury (DILI) can result from both idiosyncratic and intrinsic mechanisms. This article discusses the clinical impact of DILI from a broad range of medications as well as herbal and dietary supplements. Risk factors for idiosyncratic DILI (IDILI) are the result of multiple host, environmental, and compound factors. Some triggers of IDILI often seen in critical care include antibiotics, antiepileptic medications, statins, novel anticoagulants, proton pump inhibitors, inhaled anesthetics, nonsteroidal anti-inflammatory agents, methotrexate, sulfasalazine, and azathioprine. The mechanism of IDILI due to these medications varies, and the resulting damage can be cholestatic, hepatocellular, or mixed. The primary treatment of IDILI is to discontinue the causative agent. DILI due to acetaminophen is intrinsic because the liver damage is predictably aligned with the dose ingested. Acute acetaminophen ingestion can be treated with activated charcoal or N-acetylcysteine. Future areas of research include identification of mitochondrial stress biomarkers and of the patients at highest risk for DILI.

  1. Ganetespib radiosensitization for liver cancer therapy

    PubMed Central

    Chettiar, Sivarajan T.; Malek, Reem; Annadanam, Anvesh; Nugent, Katriana M.; Kato, Yoshinori; Wang, Hailun; Cades, Jessica A.; Taparra, Kekoa; Belcaid, Zineb; Ballew, Matthew; Manmiller, Sarah; Proia, David; Lim, Michael; Anders, Robert A.; Herman, Joseph M.; Tran, Phuoc T.

    2016-01-01

    ABSTRACT Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies. PMID:26980196

  2. Drug-Induced Liver Disease: Clinical Course.

    PubMed

    Saithanyamurthi, Hemamala; Faust, Alison Jazwinski

    2017-02-01

    Drug-induced liver injury (DILI) is a term used to describe a spectrum of clinical presentations and severity that ranges from mild elevation of liver enzymes on routine blood work to acute liver failure and death. Approximately 10% of all patients with DILI develop acute liver failure resulting in death or liver transplantation. DILI may be prolonged with persistence of elevated liver enzymes for longer than 6 months in approximately 5% to 20% of cases. Cirrhosis and long-term liver-related morbidity and mortality have also been described but are rare, occurring in 1% to 3% of cases.

  3. Liver metastases

    MedlinePlus

    Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases

  4. Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic Acid Nanoparticles To Induce Autophagy-Mediated Liver Cancer Combination Therapy.

    PubMed

    Wang, Feng-Zhen; Xing, Lei; Tang, Zheng-hai; Lu, Jin-Jian; Cui, Peng-Fei; Qiao, Jian-Bing; Jiang, Lei; Jiang, Hu-Lin; Zong, Li

    2016-04-04

    Combination therapy has been developed as a promising therapeutic approach for hepatocellular carcinoma therapy. Here we report a low toxicity and high performance nanoparticle system that was self-assembled from a poly(ethylenimine)-glycyrrhetinic acid (PEI-GA) amphiphilic copolymer as a versatile gene/drug dual delivery nanoplatform. PEI-GA was synthesized by chemical conjugation of hydrophobic GA moieties to the hydrophilic PEI backbone via an acylation reaction. The PEI-GA nanocarrier could encapsulate doxorubicin (DOX) efficiently with loading level about 12% and further condense DNA to form PEI-GA/DOX/DNA complexes to codeliver drug and gene. The diameter of the complexes is 102 ± 19 nm with zeta potential of 19.6 ± 0.2 mV. Furthermore, the complexes possess liver cancer targeting ability and could promote liver cancer HepG2 cell internalization. Apoptosis of cells could be induced by chemotherapy of DOX, and PI3K/Akt/mTOR signaling pathway acts a beneficial effect on the modulation of autophagy. Here, it is revealed that utilizing PEI-GA/DOX/shAkt1 complexes results in effective autophagy and apoptosis, which are useful to cause cell death. The induction of superfluous autophagy is reported to induce type-II cell death and also could increase the sensity of chemotherapy to tumor cells. In this case, combining autophagy and apoptosis is meaningful for oncotherapy. In this study, PEI-GA/DOX/shAkt1 has demonstrated favorable tumor target ability, little side effects, and ideal antitumor efficacy.

  5. Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway.

    PubMed

    Hsieh, Yun-Chih; Rao, Yerra Koteswara; Wu, Chun-Chi; Huang, Chi-Ying F; Geethangili, Madamanchi; Hsu, Shih-Lan; Tzeng, Yew-Min

    2010-07-19

    We investigated the effects of antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorata on the proliferation of human liver cancer cell lines Huh7, HepG2, and Hep3B and the normal cell rat hepatocytes. The three compounds selectively inhibit the proliferation of tumor cells rather than normal cells, with IC(50) values ranging from 30.2 to 286.4 microM. The compound MAA was a more potent cytotoxic agent than antcins A and C with IC(50) values of 52.2, 78.0, and 30.2 microM against HepG2, Hep3B, and Huh7 cells, respectively. To elucidate the molecular mechanism, treatment of Huh7 cells with 100 microM MAA induced an apoptotic cell death, which was characterized by the appearance of sub-G1 population, DNA fragmentation, TUNEL positive cells, and caspase activation. MAA triggered the mitochondrial apoptotic pathway, as indicated by an increase in the protein expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9. We also found that pretreatment with inhibitors of caspases-2, -3, and -9 noticeably blocked MAA-triggered apoptosis. Furthermore, intracellular reactive oxygen species (ROS) generation and NADPH oxidase activation were observed in MAA-stimulated Huh7 cells. Mechanistic studies showed that MAA induces mitochondrial translocation of cofilin. When Huh7 cells were treated with cyclosporine A and bongkrekic acid, an inhibitor of the mitochondria permeability transition pore, the levels of cell death induced by MAA were significantly attenuated. Additionally, pretreatment of Huh7 cells with antioxidants ascorbic acid and N-acetyl cysteine markedly attenuated the MAA-induced apoptosis by upregulation of Bax, Bak, and PUMA, mitochondrial translocation of cofilin, activation of caspase-3, and cell death. Taken together, our results provide the first evidence of the

  6. Atypical onset of bicalutamide-induced liver injury.

    PubMed

    Yun, Gee Young; Kim, Seok Hyun; Kim, Seok Won; Joo, Jong Seok; Kim, Ju Seok; Lee, Eaum Seok; Lee, Byung Seok; Kang, Sun Hyoung; Moon, Hee Seok; Sung, Jae Kyu; Lee, Heon Young; Kim, Kyung Hee

    2016-04-21

    Anti-androgen therapy is the leading treatment for advanced prostate cancer and is commonly used for neoadjuvant or adjuvant treatment. Bicalutamide is a non-steroidal anti-androgen, used during the initiation of androgen deprivation therapy along with a luteinizing hormone-releasing hormone agonist to reduce the symptoms of tumor-related flares in patients with advanced prostate cancer. As side effects, bicalutamide can cause fatigue, gynecomastia, and decreased libido through competitive androgen receptor blockade. Additionally, although not as common, drug-induced liver injury has also been reported. Herein, we report a case of hepatotoxicity secondary to bicalutamide use. Typically, bicalutamide-induced hepatotoxicity develops after a few days; however, in this case, hepatic injury occurred 5 mo after treatment initiation. Based on this rare case of delayed liver injury, we recommend careful monitoring of liver function throughout bicalutamide treatment for prostate cancer.

  7. Propylthiouracil-induced acute liver failure: role of liver transplantation.

    PubMed

    Carrion, Andres F; Czul, Frank; Arosemena, Leopoldo R; Selvaggi, Gennaro; Garcia, Monica T; Tekin, Akin; Tzakis, Andreas G; Martin, Paul; Ghanta, Ravi K

    2010-01-01

    Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death.

  8. MBD3 inhibits formation of liver cancer stem cells

    PubMed Central

    Li, Ruizhi; He, Qihua; Han, Shuo; Zhang, Mingzhi; Liu, Jinwen; Su, Ming; Wei, Shiruo; Wang, Xuan; Shen, Li

    2017-01-01

    Liver cancer cells can be reprogrammed into induced cancer stem cells (iCSCs) by exogenous expression of the reprogramming transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM). The nucleosome remodeling and deacetylase (NuRD) complex is essential for reprogramming somatic cells. In this study, we investigated the function of NuRD in the induction of liver CSCs. We showed that suppression of methyl-CpG binding domain protein 3 (MBD3), a core subunit of the NuRD repressor complex, together with OSKM transduction, induces conversion of liver cancer cells into stem-like cells. Expression of the transcription factor c-JUN is increased in MBD3-depleted iCSCs, and c-JUN activates endogenous pluripotent genes and regulates iCSC-related genes. These results indicate that MBD3/NuRD inhibits the induction of iCSCs, while c-JUN facilitates the generation of CSC-like properties. The iCSC reprogramming approach devised here provides a novel platform for dissection of the disordered signaling in liver CSCs. In addition, our results indicate that c-JUN may serve as a potential target for liver cancer therapy. PMID:27894081

  9. Heterogeneity of liver cancer and personalized therapy.

    PubMed

    Li, Liang; Wang, Hongyang

    2016-09-01

    Liver cancer is an extraordinarily heterogeneous malignant disease among the tumors that have so far been identified. Hepatocellular carcinoma (HCC) arises most frequently in the setting of chronic liver inflammation and fibrosis, and takes a variety of course in individual patients to process to tumor. The risk factors such as HBV and/or HCV infections, aflatoxin infection, abuse alcohol intake, metabolic syndrome, obesity and diabetes are closely related to the environmental and genetic susceptibilities to HCC. The consequent resulting genomic instability, molecular and signal transduction network disorders and microenvironmental discrepancies are characterized by the extraordinary heterogeneity of liver cancer. The histology-based definition of the morphological heterogeneity of liver cancer has been modified and refined to treat patients with targeted therapies, but this still cannot solve all the problems. Lack of consistent outcome for anticancer agents and conventional therapies in liver cancer treatment calls for assessing the benefits of new molecularly targeted drugs and combined therapy, under the heterogeneity condition of tumor. The present review article will provide the complex mechanism and phenotype of liver cancer heterogeneity, and help us to execute precision medicine in a really personalized manner.

  10. Targeted treatment of liver metastasis from gastric cancer using specific binding peptide

    PubMed Central

    Gong, Jianfeng; Tan, Gewen; Sheng, Nengquan; You, Weiqiang; Wang, Zhigang

    2016-01-01

    Gastric cancer ranks the first in China among all gastrointestinal cancers in terms of incidence, and liver metastasis is the leading cause of death for patients with advanced gastric cancer. Tumor necrosis factor (TNF) is a cytokine commonly chosen as the target for gene therapy against cancers. The specific binding peptide pd20 of gastric cancer cells with a high potential for liver metastasis was fused with human TNF to obtain the pd20-TNF gene using DNA recombinant technique. The expression of the fusion protein was induced and the protein was purified. In vitro activity test showed that the fusion protein greatly improved the membrane permeability of liver cells in nude mice with liver metastasis from gastric cancer. The tumor implantation experiment in nude mice showed that the fusion protein effectively mitigated the cancer lesions. The results provide important clues for developing the drugs for targeted treatment of liver metastasis from gastric cancer. PMID:27347305

  11. Immune-Mediated Therapies for Liver Cancer

    PubMed Central

    Aravalli, Rajagopal N.; Steer, Clifford J.

    2017-01-01

    In recent years, immunotherapy has gained renewed interest as an alternative therapeutic approach for solid tumors. Its premise is based on harnessing the power of the host immune system to destroy tumor cells. Development of immune-mediated therapies, such as vaccines, adoptive transfer of autologous immune cells, and stimulation of host immunity by targeting tumor-evasive mechanisms have advanced cancer immunotherapy. In addition, studies on innate immunity and mechanisms of immune evasion have enhanced our understanding on the immunology of liver cancer. Preclinical and clinical studies with immune-mediated therapies have shown potential benefits in patients with liver cancer. In this review, we summarize current knowledge and recent developments in tumor immunology by focusing on two main primary liver cancers: hepatocellular carcinoma and cholangiocarcinoma. PMID:28218682

  12. γ-terpineol inhibits cell growth and induces apoptosis in human liver cancer BEL-7402 cells in vitro.

    PubMed

    Wu, Zi-Li; Yin, Zhong-Qiong; Du, Yong-Hua; Feng, Rui-Zhang; Ye, Kui-Chuan; Wei, Qin; Hu, Yong; He, Lin; Liao, Lin; Wang, Yu

    2014-01-01

    To investigate the effect of γ-terpineol on cell proliferation and apoptosis of human hepatoma BEL-7402 cells to elucidate its molecular mechanism. Here, BEL-7402 cells were treated with various concentrations (40, 80, 160, 320 and 640 μg/ml) of γ-terpineol for 48 h, cell proliferation was determined by 3-(4,5-dimethyl-thiazolyl-2)-2,5-diphenyl tetrazolium bromides (MTT) assay. Cell colony inhibition was determined by soft agar assay. Apoptosis and possible molecular mechanisms were evaluated by morphological observation, flow cytometry analysis, and DNA fragmentation assay. The γ-terpineol significantly suppressed BEL-7402 cell proliferation in a dose-dependent manner. Characteristic morphological and biochemical changes associated with apoptosis such as cells shrinkage, deformation and vacuolization of mitochondria, nuclear chromatin condensation and fragmentation, formation of apoptotic bodies were observed after BEL-7402 cells treated with γ-terpineol for 24 h and 48 h. Cell cycle were displayed by flow cytometry analysis, the γ-terpineol treatment resulted in accumulation of cells at G₁ or S phase and a blockade of cell proliferation compared to control group. Treating BEL-7402 cells with 320 μg/ml of γ-terpineol for 36 h and 48 h, a typical apoptotic "DNA ladder" was observed using DNA fragmentation assay. The present study demonstrated that possible anti-cancer mechanism of γ-terpineol on human hematomas cells is through inducing cell apoptosis to suppress tumor cell growth.

  13. Chemotherapy induced liver abnormalities: an imaging perspective

    PubMed Central

    Houshyar, Roozbeh; Bhosale, Priya; Choi, Joon-Il; Gulati, Rajesh; Lall, Chandana

    2014-01-01

    Treating patients undergoing chemotherapy who display findings of liver toxicity, requires a solid understanding of these medications. It is important for any clinician to have an index of suspicion for liver toxicity and be able to recognize it, even on imaging. Cancer chemotherapy has evolved, and newer medications that target cell biology have a different pattern of liver toxicity and may differ from the more traditional cytotoxic agents. There are several hepatic conditions that can result and keen clinical as well as radiographic recognition are paramount. Conditions such as sinusoidal obstructive syndrome, steatosis, and pseudocirrhosis are more commonly associated with chemotherapy. These conditions can display clinical signs of acute hepatitis, liver cirrhosis, and even liver failure. It is important to anticipate and recognize these adverse reactions and thus appropriate clinical action can be taken. Often times, patients with these liver manifestations can be managed with supportive therapies, and liver toxicity may resolve after discontinuation of chemotherapy. PMID:25320738

  14. [Primary cancer of the liver].

    PubMed

    Orozco, H; Mercado, M A

    1997-01-01

    The epidemiologic and pathogenic aspects of primary hepatic malignancies are discussed. The role of viruses in the etiology of the disease is stressed. Imageology methods have a preponderant role for diagnosis and treatment options. Liver resection has a one years survival between 60 and 80% and a five years survival of 20 to 40%. A good surgical results is expected for tumors with no more than 5 cm in diameter, encapsulated and without vascular invasion non-cirrhotic livers, large tumors can also be removed. Surgical resection margin should be of 1 cm. For cirrhotic livers, a good liver function is needed (Child A-B) and no safe major resection can be done. History of bleeding portal hypertension has a negative role in the outcome. Liver transplantation should be limited to selected case, in which the tumors are small and asymptomatic (incidental). For larger tumors, long term results are not good with invariable recurrency of the tumor.

  15. Quercetin Potentiates Doxorubicin Mediated Antitumor Effects against Liver Cancer through p53/Bcl-xl

    PubMed Central

    Wang, Guanyu; Sharma, Sherven; Dong, Qinghua

    2012-01-01

    Background The dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, particularly in drug-resistant cancers, such as liver cancer. In this study, we investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice. Methodology and Results The MTT and Annexin V/PI staining assay demonstrated that quercetin selectively sensitized DOX-induced cytotoxicity against liver cancer cells while protecting normal liver cells. The increase in DOX-mediated apoptosis in hepatoma cells by quercetin was p53-dependent and occurred by downregulating Bcl-xl expression. Z-VAD-fmk (caspase inhibitor), pifithrin-α (p53 inhibitor), or overexpressed Bcl-xl decreased the effects of quercetin on DOX-mediated apoptosis. The combined treatment of quercetin and DOX significantly reduced the growth of liver cancer xenografts in mice. Moreover, quercetin decreased the serum levels of alanine aminotransferase and aspartate aminotransferase that were increased in DOX-treated mice. Quercetin also reversed the DOX-induced pathological changes in mice livers. Conclusion and Significance These results indicate that quercetin potentiated the antitumor effects of DOX on liver cancer cells while protecting normal liver cells. Therefore, the development of quercetin may be beneficial in a combined treatment with DOX for increased therapeutic efficacy against liver cancer. PMID:23240061

  16. What Should You Ask Your Doctor about Liver Cancer?

    MedlinePlus

    ... Staging What Should You Ask Your Health Care Team About Liver Cancer? As you cope with liver ... have honest, open discussions with your cancer care team . Ask any question, no matter how small it ...

  17. Cyproheptadine-Induced Acute Liver Failure.

    PubMed

    Chertoff, Jason; Alam, Sabikha; Clark, Virginia

    2014-07-08

    We present the case of a 55-year-old white female with no history of liver or gastrointestinal disease, admitted with acute liver failure following a trial of cyproheptadine for appetite stimulation. The patient was managed with supportive care, symptomatic treatment, and discontinuation of cyproheptadine. To our knowledge, this is the first described case of cyproheptadine-induced acute liver failure in over 20 years.

  18. Synergistic inhibition of autophagy and neddylation pathways as a novel therapeutic approach for targeting liver cancer.

    PubMed

    Chen, Ping; Hu, Tao; Liang, Yupei; Jiang, Yanan; Pan, Yongfu; Li, Chunjie; Zhang, Ping; Wei, Dongping; Li, Pei; Jeong, Lak Shin; Chu, Yiwei; Qi, Hui; Yang, Meng; Hoffman, Robert M; Dong, Ziming; Jia, Lijun

    2015-04-20

    Liver cancer is the second-most frequent cause of cancer death in the world and is highly treatment resistant. We reported previously that inhibition of neddylation pathway with specific NAE inhibitor MLN4924, suppressed the malignant phenotypes of liver cancer. However, during the process, MLN4924 induces pro-survival autophagy as a mechanism of drug resistance. Here, we report that blockage of autophagy with clinically-available autophagy inhibitors (e.g. chloroquine) significantly enhanced the efficacy of MLN4924 on liver cancer cells by triggering apoptosis. Mechanistically, chloroquine enhanced MLN4924-induced up-regulation of pro-apoptotic proteins (e.g. NOXA) and down-regulation of anti-apoptotic proteins. Importantly, the down-regulation of NOXA expression via siRNA silencing substantially attenuated apoptosis of liver cancer cells. Further mechanistic studies revealed that blockage of autophagy augmented MLN4924-induced DNA damage and reactive oxygen species (ROS) generation. The elimination of DNA damage or blockage of ROS production significantly reduced the expression of NOXA, and thereby attenuated apoptosis and reduced growth inhibition of liver cancer cells. Moreover, blockage of autophagy enhanced the efficacy of MLN4924 in an orthotopic model of human liver cancer, with induction of NOXA and apoptosis in tumor tissues. These findings provide important preclinical evidence for clinical investigation of synergistic inhibition of neddylation and autophagy in liver cancer.

  19. N-hydroxylation of 4-aminobiphenyl by CYP2E1 produces oxidative stress in a mouse model of chemically induced liver cancer.

    PubMed

    Wang, Shuang; Sugamori, Kim S; Tung, Aveline; McPherson, J Peter; Grant, Denis M

    2015-04-01

    4-Aminobiphenyl (ABP) is a trace component of cigarette smoke and hair dyes, a suspected human carcinogen and a potent rodent liver carcinogen. Postnatal exposure of mice to ABP results in a higher incidence of liver tumors in males than in females, paralleling the sex difference in human liver cancer incidence. A traditional model of ABP tumorigenesis involves initial CYP1A2-mediated N-hydroxylation, which eventually leads to production of mutagenic ABP-DNA adducts that initiate tumor growth. However, several studies have found no correlation between sex or CYP1A2 function and the DNA-damaging, mutagenic, or tumorigenic effects of ABP. Oxidative stress may be an important etiological factor for liver cancer, and it has also been linked to ABP exposure. The goals of this study were to identify novel enzyme(s) that contribute to ABP N-oxidation, and to investigate a potential role for oxidative stress in ABP liver tumorigenicity. Isozyme-selective inhibition experiments using liver microsomes from wild-type and genetically modified mice identified CYP2E1 as a major ABP N-hydroxylating enzyme. The N-hydroxylation of ABP by transiently expressed CYP2E1 produced oxidative stress in cultured mouse hepatoma cells. In vivo postnatal exposure of mice to a tumorigenic dose of ABP also produced oxidative stress in male wild-type mice, but not in male Cyp2e1(-/-) mice or in female mice. However, a stronger NRF2-associated antioxidant response was observed in females. Our results identify CYP2E1 as a novel ABP-N-oxidizing enzyme, and suggest that sex differences in CYP2E1-dependent oxidative stress and antioxidant responses to ABP may contribute to the observed sex difference in tumor incidence.

  20. 2-(Allylthio)pyrazine, a cancer chemopreventive agent, inhibits liver fibrosis induced by dimethylnitrosamine in rats: role of inhibition of transforming growth factor-beta1 expression.

    PubMed

    Kang, K W; Ha, J R; Kim, C W; Kim, N D; Kim, S G

    2001-07-01

    Exposure to nitrosamines may be the occupational risk factor for liver cirrhosis. 2-(Allylthio)pyrazine, a chemopreventive agent, inhibits CYP2E1 and induces phase II enzymes. We examined the effects of 2-(allylthio)pyrazine on hepatic fibrosis, a prepathologic state of cirrhosis, and on the expression of transforming growth factor-beta1 induced by dimethylnitrosamine. Treatment of rats with dimethylnitrosamine for 4 weeks increased plasma alanine/aspartate amino-transferase and y-glutamyl transpeptidase activities, and bilirubin content, whereas the total plasma protein and albumin levels were decreased. 2-(Allylthio)pyrazine inhibited dimethylnitrosamine-induced increases in the enzyme activities and bilirubin, and restored the plasma protein and albumin contents. Masson's trichrome staining showed that dimethylnitrosamine induced liver fibrosis, the extent of which was reduced by 2-(allylthio)pyrazine treatments. Reverse transcription-polymerase chain reaction analysis revealed that 2-(allylthio)pyrazine inhibited production of transforming growth factor-beta1 mRNA by dimethylnitrosamine. These results demonstrated that 2-(allylthio)pyrazine might inhibit dimethylnitrosamine-induced liver fibrosis due to suppression of CYP2E1 expression and transforming growth factor-beta1 production.

  1. Lamivudine-Induced Liver Injury

    PubMed Central

    Olaniyan, Lamidi W. B.; Maduagwu, Emmanuel N.; Akintunde, Olalekan Wasiu; Oluwayelu, Oladimeji O.; Brai, Bartholomew I. C.

    2015-01-01

    BACKGROUND: Lamivudine is a nucleoside analogue antiretroviral drug, known for its low toxicity at clinically prescribed dose. However, the toxicity or mechanism of toxicity and target tissue effects during prolonged administration of higher doses were hardly given sufficient laboratory attention. AIM: The present work was designed to investigate the biochemical and histopathological changes in the liver of rat administered with prolonged doses of lamivudine. MATERIAL AND METHODS: Lamivudine in multiple doses of five ranging from 4 mg/kg to 2500 mg/kg were administered, in vitro, by injection into the air-sac of 10–day old fertile embryonated eggs of Gallus domesticus. Also, female rats of the Wistar strain received oral doses, up to 500 mg/kg singly or repeatedly for 15 or 45 days, respectively. Spectrophotometric techniques were employed to monitor activities of the aminotransferases (ALT and AST), γ–glutamyltransferase (GGT) and total protein concentration in serum while activities of glutathione S–transferase (GST), GGT and superoxide dismutase (SOD) as well as concentrations of malondialdehyde (MDA) and protein were determined in liver. Histopathological studies were carried out on liver. Data were analysed using ANOVA and were considered significant when p < 0.05. RESULTS: The LD50 for the drug calculated from the incubation experiment was 427 mg/kg. Total serum protein concentration significantly reduced while enzymes activities significantly increased at 500 mg/kg only among the repeat-dosed rats. Hepatic GGT, GST and SOD activities as well as MDA concentration were significantly elevated at 20 mg/kg. Histopathological studies showed multifocal lymphoid cell population in the liver sinusoid of the chicken and hydropic degeneration of hepatocytes were recorded among rats repeatedly exposed to the drug respectively at doses ≥ 100 mg/kg. CONCLUSION: Lamivudine toxicity in rat liver appeared to be mediated by oxidative stress. PMID:27275285

  2. In vitro Antiproliferative and Apoptosis Inducing Effect of Allium atroviolaceum Bulb Extract on Breast, Cervical, and Liver Cancer Cells

    PubMed Central

    Khazaei, Somayeh; Esa, Norhaizan M.; Ramachandran, Vasudevan; Hamid, Roslida A.; Pandurangan, Ashok K.; Etemad, Ali; Ismail, Patimah

    2017-01-01

    Natural products are considered potent sources for novel drug discovery and development. The multiple therapeutic effects of natural compounds in traditional medicine motivate us to evaluate the cytotoxic activity of bulb of Allium atroviolaceum in MCF7 and MDA-MB-231, HeLa and HepG2 cell lines. The bulb methanol extract of A. atroviolaceum was found to be an active cell proliferation inhibitor at the time and dose dependent manner. Determination of DNA content by flow cytometry demonstrated S and G2/M phase arrest of MCF-7 cell, correlated to Cdk1 downregulation, S phase arrest in MDA-MB-231 which is p53 and Cdk1-dependent, sub-G0 cell cycle arrest in HeLa aligned with Cdk1 downregulation, G0/G1, S, G2/M phase arrest in HepG2 which is p53-dependent. Apoptosis as the mechanism of cell death was confirmed by morphology study, caspases activity assay, as well as apoptosis related gene expression, Bcl-2. Caspase-8, -9, and -3 activity with downregulation of Bcl-2 illustrated occurrence of both intrinsic and extrinsic pathways in MCF7, while caspase-3 and -8 activity revealed extrinsic pathway of apoptosis, although Bcl-2 downregulated. In HeLa cells, the activity of caspase-9 and -3 and downregulation of Bcl-2 shows intrinsic pathway or mitochondrial pathway, whereas HepG2 shows caspase independent apoptosis. Further, the combination of the extract with tamoxifen against MCF7 and MDA-MB-231 and combination with doxorubicin against HeLa and HeG2 demonstrated synergistic effect in most concentrations, suggests that the bulb of A. atroviolaceum may be useful for the treatment of cancer lonely or in combination with other drugs. PMID:28197098

  3. Hypoxia-induced CCL28 promotes recruitment of regulatory T cells and tumor growth in liver cancer

    PubMed Central

    Wang, Li; Zhu, Zhifeng; Lu, Rong; Yao, Zhi

    2016-01-01

    Tumor cells craft microenvironment to overcome growth disadvantages and adjust to escape the immunosurveillance during tumorigenesis and metastasis. The evolving adaption to the changing microenvironment is exemplified by the development of strategies to deal with hypoxia resulted from fast proliferation of the tumor cells. In this study, we found that hypoxia hepatocellular carcinoma (HCC) cells recruited Regulatory T cells (Tregs) and expressed more Chemokine (C-C motif) ligand 28 (CCL28). Deletion of CCL28 inhibited Treg recruitment. Furthermore, overexpression of CCL28 promoted tumor growth and Treg infiltration in vivo. Enhanced angiogenesis and VEGF expression was also observed. Moreover, inhibition of HIF1α reversed hypoxia-induced CCL28 upregulation. Taken together, our results demonstrate that HCC recruits Tregs to promote angiogenesis under hypoxic condition by upregulating CCL28 expression. These findings establish a link between Tregs and hypoxia in HCC growth and may provide a new potential therapeutic target for treating HCC. PMID:27716621

  4. Radio Frequency Ablation for Primary Liver Cancer

    PubMed Central

    2004-01-01

    Executive Summary Objective The Medical Advisory Secretariat undertook a review of the evidence on the safety, clinical effectiveness, and cost-effectiveness of radio frequency ablation (RFA) compared with other treatments for unresectable hepatocellular carcinoma (HCC) in Ontario. Background Liver cancer is the fifth most common type of cancer globally, although it is most prevalent in Asia and Africa. The incidence of liver cancer has been increasing in the Western world, primarily because of an increased prevalence of hepatitis B and C. Data from Cancer Care Ontario from 1998 to 2002 suggest that the age-adjusted incidence of liver cancer in men rose slightly from 4.5 cases to 5.4 cases per 100,000 men. For women, the rates declined slightly, from 1.8 cases to 1.4 cases per 100,000 women during the same period. Most people who present with symptoms of liver cancer have a progressive form of the disease. The rates of survival in untreated patients in the early stage of the disease range from 50% to 82% at 1 year and 26% to 32% at 2 years. Patients with more advanced stages have survival rates ranging from 0% to 36% at 3 years. Surgical resection and transplantation are the procedures that have the best prognoses; however, only 15% to 20% of patients presenting with liver cancer are eligible for surgery. Resection is associated with a 50% survival rate at 5 years. The Technology: Radio Frequency Ablation RFA is a relatively new technique for the treatment of small liver cancers that cannot be treated with surgery. This technique applies alternating high-frequency electrical currents to the cancerous tissue. The intense heat leads to thermal coagulation that can kill the tumour. RFA is done under general or local anesthesia and can be done percutaneously (through the skin with a small needle), laparoscopically (microinvasively, using a small video camera), or intraoperatively. Percutaneous RFA is usually a day procedure. Methods The leading international

  5. Diagnosis of Primary Cancer of the Liver

    PubMed Central

    Kew, M. C.; Dos Santos, H. A.; Sherlock, Sheila

    1971-01-01

    The diagnosis of primary cancer of the liver was reviewed in 75 patients. A definitive diagnosis was made during life in 63% and in a further 20% this condition was suspected though histological confirmation was obtained only at necropsy. The most common presenting complaints were abdominal pain and weight loss and the most frequent findings hepatomegaly and ascites. Less than one-half of the patients were jaundiced and when present it was usually mild. An arterial bruit was heard over the liver in 25% of the patients. A sudden and unexplained deterioration in a patient known to have cirrhosis or haemochromatosis should raise the possibility of a primary hepatic tumour; this occurred in 24% of our patients. Alpha-fetoprotein was found in the serum of 11 out of 18 cases. The presence of a mass in the liver was frequently confirmed by liver scan, portal venography, or hepatic arteriography, but these showed no features diagnostic of a primary tumour. Liver scan also proved useful in localizing the lesion for biopsy purposes. Definitive diagnosis is dependent on the histological demonstration of the features of the tumour. This can frequently be achieved by percutaneous needle biopsy, which was positive in 38 out of 57 patients. Wedge biopsies were positive in a further nine patients. PMID:5124443

  6. Autophagy in alcohol-induced liver diseases.

    PubMed

    Dolganiuc, Angela; Thomes, Paul G; Ding, Wen-Xing; Lemasters, John J; Donohue, Terrence M

    2012-08-01

    Alcohol is the most abused substance worldwide and a significant source of liver injury; the mechanisms of alcohol-induced liver disease are not fully understood. Significant cellular toxicity and impairment of protein synthesis and degradation occur in alcohol-exposed liver cells, along with changes in energy balance and modified responses to pathogens. Autophagy is the process of cellular catabolism through the lysosomal-dependent machinery, which maintains a balance among protein synthesis, degradation, and recycling of self. Autophagy is part of normal homeostasis and it can be triggered by multiple factors that threaten cell integrity, including starvation, toxins, or pathogens. Multiple factors regulate autophagy; survival and preservation of cellular integrity at the expense of inadequately folded proteins and damaged high-energy generating intracellular organelles are prominent targets of autophagy in pathological conditions. Coincidentally, inadequately folded proteins accumulate and high-energy generating intracellular organelles, such as mitochondria, are damaged by alcohol abuse; these alcohol-induced pathological findings prompted investigation of the role of autophagy in the pathogenesis of alcohol-induced liver damage. Our review summarizes the current knowledge about the role and implications of autophagy in alcohol-induced liver disease.

  7. Selenium chemoprevention of liver cancer in animals and possible human applications.

    PubMed

    Yu, S Y; Chu, Y J; Li, W G

    1988-01-01

    An inverse correlation between geographic distribution of liver cancer incidence and the selenium (Se) contents of whole blood and grains was observed in Qidong county, Jiangsu province, a high liver cancer area of the People's Republic of China. Animal experiments demonstrated that supplementation of Se reduced the incidence of liver cancer in rats exposed to aflatoxin B1. Se was also shown to inhibit the growth of transplanted tumors. A lower incidence of liver preneoplastic alterations and reduction of hepatitis B virus infection in ducks by Se-supplementation was observed, and three pilot studies for a Se-intervention trial on human liver cancer were carried out on the residents of Qidong county. A protective effect on the cellular DNA damage induced by aflatoxin B1 was observed in lympocytes from human with Se-supplements.

  8. Weekly epirubicin for breast cancer with liver metastases and abnormal liver biochemistry.

    PubMed Central

    Twelves, C. J.; O'Reilly, S. M.; Coleman, R. E.; Richards, M. A.; Rubens, R. D.

    1989-01-01

    Thirty-six consecutive patients with breast cancer and liver metastases with abnormal liver biochemistry were treated with epirubicin 25 mg m-2 i.v. weekly. No dose modification was made for abnormal liver biochemistry, but dose intensity was adjusted by delaying treatment according to myelosuppression. The UICC overall response rate according to UICC criteria was 11/36 (30%) and median response duration was 27 weeks. Liver biochemistry improved in a further seven patients. Treatment was well tolerated. Epirubicin given in this way is effective in patients with breast cancer and liver metastases. An initial deterioration in liver biochemistry may occur before there is a response to epirubicin. PMID:2605102

  9. Intrahepatic therapy for liver-dominant metastatic colorectal cancer

    PubMed Central

    De Groote, Kerlijne; Prenen, Hans

    2015-01-01

    In patients with metastatic colorectal cancer, the liver is the most common site of metastatic disease. In patients with liver-dominant disease, consideration needs to be given to locoregional treatments such as hepatic arterial infusion chemotherapy, transarterial chemoembolisation and selective internal radiation therapy because hepatic metastases are a major cause of liver failure especially in chemorefractory disease. In this review we provide insights on the published literature for locoregional treatment of liver metastases in metastatic colorectal cancer. PMID:26380058

  10. Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets

    PubMed Central

    Wang, Zhanpeng; Li, Zhuonan; Ye, Yanshuo; Xie, Lijuan

    2016-01-01

    Accumulating evidence has indicated that oxidative stress (OS) is associated with the development of hepatocellular carcinoma (HCC). However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal—from either an internal or external source—and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD). The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC. PMID:27957239

  11. Liver cancer oncogenomics: opportunities and dilemmas for clinical applications

    PubMed Central

    Marquardt, Jens U; Andersen, Jesper B

    2015-01-01

    SUMMARY Primary liver cancers are among the most rapidly evolving malignant tumors worldwide. An underlying chronic inflammatory liver disease, which precedes liver cancer development for several decades and frequently creates a pro-oncogenic microenvironment, impairs progress in therapeutic approaches. Molecular heterogeneity of liver cancer is potentiated by a crosstalk between epithelial tumor and stromal cells that complicate translational efforts to unravel molecular mechanisms of hepatocarcinogenesis with a drugable intend. Next-generation sequencing has greatly advanced our understanding of cancer development. With regards to liver cancer, the unprecedented coverage of next-generation sequencing has created a detailed map of genetic alterations and identified key somatic changes such as CTNNB1 and TP53 as well as several previously unrecognized recurrent disease-causing alterations that could contribute to new therapeutic approaches. Importantly, these investigations indicate that a classical oncogene addiction cannot be assumed for primary liver cancer. Therefore, hepatocarcinogenesis can be considered a paradigm suitable for individualized medicine. PMID:26257864

  12. Label-free detection of liver cancer cells by aptamer-based microcantilever biosensor.

    PubMed

    Chen, Xuejuan; Pan, Yangang; Liu, Huiqing; Bai, Xiaojing; Wang, Nan; Zhang, Bailin

    2016-05-15

    Liver cancer is one of the most common and highly malignant cancers in the world. There are no effective therapeutic options if an early liver cancer diagnosis is not achieved. In this work, detection of HepG2 cells by label-free microcantilever array aptasensor was developed. The sensing microcantilevers were functionalized by HepG2 cells-specific aptamers. Meanwhile, to eliminate the interferences induced by the environment, the reference microcantilevers were modified with 6-mercapto-1-hexanol self-assembled monolayers. The aptasensor exhibits high specificity over not only human liver normal cells, but also other cancer cells of breast, bladder, and cervix tumors. The linear relation ranges from 1×10(3) to 1×10(5)cells/mL, with a detection limit of 300 cells/mL (S/N=3). Our work provides a simple method for detection of liver cancer cells with advantages in terms of simplicity and stability.

  13. Cancer and liver cirrhosis: implications on prognosis and management

    PubMed Central

    Pinter, Matthias; Trauner, Michael; Peck-Radosavljevic, Markus; Sieghart, Wolfgang

    2016-01-01

    Liver cirrhosis, the end-stage of every chronic liver disease, is not only the major risk factor for the development of hepatocellular carcinoma but also a limiting factor for anticancer therapy of liver and non-hepatic malignancies. Liver cirrhosis may limit surgical and interventional approaches to cancer treatment, influence pharmacokinetics of anticancer drugs, increase side effects of chemotherapy, render patients susceptible for hepatotoxicity, and ultimately result in a competitive risk for morbidity and mortality. In this review, we provide a concise overview about the impact of liver cirrhosis on the management and prognosis of patients with primary liver cancer or non-hepatic malignancies. PMID:27843598

  14. Liver cancer in Wisconsin: The potential for prevention

    SciTech Connect

    Mirkin, I.R.; Remington, P.L.; Moss, M.; Anderson, H. )

    1990-02-01

    In this study liver cancer deaths that could be attributed to certain risk factors were calculated. Applying population attributable risk methodology, the attributable risk of liver cancer was estimated for alcohol use, hepatitis B viral exposure, and occupational and industrial exposures. We found that these three risk factors accounted for 38% of liver cancer mortality in Wisconsin; 29% was attributable to alcohol consumption, 7% to occupational exposures, and 2% to hepatitis B viral infection. More than half of liver cancer mortality, however, was not accounted for by the three risk factors studied.

  15. Stop feeding cancer: pro-inflammatory role of visceral adiposity in liver cancer.

    PubMed

    Zhao, Jun; Lawless, Matthew W

    2013-12-01

    Liver cancer is the fifth most common cancer in the world with an estimated over half a million new cases diagnosed every year. Due to the difficulty in early diagnosis and lack of treatment options, the prevalence of liver cancer continues to climb with a 5-year survival rate of between 6% and 11%. Coinciding with the rise of liver cancer, the prevalence of obesity has rapidly increased over the past two decades. Evidence from epidemiological studies demonstrates a higher risk of hepatocellular carcinoma (HCC) in obese individuals. Obesity is recognised as a low-grade inflammatory disease, this is of particular relevance as inflammation has been proposed as the seventh hallmark of cancer development with abdominal visceral adiposity considered as an important source of pro-inflammatory stimuli. Emerging evidence points towards the direct role of visceral adipose tissue rather than generalised body fat in carcinogenesis. Cytokines such as IL-6 and TNF-α secreted from visceral adipose tissue have been demonstrated to induce a chronic inflammatory condition predisposing the liver to a protumourigenic milieu. This review focuses on excess visceral adiposity rather than simple obesity; particularly adipokines and their implications for chronic inflammation, lipid accumulation, insulin resistance, Endoplasmic Reticulum (ER) stress and angiogenesis. Evidence of molecular signalling pathways that may give rise to the onset and progression of HCC in this context are depicted. Delineation of the pro-inflammatory role of visceral adiposity in liver cancer and its targeting will provide better rational and therapeutic approaches for HCC prevention and elimination. The concept of a central role for metabolism in cancer is the culmination of an effort that began with one of the 20th century's leading biochemists and Nobel laureate of 1931, Otto Warburg.

  16. Chinese Herbal Medicine-induced Liver Injury

    PubMed Central

    Ma, Xin; Peng, Jing-Hua; Hu, Yi-Yang

    2014-01-01

    The widespread use of Chinese herbal medicine (CHM) and the associated adverse reactions has attracted the attention of researchers and physicians. Reports have shown that several types of CHM can cause liver injury, with increasing numbers of cases reported every year. The difficulty in characterizing CHM-induced liver injury stems from clinical manifestations, diagnosis and pathogenesis. The clinical manifestations are varied, but gastrointestinal symptoms are the majority. The Council for International Organizations of Medical Sciences scale is currently the most commonly used method for assessing causality in cases of medicine-induced liver injury with excellent sensitivity, specificity and predictive validity. However, the pathogenesis of CHM-induced liver injury is not well understood. The classic view encompasses a contribution from “toxic metabolites” that either elicit an immune response or directly affect cellular biochemical processes or functions. In addition, poor quality and inappropriate clinical use of CHMs contribute to safety concerns. To ensure the safe use of CHMs and decrease the number of hepatotoxic cases, clinicians, researchers and pharmaceutical companies should share responsibility by regulating clinical use, strengthening basic toxicology research and establishing a strict quality control system. PMID:26355537

  17. Correlation between liver cancer pain and the HIF-1 and VEGF expression levels

    PubMed Central

    Zhang, Geng; Feng, Gui-Yin; Guo, Yan-Ru; Liang, Dong-Qi; Yuan, Yuan; Wang, Hai-Lun

    2017-01-01

    A possible correlation between liver cancer pain and the hypoxia-inducible factor (HIF)-1 and vascular endothelial growth factor (VEGF) expression levels was examined. From January, 2015 to January, 2016, 30 patients suffering from liver cancer with pain, 30 patients with liver cancer without pain and 30 hepatitis patients with pain were enrolled in the study. Pain level was evaluated by visual analogue scale (VAS), the expression levels of HIF-1 and VEGF mRNA were determined by RT-PCR and the expression levels of HIF-1 and VEGF proteins were examined by ELISA. Before intervention, the VAS in the hepatitis group was significantly higher than that of the liver cancer pain group. However, after intervention the VAS in the two groups was reduced. HIF-1 and VEGF mRNA expression levels in the liver cancer pain group were significantly higher than those in the liver cancer group before and after intervention. The expression levels of HIF-1 and VEGF mRNA in the hepatitis group were the lowest. The expression levels of HIF-1 and VEGF mRNA in the liver cancer pain group considerably increased after intervention. The expression levels of HIF-1 and VEGF mRNA in the other two groups showed no changes before or after intervention. Before and after the intervention, VAS in the liver cancer pain group was positively correlated to the expression levels of HIF-1 and VEGF. Thus, pain occurrence and the pain level in liver cancer patients were correlated with the expression levels of HIF-1 and VEGF. As the regular three-step medicine analgesic ladder is ineffective in these cases, verification of HIF-1 and VEGF expression levels may be considered the new target for pain release. PMID:28123525

  18. Polyphenol-rich Avicennia marina leaf extracts induce apoptosis in human breast and liver cancer cells and in a nude mouse xenograft model

    PubMed Central

    Tu, Ming-Chin; Chang, Jia-Hua; Chen, Yen-Ju; Tu, Yu-Hsuan; Huang, Hsiu-Chen

    2016-01-01

    Avicennia marina is the most abundant and common mangrove species and has been used as a traditional medicine for skin diseases, rheumatism, ulcers, and smallpox. However, its anticancer activities and polyphenol contents remain poorly characterized. Thus, here we investigated anticancer activities of secondary A. marina metabolites that were purified by sequential soxhlet extraction in water, ethanol, methanol, and ethyl acetate (EtOAc). Experiments were performed in three human breast cancer cell lines (AU565, MDA-MB-231, and BT483), two human liver cancer cell lines (HepG2 and Huh7), and one normal cell line (NIH3T3). The chemotherapeutic potential of A. marina extracts was evaluated in a xenograft mouse model. The present data show that EtOAc extracts of A. marina leaves have the highest phenolic and flavonoid contents and anticancer activities and, following column chromatography, the EtOAc fractions F2-5, F3-2-9, and F3-2-10 showed higher cytotoxic effects than the other fractions. 1H-NMR and 13C-NMR profiles indicated that the F3-2-10 fraction contained avicennones D and E. EtOAc extracts of A. marina leaves also suppressed xenograft MDA-MB-231 tumor growth in nude mice, suggesting that EtOAc extracts of A. marina leaves may provide a useful treatment for breast cancer. PMID:27078842

  19. Phenotypes and Pathology of Drug-Induced Liver Disease.

    PubMed

    Goodman, Zachary D

    2017-02-01

    Drug hepatotoxicity can simulate nearly any clinical syndrome or pathologic lesion that may occur in the liver, so clinical and histopathologic diagnosis of drug-induced liver injury may be difficult. Nevertheless, most drugs that are known to idiosyncratic liver injury tend to cause patterns of injury that produce characteristic phenotypes. Recognition of these patterns or phenotypes in liver biopsy material is helpful in evaluation of clinical cases of suspected drug-induced liver injury.

  20. Global Proteome Changes in Liver Tissue 6 Weeks after FOLFOX Treatment of Colorectal Cancer Liver Metastases

    PubMed Central

    Urdzik, Jozef; Vildhede, Anna; Wiśniewski, Jacek R.; Duraj, Frans; Haglund, Ulf; Artursson, Per; Norén, Agneta

    2016-01-01

    (1) Oxaliplatin-based chemotherapy for colorectal cancer liver metastasis is associated with sinusoidal injury of liver parenchyma. The effects of oxaliplatin-induced liver injury on the protein level remain unknown. (2) Protein expression in liver tissue was analyzed—from eight patients treated with FOLFOX (combination of fluorouracil, leucovorin, and oxaliplatin) and seven controls—by label-free liquid chromatography mass spectrometry. Recursive feature elimination–support vector machine and Welch t-test were used to identify classifying and relevantly changed proteins, respectively. Resulting proteins were analyzed for associations with gene ontology categories and pathways. (3) A total of 5891 proteins were detected. A set of 184 (3.1%) proteins classified the groups with a 20% error rate, but relevant change was observed only in 55 (0.9%) proteins. The classifying proteins were associated with changes in DNA replication (p < 0.05) through upregulation of the minichromosome maintenance complex and with the innate immune response (p < 0.05). The importance of DNA replication changes was supported by the results of Welch t-test (p < 0.05). (4) Six weeks after FOLFOX treatment, less than 1% of identified proteins showed changes in expression associated with DNA replication, cell cycle entry, and innate immune response. We hypothesize that the changes remain after recovery from FOLFOX treatment injury. PMID:28248240

  1. Drug-induced liver injury caused by iodine-131.

    PubMed

    Kim, Chei Won; Park, Ji Sun; Oh, Se Hwan; Park, Jae-Hyung; Shim, Hyun-Ik; Yoon, Jae Woong; Park, Jin Seok; Hong, Seong Bin; Kim, Jun Mi; Le, Trong Binh; Lee, Jin Woo

    2016-06-01

    Iodine-131 is a radioisotope that is routinely used for the treatment of differentiated thyroid cancer after total or near-total thyroidectomy. However, there is some evidence that iodine-131 can induce liver injury . Here we report a rare case of drug-induced liver injury (DILI) caused by iodine-131 in a patient with regional lymph node metastasis after total thyroidectomy. A 47-year-old woman was admitted with elevated liver enzymes and symptoms of general weakness and nausea. Ten weeks earlier she had undergone a total thyroidectomy for papillary thyroid carcinoma and had subsequently been prescribed levothyroxine to reduce the level of thyroid-stimulating hormone. Eight weeks after surgery she underwent iodine-131 ablative therapy at a dose of 100 millicuries, and subsequently presented with acute hepatitis after 10 days. To rule out all possible causative factors, abdominal ultrasonography, endoscopic ultrasonography (on the biliary tree and gall bladder), and a liver biopsy were performed. DILI caused by iodine-131 was suspected. Oral prednisolone was started at 30 mg/day, to which the patient responded well.

  2. The application of antitumor drug-targeting models on liver cancer.

    PubMed

    Yan, Yan; Chen, Ningbo; Wang, Yunbing; Wang, Ke

    2016-06-01

    Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.

  3. Erlotinib in Treating Patients With Unresectable Liver, Bile Duct, or Gallbladder Cancer

    ClinicalTrials.gov

    2013-06-03

    Adult Primary Cholangiocellular Carcinoma; Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  4. Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis.

    PubMed

    Tabariès, Sébastien; Annis, Matthew G; Hsu, Brian E; Tam, Christine E; Savage, Paul; Park, Morag; Siegel, Peter M

    2015-04-20

    Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells. We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis. Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors.

  5. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

    MedlinePlus

    ... does not represent official policy of the U.S. Government or any agency thereof. The information in LiverTox ... treatment of drug induced liver injury. The U.S. Government and its individual agencies, including the NIDDK, NLM ...

  6. Manipulation of autophagy by MIR375 generates antitumor effects in liver cancer.

    PubMed

    Chang, Ying; Lin, Jusheng; Tsung, Allan

    2012-12-01

    The exploration into the roles of autophagy in tumorigenesis, either as tumor suppressor or tumor promoter, has led to a great increase in the knowledge of cancer development, progression and treatment. However, there is currently no consensus on how to manipulate autophagy to improve antitumor effects. In this study, we investigated the role of autophagy in established liver cancer cells in response to hypoxia. Hypoxia not only is the most pervasive microenvironmental stress in solid tumors but is also a canonical stimulus for autophagy. The involvement of dysregulated microRNAs in hypoxia-induced autophagy and their therapeutic potential in advanced liver cancer were examined.

  7. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer

    PubMed Central

    Barbier-Torres, Lucía; Delgado, Teresa C.; García-Rodríguez, Juan L.; Zubiete-Franco, Imanol; Fernández-Ramos, David; Buqué, Xabier; Cano, Ainara; Juan, Virginia Gutiérrez-de; Fernández-Domínguez, Itziar; Lopitz-Otsoa, Fernando; Fernández-Tussy, Pablo; Boix, Loreto; Bruix, Jordi; Villa, Erica; Castro, Azucena; Lu, Shelly C.; Aspichueta, Patricia; Xirodimas, Dimitris; Varela-Rey, Marta; Mato, José M.; Beraza, Naiara; Martínez-Chantar, María L.

    2015-01-01

    The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma. PMID:25650664

  8. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer.

    PubMed

    Barbier-Torres, Lucía; Delgado, Teresa C; García-Rodríguez, Juan L; Zubiete-Franco, Imanol; Fernández-Ramos, David; Buqué, Xabier; Cano, Ainara; Gutiérrez-de Juan, Virginia; Fernández-Domínguez, Itziar; Lopitz-Otsoa, Fernando; Fernández-Tussy, Pablo; Boix, Loreto; Bruix, Jordi; Villa, Erica; Castro, Azucena; Lu, Shelly C; Aspichueta, Patricia; Xirodimas, Dimitris; Varela-Rey, Marta; Mato, José M; Beraza, Naiara; Martínez-Chantar, María L

    2015-02-10

    The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.

  9. Protective effect of oligomeric proanthocyanidins against alcohol-induced liver steatosis and injury in mice.

    PubMed

    Wang, Zhiguo; Su, Bo; Fan, Sumei; Fei, Haixia; Zhao, Wei

    2015-03-20

    The long-term consumption of alcohol has been associated with multiple pathologies at all levels, such as alcoholism, chronic pancreatitis, malnutrition, alcoholic liver disease (ALD) and cancer. In the current study, we investigated the protective effect of oligomeric proanthocyanidins (OPC) against alcohol-induced liver steatosis and injury and the possible mechanisms using ethanol-induced chronic liver damage mouse models. The results showed that OPC significantly improved alcohol-induced dyslipidemia and alleviated liver steatosis by reducing levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL-c) and liver malondialdehyde (MDA), and increasing levels of serum high-density lipoprotein (HDL-c), liver superoxide dismutase (SOD). Further investigation indicated that OPC markedly decreased the expressions of lipid synthesis genes and inflammation genes such as sterol regulatory element-binding protein-1c (Srebp-1c), protein-2 (Srebp2), interleukin IL-1β, IL-6 and TNF-α. Furthermore, AML-12 cells line was used to investigate the possible mechanisms which indicated that OPC might alleviate liver steatosis and damage through AMP-activated protein kinase (AMPK) activation involving oxidative stress. In conclusion, our study demonstrated excellent protective effect of OPC against alcohol-induced liver steatosis and injury, which could a potential drug for the treatment of alcohol-induced liver injury in the future.

  10. Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer.

    PubMed

    Chen, Wei-Ching; Chang, Yung-Sheng; Hsu, Hui-Ping; Yen, Meng-Chi; Huang, Hau-Lun; Cho, Chien-Yu; Wang, Chih-Yang; Weng, Tzu-Yang; Lai, Po-Ting; Chen, Ching-Shih; Lin, Yih-Jyh; Lai, Ming-Derg

    2015-12-15

    CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.

  11. Dietary Natural Products for Prevention and Treatment of Liver Cancer

    PubMed Central

    Zhou, Yue; Li, Ya; Zhou, Tong; Zheng, Jie; Li, Sha; Li, Hua-Bin

    2016-01-01

    Liver cancer is the most common malignancy of the digestive system with high death rate. Accumulating evidences suggests that many dietary natural products are potential sources for prevention and treatment of liver cancer, such as grapes, black currant, plum, pomegranate, cruciferous vegetables, French beans, tomatoes, asparagus, garlic, turmeric, ginger, soy, rice bran, and some edible macro-fungi. These dietary natural products and their active components could affect the development and progression of liver cancer in various ways, such as inhibiting tumor cell growth and metastasis, protecting against liver carcinogens, immunomodulating and enhancing effects of chemotherapeutic drugs. This review summarizes the potential prevention and treatment activities of dietary natural products and their major bioactive constituents on liver cancer, and discusses possible mechanisms of action. PMID:26978396

  12. Influence of DMBA-induced mammary cancer on the liver CPT I, mit HMG-CoA synthase and PPARalpha mRNA expression in rats fed a low or high corn oil diet.

    PubMed

    Moral, Raquel; Solanas, Montserrat; Manzanares, Eva Mónica; Haro, Diego; Escrich, Eduard

    2004-08-01

    Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I) and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) enzymes play a key role in regulation of fatty acid oxidation and in ketogenic pathways, respectively. Their expression are regulated by fatty acids mainly by the peroxisome proliferator-activated receptor alpha (PPARalpha). To investigate possible mechanisms through which cancer alters the lipid metabolism, we analyzed by Northern blot, the mRNA relative abundance of these proteins in liver from healthy and DMBA-induced mammary tumor-bearing rats fed a low or high corn oil diet. Serum levels of lipids, body weight and mass were also determined. Whereas mRNA steady-state levels of CPT I and mit HMG-CoA synthase were unaffected by the presence of the extra-hepatic tumor, the cancer state seemed to modify the regulation of the expression of these genes by high fat diet. We hypothesize that putative changes in PPARalpha mRNA levels could have contributed to such alterations. These results, together with changes in serum lipid profiles, body weight and mass, indicate fat mobilization and non-enhanced oxidation rates despite a high-fat feeding. This effect of the cancer state could be related to tumor aggressiveness and suggest a preferential redirection of long-chain fatty acids into energetic and specific pathways of the cancer cells.

  13. Radioembolization for primary and metastatic liver cancer

    PubMed Central

    Memon, Khairuddin; Lewandowski, Robert J; Kulik, Laura; Riaz, Ahsun; Mulcahy, Mary F; Salem, Riad

    2011-01-01

    The incidence of hepatocellular carcinoma is increasing. Most patients present beyond potentially curative options and are usually affected by underlying cirrhosis. In this scenario, trans-arterial therapies, such as radioembolization, are rapidly gaining acceptance as a potential therapy for hepatocellular carcinoma and liver metastases. Radioembolization is a catheter-based liver-directed therapy that involves injection of micron-sized embolic particles loaded with a radioisotope by use of percutaneous transarterial techniques. Cancer cells are preferentially supplied by arterial blood and normal hepatocytes by portal venous blood; radioembolization therefore specifically targets tumor cells with a high dose of lethal radiation and spares healthy hepatocytes. The antitumor effect mostly comes from radiation rather than embolization. The most commonly used radioisotope is Yttrium-90. The commercially available devices are TheraSphere® (glass-based) and SIR-Sphere® (resin-based). The procedure is performed on outpatient basis. The incidence of complications is generally less than other locoregional therapies and may include nausea, fatigue, abdominal pain, hepatic dysfunction, biliary injury, fibrosis, radiation pneumonitis, gastrointestinal ulcers and vascular injury. However, these can be avoided by meticulous pretreatment assessment, careful patient selection and adequate dosimetry. This article focuses on both the technical and clinical aspects of radioembolization with emphasis on patient selection, uses and complications. PMID:21939859

  14. Feature statistic analysis of ultrasound images of liver cancer

    NASA Astrophysics Data System (ADS)

    Huang, Shuqin; Ding, Mingyue; Zhang, Songgeng

    2007-12-01

    In this paper, a specific feature analysis of liver ultrasound images including normal liver, liver cancer especially hepatocellular carcinoma (HCC) and other hepatopathy is discussed. According to the classification of hepatocellular carcinoma (HCC), primary carcinoma is divided into four types. 15 features from single gray-level statistic, gray-level co-occurrence matrix (GLCM), and gray-level run-length matrix (GLRLM) are extracted. Experiments for the discrimination of each type of HCC, normal liver, fatty liver, angioma and hepatic abscess have been conducted. Corresponding features to potentially discriminate them are found.

  15. Agkihpin, a novel SVAE may inhibit the migration and invasion of liver cancer cells associated with the inversion of EMT induced by Wnt/β-catenin signaling inhibition.

    PubMed

    Huang, Miao; Wu, Shengming; Hu, Qiping; Wu, Huayu; Wei, Shu; Xie, Huiqiong; Sun, Kejian; Li, Xiaolong; Fang, Ling

    2016-10-14

    In our previous work, agkihpin, a snake venom arginine esterase (SVAE), was isolated from the Gloydius halys Pallas, which could attenuate the migration of liver cancer cells. However, the mechanism of the effect of agkihpin on attenuating migration of liver cancer cell is unknown yet. Here, to learn more about agkihpin and explore the possibility of agkihpin as an anti-metastatic drug in the future, a series of experiments about the migration and invasion of liver cancer cells with agkihpin, HepG 2 and SMMC-7721, was conducted. Epithelial-mesenchymal transition (EMT) is an initial step and a major phenotype of cancer metastasis and invasion, while a number of EMT opposite phenomenons were observed, for example, epithelial marker E-cadherin was up-regulated, mesenchymal markers N-cadherin and Vimentin, and transcription regulators Snail and twist were down-regulated after treating with agkihpin in liver cancer cells; canonical Wnt/β-catenin pathway, one of the signals initiated EMT, was inhibited by decreased expressions of FZD7 and β-catenin, phosphorylation of GSK3β (Ser9), and nuclear β-catenin accumulation in agkihpin treated cancer cells. By using bioinformatics analysis and protease activity analysis in vitro we also found that agkihpin might bind and degrade FZD7. As a result, we hypothesized that agkihpin could inhibit the Wnt/β-catenin signaling pathway by cleaving FZD7, leading to the inactivation of the TCF/LEF transcription factor, which contributed to the inversion of EMT, and finally attenuated the migration and invasion of liver cancer cells. Therefore, our findings provided novel mechanistic insights into the role of SVAEs in liver cancer controlling, and raised the possibility that agkihpin may be used therapeutically in liver cancer.

  16. Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer

    ClinicalTrials.gov

    2015-05-14

    Childhood Hepatocellular Carcinoma; Papillary Thyroid Cancer; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Rhabdomyosarcoma; Recurrent Thyroid Cancer; Recurrent Wilms Tumor and Other Childhood Kidney Tumors

  17. Lung, liver and bone cancer mortality after plutonium exposure in beagle dogs and nuclear workers.

    PubMed

    Wilson, Dulaney A; Mohr, Lawrence C; Frey, G Donald; Lackland, Daniel; Hoel, David G

    2010-01-01

    The Mayak Production Association (MPA) worker registry has shown evidence of plutonium-induced health effects. Workers were potentially exposed to plutonium nitrate [(239)Pu(NO(3))(4)] and plutonium dioxide ((239)PuO(2)). Studies of plutonium-induced health effects in animal models can complement human studies by providing more specific data than is possible in human observational studies. Lung, liver, and bone cancer mortality rate ratios in the MPA worker cohort were compared to those seen in beagle dogs, and models of the excess relative risk of lung, liver, and bone cancer mortality from the MPA worker cohort were applied to data from life-span studies of beagle dogs. The lung cancer mortality rate ratios in beagle dogs are similar to those seen in the MPA worker cohort. At cumulative doses less than 3 Gy, the liver cancer mortality rate ratios in the MPA worker cohort are statistically similar to those in beagle dogs. Bone cancer mortality only occurred in MPA workers with doses over 10 Gy. In dogs given (239)Pu, the adjusted excess relative risk of lung cancer mortality per Gy was 1.32 (95% CI 0.56-3.22). The liver cancer mortality adjusted excess relative risk per Gy was 55.3 (95% CI 23.0-133.1). The adjusted excess relative risk of bone cancer mortality per Gy(2) was 1,482 (95% CI 566.0-5686). Models of lung cancer mortality based on MPA worker data with additional covariates adequately described the beagle dog data, while the liver and bone cancer models were less successful.

  18. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression.

    PubMed

    Cheung, Otto K-W; Cheng, Alfred S-L

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.

  19. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression

    PubMed Central

    Cheung, Otto K.-W.; Cheng, Alfred S.-L.

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management. PMID:27703473

  20. Oncogenic role of the Notch pathway in primary liver cancer

    PubMed Central

    LU, JIE; XIA, YUJING; CHEN, KAN; ZHENG, YUANYUAN; WANG, JIANRONG; LU, WENXIA; YIN, QIN; WANG, FAN; ZHOU, YINGQUN; GUO, CHUANYONG

    2016-01-01

    Primary liver cancer, which includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and fibrolamellar HCC, is one of the most common malignancies and the third leading cause of cancer-associated mortality, worldwide. Despite the development of novel therapies, the prognosis of liver cancer patients remains extremely poor. Thus, investigation of the genetic background and molecular mechanisms underlying the development and progression of this disease has gained significant attention. The Notch signaling pathway is a crucial determinant of cell fate during development and disease in several organs. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis, and is also significant in the development of HCC and ICC. These findings suggest that the modulation of Notch pathway activity may have therapeutic relevance. The present review summarizes Notch signaling during HCC and ICC development and discusses the findings of recent studies regarding Notch expression, which reveal novel insights into its function in liver cancer progression. PMID:27347091

  1. TNF-{alpha} similarly induces IL-6 and MCP-1 in fibroblasts from colorectal liver metastases and normal liver fibroblasts

    SciTech Connect

    Mueller, Lars; Seggern, Lena von; Schumacher, Jennifer; Goumas, Freya; Wilms, Christian; Braun, Felix; Broering, Dieter C.

    2010-07-02

    Cancer-associated fibroblasts (CAFs) represent the predominant cell type of the neoplastic stroma of solid tumors, yet their biology and functional specificity for cancer pathogenesis remain unclear. We show here that primary CAFs from colorectal liver metastases express several inflammatory, tumor-enhancing factors, including interleukin (IL)-6 and monocyte-chemoattractant protein (MCP)-1. Both molecules were intensely induced by TNF-{alpha} on the transcript and protein level, whereas PDGF-BB, TGF-{beta}1 and EGF showed no significant effects. To verify their potential specialization for metastasis progression, CAFs were compared to fibroblasts from non-tumor liver tissue. Interestingly, these liver fibroblasts (LFs) displayed similar functions. Further analyses revealed a comparable up-regulation of intercellular adhesion molecule-1 (ICAM-1) by TNF-{alpha}, and of alpha-smooth muscle actin, by TGF-{beta}1. Moreover, the proliferation of both cell types was induced by PDGF-BB, and CAFs and LFs displayed an equivalent migration towards HT29 colon cancer cells in Boyden chamber assays. In conclusion, colorectal liver metastasis may be supported by CAFs and resident fibroblastic cells competent to generate a prometastatic microenvironment through inflammatory activation of IL-6 and MCP-1.

  2. Negative effects of curcumin on liver injury induced by alcohol.

    PubMed

    Zhao, Hai-Long; Song, Chang Ho; Chai, Ok Hee

    2012-12-01

    Curcumin is known for its antiinflammatory and antifibrotic properties in liver damage. However, the negative effects of curcumin on alcoholic liver damage are seldom reported. In this study, both advantageous and disadvantageous functions of curcumin on alcoholic liver injury were observed. In order to determine the effects of curcumin on liver fibrosis induced by alcohol, 5% ethanol and/or curcumin (1 × 10(-3) or 1 × 10(-4)  m) were injected intravenously in mice. Hematoxylin-eosin staining was performed to determine the value of liver injury by optical density analyses. Liver histology was evaluated by an experienced hepatopathologist blinded to the type of treatment received by the animals. Ethanol accelerates serum levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), liver injury, production of tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β) and nuclear factor-kappa B (NF-κB) during 5% ethanol-induced liver injury. 1 × 10(-3)  m curcumin accelerates liver injury and liver cellular edema during only 5% ethanol-induced liver injury evolution, whereas 1 × 10(-4)  m curcumin does not lead to (or protect) alcoholic liver injury. Therefore, it is suggested that curcumin may have dual effects on alcoholic liver injury depending on its concentration.

  3. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism.

    PubMed

    Yang, Yunlong; Zhang, Yin; Iwamoto, Hideki; Hosaka, Kayoko; Seki, Takahiro; Andersson, Patrik; Lim, Sharon; Fischer, Carina; Nakamura, Masaki; Abe, Mitsuhiko; Cao, Renhai; Skov, Peter Vilhelm; Chen, Fang; Chen, Xiaoyun; Lu, Yongtian; Nie, Guohui; Cao, Yihai

    2016-09-01

    The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes of the fenestrated endothelium and loss of VE-cadherin. The drug cessation caused highly leaky hepatic vasculatures permit tumour cell intravasation and extravasation. Discontinuation of an anti-VEGF antibody-based drug and sunitinib markedly promotes liver metastasis. Mechanistically, host hepatocyte, but not tumour cell-derived vascular endothelial growth factor (VEGF), is responsible for cancer metastasis. Deletion of hepatocyte VEGF markedly ablates the 'off-drug'-induced metastasis. These findings provide mechanistic insights on anti-VEGF cessation-induced metastasis and raise a new challenge for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers.

  4. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism

    PubMed Central

    Yang, Yunlong; Zhang, Yin; Iwamoto, Hideki; Hosaka, Kayoko; Seki, Takahiro; Andersson, Patrik; Lim, Sharon; Fischer, Carina; Nakamura, Masaki; Abe, Mitsuhiko; Cao, Renhai; Skov, Peter Vilhelm; Chen, Fang; Chen, Xiaoyun; Lu, Yongtian; Nie, Guohui; Cao, Yihai

    2016-01-01

    The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes of the fenestrated endothelium and loss of VE-cadherin. The drug cessation caused highly leaky hepatic vasculatures permit tumour cell intravasation and extravasation. Discontinuation of an anti-VEGF antibody-based drug and sunitinib markedly promotes liver metastasis. Mechanistically, host hepatocyte, but not tumour cell-derived vascular endothelial growth factor (VEGF), is responsible for cancer metastasis. Deletion of hepatocyte VEGF markedly ablates the ‘off-drug'-induced metastasis. These findings provide mechanistic insights on anti-VEGF cessation-induced metastasis and raise a new challenge for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers. PMID:27580750

  5. Surgical management of breast cancer liver metastases

    PubMed Central

    Cassera, Maria A; Hammill, Chet W; Ujiki, Michael B; Wolf, Ronald F; Swanström, Lee L; Hansen, Paul D

    2011-01-01

    Introduction Selected patients with isolated breast cancer liver metastases (BCLM) may benefit from surgical management; however, indications remain unclear and the risks may outweigh the benefits in patients with a generally poor prognosis. Methods Between 1998 and 2006, 17 patients diagnosed with BCLM were considered for surgical management (<4 tumours, tumour <4 cm in diameter and no/stable extrahepatic metastases). Peri-operative and outcomes data were analysed and compared. Results Eight patients were found to have extensive or untreatable disease on staging laparoscopy and intra-operative ultrasound (SL/IOUS). The remaining nine patients underwent surgical management [seven laparoscopic radiofrequency ablations (RFA) and two hepatic resections]. Median length of follow-up for patients treated surgically was 40.0 months, median disease-free survival (DFS) was 32.2 months and median time to disease progression was 17.7 months. Of the eight patients not amenable to surgery, median length of follow-up was 21.8 months. Conclusion SL/IOUS prevented unnecessary laparotomy in half of the patients taken to the operating room for surgical treatment of BCLM. In patients with BCLM, SL/IOUS should be considered standard of care before surgical intervention. The small number of patients and short follow-up may be inadequate to determine the true value of surgical management in this group of patients with BCLM. PMID:21418133

  6. Identification of Plants That Inhibit Lipid Droplet Formation in Liver Cells: Rubus suavissimus Leaf Extract Protects Mice from High-Fat Diet-Induced Fatty Liver by Directly Affecting Liver Cells

    PubMed Central

    Takahashi, Tomohiro; Sugawara, Wataru; Takiguchi, Yuya; Takizawa, Kento; Nakabayashi, Ami; Nakamura, Mitsuo; Nagano-Ito, Michiyo; Ichikawa, Shinichi

    2016-01-01

    Fatty liver disease is a condition in which abnormally large numbers of lipid droplets accumulate in liver cells. Fatty liver disease induces inflammation under conditions of oxidative stress and may result in cancer. To identify plants that protect against fatty liver disease, we examined the inhibitory effects of plant extracts on lipid droplet formation in mouse hepatoma cells. A screen of 98 water extracts of plants revealed 4 extracts with inhibitory effects. One of these extracts, Rubus suavissimus S. Lee (Tien-cha or Chinese sweet tea) leaf extract, which showed strong inhibitory effects, was tested in a mouse fatty liver model. In these mouse experiments, intake of the plant extract significantly protected mice against fatty liver disease without affecting body weight gain. Our results suggest that RSE directly affects liver cells and protects them from fatty liver disease. PMID:27429636

  7. Chemotherapy-associated liver injury: impact on surgical management of colorectal cancer liver metastases.

    PubMed

    Kneuertz, Peter J; Maithel, Shishir K; Staley, Charles A; Kooby, David A

    2011-01-01

    Chemotherapy is integral to the management of patients with advanced colorectal cancer liver metastases. Due to their improved efficacy, modern regimens can sometimes convert unresectable disease to a resectable state. As chemotherapy is often administered prior to hepatic resection, adverse effects on the liver are increasingly being recognized. Investigators have identified a wide spectrum of effects on the underlying liver parenchyma, ranging from mild forms of steatosis to severe steatohepatitis and sinusoidal obstruction syndrome. As the histopathologic definitions of these changes evolve, studies have identified specific patterns of hepatic injury related to the various chemotherapeutic agents. The impact of these changes on perioperative outcome after partial hepatectomy remains controversial. Timing and duration of chemotherapy may play a key role and account for discrepancies in outcomes seen among studies. In this review, we provide an overview of the spectrum of chemotherapy-associated liver injury and discuss its relevance to perioperative management of patients undergoing hepatic resection of colorectal cancer liver metastases.

  8. Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression

    PubMed Central

    Kotiya, Deepak; Jaiswal, Bharti; Ghose, Sampa; Kaul, Rachna; Datta, Kasturi; Tyagi, Rakesh K.

    2016-01-01

    The role of nuclear receptor PXR in detoxification and clearance of xenobiotics and endobiotics is well-established. However, its projected role in hepatic cancer is rather illusive where its expression is reported altered in different cancers depending on the tissue-type and microenvironment. The expression of PXR, its target genes and their biological or clinical significance have not been examined in hepatic cancer. In the present study, by generating DEN-induced hepatic cancer in mice, we report that the expression of PXR and its target genes CYP3A11 and GSTa2 are down-regulated implying impairment of hepatic detoxification capacity. A higher state of inflammation was observed in liver cancer tissues as evident from upregulation of inflammatory cytokines IL-6 and TNF-α along with NF-κB and STAT3. Our data in mouse model suggested a negative correlation between down-regulation of PXR and its target genes with that of higher expression of inflammatory proteins (like IL-6, TNF-α, NF-κB). In conjunction, our findings with relevant cell culture based assays showed that higher expression of PXR is involved in reduction of tumorigenic potential in hepatic cancer. Overall, the findings suggest that inflammation influences the expression of hepatic proteins important in drug metabolism while higher PXR level reduces tumorigenic potential in hepatic cancer. PMID:27760163

  9. Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression.

    PubMed

    Kotiya, Deepak; Jaiswal, Bharti; Ghose, Sampa; Kaul, Rachna; Datta, Kasturi; Tyagi, Rakesh K

    2016-01-01

    The role of nuclear receptor PXR in detoxification and clearance of xenobiotics and endobiotics is well-established. However, its projected role in hepatic cancer is rather illusive where its expression is reported altered in different cancers depending on the tissue-type and microenvironment. The expression of PXR, its target genes and their biological or clinical significance have not been examined in hepatic cancer. In the present study, by generating DEN-induced hepatic cancer in mice, we report that the expression of PXR and its target genes CYP3A11 and GSTa2 are down-regulated implying impairment of hepatic detoxification capacity. A higher state of inflammation was observed in liver cancer tissues as evident from upregulation of inflammatory cytokines IL-6 and TNF-α along with NF-κB and STAT3. Our data in mouse model suggested a negative correlation between down-regulation of PXR and its target genes with that of higher expression of inflammatory proteins (like IL-6, TNF-α, NF-κB). In conjunction, our findings with relevant cell culture based assays showed that higher expression of PXR is involved in reduction of tumorigenic potential in hepatic cancer. Overall, the findings suggest that inflammation influences the expression of hepatic proteins important in drug metabolism while higher PXR level reduces tumorigenic potential in hepatic cancer.

  10. Ulinastatin reduces the resistance of liver cancer cells to epirubicin by inhibiting autophagy.

    PubMed

    Song, Bin; Bian, Qi; Shao, Cheng Hao; Li, Gang; Liu, An An; Jing, Wei; Liu, Rui; Zhang, Yi-Jie; Zhou, Ying-Qi; Hu, Xian-Gui; Jin, Gang

    2015-01-01

    During chemotherapy, drug resistance caused by autophagy remains a major challenge to successful treatment of cancer patients. The purpose of this study is to show that ulinastatin (UTI), a trypsin inhibitor, could reduce the resistance of liver cancer cells to chemotherapeutic agent epirubicin (EPI). We achieved this conclusion by analyzing the effect of EPI alone or UTI plus EPI on SMMC-7721 and MHCC-LM3 liver cancer cells. We also generated an EPI-resistant liver cancer cell line (MHCC-LM3er cells), and found that UTI could sensitize the LM3er cells to EPI. Autophagy usually functions to protect cancer cells during chemotherapy. Our study showed that UTI inhibited the autophagy induced by EPI in liver cancer cells, which promoted apoptosis, and therefore, reduced the resistance of the cancer cells to EPI. Further studies showed that the UTI-mediated inhibition on autophagy was achieved by inhibiting transcriptional factor nuclear factor-κB (NF-κB) signaling pathway. To verify our results in vivo, we injected MHCC-LM3 liver cancer cells or EPI-resistant LM3er cells into mice, and found that EPI could only effectively inhibit the growth of tumor in MHCC-LM3 cell-injected mice, but not in LM3er cell-injected mice. However, when UTI was also administered, the growth of tumor was inhibited in the MHCC-LM3er cell-injected mice as well. Our results suggest that UTI may be used in combination with anti-cancer drugs, such as EPI, to improve the outcome of cancer therapy.

  11. Focused ultrasound as a local therapy for liver cancer.

    PubMed

    Fischer, Krisztina; Gedroyc, Wladyslaw; Jolesz, Ferenc A

    2010-01-01

    Conventional surgical treatments of liver cancer are invasive (including minimally invasive) with a high incidence of new metastasis and poor success, even after multiple resections or ablations. These limitations motivated research into new, less invasive solutions for liver cancer treatment.Focused ultrasound surgery (FUS), or high-intensity focused ultrasound, has been recognized as a noninvasive technology for benign and malignant tumor treatment. Previously, FUS was guided with ultrasound that has limited target definition and monitoring capability of the ablation process. Combining magnetic resonance imaging (MRI) with multiple-element phased-array transducers to create MRI-guided focused ultrasound thermal therapy provides more accurate targeting and real-time temperature monitoring. This treatment is hindered by the ribcage that limits the acoustic windows to the liver and the respiratory motion of the liver. New advances in MRI and transducer design will likely resolve these limitations and make MRI-guided FUS a powerful tool in local liver cancer therapy. This article reviews this technology and advances that can expand its use for cancer treatment in general and liver cancer in particular.

  12. Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis.

    PubMed

    Song, E; Chen, J; Ouyang, N; Wang, M; Exton, M S; Heemann, U

    2001-05-04

    Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl(4)-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [(3)H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.

  13. Surgical treatment of double primary liver cancer

    PubMed Central

    Li, Aijun; Ma, Senlin; Pawlik, Timothy; Wu, Bin; Yang, Xiaoyu; Cui, Longjiu; Wu, Mengchao

    2016-01-01

    Abstract Double primary liver cancer (DPLC) is a special type of clinical situation. As such, a detailed analysis of the surgical management and prognosis of patients with DPLC is lacking. The objective of the current study was to define the management and outcome of patients undergoing surgery for DPLC at a major hepatobiliary center. A total of 87 patients treated by surgical resection at the Eastern Hepatobiliary Surgery Hospital from January 1st, 2007 to October 31st, 2013 who had DPLC demonstrated by final pathological diagnosis were identified. Among these, 50 patients had complete clinical and prognostic data. Demographic and tumor characteristics as well as the prognosis were analyzed. The proportion of hepatitis B surface antigen (HBsAg) (+) and hepatitis B virus e antigen (HBeAg) (+), HBsAg (+), and HBeAg (−) hepatocirrhosis in all patients was 21.84%, 67.82%, and 63.22%, respectively. Incidental findings accounted for 58.62% of patients; among those who had symptoms, the main symptom was abdominal pain (31.03%). Nonanatomic wedge resection was the main operative approach (62.07%). Postoperatively, the main complications included seroperitoneum (11.49%), hypoproteinemia (10.34%), and pleural effusion (8.05%). Factors associated with disease-free survival (DFS) included intrahepatic cholangiocarcinoma (ICC) tumor size (P = 0.002) and use of postoperative prophylactic transcatheter arterial chemoembolization (TACE) treatment (P = 0.015). Meanwhile, hepatocellular carcinoma (HCC) size (P = 0.045), ICC size (P < 0.001), and liver function (including aspartate aminotransferase [P = 0.001] and r-glutamyl transferase [P < 0.001]) were associated with overall survival (OS). Hepatitis B virus (HBV)-related hepatitis or cirrhosis is also an important factor in the pathogenesis of DPLC and surgical treatment is safe for it with low complication rates. In addition, it is effective to prolong DFS that DPLC patients undergo postoperative

  14. A Comprehensive Method for Predicting Fatal Liver Failure of Patients With Liver Cancer Resection

    PubMed Central

    Li, Jiangfa; Lei, Biao; Nie, Xingju; Lin, Linku; Tahir, Syed Abdul; Shi, Wuxiang; Jin, Junfei; He, Songqing

    2015-01-01

    Abstract There are many methods to assess liver function, but none of them has been verified as fully effective. The purpose of this study is to establish a comprehensive method evaluating perioperative liver reserve function (LRF) in patients with primary liver cancer (PLC). In this study, 310 PLC patients who underwent liver resection were included. The cohort was divided into a training set (n = 235) and a validation set (n = 75). The factors affecting postoperative liver dysfunction (POLD) during preoperative, intraoperative, and postoperative periods were confirmed by logistic regression analysis. The equation for calculating the preoperative liver functional evaluation index (PLFEI) was established; the cutoff value of PLFEI determined through analysis by receiver-operating characteristic curve was used to predict postoperative liver function. The data showed that body mass index, international normalized ratio, indocyanine green (ICG) retention rate at 15 minutes (ICGR15), ICG elimination rate, standard remnant liver volume (SRLV), operative bleeding volume (OBV), blood transfusion volume, and operative time were statistically different (all P < 0.05) between 2 groups of patients with and without POLD. The relationship among PLFEI, ICGR15, OBV, and SRLV is expressed as an equation of “PLFEI = 0.181 × ICGR15 + 0.001 × OBV − 0.008 × SRLV.” The cutoff value of PLFEI to predict POLD was −2.16 whose sensitivity and specificity were 90.3% and 73.5%, respectively. However, when predicting fatal liver failure (FLF), the cutoff value of PLFEI was switched to −1.97 whose sensitivity and specificity were 100% and 68.8%, respectively. PLFEI will be a more comprehensive, sensitive, and accurate index assessing perioperative LRF in liver cancer patients who receive liver resection. And keeping PLFEI <−1.97 is a safety margin for preventing FLF in PLC patients who underwent liver resection. PMID:25929924

  15. A comprehensive method for predicting fatal liver failure of patients with liver cancer resection.

    PubMed

    Li, Jiangfa; Lei, Biao; Nie, Xingju; Lin, Linku; Tahir, Syed Abdul; Shi, Wuxiang; Jin, Junfei; He, Songqing

    2015-05-01

    There are many methods to assess liver function, but none of them has been verified as fully effective. The purpose of this study is to establish a comprehensive method evaluating perioperative liver reserve function (LRF) in patients with primary liver cancer (PLC).In this study, 310 PLC patients who underwent liver resection were included. The cohort was divided into a training set (n = 235) and a validation set (n = 75). The factors affecting postoperative liver dysfunction (POLD) during preoperative, intraoperative, and postoperative periods were confirmed by logistic regression analysis. The equation for calculating the preoperative liver functional evaluation index (PLFEI) was established; the cutoff value of PLFEI determined through analysis by receiver-operating characteristic curve was used to predict postoperative liver function.The data showed that body mass index, international normalized ratio, indocyanine green (ICG) retention rate at 15 minutes (ICGR15), ICG elimination rate, standard remnant liver volume (SRLV), operative bleeding volume (OBV), blood transfusion volume, and operative time were statistically different (all P < 0.05) between 2 groups of patients with and without POLD. The relationship among PLFEI, ICGR15, OBV, and SRLV is expressed as an equation of "PLFEI = 0.181 × ICGR15 + 0.001 × OBV - 0.008 × SRLV." The cutoff value of PLFEI to predict POLD was -2.16 whose sensitivity and specificity were 90.3% and 73.5%, respectively. However, when predicting fatal liver failure (FLF), the cutoff value of PLFEI was switched to -1.97 whose sensitivity and specificity were 100% and 68.8%, respectively.PLFEI will be a more comprehensive, sensitive, and accurate index assessing perioperative LRF in liver cancer patients who receive liver resection. And keeping PLFEI <-1.97 is a safety margin for preventing FLF in PLC patients who underwent liver resection.

  16. Lymphatic drainage of the liver and its implications in the management of colorectal cancer liver metastases.

    PubMed

    Lupinacci, Renato Micelli; Paye, François; Coelho, Fabricio Ferreira; Kruger, Jaime Arthur Pirolla; Herman, Paulo

    2014-12-01

    The liver is the most common site of distant metastases in patients with colorectal cancer. Surgery represents the mainstream for curative treatment of colorectal cancer liver metastases (CRCLM) with long-term survival up to 58 and 36 % at 5 and 10 years, respectively. Despite advances on diagnosis, staging and surgical strategies, 60-70 % of patients will develop recurrence of the disease even after R0 resection of CRCLM. Tumor staging, prognosis, and therapeutic approaches for cancer are most often based on the extent of involvement of regional lymph nodes (LNs) and, to a lesser extent, on the invasion of regional lymphatic vessels draining the primary tumor. For CRCLM, the presence of intra hepatic lymphatic and blood vascular dissemination has been associated with an increased risk of intra hepatic recurrence, poorer disease-free and overall survival after liver resection. Also, several studies have reviewed the role of surgery in the patient with concomitant CRCLM and liver pedicle LN metastasis. Although pedicle LN involvement is related to worst survival rates, it does not differentiate patients that will relapse from those that will not. This review aims to briefly describe the anatomy of the liver's lymphatic drainage, the incidence of intrahepatic lymphatic invasion and hilar lymph node involvement, as well as their clinical impact in CRCLM. A better understanding of the role of liver lymphatic metastasis might, in the near future, impact the strategy of systemic therapies after liver resection as for primary colorectal tumors.

  17. Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells.

    PubMed

    Ren, Ke-Wei; Li, Ya-Hua; Wu, Gang; Ren, Jian-Zhuang; Lu, Hui-Bin; Li, Zong-Ming; Han, Xin-Wei

    2017-04-01

    Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables. Quercetin prevents tumor proliferation by inducing cell cycle arrest and is a well known cancer therapeutic agent and autophagy mediator. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles was examined. In this study, we explored the role and possible underlying mechanisms of quercetin nanoparticle in regulation of antitumor activity in liver cancer cells. Treatment with quercetin nanoparticle effectively inhibited the liver cancer cell proliferation, cell migration and colony formation, thus suppressing liver cancer progression. Quercetin nanoparticle also upregulated apoptosis markedly. Further study suggested that quercetin nanoparticle accelerated the cleavage of caspase-9, caspase-3, and induced the up-releasing of cytochrome c (Cyto-c), contributing to apoptosis in liver cancer cells. Quercetin nanoparticles also promoted telomerase reverse transcriptase (hTERT) inhibition through reducing AP-2β expression and decreasing its binding to hTERT promoter. In addition, quercetin nanoparticle had an inhibitory role in cyclooxygenase 2 (COX-2) via suppressing the NF-κB nuclear translocation and its binding to COX-2 promoter. Quercetin nanoparticle also inactivated Akt and ERK1/2 signaling pathway. Taken together, our results suggested that quercetin nanoparticle had an antitumor effect by inactivating caspase/Cyto-c pathway, suppressing AP-2β/hTERT, inhibiting NF-κB/COX-2 and impeding Akt/ERK1/2 signaling pathways. Our results provided new mechanistic basis for further investigation of quercetin nanoparticles to find potential therapeutic strategies and possible targets for liver cancer inhibition.

  18. miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver

    PubMed Central

    Okamoto, Koji; Ishiguro, Tatsuya; Midorikawa, Yutaka; Ohata, Hirokazu; Izumiya, Masashi; Tsuchiya, Naoto; Sato, Ai; Sakai, Hiroaki; Nakagama, Hitoshi

    2012-01-01

    Liver metastasis is a major lethal complication associated with colon cancer, and post-intravasation steps of the metastasis are important for its clinical intervention. In order to identify inhibitory microRNAs (miRNAs) for these steps, we performed ‘dropout' screens of a miRNA library in a mouse model of liver metastasis. Functional analyses showed that miR-493 and to a lesser extent miR-493* were capable of inhibiting liver metastasis. miR-493 inhibited retention of metastasized cells in liver parenchyma and induced their cell death. IGF1R was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects. High levels of miR-493 and miR-493*, but not pri-miR-493, in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. We propose that, in a subset of colon cancer, upregulation of miR-493 during carcinogenesis prevents liver metastasis via the induction of cell death of metastasized cells. PMID:22373578

  19. Herbal and Dietary Supplement-Induced Liver Injury.

    PubMed

    de Boer, Ynto S; Sherker, Averell H

    2017-02-01

    The increase in the use of herbal and dietary supplements (HDSs) over the last decades has been accompanied by an increase in the reports of HDS-associated hepatotoxicity. The spectrum of HDS-induced liver injury is diverse and the outcome may vary from transient liver test increases to fulminant hepatic failure resulting in death or requiring liver transplant. There are no validated standardized tools to establish the diagnosis, but some HDS products have a typical clinical signature that may help to identify HDS-induced liver injury.

  20. Acute liver injury induced by weight-loss herbal supplements

    PubMed Central

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-01-01

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss. PMID:21173910

  1. Acute liver injury induced by weight-loss herbal supplements.

    PubMed

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-11-27

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

  2. [A case of sigmoid colon cancer liver metastasis accompanied by multiple liver abscesses].

    PubMed

    Murakami, Masakazu; Miyake, Yasuhiro; Uemura, Hisashi; Okada, Kaoru; Nakane, Shigeru; Higaki, Naozumi; Hayashida, Hirohito; Oka, Yoshio; Nezu, Riichiro

    2014-11-01

    We describe the case of a patient with sigmoid colon cancer liver metastasis accompanied by multiple liver abscesses. The 59-year-old female patient presented with a fever at a body temperature of 39.0°C. On abdominal computed tomography (CT), multiple liver abscesses were detected, and percutaneous transhepatic abscess drainage (PTAD) was performed. The day after the PTAD, the patient's fever subsided and her inflammatory response abated. A lower gastrointestinal examination, performed to identify the origin of her symptoms, revealed a type 1 tumor in the sigmoid colon. A biopsy indicated a moderately differentiated adenocarcinoma. Prior to surgery, a second abdominal CT scan was performed, and a single liver metastasis was detected. Laparoscopic sigmoidectomy and partial liver resection were simultaneously performed. The histopathological diagnosis of the colon cancer was tub2, pN1, pH1, P0, ly1, v1, stage IV. To date, the patient remains free from hepatic abscess and colon cancer recurrence. Gastrointestinal examinations should be performed as early as possible to identify the cause of hepatic abscesses. Moreover, therapeutic decisions should only be made after imaging and examinations have been performed, which will be sufficient to identify the presence of liver metastases.

  3. Portal venous gas following chemotherapy for colorectal cancer liver metastasis.

    PubMed

    Zalinski, S; Scatton, O; Jacqmin, S; Tacher, V; Brézault, C; Soubrane, O

    2009-05-01

    The standard of care for patients with colorectal liver metastases is a combination of chemotherapy and surgery. New chemotherapy regimens with biologic agents (cetuximab, bevacizumab) have been shown to increase tumor response rates. Although this might be beneficial and this is an expected endpoint, it should be noted that patients with synchronous colorectal and liver metastases are at risk of septic complications. We recently encountered a case of hepatic portal venous gas after two cycles of chemotherapy in a patient with right colon cancer liver metastases. Complete necrosis of the liver metastasis subsequently turned into a liver abscess, which fistulized in the right portal vein. Infection of the necrotized metastasis was thought to be promoted by the colic tumor. Although this is a dramatic situation, it does not contraindicate a curative surgical resection.

  4. Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer.

    PubMed

    Kuo, Kung-Kai; Lee, King-Teh; Chen, Ker-Kong; Yang, Ya-Han; Lin, Ying-Chu; Tsai, Ming-Ho; Wuputra, Kenly; Lee, Yen-Liang; Ku, Chia-Chen; Miyoshi, Hiroyuki; Nakamura, Yukio; Saito, Shigeo; Wu, Chun-Chieh; Chai, Chee-Yin; Eckner, Richard; Steve Lin, Chen-Lung; Wang, Sophie S-W; Wu, Deng-Chyang; Lin, Chang-Shen; Yokoyama, Kazunari K

    2016-06-24

    The network of stemness genes and oncogenes in human patient-specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2-derived induced pluripotent stem cell-like cells (HepG2-iPS-like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2-derived CSC-like cells (designated rG2-DC-1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2-DC-1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere-colony formation ability and the invasion activity of rG2-DC-1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c-JUN oncogene, but not of c-MYC, was significantly elevated in rG2-DC-1C, whereas no c-JUN expression was observed in HepG2 cells. The positive-feedback regulation via OCT4-mediated transactivation of the c-JUN promoter and the c-JUN-mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2-DC-1C. Increased expression of OCT4 and c-JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016.

  5. The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage.

    PubMed

    Bhattacharya, Arup; Klaene, Joshua J; Li, Yun; Paonessa, Joseph D; Stablewski, Aimee B; Vouros, Paul; Zhang, Yuesheng

    2015-01-20

    Bladder cancer risk is significantly higher in men than in women. 4-Aminobiphenyl (ABP) is a major human bladder carcinogen from tobacco smoke and other sources. In mice, male bladder is more susceptible to ABP-induced carcinogenesis than female bladder, but ABP is more carcinogenic in the livers of female mice than of male mice. Here, we show that castration causes male mice to acquire female phenotype regarding susceptibility of bladder and liver to ABP. However, spaying has little impact on organ susceptibility to ABP. Liver UDP-glucuronosyltransferases (UGTs) are believed to protect liver against but sensitize bladder to ABP, as glucuronidation of ABP and its metabolites generally reduces their toxicity and promotes their elimination via urine, but the metabolites are labile in urine, delivering carcinogenic species to the bladder. Indeed, liver expression of ABP-metabolizing human UGT1A3 transgene in mice increases bladder susceptibility to ABP. However, ABP-specific liver UGT activity is significantly higher in wild-type female mice than in their male counterparts, and castration also significantly increases ABP-specific UGT activity in the liver. Taken together, our data suggest that androgen increases bladder susceptibility to ABP via liver, likely by modulating an ABP-metabolizing liver enzyme, but exclude UGT as an important mediator.

  6. Mechanism of action of novel piperazine containing a toxicant against human liver cancer cells

    PubMed Central

    Kanthimathi, MS; Haerian, Batoul Sadat

    2016-01-01

    The purpose of this study was to assess the cytotoxic potential of a novel piperazine derivative (PCC) against human liver cancer cells. SNU-475 and 423 human liver cancer cell lines were used to determine the IC50 of PCC using the standard MTT assay. PCC displayed a strong suppressive effect on liver cancer cells with an IC50 value of 6.98 ± 0.11 µM and 7.76 ± 0.45 µM against SNU-475 and SNU-423 respectively after 24 h of treatment. Significant dipping in the mitochondrial membrane potential and elevation in the released of cytochrome c from the mitochondria indicated the induction of the intrinsic apoptosis pathway by PCC. Activation of this pathway was further evidenced by significant activation of caspase 3/7 and 9. PCC was also shown to activate the extrinsic pathways of apoptosis via activation of caspase-8 which is linked to the suppression of NF-κB translocation to the nucleus. Cell cycle arrest in the G1 phase was confirmed by flow cytometry and up-regulation of glutathione reductase expression was quantified by qPCR. Results of this study suggest that PCC is a potent anti-cancer agent inducing both intrinsic and extrinsic pathways of apoptosis in liver cancer cell lines. PMID:27019772

  7. Tissue inhibitor of matrix metalloproteinase-1 expression in colorectal cancer liver metastases is associated with vascular structures.

    PubMed

    Illemann, Martin; Eefsen, Rikke Helene Løvendahl; Bird, Nigel Charles; Majeed, Ali; Osterlind, Kell; Laerum, Ole Didrik; Alpízar-Alpízar, Warner; Lund, Ida Katrine; Høyer-Hansen, Gunilla

    2016-02-01

    Metastatic growth by colorectal cancer cells in the liver requires the ability of the cancer cells to interact with the new microenvironment. This interaction results in three histological growth patterns of liver metastases: desmoplastic, pushing, and replacement. In primary colorectal cancer several proteases, involved in the degradation of extracellular matrix components, are up-regulated. In liver metastases, their expression is growth pattern dependent. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a strong prognostic marker in plasma from colorectal cancer patients, with significant higher levels in patients with metastatic disease. We therefore wanted to determine the expression pattern of TIMP-1 in primary colorectal cancers and their matching liver metastases. TIMP-1 mRNA was primarily seen in α-smooth-muscle actin (α-SMA)-positive cells. In all primary tumors and liver metastases with desmoplastic growth pattern, TIMP-1 mRNA was primarily found in α-SMA-positive myofibroblasts located at the invasive front. Some α-SMA-positive cells with TIMP-1 mRNA were located adjacent to CD34-positive endothelial cells, identifying them as pericytes. This indicates that TIMP-1 in primary tumors and liver metastases with desmoplastic growth pattern has dual functions; being an MMP-inhibitor at the cancer periphery and involved in tumor-induced angiogenesis in the pericytes. In the liver metastases with pushing or replacement growth patterns, TIMP-1 was primarily expressed by activated hepatic stellate cells at the metastasis/liver parenchyma interface. These cells were located adjacent to CD34-positive endothelial cells, suggesting a function in tumor-induced angiogenesis. We therefore conclude that TIMP-1 expression is growth pattern dependent in colorectal cancer liver metastases.

  8. Chronic liver injury induced by drugs: a systematic review.

    PubMed

    Stine, Jonathan G; Chalasani, Naga

    2015-11-01

    To examine the available literature and summarize what is known about chronic drug-induced liver injury. We reviewed PubMed/MEDLINE through March 2015. We developed a MEDLINE search strategy using PubMed medical subject heading terms chronic liver injury, hepatotoxicity, drug-induced liver injury, cirrhosis and chronic liver disease. We reviewed the reference list of included articles to identify articles missed in the database search. Chronic liver injury from drugs is more common than once thought with prevalence as high as 18% based on large national registries. Patients with cholestatic injury, age ≤65 years, and a long latency period (>365 days) are at increased risk. Of the most common drugs associated with drug-induced liver injury, antibiotics (amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin) are most likely to cause chronic injury. The presence of autoantibodies is common with chronic DILI, however, it is not diagnostic nor is it specific to autoimmune-like drug-induced liver injury. Immunosuppressive therapy may be necessary for individual cases of autoimmune-like drug-induced liver injury where cessation of the drug alone does not result in resolution of injury, however, the lowest dose should be used for the shortest duration with careful attention to the development of side effects. The effectiveness of treament of cholestatic liver injury with corticosteroids or ursodiol remains unclear. Cases of drug-induced fatty liver, nodular regenerative hyperplasia and peliosis hepatitis are less common subtypes of chronic drug-induced liver injury that deserve special consideration. A high degree of clinical suspicion is required for the diagnosis of chronic drug-induced liver injury and should be suspected in any patient with liver associated enzyme abnormalities that persist out past 6 months of initial presentation. Treatment with drug removal and/or immunosuppressive therapy appears to be effective for the majority of cases

  9. Multisciplinary management of patients with liver metastasis from colorectal cancer

    PubMed Central

    De Greef, Kathleen; Rolfo, Christian; Russo, Antonio; Chapelle, Thiery; Bronte, Giuseppe; Passiglia, Francesco; Coelho, Andreia; Papadimitriou, Konstantinos; Peeters, Marc

    2016-01-01

    Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Surgery, radiotherapy and chemotherapy have been till now the main therapeutic strategies for disease control and improvement of the overall survival. Twenty-five per cent (25%) of CRC patients have clinically detectable liver metastases at the initial diagnosis and approximately 50% develop liver metastases during their disease course. Twenty-thirty per cent (20%-30%) are CRC patients with metastases confined to the liver. Some years ago various studies showed a curative potential for liver metastases resection. For this reason some authors proposed the conversion of unresectable liver metastases to resectable to achieve cure. Since those results were published, a lot of regimens have been studied for resectability potential. Better results could be obtained by the combination of chemotherapy with targeted drugs, such as anti-VEGF and anti-EGFR monoclonal antibodies. However an accurate selection for patients to treat with these regimens and to operate for liver metastases is mandatory to reduce the risk of complications. A multidisciplinary team approach represents the best way for a proper patient management. The team needs to include surgeons, oncologists, diagnostic and interventional radiologists with expertise in hepatobiliary disease, molecular pathologists, and clinical nurse specialists. This review summarizes the most important findings on surgery and systemic treatment of CRC-related liver metastases. PMID:27621569

  10. Multisciplinary management of patients with liver metastasis from colorectal cancer.

    PubMed

    De Greef, Kathleen; Rolfo, Christian; Russo, Antonio; Chapelle, Thiery; Bronte, Giuseppe; Passiglia, Francesco; Coelho, Andreia; Papadimitriou, Konstantinos; Peeters, Marc

    2016-08-28

    Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Surgery, radiotherapy and chemotherapy have been till now the main therapeutic strategies for disease control and improvement of the overall survival. Twenty-five per cent (25%) of CRC patients have clinically detectable liver metastases at the initial diagnosis and approximately 50% develop liver metastases during their disease course. Twenty-thirty per cent (20%-30%) are CRC patients with metastases confined to the liver. Some years ago various studies showed a curative potential for liver metastases resection. For this reason some authors proposed the conversion of unresectable liver metastases to resectable to achieve cure. Since those results were published, a lot of regimens have been studied for resectability potential. Better results could be obtained by the combination of chemotherapy with targeted drugs, such as anti-VEGF and anti-EGFR monoclonal antibodies. However an accurate selection for patients to treat with these regimens and to operate for liver metastases is mandatory to reduce the risk of complications. A multidisciplinary team approach represents the best way for a proper patient management. The team needs to include surgeons, oncologists, diagnostic and interventional radiologists with expertise in hepatobiliary disease, molecular pathologists, and clinical nurse specialists. This review summarizes the most important findings on surgery and systemic treatment of CRC-related liver metastases.

  11. Dietary extra-virgin olive oil and corn oil differentially modulate the mRNA expression of xenobiotic-metabolizing enzymes in the liver and in the mammary gland in a rat chemically induced breast cancer model.

    PubMed

    Manzanares, Miguel Á; Solanas, Montserrat; Moral, Raquel; Escrich, Raquel; Vela, Elena; Costa, Irmgard; Escrich, Eduard

    2015-05-01

    High extra-virgin olive oil (EVOO) and corn oil diets differentially modulate experimental mammary carcinogenesis. We have investigated their influence on the initiation stage through the modulation of the expression of xenobiotic-metabolizing enzymes (XMEs) in the liver and the mammary gland. Female Sprague-Dawley rats were fed a low-fat (LF), high corn oil (HCO), or high EVOO (HOO) diet from weaning and gavaged with 7,12-dimethylbenz(a)anthracene (DMBA). The HCO diet increased the mRNA levels of the phase I enzymes CYP1A1, CYP1A2 and, to a lesser extent, CYP1B1, in the liver. The Aryl hydrocarbon receptor (AhR) seemed to be involved in this upregulated CYP1 expression. However, a slight trend toward an increase in the mRNA levels of the phase II enzymes GSTP1 and NQO1 was observed with the HOO diet. At least in the case of GSTP1, this effect was linked to an increased Nrf2 transactivation activity. This different regulation of the XMEs expression led, in the case of the HCO diet, to a balance between the production of active carcinogenic compounds and their inactivation tilted toward phase I, which would stimulate DMBA-induced cancer initiation, whereas the HOO diet was associated with a slower phase I metabolism accompanied by a faster phase II detoxification, thus reducing the output of the active compounds to the target tissues. In the mammary gland, the differential effects of diets may be conditioned by the state of cell differentiation, sexual maturity, and hormone metabolism.

  12. Obesity, autophagy and the pathogenesis of liver and pancreatic cancers.

    PubMed

    Aghajan, Mariam; Li, Ning; Karin, Michael

    2012-03-01

    Liver and pancreatic cancers are both highly lethal diseases with limited to no therapeutic options for patients. Recent studies suggest that deregulated autophagy plays a role in the pathogenesis of these diseases by perturbing cellular homeostasis and laying the foundation for disease development. While accumulation of p62 upon impaired autophagy has been implicated in hepatocellular carcinoma, its role in pancreatic ductal adenocarcinoma remains less clear. This review will focus on recent studies illustrating the role of autophagy in liver and pancreatic cancers. The relationships between autophagy, nuclear factor-κB signaling and obesity in hepatocellular carcinoma will be discussed, as well as the dual role of autophagy in pancreatic ductal adenocarcinoma.

  13. Comprehensive genome sequencing of the liver cancer genome.

    PubMed

    Nakagawa, Hidewaki; Shibata, Tatsuhiro

    2013-11-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Recently, comprehensive whole genome and exome sequencing analyses for HCC revealed new cancer-associated genes and a variety of genomic alterations. In particular, frequent genetic alterations of the chromatin remodeling genes were observed, suggesting a new potential therapeutic target for HCC. Sequencing analysis has further identified the molecular complexities of multicentric lesions and intratumoral heterogeneity. Detailed analyses of the somatic substitution pattern of the cancer genome and the HBV virus genome integration sites by using whole-genome sequencing will elucidate the molecular basis and diverse etiological factors involved in liver cancer development.

  14. Copper deficiency potentiates ethanol induced liver damage

    SciTech Connect

    Zidenberg-Cherr, S.; Han, B.; Graham, T.W.; Keen, C.L. )

    1992-02-26

    Copper sufficient (+Cu) and deficient ({minus}Cu) rats were fed liquid diets with EtOH or dextrose at 36% of kcals for 2 mo. Consumption of either the {minus}Cu diet or EtOH resulted in lower liver CuZn superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPx) activities were lowest in EtOH/{minus}Cu rats; being 20% and 50% of control values, respectively. Ethanol resulted in higher MnSOD activity in +Cu and {minus}Cu rats. Low Cu intake as well as EtOH resulted in lower mitochondrial (Mit) TBARS relative to controls. TBARS were lowest in Mit from EtOH/{minus}Cu rats. Microsomal (Micro) TBARS were lower in {minus}Cu and EtOH-fed rats than in controls. The peroxidizability index (PI) was calculated as an index of substrate availability for lipid peroxidation. Ethanol feeding resulted in lower PI's in Mit and Micro than measured in non-EtOH rats. There was a positive correlation between Micro PI's and TBARS. These results show that despite reductions in components of antioxidant defense, compensatory mechanism arise resulting in reduction in peroxidation targets and/or an increase in alternate free radical quenching factors. Histological examination demonstrated increased portal and intralobular connective tissue and cell necrosis in EtOH/{minus}Cu rats, suggesting that Cu may be a critical modulator of EtOH induced tissue damage.

  15. Chemoembolization Using Irinotecan in Treating Patients With Liver Metastases From Metastatic Colon or Rectal Cancer

    ClinicalTrials.gov

    2015-09-10

    Liver Metastases; Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Stage IV Colon Cancer; Stage IV Rectal Cancer

  16. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    SciTech Connect

    Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro; and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  17. MicroRNA Expression Profiling in CCl4-Induced Liver Fibrosis of Mus musculus

    PubMed Central

    Hyun, Jeongeun; Park, Jungwook; Wang, Sihyung; Kim, Jieun; Lee, Hyun-Hee; Seo, Young-Su; Jung, Youngmi

    2016-01-01

    Liver fibrosis is a major pathological feature of chronic liver diseases, including liver cancer. MicroRNAs (miRNAs), small noncoding RNAs, regulate gene expression posttranscriptionally and play important roles in various kinds of diseases; however, miRNA-associated hepatic fibrogenesis and its acting mechanisms are poorly investigated. Therefore, we performed an miRNA microarray in the fibrotic livers of Mus musculus treated with carbon-tetrachloride (CCl4) and analyzed the biological functions engaged by the target genes of differentially-expressed miRNAs through gene ontology (GO) and in-depth pathway enrichment analysis. Herein, we found that four miRNAs were upregulated and four miRNAs were downregulated more than two-fold in CCl4-treated livers compared to a control liver. Eight miRNAs were predicted to target a total of 4079 genes. GO analysis revealed that those target genes were located in various cellular compartments, including cytoplasm, nucleolus and cell surface, and they were involved in protein-protein or protein-DNA bindings, which influence the signal transductions and gene transcription. Furthermore, pathway enrichment analysis demonstrated that the 72 subspecialized signaling pathways were associated with CCl4-induced liver fibrosis and were mostly classified into metabolic function-related pathways. These results suggest that CCl4 induces liver fibrosis by disrupting the metabolic pathways. In conclusion, we presented several miRNAs and their biological processes that might be important in the progression of liver fibrosis; these findings help increase the understanding of liver fibrogenesis and provide novel ideas for further studies of the role of miRNAs in liver fibrosis. PMID:27322257

  18. Drug-induced liver injury: hepatotoxicity of quetiapine revisited.

    PubMed

    Shpaner, Alexander; Li, Wei; Ankoma-Sey, Victor; Botero, Rafael Claudino

    2008-11-01

    Drug hepatotoxicity is the most common cause of fulminant hepatic failure in the USA. We describe a rare case of a patient who developed an acute liver injury after initiation of therapy with quetiapine, but after conservative management and a trial of steroids, has fully recovered. This is the second reported case of quetiapine-induced liver injury in the published literature.

  19. Mechanisms of Diabetes-Induced Liver Damage

    PubMed Central

    Mohamed, Jamaludin; Nazratun Nafizah, A. H.; Zariyantey, A. H.; Budin, S. B.

    2016-01-01

    Diabetes mellitus is a non-communicable disease that occurs in both developed and developing countries. This metabolic disease affects all systems in the body, including the liver. Hyperglycaemia, mainly caused by insulin resistance, affects the metabolism of lipids, carbohydrates and proteins and can lead to non-alcoholic fatty liver disease, which can further progress to non-alcoholic steatohepatitis, cirrhosis and, finally, hepatocellular carcinomas. The underlying mechanism of diabetes that contributes to liver damage is the combination of increased oxidative stress and an aberrant inflammatory response; this activates the transcription of pro-apoptotic genes and damages hepatocytes. Significant involvement of pro-inflammatory cytokines—including interleukin (IL)-1β, IL-6 and tumour necrosis factor-α—exacerbates the accumulation of oxidative damage products in the liver, such as malondialdehyde, fluorescent pigments and conjugated dienes. This review summarises the biochemical, histological and macromolecular changes that contribute to oxidative liver damage among diabetic individuals. PMID:27226903

  20. Acetaminophen-induced acute liver injury in HCV transgenic mice

    SciTech Connect

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U.; Tech, Katherine; Macdonald, Jeffrey M.; Boorman, Gary A.; Chatterjee, Saurabh; Mason, Ronald P.; Melnyk, Stepan B.; Tryndyak, Volodymyr P.; Pogribny, Igor P.; Rusyn, Ivan

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  1. Protective effect of crocin on liver toxicity induced by morphine

    PubMed Central

    Salahshoor, Mohammad Reza; khashiadeh, Mojtaba; Roshankhah, Shiva; Kakabaraei, Seyran; Jalili, Cyrus

    2016-01-01

    Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters. PMID:27168751

  2. Role of microRNAs in inflammation-associated liver cancer

    PubMed Central

    Huan, Lin; Liang, Lin-Hui; He, Xiang-Huo

    2016-01-01

    Liver cancer, primarily hepatocellular carcinoma (HCC), is a major cause of cancer-related death worldwide. HCC is a suitable model of inflammation-induced cancer because more than 90% of HCC cases are caused by liver damage and chronic inflammation. Several inflammatory response pathways, such as NF-κB and JAK/STAT3 signaling pathways, play roles in the crosstalk between inflammation and HCC. MicroRNAs (miRNAs) are evolutionarily conserved, short endogenous, non-coding single-stranded RNAs that are involved in various biological and pathological processes by regulating gene expression and protein translation. Evidence showed that miRNAs play a pivotal role in hepatitis virus infection and serve as promoters or inhibitors of inflammatory response. Aberrant miRNA was observed during liver inflammation and HCC. Many dysregulated miRNAs modulate the initiation and progression of inflammation-induced HCC. This review summarizes the role and functions of miRNAs in inflammation-associated HCC, as well as the designed therapeutics targeting miRNAs to treat liver inflammation and HCC. PMID:28154773

  3. Hemostatic issues in pregnancy-induced liver disease.

    PubMed

    Lisman, Ton; Bernal, William

    2017-03-01

    Liver diseases may be accompanied by profound changes in the hemostatic system including thrombocytopenia, decreased plasma levels of pro- and anticoagulants, and alterations in plasma levels of fibrinolysis. The net effect of the hemostatic changes in chronic and acute liver diseases is a hemostatic system that is in relative balance due to the simultaneous decline in pro- and antihemostatic drivers. A unique category of liver diseases are those induced by pregnancy. In acute fatty liver of pregnancy, profound hemostatic changes occur, which may be caused by a combination of liver failure and disseminated intravascular coagulation. Hemostatic changes in preeclampsia and HELLP syndrome are dominated by thrombocytopenia, although alterations in plasmatic coagulation may also occur. Post-partum bleeds, bleeding from cesarean section wounds, and hepatobiliary bleeds may occur in both patient groups. Patients with intrahepatic cholestasis of pregnancy do not show clinically relevant hemostatic alterations, despite biochemical evidence of liver injury.

  4. Liver cancer diagnosis by fluorescence spectra of blood and urine

    NASA Astrophysics Data System (ADS)

    AlSalhi, Mohamad Saleh; Al Mehmadi, Abdulaziz Mayuof; Abdoo, Aiman; Masilamani, Vadivel

    2012-03-01

    Liver cancer or hepatocellular carcinoma (HCC) is a serious malady with only 10% survival rate. HCC incidence and mortality both are highest in China. This disease is detected and diagnosed by ultra sound, CT or MRI scans which are quite expensive. Also the discrimination between cirrhosis and HCC are poor by this imaging technique. The conventional tissue biopsy is quite invasive and painful. In this context, in the new diagnostic procedure presented in this paper, all the three liver malfunctions, particularly liver cancer, could be detected and discriminated by the spectral feature of blood and urine with accuracy about 80%. All that we need are 5 ml of blood and 5 ml of urine. Hence this inexpensive non invasive, optical technique will have significant impact in screening, diagnosis and also prognosis of HCC in large segment of people in the populous Asian countries.

  5. Liver cancer diagnosis by fluorescence spectra of blood and urine

    NASA Astrophysics Data System (ADS)

    AlSalhi, Mohamad Saleh; Al Mehmadi, Abdulaziz Mayuof; Abdoo, Aiman; Masilamani, Vadivel

    2011-11-01

    Liver cancer or hepatocellular carcinoma (HCC) is a serious malady with only 10% survival rate. HCC incidence and mortality both are highest in China. This disease is detected and diagnosed by ultra sound, CT or MRI scans which are quite expensive. Also the discrimination between cirrhosis and HCC are poor by this imaging technique. The conventional tissue biopsy is quite invasive and painful. In this context, in the new diagnostic procedure presented in this paper, all the three liver malfunctions, particularly liver cancer, could be detected and discriminated by the spectral feature of blood and urine with accuracy about 80%. All that we need are 5 ml of blood and 5 ml of urine. Hence this inexpensive non invasive, optical technique will have significant impact in screening, diagnosis and also prognosis of HCC in large segment of people in the populous Asian countries.

  6. Nuclear Receptor Activity and Liver Cancer Lesion Progression

    EPA Science Inventory

    Nuclear receptors (NRs) are ligand-activated transcription factors that control diverse cellular processes. Chronic stimulation of some NRs is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. We explored this question using human CAR, PXR, PPARα,...

  7. Streptococcus intermedius liver abscesses and colon cancer: a case report.

    PubMed

    Millichap, J J; McKendrick, A I; Drelichman, V S

    2005-10-01

    Certain species of bacteria are known to be associated with colorectal cancer. We report a case of adenocarcinoma of the colon with bacteraemia and liver abscesses due to Streptococcus intermedius. The isolation of this organism should prompt investigation for colorectal neoplasm, which may be present but asymptomatic, without metastases, and therefore at a curative stage.

  8. Survey of thorotrast-associated liver cancers in Japan

    SciTech Connect

    Yamada, S.; Hosoda, S.; Tateno, H.; Kido, C.; Takahashi, S.

    1983-01-01

    Data on 93 autopsy cases (group A) of thorotrast-associated liver cancers were obtained from the Annual of Pathological Autopsy Cases in Japan from 1958 to 1979, and data on 78 autopsy cases (group B) of thorotrast-associated liver cancers were obtained from the Japanese literature from 1953 to 1980. Cholangiocarcinoma (CLC) constituted 58% of group A and 55% of group B. The curve of the cumulative numbers of patients with CLC versus year in group A was almost linear, showing an increasing risk per surviving patients with advancing time. Angiosarcoma (AGS) occurred in 25% of group A and 24% of group B. The number of patients with AGS increased significantly after 1969 in both groups (P less than 0.05). In group B, age and years after thorotrast injection of patients with AGS were statistically higher than those of patients with CLC (age: P less than 0.05; years after thorotrast injection: P less than 0.0001). Hepatocellular carcinoma (HPC) accounted for 17 and 21% of groups A and B, respectively. When yearly distribution, age, and time after thorotrast injection of patients with HPC were correlated with those of patients with other liver cancers, the only statistically significant difference between patients with HPC and patients with CLC (P less than 0.02) was in the years after thorotrast administration. Since 1977 multiple primary liver cancers including AGS developed in thorotrast-administered patients in both groups.

  9. Clinical course of breast cancer patients with liver metastases.

    PubMed

    Zinser, J W; Hortobagyi, G N; Buzdar, A U; Smith, T L; Fraschini, G

    1987-05-01

    Between June 1973 and November 1980, 1,171 patients with metastatic breast cancer were treated with various doxorubicin-containing regimens at our institution (M.D. Anderson Hospital and Tumor Institute, Houston). Retrospective analysis of all 233 cases (20%) with liver metastases was done to correlate various clinical and biochemical characteristics with response to treatment, survival, and causes of death. A similar analysis was performed for 58 consecutive patients with liver metastases treated at this hospital between December 1955 and December 1957 with hormone therapy or single-agent chemotherapy. Objective responses were observed in 132 of 233 patients (57%) treated with combination chemotherapy. The median survival was 14 months in the 1970s and 5 months in the 1950s. Among patients who had liver metastases at the time of initial diagnosis of breast cancer, survival was longer for the group treated with combination chemotherapy. All cases were classified according to the number of organ sites involved by metastases. Patients with only liver metastases, or liver plus bone lesions had the longest survival. Other clinical and biochemical factors that correlated significantly with longer survival were: no prior chemotherapy, performance status of 1 to 2, absence of ascites, normal bilirubin and lactic dehydrogenase (LDH), SGOT less than or equal to 2 times normal and albumin greater than 4.5 g/dL. The main cause of death was multiorgan failure, with only 20% of patients dying of liver failure. The present study shows that the presence of liver metastases in breast cancer is not by itself an ominous factor. Most patients respond to therapy, and significant palliation with extended survival is possible for several prognostic subgroups. Further improvement in length and quality of survival is expected with earlier diagnosis.

  10. Cancer Stem Cells in Primary Liver Cancers: Pathological Concepts and Imaging Findings

    PubMed Central

    Joo, Ijin; Kim, Haeryoung

    2015-01-01

    There is accumulating evidence that cancer stem cells (CSCs) play an integral role in the initiation of hepatocarcinogenesis and the maintaining of tumor growth. Liver CSCs derived from hepatic stem/progenitor cells have the potential to differentiate into either hepatocytes or cholangiocytes. Primary liver cancers originating from CSCs constitute a heterogeneous histopathologic spectrum, including hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma with various radiologic manifestations. In this article, we reviewed the recent concepts of CSCs in the development of primary liver cancers, focusing on their pathological and radiological findings. Awareness of the pathological concepts and imaging findings of primary liver cancers with features of CSCs is critical for accurate diagnosis, prediction of outcome, and appropriate treatment options for patients. PMID:25598674

  11. Radiotherapeutic Parameters Predictive of Liver Complications Induced by Liver Tumor Radiotherapy

    SciTech Connect

    Lee, Ik Jae; Seong, Jinsil Shim, Su Jung; Han, Kwang Hyub

    2009-01-01

    Purpose: The purpose of this study was to identify radiotherapeutic parameters for predicting the occurrence of liver complications induced by radiotherapy of a liver tumor. Methods and Materials: From 2001 to 2003, a total of 131 patients with hepatocellular carcinoma received three-dimensional conformal radiotherapy. The total dose was determined by the fraction of nontumor liver receiving 50% of the isocenter dose (V{sub 50%}). We evaluated three sets of published radiation dose guidelines using nontumor liver volume or a combination of nontumor liver volume and hepatic functional reserve. The V{sub 50%} was divided into three intervals (<33%, 33-66%, and >66%) and four categories (<25%, 25-49%, 50-75%, and >75%) according to guidelines by University of Michigan and the Yonsei University, respectively. According to the guideline of Cheng et al., the radiation dose was determined by the indocyanin green retention rate at 15 min (ICG-R15) and the nontumor liver volume. Results: Of the 131 patients, 13 patients (9.9%) presented with liver complications. The incidence was 11.1%, 10.3%, and 18.2%, respectively, for a V{sub 50%} of less than 33%, 33% to 66%, and more than 66%. The observed hepatic toxicity incidence was 10%, 12.1%, and 10.4% respectively for a V{sub 50%} of less than 25%, 25% to 49%, and 50% to 75%, respectively. Nontumor liver volume and ICG-R15 were not predictors of liver complications. The incidence of liver complications was significantly increased in patients with Child-Pugh Class B (p = 0.044). Conclusions: The parameter, V{sub 50%}, can be divided into 4 categories and used to predict acceptable toxicity. Furthermore, indicators of liver functional status like the Child-Pugh class may be more important and useful parameters than ICG-R15 for predicting radiation-related liver disease.

  12. Shizukaol D, a Dimeric Sesquiterpene Isolated from Chloranthus serratus, Represses the Growth of Human Liver Cancer Cells by Modulating Wnt Signalling Pathway.

    PubMed

    Tang, Lisha; Zhu, Hengrui; Yang, Xianmei; Xie, Fang; Peng, Jingtao; Jiang, Deke; Xie, Jun; Qi, Meiyan; Yu, Long

    2016-01-01

    Natural products have become sources of developing new drugs for the treatment of cancer. To seek candidate compounds that inhibit the growth of liver cancer, components of Chloranthus serratus were tested. Here, we report that shizukaol D, a dimeric sesquiterpene from Chloranthus serratus, exerted a growth inhibition effect on liver cancer cells in a dose- and time-dependent manner. We demonstrated that shizukaol D induced cells to undergo apoptosis. More importantly, shizukaol D attenuated Wnt signalling and reduced the expression of endogenous Wnt target genes, which resulted in decreased expression of β-catenin. Collectively, this study demonstrated that shizukaol D inhibited the growth of liver cancer cells by modulating Wnt pathway.

  13. Phage display library selection of a hypoxia-binding scFv antibody for liver cancer metabolic marker discovery

    PubMed Central

    Chen, Hang; Gao, Zhihui; Li, Yao; Sun, Zhongyuan; Xiang, Rong; Zhang, Sihe

    2016-01-01

    Hypoxia, which is frequently observed in liver cancer and metastasis, influences tumor progression and resistance to therapy. Although hypoxia-associated biomarkers are of use in other cancers, none is recognized as a surrogate for hypoxia in liver cancer. In this study, we generated seven unique human single-chain Fv (scFv) antibodies (Abs) specific to hypoxic liver cancer cells, using normoxia-depleted vs hypoxia-selected phage library panning technology. By developing the scFv immunoprecipitation-based mass spectrometry method, the antigen that bound with one of the Abs (H103) was identified as the M2 splice isoform of pyruvate kinase (PKM2), an enzyme that is a key regulator of aerobic glycolysis in cancer cells. Increased expression of PKM2 was induced by hypoxia in liver cancer cell lines. Immunohistochemical (IHC) staining showed that PKM2 was highly expressed in moderately and well differentiated hepatocellular carcinoma (HCC) tissues with a hypovascular staining pattern. High expression of PKM2 was also localized in the perinecrotic area of intrahepatic cholangiocarcinoma (ICC) tissues. The percentage of the HCC or ICC tumor expressing PKM2 was significantly higher with more tumor necrosis, low microvessel density, and advanced stage. Moreover, the H103 scFv Ab was efficiently internalized into hypoxic liver cancer cells and could have potential for targeted drug delivery. Conclusion: our study, for the first time, developed hypoxia-specific scFv Ab H103 to liver cancer cells, and revealed that PKM2 is a promising biomarker for hypoxia in HCC and ICC tissues. These allow further exploration of this valuable Ab and PKM2 antigen for hypoxia targeting in liver cancer. PMID:27203546

  14. Hepatoprotective effect of Taraxacum officinale leaf extract on sodium dichromate-induced liver injury in rats.

    PubMed

    Hfaiedh, Mbarka; Brahmi, Dalel; Zourgui, Lazhar

    2016-03-01

    Taraxacum officinale (L.) Weber, commonly known as Dandelion, has been widely used as a folkloric medicine for the treatment of liver and kidney disorders and some women diseases such as breast and uterus cancers. The main objective of the present study was to assess the efficiency of T. officinale leaf extract (TOE) in treating sodium dichromate hazards; it is a major environmental pollutant known for its wide toxic manifestations witch induced liver injury. TOE at a dose of 500 mg/kg b.w was orally administered once per day for 30 days consecutively, followed by 10 mg/kg b.w sodium dichromate was injected (intraperitoneal) for 10 days. Our results using Wistar rats showed that sodium dichromate significantly increased serum biochemical parameters. In the liver, it was found to induce an oxidative stress, evidenced from increase in lipid peroxidation and changes in antioxidative activities. In addition, histopathological observation revealed that sodium dichromate causes acute liver damage, necrosis of hepatocytes, as well as DNA fragmentation. Interestingly, animals that were pretreated with TOE, prior to sodium dichromate administration, showed a significant hepatoprotection, revealed by a significant reduction of sodium dichromate-induced oxidative damage for all tested markers. These finding powerfully supports that TOE was effective in the protection against sodium dichromate-induced hepatotoxicity and genotoxicity and, therefore, suggest a potential therapeutic use of this plant as an alternative medicine for patients with acute liver diseases.

  15. Inflammatory stress potentiates emodin-induced liver injury in rats

    PubMed Central

    Tu, Can; Gao, Dan; Li, Xiao-Fei; Li, Chun-Yu; Li, Rui-Sheng; Zhao, Yan-Ling; Li, Na; Jia, Ge-Liu-Chang; Pang, Jing-Yao; Cui, He-Rong; Ma, Zhi-Jie; Xiao, Xiao-He; Wang, Jia-Bo

    2015-01-01

    Herbal medicines containing emodin, widely used for the treatment of hepatitis in clinic, have been reported with hepatotoxicity in individuals. A modest inflammatory stress potentiating liver injury has been linked to the idiosyncratic drug-induced liver injury (IDILI). In this study, we investigated the hypothesis that lipopolysaccharide (LPS) interacts with emodin could synergize to cause liver injury in rats. Emodin (ranging from 20, 40, to 80 mg/kg), which is in the range of liver protection, was administered to rats, before LPS (2.8 mg/kg) or saline vehicle treatment. The biochemical tests showed that non-toxic dosage of LPS coupled with emodin caused significant increases of plasma ALT and AST activities as compared to emodin alone treated groups (P < 0.05). In addition, with LPS or emodin alone could not induce any changes in ALT and AST activity, as compared with the control group (0.5% CMC-Na treatment). Meanwhile, the plasma proinflammatory cytokines, TNF-α, IL-1β, and IL-6 increased significantly in the emodin/LPS groups compared to either emodin groups or the LPS (P < 0.05). Histological analysis showed that liver damage was only found in emodin/LPS cotreatmented rat livers samples. These results indicate that non-toxic dosage of LPS potentiates the hepatotoxicity of emodin. This discovery raises the possibility that emodin and herbal medicines containing it may induce liver injury in the inflammatory stress even in their therapeutic dosages. PMID:26557087

  16. Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today?

    PubMed

    Teschke, Rolf; Frenzel, Christian

    For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.

  17. Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

    PubMed Central

    Lin, Christine

    2016-01-01

    Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans. PMID:27725933

  18. EASL HCC summit: liver cancer management.

    PubMed

    Sacco, Rodolfo; Gadaleta-Caldarola, Gennaro; Galati, Giovanni; Lombardi, Giuseppe; Mazza, GianCarlo; Cabibbo, Giuseppe

    2014-05-01

    EASL HCC Summit, Geneva, Switzerland, 13-16 February 2014. The European Association for the Study of the Liver (EASL) organized the 2014 EASL HCC Summit in Geneva, Switzerland. We discuss here the most interesting and provocative contents from the clinical program of the summit. The objective of this segment was to provide an in-depth review on the different management issues related to early detection, diagnosis and treatment of hepatocellular carcinoma, and, in addition, to highlight the ways of dealing with such an important and rapidly involving field.

  19. Schisandra chinensis Prevents Alcohol-Induced Fatty Liver Disease in Rats

    PubMed Central

    Park, Hyoung Joon; Lee, Soo-Jung; Song, Yuno; Jang, Sun-Hee; Ko, Yeoung-Gyu; Kang, Suk Nam; Chung, Byung Yeoup; Kim, Hong-Duck; Kim, Gon-Sup

    2014-01-01

    Abstract Schisandra chinensis (SC), a traditional herbal medicine, has been prescribed for patients suffering from various liver diseases, including hepatic cancer, hypercholesterolemia, and CCl4-induced liver injury. We investigated whether SC extract has a protective effect on alcohol-induced fatty liver and studied its underlying mechanisms. Rats were fed with ethanol by intragastric administration every day for 5 weeks to induce alcoholic fatty liver. Ethanol treatment resulted in a significant increase in alanine aminotransferase, aspartate aminotransferase, and hepatic triglyceride (TG) levels and caused fatty degeneration of liver. Ethanol administration also elevated serum TG and total cholesterol (TC) and decreased high-density lipoprotein (HDL) cholesterol levels. However, after administration of ethanol plus SC extracts, the ethanol-induced elevation in liver TC and TG levels was reversed. Elevation in serum TG was not observed after treatment with SC. Moreover, compared with the ethanol-fed group, the rats administered ethanol along with SC extracts for 5 weeks showed attenuated fatty degeneration and an altered lipid profile with decreased serum TC and TG, and increased HDL cholesterol levels. Chronic ethanol consumption did not affect peroxisome proliferator-activated receptor γ (PPARγ) levels, but it decreased PPARα and phospho-AMP-activated protein kinase (AMPK) levels in the liver. However, SC prevented the ethanol-induced decrease in PPARα expression and induced a significant decrease in sterol regulatory element-binding protein-1 expression and increase in phospho-AMPK expression in rats with alcoholic fatty liver. SC administration resulted in a significant decrease in intracellular lipid accumulation in hepatocytes along with a decrease in serum TG levels, and it reversed fatty liver to normal conditions, as measured by biochemical and histological analyses. Our results indicate that the protective effect of SC is accompanied by a

  20. Cyanide-induced injury to the isolated perfused rat liver.

    PubMed

    Younes, M; Strubelt, O

    1988-11-01

    In order to study the events that follow cyanide-induced inhibition of oxidative metabolism and produce cellular injury, isolated, haemoglobin-free perfused rat livers from fasted rats were exposed to KCN (100 mg/l). KCN reduced the oxygen consumption of the livers by about 80%. Hepatotoxicity was evident by a marked release of enzymes (LDH, SDH) and of glutathione (mainly GSSG) into the perfusate, by a depletion of hepatic glutathione and by an accumulation of calcium in the liver. Cyanide-induced hepatotoxicity could be prevented completely by feeding the rats before preparing the liver as well as by addition of fructose to the perfusate of fasted livers. Both treatments resulted in an increased energy supply from anaerobic glycolysis as evidenced by a large release of lactate + pyruvate into the perfusate. The toxic actions of cyanide were markedly attenuated by deferrioxamine as well as by allopurinol. These antitoxic actions occurred without changes in anaerobic glycolysis. Omission of calcium from the perfusate, however, did not influence cyanide toxicity. Thus, energy supply from anaerobic glycolysis seems to be sufficient for the basic functions of the liver to occur, when oxidative metabolism is inhibited by cyanide. The effects of deferrioxamine and allopurinol indicate the involvement of radical intermediates and/or Fe2+ in cyanide-induced cellular toxicity. An influx of calcium from the extracellular to the intracellular space is not involved in cyanide-induced hepatocellular injury.

  1. Updated options for liver-limited metastatic colorectal cancer.

    PubMed

    Alberts, Steven R

    2008-12-01

    Liver metastases from colorectal cancer (CRC) are common in patients presenting with an initial diagnosis of metastatic disease or at the time of recurrence. Without treatment, patients with metastatic disease have a poor prognosis. Surgical resection of the metastases might provide long-term benefit.; however, the size, number, or location of the metastases can limit the ability to perform a resection. The use of chemotherapy, both systemic and via hepatic artery infusion, in patients undergoing surgery for liver metastases from CRC has augmented the long-term survival benefits and even the cure obtained in some patients with surgery. Chemotherapy might also convert a portion of patients with initially unresectable liver metastases to resectable. A growing body of literature is helping to define the role of chemotherapy for potentially resectable liver metastases and for initially unresectable liver metastases. The introduction of newer agents such as oxaliplatin and irinotecan, and targeted agents such as cetuximab and bevacizumab, has led to meaningful improvements in response rates and survival over those previously achieved with 5-fluorouracil. Further trials are needed to refine the use of chemotherapy and targeted agents in the management of patients with liver metastases.

  2. Dehydroepiandrosterone (DHEA) Feeding Protects Liver Steatosis in Obese Breast Cancer Rat Model.

    PubMed

    Hakkak, Reza; Bell, Andrea; Korourian, Soheila

    2017-03-20

    Obesity is a major health problem in the US and globally. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, cancers, hyperlipidemia, and liver steatosis development. Dehydroepiandrosterone (DHEA) is a dietary supplement used as an anti-obesity supplement. Previously, we reported that DHEA feeding protects 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The objectives of this study were to investigate the effects of obesity and DHEA feeding on liver steatosis, body weight gain, and serum DHEA, DHEA sulfate (DHEA-S), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) levels. Female Zucker rats were randomly assigned to either a control diet or a control diet with DHEA supplementation for 155 days. Livers were collected for histological examination. Serum was collected to measure DHEA, DHEA-S, IGF-1, and IGFBP-3. Our results show that DHEA-fed rats had significantly less liver steatosis (p < 0.001) than control-fed rats and gained less weight (p < 0.001). DHEA feeding caused significant decreases (p < 0.001) in the serum levels of IGF-1 and IGFBP-3 and significantly increased (p < 0.001) serum levels of DHEA and DHEA-S. Our results suggest that DHEA feeding can protect against liver steatosis by reducing body weight gain and modulating serum IGF-1 and IGFBP-3 levels in an obese breast cancer rat model.

  3. Dapagliflozin-Induced Acute-on-Chronic Liver Injury

    PubMed Central

    Levine, Joshua A.; Ann Lo, Amy; Wallia, Amisha; Rogers, Melinda

    2016-01-01

    Sodium-glucose cotransporter 2 inhibitors are a new class of oral hypoglycemic agents, and thus safety data are limited. We present a 48-year-old woman with type 2 diabetes mellitus and Child’s Class A cirrhosis secondary to nonalcoholic steatohepatitis presenting with jaundice and acute cholestatic liver injury. Other than starting dapagliflozin, she reported no medication changes or supplement use. Before treatment, her total bilirubin was 1.2 mg/dL. On admission, her liver values were elevated and liver biopsy was consistent with drug-induced liver injury. This report raises awareness about the potential hepatotoxic effects of dapagliflozin, particularly in patients with chronic liver disease. PMID:28008402

  4. Cetuximab strongly enhances immune cell infiltration into liver metastatic sites in colorectal cancer.

    PubMed

    Inoue, Yuka; Hazama, Shoichi; Suzuki, Nobuaki; Tokumitsu, Yukio; Kanekiyo, Shinsuke; Tomochika, Shinobu; Tsunedomi, Ryouichi; Tokuhisa, Yoshihiro; Iida, Michihisa; Sakamoto, Kazuhiko; Takeda, Shigeru; Ueno, Tomio; Yoshino, Shigefumi; Nagano, Hiroaki

    2017-03-01

    Cetuximab has activity against colorectal cancers. Recent studies demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity via immune cells, and a new immune-related mechanism of inducing immunogenic cell death. This study aimed to evaluate the immune responses induced by cetuximab in tumor microenvironments at liver metastasis sites of metastatic colorectal cancer patients. We assessed immune cell infiltration in the liver metastatic sites of 53 colorectal cancer patients. These patients were divided into three groups according to the treatment before operation: chemotherapy with cetuximab, chemotherapy without cetuximab, and no chemotherapy. The inflammatory cells in the liver metastatic sites were assessed by hematoxylin-eosin staining, focusing on the invasive margin. The overall inflammatory reaction and number of lymphoid cells were assessed with a four-point scoring system. We then assessed immune cell infiltration (CD3, CD8 and CD56) in 15 liver metastatic sites. Hematoxylin-eosin staining demonstrated more inflammatory cells in the chemotherapy with cetuximab group than in the other groups (P < 0.001). Of note, inflammatory cells were found in intratumoral areas, and the destruction of cancer cell foci was observed in the chemotherapy with cetuximab group. Moreover, a higher infiltration of CD3+ (P = 0.003), CD8+ (P = 0.003) and CD56+ (P = 0.001) cells was observed in the chemotherapy with cetuximab group than in the other groups. These results suggest that cetuximab might have an immune-enhancing effect. As such, the immune-related mechanism of action of cetuximab may enhance the efficacy of combination therapy, such as chemotherapy and immunotherapy using therapeutic peptides.

  5. Dietary factors can protect against liver cancer development

    PubMed Central

    Koumbi, Lemonica

    2017-01-01

    Liver cancer is the third leading cause of cancer mortality worldwide with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Most HCC patients are also suffering from chronic liver disease (CLD). Evidence is emerging that the composition of diet plays an important role in HCC and CLD development and may also have a chemoprotective role. In contrast to other types of cancer, there are few studies investigating the role of diet in hepatocarcinogenesis. From the available data it is evident that high intakes of red meat and dietary sugar positively correlate with HCC occurrence. On the contrary, high consumption of white meat, fish, vegetables, fruits and cereals are inversely associated with HCC risk. This letter discusses the potential role of dietary interventions in the prevention of hepatocarcinogenesis. The increasing HCC incidence and its high fatality are making HCC prevention an urgent matter. Dietary modifications are found to offer protection against HCC, however, new studies from well-designed and large prospective trials are required to confirm these results. PMID:28217247

  6. Gene Expression Patterns in Human Liver Cancers

    PubMed Central

    Chen, Xin; Cheung, Siu Tim; So, Samuel; Fan, Sheung Tat; Barry, Christopher; Higgins, John; Lai, Kin-Man; Ji, Jiafu; Dudoit, Sandrine; Ng, Irene O.L.; van de Rijn, Matt; Botstein, David; Brown, Patrick O.

    2002-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression patterns intrinsic to each tumor were sufficiently distinctive that multiple tumor nodules from the same patient could usually be recognized and distinguished from all the others in the large sample set on the basis of their gene expression patterns alone. The distinctive gene expression patterns are characteristic of the tumors and not the patient; the expression programs seen in clonally independent tumor nodules in the same patient were no more similar than those in tumors from different patients. Moreover, clonally related tumor masses that showed distinct expression profiles were also distinguished by genotypic differences. Some features of the gene expression patterns were associated with specific phenotypic and genotypic characteristics of the tumors, including growth rate, vascular invasion, and p53 overexpression. PMID:12058060

  7. Inhibitory Effects of Verrucarin A on Tunicamycin-Induced ER Stress in FaO Rat Liver Cells.

    PubMed

    Bae, Eun Young; Lee, Seung Woong; Seong, Sin; Cho, Wonjun; Ahn, Jong Seog; Cho, Hyun-Sug

    2015-05-19

    Endoplasmic reticulum (ER) stress is linked with development and maintenance of cancer, and serves as a therapeutic target for treatment of cancer. Verrucarin A, isolated from the broth of Fusarium sp. F060190, showed potential inhibitory activity on tunicamycin-induced ER stress in FaO rat liver cells. In addition, the compound decreased tunicamycin-induced GRP78 promoter activity in a dose dependent manner without inducing significant inhibition of luciferase activity and cell growth for 6 and 12 h. Moreover, the compound decreased the expression of GRP78, CHOP, XBP-1, and suppressed XBP-1, and reduced phosphorylation of IRE1α in FaO rat liver cells. This evidence suggests for the first time that verrucarin A inhibited tunicamycin-induced ER stress in FaO rat liver cells.

  8. A case of levocetirizine-induced liver injury

    PubMed Central

    Jung, Moon Chan; Kim, Ja Kyung; Cho, Jae Yeon; Song, Jae Won; Lee, Bohyun; Park, Ji Won; Seo, Jinwon; Kim, Sung Eun

    2016-01-01

    Levocetirizine is a second-generation nonsedative antihistaminic agent that has been demonstrated to be safe and effective for treating allergic disease. There was only one case report of levocetirizine-induced liver toxicity, but a liver biopsy was not performed. In this article, we present the first case of levocetirizine-induced liver injury with histologic findings. A 48-year-old man was hospitalized with jaundice and generalized pruritus that had developed after 2 months of therapy with levocetirizine for prurigo nodularis. Laboratory findings revealed acute hepatitis with cholestasis. A liver biopsy demonstrated portal inflammation and hepatitis with apoptotic hepatocytes. The patient fully recovered 3 weeks after withdrawing levocetirizine. Although levocetirizine is safe and effective, physicians should be aware of its potential hepatotoxicity. PMID:28081586

  9. Radiographically occult intrasinusoidal liver metastases leading to hepatic failure in a case of breast cancer.

    PubMed

    Gulia, Seema; Khurana, Sachin; Shet, Tanuja; Gupta, Sudeep

    2016-02-15

    The liver is one of the commonest sites of metastatic involvement in breast cancer, usually evident as focal lesions on imaging tests. Rarely, the pattern of metastatic spread is so diffuse that it remains radiologically occult. Such patients usually present with signs of hepatic insufficiency without any focal lesions on liver imaging. In such cases, liver biopsy is required to make a definitive diagnosis. We report a case of a 56-year-old postmenopausal woman with metastatic breast cancer who presented with subacute progressive liver failure. Repeated imaging of the liver was normal or non-descript. Liver biopsy finally established the diagnosis of intrasinusoidal metastases from breast cancer.

  10. Overview: Where does radiation therapy fit in the spectrum of liver cancer local-regional therapies?

    PubMed

    Dawson, Laura A

    2011-10-01

    Experience with radiation therapy for the treatment of hepatocellular carcinoma (HCC) and liver metastases has increased rapidly in the past decade. This is principally because of advances in imaging and radiation techniques that can conform high doses to focal cancers and to a better understanding of how to avoid radiation-induced liver toxicity. Guidelines on how to use radiation therapy safely are becoming more clearly established, and reports of tumor control at 2 to 5 years show the potential for cure after radiation therapy for early-stage HCC and liver metastases. For both HCC and liver metastases, the best outcomes after radiation therapy are found in patients with fewer than 3 lesions that are <6 cm in size, with intact liver function and no extrahepatic metastases. There is a strong rationale for using radiation therapy in patients unsuitable for or with expected poor outcomes after standard local-regional therapies. These patients tend to have advanced tumors (large, multifocal, or invading vessels) and/or impaired liver function, reducing the chance of cure and increasing the chance of toxicity. In these patients, the benefits of radiation therapy over systemic therapy or best supportive therapy should be established in randomized trials.

  11. Diphenhydramine as a Cause of Drug-Induced Liver Injury

    PubMed Central

    Cui, Isabelle H.

    2017-01-01

    Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E), autoimmune, toxic, ischemic, and metabolic etiologies including Wilson's disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen. PMID:28246565

  12. Rectal cancer with synchronous liver metastases: Do we have a clear direction?

    PubMed

    Pathak, S; Nunes, Q M; Daniels, I R; Smart, N J; Poston, G J; Påhlman, L

    2015-12-01

    Rectal cancer is a common entity and often presents with synchronous liver metastases. There are discrepancies in management guidelines throughout the world regarding the treatment of advanced rectal cancer, which are further compounded when it presents with synchronous liver metastases. The following article examines the evidence regarding treatment options for patients with synchronous rectal liver metastases and suggests potential treatment algorithms.

  13. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis.

    PubMed

    Gao, Wei; Tang, Zhewei; Zhang, Yi-Fan; Feng, Mingqian; Qian, Min; Dimitrov, Dimiter S; Ho, Mitchell

    2015-03-11

    Glypican-3 is a cell surface glycoprotein that associates with Wnt in liver cancer. We develop two antibodies targeting glypican-3, HN3 and YP7. The first antibody recognizes a functional epitope and inhibits Wnt signalling, whereas the second antibody recognizes a C-terminal epitope but does not inhibit Wnt signalling. Both are fused to a fragment of Pseudomonas exotoxin A (PE38) to create immunotoxins. Interestingly, the immunotoxin based on HN3 (HN3-PE38) has superior antitumor activity as compared with YP7 (YP7-PE38) both in vitro and in vivo. Intravenous administration of HN3-PE38 alone, or in combination with chemotherapy, induces regression of Hep3B and HepG2 liver tumour xenografts in mice. This study establishes glypican-3 as a promising candidate for immunotoxin-based liver cancer therapy. Our results demonstrate immunotoxin-induced tumour regression via dual mechanisms: inactivation of cancer signalling via the antibody and inhibition of protein synthesis via the toxin.

  14. Induction of an altered lipid phenotype by two cancer promoting treatments in rat liver.

    PubMed

    Riedel, S; Abel, S; Swanevelder, S; Gelderblom, W C A

    2015-04-01

    Changes in lipid metabolism have been associated with tumor promotion in rat liver. Similarities and differences of lipid parameters were investigated using the mycotoxin fumonisin B1 (FB1) and the 2-acetylaminofluorene/partial hepatectomy (AAF/PH) treatments as cancer promoters in rat liver. A typical lipid phenotype was observed, including increased membranal phosphatidylethanolamine (PE) and cholesterol content, increased levels of C16:0 and monounsaturated fatty acids in PE and phosphatidylcholine (PC), as well as a decrease in C18:0 and long-chained polyunsaturated fatty acids in the PC fraction. The observed lipid changes, which likely resulted in changes in membrane structure and fluidity, may represent a growth stimulus exerted by the cancer promoters that could provide initiated cells with a selective growth advantage. This study provided insight into complex lipid profiles induced by two different cancer promoting treatments and their potential role in the development of hepatocyte nodules, which can be used to identify targets for the development of chemopreventive strategies against cancer promotion in the liver.

  15. Laparoscopic combined colorectal and liver resections for primary colorectal cancer with synchronous liver metastases

    PubMed Central

    Takorov, Ivelin; Lukanova, Tsonka; Atanasov, Boiko; Dzharov, Georgi; Djurkov, Ventzeslav; Odisseeva, Evelina; Vladov, Nikola

    2016-01-01

    Backgrounds/Aims Synchronous liver metastases (SLMs) are found in 15-25% of patients at the time of diagnosis with colorectal cancer, which is limited to the liver in 30% of patients. Surgical resection is the most effective and potentially curative therapy for metastatic colorectal carcinoma (CRC) of the liver. The comparison of simultaneous resection of primary CRC and synchronous liver metastases with staged resections is the subject of debate with respect to morbidity. Laparoscopic surgery improves postoperative recovery, diminishes postoperative pain, reduces wound infections, shortens hospitalization, and yields superior cosmetic results, without compromising the oncological outcome. The aim of this study is therefore to evaluate our initial experience with simultaneous laparoscopic resection of primary CRC and SLM. Methods Currently, laparoscopic resection of primary CRC is performed in more than 53% of all patients in our surgical department. Twenty-six patients with primary CRC and a clinical diagnosis of SLM underwent combined laparoscopic colorectal and liver surgery. Six of them underwent laparoscopic colorectal resection combined with major laparoscopic liver resection. Results The surgical approaches were total laparoscopic (25 patients) or hybrid technique (1 patients). The incision created for the extraction of the specimen varied between 5 and 8cm. The median operation time was 223 minutes (100 to 415 min.) with a total blood loss of 180 ml (100-300 ml). Postoperative hospital stay was 6.8 days (6-14 days). Postoperative complications were observed in 6 patients (22.2%). Conclusions Simultaneous laparoscopic colorectal and liver resection appears to be safe, feasible, and with satisfying short-term results in selected patients with CRC and SLM. PMID:28261695

  16. Non-viral causes of liver cancer: does obesity led inflammation play a role?

    PubMed

    Alzahrani, Badr; Iseli, Tristan J; Hebbard, Lionel W

    2014-04-10

    Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for around 90% of primary liver cancers. Chronic infection with hepatitis B and hepatitis C viruses are two of most common causes of liver cancer. However, there are non-viral factors that are associated with liver cancer development. Numerous population studies have revealed strong links between obesity and the development of liver cancer. Obesity can alter hepatic pathology, metabolism and promote inflammation, leading to nonalcoholic fatty liver disease (NAFLD) and the progression to the more severe form, non-alcoholic steatohepatitis (NASH). NASH is characterised by prominent steatosis and inflammation, and can lead to HCC. Here, we discuss the role of obesity in inflammation and the principal signalling mechanisms involved in HCC formation.

  17. Liver myofibroblasts up-regulate monocyte CD163 expression via PGE2 during hepatitis B induced liver failure

    PubMed Central

    2014-01-01

    Background Although patients with liver failure exhibit a generalized inflammatory-imbalance status, substantial evidence indicates that this immunosuppressive or anti-inflammatory state may be deleterious. Increased expression of CD163 (known to be involved in several anti-inflammatory functions of the immune system) in patients with liver failure is significantly correlated with a fatal outcome. However, little is known of the regulatory mechanisms that influence the expression of CD163. Methods We assessed the expression of CD163 on monocytes from both circulating cells and the liver tissues of patients with hepatitis B induced liver failure using flow cytometry and isolated the myofibroblasts from diseased livers. The ability of human liver myofibroblasts to regulate CD163 expression on monocytes was studied in vitro. Results We showed that CD163+ monocytes were enriched primarily in diseased livers and that they were associated with liver myofibroblasts in the same area. Accordingly, liver myofibroblasts were significantly superior to normal skin fibroblasts in inducing the expression of CD163 on monocytes in vitro. Moreover, we found that liver myofibroblasts triggered the activation of monocytes by secreting PGE2. Inhibition of PGE2 production in liver myofibroblasts using NS-398 markedly reduced CD163 expression in vitro. Conclusion These results suggest that liver myofibroblasts play a direct role in regulating the expression of CD163 on monocytes in human liver tissues and thereby may regulate monocyte function during hepatitis B induced liver failure. PMID:24597777

  18. Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

    PubMed Central

    Fleming, Bryan D.; Ho, Mitchell

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies. PMID:27669301

  19. Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis

    PubMed Central

    Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

    2016-01-01

    AIM To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. METHODS Liver stiffness was measured in sixty-eight rabbits with CCl4-induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. RESULTS LSM by ElastPQ was significantly correlated with histologic fibrosis stage (r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. CONCLUSION ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl4-induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy. PMID:28028365

  20. Methylglyoxal Induces Mitochondrial Dysfunction and Cell Death in Liver

    PubMed Central

    Seo, Kyuhwa; Ki, Sung Hwan

    2014-01-01

    Degradation of glucose is aberrantly increased in hyperglycemia, which causes various harmful effects on the liver. Methylglyoxal is produced during glucose degradation and the levels of methylglyoxal are increased in diabetes patients. In this study we investigated whether methylglyoxal induces mitochondrial impairment and apoptosis in HepG2 cells and induces liver toxicity in vivo. Methylglyoxal caused apoptotic cell death in HepG2 cells. Moreover, methylglyoxal significantly promoted the production of reactive oxygen species (ROS) and depleted glutathione (GSH) content. Pretreatment with antioxidants caused a marked decrease in methylglyoxal-induced apoptosis, indicating that oxidant species are involved in the apoptotic process. Methylglyoxal treatment induced mitochondrial permeability transition, which represents mitochondrial impairment. However, pretreatment with cyclosporin A, an inhibitor of the formation of the permeability transition pore, partially inhibited methylglyoxal-induced cell death. Furthermore, acute treatment of mice with methylglyoxal increased the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating liver toxicity. Collectively, our results showed that methylglyoxal increases cell death and induces liver toxicity, which results from ROS-mediated mitochondrial dysfunction and oxidative stress. PMID:25343013

  1. Somatic microsatellite variability as a predictive marker for colorectal cancer and liver cancer progression

    PubMed Central

    Vaksman, Zalman; Garner, Harold R.

    2015-01-01

    Microsatellites (MSTs) are short tandem repeated genetic motifs that comprise ~3% of the genome. MST instability (MSI), defined as acquired/lost primary alleles at a small subset of microsatellite loci (e.g. Bethesda markers), is a clinically relevant marker for colorectal cancer. However, these markers are not applicable to other types of cancers, specifically, for liver cancer which has a high mortality rate. Here we show that somatic MST variability (SMV), defined as the presence of additional, non-primary (aka minor) alleles at MST loci, is a complementary measure of MSI, and a genetic marker for colorectal and liver cancer. Re-analysis of Illumina sequenced exomes from The Cancer Genome Atlas indicates that SMV may distinguish a subpopulation of African American patients with colorectal cancer, which represents ~33% of the population in this study. Further, for liver cancer, a higher rate of SMV may be indicative of an earlier age of onset. The work presented here suggests that classical MSI should be expanded to include SMV, going beyond alterations of the primary alleles at a small number of microsatellite loci. This measure of SMV may represent a potential new diagnostic for a variety of cancers and may provide new information for colorectal cancer patients. PMID:25691061

  2. Liver injury from Herbals and Dietary Supplements in the US Drug Induced Liver Injury Network

    PubMed Central

    Navarro, Victor J.; Barnhart, Huiman; Bonkovsky, Herbert L.; Davern, Timothy; Fontana, Robert J.; Grant, Lafaine; Reddy, K. Rajender; Seeff, Leonard B.; Serrano, Jose; Sherker, Averell H.; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-01-01

    Background The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity due to conventional medications as well as herbals and dietary supplements (HDS). Rationale To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight US referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury due to HDS. Hepatotoxicity due to HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments including death and liver transplantation were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury due to bodybuilding HDS, 85 due to non-bodybuilding HDS, and 709 due to medications. Main Results Liver injury due to HDS increased from 7% to 20% (p < 0.001) during the study period. Bodybuilding HDS caused prolonged jaundice (median 91 days) in young men but did not result in any fatalities or liver transplantation. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women and more frequently led to death or transplantation compared to injury from medications (13% vs. 3%, p < 0.05). Conclusions The proportion of liver injury cases attributed to HDS in DILIN has increased significantly. Liver injury from non-bodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes; death and transplantation. PMID:25043597

  3. Know HBV: What Every Asian and Pacific Islander Should Know About Hepatitis B and Liver Cancer

    MedlinePlus

    ... chronic hepatitis B. For more information visit http://liver.stanford.edu » Get Vaccinated If both your HBsAg ... vaccine is so effective at preventing HBV and liver cancer that it is called “the first anti- ...

  4. LiverCancerMarkerRIF: a liver cancer biomarker interactive curation system combining text mining and expert annotations

    PubMed Central

    Dai, Hong-Jie; Wu, Johnny Chi-Yang; Lin, Wei-San; Reyes, Aaron James F.; dela Rosa, Mira Anne C.; Syed-Abdul, Shabbir; Tsai, Richard Tzong-Han; Hsu, Wen-Lian

    2014-01-01

    Biomarkers are biomolecules in the human body that can indicate disease states and abnormal biological processes. Biomarkers are often used during clinical trials to identify patients with cancers. Although biomedical research related to biomarkers has increased over the years and substantial effort has been expended to obtain results in these studies, the specific results obtained often contain ambiguities, and the results might contradict each other. Therefore, the information gathered from these studies must be appropriately integrated and organized to facilitate experimentation on biomarkers. In this study, we used liver cancer as the target and developed a text-mining–based curation system named LiverCancerMarkerRIF, which allows users to retrieve biomarker-related narrations and curators to curate supporting evidence on liver cancer biomarkers directly while browsing PubMed. In contrast to most of the other curation tools that require curators to navigate away from PubMed and accommodate distinct user interfaces or Web sites to complete the curation process, our system provides a user-friendly method for accessing text-mining–aided information and a concise interface to assist curators while they remain at the PubMed Web site. Biomedical text-mining techniques are applied to automatically recognize biomedical concepts such as genes, microRNA, diseases and investigative technologies, which can be used to evaluate the potential of a certain gene as a biomarker. Through the participation in the BioCreative IV user-interactive task, we examined the feasibility of using this novel type of augmented browsing-based curation method, and collaborated with curators to curate biomarker evidential sentences related to liver cancer. The positive feedback received from curators indicates that the proposed method can be effectively used for curation. A publicly available online database containing all the aforementioned information has been constructed at http

  5. Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis

    PubMed Central

    Stiedl, Patricia; McMahon, Robert; Blaas, Leander; Stanek, Victoria; Svinka, Jasmin; Grabner, Beatrice; Zollner, Gernot; Kessler, Sonja M.; Claudel, Thierry; Müller, Mathias; Mikulits, Wolfgang; Bilban, Martin; Esterbauer, Harald; Eferl, Robert; Haybaeck, Johannes; Trauner, Michael; Casanova, Emilio

    2016-01-01

    Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the Growth hormone receptor gene (Ghr-/-, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2-/-), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr-/-;Mdr2-/- mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation and increased collagen deposition relative to Mdr2 -/- mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr-/-;Mdr2-/- mice had a pronounced down-regulation of hepato-protective genes Hnf6, Egfr and Igf-1, and significantly increased levels of ROS and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr-/-) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis and bile infarcts compared to their wildtype littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr-/-;Mdr2-/- mice displayed a significant decrease in tumour incidence compared to Mdr2-/- mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver. Conclusion Our findings suggest that GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments. PMID:25179284

  6. The effects of melatonin on liver functions in arsenic-induced liver damage

    PubMed Central

    Bali, İlhan; Bilir, Bülent; Emir, Seyfi; Turan, Filiz; Yılmaz, Ahsen; Gökkuş, Tuba; Aydın, Murat

    2016-01-01

    Objective Arsenic exposure is increasing in communities due to environmental pollution and industrial development. Arsenic is toxic to organ systems because it causes oxidative stress, enzymatic inhibition, and damage to protein structures. The liver, for example, is an organ that may be damaged by arsenic, and this damage may cause various clinical conditions like hepatic failure or cancer. Melatonin is a hormone that acts like an antioxidant, an anti-inflammatory agent, and a cytoprotective agent. In this study, we aimed to evaluate melatonin’s protective effects on livers damaged by arsenic toxicity. Materials and Methods Twenty-four Sprague-Dawley male rats were classified into three groups: a control group, an arsenic applied group, and an arsenic plus 10 mg/kg melatonin applied group. At the end of the fifteen-day experiment, the rats were sacrificed. Albumin, interleukin-6 (IL-6), total protein, alanine transaminase, aspartate transaminase, macrophage migration inhibitory factor, and monocyte chemotactic protein-1 measurements were obtained. Results In rats with liver damage due to arsenic exposure, melatonin administration significantly decreased the levels of IL-6, macrophage migration inhibitory factor, and monocyte chemotactic protein-1 (p<0.001, p=0.02 and p=0.04, respectively). Conclusion After evaluating liver enzymes and inflammatory markers, this study determined that melatonin exposure improves liver tissue damage caused by arsenic exposure, with the degree of improvement varying based on the levels of arsenic exposure. PMID:28149117

  7. The Geographic Distribution of Liver Cancer in Canada Does Not Associate with Cyanobacterial Toxin Exposure

    PubMed Central

    Labine, Meaghan A.; Green, Chris; Mak, Giselle; Xue, Lin; Nowatzki, Janet; Griffith, Jane; Minuk, Gerald Y.

    2015-01-01

    Background: The incidence of liver cancer has been increasing in Canada over the past decade, as has cyanobacterial contamination of Canadian freshwater lakes and drinking water sources. Cyanotoxins released by cyanobacteria have been implicated in the pathogenesis of liver cancer. Objective: To determine whether a geographic association exists between liver cancer and surrogate markers of cyanobacterial contamination of freshwater lakes in Canada. Methods: A negative binomial regression model was employed based on previously identified risk factors for liver cancer. Results: No association existed between the geographic distribution of liver cancer and surrogate markers of cyanobacterial contamination. As predicted, significant associations existed in areas with a high prevalence of hepatitis B virus infection, large immigrant populations and urban residences. Discussion and Conclusions: The results of this study suggest that cyanobacterial contamination of freshwater lakes does not play an important role in the increasing incidence of liver cancer in Canada. PMID:26633441

  8. Traditional Chinese Medicine Induced Liver Injury

    PubMed Central

    2014-01-01

    Traditional Chinese Medicine (TCM) is popular around the world and encompasses many different practices with particular emphasis on herbal TCM. Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. Among these were An Shu Ling, Bai Fang, Bai Xian Pi, Ban Tu Wan, Bo He, Bo Ye Qing Niu Dan, Bofu Tsu Sho San, Boh Gol Zhee, Cang Er Zi, Chai Hu, Chaso, Chi R Yun, Chuan Lian Zi, Ci Wu Jia, Da Chai Hu Tang, Da Huang, Du Huo, Gan Cao, Ge Gen, Ho Shou Wu, Hu Bohe You, Hu Zhang, Huang Qin, Huang Yao Zi, Hwang Geun Cho, Ji Gu Cao, Ji Ji, Ji Xue Cao, Jiguja, Jin Bu Huan, Jue Ming Zi, Kamishoyosan, Kudzu, Lei Gong Teng, Long Dan Xie Gan Tang, Lu Cha, Ma Huang, Mao Guo Tian Jie Cai, Onshido, Polygonum multiflorum, Qian Li Guang, Ren Shen, Sairei To, Shan Chi, Shen Min, Shi Can, Shi Liu Pi, Shou Wu Pian, Tian Hua Fen, White flood, Wu Bei Zi, Xi Shu, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, Zhen Chu Cao, and various unclassified Chinese herbal mixtures. Causality was firmly established for a number of herbal TCM products by a positive reexposure test result, the liver specific scale of CIOMS (Council for International Organizations of Medical Sciences), or both. Otherwise, the quality of case data was mixed, especially regarding analysis of the herb ingredients because of adulteration with synthetic drugs, contamination with heavy metals, and misidentification. In addition, non-herbal TCM elements derived from Agaricus blazei, Agkistrodon, Antelope, Bombyx, Carp, Fish gallbladder, Phellinus, Scolopendra, Scorpio, and Zaocys are also known or potential hepatotoxins. For some patients, the clinical course was severe, with risks for acute liver failure, liver transplantation requirement, and lethality. In conclusion, the use of few herbal TCM products may rarely be associated with hepatotoxicity in some

  9. Dual-contrast MR imaging of liver cancer in rats.

    PubMed

    Weissleder, R; Saini, S; Stark, D D; Wittenberg, J; Ferrucci, J T

    1988-03-01

    MR contrast agents increase hepatic tumor conspicuity, as measured in terms of contrast-to-noise (C/N) ratios. With an animal model of hepatic metastases from breast cancer, IV administration of Gd-DTPA (0.2 mmol/kg) shows a biphasic time response, transiently increasing the signal intensity of liver relative to tumor, with C/N ratio magnitudes increasing from -5.7 to -16.3 (SE 250/20); after a delay, the signal intensity of tumor increases relative to liver with a reversal of the C/N sign from negative to positive and an increase in the C/N magnitude to +25.0. IV administration of ferrite particles (0.05 mmol Fe/kg) shows a monophasic time response, increasing signal intensity of tumor relative to liver from +1.5 to +49.5 (SE 500/30). When both contrast agents were administered together (dual-contrast technique), the tumor-liver C/N magnitude reached a maximum of +67.8 (SE 500/30) 12 min after drug infusion. Analysis of individual contrast and noise factors contributing to this technique revealed a strong correlation between the signal intensity of liver and the signal intensity of ghost artifacts, which increase after administration of Gd-DTPA (r = .89) and decrease after administration of ferrite (r = 1.0). Dual-contrast imaging shows a synergistic addition of contrast and suppression of noise from ghost artifacts, maximizing the C/N and increasing the conspicuity of focal liver lesions.

  10. Blockade of Notch signaling promotes acetaminophen-induced liver injury.

    PubMed

    Jiang, Longfeng; Ke, Michael; Yue, Shi; Xiao, Wen; Yan, Youde; Deng, Xiaozhao; Ying, Qi-Long; Li, Jun; Ke, Bibo

    2017-03-13

    Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS. Some animals were injected with γ-secretase inhibitor DAPT or DMSO vehicle. For the in vitro study, bone marrow-derived macrophages (BMMs) were transfected with Notch1 siRNA, TLR4 siRNA, and non-specific (NS) siRNA and stimulated with LPS. Indeed, paracetamol/acetaminophen-induced liver damage was worse after Notch blockade with DAPT in wild-type mice, which was accompanied by significantly increased ALT levels, diminished hairy and enhancer of split-1 (Hes1), and phosphorylated Stat3 and Akt but enhanced high mobility group box 1 (HMGB1), TLR4, NF-κB, and NLRP3 activation after APAP challenge. Mice receiving DAPT increased macrophage and neutrophil accumulation and hepatocellular apoptosis. However, TLR4 KO mice that received DAPT reduced APAP-induced liver damage and NF-κB, NLRP3, and cleaved caspase-1 activation. BMMs transfected with Notch1 siRNA reduced Hes1 and phosphorylated Stat3 and Akt but augmented HMGB1, TLR4, NF-κB, and NLRP3. Furthermore, TLR4 siRNA knockdown resulted in decreased NF-κB and NLRP3 and cleaved caspase-1 and IL-1β levels following LPS stimulation. These results demonstrate that Notch signaling regulates innate NLRP3 inflammasome activation through regulation of HMGB1/TLR4/NF-κB activation in APAP-induced liver injury. Our novel findings underscore the critical role of the Notch1-Hes1 signaling cascade in the regulation of innate immunity in APAP-triggered liver inflammation. This might imply a novel therapeutic

  11. CRISPR-mediated direct mutation of cancer genes in the mouse liver.

    PubMed

    Xue, Wen; Chen, Sidi; Yin, Hao; Tammela, Tuomas; Papagiannakopoulos, Thales; Joshi, Nikhil S; Cai, Wenxin; Yang, Gillian; Bronson, Roderick; Crowley, Denise G; Zhang, Feng; Anderson, Daniel G; Sharp, Phillip A; Jacks, Tyler

    2014-10-16

    The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the β-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of β-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics.

  12. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    PubMed

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  13. Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats.

    PubMed

    Elshazly, Shimaa M; Mahmoud, Amr A A

    2014-06-01

    Hepatic fibrosis is a significant health problem that may progress to cirrhosis and cancer. It may be caused by viruses or chemicals such as dimethylnitrosamine, which is used as a preservative in processed meats and industrial products. The present study was designed to investigate the antifibrotic effect of hesperidin (100 or 200 mg/kg, a flavanone glycoside with potent anti-inflammatory and antioxidant activities) against liver fibrosis in rats compared to silymarin (100 mg/kg). Liver fibrosis was induced in rats using dimethylnitrosamine (10 mg/kg/day, i.p.) three times per week on alternating days for 4 weeks. After 28 days, tissue and blood samples were collected to assess the protective effect of hesperidin. Dimethylnitrosamine caused liver fibrosis as evidenced by the elevation in the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin, as well as hepatic malondialdehyde content, gene expression of inducible nitric oxide synthase, α-smooth muscle actin and caspase-3. In addition, dimethylnitrosamine caused a reduction in serum total protein, albumin and hepatic glutathione content. Treatment with hesperidin (100 or 200 mg/kg) successfully ameliorated the deleterious effects of dimethylnitrosamine on all tested parameters. Our study indicates a novel protective effect of hesperidin against dimethylnitrosamine-induced liver fibrosis. Interestingly, the protection evoked by hesperidin (200 mg/kg) was superior to that of the standard silymarin.

  14. Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer

    ClinicalTrials.gov

    2017-03-08

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Advanced Adult Hepatocellular Carcinoma; BCLC Stage B Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma

  15. Chlorpromazine-induced cholestatic liver disease with ductopenia.

    PubMed

    Chlumská, A; Curík, R; Boudová, L; Mukensnabl, P; Klvana, P

    2001-07-01

    We describe a 30-year-old pregnant woman in whom cholestatic liver disease developed 16 resp. 18 days after the medication of chlorprothixeni hydrochloridum and chlorpromazine treatment in the 33rd week of pregnancy. Clinically, the course was characterized by severe jaundice lasting 10 months, fever, pruritus, high serum alkaline phosphatase level, transient aminotransferase elevation, and hypercholesterolemia. The pregnancy was terminated in the 35th week by cesarean section with the birth of a premature female newborn without any signs of liver damage. The histological examination of the mother's liver revealed ductopenia, defined by the absence of interlobular bile ducts in at least 50% of the small portal tracts, and long-standing cholestasis with pseudoxanthomatous transformation of hepatocytes and ductular epithelia, and small lobular xanthomas. The jaundice resolved very slowly after ursodeoxycholic acid therapy. The liver function tests 26 months after the onset of jaundice showed only a slight elevation of alkaline phosphatase and aminotransferases. In the control liver biopsy, non-active periportal and septal fibrosis without signs of cholestasis was seen. To our knowledge this is the sixth report to document chlorpromazine-induced ductopenia in pregnancy and the first to describe a newborn without any liver damage.

  16. Treatment advances in liver-limited metastatic colorectal cancer.

    PubMed

    Alberts, Steven R; Poston, Graeme J

    2011-12-01

    Over the last several decades advances in the management and treatment of patients with liver metastases from colorectal cancer (CRC) has changed a disease with a dismal prognosis to one with a potential for cure in some patients. Advances have been made through coordinated management of patients by surgeons, medical oncologists, radiologists, and other health care professionals coupled with advances in treatment options. Although these advances have clearly impacted patient outcomes, it is clear that the benefit of traditional surgical approaches and the use of cytoxic chemotherapy are reaching a plateau. Continued research to develop new and more active therapies, including targeted or biologic agents, is needed. This review discusses the advances made in management of patients with liver-limited metastatic disease.

  17. A case of leptospirosis simulating colon cancer with liver metastases

    PubMed Central

    Granito, Alessandro; Ballardini, Giorgio; Fusconi, Marco; Volta, Umberto; Muratori, Paolo; Sambri, Vittorio; Battista, Giuseppe; Bianchi, Francesco B.

    2004-01-01

    We report a case of a 61-year-old man who presented with fatigue, abdominal pain and hepatomegaly. Computed tomography (CT) of the abdomen showed hepatomegaly and multiple hepatic lesions highly suggestive of metastatic diseases. Due to the endoscopic finding of colon ulcer, colon cancer with liver metastases was suspected. Biochemically a slight increase of transaminases, alkaline phosphatase and gammaglutamyl transpeptidase were present; α - fetoprotein, carcinoembryogenic antigen and carbohydrate 19-9 antigen serum levels were normal. Laboratory and instrumental investigations, including colon and liver biopsies revealed no signs of malignancy. In the light of spontaneous improvement of symptoms and CT findings, his personal history was revaluated revealing direct contact with pigs and their tissues. Diagnosis of leptospirosis was considered and confirmed by detection of an elevated titer of antibodies to leptospira. After two mo, biochemical data, CT and colonoscopy were totally normal. PMID:15285043

  18. Nrf2 activation prevents cadmium-induced acute liver injury

    SciTech Connect

    Wu, Kai C.; Liu, Jie J.; Klaassen, Curtis D.

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

  19. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases.

  20. Ethanol and liver: recent insights into the mechanisms of ethanol-induced fatty liver.

    PubMed

    Liu, Jinyao

    2014-10-28

    Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease.

  1. [The aflatoxins and liver cancer in Guangxi, China].

    PubMed

    Yu, S Z

    1992-05-01

    The AFB1 intake and the AFM1 excretion of 81 households in 10 villages, Guanxi were investigated using the ELISA method. The results showed that there was positive correlation between PLC mortality and AFB1 intake from corn and peanut oil, but not from rice. The results of stepwise regression showed that main factors were AFB1 intake of males, AFM1 excretion of females and consumption of corn. The results showed that aflatoxins were correlated with mortality rates of liver cancer. Further investigation needs to be carried out in case-control and cohort studies.

  2. Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors.

    PubMed

    Wang, Zemin; Neal, Barbara H; Lamb, James C; Klaunig, James E

    2015-10-01

    Chronic exposure to toxaphene resulted in an increase in liver tumors in B6C3F1 mice. This study was performed to investigate the mode of action of toxaphene induced mouse liver tumors. Following an initial 14 day dietary dose range-finding study in male mice, a mechanistic study (0, 3, 32, and 320 ppm toxaphene in diet for 7, 14, and 28 days of treatment) was performed to examine the potential mechanisms of toxaphene induced mouse liver tumors. Toxaphene induced a significant increase in expression of constitutive androstane receptor (CAR) target genes (Cyp2b10, Cyp3a11) at 32 and 320 ppm toxaphene. aryl hydrocarbon receptor (AhR) target genes (Cyp1a1 and Cyp1a2) were slightly increased in expression at the highest toxaphene dose (320 ppm). No increase in peroxisome proliferator-activated receptor alpha activity or related genes was seen following toxaphene treatment. Lipid peroxidation was seen following treatment with 320 ppm toxaphene. These changes correlated with increases in hepatic DNA synthesis. To confirm the role of CAR in this mode of action, CAR knockout mice (CAR(-/-)) treated with toxaphene confirmed that the induction of CAR responsive genes seen in wild-type mice was abolished following treatment with toxaphene for 14 days. These findings, taken together with previously reported studies, support the mode of action of toxaphene induced mouse liver tumors is through a nongenotoxic mechanism involving primarily a CAR-mediated processes that results in an increase in cell proliferation in the liver, promotes the clonal expansion of preneoplastic lesions leading to adenoma formation.

  3. Autophagy-related cell death by pan-histone deacetylase inhibition in liver cancer.

    PubMed

    Di Fazio, Pietro; Waldegger, Petra; Jabari, Samir; Lingelbach, Susanne; Montalbano, Roberta; Ocker, Matthias; Slater, Emily P; Bartsch, Detlef K; Illig, Romana; Neureiter, Daniel; Wissniowski, Thaddeus T

    2016-05-17

    Autophagy is a homeostatic, catabolic degradation process and cell fate essential regulatory mechanism. Protracted autophagy triggers cell death; its aberrant function is responsible for several malignancies. Panobinostat, a potent pan-deacetylase inhibitor, causes endoplasmic reticulum stress-induced cell death. The aim of this study was to investigate the role of autophagy in deacetylase inhibitor-triggered liver cancer cell death.HepG2 (p53wt) and Hep3B (p53 null) liver cancer cell lines were exposed to panobinostat. RT-qPCR and western blot confirmed autophagic factor modulation. Immuno-fluorescence, -precipitation and -histochemistry as well as transmission electron microscopy verified autophagosome formation. The cytotoxicity of panobinostat and autophagy modulators was detected using a real time cell viability assay.Panobinostat induced autophagy-related factor expression and aggregation. Map1LC3B and Beclin1 were significantly over-expressed in HepG2 xenografts in nude mice treated with panobinostat for 4 weeks. Subcellular distribution of Beclin1 increased with the appearance of autophagosomes-like aggregates. Cytosolic loss of p53, in HepG2, and p73, in Hep3B cells, and a corresponding gain of their nuclear level, together with modulation of DRAM1, were observed. Autophagosome aggregation was visible after 6 h of treatment. Treatment of cells stably expressing GFP-RFPtag Map1LC3B resulted in aggregation and a fluorescence switch, thus confirming autophagosome formation and maturation. Tamoxifen, an inducer of autophagy, caused only a block in cell proliferation; but in combination with panobinostat it resulted in cell death.Autophagy triggers cell demise in liver cancer. Its modulation by the combination of tamoxifen and panobinostat could be a new option for palliative treatment of hepatocellular carcinoma.

  4. Association of serum α-tocopherol, β-carotene, and retinol with liver cancer incidence and chronic liver disease mortality

    PubMed Central

    Lai, G Y; Weinstein, S J; Albanes, D; Taylor, P R; Virtamo, J; McGlynn, K A; Freedman, N D

    2014-01-01

    Background: Micronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum α-tocopherol, β-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers. Methods: Baseline and 3-year follow-up serum were available from 29 046 and 22 805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models. Results: Higher β-carotene and retinol levels were associated with less liver cancer (β-carotene: 0.35, 0.22–0.55, P-trend <0.0001; retinol: 0.58, 0.39–0.85, P-trend=0.0009) and CLD mortality (β-carotene: 0.47, 0.30–0.75, P-trend=0.001; retinol: 0.55, 0.38–0.78, P-trend=0.0007). α-Tocopherol was associated with CLD mortality (0.63, 0.40–0.99, P-trend=0.06), but not with liver cancer (1.06, 0.64–1.74, P-trend=0.77). Participants with higher levels of β-carotene and retinol, but not α-tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels. Conclusions: Our findings suggest that higher concentrations of β-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases. PMID:25314058

  5. A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells

    PubMed Central

    Yu, Wenying; Jou, David; Wang, Yina; Ma, Haiyan; Xiao, Hui; Qin, Hua; Zhang, Cuntai; Lü, Jiagao; Li, Sheng; Li, Chenglong; Lin, Jiayuh; Lin, Li

    2016-01-01

    Signal Transducer and Activator of Transcription 3 (STAT3) is persistently activated in human liver and colon cancer cells and is required for cancer cell viability, survival and migration. Therefore, inhibition of STAT3 signaling may be a viable therapeutic approach for these two cancers. We recently designed a non-peptide small molecule STAT3 inhibitor, LY5, using in silico site-directed Fragment-based drug design (FBDD). The inhibitory effect on STAT3 phosphorylation, cell viability, migration and colony forming ability by LY5 were examined in human liver and colon cancer cells. We demonstrated that LY5 inhibited constitutive Interleukin-6 (IL-6)-induced STAT3 phosphorylation, STAT3 nuclear translocation, decreased STAT3 downstream targeted gene expression and induced apoptosis in liver and colon cancer cells. LY5 had little effect on STAT1 phosphorylation mediated by IFN-γ. Inhibition of persistent STAT3 phosphorylation by LY5 also inhibited colony formation, cell migration, and decreased the viability of liver cancer and colon cancer cells. Furthermore, LY5 inhibited STAT3 phosphorylation and suppressed colon tumor growth in a mouse model in vivo. Our results suggest that LY5 is a potent STAT3 inhibitor and may be a potential drug candidate for liver and colon cancer therapy. PMID:26883202

  6. Colorectal Cancer Associated with Streptococcus anginosus Bacteremia and Liver Abscesses

    PubMed Central

    Masood, Umair; Sharma, Anuj; Lowe, Dhruv; Khan, Rashad; Manocha, Divey

    2016-01-01

    Streptococcus anginosus is part of the normal flora of the human gastrointestinal tract. Their ability to cause abscesses is very unique and sets them apart from the rest of the streptococci groups. While an association of group D streptococcus bacteremia and endocarditis with colorectal carcinoma is well established, S. anginosus infections are rarely implicated with colonic malignancy. We present a case of a 62-year-old male who presented to the hospital with fatigue and generalized abdominal pain. Computed tomography of the abdomen revealed multiple liver abscesses and rectal thickening. Blood cultures were found to grow S. anginosus bacteria. Colonoscopy revealed a rectal mass which was later confirmed to be rectal adenocarcinoma. This case presents an association between S. anginosus bacteremia and presence of colorectal cancer which has been highlighted in only a few case reports in literature. This should prompt clinicians to screen for colorectal cancer in patients with S. anginosus bacteremia. PMID:28100999

  7. Glypican-3 antibodies: a new therapeutic target for liver cancer

    PubMed Central

    Ho, Mingqian Feng, Mitchell

    2013-01-01

    Glypican-3 (GPC3) is an emerging therapeutic target in hepatocellular carcinoma (HCC), even though the biological function of GPC3 remains elusive. Currently human (MDX-1414 and HN3) and humanized mouse (GC33 and YP7) antibodies that target GPC3 for HCC treatment are under different stages of preclinical or clinical development. Humanized mouse antibody GC33 is being evaluated in a phase II clinical trial. Human antibodies MDX-1414 and HN3 are under different stages of preclinical evaluation. Here, we summarize current evidence for GPC3 as a new target in liver cancer, discuss both its oncogenic function and its mode of actions for current antibodies, and evaluate potential challenges for GPC3-targeted anti-cancer therapies. PMID:24140348

  8. Nested polymerase chain reaction technique for the detection of Gpc3 and Afp mRNA in liver cancer micrometastases.

    PubMed

    Luo, J; Yang, K; Wen, Y G

    2017-02-08

    The incidence of liver cancer has gradually risen to a high level in China, and tumor metastasis occurs via multiple pathways. Alpha fetal protein (AFP) is the main biomarker of liver cancer micrometastases. A recent study showed that glypican-3 (GPC3), which is abundant in hepatoma cells, has promising specificity and could be used to determine the presence of malignant cells. The nested polymerase chain reaction (PCR) technique is superior in experimental sensitivity. Using rat models of liver cancer in the current study, we utilized nested PCR to detect Gpc3 and Afp mRNA to determine their relationship with liver cancer micrometastases. The aim was to provide an experimental basis for clinical examination. We randomly assigned male Sprague-Dawley rats to sham and experimental groups. The experimental group constituted a liver cancer model induced by diethylnitrosamine, whereas the sham group was administered with an equivalent volume of normal saline. Gpc3 and Afp mRNA was detected using nested PCR. Analysis was performed to determine statistical significance. Compared with the sham group, the rates of occurrence of Gpc3 and Afp mRNA were significantly higher in the experimental group (P < 0.05). Compared with the total positive ratio of hepatoma cells examined by joint detection, the rates of occurrence of Gpc3 and Afp mRNA increased significantly in the four subgroups of the experimental group (P < 0.05). The use of nested PCR significantly improved sensitivity for the detection of Gpc3 and Afp mRNA in liver cancer micrometastases.

  9. Pregnane X receptor and drug-induced liver injury

    PubMed Central

    Wang, Yue-Ming; Chai, Sergio C.; Brewer, Christopher T; Chen, Taosheng

    2014-01-01

    Introduction The liver plays a central role in transforming and clearing foreign substances. The continuous exposure of the liver to xenobiotics sometimes leads to impaired liver function, referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) tightly regulates the expression of genes in the hepatic drug-clearance system and its undesired activation plays a role in DILI. Areas covered This review focuses on the recent progress in understanding PXR-mediated DILI and highlights the efforts made to assess and manage PXR-mediated DILI during drug development. Expert opinion Future efforts are needed to further elucidate the mechanisms of PXR-mediated liver injury, including the epigenetic regulation and polymorphisms of PXR. Novel in vitro models containing functional PXR could improve our ability to predict and assess DILI during drug development. PXR inhibitors may provide chemical tools to validate the potential of PXR as a therapetic target and to develop drugs to be used in the clinic to manage PXR-mediated DILI. PMID:25252616

  10. Delineating liver events in trichloroethylene-induced autoimmune hepatitis.

    PubMed

    Gilbert, Kathleen M; Przybyla, Beata; Pumford, Neil R; Han, Tao; Fuscoe, James; Schnackenberg, Laura K; Holland, Ricky D; Doss, Jason C; Macmillan-Crow, Lee Ann; Blossom, Sarah J

    2009-04-01

    Exposure to the environmental pollutant trichloroethylene (TCE) has been linked to autoimmune disease development in humans. Chronic (32-week) low-level exposure to TCE has been shown to promote autoimmune hepatitis in association with CD4(+) T cell activation in autoimmune-prone MRL+/+ mice. MRL+/+ mice are usually thought of as a model of systemic lupus rather than an organ-specific disease such as autoimmune hepatitis. Consequently, the present study examined gene expression and metabolites to delineate the liver events that skewed the autoimmune response toward that organ in TCE-treated mice. Female MRL+/+ mice were treated with 0.5 mg/mL TCE in their drinking water. The results showed that TCE-induced autoimmune hepatitis could be detected in as little as 26 weeks. TCE exposure also generated a time-dependent increase in the number of antibodies specific for liver proteins. The gene expression correlated with the metabolite analysis to show that TCE upregulated the methionine/homocysteine pathway in the liver after 26 weeks of exposure. The results also showed that TCE exposure altered the expression of selective hepatic genes associated with immunity and inflammation. On the basis of these results, future mechanistic studies will focus on how alterations in genes associated with immunity and inflammation, in conjunction with protein alterations in the liver, promote liver immunogenicity in TCE-treated MRL+/+ mice.

  11. Assessment of drug-induced liver injury in clinical practice.

    PubMed

    Lucena, Ma Isabel; García-Cortés, Miren; Cueto, Raquel; Lopez-Duran, Jl; Andrade, Raúl J

    2008-04-01

    Currently, pharmaceutical preparations are serious contributors to liver disease, with hepatotoxicity ranking as the most frequent cause for acute liver failure and post-marketing regulatory decisions. The diagnostic approach of drug-induced liver injury (DILI) is still rudimentary and inaccurate because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage, and the ability to detect the presence of subtle data that favour a toxic aetiology. Clinical and laboratory data may also be assessed with algorithms or clinical scales, which may add consistency to the clinical judgment by translating the suspicion into a quantitative score. The CIOMS/RUCAM instrument is considered at present the best method for assessing causality in DILI, although it could be improved through the use of large database of bona fide DILI cases for validation criteria.

  12. Xmrk, Kras and Myc Transgenic Zebrafish Liver Cancer Models Share Molecular Signatures with Subsets of Human Hepatocellular Carcinoma

    PubMed Central

    Zheng, Weiling; Li, Zhen; Nguyen, Anh Tuan; Li, Caixia; Emelyanov, Alexander; Gong, Zhiyuan

    2014-01-01

    Previously three oncogene transgenic zebrafish lines with inducible expression of xmrk, kras or Myc in the liver have been generated and these transgenic lines develop oncogene-addicted liver tumors upon chemical induction. In the current study, comparative transcriptomic approaches were used to examine the correlation of the three induced transgenic liver cancers with human liver cancers. RNA profiles from the three zebrafish tumors indicated relatively small overlaps of significantly deregulated genes and biological pathways. Nevertheless, the three transgenic tumor signatures all showed significant correlation with advanced or very advanced human hepatocellular carcinoma (HCC). Interestingly, molecular signature from each oncogene-induced zebrafish liver tumor correlated with only a small subset of human HCC samples (24–29%) and there were conserved up-regulated pathways between the zebrafish and correlated human HCC subgroup. The three zebrafish liver cancer models together represented nearly half (47.2%) of human HCCs while some human HCCs showed significant correlation with more than one signature defined from the three oncogene-addicted zebrafish tumors. In contrast, commonly deregulated genes (21 up and 16 down) in the three zebrafish tumor models generally showed accordant deregulation in the majority of human HCCs, suggesting that these genes might be more consistently deregulated in a broad range of human HCCs with different molecular mechanisms and thus serve as common diagnosis markers and therapeutic targets. Thus, these transgenic zebrafish models with well-defined oncogene-induced tumors are valuable tools for molecular classification of human HCCs and for understanding of molecular drivers in hepatocarcinogenesis in each human HCC subgroup. PMID:24633177

  13. Ebselen prevents early alcohol-induced liver injury in rats.

    PubMed

    Kono, H; Arteel, G E; Rusyn, I; Sies, H; Thurman, R G

    2001-02-15

    Oxidants have been shown to be involved in alcohol-induced liver injury. Moreover, 2-phenyl-1,2-benzisoselenazole-3(2H)-one (ebselen), an organoselenium compound and glutathione peroxidase mimic, decreases oxidative stress and protects against stroke clinically. This study was designed to test the hypothesis that ebselen protects against early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-16 g/kg/d) continuously for up to 4 weeks using the intragastric enteral feeding protocol developed by Tsukamoto and French. Ebselen (50 mg/kg twice daily, intragastrically) or vehicle (1% tylose) was administered throughout the experiment. Mean urine ethanol concentrations were not significantly different between treatment groups, and ebselen did not affect body weight gains or cyclic patterns of ethanol concentrations in urine. After 4 weeks, serum ALT levels were increased significantly about 4-fold over control values (37 +/- 5 IU/l) by enteral ethanol (112 +/- 7 IU/l); ebselen blunted this increase significantly (61 +/- 8 IU/l). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver (pathology score: 4.3 +/- 0.3). In contrast, these pathological changes were blunted significantly by ebselen (pathology score: 2.5 +/- 0.4). While there were no significant effects of either ethanol or ebselen on glutathione peroxidase activity in serum or liver tissue, ebselen blocked the increase in serum nitrate/nitrite caused by ethanol. Furthermore, ethanol increased the activity of NF-kappaB over 5-fold, the number of infiltrating neutrophils 4-fold, and the accumulation of 4-hydroxynonenal over 5-fold. Ebselen blunted all of these effects significantly. These results indicate that ebselen prevents early alcohol-induced liver injury, most likely by preventing oxidative stress, which decreases inflammation.

  14. Novel Mechanism of Arenavirus-Induced Liver Pathology

    PubMed Central

    Beier, Juliane I.; Jokinen, Jenny D.; Holz, Gretchen E.; Whang, Patrick S.; Martin, Amah M.; Warner, Nikole L.; Arteel, Gavin E.; Lukashevich, Igor S.

    2015-01-01

    Viral hemorrhagic fevers (VHFs) encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. The liver is a critical mediator of VHF disease pathogenesis and high levels of ALT/AST transaminases in plasma correlate with poor prognosis. In fact, Lassa Fever (LF), the most prevalent VHF in Africa, was initially clinically described as hepatitis. Previous studies in non-human primate (NHP) models also correlated LF pathogenesis with a robust proliferative response in the liver. The purpose of the current study was to gain insight into the mechanism of liver injury and to determine the potential role of proliferation in LF pathogenesis. C57Bl/6J mice were infected with either the pathogenic (for NHPs) strain of lymphocytic choriomeningitis virus (LCMV, the prototypic arenavirus), LCMV-WE, or with the non-pathogenic strain, LCMV-ARM. As expected, LCMV-WE, but not ARM, caused a hepatitis-like infection. LCMV-WE also induced a robust increase in the number of actively cycling hepatocytes. Despite this increase in proliferation, there was no significant difference in liver size between LCMV-WE and LCMV-ARM, suggesting that cell cycle was incomplete. Indeed, cells appeared arrested in the G1 phase and LCMV-WE infection increased the number of hepatocytes that were simultaneously stained for proliferation and apoptosis. LCMV-WE infection also induced expression of a non-conventional virus receptor, AXL-1, from the TAM (TYRO3/AXL/MERTK) family of receptor tyrosine kinases and this expression correlated with proliferation. Taken together, these results shed new light on the mechanism of liver involvement in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation contributes to expansion of the infection to parenchymal cells. Elevated levels of plasma transaminases are likely explained, at least in part, by abortive cell cycle arrest induced by the infection. These results may lead to the development of new

  15. Transcatheter embolization therapy in liver cancer: an update of clinical evidences

    PubMed Central

    De Baere, Thierry; Idée, Jean-Marc; Ballet, Sébastien

    2015-01-01

    Transarterial chemoembolization (TACE) is a form of intra-arterial catheter-based chemotherapy that selectively delivers high doses of cytotoxic drug to the tumor bed combining with the effect of ischemic necrosis induced by arterial embolization. Chemoembolization and radioembolization are at the core of the treatment of liver hepatocellular carcinoma (HCC) patients who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. TACE for liver cancer has been proven to be useful in local tumor control, to prevent tumor progression, prolong patients’ life and control patient symptoms. Recent evidence showed in patients with single-nodule HCC of 3 cm or smaller without vascular invasion, the 5-year overall survival (OS) with TACE was similar to that with hepatic resection and radiofrequency ablation. Although being used for decades, Lipiodol® (Lipiodol® Ultra Fluid®, Guerbet, France) remains important as a tumor-seeking and radio-opaque drug delivery vector in interventional oncology. There have been efforts to improve the delivery of chemotherapeutic agents to tumors. Drug-eluting bead (DEB) is a relatively novel drug delivery embolization system which allows for fixed dosing and the ability to release the anticancer agents in a sustained manner. Three DEBs are available, i.e., Tandem® (CeloNova Biosciences Inc., USA), DC-Beads® (BTG, UK) and HepaSphere® (BioSphere Medical, Inc., USA). Transarterial radioembolization (TARE) technique has been developed, and proven to be efficient and safe in advanced liver cancers and those with vascular complications. Two types of radioembolization microspheres are available i.e., SIR-Spheres® (Sirtex Medical Limited, Australia) and TheraSphere® (BTG, UK). This review describes the basic procedure of TACE, properties and efficacy of some chemoembolization systems and radioembolization agents which are commercially available and/or currently under clinical evaluation. The key

  16. Epigenetic changes in the rat livers induced by pyrazinamide treatment

    SciTech Connect

    Kovalenko, V.M.; Bagnyukova, T.V.; Sergienko, O.V.; Bondarenko, L.B.; Shayakhmetova, G.M.; Matvienko, A.V.; Pogribny, I.P.

    2007-12-15

    Drug-induced liver injury, including drug-induced hepatotoxicity during the treatment of tuberculosis infection, is a major health problem with increasingly significant challenges to modern hepatology. Therefore, the assessment and monitoring of the hepatotoxicity of antituberculosis drugs for prevention of liver injury are great concerns during disease treatment. The recently emerged data showing the ability of toxicants, including pharmaceutical agents, to alter cellular epigenetic status, open a unique opportunity for early detection of drug hepatotoxicity. Here we report that treatment of male Wistar rats with antituberculosis drug pyrazinamide at doses of 250, 500 or 1000 mg/kg/day body weight for 45 days leads to an early and sustained decrease in cytosine DNA methylation, progressive hypomethylation of long interspersed nucleotide elements (LINE-1), and aberrant promoter hypermethylation of placental form glutathione-S-transferase (GSTP) and p16{sup INK4A} genes in livers of pyrazinamide-treated rats, while serum levels of bilirubin and activity of aminotransferases changed modestly. The early occurrence of these epigenetic alterations and their association with progression of liver injury specific pathological changes indicate that alterations in DNA methylation may be useful predictive markers for the assessment of drug hepatotoxicity.

  17. Web site construction for information and treatment on liver cancer.

    PubMed

    Roussakis, Sotiris; Ponirou, Paraskevi; Bizopoulou, Zoi; Diomidous, Marianna

    2013-01-01

    Liver cancer requires a considerable attention of health care scientists worldwide. A holistic treatment includes patient information about risk factors, education on pragmatic evaluation of the symptoms, as well as presentation of best and individualized treatment methods. In this direction, Internet seems to be a powerful tool that has an essential role. The aim of this study is the development of a web site in order to inform and present treatment options on liver cancer, it consists of four parts. In the first part, the presentation of the disease's knowledge base is attempted, whereas in the second part this knowledge base is organized in two conceptual entities: (a) information and (b) treatment. In the third part the importance of internet in the health care sector is highlighted. In the fourth and last part the web site is presented and a brief illustration of several relevant theories and specific implementation tools. The critical success factor of the implementation phase is considered to be the selection of the appropriate methods and development tools. Finally, the constant need for ongoing site maintenance is discussed and thus, is proposed to formulate one of the main aspects for further research, along with several issues concerning site usability.

  18. Metformin use improves survival of diabetic liver cancer patients: systematic review and meta-analysis

    PubMed Central

    Ma, Shu-Juan; Zheng, Yi-Xiang; Zhou, Peng-Cheng; Xiao, Yan-Ni; Tan, Hong-Zhuan

    2016-01-01

    Metformin has garnered considerable interest as a chemo-preventive and chemo-therapeutic agent given the increased risk of liver cancer among diabetic patients. This work was performed to illustrate the association between metformin use and survival of diabetic liver cancer patients. We conducted a comprehensive literature search of PubMed, Web of Science, Embase, BIOSIS Previews, Cochrane Library from inception to 12 May 2016. Meta-analyses were performed using Stata (version 12.0), with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) as effect measures. Eleven cohort studies involving 3452 liver cancer patients fulfilled the inclusion criteria. Meta-analyses showed that metformin use was associated with better survival (HR = 0.59; 95% CI, 0.42-0.83; p = 0.002) of liver cancer patients, and the beneficial effect persisted (HR = 0.64; 95% CI, 0.42-0.97; p = 0.035) when the population was restricted to diabetic liver cancer patients. After adjusting for age, etiology, index of tumor severity and treatment of liver cancer, the association between metformin use and better survival of liver cancer patients was stable, pooled HR ranged from 0.47 to 0.57. The results indicated that metformin use improved survival of diabetic liver cancer patients. However, the results should be interpreted with caution given the possibility of residual confounding. Further prospective studies are still needed to confirm the prognostic benefit of metformin use. PMID:27494848

  19. Ultrasound-guided interventional PDT of liver cancer

    NASA Astrophysics Data System (ADS)

    Zeng, Chaoying; Yang, Dong; Huang, Ping; Zhang, Huijuan; Huang, Muyin; Chen, Ji; Lu, Guorong

    1996-09-01

    Thirty patients with advanced liver cancer were treated by interstitial photodynamic therapy (PDT). These included 28 hepatocellular carcinoma and two adenocarcinoma, 19 primary tumors and 11 recurred follow other treatments. The diameter of tumors were 7-10cm in 13 cases and 10-16cm in 17 cases. In this study, an argon laser pumped dye laser system was used to give a CW laser beam at 630 nm which was split and coupled into there optical fibers. The patients were injected intravenously with photosensitizer hematoporphyrin derivative at a dose of 5mg/kg body weight 48 hours before PDT. Then the fibers were inserted into tumor by ultrasound- guided percutaneous puncture. The inserted irradiation points were spaced in entire tumor with the light release power 300mW and the irradiation time 12 minutes per point. Total 52 treatments were performed in 30 patients. Among them, 14 cases were treated only one time and 16 cases via 2-3 times. The follow-up was carried out in 25 cases for 12- 24 months. The results show that significant remission was 22 percent in those patients by only one treatment and 62 percent in those via 2 to 3 treatments. The shrink rate of tumor size was over 90 percent in five of six cases after treatment 3. The survival time has been over one year in 12 cases. No obvious change to be found for all patients in liver function test, renal function test and blood routine examination. The level of AFP indicated a descending trend after PDT. This work indicate that PDT is effective and safe for the treatment of large liver cancers including those recurred follow hepatic resection and those failed in hepatic artery infusion embolic chemotherapy.

  20. Factors predicting early postoperative liver cirrhosis-related complications after lung cancer surgery in patients with liver cirrhosis.

    PubMed

    Iwata, Takashi; Inoue, Kiyotoshi; Nishiyama, Noritoshi; Nagano, Koshi; Izumi, Nobuhiro; Tsukioka, Takuma; Hanada, Shoji; Suehiro, Shigefumi

    2007-12-01

    We aimed to determine the factors predicting liver cirrhosis-related complications in the early postoperative period after lung cancer surgery in patients with liver cirrhosis. We retrospectively reviewed the medical records of patients who underwent curative surgery for primary lung cancer in our institute from January 1990 to March 2007, finding 37 cases with comorbid liver cirrhosis. These patients were divided into two groups, according to whether liver failure, bleeding, and critical infection had occurred postoperatively. Various clinical parameters were analyzed statistically between the bigeminal groups. Liver cirrhosis-related complications occurred in seven of the 37 patients (18.9%). Transient liver failure occurred in two patients (5.4%) after pulmonary resection. Acute intrathoracic bleeding occurred in four cases (10.8%). Two patients died (5.4%) in both cases due to sepsis. Preoperative total bilirubin (P<0.05), and indocyanine green retention rate at 15 min (P<0.05) were significantly higher in patients with liver failure. Only serum value of total bilirubin was an independent risk factor (P<0.05) by multivariate analysis. In predicting death from infection, only preoperative nutritional status was a significant risk factor (P<0.05). To avoid postoperative cirrhosis-related complications, preoperative preparation to improve their liver function and nutrition status is essential.

  1. Dynamic Contrast Enhanced MRI in Patients With Advanced Breast or Pancreatic Cancer With Metastases to the Liver or Lung

    ClinicalTrials.gov

    2014-05-28

    Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Liver Metastases; Lung Metastases; Recurrent Breast Cancer; Recurrent Pancreatic Cancer; Stage IV Breast Cancer; Stage IV Pancreatic Cancer

  2. Drug-induced liver injury: Is it somehow foreseeable?

    PubMed Central

    Tarantino, Giovanni; Di Minno, Matteo Nicola Dario; Capone, Domenico

    2009-01-01

    The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neo-substances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients’ health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider. PMID:19533803

  3. Propylthiouracil-induced liver failure and artificial liver support systems: a case report and review of the literature

    PubMed Central

    Wu, Dong-Bo; Chen, En-Qiang; Bai, Lang; Tang, Hong

    2017-01-01

    Background Antithyroid drugs carry a potential risk of hepatotoxicity. Propylthiouracil (PTU) is commonly prescribed for patients with hyperthyroidism. PTU, however, can induce liver injury, ranging from mild asymptomatic elevation of aminotransferases to acute liver failure (ALF). Case presentation This case reports on a 16-year-old Chinese girl with hyperthyroidism, who was admitted to our hospital for jaundice, nausea, and fatigue associated with severe hyperbilirubinemia and coagulopathy. She had been prescribed PTU 5 months earlier. There was no history of hypersensitivity to drugs, viral liver diseases, blood transfusion, or surgery. On the basis of her symptoms and the clinical data, she was diagnosed with PTU-induced ALF. Due to the limited number of available donor organs for liver transplantation, she was started on treatment with artificial liver support system (ALSS). After four sessions of ALSS, her clinical signs and symptoms were found to be markedly improved, and she was discharged 25 days after admission. Four months later, her liver function normalized. Conclusion Although PTU-induced liver failure is rare in clinical practice, liver function should be appropriately monitored during treatment with PTU. PTU-induced ALF in this patient was successfully managed with an ALSS, suggesting that the latter may be an alternative to liver transplantation. PMID:28138249

  4. Significance of liver biopsy for the evaluation of methotrexate-induced liver damage in patients with rheumatoid arthritis

    PubMed Central

    Osuga, Tatsuya; Ikura, Yoshihiro; Kadota, Chikara; Hirano, Seiichi; Iwai, Yasuhiro; Hayakumo, Takanobu

    2015-01-01

    It is well recognized that long-term administration of methotrexate (MTX) in patients with rheumatoid arthritis (RA) can induce liver fibrosis via a steatohepatitis-like inflammatory process. Several non-invasive tests have been investigated as alternatives to liver biopsy, which is, however, still recognized as a final diagnostic modality to detect the MTX-induced liver damage. To clarify whether there is a significant discrepancy between clinical estimations and pathologic findings of this hepatic condition, we performed a following comparative study. Four RA patients (4 women, age 67-80 yr) with MTX-induced liver damage were reviewed. The severity of hepatic damage estimated clinically was compared with histopathologic findings. Consequently, the liver biopsies showed the relatively earlier stages of and milder degrees of hepatic damages than the clinical estimations. The histopathologic findings were more reliable and useful than any other clinical examinations, to plan and modify the treatment strategies, especially in cases of liver damages with multiple etiologies besides MTX. These findings suggest that liver biopsy is an unavoidable examination to assess precisely MTX-induced liver damage. Non-invasive tests may be useful to monitor the hepatic condition of RA patients receiving MTX but do not constitute an acceptable alternative to liver biopsy. PMID:25973089

  5. Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer

    SciTech Connect

    Tomasi, Maria Lauda; Ryoo, Minjung; Skay, Anna; Tomasi, Ivan; Giordano, Pasquale; Mato, José M.; Lu, Shelly C.

    2013-07-15

    Methionine adenosyltransferase (MAT) is an essential enzyme that is responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. MAT1A is expressed in normal liver and MAT2A is expressed in all extrahepatic tissues. MAT2A expression is increased in human colon cancer and in colon cancer cells treated with mitogens, whereas silencing MAT2A resulted in apoptosis. The aim of the current work was to examine the mechanism responsible for MAT2A-dependent growth and apoptosis. We found that in RKO (human adenocarcinoma cell line) cells, MAT2A siRNA treatment lowered cellular SAMe and putrescine levels by 70–75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100 pmol/L) raised MAT2A mRNA level to 4.3-fold of control, increased the expression of c-Jun and c-Fos and binding to an AP-1 site in the human MAT2A promoter and the promoter activity. In human colon cancer specimens, the expression levels of MAT2A, ornithine decarboxylase (ODC), c-Jun and c-Fos are all elevated as compared to adjacent non-tumorous tissues. Overexpression of ODC in RKO cells also raised MAT2A mRNA level and MAT2A promoter activity. ODC and MAT2A are also overexpressed in liver cancer and consistently, similar MAT2A-ODC-putrescine interactions and effects on growth and apoptosis were observed in HepG2 cells. In conclusion, there is a crosstalk between polyamines and MAT2A. Increased MAT2A expression provides more SAMe for polyamines biosynthesis; increased polyamine (putrescine in this case) can activate MAT2A at the transcriptional level. This along with increased ODC expression in cancer all feed forward to further enhance the proliferative capacity of the cancer cell. -- Highlights: • MAT2A knockdown depletes putrescine and leads to apoptosis. • Putrescine attenuates MAT2A knockdown-induced apoptosis and growth

  6. Drug Rechallenge Following Drug-Induced Liver Injury.

    PubMed

    Hunt, Christine M; Papay, Julie I; Stanulovic, Vid; Regev, Arie

    2017-03-13

    Drug induced hepatocellular injury is identified internationally by ALT 5x upper limits normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decreases by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT 3-5xULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials, central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems enable safer drug rechallenge with weekly liver chemistry monitoring during the high risk period and exclusion of patients with hypersensitivity. Yet, high positive rechallenge rates with other innovative therapeutics suggest caution with rechallenge of high risk drugs.

  7. TRAIL-secreting mesenchymal stem cells promote apoptosis in heat-shock-treated liver cancer cells and inhibit tumor growth in nude mice.

    PubMed

    Deng, Q; Zhang, Z; Feng, X; Li, T; Liu, N; Lai, J; Shuai, L; Xiong, Q; Fu, C; Zou, H; Wang, Y; Li, X; Ma, K; Bie, P

    2014-03-01

    Liver cancer is one of the top six leading causes of cancer-related death. Radiofrequency ablation (RFA) is an important means of treating liver cancer. Residual cancer after RFA is the most frequent cause of recurrence in cases of liver cancer. The main difference between residual cancer cells and ordinary liver cancer cells is that residual cancer cells experience heat shock. The secretable form of trimeric human tumor necrosis factor-related apoptosis-inducing ligand (stTRAIL) induces apoptosis in a variety of human cancers but not in normal tissues. It has shown potent cancer-selective killing activity and has drawn considerable attention as a possible cancer therapy. In the present work, the therapeutic potential of this stTRAIL-based gene therapy was evaluated in hepatocellular carcinoma subjected to RFA. Rat bone marrow mesenchymal stem cells (BM-MSCs) were isolated and transduced with a lentiviral vector encoding stTRAIL (stTRAIL-MSCs, T-MSCs). Cells treated with heat treatment at 43 °C for 45 min served as simulated residual cancer cells. After treatment with T-MSCs, apoptosis in heat-shock-treated liver cancer cells increased significantly, and caspase-3 was upregulated. When T-MSCs were subcutaneously injected into nude mice, they localized to the tumors and inhibited tumor growth, significantly increasing survival. Collectively, the results of the present study indicate that BM-MSC can provide a steady source of stTRAIL and may be suitable for use in the prevention of the recurrence of hepatocellular carcinoma after RFA with secretable trimeric TRAIL.

  8. Studying liver cancer metastasis by in vivo imaging and flow cytometer

    NASA Astrophysics Data System (ADS)

    Wang, Chen; Gu, Zhengqin; Guo, Jin; Li, Yan; Liu, Guangda; Wei, Xunbin

    2009-11-01

    Primary liver cancer (hepatocellular carcinoma, or HCC) is associated with liver cirrhosis 60-80% of the time. Liver cancer is one of the most common malignancies in the world, with approximately 1,000,000 cases reported every year. About 80% of people with primary liver cancer are male. Although two-thirds of people have advanced liver disease when they seek medical help, one third of the patients have cancer that has not progressed beyond the liver. HCC may metastasize to the lung, bones, kidney, and many other organs. Surgical resection, liver transplantation, chemotherapy and radiation therapy are the foundation of current HCC therapies. However the outcomes are poor: the survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of HCC cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern liver tumor cell spread through the microenvironment in vivo with real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess liver tumor cell spreading and the circulation kinetics of liver tumor cells. A real- time quantitative monitoring of circulating liver tumor cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

  9. An Update on Drug-induced Liver Injury.

    PubMed

    Devarbhavi, Harshad

    2012-09-01

    Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

  10. Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis.

    PubMed

    Dong, Bingning; Lee, Ju-Seog; Park, Yun-Yong; Yang, Feng; Xu, Ganyu; Huang, Wendong; Finegold, Milton J; Moore, David D

    2015-02-09

    Aberrant β-catenin activation contributes to a third or more of human hepatocellular carcinoma (HCC), but β-catenin activation alone is not sufficient to induce liver cancer in mice. Differentiated hepatocytes proliferate upon acute activation of either β-catenin or the nuclear xenobiotic receptor CAR. These responses are strictly limited and are tightly linked, since β-catenin is activated in nearly all of the CAR-dependent tumours generated by the tumour promoter phenobarbital. Here, we show that full activation of β-catenin in the liver induces senescence and growth arrest, which is overcome by combined CAR activation, resulting in uncontrolled hepatocyte proliferation, hepatomegaly and rapid lethality despite maintenance of normal liver function. Combining CAR activation with limited β-catenin activation induces tumorigenesis, and the tumours share a conserved gene expression signature with β-catenin-positive human HCC. These results reveal an unexpected route for hepatocyte proliferation and define a murine model of hepatocarcinogenesis with direct relevance to human HCC.

  11. Activating CAR and β-Catenin Induces Uncontrolled Liver Growth and Tumorigenesis

    PubMed Central

    Dong, Bingning; Lee, Ju-Seog; Park, Yun-Yong; Yang, Feng; Xu, Ganyu; Huang, Wendong; Finegold, Milton; Moore, David D.

    2014-01-01

    Aberrant β-catenin activation contributes to a third or more of human hepatocellular carcinoma (HCC), but β-catenin activation alone is not sufficient to induce liver cancer in mice. Differentiated hepatocytes proliferate upon acute activation of either β-catenin or the nuclear xenobiotic receptor CAR. These responses are strictly limited and are tightly linked, since β-catenin is activated in nearly all of the CAR-dependent tumors generated by the tumor promoter phenobarbital. Here we show that full activation of β-catenin in the liver induces senescence and growth arrest, which is overcome by combined CAR activation, resulting in uncontrolled hepatocyte proliferation, hepatomegaly, and rapid lethality despite maintenance of normal liver function. Combining CAR activation with limited β-catenin activation induces tumorigenesis, and the tumors share a conserved gene expression signature with β-catenin positive human HCC. These results reveal an unexpected route for hepatocyte proliferation and define a murine model of hepatocarcinogenesis with direct relevance to human HCC. PMID:25661872

  12. Linkage Specific Fucosylation of Alpha-1-Antitrypsin in Liver Cirrhosis and Cancer Patients: Implications for a Biomarker of Hepatocellular Carcinoma

    PubMed Central

    Comunale, Mary Ann; Rodemich-Betesh, Lucy; Hafner, Julie; Wang, Mengjun; Norton, Pamela; Di Bisceglie, Adrian M.; Block, Timothy; Mehta, Anand

    2010-01-01

    Background We previously reported increased levels of protein-linked fucosylation with the development of liver cancer and identified many of the proteins containing the altered glycan structures. One such protein is alpha-1-antitrypsin (A1AT). To advance these studies, we performed N-linked glycan analysis on the five major isoforms of A1AT and completed a comprehensive study of the glycosylation of A1AT found in healthy controls, patients with hepatitis C- (HCV) induced liver cirrhosis, and in patients infected with HCV with a diagnosis of hepatocellular carcinoma (HCC). Methodology/Principal Findings Patients with liver cirrhosis and liver cancer had increased levels of triantennary glycan-containing outer arm (α-1,3) fucosylation. Increases in core (α-1,6) fucosylation were observed only on A1AT from patients with cancer. We performed a lectin fluorophore-linked immunosorbent assay using Aleuria Aurantia lectin (AAL), specific for core and outer arm fucosylation in over 400 patients with liver disease. AAL-reactive A1AT was able to detect HCC with a sensitivity of 70% and a specificity of 86%, which was greater than that observed with the current marker of HCC, alpha-fetoprotein. Glycosylation analysis of the false positives was performed; results indicated that these patients had increases in outer arm fucosylation but not in core fucosylation, suggesting that core fucosylation is cancer specific. Conclusions/Significance This report details the stepwise change in the glycosylation of A1AT with the progression from liver cirrhosis to cancer and identifies core fucosylation on A1AT as an HCC specific modification. PMID:20811639

  13. The role of autophagy in liver cancer: molecular mechanisms and potential therapeutic targets.

    PubMed

    Cui, Jianzhou; Gong, Zhiyuan; Shen, Han-Ming

    2013-08-01

    Autophagy is an evolutionarily conserved pathway for degradation of cytoplasmic proteins and organelles via lysosome. Proteins coded by the autophagy-related genes (Atgs) are the core molecular machinery in control of autophagy. Among the various biological functions of autophagy identified so far, the link between autophagy and cancer is probably among the most extensively studied and is often viewed as controversial. Autophagy might exert a dual role in cancer development: autophagy can serve as an anti-tumor mechanism, as defective autophagy (e.g., heterozygous knockdown Beclin 1 and Atg7 in mice) promotes the malignant transformation and spontaneous tumors. On the other hand, autophagy functions as a protective or survival mechanism in cancer cells against cellular stress (e.g., nutrient deprivation, hypoxia and DNA damage) and hence promotes tumorigenesis and causes resistance to therapeutic agents. Liver cancer is one of the common cancers with well-established etiological factors including hepatitis virus infection and environmental carcinogens such as aflatoxin and alcohol exposure. In recent years, the involvement of autophagy in liver cancer has been increasingly studied. Here, we aim to provide a systematic review on the close cross-talks between autophagy and liver cancer, and summarize the current status in development of novel liver cancer therapeutic approaches by targeting autophagy. It is believed that understanding the molecular mechanisms underlying the autophagy modulation and liver cancer development may provoke the translational studies that ultimately lead to new therapeutic strategies for liver cancer.

  14. Cancer Incidence among Heart, Kidney, and Liver Transplant Recipients in Taiwan

    PubMed Central

    Lee, Kwai-Fong; Tsai, Yi-Ting; Lin, Chih-Yuan; Hsieh, Chung-Bao; Wu, Sheng-Tang; Ke, Hung-Yen; Lin, Yi-Chang; Lin, Feng-Yen; Lee, Wei-Hwa; Tsai, Chien-Sung

    2016-01-01

    Population-based evidence of the relative risk of cancer among heart, kidney, and liver transplant recipients from Asia is lacking. The Taiwan National Health Insurance Research Database was used to conduct a population-based cohort study of transplant recipients (n = 5396), comprising 801 heart, 2847 kidney, and 1748 liver transplant recipients between 2001 and 2012. Standardized incidence ratios and Cox regression models were used. Compared with the general population, the risk of cancer increased 3.8-fold after heart transplantation, 4.1-fold after kidney transplantation and 4.6-fold after liver transplantation. Cancer occurrence showed considerable variation according to transplanted organs. The most common cancers in all transplant patients were cancers of the head and neck, liver, bladder, and kidney and non-Hodgkin lymphoma. Male recipients had an increased risk of cancers of the head and neck and liver, and female kidney recipients had a significant risk of bladder and kidney cancer. The adjusted hazard ratio for any cancer in all recipients was higher in liver transplant recipients compared with that in heart transplant recipients (hazard ratio = 1.5, P = .04). Cancer occurrence varied considerably and posttransplant cancer screening should be performed routinely according to transplanted organ and sex. PMID:27196400

  15. Systematic Review on Chinese Herbal Medicine Induced Liver Injury

    PubMed Central

    Zhang, Peng; Yang, Xianzhao

    2016-01-01

    Background. In recent years, with the popularity of CHM, its hepatotoxicity has also been increasingly noticed. However, there are still veils on causative herbs and clinical characteristics. Aim. To systematically review data on CHM induced liver injury with particular focus on causative herbs and clinical characteristics. Methods. Using terms related to CHM and liver injury, PubMed and three Chinese electronic databases were searched, which was limited to the past 5 years. Publications meeting our eligibility criteria were included and further analyzed. Results. In total, 4 single herbs, 21 patent drugs, and 4 decoctions were reported to be of hepatotoxicity, with He-Shou-Wu being the most common one (65/114). Dang-Gui and other 5 herbs were the most common ingredients of patent drugs and decoctions. All patients were assessed using the RUCAM scale, with 26 being highly probable and 28 being probable. For these 54 cases, the latent period was 30 (47) days, and 81.48% were labeled as hepatocellular injuries. Most patients (96.3%) recovered, apart from the fact that one died and one is receiving liver transplantation. Conclusions. CHM should be used carefully for hepatotoxicity. Liver injury from CHM is similar to that from conventional medicines in clinical characteristics. Details about causative herbs should be illustrated, and more RUCAM should be used in future. PMID:27651817

  16. Quercetin protection against ciprofloxacin induced liver damage in rats.

    PubMed

    Taslidere, E; Dogan, Z; Elbe, H; Vardi, N; Cetin, A; Turkoz, Y

    2016-01-01

    Ciprofloxacin is a common, broad spectrum antibacterial agent; however, evidence is accumulating that ciprofloxacin may cause liver damage. Quercetin is a free radical scavenger and antioxidant. We investigated histological changes in hepatic tissue of rats caused by ciprofloxacin and the effects of quercetin on these changes using histochemical and biochemical methods. We divided 28 adult female Wistar albino rats into four equal groups: control, quercetin treated, ciprofloxacin treated, and ciprofloxacin + quercetin treated. At the end of the experiment, liver samples were processed for light microscopic examination and biochemical measurements. Sections were prepared and stained with hematoxylin and eosin, and a histopathologic damage score was calculated. The sections from the control group appeared normal. Hemorrhage, inflammatory cell infiltration and intracellular vacuolization were observed in the ciprofloxacin group. The histopathological findings were reduced in the group treated with quercetin. Significant differences were found between the control and ciprofloxacin groups, and between the ciprofloxacin and ciprofloxacin + quercetin groups. Quercetin administration reduced liver injury caused by ciprofloxacin in rats. We suggest that quercetin may be useful for preventing ciprofloxacin induced liver damage.

  17. Microbiota protects mice against acute alcohol-induced liver injury

    PubMed Central

    Chen, Peng; Miyamoto, Yukiko; Mazagova, Magdalena; Lee, Kuei-Chuan; Eckmann, Lars; Schnabl, Bernd

    2015-01-01

    Background Chronic alcohol abuse is associated with intestinal bacterial overgrowth, increased intestinal permeability, and translocation of microbial products from the intestine to the portal circulation and liver. Translocated microbial products contribute to experimental alcoholic liver disease. Aim To investigate the physiological relevance of the intestinal microbiota in alcohol-induced liver injury. Methods We subjected germ-free and conventional C57BL/6 mice to a model of acute alcohol exposure that mimics binge drinking. Results Germ-free mice showed significantly greater liver injury and inflammation after oral gavage of ethanol compared with conventional mice. In parallel, germ-free mice exhibited increased hepatic steatosis and upregulated expression of genes involved in fatty acid and triglyceride synthesis compared with conventional mice after acute ethanol administration. The absence of microbiota was also associated with increased hepatic expression of ethanol metabolizing enzymes, which led to faster ethanol elimination from the blood and lower plasma ethanol concentrations. Intestinal levels of ethanol metabolizing genes showed regional expression differences, and were overall higher in germ-free relative to conventional mice. Conclusion Our findings indicate that absence of the intestinal microbiota increases hepatic ethanol metabolism and the susceptibility to binge-like alcohol drinking. PMID:26556636

  18. Regulation of UGT2B4 and UGT2B7 by miRNAs in liver cancer cells.

    PubMed

    Wijayakumara, Dhilushi; Mackenzie, Peter Ian; McKinnon, Ross A; Hu, Dong Gui; Meech, Robyn

    2017-04-07

    The transcriptional regulation of UGT2B4 and UGT2B7 has been well studied using liver cancer cell lines and recently post-transcriptional regulation of these two UGTs by miR-216b-5p was reported. The present study describes novel miRNA-mediated regulation of UGT2B4 and UGT2B7 in liver cancer cells. Bioinformatic analyses identified a putative miR-3664-3p binding site in the UGT2B7 3'-UTR, and binding sites for both miR-135a-5p and miR-410-3p in the UGT2B4 3'-UTR. These sites were functionally characterized using miRNA mimics and reporter constructs. A miR-3664-3p mimic induced repression of a luciferase reporter carrying the UGT2B7 3'-UTR in liver cancer cell lines; mutation of the miR-3664-3p site abrogated the response of the reporter to the mimic. Similarly, mutation of the miR-135a-5p site or miR-410-3p site in a luciferase reporter bearing UGT2B4 3'-UTR abrogated the ability of miR-135a-5p or miR-410-3p mimics to reduce reporter activity. Transfection of miR-3664-3p mimics in HepG2 liver cancer cells significantly reduced mRNA and protein levels of UGT2B7, and this led to reduced enzymatic activity. Transfection of miR-135a-5p or miR-410-3p mimics significantly decreased UGT2B4 mRNA levels in Huh7 liver cancer cells. The expression levels of miR-410-3p were inversely correlated with UGT2B4 mRNA levels in the TCGA cohort of Liver Hepatocellular Carcinoma (370 specimens) and a panel of 9 normal human tissues. Similarly, there was an inverse correlation between miR-135a and UGT2B4 mRNA levels in a panel of 18 normal human liver tissues. Together these data suggest that miR-135a and miR-410 control UGT2B4 and that miR-3664 controls UGT2B7 expression in liver cancer and/or normal liver cells.

  19. Possible action mechanism of the electromagnetic fields in the liver cancer development: A mathematical proposal

    SciTech Connect

    Jiménez-García, Mónica Noemí; Godina-Nava, Juan José

    2012-02-08

    Currently it is known that electromagnetic field exposure can induce biological changes, although the precise effects and action mechanism of the interaction between the electromagnetic field and biological systems are not well understood. In this work we propose a possible action mechanism, concerning the effect that the extremely low frequency electromagnetic field exposure has on the early stage of liver cancer development. The model is developed studying the phenomena called oxidative stress that it appears after it is applied a carcinogenic agent used to induce hepatic cancer chemically in an experimental animal model. This physical-chemical process involves the movement of magnetic field dependent free charged particles, called free radicals. We will consider the use of the radical pairs theory as a framework, in which we will describe the spin density operator evolution by implementing the stochastic Liouville equation with hyperfine interaction. This describes how the selectivity of the interaction between spin states of the free radicals with the applied electromagnetic field, influences the development of pre-neoplastic lesions in the liver. AIP Publishing is retracting this article due to the substantial use of content in the Results and Conclusions section without proper citation of a previously published paper in Chemical Physics Letters 361 (2012) 219-225. This article is retracted from the scientific record with effect from 15 October 2015.

  20. Possible action mechanism of the electromagnetic fields in the liver cancer development: A mathematical proposal

    NASA Astrophysics Data System (ADS)

    Jiménez-García, Mónica Noemí; Godina-Nava, Juan José

    2012-02-01

    Currently it is known that electromagnetic field exposure can induce biological changes, although the precise effects and action mechanism of the interaction between the electromagnetic field and biological systems are not well understood. In this work we propose a possible action mechanism, concerning the effect that the extremely low frequency electromagnetic field exposure has on the early stage of liver cancer development. The model is developed studying the phenomena called oxidative stress that it appears after it is applied a carcinogenic agent used to induce hepatic cancer chemically in an experimental animal model. This physical-chemical process involves the movement of magnetic field dependent free charged particles, called free radicals. We will consider the use of the radical pairs theory as a framework, in which we will describe the spin density operator evolution by implementing the stochastic Liouville equation with hyperfine interaction. This describes how the selectivity of the interaction between spin states of the free radicals with the applied electromagnetic field, influences the development of pre-neoplastic lesions in the liver. AIP Publishing is retracting this article due to the substantial use of content in the Results and Conclusions section without proper citation of a previously published paper in Chemical Physics Letters 361 (2012) 219-225. This article is retracted from the scientific record with effect from 15 October 2015.

  1. Surveillance, Diagnosis, Treatment, and Outcome of Liver Cancer in Japan

    PubMed Central

    Kudo, Masatoshi

    2015-01-01

    Background Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third leading cause of cancer-related death worldwide. HCC is most common in Asia, but its prevalence is rapidly increasing in Western countries; consequently, HCC is a global medical issue that urgently needs to be addressed. Japan is the only developed country that has experienced both hepatitis B-related and hepatitis C-related HCC and has a long history of innovation when it comes to new diagnostic and therapeutic modalities, such as computed tomography angiography, anatomical resection, ablation, and transarterial chemoembolization. Among these innovations, a nationwide surveillance program was well established by the 1980s, and such a long-term national program does not exist anywhere else in the world. Summary More than 60% of the initially detected HCCs in Japan are Barcelona Clinic Liver Cancer stage 0 or A, which can undergo curative therapies such as resection, ablation, or transplantation. The recent 5-year survival rate of HCC patients in Japan was 43% and the median survival time was 50 months. In addition, both incidence and mortality rates are drastically declining as a result of the successful surveillance program, careful diagnostic flow, and extensive repeated treatments. Key Message Japan's successful model in the surveillance, diagnosis, and treatment of HCC should be adopted as widely as possible to improve the survival of HCC patients worldwide. PMID:26020028

  2. Investigation of the roles of exosomes in colorectal cancer liver metastasis.

    PubMed

    Wang, Xia; Ding, Xiaoling; Nan, Lijuan; Wang, Yiting; Wang, Jing; Yan, Zhiqiang; Zhang, Wei; Sun, Jihong; Zhu, Wei; Ni, Bing; Dong, Suzhen; Yu, Lei

    2015-05-01

    The leading cause of death among cancer patients is tumor metastasis. Tumor-derived exosomes are emerging as mediators of metastasis. In the present study, we demonstrated that exosomes play a pivotal role in the metastatic progression of colorectal cancer. First, a nude mouse model of colorectal cancer liver metastasis was established and characterized. Then, we demonstrated that exosomes from a highly liver metastatic colorectal cancer cell line (HT-29) could significantly increase the metastatic tumor burden and distribution in the mouse liver of Caco-2 colorectal cancer cells, which ordinarily exhibit poor liver metastatic potential. We further investigated the mechanisms by which HT-29-derived-exosomes influence the liver metastasis of colorectal cancer and found that mice treated with HT-29-derived exosomes had a relatively higher level of CXCR4 in the metastatic microenvironment, indicating that exosomes may promote colorectal cancer metastasis by recruiting CXCR4-expressing stromal cells to develop a permissive metastatic microenvironment. Finally, the migration of Caco-2 cells was significantly increased following treatment with HT-29-derived exosomes in vitro, further supporting a role for exosomes in modulating colorectal tumor-derived liver metastasis. The data from the present study may facilitate further translational medicine research into the prevention and treatment of colorectal cancer liver metastasis.

  3. Genomic characterization of liver metastases from colorectal cancer patients

    PubMed Central

    Sayagués, José María; Corchete, Luís Antonio; Gutiérrez, María Laura; Sarasquete, Maria Eugenia; del Mar Abad, María; Bengoechea, Oscar; Fermiñán, Encarna; Anduaga, María Fernanda; del Carmen, Sofia; Iglesias, Manuel; Esteban, Carmen; Angoso, María; Alcazar, Jose Antonio

    2016-01-01

    Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis. PMID:27662660

  4. Preclinical study of using multiphoton microscopy to diagnose liver cancer and differentiate benign and malignant liver lesions

    NASA Astrophysics Data System (ADS)

    Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Wu, Xiufeng; Zhou, Dong; Xie, Shusen; Jiang, Jiahao; Ying, Mingang; Jia, Fan; Chen, Jianxin; Zhou, Jian

    2012-02-01

    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.

  5. Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

    NASA Astrophysics Data System (ADS)

    Xia, Dong; Liu, Bing; Luan, Xiying; Sun, Junyan; Liu, Nana; Qin, Song; Du, Zhenning

    2016-03-01

    Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective effects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

  6. Lymph node-independent liver metastasis in a model of metastatic colorectal cancer.

    PubMed

    Enquist, Ida B; Good, Zinaida; Jubb, Adrian M; Fuh, Germaine; Wang, Xi; Junttila, Melissa R; Jackson, Erica L; Leong, Kevin G

    2014-03-26

    Deciphering metastatic routes is critically important as metastasis is a primary cause of cancer mortality. In colorectal cancer (CRC), it is unknown whether liver metastases derive from cancer cells that first colonize intestinal lymph nodes, or whether such metastases can form without prior lymph node involvement. A lack of relevant metastatic CRC models has precluded investigations into metastatic routes. Here we describe a metastatic CRC mouse model and show that liver metastases can manifest without a lymph node metastatic intermediary. Colorectal tumours transplanted onto the colonic mucosa invade and metastasize to specific target organs including the intestinal lymph nodes, liver and lungs. Importantly, this metastatic pattern differs from that observed following caecum implantation, which invariably involves peritoneal carcinomatosis. Anti-angiogenesis inhibits liver metastasis, yet anti-lymphangiogenesis does not impact liver metastasis despite abrogating lymph node metastasis. Our data demonstrate direct hematogenous spread as a dissemination route that contributes to CRC liver malignancy.

  7. Thermal ablation of liver metastases from colorectal cancer: radiofrequency, microwave and laser ablation therapies.

    PubMed

    Vogl, Thomas J; Farshid, Parviz; Naguib, Nagy N N; Darvishi, Abbas; Bazrafshan, Babak; Mbalisike, Emmanuel; Burkhard, Thorsten; Zangos, Stephan

    2014-07-01

    Surgery is currently considered the treatment of choice for patients with colorectal cancer liver metastases (CRLM) when resectable. The majority of these patients can also benefit from systemic chemotherapy. Recently, local or regional therapies such as thermal ablations have been used with acceptable outcomes. We searched the medical literature to identify studies and reviews relevant to radiofrequency (RF) ablation, microwave (MW) ablation and laser-induced thermotherapy (LITT) in terms of local progression, survival indexes and major complications in patients with CRLM. Reviewed literature showed a local progression rate between 2.8 and 29.7 % of RF-ablated liver lesions at 12-49 months follow-up, 2.7-12.5 % of MW ablated lesions at 5-19 months follow-up and 5.2 % of lesions treated with LITT at 6-month follow-up. Major complications were observed in 4-33 % of patients treated with RF ablation, 0-19 % of patients treated with MW ablation and 0.1-3.5 % of lesions treated with LITT. Although not significantly different, the mean of 1-, 3- and 5-year survival rates for RF-, MW- and laser ablated lesions was (92.6, 44.7, 31.1 %), (79, 38.6, 21 %) and (94.2, 61.5, 29.2 %), respectively. The median survival in these methods was 33.2, 29.5 and 33.7 months, respectively. Thermal ablation may be an appropriate alternative in patients with CRLM who have inoperable liver lesions or have operable lesions as an adjunct to resection. However, further competitive evaluation should clarify the efficacy and priority of these therapies in patients with colorectal cancer liver metastases.

  8. NAD(+) administration decreases doxorubicin-induced liver damage of mice by enhancing antioxidation capacity and decreasing DNA damage.

    PubMed

    Wang, Ban; Ma, Yingxin; Kong, Xiaoni; Ding, Xianting; Gu, Hongchen; Chu, Tianqing; Ying, Weihai

    2014-04-05

    One of the major obstacles for cancer treatment is the toxic side effects of anti-cancer drugs. Doxorubicin (DOX) is one of the most widely used anti-cancer drugs, which produces significant toxic side effects on the heart and such organs as the liver. Because NAD(+) can decrease cellular or tissue damage under multiple conditions, we hypothesized that NAD(+) administration may decrease DOX-induced hepatotoxicity. In this study we tested this hypothesis by using a mouse model, showing that NAD(+) administration can significantly attenuate DOX-induced increase in serum glutamate oxaloacetate transaminase activity and decrease in liver weight. The NAD(+) administration also attenuated the DOX-induced increases in the levels of double-strand DNA (dsDNA) damage, TUNEL signals, and active caspase-3. Furthermore, our data has suggested that the NAD(+) administration could produce protective effects at least partially by restoring the antioxidation capacity of the liver, because NAD(+) administration can attenuate the decreases in both the GSH levels and the glutathione reductase activity of the DOX-treated liver, which could play a significant role in the DOX-induced hepatotoxicity. This finding has provided the first evidence indicating that NAD(+) is capable of increasing the antioxidation capacity of tissues. Collectively, our study has found that NAD(+) can significantly decrease DOX-induced liver damage at least partially by enhancing antioxidation capacity and decreasing dsDNA damage. Because it can also selectively decrease tumor cell survival, NAD(+) may have significant merits over antioxidants for applying jointly with DOX to decrease the toxic side effects of DOX.

  9. Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes.

    PubMed

    Tabariès, Sébastien; Dupuy, Fanny; Dong, Zhifeng; Monast, Anie; Annis, Matthew G; Spicer, Jonathan; Ferri, Lorenzo E; Omeroglu, Atilla; Basik, Mark; Amir, Eitan; Clemons, Mark; Siegel, Peter M

    2012-08-01

    We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes.

  10. Genipin alleviates sepsis‐induced liver injury by restoring autophagy

    PubMed Central

    Cho, Hong‐Ik; Kim, So‐Jin; Choi, Joo‐Wan

    2016-01-01

    Background and Purpose Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli including inflammation and microbial infection. Genipin, an aglycon of geniposide found in gardenia fruit, is well known to have anti‐inflammatory, antibacterial and antioxidative properties. This study examined the protective mechanisms of genipin against sepsis, with particular focus on the autophagic signalling pathway. Experimental Approach Mice were subjected to sepsis by caecal ligation and puncture (CLP). Genipin (1, 2.5 and 5 mg·kg−1) or vehicle (saline) was injected i.v. immediately (0 h) after CLP, and chloroquine (60 mg·kg−1), an autophagy inhibitor, was injected i.p. 1 h before CLP. Blood and liver tissues were isolated 6 h after CLP. Key Results Genipin improved survival rate and decreased serum levels of aminotransferases and pro‐inflammatory cytokines after CLP; effects abolished by chloroquine. The liver expression of autophagy‐related protein (Atg)12‐Atg5 conjugate increased after CLP, and this increase was enhanced by genipin. CLP decreased Atg3 protein liver expression, and genipin attenuated this decrease. CLP impaired autophagic flux, as indicated by increased liver expression of microtubule‐associated protein‐1 light chain 3‐II and sequestosome‐1/p62 protein; this impaired autophagic flux was restored by genipin, and chloroquine abolished this effect. Genipin also attenuated the decreased expression of lysosome‐associated membrane protein‐2 and Rab7 protein and increased expression of calpain 1 protein induced by CLP in the liver. Conclusions and Implications Our findings suggest that genipin protects against septic injury by restoring impaired autophagic flux. Therefore, genipin might be a potential therapeutic agent for the treatment of sepsis. PMID:26660048

  11. Albendazole-induced liver injury: a case report

    PubMed Central

    Restrepo, Juan C

    2013-01-01

    We report a case of a 47-year-old male, who was referred to the clinical hepatology services at Pablo Tobón Uribe Hospital for evaluation of a jaundice syndrome. After undergoing several exams, we diagnosed hepatic hydatidosis and the patient was treated with albendazole; however, after five months of uninterrupted treatment the patient again consulted and his liver test showed marked hepatocellular damage. This time, the patient was diagnosed with drug-induced liver injury due to albendazole, based on information from the clinical record, history of drug consumption, clinical and laboratory tests improved after discontinuing the medication and after discarding other possible causes; this diagnosis was supported by the CIOMS/RUCAM scale, which showed a "likely" correlation between hepatocellular damage and drug toxicity etiology. PMID:24892458

  12. Albendazole-induced liver injury: a case report.

    PubMed

    Ríos, David; Restrepo, Juan C

    2013-04-01

    We report a case of a 47-year-old male, who was referred to the clinical hepatology services at Pablo Tobón Uribe Hospital for evaluation of a jaundice syndrome. After undergoing several exams, we diagnosed hepatic hydatidosis and the patient was treated with albendazole; however, after five months of uninterrupted treatment the patient again consulted and his liver test showed marked hepatocellular damage. This time, the patient was diagnosed with drug-induced liver injury due to albendazole, based on information from the clinical record, history of drug consumption, clinical and laboratory tests improved after discontinuing the medication and after discarding other possible causes; this diagnosis was supported by the CIOMS/RUCAM scale, which showed a "likely" correlation between hepatocellular damage and drug toxicity etiology.

  13. IDH mutations in liver cell plasticity and biliary cancer.

    PubMed

    Saha, Supriya K; Parachoniak, Christine A; Bardeesy, Nabeel

    2014-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer associated with the bile ducts within the liver. These tumors are characterized by frequent gain-of-function mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes-that are also common in subsets of neural, haematopoietic and bone tumors, but rare or absent in the other types of gastrointestinal malignancy. Mutant IDH acts through a novel mechanism of oncogenesis, producing high levels of the metabolite 2-hydroxyglutarate, which interferes with the function of α-ketoglutarate-dependent enzymes that regulate diverse cellular processes including histone demethylation and DNA modification. Recently, we used in vitro stem cell systems and genetically engineered mouse models (GEMMs) to demonstrate that mutant IDH promotes ICC formation by blocking hepatocyte differentiation and increasing pools of hepatic progenitors that are susceptible to additional oncogenic hits leading to ICC. We found that silencing of HNF4A-encoding a master transcriptional regulator of hepatocyte identity and quiescence-was critical to mutant IDH-mediated inhibition of liver differentiation. In line with these findings, human ICC with IDH mutations are characterized by a hepatic progenitor cell transcriptional signature suggesting that they are a distinct ICC subtype as compared to IDH wild type tumors. The role of mutant IDH in controlling hepatic differentiation state suggests the potential of newly developed inhibitors of the mutant enzyme as a form of differentiation therapy in a solid tumor.

  14. Clinical Characteristics of Patients with Drug-induced Liver Injury

    PubMed Central

    Yang, Li-Xia; Liu, Cheng-Yuan; Zhang, Lun-Li; Lai, Ling-Ling; Fang, Ming; Zhang, Chong

    2017-01-01

    Background: Drug is an important cause of liver injury and accounts for up to 40% of instances of fulminant hepatic failure. Drug-induced liver injury (DILI) is increasing while the diagnosis becomes more difficult. Though many drugs may cause DILI, Chinese herbal medicines have recently emerged as a major cause due to their extensive use in China. We aimed to provide drug safety information to patients and health carers by analyzing the clinical and pathological characteristics of the DILI and the associated drug types. Methods: A retrospective analysis was conducted in 287 patients diagnosed with DILI enrolled in our hospital from January 2011 to December 2015. The categories of causative drugs, clinical and pathological characteristics were reviewed. Results: Western medicines ranked as the top cause of DILI, accounting for 163 out of the 287 DILI patients (56.79%) in our study. Among the Western medicine, antituberculosis drugs were the highest cause (18.47%, 53 patients) of DILI. Antibiotics (18 patients, 6.27%) and antithyroid (18 patients, 6.27%) drugs also ranked among the major causes of DILI. Chinese herbal medicines are another major cause of DILI, accounting for 36.59% of cases (105 patients). Most of the causative Chinese herbal medicines were those used to treat osteopathy, arthropathy, dermatosis, gastropathy, leukotrichia, alopecia, and gynecologic diseases. Hepatocellular hepatitis was prevalent in DILI, regardless of Chinese herbal medicine or Western medicine-induced DILI. Conclusions: Risks and the rational use of medicines should be made clear to reduce the occurrence of DILI. For patients with liver injury of unknown origin, liver tissue pathological examination is recommended for further diagnosis. PMID:28091407

  15. Chemical inhibition reveals differential requirements of signaling pathways in krasV12- and Myc-induced liver tumors in transgenic zebrafish

    PubMed Central

    Yan, Chuan; Yang, Qiqi; Huo, Xiaojing; Li, Hankun; Zhou, Li; Gong, Zhiyuan

    2017-01-01

    Previously we have generated inducible liver tumor models by transgenic expression of an oncogene and robust tumorigenesis can be rapidly induced by activation of the oncogene in both juvenile and adult fish. In the present study, we aimed at chemical intervention of tumorigenesis for understanding molecular pathways of tumorigenesis and for potential development of a chemical screening tool for anti-cancer drug discovery. Thus, we evaluated the roles of several major signaling pathways in krasV12- or Myc-induced liver tumors by using several small molecule inhibitors: SU5402 and SU6668 for VEGF/FGF signaling; IWR1 and cardionogen 1 for Wnt signaling; and cyclopamine and Gant61 for Hedgehog signaling. Inhibition of VEGF/FGF signaling was found to deter both Myc- and krasV12-induced liver tumorigenesis while suppression of Wnt signaling relaxed only Myc- but not krasV12-induced liver tumorigenesis. Inhibiting Hedgehog signaling did not suppress either krasV12 or Myc-induced tumors. The suppression of liver tumorigenesis was accompanied with a decrease of cell proliferation, increase of apoptosis, distorted liver histology. Collectively, our observations suggested the requirement of VEGF/FGF signaling but not the hedgehog signaling in liver tumorigenesis in both transgenic fry. However, Wnt signaling appeared to be required for liver tumorigenesis only in Myc but not krasV12 transgenic zebrafish. PMID:28378824

  16. Establishment of Hepatocellular Cancer Induced Pluripotent Stem Cells Using a Reprogramming Technique

    PubMed Central

    Kim, Han Joon; Jeong, Jaemin; Park, Sunhoo; Jin, Young-Woo; Lee, Seung-Sook; Lee, Seung Bum; Choi, Dongho

    2017-01-01

    Background/Aims Cancer is known to be a disease by many factors. However, specific results of reprogramming by pluripotency-related transcription factors remain to be scarcely reported. Here, we verified potential effects of pluripotent-related genes in hepatocellular carcinoma cancer cells. Methods To better understand reprogramming of cancer cells in different genetic backgrounds, we used four liver cancer cell lines representing different states of p53 (HepG2, Hep3B, Huh7 and PLC). Retroviral-mediated introduction of reprogramming related genes (KLF4, Oct4, Sox2, and Myc) was used to induce the expression of proteins related to a pluripotent status in liver cancer cells. Results Hep3B cells (null p53) exhibited a higher efficiency of reprogramming in comparison to the other liver cancer cell lines. The reprogrammed Hep3B cells acquired similar characteristics to pluripotent stem cells. However, loss of stemness in Hep3B-iPCs was detected during continual passage. Conclusions We demonstrated that reprogramming was achieved in tumor cells through retroviral induction of genes associated with reprogramming. Interestingly, the reprogrammed pluripotent cancer cells (iPCs) were very different from original cancer cells in terms of colony shape and expressed markers. The induction of pluripotency of liver cancer cells correlated with the status of p53, suggesting that different expression level of p53 in cancer cells may affect their reprogramming. PMID:27728962

  17. Effects of carnosine, taurine, and betaine pretreatments on diethylnitrosamine-induced oxidative stress and tissue injury in rat liver.

    PubMed

    Başaran-Küçükgergin, C; Bingül, I; Tekkeşin, M Soluk; Olgaç, V; Doğru-Abbasoğlu, S; Uysal, M

    2016-08-01

    Several chemicals such as N-diethylnitrosamine (DEN) promote hepatocellular cancer in rodents and induce hepatocyte injury. DEN affects the initiation stage of carcinogenesis together with enhanced cell proliferation accompanied by hepatocellular necrosis. DEN-induced hepatocellular necrosis is reported to be related to enhanced generation of reactive oxygen species. Carnosine (CAR), taurine (TAU), and betaine (BET) are known to have powerful antioxidant properties. We aimed to investigate the effects of CAR, TAU, and BET pretreatments on DEN-induced oxidative stress and liver injury in male rats. Rats were given CAR (2 g L(-1) in drinking water), TAU (2.5% in chow), and BET (2.5% in chow) for 6 weeks and DEN (200 mg kg(-1) intraperitoneally) was given 2 days before the end of this period. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and γ-glutamyl transferase activities were determined and a histopathologic evaluation was performed on the liver tissue. Oxidative stress was detected in the liver by measuring malondialdehyde, diene conjugate, protein carbonyl and nitrotyrosine levels, glutathione and glutathione peroxidase levels, and superoxide dismutase and glutathione transferase activities. Pretreatments with CAR, TAU, and BET decreased liver prooxidant status without remarkable changes in antioxidant parameters in DEN-treated rats. Pretreatments with TAU and BET, but not CAR, were also found to be effective to reduce liver damage in DEN-treated rats. In conclusion, TAU, BET, and possibly CAR may have an ameliorating effect on DEN-induced hepatic injury by reducing oxidative stress in rats.

  18. Quantitation of TCE-Induced Radicals in Liver of B6C3Fl Mice In Vivo: An EPR Study

    DTIC Science & Technology

    1996-02-01

    PAGE 1 First derivative EPR spectrum of B6C3F1 mouse liver (a) after and (b) before lyophilization 8 2 GC/MS of PBN extract (a) Total ion current...of TCE-induced cancer in a number of animal species remains to be elucidated. The biological effects of TCE are of special interest to us because TCE...injection the mouse was killed and the liver was harvested. Figure 2A shows the total ion current gas chromatogram of the GC/MS analysis of.a non polar

  19. Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells.

    PubMed

    Yang, D; Li, L; Liu, H; Wu, L; Luo, Z; Li, H; Zheng, S; Gao, H; Chu, Y; Sun, Y; Liu, J; Jia, L

    2013-02-01

    Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.

  20. Liver iron overload induced by tamoxifen in diabetic and non-diabetic female Wistar rats.

    PubMed

    Jatobá, Carlos André Nunes; de Rezende, Adriana Augusto; de Paiva Rodrigues, Sarah Jane; de Almeida Câmara, Maria Margareth; das Graças Almeida, Maria; Freire-Neto, Francisco; da Rocha, Luiz Reginaldo Menezes; da Medeiros, Aldo Cunha; Brandão-Neto, José; de Carvalho Formiga, Maria Célia; de Azevedo, Italo Medeiros; de Oliveira Ramos, Ana Maria

    2008-04-01

    Tamoxifen (TX), a drug used in the treatment of breast cancer, may cause hepatic changes in some patients. The consequences of its use on the liver tissues of rats with or without diabetes mellitus (DM) have not been fully explored. The purpose of this study was to evaluate the correlation between plasma hepatic enzyme levels and the presence of iron overload in the hepatic tissue of female Wistar rats with or without streptozotocin-induced DM and using TX. Female rats were studied in control groups: C-0 (non-drug users), C-V (sorbitol vehicle only) and C-TX (using TX). DM (diabetic non-drug users) and DM-TX (diabetics using TX) were the test groups. Sixty days after induced DM, blood samples were collected for glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST) alkaline phosphatase (ALP) and bilirubin measures. Hepatic fragments were processed and stained with hematoxylin and eosin, Masson's trichrome, Perls. The hepatic iron content was quantified by atomic absorption spectrometry. AST, ALT and ALP levels were significantly elevated in the DM and DM-TX groups, with unchanged bilirubin levels. Liver iron overload using Perls stain and atomic absorption spectrometry were observed exclusively in groups C-TX and DM-TX. There was positive correlation between AST, ALT and ALP levels and microscopic hepatic siderosis intensity in group DM-TX. In conclusion, TX administration is associated with liver siderosis in diabetic and non-diabetic rats. In addition, TX induced liver iron overload with unaltered hepatic function in non-diabetic rats and may be a useful tool for investigating the biological control of iron metabolism.

  1. The Link Between Hepatitis B and Liver Cancer: The Asian American Community

    Cancer.gov

    Dr. Moon Chen, Professor of the Department of Internal Medicine and Associate Director of Cancer Control at the University of California-Davis Comprehensive Cancer Center, speaks about Hepatitis B and Liver Cancer as a more prevalent problem in the Asian American community.

  2. Liver Contrast-Enhanced Ultrasound Improves Detection of Liver Metastases in Patients with Pancreatic or Periampullary Cancer.

    PubMed

    Taimr, Pavel; Jongerius, Vivian L; Pek, Chulja J; Krak, Nanda C; Hansen, Bettina E; Janssen, Harry L A; Metselaar, Herold J; van Eijck, Casper H J

    2015-12-01

    The aim of this study is to provide a diagnostic performance evaluation of contrast-enhanced ultrasonography (CEUS) in detecting liver metastases in patients with suspected of pancreatic or periampullary cancer. Computed tomography (CT) is often insufficient for detection of liver metastases, but their presence plays a crucial role in the choice of therapy. Eighty-nine patients with suspected pancreatic or periampullary cancer were included in this prospective study with retrospective analysis. Patients underwent an abdominal CT and CEUS. Fifteen patients had liver metastases. The CT sensitivity was 73.3% (11/15), the specificity 93.2% (69/74), the positive predictive value (PPV) 68.8% (11/16) and the negative predictive value (NPV) 94.6% (69/73). Based on CEUS, the sensitivity was 80% (12/15), specificity 98.6% (73/74), PPV 92.3% (12/13) and NPV 96.1% (73/76). CEUS improved characterization of liver lesions in patients with suspected pancreatic or periampullary cancer compared with CT. CEUS can better detect benign liver lesions and distinguish false-positive or indeterminate CT results.

  3. Thrombocytosis of Liver Metastasis from Colorectal Cancer as Predictive Factor.

    PubMed

    Jósa, Valéria; Krzystanek, Marcin; Vass, Tamás; Lang, Tamás; Juhász, Viktória; Szilágyi, Kamilla; Tihanyi, Balázs; Harsányi, László; Szállási, Zoltán; Salamon, Ferenc; Baranyai, Zsolt

    2015-09-01

    There is increasing evidence that thrombocytosis is associated with tumor invasion and metastasis formation. It was shown in several solid tumor types that thrombocytosis prognosticates cancer progression. The aim of this study was to evaluate preoperative thrombocytosis as a potential prognostic biomarker in isolated metastases, in patients with liver metastasis of colorectal cancer (mCRC). Clinicopathological data of 166 patients with mCRC who had surgical resection between 2001 and 2011 were collected retrospectively. All primary tumors have been already resected. The platelet count was evaluated based on the standard preoperative blood profile. The patients were followed-up on average for 28 months. Overall survival (OS) of patients with thrombocytosis was significantly worse both in univariate (HR = 3.00, p = 0.03) and in multivariate analysis (HR = 4.68, p = 0.056) when adjusted for gender, age, tumor size and surgical margin. Thrombocytosis was also a good prognosticator of disease-free survival (DFS) with HR = 2.7, p = 0.018 and nearly significant in multivariate setting (HR = 2.26, p = 0.073). The platelet count is a valuable prognostic marker for the survival in patients with mCRC.

  4. Protective role of thymoquinone against liver damage induced by tamoxifen in female rats.

    PubMed

    Suddek, Ghada M

    2014-08-01

    One of the major reasons for terminating a clinical trial is the liver toxicity induced by chemotherapy. Tamoxifen (TAM) is an anti-estrogen used in the treatment and prevention of hormone-dependent breast cancer. Tamoxifen therapy may cause hepatic injury. The seeds of Nigella sativa, which contain the active ingredient thymoquinone (TQ), have been used in folk medicine for diverse ailments. TQ is reported to possess anticancer and hepatoprotective effects. In this study, the protective effects of TQ against TAM-induced hepatotoxicity in female rats were evaluated. Four groups of rats were used: control; TAM; TQ; TAM+TQ. TAM (45 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection (i.p.), for 10 consecutive days) resulted in elevated serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, and gamma glutamyl transferase, as well as depletion of reduced glutathione in the liver and accumulation of lipid peroxides. Also, TAM treatment inhibited the hepatic activity of superoxide dismutase. Further, it raised the levels of tumor necrosis factor alpha in the liver and induced histopathological changes. Pretreatment with TQ (50 mg·(kg body mass)(-1)·day(-1); orally, for 20 consecutive days, starting 10 days before TAM injection) significantly prevented the elevation in serum activity of the assessed enzymes. TQ significantly inhibited TAM-induced hepatic GSH depletion and LPO accumulation. Consistently, TQ normalized the activity of SOD, inhibited the rise in TNF-α and ameliorated the histopathological changes. In conclusion, TQ protects against TAM-induced hepatotoxicity.

  5. Analysis of liver-directed therapies in U.S. cancer patients

    PubMed Central

    Alese, O.B.; Kim, S.; Chen, Z.; Ramalingam, S.S.; Owonikoko, T.K.; El-Rayes, B.F.

    2015-01-01

    Background The liver is a common site of primary and metastatic cancer. Liver-directed therapies are commonly used to treat cancer involving the liver. We report on the patterns, predictors, and outcomes of liver-directed therapies in hospitalized cancer patients in the United States. Methods Data were obtained from all U.S. states that contributed to the Nationwide Inpatient Sample maintained by the Agency for Healthcare Research and Quality between 2006 and 2010. Univariate and multivariate testing was used to identify factors significantly associated with patient outcome. Results For the 5-year period of interest, 12,540 patient discharges were identified. Mean age in the sample was 60 years. Primary liver lesions (n = 8840) made up 26.9% of the sample; the remaining cases were metastases. Most procedures were performed in large (79%) urban (98%) hospitals and in patients with insurance (97.9%). The most common intervention was partial hepatectomy (42.7%), followed by open (9.9%), percutaneous (7.2%), and laparoscopic (5.04%) ablation of liver lesions; embolization (9.8%); and liver transplantation (2.64%). The incidence of in-hospital mortality was very low (2.4%), and the complication rate was 12.2%. Complications such as acute liver necrosis, ascites, hepatic coma, hepatorenal syndrome, liver abscess, and high number of comorbid illnesses (>8) accounted for 60% of the in-hospital mortality. Conclusions The low rate of morbidity and mortality associated with liver-directed therapies in hospitalized cancer patients supports the continuing utility of such procedures in the management of primary and metastatic liver cancer. The patterns of health disparities observed with respect to the use of liver-directed therapies are concerning. PMID:26715883

  6. ATOH1 Can Regulate the Tumorigenicity of Gastric Cancer Cells by Inducing the Differentiation of Cancer Stem Cells

    PubMed Central

    Han, Myoung-Eun; Baek, Su-Jin; Kim, Seon-Young; Kang, Chi-Dug; Oh, Sae-Ock

    2015-01-01

    Cancer stem cells (CSCs) have been shown to mediate tumorigenicity, chemo-resistance, radio-resistance and metastasis, which suggest they be considered therapeutic targets. Because their differentiated daughter cells are no longer tumorigenic, to induce the differentiation of CSCs can be one of strategies which can eradicate CSCs. Here we show that ATOH1 can induce the differentiation of gastric cancer stem cells (GCSCs). Real time PCR and western blot analysis showed that ATOH1 was induced during the differentiation of GCSCs. Furthermore, the lentivirus-induced overexpression of ATOH1 in GCSCs and in gastric cancer cell lines significantly induced differentiation, reduced proliferation and sphere formation, and reduced in vivo tumor formation in the subcutaneous injection and liver metastasis xenograft models. These results suggest ATOH1 be considered for the development of a differentiation therapy for gastric cancer. PMID:25950549

  7. Combined Therapy with Cytokine-Induced Killer Cells and Oncolytic Adenovirus Expressing IL-12 Induce Enhanced Antitumor Activity in Liver Tumor Model

    PubMed Central

    Shan, Juanjuan; Shen, Junjie; Liu, Limei; Xu, Yanmin; Xia, Feng; Bie, Ping; Zhang, Xia; Cui, Youhong; Bian, Xiu-wu; Qian, Cheng

    2012-01-01

    Both adoptive immunotherapy and gene therapy hold a great promise for treatment of malignancies. However, these strategies exhibit limited anti-tumor activity, when they are used alone. In this study, we explore whether combination of cytokine-induced killer (CIK) adoptive immunotherapy with oncolytic adenovirus-mediated transfer of human interleukin-12 (hIL-12) gene induce the enhanced antitumor potency. Our results showed that oncolytic adenovirus carrying hIL-12 (AdCN205-IL12) could produce high levels of hIL-12 in liver cancer cells, as compared with replication-defective adenovirus expressing hIL-12 (Ad-IL12). AdCN205-IL12 could specifically induce cytotoxocity to liver cancer cells. Combination of CIK cells with AdCN205-IL12 could induce higher antitumor activity to liver cancer cells in vitro than that induced by either CIK or AdCN205-IL12 alone, or combination of CIK and control vector AdCN205-GFP. Furthermore, treatment of the established liver tumors with the combined therapy of CIK cells and AdCN205-IL12 resulted in tumor regression and long-term survival. High level expression of hIL-12 in tumor tissues could increase traffic of CIK cells to tumor tissues and enhance their antitumor activities. Our study provides a novel strategy for the therapy of cancer by the combination of CIK adoptive immunotherapy with oncolytic adenovirus-mediated transfer of immune stimulatory molecule hIL-12. PMID:23028626

  8. Schistosome and liver fluke derived catechol-estrogens and helminth associated cancers

    PubMed Central

    Correia da Costa, José M.; Vale, Nuno; Gouveia, Maria J.; Botelho, Mónica C.; Sripa, Banchob; Santos, Lúcio L.; Santos, Júlio H.; Rinaldi, Gabriel; Brindley, Paul J.

    2014-01-01

    Infection with helminth parasites remains a persistent public health problem in developing countries. Three of these pathogens, the liver flukes Clonorchis sinensis, Opisthorchis viverrini and the blood fluke Schistosoma haematobium, are of particular concern due to their classification as Group 1 carcinogens: infection with these worms is carcinogenic. Using liquid chromatography-mass spectrometry (LC-MS/MS) approaches, we identified steroid hormone like (e.g., oxysterol-like, catechol estrogen quinone-like, etc.) metabolites and related DNA-adducts, apparently of parasite origin, in developmental stages including eggs of S. haematobium, in urine of people with urogenital schistosomiasis, and in the adult stage of O. viverrini. Since these kinds of sterol derivatives are metabolized to active quinones that can modify DNA, which in other contexts can lead to breast and other cancers, helminth parasite associated sterols might induce tumor-like phenotypes in the target cells susceptible to helminth parasite associated cancers, i.e., urothelial cells of the bladder in the case of urogenital schistosomiasis and the bile duct epithelia or cholangiocytes, in the case of O. viverrini and C. sinensis. Indeed we postulate that helminth induced cancers originate from parasite estrogen-host epithelial/urothelial cell chromosomal DNA adducts, and here we review recent findings that support this conjecture. PMID:25566326

  9. Radiation-Induced Vaccination to Breast Cancer

    DTIC Science & Technology

    2014-10-01

    Award Number: W81XWH-11-1-0531 TITLE: Radiation-Induced Vaccination to Breast Cancer PRINCIPAL INVESTIGATOR: William H. McBride CONTRACTING...TITLE AND SUBTITLE Radiation-Induced Vaccination to Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0531 5c. PROGRAM ELEMENT NUMBER

  10. Whole-liver CT texture analysis in colorectal cancer: Does the presence of liver metastases affect the texture of the remaining liver?

    PubMed Central

    Rao, Sheng-Xiang; Lambregts, Doenja MJ; Schnerr, Roald S; van Ommen, Wenzel; van Nijnatten, Thiemo JA; Martens, Milou H; Heijnen, Luc A; Backes, Walter H; Verhoef, Cornelis; Zeng, Meng-Su; Beets, Geerard L

    2014-01-01

    Background Liver metastases limit survival in colorectal cancer. Earlier detection of (occult) metastatic disease may benefit treatment and survival. Objective The objective of this article is to evaluate the potential of whole-liver CT texture analysis of apparently disease-free liver parenchyma for discriminating between colorectal cancer (CRC) patients with and without hepatic metastases. Methods The primary staging CT examinations of 29 CRC patients were retrospectively analysed. Patients were divided into three groups: patients without liver metastases (n = 15), with synchronous liver metastases (n = 10) and metachronous liver metastases within 18 months following primary staging (n = 4). Whole-liver texture analysis was performed by delineation of the apparently non-diseased liver parenchyma (excluding metastases or other focal liver lesions) on portal phase images. Mean grey-level intensity (M), entropy (E) and uniformity (U) were derived with no filtration and different filter widths (0.5 = fine, 1.5 = medium, 2.5 = coarse). Results Mean E1.5 and E2.5 for the whole liver in patients with synchronous metastases were significantly higher compared with the non-metastatic patients (p = 0.02 and p = 0.01). Mean U1.5 and U2.5 were significantly lower in the synchronous metastases group compared with the non-metastatic group (p = 0.04 and p = 0.02). Texture parameters for the metachronous metastases group were not significantly different from the non-metastatic group or synchronous metastases group (p > 0.05), although – similar to the synchronous metastases group – there was a subtle trend towards increased E1.5, E2.5 and decreased U1.5, U2.5 values. Areas under the ROC curve for the diagnosis of synchronous metastatic disease based on the texture parameters E1.5,2.5 and U1.5,2.5 ranged between 0.73 and 0.78. Conclusion Texture analysis of the apparently non-diseased liver holds promise to differentiate between CRC

  11. Prognostic significance of B7-H4 expression in matched primary pancreatic cancer and liver metastases

    PubMed Central

    Qian, Yun; Sang, Yiwen; Wang, Frederick X.C.; Hong, Bo; Wang, Qi; Zhou, Xinhui; Weng, Tianhao; Wu, Zhigang; Zheng, Min; Zhang, Hong; Yao, Hangping

    2016-01-01

    Liver metastasis development in pancreatic cancer patients is common and confers a poor prognosis. Clinical relevance of biomarker analysis in metastatic tissue is necessary. B7-H4 has an inhibitory effect on T cell mediated response and may be involved in tumor development. Although B7-H4 expression has been detected in pancreatic cancer, its expression in liver metastases from pancreatic cancer is still unknown. In this study, overall 43 pancreatic cancer liver metastases (with matched primaries in 15/43 cases) and 57 pancreatic cancer cases without liver metastases or other distant metastases were analyzed for their expression of B7-H4 by immunohistochemistry. Survival curves and log-rank tests were used to test the association of B7-H4 expression with survival. B7-H4 was highly expressed in 28 (65.1%) of the 43 liver metastases and 9 (60.0%) of the 15 matched primary tumors. The expression of B7-H4 in liver metastases was significantly higher than in the matched primary tumors (p < 0.05). Patients with high B7-H4 expression in their primary pancreatic cancer had higher risk of developing liver metastases (p < 0.05). In univariate analysis, B7-H4 expression was significantly associated with the risk of death (p < 0.05). And the multivariate analysis identified that B7-H4 was an independent prognostic indicator (p < 0.05). Our results revealed B7-H4 to be associated with poor prognosis in patients with pancreatic cancer liver metastasis. B7-H4 may promote pancreatic cancer metastasis and was promising to be a potential prognostic indicator of pancreatic cancer. PMID:27750217

  12. Isolated Liver Metastasis in Hürthle Cell Thyroid Cancer Treated with Microwave Ablation.

    PubMed

    Segkos, Konstantinos; Schmidt, Carl; Nabhan, Fadi

    2017-01-01

    Hürthle cell thyroid cancer (HCTC) is a less common form of differentiated thyroid cancer. It rarely metastasizes to the liver, and when it does, the metastasis is almost never isolated. Here we report a 62-year-old male with widely invasive Hürthle cell thyroid cancer, who underwent total thyroidectomy and received adjuvant treatment with I-131 with posttreatment scan showing no evidence of metastatic disease. His thyroglobulin however continued to rise after that and eventually an isolated liver metastasis was identified. He underwent laparoscopic microwave ablation of the liver metastasis, with dramatic decline in thyroglobulin and no structural disease identified to date. This case highlights the rare occurrence of isolated liver metastasis from HCTC and also illustrates the utility of thermoablation as an alternative to surgical resection in the treatment of small isolated liver metastases from HCTC.

  13. Isolated Liver Metastasis in Hürthle Cell Thyroid Cancer Treated with Microwave Ablation

    PubMed Central

    2017-01-01

    Hürthle cell thyroid cancer (HCTC) is a less common form of differentiated thyroid cancer. It rarely metastasizes to the liver, and when it does, the metastasis is almost never isolated. Here we report a 62-year-old male with widely invasive Hürthle cell thyroid cancer, who underwent total thyroidectomy and received adjuvant treatment with I-131 with posttreatment scan showing no evidence of metastatic disease. His thyroglobulin however continued to rise after that and eventually an isolated liver metastasis was identified. He underwent laparoscopic microwave ablation of the liver metastasis, with dramatic decline in thyroglobulin and no structural disease identified to date. This case highlights the rare occurrence of isolated liver metastasis from HCTC and also illustrates the utility of thermoablation as an alternative to surgical resection in the treatment of small isolated liver metastases from HCTC. PMID:28163939

  14. Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

    ClinicalTrials.gov

    2017-03-17

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  15. Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population

    PubMed Central

    Jung, Jae Woo; Yoon, So-Mi; Kim, Subin; Jeon, Yun-Hui; Yoon, Byung-Hak; Yang, Su-Geun; Kim, Min Kyoung; Choe, Senyon; Kuo, Mario Meng-Chiang

    2016-01-01

    The biological role of BMP-9 signaling in liver cancer remains dubious. To explore the potential use of BMP-9 signaling for anti-cancer therapy, we used recombinant human BMP-9, which we referred to as MB109, to study the effect on growth of fifteen hepatocellular carcinoma (HCC) cell lines. MB109 effectively inhibits the proliferation of nine HCC cells in vitro. The anti-proliferative effect was found to be induced by turning on p21 signaling, which caused survivin suppression and G0/G1 cell cycle arrest. ID3 was identified to be the mediator of the MB109-induced p21 expression. Blocking the activity of p38 MAPK diminished ID3 and p21 expression, indicating that MB109 signals through a p38 MAPK/ID3/p21 pathway to arrest cell cycle progression. Moreover, prolonged MB109 treatment suppressed the expression of five prominent liver cancer stem cell (LCSC) markers, including CD44, CD90, AFP, GPC3 and ANPEP. Xenograft model confirmed the anti-tumor and LCSC-suppression capability of MB109 in vivo. Contrary to ongoing efforts of suppressing BMP-9 signaling to inhibit angiogenesis of cancer tissue, these results demonstrate an unexpected therapeutic potential of MB109 to stimulate BMP-9 signaling for anti-cancer therapies. PMID:27650540

  16. Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure.

    PubMed

    van Mierlo, Kim M C; Schaap, Frank G; Dejong, Cornelis H C; Olde Damink, Steven W M

    2016-12-01

    Hepatic failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. Despite improved perioperative care, the increasing complexity and extensiveness of surgical interventions, in combination with an expanding number of resections in patients with compromised liver function, still results in an incidence of postresectional liver failure (PLF) of 1-9%. Preventive measures aim to enhance future remnant liver size and function. Numerous non-invasive techniques to assess liver function and predict remnant liver volume are being developed, along with introduction of novel surgical strategies that augment growth of the future remnant liver. Detection of PLF is often too late and treatment is primarily symptomatic. Current therapeutic research focuses on ([bio]artificial) liver function support and regenerative medicine. In this review we discuss the current state and new developments in prediction, prevention and management of PLF, in light of novel insights into the aetiology of this complex syndrome.

  17. Prediction of drug-induced liver injury using keratinocytes.

    PubMed

    Hirashima, Rika; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2017-01-31

    Drug-induced liver injury (DILI) is one of the most common adverse drug reactions. DILI is often accompanied by skin reactions, including rash and pruritus. However, it is still unknown whether DILI-associated genes such as S100 calcium-binding protein A and interleukin (IL)-1β are involved in drug-induced skin toxicity. In the present study, most of the tested hepatotoxic drugs such as pioglitazone and diclofenac induced DILI-associated genes in human and mouse keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased IL-1β basal expression. They also showed a higher inducibility of IL-1β when treated by pioglitazone. Mice at higher risk for DILI showed even higher sums of DILI-associated gene basal expression levels and induction rates in keratinocytes. Our data suggest that DILI-associated genes might be involved in the onset and progression of drug-induced skin toxicity. Furthermore, we might be able to identify individuals at higher risk of developing DILI less invasively by examining gene expression patterns in keratinocytes. Copyright © 2017 John Wiley & Sons, Ltd.

  18. Irinotecan-Eluting Beads in Treating Patients With Refractory Metastatic Colon or Rectal Cancer That Has Spread to the Liver

    ClinicalTrials.gov

    2017-01-24

    Liver Metastases; Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

  19. HBV infection decreases risk of liver metastasis in patients with colorectal cancer: A cohort study

    PubMed Central

    Qiu, Hai-Bo; Zhang, Li-Yi; Zeng, Zhao-Lei; Wang, Zhi-Qiang; Luo, Hui-Yan; Keshari, Rajiv Prasad; Zhou, Zhi-Wei; Xu, Rui-Hua

    2011-01-01

    AIM: To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer. METHODS: A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study. Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer. Patients were divided into study (infection) group and control (non-infection) group. Clinical features of patients in two groups were compared. RESULTS: Liver metastasis was found in 319 out of the 1298 colorectal cancer patients. The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%, P < 0.01). HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR): 0.50, 95% confidence interval (95% CI): 0.38-0.66], but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%, P < 0.01). The HR was the lowest in chronic hepatitis B group (HR: 0.29, 95% CI: 0.12-0.72). The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate. However, no significant difference was found in survival rate between the two groups (P = 0.95). CONCLUSION: HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions. PMID:21390153

  20. Resection after preoperative chemotherapy versus synchronous liver resection of colorectal cancer liver metastases

    PubMed Central

    Kim, Chan W.; Lee, Jong L.; Yoon, Yong S.; Park, In J.; Lim, Seok-Byung; Yu, Chang S.; Kim, Tae W.; Kim, Jin C.

    2017-01-01

    Abstract This study aimed to determine the prognostic effects of preoperative chemotherapy for colorectal cancer liver metastasis (CLM). We retrospectively evaluated 2 groups of patients between January 2006 and August 2012. A total of 53 patients who had ≥3 hepatic metastases underwent resection after preoperative chemotherapy (preoperative chemotherapy group), whereas 96 patients who had ≥3 hepatic metastases underwent resection with a curative intent before chemotherapy for CLM (primary resection group). A propensity score (PS) model was used to compare the both groups. The 3-year disease-free survival (DFS) rates were 31.7% and 20.4% in the preoperative chemotherapy and primary resection groups, respectively (log-rank = 0.015). Analyzing 32 PS matched pairs, we found that the DFS rate was significantly higher in the preoperative chemotherapy group than in the primary resection group (3-year DFS rates were 34.2% and 16.8%, respectively [log-rank = 0.019]). Preoperative chemotherapy group patients had better DFSs than primary resection group patients in various multivariate analyses, including crude, multivariable, average treatment effect with inverse probability of treatment weighting model and PS matching. Responses to chemotherapy are as important as achieving complete resection in cases of multiple hepatic metastases. Preoperative chemotherapy may therefore be preferentially considered for patients who experience difficulty undergoing complete resection for multiple hepatic metastases. PMID:28207557

  1. Sensitivity to Radiation-Induced Cancer in Hemochromatosis

    SciTech Connect

    Bull. Richard J.; Anderson, Larry E.

    2000-06-01

    The objectives of this pilot project using HFE-knockout homozygotes and heterozygotes are to (1) determine whether the knock-out mice have greater sensitivity to radiation-induced cancer of the colon, liver and breast, (2) establish the dependence of this sensitivity on the accumulation of iron, (3) determine the extent to which cell replication and apoptosis occur in these target tissues with varying iron load, and (4) correlate the increases in sensitivity with changes in insulin-related signaling in tumors and normal tissue from each target organ. Three experimental designs will be used in the pilot project. The sequence of experiments is designed to first explore the influence of iron load on the response and demonstrate that HFE knockout mice are more sensitive than the wild type to radiation-induced cancer in one or more of three target tissues (liver, colon and breast). The dose response relationships with a broader set of radiation doses will be explored in the second experiment. The final experiment is designed to explore the extent to which heterozygotes display the increased susceptibility to cancer induction and to independently assess the importance of iron load to the initiation versus promotion of tumors.

  2. Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced fatty liver disease

    PubMed Central

    Shi, Xue; Wei, Xiaoli; Koo, Imhoi; Schmidt, Robin H.; Yin, Xinmin; Kim, Seong Ho; Vaughn, Andrew; McClain, Craig J.; Arteel, Gavin E.

    2014-01-01

    Arsenic is a widely-distributed environmental component that is associated with a variety of cancer and non-cancer adverse health effects. Additional lifestyle factors, such as diet, contribute to the manifestation of disease. Recently, arsenic was found to increase inflammation and liver injury in a dietary model of fatty liver disease. The purpose of the present study was to investigate potential mechanisms of this diet-environment interaction via a high throughput metabolomics approach. GC×GC-TOF MS was used to identify metabolites that were significantly increased or decreased in the livers of mice fed a Western diet (a diet high in fat and cholesterol) and co-exposed to arsenic-contaminated drinking water. The results showed that there are distinct hepatic metabolomic profiles associated with eating a high fat diet, drinking arsenic-contaminated water, and the combination of the two. Among the metabolites that were decreased when arsenic exposure was combined with a high fat diet were short-chain and medium-chain fatty acid metabolites and the anti-inflammatory amino acid, glycine. These results are consistent with the observed increase in inflammation and cell death in the livers of these mice, and they point to potentially novel mechanisms by which these metabolic pathways could be altered by arsenic in the context of diet-induced fatty liver disease. PMID:24328084

  3. Arsenic levels in drinking water and mortality of liver cancer in Taiwan.

    PubMed

    Lin, Hung-Jung; Sung, Tzu-I; Chen, Chi-Yi; Guo, How-Ran

    2013-11-15

    The carcinogenic effect of arsenic is well documented, but epidemiologic data on liver cancer were limited. To evaluate the dose-response relationship between arsenic in drinking water and mortality of liver cancer, we conducted a study in 138 villages in the southwest coast area of Taiwan. We assessed arsenic levels in drinking water using data from a survey conducted by the government and reviewed death certificates from 1971 to 1990 to identify liver cancer cases. Using village as the unit, we conducted multi-variate regression analyses and then performed post hoc analyses to validate the findings. During the 20-year period, 802 male and 301 female mortality cases of liver cancer were identified. After adjusting for age, arsenic levels above 0.64 mg/L were associated with an increase in the liver cancer mortality in both genders, but no significant effect was observed for lower exposure categories. Post hoc analyses and a review of literature supported these findings. We concluded that exposures to high arsenic levels in drinking water are associated with the occurrence of liver cancer, but such an effect is not prominent at exposure levels lower than 0.64 mg/L.

  4. Green Tea Consumption and the Risk of Liver Cancer: A Meta-Analysis.

    PubMed

    Ni, Chen-Xu; Gong, Hong; Liu, Ying; Qi, Yang; Jiang, Chun-Lei; Zhang, Jun-Ping

    2017-01-01

    Green tea is a commonly consumed beverage in Asia and has been suggested to have anticarcinogenic properties. To date, epidemiological evidence of the effect of green tea consumption on liver cancer risk remains ambiguous. The aim of this meta-analysis is to evaluate the association between green tea consumption and the risk of liver cancer. The summary relative risk for the highest consumption (≥5 cups/day) of green tea on liver cancer incidence compared with nondrinkers was 0.62 (95% confidence interval: 0.49-0.79). We also found a trend that the incidence of liver cancer was reduced with the increasing years of green tea intake (significance at >20 yr). A significant dose-response association was found between green tea drinking and liver cancer risk. The downward trend was most obvious when the consumption of green tea increased up to about 4 cups/day. The results showed that the increasing green tea intake may have a preventive effect against liver cancer.

  5. Abate Cytochrome C induced apoptosome to protect donor liver against ischemia reperfusion injury on rat liver transplantation model

    PubMed Central

    Zhuang, Zhuonan; Lian, Peilong; Wu, Xiaojuan; Shi, Baoxu; Zhuang, Maoyou; Zhou, Ruiling; Zhao, Rui; Zhao, Zhen; Guo, Sen; Ji, Zhipeng; Xu, Kesen

    2016-01-01

    Objective: Aim of this study is to protect donor liver against ischemia-reperfusion injury by abating Cytochrome C induced apoptosome on rat model. Methods: A total of 25 clean SD inbred male rats were used in this research. The rats in ischemia-reperfusion injury group (I/R group, n=5) were under liver transplantation operation; rats in dichloroacetate diisopropylamine group (DADA group, n=5) were treated DADA before liver transplantation; control group (Ctrl group, n=5); other 10 rats were used to offer donor livers. Results: In DADA therapy group, Cytochrome C expression in donor hepatocellular cytoplasm was detected lower than that in I/R group. And the Cytochrome C induced apoptosome was also decreased in according to the lower expressions of Apaf-1 and Caspase3. Low level of cleaved PARP expression revealed less apoptosis in liver tissue. The morphology of donor liver mitochondria in DADA group was observed to be slightly edema but less than I/R group after operation 12 h. The liver function indexes of ALT and AST in serum were tested, and the results in DADA group showed it is significantly lower than I/R group after operation 12 h. The inflammation indexes of IL-6 and TNF-α expressions in DADA group were significantly lower than that in I/R group after operation 24 h. Conclusion: The dichloroacetate diisopropylamine treatment could protect the hepatocellular mitochondria in case of the spillage of Cytochrome C induced apoptosome, and protect the liver against ischemia-reperfusion injury. Thus, it may be a method to promote the recovery of donor liver function after transplantation. PMID:27186297

  6. A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

    PubMed Central

    Goddard, Erica T.; Fischer, Jacob; Schedin, Pepper

    2016-01-01

    Breast cancer is the leading cause of cancer-related mortality in women worldwide. Liver metastasis is involved in upwards of 30% of cases with breast cancer metastasis, and results in poor outcomes with median survival rates of only 4.8 - 15 months. Current rodent models of breast cancer metastasis, including primary tumor cell xenograft and spontaneous tumor models, rarely metastasize to the liver. Intracardiac and intrasplenic injection models do result in liver metastases, however these models can be confounded by concomitant secondary-site metastasis, or by compromised immunity due to removal of the spleen to avoid tumor growth at the injection site. To address the need for improved liver metastasis models, a murine portal vein injection method that delivers tumor cells firstly and directly to the liver was developed. This model delivers tumor cells to the liver without complications of concurrent metastases in other organs or removal of the spleen. The optimized portal vein protocol employs small injection volumes of 5 - 10 μl, ≥ 32 gauge needles, and hemostatic gauze at the injection site to control for blood loss. The portal vein injection approach in Balb/c female mice using three syngeneic mammary tumor lines of varying metastatic potential was tested; high-metastatic 4T1 cells, moderate-metastatic D2A1 cells, and low-metastatic D2.OR cells. Concentrations of ≤ 10,000 cells/injection results in a latency of ~ 20 - 40 days for development of liver metastases with the higher metastatic 4T1 and D2A1 lines, and > 55 days for the less aggressive D2.OR line. This model represents an important tool to study breast cancer metastasis to the liver, and may be applicable to other cancers that frequently metastasize to the liver including colorectal and pancreatic adenocarcinomas. PMID:28060292

  7. Persistent Liver Biochemistry abnormalities are more common in older patients and those with Cholestatic Drug induced Liver Injury

    PubMed Central

    Fontana, Robert J.; Hayashi, Paul H.; Barnhart, Huiman; Kleiner, David E.; Reddy, K. Rajender; Chalasani, Naga; Lee, William M; Stolz, Andrew; Phillips, Thomas; Serrano, Jose; Watkins, Paul B.

    2016-01-01

    OBJECTIVES The long-term outcomes of patients with drug induced liver injury (DILI) are not well described. The aim of this study was to determine the frequency and severity of persistent liver biochemistry abnormalities in DILI patients followed over 2 years. METHODS Subjects with evidence of liver injury at 6 months after DILI onset were offered a month 12 and 24 study visit. RESULTS Amongst the 99 patients with definite, probable, or very likely DILI and available laboratory data at 12 months after DILI onset, 74 (75%) had persistent liver injury (persisters) defined as a serum AST or ALT > 1.5 × upper limit of normal (ULN) or an alkaline phosphatase > ULN, while 25 (25%) had resolved liver injury (resolvers). On multivariate analysis, month 12 persisters were significantly older (52.6 vs 43.7 years, p=0.01) and more likely to have a cholestatic lab profile at DILI onset (54% vs 20%, p < 0.01) than resolvers. The month 12 persisters also had significantly poorer SF-36 Physical summary scores at DILI onset and throughout follow-up compared to the resolvers (p < 0.01). Amongst the 17 subjects with a liver biopsy obtained at a median of 387 days after DILI onset, 9 had chronic cholestasis, 3 had steatohepatitis, and 3 had chronic hepatitis. CONCLUSION 75% of subjects with liver injury at 6 months after DILI onset have laboratory evidence of persistent liver injury during prolonged follow-up. Higher serum alkaline phosphatase levels at presentation and older patient age were independent predictors of persistent liver injury. Subjects with persistent liver injury at 12 months after DILI onset should be carefully monitored and assessed for liver disease progression. PMID:26346867

  8. Liver-targeting Resibufogenin-loaded poly(lactic-co-glycolic acid)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for liver cancer therapy

    PubMed Central

    Chu, Qiuchen; Xu, Hong; Gao, Meng; Guan, Xin; Liu, Hongyan; Deng, Sa; Huo, Xiaokui; Liu, Kexin; Tian, Yan; Ma, Xiaochi

    2016-01-01

    Liver cancer remains a major problem around the world. Resibufogenin (RBG) is a major bioactive compound that was isolated from Chansu (also called toad venom or toad poison), which is a popular traditional Chinese medicine that is obtained from the skin secretions of giant toads. RBG has strong antitumor effects, but its poor aqueous solubility and its cardiotoxicity have limited its clinical use. The aim of this study was to formulate RBG-loaded poly(lactic-co-glycolic acid) (PLGA)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RPTN) to enhance the treatment of liver cancer. RPTN, RBG-loaded PLGA nanoparticle (RPN), and RBG/coumarin-6-loaded PLGA-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RCPTN) were prepared. The cellular uptake of RCPTN by HepG2 and HCa-F cells was analyzed using confocal laser scanning microscopy. Apoptosis was induced in HepG2 cells by RPTN, RBG solution (RS), and 5-fluorouracil solution (used as the negative controls), as assayed using flow cytometry. LD50 (median lethal dose) values were determined for RS and RPTN, and the liver-targeting properties were determined for RCPTN in intravenously injected mice. A pharmacokinetic study was conducted in rats, and the in vivo therapeutic effects of RPTN, RPN, and RS were examined in a mouse tumor model. The results showed that RCPTN simultaneously delivered both coumarin-6 and RBG into HepG2 and HCa-F cells. The ratio of apoptotic cells was increased in the RPTN group. The LD50 for RPTN was 2.02-fold higher than the value for RS. Compared to RS, RPTN and RPN both showed a significant difference in vivo not only in the pharmacodynamic study but also in anticancer efficacy, and RPTN performed much better than RPN. The detection indexes for drug concentration and fluorescence inversion microscopy images both demonstrated that RCPTN was much better at targeting the liver than RS. The liver-targeting RPTN, which displayed enhanced pharmacological effects and

  9. MiR-506 suppresses liver cancer angiogenesis through targeting sphingosine kinase 1 (SPHK1) mRNA.

    PubMed

    Lu, Zhanping; Zhang, Weiying; Gao, Shan; Jiang, Qiulei; Xiao, Zelin; Ye, Lihong; Zhang, Xiaodong

    MicroRNAs acting as oncogenes or tumor suppressor genes play crucial roles in human cancers. Sphingosine kinase 1 (SPHK1) and its metabolite sphingosine 1-phosphate (S1P) contribute to tumor angiogenesis. We have reported that the down-regulation of miR-506 targeting YAP mRNA results in the hepatocarcinogenesis. In the present study, we report a novel function of miR-506, which suppresses tumor angiogenesis through targeting SPHK1 mRNA in liver cancer. Bioinformatics analysis showed that miR-506 might target 3'-untranslated region (3'UTR) of SPHK1 mRNA. Then, we validated that by luciferase reporter gene assays. MiR-506 was able to reduce the expression of SPHK1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blot analysis in hepatoma HepG2 cells. Functionally, human umbilical vein endothelial cell (HUVEC) tube formation assays demonstrated that the forced miR-506 expression remarkably inhibited the production of S1P in the supernatant of hepatoma cells. The supernatant resulted in the inhibition of tumor angiogenesis. Interestingly, the supernatant with overexpression of SPHK1 could rescue the inhibition of angiogenesis of liver cancer mediated by miR-506. Anti-miR-506 increased the production of S1P in the supernatant of hepatoma cells, but the supernatant with silencing of SPHK1 abolished anti-miR-506-induced acceleration of tumor angiogenesis. Clinically, we observed that the levels of miR-506 were negatively related to those of SPHK1 mRNA in liver cancer tissues. Thus, we conclude that miR-506 depresses the angiogenesis of liver cancer through targeting 3'UTR of SPHK1 mRNA. Our finding provides new insights into the mechanism of tumor angiogenesis.

  10. Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation

    PubMed Central

    Klerk, CPW; Smorenburg, SM; Spek, CA; Van Noorden, CJF

    2007-01-01

    Abstract Clinical trials have shown life-prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild-type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre-dominance for vessel-rich or vessel-poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model. PMID:17635646

  11. Lactoferrin Enhanced Apoptosis and Protected Against Thioacetamide-Induced Liver Fibrosis in Rats

    PubMed Central

    Hessin, Alyaa; Hegazy, Rehab; Hassan, Azza; Yassin, Nemat; Kenawy, Sanaa

    2015-01-01

    BACKGROUND: Liver fibrosis is the common pathologic consequence of all chronic liver diseases. AIM: Lactoferrin (Lf) was investigated for its possible hepatoprotective effect against thioacetamide (TAA)-induced liver fibrosis rat model. MATERIAL AND METHODS: Rats received TAA (200 mg/kg/biweekly, ip) for four successive weeks. Lf (200 mg/kg/day, p.o.) or vehicle (VHC) was administered for one month before and another month during TAA injection. Body weight and mortality rate were assessed during the month of TAA-intoxication. Thereafter, serum and liver tissues were analyzed for liver function, oxidative, fibrotic and apoptotic markers. RESULTS: Lf conserved rats against TAA-induced body weight-loss and mortality. Preservation of serum albumin, alkaline phosphatase and total bilirubin levels was also observed. Lf also protected rats against TAA-induced decrease in reduced glutathione and increase in malondialdehyde liver contents. Normal liver contents of hydroxyproline, nuclear factor kappa B and alpha fetoprotein; as markers of fibrosis; were increased with TAA and conserved with Lf-TAA. Lf maintained the normal architecture of the liver and immunohistochemical findings revealed increase in apoptotic bodies compared to TAA that favored necrosis. CONCLUSION: In conclusion, Lf improved liver function, reduced oxidative stress and liver fibrosis, and enhanced apoptosis in rats with liver fibrosis, suggesting it to have useful therapeutic potential in patients with liver fibrosis. PMID:27275221

  12. Drug-induced liver injury and drug development: industry perspective.

    PubMed

    Regev, Arie

    2014-05-01

    Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

  13. Silencing of WWP2 inhibits adhesion, invasion, and migration in liver cancer cells.

    PubMed

    Qin, Yong; Xu, Sheng-Qian; Pan, De-Biao; Ye, Guan-Xiong; Wu, Cheng-Jun; Wang, Shi; Wang, Chao-Jun; Jiang, Jin-Yan; Fu, Jing

    2016-05-01

    The role and clinical implication of the WWP2 E3 ubiquitin ligase in liver cancer are poorly understood. In the current study, we investigated the expression level of WWP2 and its functions in cell adhesion, invasion, and migration in liver cancer. We used real-time PCR to detect the expression of WWP2 in liver cancer and adjacent samples from the People's Hospital of Lishui and also analyzed The Cancer Genome Atlas (TCGA) RNA-seq data by bioinformatics. Migration and invasion were detected by transwell analysis. We detected a strong WWP2 expression in tumor tissues of the People's Hospital of Lishui, and the survival rate was significantly higher in patients with lower WWP2-expressing tumors. WWP2 small hairpin RNA (shRNA) lentivirus stably infected cells (shWWP2), Huh7, showed slower growth speed compared with scramble control-infected cells in a xenograft mouse model. Knockdown of WWP2 Huh7 and BEL-7404 cells demonstrated a reduction in adhesion, invasion, and migration. Gene set enrichment analysis (GSEA) showed that WWP2 is positively correlated to cancer-related pathways including the chemokine signaling pathway. WWP2 also regulated MMP-9, caspase-9, CXCR3, and CCR5 expression in liver cancer cells. In addition, knockdown of CXCR3 and CCR5 significantly inhibited cell proliferation, adhesion, invasion, and migration in Huh7 and BEL-7404 cells. Our data suggest that targeting of WWP2 may be a therapeutic strategy for liver cancer treatment.

  14. The MAP30 protein from bitter gourd (Momordica charantia) seeds promotes apoptosis in liver cancer cells in vitro and in vivo.

    PubMed

    Fang, Evandro Fei; Zhang, Chris Zhi Yi; Wong, Jack Ho; Shen, Jia Yun; Li, Chuan Hao; Ng, Tzi Bun

    2012-11-01

    Human hepatocellular carcinoma Hep G2 cells and Hep G2-bearing mice were used as in vitro and in vivo models to assess the efficacy and safety of MAP30, a natural component from Momordica charantia, as an anticancer agent against liver cancer. Molecular studies disclosed the contribution of both caspase-8 regulated extrinsic and caspase-9 regulated intrinsic caspase cascades in MAP30-induced cell apoptosis. The antitumor potential was also effective in Hep G2-bearing nude mice. Since bitter gourd is a staple in many Asian countries, MAP30 would serve as a novel and relatively safe agent for prophylaxis and treatment of liver cancer.

  15. Radiation-Induced Liver Damage: Correlation of Histopathology with Hepatobiliary Magnetic Resonance Imaging, a Feasibility Study

    SciTech Connect

    Seidensticker, Max; Burak, Miroslaw; Kalinski, Thomas; Garlipp, Benjamin; Koelble, Konrad; Wust, Peter; Antweiler, Kai; Seidensticker, Ricarda; Mohnike, Konrad; Pech, Maciej; Ricke, Jens

    2015-02-15

    PurposeRadiotherapy of liver malignancies shows promising results (radioembolization, stereotactic irradiation, interstitial brachytherapy). Regardless of the route of application, a certain amount of nontumorous liver parenchyma will be collaterally damaged by radiation. The functional reserve may be significantly reduced with an impact on further treatment planning. Monitoring of radiation-induced liver damage by imaging is neither established nor validated. We performed an analysis to correlate the histopathological presence of radiation-induced liver damage with functional magnetic resonance imaging (MRI) utilizing hepatobiliary contrast media (Gd-BOPTA).MethodsPatients undergoing local high-dose-rate brachytherapy for whom a follow-up hepatobiliary MRI within 120 days after radiotherapy as well as an evaluable liver biopsy from radiation-exposed liver tissue within 7 days before MRI were retrospectively identified. Planning computed tomography (CT)/dosimetry was merged to the CT-documentation of the liver biopsy and to the MRI. Presence/absence of radiation-induced liver damage (histopathology) and Gd-BOPTA uptake (MRI) as well as the dose applied during brachytherapy at the site of tissue sampling was determined.ResultsFourteen biopsies from eight patients were evaluated. In all cases with histopathological evidence of radiation-induced liver damage (n = 11), no uptake of Gd-BOPTA was seen. In the remaining three, cases no radiation-induced liver damage but Gd-BOPTA uptake was seen. Presence of radiation-induced liver damage and absence of Gd-BOPTA uptake was correlated with a former high-dose exposition.ConclusionsAbsence of hepatobiliary MRI contrast media uptake in radiation-exposed liver parenchyma may indicate radiation-induced liver damage. Confirmatory studies are warranted.

  16. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    PubMed Central

    Udoh, Uduak S.; Valcin, Jennifer A.; Gamble, Karen L.; Bailey, Shannon M.

    2015-01-01

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases. PMID:26473939

  17. Pterostilbene inhibits dimethylnitrosamine-induced liver fibrosis in rats.

    PubMed

    Lee, Ming-Fen; Liu, Min-Lung; Cheng, An-Chin; Tsai, Mei-Ling; Ho, Chi-Tang; Liou, Wen-Shiung; Pan, Min-Hsiung

    2013-06-01

    Pterostilbene, found in grapes and berries, exhibits pleiotropic effects, including anti-inflammatory, antioxidant, and anti-proliferative activities. This study was conducted to investigate the effect of pterostilbene on liver fibrosis and the potential underlying mechanism for such effect. Sprague-Dawley rats were intraperitoneally given dimethyl n-nitrosamine (DMN) (10mg/kg) 3 days per week for 4 weeks. Pterostilbene (10 or 20mg/kg) was administered by oral gavage daily. Liver function, morphology, histochemistry, and fibrotic parameters were examined. Pterostilbene supplementation alleviated the DMN-induced changes in the serum levels of alanine transaminase and aspartate transaminase (p<0.05). Fibrotic status and the activation of hepatic stellate cells were improved upon pterostilbene supplementation as evidenced by histopathological examination as well as the expression of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and matrix metalloproteinase 2 (MMP2). These data demonstrated that pterostilbene exhibited hepatoprotective effects on experimental fibrosis, potentially by inhibiting the TGF-β1/Smad signaling.

  18. Epidemiology of Idiosyncratic Drug-Induced Liver Injury

    PubMed Central

    Bell, Lauren N.; Chalasani, Naga

    2010-01-01

    Idiosyncratic drug-induced liver injury (DILI) is a significant health problem because of its unpredictable nature, poorly understood pathogenesis, and potential to cause fatal outcomes. It is also a significant hurdle for drug development and marketing of safe prescription medications. Idiosyncratic DILI is generally rare, but its occurrence is likely underappreciated due to the lack of active reporting or surveillance systems and substantial challenges involved in its recognition and diagnosis. Nonetheless, DILI is a common cause of potentially serious and fatal acute liver failure in both children and adults. Population-based studies that accurately estimate the incidence and full spectrum of DILI are limited. However, using a prospective, population-based French study with an annual estimated incidence of 13.9 ± 2.4 DILI cases per 100,000 inhabitants, it has been extrapolated that nearly 44,000 individuals in the United States will suffer from DILI each year. Although increasing numbers of patients are also being seen with DILI due to herbal and dietary supplements, the epidemiology of this entity requires further investigation. In this article, the epidemiology of DILI, both in the general population and in potentially high-risk subgroups, is reviewed. PMID:19826967

  19. The correlation of contrast-enhanced ultrasound and MRI perfusion quantitative analysis in rabbit VX2 liver cancer.

    PubMed

    Xiang, Zhiming; Liang, Qianwen; Liang, Changhong; Zhong, Guimian

    2014-12-01

    Our objective is to explore the value of liver cancer contrast-enhanced ultrasound (CEUS) and MRI perfusion quantitative analysis in liver cancer and the correlation between these two analysis methods. Rabbit VX2 liver cancer model was established in this study. CEUS was applied. Sono Vue was applied in rabbits by ear vein to dynamically observe and record the blood perfusion and changes in the process of VX2 liver cancer and surrounding tissue. MRI perfusion quantitative analysis was used to analyze the mean enhancement time and change law of maximal slope increasing, which were further compared with the pathological examination results. Quantitative indicators of liver cancer CEUS and MRI perfusion quantitative analysis were compared, and the correlation between them was analyzed by correlation analysis. Rabbit VX2 liver cancer model was successfully established. CEUS showed that time-intensity curve of rabbit VX2 liver cancer showed "fast in, fast out" model while MRI perfusion quantitative analysis showed that quantitative parameter MTE of tumor tissue increased and MSI decreased: the difference was statistically significant (P < 0.01). The diagnostic results of CEUS and MRI perfusion quantitative analysis were not significantly different (P > 0.05). However, the quantitative parameter of them were significantly positively correlated (P < 0.05). CEUS and MRI perfusion quantitative analysis can both dynamically monitor the liver cancer lesion and surrounding liver parenchyma, and the quantitative parameters of them are correlated. The combined application of both is of importance in early diagnosis of liver cancer.

  20. Association of Fasciola hepatica Infection with Liver Fibrosis, Cirrhosis, and Cancer: A Systematic Review

    PubMed Central

    Machicado, Claudia; Machicado, Jorge D.; Maco, Vicente; Terashima, Angelica; Marcos, Luis A.

    2016-01-01

    Background Fascioliasis has been sporadically associated with chronic liver disease on previous studies. In order to describe the current evidence, we carried out a systematic review to assess the association between fascioliasis with liver fibrosis, cirrhosis and cancer. Methodology and Principal Findings A systematic search of electronic databases (PubMed, LILACS, Scopus, Embase, Cochrane, and Scielo) was conducted from June to July 2015 and yielded 1,557 published studies. Among 21 studies that met inclusion and exclusion criteria, 12 studies explored the association of F. hepatica with liver fibrosis, 4 with liver cirrhosis, and 5 with cancer. Globally these studies suggested the ability of F. hepatica to promote liver fibrosis and cirrhosis. The role of F. hepatica in cancer is unknown. Given the heterogeneity of the studies, a meta-analysis could not be performed. Conclusions Future high-quality studies are needed to determine the role of F. hepatica on the development of liver fibrosis, liver cirrhosis, and cancer in humans. PMID:27681524

  1. Evidence-based medical oncology and interventional radiology paradigms for liver-dominant colorectal cancer metastases.

    PubMed

    Sag, Alan Alper; Selcukbiricik, Fatih; Mandel, Nil Molinas

    2016-03-21

    Colorectal cancer metastasizes predictably, with liver predominance in most cases. Because liver involvement has been shown to be a major determinant of survival in this population, liver-directed therapies are increasingly considered even in cases where there is (limited) extrahepatic disease. Unfortunately, these patients carry a known risk of recurrence in the liver regardless of initial therapy choice. Therefore, there is a demand for minimally invasive, non-surgical, personalized cancer treatments to preserve quality of life in the induction, consolidation, and maintenance phases of cancer therapy. This report aims to review evidence-based conceptual, pharmacological, and technological paradigm shifts in parenteral and percutaneous treatment strategies as well as forthcoming evidence regarding next-generation systemic, locoregional, and local treatment approaches for this patient population.

  2. Evidence-based medical oncology and interventional radiology paradigms for liver-dominant colorectal cancer metastases

    PubMed Central

    Sag, Alan Alper; Selcukbiricik, Fatih; Mandel, Nil Molinas

    2016-01-01

    Colorectal cancer metastasizes predictably, with liver predominance in most cases. Because liver involvement has been shown to be a major determinant of survival in this population, liver-directed therapies are increasingly considered even in cases where there is (limited) extrahepatic disease. Unfortunately, these patients carry a known risk of recurrence in the liver regardless of initial therapy choice. Therefore, there is a demand for minimally invasive, non-surgical, personalized cancer treatments to preserve quality of life in the induction, consolidation, and maintenance phases of cancer therapy. This report aims to review evidence-based conceptual, pharmacological, and technological paradigm shifts in parenteral and percutaneous treatment strategies as well as forthcoming evidence regarding next-generation systemic, locoregional, and local treatment approaches for this patient population. PMID:27003990

  3. Management of Liver Cancer Argon-helium Knife Therapy with Functional Computer Tomography Perfusion Imaging.

    PubMed

    Wang, Hongbo; Shu, Shengjie; Li, Jinping; Jiang, Huijie

    2016-02-01

    The objective of this study was to observe the change in blood perfusion of liver cancer following argon-helium knife treatment with functional computer tomography perfusion imaging. Twenty-seven patients with primary liver cancer treated with argon-helium knife and were included in this study. Plain computer tomography (CT) and computer tomography perfusion (CTP) imaging were conducted in all patients before and after treatment. Perfusion parameters including blood flows, blood volume, hepatic artery perfusion fraction, hepatic artery perfusion, and hepatic portal venous perfusion were used for evaluating therapeutic effect. All parameters in liver cancer were significantly decreased after argon-helium knife treatment (p < 0.05 to all). Significant decrease in hepatic artery perfusion was also observed in pericancerous liver tissue, but other parameters kept constant. CT perfusion imaging is able to detect decrease in blood perfusion of liver cancer post-argon-helium knife therapy. Therefore, CTP imaging would play an important role for liver cancer management followed argon-helium knife therapy.

  4. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells

    SciTech Connect

    Obara, Akio; Fujita, Yoshihito; Abudukadier, Abulizi; Fukushima, Toru; Oguri, Yasuo; Ogura, Masahito; Harashima, Shin-ichi; Hosokawa, Masaya; Inagaki, Nobuya

    2015-05-15

    Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action.

  5. Antituberculosis Drug-Induced Liver Injury with Autoimmune Features: Facing Diagnostic and Treatment Challenges

    PubMed Central

    Pinto Pais, Isabel; Duarte, Raquel; Carvalho, Isabel

    2017-01-01

    The authors present a case report of antituberculosis drug-induced liver injury that offered diagnostic challenges (namely, the possibility of drug-induced autoimmune hepatitis) and treatment difficulties. PMID:28116201

  6. Gene expression changes induced by the tumorigenic pyrrolizidine alkaloid riddelliine in liver of Big Blue rats

    PubMed Central

    Mei, Nan; Guo, Lei; Liu, Ruqing; Fuscoe, James C; Chen, Tao

    2007-01-01

    Background Pyrrolizidine alkaloids (PAs) are probably the most common plant constituents that poison livestock, wildlife, and humans worldwide. Riddelliine is isolated from plants grown in the western United States and is a prototype of genotoxic PAs. Riddelliine was used to investigate the genotoxic effects of PAs via analysis of gene expression in the target tissue of rats in this study. Previously we observed that the mutant frequency in the liver of rats gavaged with riddelliine was 3-fold higher than that in the control group. Molecular analysis of the mutants indicated that there was a statistically significant difference between the mutational spectra from riddelliine-treated and control rats. Results Riddelliine-induced gene expression profiles in livers of Big Blue transgenic rats were determined. The female rats were gavaged with riddelliine at a dose of 1 mg/kg body weight 5 days a week for 12 weeks. Rat whole genome microarray was used to perform genome-wide gene expression studies. When a cutoff value of a two-fold change and a P-value less than 0.01 were used as gene selection criteria, 919 genes were identified as differentially expressed in riddelliine-treated rats compared to the control animals. By analysis with the Ingenuity Pathway Analysis Network, we found that these significantly changed genes were mainly involved in cancer, cell death, tissue development, cellular movement, tissue morphology, cell-to-cell signaling and interaction, and cellular growth and proliferation. We further analyzed the genes involved in metabolism, injury of endothelial cells, liver abnormalities, and cancer development in detail. Conclusion The alterations in gene expression were directly related to the pathological outcomes reported previously. These results provided further insight into the mechanisms involved in toxicity and carcinogenesis after exposure to riddelliine, and permitted us to investigate the interaction of gene products inside the signaling networks

  7. CXCR4/CXCL12 Participate in Extravasation of Metastasizing Breast Cancer Cells within the Liver in a Rat Model

    PubMed Central

    Krasnyanska, Julia; Mees, Sören Torge; Kochetkova, Marina; Stoeppeler, Sandra; Haier, Jörg

    2012-01-01

    Introduction Organ-specific composition of extracellular matrix proteins (ECM) is a determinant of metastatic host organ involvement. The chemokine CXCL12 and its receptor CXCR4 play important roles in the colonization of human breast cancer cells to their metastatic target organs. In this study, we investigated the effects of chemokine stimulation on adhesion and migration of different human breast cancer cell lines in vivo and in vitro with particular focus on the liver as a major metastatic site in breast cancer. Methods Time lapse microscopy, in vitro adhesion and migration assays were performed under CXCL12 stimulation. Activation of small GTPases showed chemokine receptor signalling dependence from ECM components. The initial events of hepatic colonisation of MDA-MB-231 and MDA-MB-468 cells were investigated by intravital microscopy of the liver in a rat model and under shRNA inhibition of CXCR4. Results In vitro, stimulation with CXCL12 induced increased chemotactic cell motility (p<0.05). This effect was dependent on adhesive substrates (type I collagen, fibronectin and laminin) and induced different responses in small GTPases, such as RhoA and Rac-1 activation, and changes in cell morphology. In addition, binding to various ECM components caused redistribution of chemokine receptors at tumour cell surfaces. In vivo, blocking CXCR4 decreased extravasation of highly metastatic MDA-MB-231 cells (p<0.05), but initial cell adhesion within the liver sinusoids was not affected. In contrast, the less metastatic MDA-MB-468 cells showed reduced cell adhesion but similar migration within the hepatic microcirculation. Conclusion: Chemokine-induced extravasation of breast cancer cells along specific ECM components appears to be an important regulator but not a rate-limiting factor of their metastatic organ colonization. PMID:22253872

  8. RUCAM in Drug and Herb Induced Liver Injury: The Update

    PubMed Central

    Danan, Gaby; Teschke, Rolf

    2015-01-01

    RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common

  9. Resveratrol Ameliorates Alcoholic Fatty Liver by Inducing Autophagy.

    PubMed

    Tang, Liying; Yang, Fengli; Fang, Zhirui; Hu, Chengmu

    2016-01-01

    Alcoholic fatty liver (AFL) is early stage of alcoholic liver disease, which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. The pathogenesis of AFL is associated with excessive lipid accumulation in hepatocytes. Resveratrol (RES), a dietary polyphenol found in red wines and grapes, has been shown to have a hepatoprotective effect. Autophagy is a crucial physiological process in cellular catabolism that involves the regulation of lipid droplets. Autophagy maintains a balance between protein synthesis, degradation and self-recycling. In the present study, we evaluated the protective effects of RES (10[Formula: see text]mg/kg, 30[Formula: see text]mg/kg, 100[Formula: see text]mg/kg) on AFL mice fed with an ethanol Lieber-DeCarli liquid diet, and HepG2 cells in the presence of oleic acid and alcohol to investigate whether resveratrol could induce autophagy to attenuate lipid accumulation. The results showed that RES (30[Formula: see text]mg/kg and 100[Formula: see text]mg/kg) treatment significantly attenuated hepatic steatosis and lowered the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low density lipoprotein cholesterol (LDL-C). H&E staining showed that RES reduced hepatic lipid accumulation. Transmission electron microscopy (TEM) images showed that RES treatment increased the number of autophagosomes and promoted the formation of autophagy. Western blot analysis showed that RES treatment increased the levels of microtubule-associated protein light chain3- II (LC3-II) and Beclin1, decreased expression of p62 protein. In addition, in vitro studies also demonstrated that RES led to the formation of acidic vesicular organelles (AVOs), however, 3-Methyladenine (3-MA), a specific inhibitor of autophagy, obviously inhibited the above effects of RES. In conclusion, RES has protective effects on alcoholic hepatic steatosis, and the potential mechanism might be involved

  10. Chlorpromazine-induced liver and bone marrow granulomas associated with agranulocytosis.

    PubMed

    Ben-Yehuda, A; Bloom, A; Lijovetzky, G; Flusser, D; Tur-Kaspa, R

    1990-08-01

    Chlorpromazine-induced liver damage is usually manifested by intrahepatic cholestasis. Hypoplastic bone marrow associated with agranulocytosis is a well-known side effect of chlorpromazine treatment. A 35-year-old woman with liver and bone marrow granulomas associated with agranulocytosis induced by chlorpromazine treatment is described.

  11. Synthesis and anticancer activity of novel benzimidazole and benzothiazole derivatives against HepG2 liver cancer cells.

    PubMed

    Youssef, Amal M; Malki, Ahmed; Badr, Mona H; Elbayaa, Rasha Y; Sultan, Ahmed S

    2012-03-01

    Most of cancer chemotherapeutics and chemopreventives exert their effects by triggering apoptotic cell death. In this study, novel benzimidazole and benzothiazole derivatives have been synthesized to investigate their effects on HepG2 liver cancer cell lines after initial screening study. A dose response curve was constructed and the most active derivatives were further studied for apoptotic analysis. Six active benzimidazole derivatives (8, 9, 10, 12, 13 and 14) significantly induced apoptosis compared to control group. Two compounds 10 and 12 induced apoptosis by arresting cells in G1 phase of cell cycle which is confirmed by increased expression level of p21. The activity of caspase-3 which is well known as one of the key executioners of apoptosis was determined in the presence and absence of the tested derivatives. Our results indicated that compounds 10 and 12 significantly increased caspase-3 activity compared to control group. Moreover, a docked pose of compounds 10 and 12 was obtained bound to caspase-3 active site using Molecular Operating Environment module. This study demonstrated that benzimidazole derivatives 10 and 12 provoke cytotoxicity and induced apoptosis in liver cancer cells HepG2.

  12. Increased liver-specific proteins in circulating extracellular vesicles as potential biomarkers for drug- and alcohol-induced liver injury

    PubMed Central

    Cho, Young-Eun; Im, Eun-Ju; Moon, Pyong-Gon; Mezey, Esteban; Song, Byoung-Joon; Baek, Moon-Chang

    2017-01-01

    Drug- and alcohol-induced liver injury are a leading cause of liver failure and transplantation. Emerging evidence suggests that extracellular vesicles (EVs) are a source of biomarkers because they contain unique proteins reflecting the identity and tissue-specific origin of the EV proteins. This study aimed to determine whether potentially hepatotoxic agents, such as acetaminophen (APAP) and binge alcohol, can increase the amounts of circulating EVs and evaluate liver-specific EV proteins as potential biomarkers for liver injury. The circulating EVs, isolated from plasma of APAP-exposed, ethanol-fed mice, or alcoholic hepatitis patients versus normal control counterparts, were characterized by proteomics and biochemical methods. Liver specific EV proteins were analyzed by immunoblots and ELISA. The amounts of total and liver-specific proteins in circulating EVs from APAP-treated mice significantly increased in a dose- and time-dependent manner. Proteomic analysis of EVs from APAP-exposed mice revealed that the amounts of liver-specific and/or hepatotoxic proteins were increased compared to those of controls. Additionally, the increased protein amounts in EVs following APAP exposure returned to basal levels when mice were treated with N-acetylcysteine or glutathione. Similar results of increased amounts and liver-specific proteins in circulating EVs were also observed in mice exposed to hepatotoxic doses of thioacetamide or d-galactosamine but not by non-hepatotoxic penicillin or myotoxic bupivacaine. Additionally, binge ethanol exposure significantly elevated liver-specific proteins in circulating EVs from mice and alcoholics with alcoholic hepatitis, compared to control counterparts. These results indicate that circulating EVs in drug- and alcohol-mediated hepatic injury contain liver-specific proteins that could serve as specific biomarkers for hepatotoxicity. PMID:28225807

  13. Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

    PubMed Central

    Abo-Haded, Hany M.; Elkablawy, Mohamed A.; Al-johani, Zeyad; Al-ahmadi, Osama; El-Agamy, Dina S.

    2017-01-01

    Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes. PMID:28334048

  14. [Current management of liver metastases from colorectal cancer: recommendations of the São Paulo Liver Club].

    PubMed

    Lupinacci, Renato Micelli; Coelho, Fabricio Ferreira; Perini, Marcos Vinicius; Lobo, Edson José; Ferreira, Fabio Gonçalves; Szutan, Luiz Arnaldo; Lopes, Gaspar de Jesus; Herman, Paulo

    2013-01-01

    Approximately half of patients with colorectal cancer present with liver metastases during the course of their disease, which directly affect prognosis and is responsible for two thirds of deaths related to the disease. In the last two decades the treatment of liver metastases from colorectal cancer (CRCLM) provided significant gain in survival when all treatment options are available to the patient. In this context, surgical treatment remains as the only chance of cure, with five-year survival rates of 25-58%. However, only 1/4 of the patients have resectable disease at diagnosis. For this reason, one of the key points in the current management of patients with CRCLM is the development of strategies that facilitate complete resection of liver lesions. The advent and refinement of ablative methods have expanded the possibilities of surgical therapy. The emergence of new chemotherapy regimens and the introduction of targeted therapies has provided high response rates and has permanently altered the management of these patients. The multimodal therapy and the involvement of different medical specialties has increasingly enabled CRCLM treatment to approached the ideal treatment, i.e., an individualized one. Based on an extensive review of literature and on experience from some of the most important specialized centers of Brazil, the São Paulo Liver Club began a process of multi-institutional discussions that resulted in the recommendations that follow. These recommendations, however, are not intended to be absolute, but useful tools in the therapeutic decision process for this complex group of patients.

  15. Therapeutic targeting of liver cancer with a recombinant DNA vaccine containing the hemagglutinin-neuraminidase gene of Newcastle disease virus via apoptotic-dependent pathways

    PubMed Central

    Chen, Li-Gang; Liu, Yuan-Sheng; Zheng, Tang-Hui; Chen, Xu; Li, Ping; Xiao, Chuan-Xing; Ren, Jian-Lin

    2016-01-01

    A total of ~38.6 million mortalities occur due to liver cancer annually, worldwide. Although a variety of therapeutic methods are available, the efficacy of treatment at present is extremely limited due to an increased risk of malignancy and inherently poor prognosis of liver cancer. Gene therapy is considered a promising option, and has shown notable potential for the comprehensive therapy of liver cancer, in keeping with advances that have been made in the development of cancer molecular biology. The present study aimed to investigate the synergistic effects of the abilities of the hemagglutinin neuraminidase protein of Newcastle disease virus (NDV), the pro-apoptotic factor apoptin from chicken anaemia virus, and the interferon-γ inducer interleukin-18 (IL-18) in antagonizing liver cancer. Therefore, a recombinant DNA plasmid expressing the three exogenous genes, VP3, IL-18 and hemagglutinin neuraminidase (HN), was constructed. Flow cytometry, acridine orange/ethidium bromide staining and analysis of caspase-3 activity were performed in H22 cell lines transfected with the recombinant DNA plasmid. In addition, 6-week-old C57BL/6 mice were used to establish a H22 hepatoma-bearing mouse model. Mice tumor tissue was analyzed by immunohistochemistry and scanning electron microscopy. The results of the present study revealed that the recombinant DNA vaccine containing the VP3, IL-18 and HN genes inhibited cell proliferation and induced autophagy via the mitochondrial pathway in vivo and in vitro. PMID:27900002

  16. Therapeutic targeting of liver cancer with a recombinant DNA vaccine containing the hemagglutinin-neuraminidase gene of Newcastle disease virus via apoptotic-dependent pathways.

    PubMed

    Chen, Li-Gang; Liu, Yuan-Sheng; Zheng, Tang-Hui; Chen, Xu; Li, Ping; Xiao, Chuan-Xing; Ren, Jian-Lin

    2016-11-01

    A total of ~38.6 million mortalities occur due to liver cancer annually, worldwide. Although a variety of therapeutic methods are available, the efficacy of treatment at present is extremely limited due to an increased risk of malignancy and inherently poor prognosis of liver cancer. Gene therapy is considered a promising option, and has shown notable potential for the comprehensive therapy of liver cancer, in keeping with advances that have been made in the development of cancer molecular biology. The present study aimed to investigate the synergistic effects of the abilities of the hemagglutinin neuraminidase protein of Newcastle disease virus (NDV), the pro-apoptotic factor apoptin from chicken anaemia virus, and the interferon-γ inducer interleukin-18 (IL-18) in antagonizing liver cancer. Therefore, a recombinant DNA plasmid expressing the three exogenous genes, VP3, IL-18 and hemagglutinin neuraminidase (HN), was constructed. Flow cytometry, acridine orange/ethidium bromide staining and analysis of caspase-3 activity were performed in H22 cell lines transfected with the recombinant DNA plasmid. In addition, 6-week-old C57BL/6 mice were used to establish a H22 hepatoma-bearing mouse model. Mice tumor tissue was analyzed by immunohistochemistry and scanning electron microscopy. The results of the present study revealed that the recombinant DNA vaccine containing the VP3, IL-18 and HN genes inhibited cell proliferation and induced autophagy via the mitochondrial pathway in vivo and in vitro.

  17. Chronic hepatitis C infection–induced liver fibrogenesis is associated with M2 macrophage activation

    PubMed Central

    Bility, Moses T.; Nio, Kouki; Li, Feng; McGivern, David R.; Lemon, Stanley M.; Feeney, Eoin R.; Chung, Raymond T.; Su, Lishan

    2016-01-01

    The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV–induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV–induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis. PMID:28000758

  18. Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation.

    PubMed

    Bility, Moses T; Nio, Kouki; Li, Feng; McGivern, David R; Lemon, Stanley M; Feeney, Eoin R; Chung, Raymond T; Su, Lishan

    2016-12-21

    The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV-induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV-induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis.

  19. Aggressive surgical resection for concomitant liver and lung metastasis in colorectal cancer

    PubMed Central

    Lee, Sung Hwan; Kim, Sung Hyun; Lim, Jin Hong; Kim, Sung Hoon; Lee, Jin Gu; Kim, Dae Joon; Choi, Gi Hong; Choi, Jin Sub

    2016-01-01

    Backgrounds/Aims Aggressive surgical resection for hepatic metastasis is validated, however, concomitant liver and lung metastasis in colorectal cancer patients is equivocal. Methods Clinicopathologic data from January 2008 through December 2012 were retrospectively reviewed in 234 patients with colorectal cancer with concomitant liver and lung metastasis. Clinicopathologic factors and survival data were analyzed. Results Of the 234 patients, 129 (55.1%) had synchronous concomitant liver and lung metastasis from colorectal cancer and 36 (15.4%) had metachronous metastasis. Surgical resection was performed in 33 patients (25.6%) with synchronous and 6 (16.7%) with metachronous metastasis. Surgical resection showed better overall survival in both groups (synchronous, p=0.001; metachronous, p=0.028). In the synchronous metastatic group, complete resection of both liver and lung metastatic lesions had better survival outcomes than incomplete resection of two metastatic lesions (p=0.037). The primary site of colorectal cancer and complete resection were significant prognostic factors (p=0.06 and p=0.003, respectively). Conclusions Surgical resection for hepatic and pulmonary metastasis in colorectal cancer can improve complete remission and survival rate in resectable cases. Colorectal cancer with concomitant liver and lung metastasis is not a poor prognostic factor or a contraindication for surgical treatments, hence, an aggressive surgical approach may be recommended in well-selected resectable cases. PMID:27621747

  20. Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.

    PubMed

    Phillips, Jennifer M; Goodman, Jay I

    2009-04-01

    The constitutive active/androstane receptor (CAR) mediates responses to the nongenotoxic rodent liver tumor promoter phenobarbital (PB), including certain gene expression changes, hepatomegaly, and tumor formation. Aberrant DNA methylation represents epigenetic events that can play multiple roles in tumorigenesis. Previously, 146 unique PB-induced regions of altered DNA methylation (RAMs) were observed in liver tumor-susceptible CAR wild-type (WT) mice (in 23 weeks, precancerous tissue, and 32 weeks, tumor tissue), as compared to the resistant knockout (KO). We believe that at least some of these might be key for tumorigenesis. In the current study, cloning and annotation of a subset (82%) of the unique RAMs revealed 47 genes exhibiting altered methylation; 17 are already implicated in cancer or related processes and, thus, we have identified 30 "new" candidate genes that might be involved in carcinogenesis due to an epigenetic alteration. These may contribute to tumor development through their involvement in angiogenesis, apoptosis, epithelial-mesenchymal cell transition, growth/survival, and invasion/migration/metastasis. We have also, previously, discerned unique PB-elicited RAMs in liver tumor-prone B6C3F1 mice, as compared to the relatively resistant C57BL/6 strain, at 2 or 4 weeks, and identified 51 genes exhibiting altered methylation. Importantly, 11 of these genes were identified from identical, unique RAMs discerned in both the sensitive B6C3F1 and CAR WT mice, thus representing an initial, potential candidate "fingerprint" which might serve as a biomarker for PB-induced tumorigenesis. These two studies reveal "new" genes whose epigenetic statuses changed uniquely in liver tumor-susceptible mice (B6C3F1 and CAR WT), as compared to their resistant counterparts (C57BL/6 and CAR KO, respectively), within a continuum of PB-induced tumorigenesis.

  1. Magnesium in drinking water and liver cancer morbidity--a possible relation?

    PubMed

    Tukiendorf, A

    2002-12-01

    The paper presents results of a research on liver cancer morbidity in Opole province, Poland, in relation to magnesium exposure in drinking water. Based on the extensive empirical materials of cancer registry information and water quality, the well known statistical approach using BUGS software was applied in the study. The results support a hypothesis of a possible association between the deficiency of magnesium in drinking water and the increase of liver cancer morbidity in the population exposed. The outcomes were presented in a table and graphically in histograms, scatterplots and maps.

  2. The protective effect of resveratrol on dimethylnitrosamine-induced liver fibrosis in rats.

    PubMed

    Hong, Sang-Won; Jung, Kyung Hee; Zheng, Hong-Mei; Lee, Hee-Seung; Suh, Jun-Kyu; Park, In-Suh; Lee, Don-Haeng; Hong, Soon-Sun

    2010-04-01

    Oxidative stress in liver injury is a major pathogenetic factor in progress of liver fibrosis. Resveratrol, a representative antioxidant derived from grapes, has been reported to show widespread pharmacological properties. In this study, we investigated the protective effects of resveratrol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Rats were treated with resveratrol daily by oral gavage for seven days after a single intraperitoneal injection of DMN (40 mg/kg). Resveratrol remarkably recovered body and liver weight loss due to DMN-induced liver fibrosis. Liver histology showed that resveratrol alleviated the infiltration of inflammatory cells and fibrosis of liver tissue. Resveratrol decreased the level of malondialdehyde and increased the levels of glutathione peroxidase and superoxide dismutase. Also, resveratrol significantly inhibited the mRNA expression of inflammatory mediators including inducible nitric oxide, tumor necrosis factor-alpha and interleukin-1beta. In addition, resveratrol showed not only reduced mRNA expression of fibrosis-related genes such as transforming growth factor beta 1, collagen type I, and alpha-smooth muscle actin, but also a significant decrease of hydroxyproline in rats with DMN-induced liver fibrosis. Our results suggest that resveratrol could be used to treat liver injury and fibrosis and be useful in preventing the development of liver fibrosis and cirrhosis.

  3. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

    PubMed Central

    Bell, Catherine C.; Hendriks, Delilah F. G.; Moro, Sabrina M. L.; Ellis, Ewa; Walsh, Joanne; Renblom, Anna; Fredriksson Puigvert, Lisa; Dankers, Anita C. A.; Jacobs, Frank; Snoeys, Jan; Sison-Young, Rowena L.; Jenkins, Rosalind E.; Nordling, Åsa; Mkrtchian, Souren; Park, B. Kevin; Kitteringham, Neil R.; Goldring, Christopher E. P.; Lauschke, Volker M.; Ingelman-Sundberg, Magnus

    2016-01-01

    Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI. PMID:27143246

  4. Animals models of gastrointestinal and liver diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges.

    PubMed

    Mathews, Stephanie; Xu, Mingjiang; Wang, Hua; Bertola, Adeline; Gao, Bin

    2014-05-15

    Over the last four decades, chronic ethanol feeding studies in rodents using either ad libitum feeding or intragastric infusion models have significantly enhanced our understanding of the pathogenesis of alcoholic liver disease (ALD). Recently, we developed a chronic plus binge alcohol feeding model in mice that is similar to the drinking patterns of many alcoholic hepatitis patients: a history of chronic drinking and recent excessive alcohol consumption. Chronic+binge ethanol feeding synergistically induced steatosis, liver injury, and neutrophil infiltration in mice, which may be useful for the study of early alcoholic liver injury and inflammation. Using this chronic+binge model, researchers have begun to identify novel mechanisms that participate in the pathogenesis of alcoholic liver injury, thereby revealing novel therapeutic targets. In this review article, we briefly discuss several mouse models of ALD with a focus on the chronic+binge ethanol feeding model.

  5. Foxa1 and Foxa2 are Essential for Sexual Dimorphism in Liver Cancer

    PubMed Central

    Li, Zhaoyu; Tuteja, Geetu; Schug, Jonathan; Kaestner, Klaus H.

    2011-01-01

    SUMMARY Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually-dimorphic HCC is completely reversed in Foxa1- and Foxa2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Co-regulation of target genes by Foxa1/a2 and either the estrogen receptor (ERα) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on Foxa1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERα to their targets in human liver, and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC. PMID:22265403

  6. Clonal xenobiotic resistance during pollution-induced toxic injury and hepatocellular carcinogenesis in liver of female flounder (Platichthys flesus (L.)).

    PubMed

    Koehler, Angela; Alpermann, Tilmann; Lauritzen, Bjarne; Van Noorden, Cornelis J F

    2004-01-01

    Juvenile and adult female flounder (Platichthys flesus (L.)) were caught either in the estuary of the most polluted European river, the Elbe, or as controls in a reference site to study pollution-induced xenobiotic resistance in their livers in relation to pathological alterations. In juvenile fish, livers displayed reversible and irreversible degenerative toxipathic lesion types but never showed (pre)neoplastic changes. Tumour frequencies up to 70% were found macroscopically in livers of adult female flounder which had progressed to adenomas and carcinomas in the most polluted site. Because male adult flounder show only up to 50% of livers containing early preneoplastic foci but never malignancies, we focussed our study on female individuals. (Pre)neoplastic changes ranged from early eosinophilic foci to basophilic foci, adenomas and hepatocellular carcinomas. Adenomas were generally eosinophilic whereas carcinomas were mainly basophilic. These phenotypical sequential changes strongly resemble those found in chemically-induced liver carcinogenesis in mammals. Characteristic mutations known from mammalian cancers have not been found so far in these flounder livers. Therefore, we investigated whether epigenetic events had induced a metabolic "resistant phenotype" of (pre)malignant cancer cells during hepatocellular carcinogenesis. With a quantitative immunohistochemical approach, we studied expression of P-glycoprotein (P-gp)-mediated multixenobiotic resistance (MXR), cytochrome P4501A1, glutathione-S-transferase-A which are key proteins in xenobiotic metabolism and elimination. Glucose-6-phosphate dehydrogenase (G6PDH) activity, the major source of the reducing power NADPH which is needed for biotransformation, oxyradical scavenging and biosynthesis, was detected as well. We observed upregulation of G6PDH activity already in early preneoplastic eosinophilic foci and subsequent further upregulation in basophilic foci and carcinomas. P-gp started to become

  7. Connexin32: a mediator of acetaminophen-induced liver injury?

    PubMed Central

    Maes, Michaël; McGill, Mitchell R.; da Silva, Tereza Cristina; Lebofsky, Margitta; de Araújo, Cintia Maria Monteiro; Tiburcio, Taynã; Pereira, Isabel Veloso Alves; Willebrords, Joost; Yanguas, Sara Crespo; Farhood, Anwar; Dagli, Maria Lucia Zaidan; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2016-01-01

    Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-hour time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione, and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity. PMID:26739117

  8. Connexin32: a mediator of acetaminophen-induced liver injury?

    PubMed

    Maes, Michaël; McGill, Mitchell R; da Silva, Tereza Cristina; Lebofsky, Margitta; Maria Monteiro de Araújo, Cintia; Tiburcio, Taynã; Veloso Alves Pereira, Isabel; Willebrords, Joost; Crespo Yanguas, Sara; Farhood, Anwar; Zaidan Dagli, Maria Lucia; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2016-02-01

    Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-h time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity.

  9. Baculovirus-mediated interferon alleviates dimethylnitrosamine-induced liver cirrhosis symptoms in a murine model.

    PubMed

    Nishibe, Y; Kaneko, H; Suzuki, H; Abe, T; Matsuura, Y; Takaku, H

    2008-07-01

    The wild-type baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) infects a range of mammalian cell types in vitro but does not replicate in these cells. The current study investigated the in vivo effect of AcMNPV in the mouse model of liver cirrhosis induced by the mutagen dimethylnitrosamine. Intraperitoneal injection of AcMNPV induced an immune response. The baculovirus was taken up by the liver and spleen where it suppressed liver injury and fibrosis through the induction of interferons. This study presents the first evidence of the feasibility of using baculovirus to treat liver cirrhosis.

  10. [Liver injury and hepatic encephalopathy induced by the herbal medicine Hochuekkito].

    PubMed

    Negishi, Ryoju; Ichikawa, Takeshi; Tawa, Yoshiyuki; Fujimura, Akira; Tanaka, Sayo; Tenmoku, Akira; Akazawa, Kimika; Kanno, Masataka; Sasaki, Hiroshi; Okubo, Sae; Machida, Nobuaki; Fukuda, Yuh; Oi, Itaru; Fujino, Masayuki A

    2014-06-01

    A 57-year-old man was admitted with pruritus and jaundice following treatment for fatigue with the herbal medicine Hochuekkito. The patient was prescribed prednisolone and ursodeoxycholic acid, but he developed progressive cholestasis that required intravenous methylprednisolone pulse therapy. After treatment with plasma exchange for prolonged prothrombin time, the patient recovered; however, his liver function deteriorated because of liver injury induced by trimethoprim-sulfamethoxazole for pneumocystis pneumonia. After reduction of trimethoprim-sulfamethoxazole, his liver function almost returned to normal by day 130 of admission. It has remained normal for 10 months since then. Therefore, when prescribing Hochuekkito, the possibility of drug-induced liver injury should be taken in account.

  11. Molecular responses of radiation-induced liver damage in rats.

    PubMed

    Cheng, Wei; Xiao, Lei; Ainiwaer, Aimudula; Wang, Yunlian; Wu, Ge; Mao, Rui; Yang, Ying; Bao, Yongxing

    2015-04-01

    The aim of the present study was to investigate the molecular responses involved in radiation‑induced liver damage (RILD). Sprague‑Dawley rats (6‑weeks‑old) were irradiated once at a dose of 20 Gy to the right upper quadrant of the abdomen. The rats were then sacrificed 3 days and 1, 2, 4, 8 and 12 weeks after irradiation and rats, which were not exposed to irradiation were used as controls. Weight measurements and blood was obtained from the rats and liver tissues were collected for histological and apoptotic analysis. Immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis were performed to measure the expression levels of mRNAs and proteins, respectively. The serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were increased significantly in the RILD rats. Histological investigation revealed the proliferation of collagen and the formation of fibrotic tissue 12 weeks after irradiation. Apoptotic cells were observed predominantly 2 and 4 weeks after irradiation. The immunohistochemistry, RT‑qPCR and western blot analysis all revealed the same pattern of changes in the expression levels of the molecules assessed. The expression levels of transforming growth factor‑β1 (TGF‑β1), nuclear factor (NF)‑κB65, mothers against decapentaplegic homolog 3 (Smad3) and Smad7 and connective tissue growth factor were increased during the recovery period following irradiation up to 12 weeks. The expression levels of tumor necrosis factor‑α, Smad7 and Smad4 were only increased during the early phase (first 4 weeks) of recovery following irradiation. In the RILD rat model, the molecular responses indicated that the TGF‑β1/Smads and NF‑κB65 signaling pathways are involved in the mechanism of RILD recovery.

  12. Quercetin Prevents Pyrrolizidine Alkaloid Clivorine-Induced Liver Injury in Mice by Elevating Body Defense Capacity

    PubMed Central

    Ji, Lili; Ma, Yibo; Wang, Zaiyong; Cai, Zhunxiu; Pang, Chun; Wang, Zhengtao

    2014-01-01

    Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin. PMID:24905073

  13. Inhibition of Kupffer Cell Autophagy Abrogates Nanoparticle-Induced Liver Injury.

    PubMed

    Zhu, Shasha; Zhang, Jiqian; Zhang, Li; Ma, Wentao; Man, Na; Liu, Yiming; Zhou, Wei; Lin, Jun; Wei, Pengfei; Jin, Peipei; Zhang, Yunjiao; Hu, Yi; Gu, Erwei; Lu, Xianfu; Yang, Zhilai; Liu, Xuesheng; Bai, Li; Wen, Longping

    2017-02-24

    The possible adverse effects of engineered nanomaterials on human health raise increasing concern as our research on nanosafety intensifies. Upon entry into a human body, whether intended for a theranostic purpose or through unintended exposure, nanomaterials tend to accumulate in the liver, leading to hepatic damage. A variety of nanoparticles, including rare earth upconversion nanoparticles (UCNs), have been reported to elicit hepatotoxicity, in most cases through inducing immune response or activating reactive oxygen species. Many of these nanoparticles also induce autophagy, and autophagy inhibition has been shown to decrease UCN-induced liver damage. Herein, using UCNs as a model engineered nanomaterial, this study uncovers a critical role for Kupffer cells in nanomaterial-induced liver toxicity, as depletion of Kupffer cells significantly exacerbates UCN-induced liver injury. Furthermore, UCN-induced prodeath autophagy in Kupffer cells, and inhibition of autophagy with 3-MA, a well-established chemical inhibitor of autophagy, enhances Kupffer cell survival and further abrogates UCN-induced liver toxicity. The results reveal the critical importance of Kupffer cell autophagy for nanoparticle-induced liver damage, and inhibition of autophagy may constitute a novel strategy for abrogating nanomaterial-elicited liver toxicity.

  14. Several microRNAs could predict survival in patients with hepatitis B-related liver cancer

    PubMed Central

    Zhen, Ye; Xinghui, Zhao; Chao, Wu; Yi, Zhao; Jinwen, Chen; Ruifang, Gao; Chao, Zhang; Min, Zhao; Chunlei, Guo; Yan, Fang; Lingfang, Du; Long, Shen; Wenzhi, Shen; Xiaohe, Luo; Rong, Xiang

    2017-01-01

    MicroRNAs as biomarkers play an important role in the tumorigenesis process, including hepatocellular carcinomas (HCCs). In this paper, we used The Cancer Genome Atlas (TCGA) database to mine hepatitis B-related liver cancer microRNAs that could predict survival in patients with hepatitis B-related liver cancer. There were 93 cases of HBV-HCC and 49 cases of adjacent normal controls included in the study. Kaplan–Meier survival analysis of a liver cancer group versus a normal control group of differentially expressed genes identified eight genes with statistical significance. Compared with the normal liver cell line, hepatocellular carcinoma cell lines had high expression of 8 microRNAs, albeit at different levels. A Cox proportional hazards regression model for multivariate analysis showed that four genes had a significant difference. We established classification models to distinguish short survival time and long survival time of liver cancers. Eight genes (mir9-3, mir10b, mir31, mir519c, mir522, mir3660, mir4784, and mir6883) were identified could predict survival in patients with HBV-HCC. There was a significant correlation between mir10b and mir31 and clinical stages (p < 0.05). A random forests model effectively estimated patient survival times. PMID:28322348

  15. Tomatine-containing green tomato extracts inhibit growth of human breast, colon, liver, and stomach cancer cells.

    PubMed

    Friedman, Mendel; Levin, Carol E; Lee, Seung-Un; Kim, Hyun-Jeong; Lee, In-Seon; Byun, Jae-Oke; Kozukue, Nobuyuki

    2009-07-08

    Tomato plants ( Lycopersicon esculentum ) synthesize the glycoalkaloids dehydrotomatine and alpha-tomatine, possibly as a defense against bacteria, fungi, viruses, and insects. Six green and three red tomato extracts were investigated for their ability to induce cell death in human cancer and normal cells using a microculture tetrazolium (MTT) assay. Compared to untreated controls, the high-tomatine green tomato extracts strongly inhibited the following human cancer cell lines: breast (MCF-7), colon (HT-29), gastric (AGS), and hepatoma (liver) (HepG2), as well as normal human liver cells (Chang). There was little inhibition of the cells by the three low-tomatine red tomato extracts. Cell death induced by the pure glycoalkaloids dehydrotomatine and alpha-tomatine isolated from green tomatoes and characterized by HPLC, GC, and GC-MS, as well as their respective aglycones tomatidenol and tomatidine, was also evaluated. alpha-Tomatine was highly effective in inhibiting all of the cell lines. Dehydrotomatine, tomatidenol, and tomatidine had little, if any, effect on cell inhibition. The results show that the susceptibility to destruction varies with the nature of the alkaloid and plant extract and the type of cancer cell. These findings extend related observations on the anticarcinogenic potential of glycoalkaloids and suggest that consumers may benefit by eating not only high-lycopene red tomatoes but also green tomatoes containing glycoalkaloids. Possible mechanisms of the anticarcinogenic and other beneficial effects and the significance of the cited observations for breeding improved tomatoes and for the human diet are discussed.

  16. Environmental Factors Inducing Human Cancers

    PubMed Central

    Parsa, N

    2012-01-01

    Background An explosion of research has been done in discovering how human health is affected by environmental factors. I will discuss the impacts of environmental cancer causing factors and how they continue to cause multiple disruptions in cellular networking. Some risk factors may not cause cancer. Other factors initiate consecutive genetic mutations that would eventually alter the normal pathway of cellular proliferations and differentiation. Genetic mutations in four groups of genes; (Oncogenes, Tumor suppressor genes, Apoptosis genes and DNA repairing genes) play a vital role in altering the normal cell division. In recent years, molecular genetics have greatly increased our understanding of the basic mechanisms in cancer development and utilizing these molecular techniques for cancer screening, diagnosis, prognosis and therapies. Inhibition of carcinogenic exposures wherever possible should be the goal of cancer prevention programs to reduce exposures from all environmental carcinogens. PMID:23304670

  17. The constitutive active/androstane receptor facilitates unique phenobarbital-induced expression changes of genes involved in key pathways in precancerous liver and liver tumors.

    PubMed

    Phillips, Jennifer M; Burgoon, Lyle D; Goodman, Jay I

    2009-08-01

    Our overall goal is to elucidate progressive changes, in expression and methylation status, of genes which play key roles in phenobarbital (PB)-induced liver tumorigenesis, with an emphasis on their potential to affect signaling through critical pathways involved in the regulation of cell growth and differentiation. PB-elicited unique expression changes of genes, including some of those identified previously as exhibiting regions of altered DNA methylation, were discerned in precancerous liver tissue and/or individual liver tumors from susceptible constitutive active/androstane receptor (CAR) wild-type (WT) compared with resistant CAR knockout (KO) mice. Many of these function in crucial cancer-related processes, for example, angiogenesis, apoptosis, cell cycle, DNA methylation, Hedgehog signaling, invasion/metastasis, Notch signaling, and Wnt signaling. Furthermore, a subset of the uniquely altered genes contained CAR response elements (CAREs). This included Gadd45b, a coactivator of CAR and inhibitor of apoptosis, and two DNA methyltransferases (Dnmt1, Dnmt3a). The presence of CAREs in Dnmts suggests a potential direct link between PB and altered DNA methylation. The current data are juxtaposed with the effects of PB on DNA methylation and gene expression which occurred uniquely in liver tumor-prone B6C3F1 mice, as compared with the resistant C57BL/6, following 2 or 4 weeks of treatment. Collectively, these data reveal a comprehensive view of PB-elicited molecular alterations (i.e., changes in gene expression and DNA methylation) that can facilitate hepatocarcinogenesis. Notably, candidate genes for initial "fingerprints" of early and late stages of PB-induced tumorigenesis are proposed.

  18. The Constitutive Active/Androstane Receptor Facilitates Unique Phenobarbital-Induced Expression Changes of Genes Involved in Key Pathways in Precancerous Liver and Liver Tumors

    PubMed Central

    Phillips, Jennifer M.; Burgoon, Lyle D.; Goodman, Jay I.

    2009-01-01

    Our overall goal is to elucidate progressive changes, in expression and methylation status, of genes which play key roles in phenobarbital (PB)–induced liver tumorigenesis, with an emphasis on their potential to affect signaling through critical pathways involved in the regulation of cell growth and differentiation. PB-elicited unique expression changes of genes, including some of those identified previously as exhibiting regions of altered DNA methylation, were discerned in precancerous liver tissue and/or individual liver tumors from susceptible constitutive active/androstane receptor (CAR) wild-type (WT) compared with resistant CAR knockout (KO) mice. Many of these function in crucial cancer-related processes, for example, angiogenesis, apoptosis, cell cycle, DNA methylation, Hedgehog signaling, invasion/metastasis, Notch signaling, and Wnt signaling. Furthermore, a subset of the uniquely altered genes contained CAR response elements (CAREs). This included Gadd45b, a coactivator of CAR and inhibitor of apoptosis, and two DNA methyltransferases (Dnmt1, Dnmt3a). The presence of CAREs in Dnmts suggests a potential direct link between PB and altered DNA methylation. The current data are juxtaposed with the effects of PB on DNA methylation and gene expression which occurred uniquely in liver tumor-prone B6C3F1 mice, as compared with the resistant C57BL/6, following 2 or 4 weeks of treatment. Collectively, these data reveal a comprehensive view of PB-elicited molecular alterations (i.e., changes in gene expression and DNA methylation) that can facilitate hepatocarcinogenesis. Notably, candidate genes for initial “fingerprints” of early and late stages of PB-induced tumorigenesis are proposed. PMID:19482888

  19. Epigenetic silencing of glutaminase 2 in human liver and colon cancers

    PubMed Central

    2013-01-01

    Background Glutaminase 2 (Gls2) is a p53 target gene and is known to play an important role in energy metabolism. Gls2 has been reported to be downregulated in human hepatocellular carcinomas (HCC). However, the underlying mechanism responsible for its downregulation is still unclear. Here, we investigated Gls2 expression and its promoter methylation status in human liver and colon cancers. Methods mRNA expression of Gls2 was determined in human liver and colon cancer cell lines and HCC tissues by real-time PCR and promoter methylation was analyzed by methylation-specific PCR (MSP) and validated by bisulfite genome sequencing (BGS). Cell growth was determined by colony formation assay and MTS assay. Statistical analysis was performed by Wilcoxon matched-pairs test or non-parametric t test. Results First, we observed reduced Gls2 mRNA level in a selected group of liver and colon cancer cell lines and in the cancerous tissues from 20 HCC and 5 human colon cancer patients in comparison to their non-cancerous counter parts. Importantly, the lower level of Gls2 in cancer cells was closely correlated to its promoter hypermethylation; and chemical demethylation treatment with 5-aza-2′-deoxycytidine (Aza) increased Gls2 mRNA level in both liver and colon cancer cells, indicating that direct epigenetic silencing suppressed Gls2 expression by methylation. Next, we further examined this correlation in human HCC tissues, and 60% of primary liver tumor tissues had higher DNA methylation levels when compared with adjacent non-tumor tissues. Detailed methylation analysis of 23 CpG sites at a 300-bp promoter region by bisulfite genomic sequencing confirmed its methylation. Finally, we examined the biological function of Gls2 and found that restoring Gls2 expression in cancer cells significantly inhibited cancer cell growth and colony formation ability through induction of cell cycle arrest. Conclusions We provide evidence showing that epigenetic silencing of Gls2 via promoter

  20. Anabolic steroid-induced cardiomyopathy underlying acute liver failure in a young bodybuilder

    PubMed Central

    Bispo, Miguel; Valente, Ana; Maldonado, Rosário; Palma, Rui; Glória, Helena; Nóbrega, João; Alexandrino, Paula

    2009-01-01

    Heart failure may lead to subclinical circulatory disturbances and remain an unrecognized cause of ischemic liver injury. We present the case of a previously healthy 40-year-old bodybuilder, referred to our Intensive-Care Unit of Hepatology for treatment of severe acute liver failure, with the suspicion of toxic hepatitis associated with anabolic steroid abuse. Despite the absence of symptoms and signs of congestive heart failure at admission, an anabolic steroid-induced dilated cardiomyopathy with a large thrombus in both ventricles was found to be the underlying cause of the liver injury. Treatment for the initially unrecognized heart failure rapidly restored liver function to normal. To our knowledge, this is the first reported case of severe acute liver failure due to an unrecognized anabolic steroid-induced cardiomyopathy. Awareness of this unique presentation will allow for prompt treatment of this potentially fatal cause of liver failure. PMID:19533818

  1. Musashi2 as a novel predictive biomarker for liver metastasis and poor prognosis in colorectal cancer.

    PubMed

    Zong, Zhen; Zhou, Taicheng; Rao, Liangjun; Jiang, Zhipeng; Li, Yingru; Hou, Zehui; Yang, Bin; Han, Fanghai; Chen, Shuang

    2016-04-01

    Aberrant expression of musashi2 (MSI-2) has been detected in several malignancies. However, its role in the progression of colorectal cancer (CRC) remains unknown. Our study was designed to investigate the expression and prognostic significance of MSI-2 protein in patients with colorectal cancer. The expression of MSI-2 was detected in 164 patients' colorectal cancer and control specimens by the tissue microarray technique and immunohistochemical staining. The correlations between MSI-2 expression and clinicopathological variables including overall survival were analyzed. The prognostic value of liver metastasis is evaluated by logistic regression and receiver operating characteristic (ROC) analysis. MSI-2 was highly expressed in 32.9% (54/164) of the colorectal cancer. Overexpression of MSI-2 was associated with depth of invasion, lymph node metastasis, distant metastasis, liver metastasis, Tumor Node Metastasis (TNM) clinical stage, and Carcinoembryonicantigen (CEA) level (P = 0.040, 0.014, <0.001, <0.001, 0.003, and 0.002, respectively). In the Cox multivariate test, MSI-2 overexpression, lymph node metastasis, and distant metastasis were found to be the independent prognostic factors (P = 0.027, 0.010, and 0.001, respectively). Further logistic regression suggested that TNM stage and MSI-2 high expression were related to liver metastasis in colorectal cancer patients. Conclusively, our study indicates that MSI-2 overexpression is associated with an unfavorable prognosis and may be a potential biomarker for liver metastasis in colorectal cancer patients.

  2. An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer.

    PubMed

    Andersen, Jesper B; Factor, Valentina M; Marquardt, Jens U; Raggi, Chiara; Lee, Yun-Han; Seo, Daekwan; Conner, Elizabeth A; Thorgeirsson, Snorri S

    2010-10-20

    Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome.

  3. In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

    PubMed Central

    2011-01-01

    Background Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability. Methods 6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA. Results MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm3+/-243 mm3) with MRI (mean 918 mm3+/-193 mm3) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm2+/-22.8 mm2 versus 32.6 mm2+/-22.6 mm2 (histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm3+/-56.7 mm3 after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals. Conclusions This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and

  4. Combination of internal radiation therapy and hyperthermia to treat liver cancer

    SciTech Connect

    Grady, E.D.; McLaren, J.; Auda, S.P.; McGinley, P.H.

    1983-09-01

    Sixteen patients were treated for liver cancer (primary and metastatic) by a combination of internal radiation therapy with intra-arterial yttrium 90 microspheres and regional hyperthermia with electromagnetic radiation. Four patients have their liver disease apparently controlled; two had a partial regression of more than 50%; and two had a partial regression of less than 50%. The complications consisted of one case of radiation hepatitis and one of peptic ulcer.

  5. Radiation-Induced Vaccination to Breast Cancer

    DTIC Science & Technology

    2015-10-01

    Award Number: W81XWH-11-1-0531 TITLE: Radiation-Induced Vaccination to Breast Cancer PRINCIPAL INVESTIGATOR: William H. McBride CONTRACTING...FORM TO THE ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE Annual 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Radiation-Induced Vaccination to...determine abscopal responses that are hypothesized to be due to RT- induced vaccination . RT was started 10 days after the first and 3rd dose of

  6. Characterization of Chemically Induced Liver Injuries Using Gene Co-Expression Modules

    DTIC Science & Technology

    2014-09-16

    Characterization of Chemically Induced Liver Injuries Using Gene Co-Expression Modules Gregory J. Tawa1*, Mohamed Diwan M. AbdulHameed1, Xueping Yu1...Abstract Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due...identify groups of co-expressed genes (modules) specific to injury endpoints in the liver . We identified 78 such gene co-expression modules associated

  7. [Stereotactic Body Radiotherapy with CyberKnife®for Liver Metastases from Colorectal Cancer].

    PubMed

    Mihara, Koki; Kaihara, Masaki; Sunahori, Sayaka; Yamashiro, Naotsugu; Nishiya, Shin; Ito, Yasuhiro; Funakoshi, Kazuto; Egawa, Tomohisa; Tsukamoto, Nobuhiro; Nagashima, Atsushi

    2015-10-01

    For treatment of colorectal liver metastases, liver resection is recommended for resectable cases in the clinical guidelines for colorectal cancer. On the other hand, there are currently no data supporting the efficacy of radiation therapy as a topical treatment, and this treatment can therefore not presently be recommended. With CyberKnife®, it is possible to perform stereotactic radiation therapy using a linear accelerator with high accuracy, even for lesions in the trunk area such as liver metastases. Between December 2009 and September 2014 in our hospital, we performed radiation treatment using CyberKnife® for 14 cases with 22 colorectal liver metastases. As a result, we obtained response and local control rates of 76.2%and 81.0%, respectively. Moreover, no advanced adverse events were observed. Thus, we consider that CyberKnife® treatment for colorectal liver metastases is effective as a topical treatment, with low invasiveness and high safety.

  8. Liver X receptor ligand cytotoxicity in colon cancer cells and not in normal colon epithelial cells depends on LXRβ subcellular localization.

    PubMed

    Courtaut, Flavie; Derangère, Valentin; Chevriaux, Angélique; Ladoire, Sylvain; Cotte, Alexia K; Arnould, Laurent; Boidot, Romain; Rialland, Mickaël; Ghiringhelli, François; Rébé, Cédric

    2015-09-29

    Increasing evidence indicates that Liver X Receptors (LXRs) have some anticancer properties. We recently demonstrated that LXR ligands induce colon cancer cell pyroptosis through an LXRβ-dependent pathway. In the present study, we showed that human colon cancer cell lines presented differential cytoplasmic localizations of LXRβ. This localization correlated with caspase-1 activation and cell death induction under treatment with LXR ligand. The association of LXRβ with the truncated form of RXRα (t-RXRα) was responsible for the sequestration of LXRβ in the cytoplasm in colon cancer cells. Moreover t-RXRα was not expressed in normal colon epithelial cells. These cells presented a predominantly nuclear localization of LXRβ and were resistant to LXR ligand cytotoxicity. Our results showed that predominant cytoplasmic localization of LXRβ, which occurs in colon cancer cells but not in normal colon epithelial cells, allowed LXR ligand-induced pyroptosis. This study strengthens the hypothesis that LXRβ could be a promising target in cancer therapy.

  9. Combining Angiogenesis-Targeted Treatments for Liver Cancer

    Cancer.gov

    In this trial, patients with unresectable hepatocellular carcinoma who are ineligible for a liver transplant or other local therapies will be given oral sorafenib at the standard approved dose and intravenous TRC105.

  10. Cadmium Chloride Induces DNA Damage and Apoptosis of Human Liver Carcinoma Cells via Oxidative Stress.

    PubMed

    Skipper, Anthony; Sims, Jennifer N; Yedjou, Clement G; Tchounwou, Paul B

    2016-01-02

    Cadmium is a heavy metal that has been shown to cause its toxicity in humans and animals. Many documented studies have shown that cadmium produces various genotoxic effects such as DNA damage and chromosomal aberrations. Ailments such as bone disease, renal damage, and several forms of cancer are attributed to overexposure to cadmium. Although there have been numerous studies examining the effects of cadmium in animal models and a few case studies involving communities where cadmium contamination has occurred, its molecular mechanisms of action are not fully elucidated. In this research, we hypothesized that oxidative stress plays a key role in cadmium chloride-induced toxicity, DNA damage, and apoptosis of human liver carcinoma (HepG₂) cells. To test our hypothesis, cell viability was determined by MTT assay. Lipid hydroperoxide content stress was estimated by lipid peroxidation assay. Genotoxic damage was tested by the means of alkaline single cell gel electrophoresis (Comet) assay. Cell apoptosis was measured by flow cytometry assessment (Annexin-V/PI assay). The result of MTT assay indicated that cadmium chloride induces toxicity to HepG₂ cells in a concentration-dependent manner, showing a 48 hr-LD50 of 3.6 µg/mL. Data generated from lipid peroxidation assay resulted in a significant (p < 0.05) increase of hydroperoxide production, specifically at the highest concentration tested. Data obtained from the Comet assay indicated that cadmium chloride causes DNA damage in HepG₂ cells in a concentration-dependent manner. A strong concentration-response relationship (p < 0.05) was recorded between annexin V positive cells and cadmium chloride exposure. In summary, these in vitro studies provide clear evidence that cadmium chloride induces oxidative stress, DNA damage, and programmed cell death in human liver carcinoma (HepG₂) cells.

  11. MIF, secreted by human hepatic sinusoidal endothelial cells, promotes chemotaxis and outgrowth of colorectal cancer in liver prometastasis.

    PubMed

    Hu, Chun-Ting; Guo, Li-Li; Feng, Na; Zhang, Lei; Zhou, Na; Ma, Li-Li; Shen, Lan; Tong, Gui-Hui; Yan, Qian-Wen; Zhu, Shi-Jie; Bian, Xiu-Wu; Lai, Mao D; Deng, Yong-Jian; Ding, Yan-Qing

    2015-09-08

    Growth and invasion of metastatic colorectal cancer (CRC) cells in the liver depend on microenvironment. Here, we showed that human hepatic sinusoidal endothelial cells (HHSECs) induce chemotaxis and outgrowth of CRC cells. Macrophage migration inhibitory factor (MIF), released by HHSECs, stimulated chemotaxis of CRC cells. MIF secreted by HHSECs, but not by CRC cells themselves, promoted migration and epithelial-mesenchymal transition (EMT) and facilitated proliferation and apoptotic resistance of CRC cells. In orthotopic implantation models in nude mice, exogenous MIF stimulated growth of CRC cells and metastasis. Furthermore, MIF accelerated mobility of CRC cells by suppressing F-actin depolymerization and phosphorylating cofilin. Noteworthy, MIF levels were correlated with the size of hepatic metastases. We suggest that HHSECs and paracrine MIF promote initial migration and proliferation of CRC cells in the hepatic sinusoids to generate liver metastases.

  12. Experimentally induced "fatty liver syndrome" condition in laying hens.

    PubMed

    Harms, R H; Roland, D A; Simpson, C F

    1977-03-01

    Two experiments were conducted with aged laying hens to determine the influence of feeding 5,000 p.p.m. of iodine as potassium iodine (KI) and/or injecting 12 mg. of estradiol upon fat accumulation in the liver and serum cholesterol levels. The KI was fed for 8 days before making liver and blood determinations, and the estradiol was injected 3 days prior to making the determinations. The feeding of KI or injection of estradiol resulted in significantly increased liver weight. When the two treatments were combined a further significant increase in liver weights was obtained. The percent of fat in the liver was significantly increased by the injection of estradiol. However, the feeding of KI in the presence or absence of estradiol did not affect the percentage of fat in the liver. Neither of the treatments significantly affected the fatty acid composition of the liver fat. Feeding of KI or injection of estradiol significantly increased total serum cholesterol levels. When the two treatments were combined a further increase in serum cholesterol level was observed. Histological changes of the livers of hens treated with KI and estradiol were similar to those previously described for the "fatty liver syndrome."

  13. [A case with liver resection of metastasis from rectal cancer after FOLFOX4+bevacizumab treatment].

    PubMed

    Kojima, Taiki; Matsui, Takanori; Uemura, Takanori; Fujimitsu, Yasunobu; Kure, Narihiro; Kojima, Hiroshi

    2008-10-01

    We report a 59-year-old woman with rectal cancer who underwent low anterior resection in March 2007. After curative operation at Stage IIIb(pT3N2M0), multiple liver metastasis was diagnosed in May 2007. Chemotherapy with FOLFOX4+bevacizumab was performed from June to August in 2007, and liver resection(left lobectomy and partial resection)was performed in September 2007. Bevacizumab was newly available from June 2007 in Japan, and liver resection after bevacizumab administration was safely performed.

  14. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues.

    PubMed

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health.Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper,we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameter scan provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  15. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues

    NASA Astrophysics Data System (ADS)

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health. Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper, we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameters can provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  16. Amiodarone-Induced Cirrhosis of Liver: What Predicts Mortality?

    PubMed Central

    Hussain, Nasir

    2013-01-01

    Introduction. Amiodarone has been used for more than 5 decades for the treatment of various tachyarrhythmias and previously for the treatment of refractory angina. There are multiple well-established side effects of amiodarone. However, amiodarone-induced cirrhosis (AIC) of liver is an underrecognized complication. Methods. A systematic search of Medline from January 1970 to November 2012 by using the following terms, amiodarone and cirrhosis, identified 37 reported cases of which 30 were used in this analysis. Patients were divided into 2 subsets, survivors versus nonsurvivors, at 5 months. Results. Aspartate aminotransferase was significantly lower (P = 0.03) in patients who survived at 5-months (mean 103.33 IU/L) compared to nonsurvivors (mean 216.88 IU/L). There was no statistical difference in the levels of prothrombin time, total bilirubin, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, cumulative dose, and latency period between the two groups. The prevalence of DM, HTN, HLD, CAD, and CHF was similar in the two groups. None of the above-mentioned variables could be identified as a predictor of survival at 5 months. Conclusion. AIC carries a mortality risk of 60% at 5 months once the diagnosis is established. Further prospective studies are needed to identify predictors of AIC and of mortality or survival in cases of AIC. PMID:23577267

  17. Role of bone and liver scans in surveying patients with breast cancer for metastatic disease

    SciTech Connect

    Evans, D.M.; Wright, D.J.

    1987-10-01

    The objective of this study is to correlate the presence of bone and liver metastases in patients with breast cancer with respect to the results of bone and liver scans, axillary nodal status, and serum alkaline phosphatase levels. One hundred ninety-seven patients with breast cancer treated by modified radical mastectomy between the years 1978 and 1981 were studied. Fifty-nine (30%) of the total group had distant metastases during the course of observation of 60 to 96 months; of 35 patients in whom bone metastases developed, 30 had normal preoperative bone scan results. Of 21 patients who had liver metastases, 19 had normal preoperative liver scans. Nineteen (70%) of the 27 patients with abnormal bone scans had normal alkaline phosphatase levels. Seven (63%) of the 11 patients who had abnormal liver scans had a normal alkaline phosphatase. The study supports the concept that preoperative bone and liver scans are ineffective indicators of metastatic involvement. Selection of patients for screening by bone and liver scans according to alkaline phosphatase determinations was not supported by this study. The appropriate use of bone scans for screening in patients with breast carcinoma is suggested as a follow-up device in patients with positive lymph nodes.

  18. Hepatoprotective Activity of Heptoplus on Isoniazid and Rifampicin Induced Liver Damage in Rats

    PubMed Central

    Sankar, M.; Rajkumar, Johanna; Sridhar, Dorai

    2015-01-01

    The present study is designed to evaluate the efficacy of heptoplus a polyherbal formulation as an oral supplementary agent for isoniazid and rifampicin induced hepatotoxicity in rats. 50 and 100 mg/kg of heptoplus supplement were fed orally to the rats along with isoniazid and rifampicin and compared to rats treated with 100 mg/kg Liv 52 standard drug. Rats treated with isoniazid and rifampicin suffered from severe oxidative stress by the virtue of free radicals induced lipid per oxidation. As a result abnormal index of serum biochemical markers for liver function and increased liver lysosomal enzymes activity was observed. However rats nourished with 100 mg/kg of heptoplus and Liv 52 protected the liver from oxidative damage by maintaining normal antioxidant profile status and restored normal serum liver biochemical markers. Increased liver lysosomal enzymes activity is prevented in the rats supplemented with heptoplus and Liv 52. Histopathological analysis also revealed severe vascular changes and lobular necrosis in the treatment of isoniazid and rifampicin. Heptoplus (100 mg/kg) and Liv 52 supplemented rats liver apparently revealed normal architecture of liver. This study confirms that heptoplus has liver protective activity against Isoniazid and Rifampicin induced liver injury in rats, in par with Liv 52. PMID:26798170

  19. Biochemical and histopathological changes induced by different time intervals of methomyl treatment in mice liver.

    PubMed

    El-Demerdash, Fatma; Attia, Azza A; Elmazoudy, Reda H

    2012-01-01

    The present study was designed to evaluate the toxic effects induced by different time intervals of methomyl exposure on liver antioxidant defense system, oxidative stress, liver function biomarkers and histopathology in CD-1 mice. Ten male mice per group were assigned to one of four treatment groups. Group one served as control while group 2, 3 and 4 were orally treated with one mg methomyl/kg BW for 10, 20 and 30 days, respectively. Results obtained showed that methomyl significantly induced TBARS and decreased the activity of antioxidant enzymes, glutathione S-transferase, superoxide dismutase and catalase and the levels of reduced glutathione in mice liver. Aminotransferases and alkaline phosphatase activities were significantly decreased in liver due to methomyl administration, while the activities of these enzymes were significantly increased in serum. In addition, liver lactate dehydrogenase activity was significantly increased. On the contrary, methomyl treatment caused a significant decrease in liver acid phosphatase. The histology of mice liver treated with methomyl for 10, 20 and 30 days of duration showed dilation of central vein, sinusoids between hypertrophied hepatocytes and nuclear degeneration with mononuclear cell infiltration. In conclusion, exposure to methomyl induced toxicity and oxidative stress in mice liver via free radicals mechanism. Also, methomyl might have affected cell metabolism, cell membrane permeability and the detoxification system in liver.

  20. FGF21 ameliorates nonalcoholic fatty liver disease by inducing autophagy.

    PubMed

    Zhu, Shenglong; Wu, Yunzhou; Ye, Xianlong; Ma, Lei; Qi, Jianying; Yu, Dan; Wei, Yuquan; Lin, Guangxiao; Ren, Guiping; Li, Deshan

    2016-09-01

    The aim of this study is to evaluate the role of fibroblast growth factor 21 (FGF21) in nonalcoholic fatty liver disease (NAFLD) and seek to determine if its therapeutic effect is through induction of autophagy. In this research, Monosodium L-glutamate (MSG)-induced obese mice or normal lean mice were treated with vehicle, Fenofibrate, and recombinant murine FGF21, respectively. After 5 weeks of treatment, metabolic parameters including body weight, blood glucose and lipid levels, hepatic and fat gene expression levels were monitored and analyzed. Also, fat-loaded HepG2 cells were treated with vehicle or recombinant murine FGF21. The expression levels of proteins associated with autophagy were detected by western blot, real-time PCR, and transmission electron microscopy (TEM). Autophagic flux was monitored by laser confocal microscopy and western blot. Results showed that FGF21 significantly reduced body weight (P < 0.01) and serum triglyceride, improved insulin sensitivity, and reversed hepatic steatosis in the MSG model mice. In addition, FGF21 significantly increased the expression of several proteins related to autophagy both in MSG mice and fat-loaded HepG2 cells, such as microtubule associated protein 1 light chain 3, Bcl-2-interacting myosin-like coiled-coil protein-1 (Beclin-1), and autophagy-related gene 5. Furthermore, the evidence of TEM revealed an increased number of autophagosomes and lysosomes in the model cells treated with FGF21. In vitro experimental results also showed that FGF21 remarkably increased autophagic flux. Taken together, FGF21 corrects multiple metabolic parameters on NAFLD in vitro and in vivo by inducing autophagy.

  1. AAV8-mediated Sirt1 gene transfer to the liver prevents high carbohydrate diet-induced nonalcoholic fatty liver disease

    PubMed Central

    Vilà, Laia; Elias, Ivet; Roca, Carles; Ribera, Albert; Ferré, Tura; Casellas, Alba; Lage, Ricardo; Franckhauser, Sylvie; Bosch, Fatima

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease worldwide, and evidence suggests that it promotes insulin resistance and type 2 diabetes. Caloric restriction (CR) is the only available strategy for NAFLD treatment. The protein deacetylase Sirtuin1 (SIRT1), which is activated by CR, increases catabolic metabolism and decreases lipogenesis and inflammation, both involved in the development of NAFLD. Here we show that adeno-associated viral vectors of serotype 8 (AAV8)-mediated liver-specific Sirt1 gene transfer prevents the development of NAFLD induced by a high carbohydrate (HC) diet. Long-term hepatic SIRT1 overexpression led to upregulation of key hepatic genes involved in β-oxidation, prevented HC diet-induced lipid accumulation and reduced liver inflammation. AAV8-Sirt1–treated mice showed improved insulin sensitivity, increased oxidative capacity in skeletal muscle and reduced white adipose tissue inflammation. Moreover, HC feeding induced leptin resistance, which was also attenuated in AAV8-Sirt1–treated mice. Therefore, AAV-mediated gene transfer to overexpress SIRT1 specifically in the liver may represent a new gene therapy strategy to counteract NAFLD and related diseases such as type 2 diabetes. PMID:26015978

  2. Oral Consumption of Bitter Gourd and Tomato Prevents Lipid Peroxidation in Liver Associated with DMBA Induced Skin Carcinogenesis in Mice.

    PubMed

    De, Sarmishtha; Chakraborty, Jamuna; Das, Sukta

    2000-01-01

    The protective role of two commonly consumed natural dietary items- bitter gourd and tomato against endogenous as well as 7,12- dimethylbenz(a)anthracene (DMBA) induced lipid peroxidation in the livers of mice was investigated. The rationale for such an approach is that lipid peroxidation has been suggested to play a key role in human cancer development. There was a sharp rise in lipid peroxidation (measured as thiobarbituric acid reactive substances formation) during skin carcinogenesis induced by DMBA in mice. Aqueous extracts of bitter gourd and tomato juice were found to be very potent inhibitors of lipid peroxidation both in normal and DMBA treated mice. Our observations support the hypothesis that natural combinations of phytochemicals present in the fruit juices exert cancer-protective effects via a decrease in lipid peroxidation.

  3. Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

    PubMed Central

    Shirozu, Kazuhiro; Tokuda, Kentaro; Marutani, Eizo; Lefer, David; Wang, Rui

    2014-01-01

    Abstract Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Results: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. Innovation: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver. Conclusion: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms. Antioxid. Redox Signal. 20, 204

  4. H. hepaticus-induced liver tumor promotion is associated with increased serum bile acid and a persistent microbial-induced immune response

    PubMed Central

    García, Alexis; Zeng, Yu; Muthupalani, Sureshkumar; Ge, Zhongming; Potter, Amanda; Mobley, Melissa W.; Boussahmain, Chakib; Feng, Yan; Wishnok, John S.; Fox, James G.

    2011-01-01

    Chronic microbial infection influence cancer progression but the mechanisms that link them remain unclear. Constitutive androstane receptor (CAR) is a nuclear receptor that regulates enzymes involved in endobiotic and xenobiotic metabolism. CAR activation is a mechanism of xenobiotic tumor promotion, however, the effects of chronic microbial infection on tumor promotion have not been studied in the context of CAR function. Here we report that CAR limits the effects of chronic infection-associated progression of liver cancer. CAR knockout (KO) and wild-type (WT) male mice were treated or not with the tumor initiator diethylnitrosamine (DEN) at 5 weeks of age and then orally inoculated with Helicobacter hepaticus (Hh) or sterile media at 8 weeks of age. At 50 weeks postinoculation mice were euthanized for histopathological, microbiological, molecular, and metabolomic analyses. Hh infection induced comparable hepatitis in WT and KO mice with or without DEN that correlated with significant upregulation of Tnfα and toll receptor Tlr2. Notably, DEN-treated Hh-infected KO mice exhibited increased numbers of liver lobes with dysplasia and neoplasia, as well as increased multiplicity of neoplasia, relative to similarly treated WT mice. Enhanced tumor promotion was associated with decreased hepatic expression of P450 enzymes Cyp2b10 and Cyp3a11, increased expression of Camp, and increased serum concentrations of chenodeoxycholic acid. Together, our findings suggest that liver tumor promotion is enhanced by an impaired metabolic detoxification of endobiotics and a persistent microbial-induced immune response. PMID:21335546

  5. The nanomechanical signature of liver cancer tissues and its molecular origin

    NASA Astrophysics Data System (ADS)

    Tian, Mengxin; Li, Yiran; Liu, Weiren; Jin, Lei; Jiang, Xifei; Wang, Xinyan; Ding, Zhenbin; Peng, Yuanfei; Zhou, Jian; Fan, Jia; Cao, Yi; Wang, Wei; Shi, Yinghong

    2015-07-01

    Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the ``gold standard'' in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus distribution of surgically removed liver cancer tissues can serve as a mechanical fingerprint to evaluate the malignancy of liver cancer. Cirrhotic tissues shared the same LEP as normal tissues. However, a noticeable downward shift in the LEP was detected when the cirrhotic tissues progressed to a malignant state, making the tumor tissues more prone to microvascular invasion. Cell-level mechanistic studies revealed that the expression level of a Rho-family effector (mDia1) was consistent with the mechanical trend exhibited by the tissue. Our findings indicate that the mechanical profiles of liver cancer tissues directly varied with tumor progression, providing an additional platform for the future diagnosis of HCC.Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the ``gold standard'' in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus

  6. Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer

    PubMed Central

    Miao, Ruoyu; Wu, Yan; Zhang, Haohai; Zhou, Huandi; Sun, Xiaofeng; Csizmadia, Eva; He, Lian; Zhao, Yi; Jiang, Chengyu; Miksad, Rebecca A.; Ghaziani, Tahereh; Robson, Simon C.; Zhao, Haitao

    2016-01-01

    Therapies for primary liver cancer, the third leading cause of cancer-related death worldwide, remain limited. Following multi-omics analysis (including whole genome and transcriptome sequencing), we were able to identify the dual-specific protein kinase TTK as a putative new prognostic biomarker for liver cancer. Herein, we show that levels of TTK protein are significantly elevated in neoplastic tissues from a cohort of liver cancer patients, when compared with adjacent hepatic tissues. We also tested the utility of TTK targeted inhibition and have demonstrated therapeutic potential in an experimental model of liver cancer in vivo. Following lentiviral shRNA knockdown in several human liver cancer cell lines, we demonstrated that TTK boosts cell growth and promotes cell spreading; as well as protects against senescence and decreases autophagy. In an experimental animal model, we show that in vitro knockdown of TTK effectively blocks intrahepatic growth of human HCC xenografts. Furthermore, we note that, in vivo silencing of TTK, by systemically delivering TTK siRNAs to already tumor-bearing liver, limits intrahepatic spread of liver cancer cells. This intervention is associated with decreased tumor aggressiveness, as well as increased senescence and autophagy. Taken together, our data suggest that targeted TTK inhibition might have clinical utility as an adjunct therapy in management of liver cancer. PMID:27618777

  7. Alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV.

    PubMed

    Qin, Yannan; Zhong, Yaogang; Ma, Tianran; Wu, Fei; Wu, Haoxiang; Yu, Hanjie; Huang, Chen; Li, Zheng

    2016-04-01

    The incidence of hepatocellular carcinoma (HCC) is closely correlated with hepatitis B virus (HBV)-induced liver cirrhosis. Structural changes in the glycans of serum and tissue proteins are reliable indicators of liver damage. However, little is known about the alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV infection. This study compared the differential expression of liver glycopatterns in 7 sets of normal pericarcinomatous tissues (PCTs), cirrhotic, and tumor tissues from patients with liver cirrhosis and HCC induced by HBV using lectin microarrays. Fluorescence-based lectin histochemistry and lectin blotting were further utilized to validate and assess the expression and distribution of certain glycans in 9 sets of corresponding liver tissue sections. Eight lectins (e.g., Jacalin and AAL) revealed significant difference in cirrhotic tissues versus PCTs. Eleven lectins (e.g., EEL and SJA) showed significant alteration during cirrhotic and tumor progression. The expression of Galα1-3(Fucα1-2)Gal (EEL) and fucosyltransferase 1 was mainly increasing in the cytoplasm of hepatocytes during PCTs-cirrhotic-tumor tissues progression, while the expression of T antigen (ACA and PNA) was decreased sharply in cytoplasm of tumor hepatocytes. Understanding the precision alteration of liver glycopatterns related to the development of hepatitis, cirrhosis, and tumor induced by HBV infection may help elucidate the molecular mechanisms underlying the progression of chronic liver diseases and develop new antineoplastic therapeutic strategies.

  8. Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Total parenteral nutrition (TPN) induces a high rate of liver disease in infants, yet the pathogenesis remains elusive. We used neonatal piglets as an animal model to assess early events leading to TPN-mediated liver injury. Newborn piglets (n = 7) were nourished for 7 d on TPN or enteral nutrition ...

  9. Increased childhood liver cancer mortality and arsenic in drinking water in northern Chile.

    PubMed

    Liaw, Jane; Marshall, Guillermo; Yuan, Yan; Ferreccio, Catterina; Steinmaus, Craig; Smith, Allan H

    2008-08-01

    Arsenic in drinking water is an established cause of lung, bladder, and skin cancers in adults and may also cause adult kidney and liver cancers. Some evidence for these effects originated from region II of Chile, which had a period of elevated arsenic levels in drinking water, in particular from 1958 to 1970. This unique exposure scenario provides a rare opportunity to investigate the effects of early-life arsenic exposure on childhood mortality; to our knowledge, this is the first study of childhood cancer mortality and high concentrations of arsenic in drinking water. In this article, we compare cancer mortality rates under the age of 20 in region II during 1950 to 2000 with those of unexposed region V, dividing subjects into those born before, during, or after the peak exposure period. Mortality from the most common childhood cancers, leukemia and brain cancer, was not increased in the exposed population. However, we found that childhood liver cancer mortality occurred at higher rates than expected. For those exposed as young children, liver cancer mortality between ages 0 and 19 was especially high: the relative risk (RR) for males born during this period was 8.9 [95% confidence interval (95% CI), 1.7-45.8; P = 0.009]; for females, the corresponding RR was 14.1 (95% CI, 1.6-126; P = 0.018); and for males and females pooled, the RR was 10.6 (95% CI, 2.9-39.2; P < 0.001). These findings suggest that exposure to arsenic in drinking water during early childhood may result in an increase in childhood liver cancer mortality.

  10. Increased childhood liver cancer mortality and arsenic in drinking water in Northern Chile

    PubMed Central

    Liaw, Jane; Marshall, Guillermo; Yuan, Yan; Ferreccio, Catterina; Steinmaus, Craig; Smith, Allan H.

    2009-01-01

    Arsenic in drinking water is an established cause of lung, bladder and skin cancers in adults, and may also cause adult kidney and liver cancer. Some evidence for these effects originated from Region II of Chile which had a period of elevated arsenic levels in drinking water, in particular from 1958 to 1970. This unique exposure scenario provides a rare opportunity to investigate the effects of early-life arsenic exposure on childhood mortality; to our knowledge, this is the first study of childhood cancer mortality and high concentrations of arsenic in drinking water. In this paper, we compare cancer mortality rates under the age of 20 in Region II during 1950–2000 with those of unexposed Region V, dividing subjects into those born before, during or after the peak exposure period. Mortality from the most common childhood cancers, leukemia and brain cancer, were not increased in the exposed population. However, we found childhood liver cancer mortality occurred at higher rates than expected; for those exposed as young children liver cancer mortality between ages 0–19 was especially high: the relative risk (RR) for males born during this period was 8.9 (95% CI 1.7–45.8; p=0.009), for females the corresponding RR was 14.1 (95% CI 1.6–126; p=0.018), and for males and females pooled, the RR was 10.6 (95% CI 2.9–39.2; p<0.001). These findings suggest exposure to arsenic in drinking water during early childhood may result in an increase in childhood liver cancer mortality. PMID:18708388

  11. [Examination of percutaneous microwave coagulation and radiofrequency ablation therapy for metastatic liver cancer].

    PubMed

    Ohkawa, Shinichi; Hirokawa, Satoru; Masaki, Takahiro; Miyakawa, Kaoru; Tarao, Kazuo; Akaike, Makoto; Sugimasa, Yukio; Takemiya, Shoji; Sairenji, Motonori; Motohashi, Hisahiko

    2002-11-01

    Percutaneous microwave coagulation therapy (PMCT) and radio frequency ablation therapy (RFA) as treatments for metastatic liver cancer were examined. PMCT or RFA was administered for 18 metastatic liver cancer lesions (primary lesion: 11 colon rectal cancer, one esophagus cancer, one thyroid cancer, one pancreatic cancer, one pheochromocytoma) in 16 patients from July 1999 to March 2002. RFA was performed 1 time for 12 minutes in principle, using a Cool-tip RF system from Radionics. Patients had a mean age of 58.8 years and the mean diameter of the neoplasms was about 22 mm. Critical complications were not seen. The rate of partial recurrence was 35.3% as of March, 2002, in an average observation period of 7.3 months. On the other hand, with the medical treatment for the hepatocellular carcinoma provided during this period, the rate of partial recurrence was 14.8%. The treatment of metastatic liver cancer by PMCT and RFA is associated with a high rate of a recurrence as compared with hepatocellular carcinoma, and needs to be examined to discover ways of adaptation and improvement of the technology.

  12. A Virtual Liver for Simulating Chemical-Induced Injury

    EPA Science Inventory

    The US EPA Virtual Liver – vLiver™ --is a tissue simulator that is designed to predict histopathologic lesions – the gold-standard for toxicity. We have developed an approach for a biologically motivated model of a canonical liver lobule. The simulated lobule is composed of discr...

  13. Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice

    PubMed Central

    VanderVeen, Brandon N.; Enos, Reilly T.; Murphy, E. Angela; Carson, James A.

    2016-01-01

    Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6. PMID:27449092

  14. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer.

    PubMed

    Sun, Cheng; Xu, Jing; Huang, Qiang; Huang, Mei; Wen, Hao; Zhang, Chuanshan; Wang, Jinyu; Song, Jiaxi; Zheng, Meijuan; Sun, Haoyu; Wei, Haiming; Xiao, Weihua; Sun, Rui; Tian, Zhigang

    2017-01-01

    Background and Aims: As the predominant lymphocyte subset in the liver, natural killer (NK) cells have been shown to be highly associated with the outcomes of patients with chronic hepatitis B virus infection (CHB) and hepatocellular carcinoma (HCC). Previously, we reported that NKG2A, a checkpoint candidate, mediates human and murine NK cell dysfunction in CHB. However, NK cell exhaustion and, particularly, the level of NKG2A expression within liver tumors have not been reported. Methods: In this study, we analyzed NKG2A expression and the related dysfunction of NK cells located in intra- or peritumor regions of liver tissue samples from 207 HCC patients, in addition to analyzing disease outcomes. Results: The expression of NKG2A in NK cells and the NKG2A ligand, HLA-E, in intratumor HCC tissues was observed to be increased. These NK cells, and particularly CD56(dim) NK cells, with higher NKG2A expression showed features of functional exhaustion and were associated with a poor prognosis. The increase in NKG2A expression might be induced by IL-10, which was present at a high level in the plasma of HCC patients. Blocking IL-10 could specifically inhibit NKG2A expression in NK cells. Conclusions: These findings indicate that NKG2A expression is influenced by factors from cancer nests and contributes to NK cell exhaustion, suggesting that NKG2A blockade has the potential to restore immunity against liver tumors by reversing NK cell exhaustion.

  15. Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation

    PubMed Central

    Hong, Sung Woo; Hur, Wonhee; Choi, Jung Eun; Kim, Jung-Hee; Hwang, Daehee; Yoon, Seung Kew

    2016-01-01

    We investigated the biological role of CD133-expressing liver cancer stem cells (CSCs) enriched after irradiation of Huh7 cells in cell invasion and migration. We also explored whether a disintegrin and metalloproteinase-17 (ADAM17) influences the metastatic potential of CSC-enriched hepatocellular carcinoma (HCC) cells after irradiation. A CD133-expressing Huh7 cell subpopulation showed greater resistance to sublethal irradiation and specifically enhanced cell invasion and migration capabilities. We also demonstrated that the radiation-induced MMP-2 and MMP-9 enzyme activities as well as the secretion of vascular endothelial growth factor were increased more predominantly in Huh7CD133+ cell subpopulations than Huh7CD133− cell subpopulations. Furthermore, we showed that silencing ADAM17 significantly inhibited the migration and invasiveness of enriched Huh7CD133+ cells after irradiation; moreover, Notch signaling was significantly reduced in irradiated CD133-expressing liver CSCs following stable knockdown of the ADAM17 gene. In conclusion, our findings indicate that CD133-expressing liver CSCs have considerable metastatic capabilities after irradiation of HCC cells, and their metastatic capabilities might be maintained by ADAM17. Therefore, suppression of ADAM17 shows promise for improving the efficiency of current radiotherapies and reducing the metastatic potential of liver CSCs during HCC treatment. PMID:26993601

  16. Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver.

    PubMed

    Jiang, Yan; Chen, Jiahong; Tong, Jian; Chen, Tao

    2014-01-01

    Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.

  17. Safety and efficacy of FOLFOX followed by cetuximab for metastatic colorectal cancer with severe liver dysfunction.

    PubMed

    Elsoueidi, Raymond; Craig, Jessica; Mourad, Hesham; Richa, Elie M

    2014-02-01

    Both 5-FU and oxaliplatin have been used as single agents in patients with colorectal cancer and severe liver dysfunction, but the combination of these drugs has not yet been investigated. A 67-year-old man diagnosed with colorectal cancer in 2008 presented in April 2011 to Appalachian Regional Healthcare Cancer Center with obstructive jaundice and weight loss. Imaging studies were compatible with a liver mass and dilatation of the intrahepatic bile ducts. A liver biopsy confirmed metastatic colorectal cancer. Because his total bilirubin level was 23.1 mg/dL, a percutaneous catheter was placed in May 2011. His total bilirubin level decreased to 5.9 mg/dL, but then increased to 9.4 mg/dL in June 2011. He was started on a FOLFOX regimen, with a 50% dose reduction of 5-FU bolus (200 mg/m(2)) and continuous infusion (1200 mg/m(2)) over 46 hours, and a 15% dose reduction of oxaliplatin (75 mg/m(2)) every 2 weeks. He tolerated this regimen very well, with normalization of his bilirubin level, a significant decrease in his tumor markers, and a partial response seen on PET/CT scan. His only significant toxicity was a grade 2 stomatitis. He received 21 cycles of FOLFOX, and was later switched to cetuximab treatment after disease progression. These findings suggest that FOLFOX might be effective in metastatic colon cancer with severe liver dysfunction, with minimal toxicity, and deserves further investigation.

  18. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Mesarwi, Omar A.; Shin, Mi-Kyung; Bevans-Fonti, Shannon; Schlesinger, Christina; Shaw, Janet; Polotsky, Vsevolod Y.

    2016-01-01

    Background Obstructive sleep apnea (OSA) is associated with the progression of non-alcoholic fatty liver disease (NAFLD) to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1), a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis. Methods Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep) were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2) or normoxia (16% O2) for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking. Results Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03), which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia. Conclusions Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of

  19. Alcohol, TLR4-TGF-β Antagonism, and Liver Cancer

    PubMed Central

    Tsukamoto, Hidekazu; Mishra, Lopa; Machida, Keigo

    2016-01-01

    Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also synergistically promote HBV/HCV-related carcinogenesis. TLR4, the PAMP for endotoxin participates in inflammatory processes such as M1 activation of hepatic macrophages in alcoholic liver disease. However its role in liver carcinogenesis via ectopic expression and activation, has only recently been revealed in alcohol/HCV-associated HCC models. Alcohol feeding to mice expressing the HCV Ns5a in a hepatocyte specific manner, aggravates liver inflammation via activation of overexpressed TLR4 in the parenchymal cells. Long-term alcohol feeding produces liver tumors in these transgenic mice in a manner dependent on TLR4. From these mice, CD133+/CD49f+ tumor initiating stem cell-like cells (TICs) have been isolated. These TICs exhibit self-renewal and tumorigenic activities driven by TLR4-dependent upregulation of the stem cell factor NANOG. Defective TGF-β tumor suppressor pathway is identified in the TICs and mediated by NANOG target genes Igf2bp3 and Yap1. This TGF-β pathway antagonism is responsible in part for TIC’s tumorigenic activity and chemoresistance. Conversely, mice with attenuated TGF-β pathway due to haploinsufficiency of β2-Spectrin, spontaneously develop liver tumors and alcohol-feeding increases tumor incidence in a TLR4 dependent manner. This reciprocal antagonism between TLR4 and TGF-β pathways may serve as a novel therapeutic target for HCC. PMID:26201318

  20. 8-bromo-7-methoxychrysin inhibits properties of liver cancer stem cells via downregulation of β-catenin

    PubMed Central

    Quan, Mei-Fang; Xiao, Li-Hong; Liu, Zhi-Hong; Guo, Hui; Ren, Kai-Qun; Liu, Fei; Cao, Jian-Guo; Deng, Xi-Yun

    2013-01-01

    AIM: To evaluate whether 8-bromo-7-methoxychrysin (BrMC), a synthetic analogue of chrysin, inhibits the properties of cancer stem cells derived from the human liver cancer MHCC97 cell line and to determine the potential mechanisms. METHODS: CD133+ cells were sorted from the MHCC97 cell line by magnetic activated cell sorting, and amplified in stem cell-conditioned medium to obtain the enriched CD133+ sphere forming cells (SFCs). The stem cell properties of CD133+ SFCs were validated by the tumorsphere formation assay in vitro and the xenograft nude mouse model in vivo, and termed liver cancer stem cells (LCSCs). The effects of BrMC on LCSCs in vitro were evaluated by MTT assay, tumorsphere formation assay and transwell chamber assay. The effects of BrMC on LCSCs in vivo were determined using a primary and secondary xenograft model in Balb/c-nu mice. Expressions of the stem cell markers, epithelial-mesenchymal transition (EMT) markers and β-catenin protein were analyzed by western blotting or immunohistochemical analysis. RESULTS: CD133+ SFCs exhibited stem-like cell properties of tumorsphere formation and tumorigenesis capacity in contrast to the parental MHCC97 cells. We found that BrMC preferentially inhibited proliferation and self-renewal of LCSCs (P < 0.05). Furthermore, BrMC significantly suppressed EMT and invasion of LCSCs. Moreover, BrMC could efficaciously eliminate LCSCs in vivo. Interestingly, we showed that BrMC decreased the expression of β-catenin in LCSCs. Silencing of β-catenin by small interfering RNA could synergize the inhibition of self-renewal of LCSCs induced by BrMC, while Wnt3a treatment antagonized the inhibitory effects of BrMC. CONCLUSION: BrMC can inhibit the functions and characteristics of LCSCs derived from the liver cancer MHCC97 cell line through downregulation of β-catenin expression. PMID:24431896

  1. Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice

    PubMed Central

    Kumar, Sudhir; Wang, Jiang; Rani, Richa; Gandhi, Chandrashekhar R.

    2016-01-01

    Why only a subpopulation (about 15%) of humans develops liver cirrhosis due to alcohol is a critical as yet unanswered question. Liver-specific depletion of augmenter of liver regeneration (ALR) protein in mice causes robust steatosis and hepatocyte apoptosis by 2 weeks; these pathologies regress subsequently with return of ALR expression even at lower than control levels, but the mice develop modest steatohepatitis by 8 weeks. We aimed to investigate whether chronic alcohol ingestion promotes excessive hepatic fibrosis in these ALR-deficient mice. Liver-specific ALR-deficient and wild type (WT) female mice (8–10 weeks old) were placed on 4% alcohol-supplemented or isocaloric diet for 4 weeks. Liver sections were examined for histopathology, and parameters of steatosis and fibrosis were quantified. The mRNA expression of alcohol dehydrogenase-1, acetaldehyde dehydrogenase-1 and cytochrome P450-2E1 increased in WT mice but decreased in ALR-deficient mice upon alcohol ingestion. While alcohol induced steatosis and mild inflammation in WT mice, ALR-deficient mice showed minimal steatosis, strong hepatocellular injury and inflammation, prominent ductular proliferation, and robust fibrosis. Compared to the WT mice, alcohol feeding of ALR-deficient mice resulted in significantly greater increase in hepatic TNFα and TGFβ, and oxidative stress; there was also hepatic iron accumulation, robust lipid peroxidation and mitochondrial DNA damage. Importantly, similar to ALR-deficient mice, lower hepatic ALR levels in human alcoholic liver cirrhosis were associated with increased iron content, reduced expression of alcohol dehydrogenase and acetaldehyde dehydrogenase, and elevated fibrogenic markers. We conclude that ALR deficiency or anomaly can play a critical role in alcohol-induced hepatic fibrosis/cirrhosis, mechanisms of which may involve dysregulation of alcohol metabolism and iron homeostasis, mitochondrial damage and oxidative injury. PMID:26808690

  2. Hepatoprotective effects of zingerone on carbon tetrachloride- and dimethylnitrosamine-induced liver injuries in rats.

    PubMed

    Cheong, Kyoung Ook; Shin, Dong-Su; Bak, Jeonghyeon; Lee, Changyong; Kim, Kyung Wook; Je, Nam Kyung; Chung, Hae Young; Yoon, Sik; Moon, Jeon-Ok

    2016-02-01

    In this study, we investigated the hepatoprotective and anti-fibrotic effects of zingerone, one of the active components of ginger, against carbon tetrachloride (CCl4)- and dimethylnitrosamine (DMN)-induced liver injuries in rats, respectively. Oral administration of zingerone (10 mg/kg) reduced CCl4-induced abnormalities in liver histology, serum alanine aminotransferase and aspartate aminotransferase levels, and liver malondialdehyde levels. Zingerone treatment attenuated CCl4-induced increases in inflammatory mediators, including tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and inducible nitric oxide synthase mRNA levels. Western blot analysis showed that zingerone suppressed activation of nuclear factor-kappa B (NF-κB) p65 and phosphorylation of extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinases (MAPKs). Liver fibrosis induced by DMN (10 mg/kg, intraperitoneally) was ameliorated by administration of zingerone (10 and 20 mg/kg, orally). Zingerone treatment reduced DMN-induced elevation of hydroxyproline content and hepatic stellate cell activation. In conclusion, zingerone showed antioxidative and anti-inflammatory effects in CCl4-intoxicated rats by inhibiting oxidative stress and NF-κB activation via blockade of the activation of upstream MAPKs. Moreover, zingerone had hepatoprotective and anti-fibrotic effects against DMN-induced liver injury suggesting its usefulness in the prevention of liver inflammation and the development of hepatic fibrosis.

  3. Protective effect of L-theanine on carbon tetrachloride-induced acute liver injury in mice.

    PubMed

    Jiang, Wei; Gao, Min; Sun, Shuai; Bi, Aijing; Xin, Yinqiang; Han, Xiaodong; Wang, Liangbin; Yin, Zhimin; Luo, Lan

    2012-06-01

    We studied effects of L-theanine, a unique amino acid in tea, on carbon tetrachloride (CCl(4))-induced liver injury in mice. The mice were pre-treated orally with L-theanine (50, 100 or 200 mg/kg) once daily for seven days before CCl(4) (10 ml/kg of 0.2% CCl(4) solution in olive oil) injection. L-theanine dose-dependently suppressed the increase of serum activity of ALT and AST and bilirubin level as well as liver histopathological changes induced by CCl(4) in mice. L-theanine significantly prevented CCl(4)-induced production of lipid peroxidation and decrease of hepatic GSH content and antioxidant enzymes activities. Our further studies demonstrated that L-theanine inhibited metabolic activation of CCl(4) through down-regulating cytochrome P450 2E1 (CYP2E1). As a consequence, L-theanine inhibited oxidative stress-mediated inflammatory response which included the increase of TNF-α and IL-1β in sera, and expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in livers. CCl(4)-induced activation of apoptotic related proteins including caspase-3 and PARP in mouse livers was also prevented by L-theanine treatment. In summary, L-theanine protects mice against CCl(4)-induced acute liver injury through inhibiting metabolic activation of CCl(4) and preventing CCl(4)-induced reduction of anti-oxidant capacity in mouse livers to relieve inflammatory response and hepatocyte apoptosis.

  4. The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence.

    PubMed

    Orci, Lorenzo A; Lacotte, Stéphanie; Oldani, Graziano; Morel, Philippe; Mentha, Gilles; Toso, Christian

    2014-09-01

    Hepatic ischemia/reperfusion (I/R) injury is a common clinical challenge. Despite accumulating evidence regarding its mechanisms and potential therapeutic approaches, hepatic I/R is still a leading cause of organ dysfunction, morbidity, and resource utilization, especially in those patients with underlying parenchymal abnormalities. In the oncological setting, there are growing concerns regarding the deleterious impact of I/R injury on the risk of post-surgical tumor recurrence. This review aims at giving the last updates regarding the role of hepatic I/R and liver parenchymal quality injury in the setting of oncological liver surgery, using a "bench-to-bedside" approach. Relevant medical literature was identified by searching PubMed and hand scanning of the reference lists of articles considered for inclusion. Numerous preclinical models have depicted the impact of I/R injury and hepatic parenchymal quality (steatosis, age) on increased cancer growth in the injured liver. Putative pathophysiological mechanisms linking I/R injury and liver cancer recurrence include an increased implantation of circulating cancer cells in the ischemic liver and the upregulation of proliferation and angiogenic factors following the ischemic insult. Although limited, there is growing clinical evidence that I/R injury and liver quality are associated with the risk of post-surgical cancer recurrence. In conclusion, on top of its harmful early impact on organ function, I/R injury is linked to increased tumor growth. Therapeutic strategies tackling I/R injury could not only improve post-surgical organ function, but also allow a reduction in the risk of cancer recurrence.

  5. Rhinacanthus nasutus Improves the Levels of Liver Carbohydrate, Protein, Glycogen, and Liver Markers in Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Visweswara Rao, Pasupuleti; Madhavi, K.; Dhananjaya Naidu, M.; Gan, Siew Hua

    2013-01-01

    The present study was designed to investigate the total carbohydrate, total protein, and glycogen levels in the liver and to measure functional liver markers such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in streptozotocin-(STZ-) induced diabetic rats after treatment with methanolic extract of Rhinacanthus nasutus (R. nasutus). The methanolic extract of R. nasutus was orally administered at 200 mg/kg/day while glibenclamide was administered at 50 mg/kg/day. All animals were treated for 30 days before being sacrificed. The amounts of carbohydrate, glycogen, proteins, and liver markers (AST and ALT) were measured in the liver tissue of the experimental animals. The levels of carbohydrate, glycogen, and proteins were significantly reduced in the diabetic rats but were augmented considerably after 30 days of R. nasutus treatment. The elevated AST and ALT levels in diabetic rats showed a significant decline after treatment with R. nasutus for 30 days. These results show that the administration of R. nasutus ameliorates the altered levels of carbohydrate, glycogen, proteins, and AST and ALT observed in diabetic rats and indicate that R. nasutus restores overall metabolism and liver function in experimental diabetic rats. In conclusion, the outcomes of the present study support the traditional belief that R. nasutus could ameliorate the diabetic state. PMID:24204387

  6. The Effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on Alcohol-Induced Liver Injury

    PubMed Central

    Zhang, Yu-Jie; Zhou, Tong; Wang, Fang; Zhou, Yue; Li, Ya; Zhang, Jiao-Jiao; Zheng, Jie; Xu, Dong-Ping; Li, Hua-Bin

    2016-01-01

    Previous studies have shown that fruits have different effects on alcohol metabolism and alcohol-induced liver injury. The present work selected three fruits and aimed at studying the effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on alcohol-induced liver injury in mice. The animals were treated daily with alcohol and fruit juices for fifteen days. Chronic treatment with alcohol increased the levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin (TBIL), triglyceride (TG), malondialdehyde (MDA), and decreased total protein (TP). Histopathological evaluation also showed that ethanol induced extensive fat droplets in hepatocyte cytoplasm. Syzygium samarangense and Passiflora edulis normalized various biochemical parameters. Solanum muricatum increased the level of ALT and induced infiltration of inflammatory cells in the liver. These results strongly suggest that treatment with Syzygium samarangense and Passiflora edulis could protect liver from the injury of alcohol, while Solanum muricatum could aggravate the damage. PMID:27681723

  7. Thiamethoxam induced mouse liver tumors and their relevance to humans. Part 1: mode of action studies in the mouse.

    PubMed

    Green, Trevor; Toghill, Alison; Lee, Robert; Waechter, Felix; Weber, Edgar; Noakes, James

    2005-07-01

    Thiamethoxam, a neonicotinoid insecticide, which is not mutagenic either in vitro or in vivo, caused an increased incidence of liver tumors in mice when fed in the diet for 18 months at concentrations in the range 500 to 2500 ppm. A number of dietary studies of up to 50 weeks duration have been conducted in order to identify the mode of action for the development of the liver tumors seen at the end of the cancer bioassay. Both thiamethoxam and its major metabolites have been tested in these studies. Over the duration of a 50-week thiamethoxam dietary feeding study in mice, the earliest change, within one week, is a marked reduction (by up to 40%) in plasma cholesterol. This was followed 10 weeks later by evidence of liver toxicity including single cell necrosis and an increase in apoptosis. After 20 weeks there was a significant increase in hepatic cell replication rates. All of these changes persisted from the time they were first observed until the end of the study at 50 weeks. They occurred in a dose-dependent manner and were only observed at doses (500, 1250, 2500 ppm) where liver tumors were increased in the cancer bioassay. There was a clear no-effect level of 200 ppm. The changes seen in this study are consistent with the development of liver cancer in mice and form the basis of the mode of action. When the major metabolites of thiamethoxam, CGA322704, CGA265307, and CGA330050 were tested in dietary feeding studies of up to 20 weeks duration, only metabolite CGA330050 induced the same changes as those seen in the liver in the thiamethoxam feeding study. It was concluded that thiamethoxam is hepatotoxic and hepatocarcinogenic as a result of its metabolism to CGA330050. Metabolite CGA265307 was also shown to be an inhibitor of inducible nitric oxide synthase and to increase the hepatotoxicity of carbon tetrachloride. It is proposed that CGA265307, through its effects on nitric oxide synthase, exacerbates the toxicity of CGA330050 in thiamethoxam treated mice.

  8. Locally ablative therapies for primary and metastatic liver cancer.

    PubMed

    Li, David; Kang, Josephine; Madoff, David C

    2014-08-01

    Locally ablative therapies have an increasing role in the effective multidisciplinary approach towards the treatment of both primary and metastatic liver tumors. In patients who are not considered surgical candidates and have low volume disease, these therapies have now become established into consensus practice guidelines. A large range of therapeutic options exist including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, percutaneous laser ablation (PLA), irreversible electroporation (IRE), stereotactic body radiation therapy (SBRT) and high intensity focused ultrasound (HIFU); each having benefits and drawbacks. The greatest body of evidence supporting clinical utility in the liver currently exists for RFA, with PEI having fallen out of favor. MWA, IRE, SBRT and HIFU are relatively nascent technologies, and outcomes data supporting their use is promising. Future directions of ablative therapies include tandem approaches to improve efficacy in the treatment of liver tumors.

  9. Totally laparoscopic associating liver tourniquet and portal vein occlusion for staged hepatectomy combined with simultaneous left hemicolectomy for bilateral liver metastases of the primary colon cancer

    PubMed Central

    Xu, Hong-wei; Li, Hong-yu; Liu, Fei; Wei, Yong-gang; Li, Bo

    2017-01-01

    Abstract Background: Resection of the liver is often limited to the insufficient future liver remnant (FLR). To address this problem, the modification surgical technique “associating liver tourniquet and portal vein occlusion for staged hepatectomy” (ALTPS) was developed and led to quick hypertrophy in a short interval. In some colorectal cancer patients with multiple and bilobar metastases, the resection of the primary is often protracted immensely to the unpredictable postoperative complications for whom is to be treated with a liver-first approach. To overcome this problem, a simultaneous resection of the primary tumor and totally laparoscopic ALTPS for bilateral liver metastases of the primary colon cancer were performed. Case summary: A 63-year-old female patient with left colon cancer and synchronous bilateral colorectal liver metastases underwent a totally laparoscopic ALTPS and simultaneous left hemicolectomy because of the small FLR. The operative times were 460 minutes for the first stage and 240 minutes for the second stage without the need for blood transfusions. The recoveries after the first and the second operations were uneventful, and the patient was discharged on postoperative day 11 of the second stage operation. Conclusion: Our case shows the totally laparoscopic ALTPS and simultaneous left hemicolectomy at step 1 for bilobar liver metastases of the primary colon cancer with no severe postoperative complications. If a resection of the primary tumor does not compromise the split procedure, the combination of pure laparoscopic ALTPS and primary resection is feasible and safe. PMID:28296776

  10. Application of an in silico liver model to determine nuclear receptor mediated pathways in liver cancer

    EPA Science Inventory

    Nuclear receptors (NRs) are ligand-activated transcription factors that control diverse cellular processes. Chronic stimulation of some NRs in rodents can result in increased incidence of liver tumors. These are generally thought to develop through a non-genotoxic mechanism with...

  11. Evaluation of the Medicinal Herb Graptopetalum paraguayense as a Treatment for Liver Cancer

    PubMed Central

    Hsu, Wei-Hsiang; Chang, Chia-Chuan; Huang, Kai-Wen; Chen, Yi-Chen; Hsu, Shih-Lan; Wu, Li-Chen; Tsou, Ann-Ping; Lai, Jin-Mei; Huang, Chi-Ying F.

    2015-01-01

    Background Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death worldwide. Sorafenib is the only drug for patients with advanced-stage hepatocellular carcinoma (HCC) that has been shown to confer a survival benefit to patients with HCC; however, it has many side effects. Thus, alternate therapeutic strategies with improved safety and therapeutic efficacy for the management of HCC should be developed. Methods and Findings We demonstrate that an extract of Graptopetalum paraguayense (GP) down-regulated the expression levels of several onco-proteins, including AURKA, AURKB, and FLJ10540, in HCC cells. To isolate the active components in the GP extracts, we prepared extracts fractions and assessed their effects on the expression of onco-proteins in HCC cells. The fraction designated HH-F3 was enriched in active ingredients, exhibited cytotoxic effects, and suppressed the expression of the onco-proteins in HCC cells. The structure of the main active compound in HH-F3 was found to be similar to that of the proanthocyanidin compounds derived from Rhodiola rosea. In addition, a distinct new compound rich in 3, 4, 5-trihydroxy benzylic moieties was identified in the HH-F3 preparations. Mechanistic studies indicated that HH-F3 induced apoptosis in HCC cells by promoting the loss of mitochondrial membrane potential and the production of reactive oxygen species. HH-F3 also enhanced PTEN expression and decreased AKT phosphorylation at Ser473 in a concentration-dependent manner in HCC cells. Moreover combination of GP or HH-F3 and sorafenib synergistically inhibits the proliferation of Huh7 cells. The treatment of a rat model with diethylnitrosamine (DEN)-induced liver cancer with extracts of GP and HH-F3 decreased hepatic collagen contents and inhibited tumor growth. Conclusions These results indicate that GP extracts and HH-F3 can protect the liver by suppressing tumor growth; consequently, these compounds

  12. Supplementation of Seaweeds Extracts Suppresses Azoxymethane-induced Aberrant DNA Methylation in Colon and Liver of ICR Mice

    PubMed Central

    Bu, So Young; Kwon, Hoonjeong; Sung, Mi-Kyung

    2014-01-01

    Background: Seamustard and seatangle are commonly consumed seaweeds in Korea and rich sources of non-digestible polysaccharides which possess biological activities. However anti-mutagenic and anti-cancer activities of these seaweeds under physiological condition have not been clarified yet. The objective of this study was to investigate the effect of seaweeds consumption on azoxymethane (AOM) -induced DNA methylation at N7 and O6 position of guanine base, an indicator of DNA damage related to cancer initiation. Methods: Thirty ICR mice were divided into five groups and fed one of the following diets for two weeks: control diet, diet containing 10% water-soluble or water-insoluble fraction of seamustard or seatangle. After two weeks of experimental diet AOM was injected at 6 hours before sacrifice and N7-methylguanine (N7-meG) and O6-methylguanine (O6-meG) from the colon and liver DNA were quantified using a gas chromatography-mass spectroscopy. Results: Water-soluble fractions of both seamustard and seatangle significantly reduced AOM-induced production of N7-meG guanine in colon and liver. Also water-soluble fractions of these seaweeds suppressed the level of methylation at O6-guanine of colon and liver directly responsible for tumorigenesis. While water-insoluble fraction of seamustard suppressed the production of N7-meG in liver this seaweed fraction decreased O6-meG and the ratio of O6/N7-meG in liver. Water insoluble fraction of seatangle decreased both O6- and N7-meG in colon and liver. Supplementation of all seaweeds extracts increased fecal weight of animals and the increase of fecal weight by water-insoluble fraction of seaweeds were higher than that by water-soluble fraction. Conclusion: Seamustard and seatangle intake may effectively prevent colon and liver carcinogenesis by decreasing DNA damage and the mechanism of inhibiting carcinogenesis by seaweeds in a long term study are warranted. PMID:25337591

  13. Failure of oestradiol administration to induce fatty liver haemorrhagic syndrome in the laying hen.

    PubMed

    Pearce, J; Johnson, A H

    1986-03-01

    Studies were carried out to investigate whether the administration of oestradiol to laying hens induced fatty liver-haemorrhagic syndrome (FLHS). Short term oestradiol administration (up to 6 d) significantly increased liver size and plasma lipid concentration but had no effect on liver lipid concentration or hepatic lipogenic enzyme activities. Longer-term hormone treatment (up to 28 d) again significantly increased liver size and plasma lipid concentration. Liver lipid concentration was substantially reduced and lipogenic enzyme activity significantly reduced in oestradiol-treated birds. These effects had some similarities to those seen in oestrogenised immature birds and were additive to the effects of endogenous oestrogen in the laying bird. There were no deaths from FLHS and oestradiol treatment did not cause liver haemorrhages or affect egg production.

  14. Bacterial translocation aggravates CCl4-induced liver cirrhosis by regulating CD4+ T cells in rats

    PubMed Central

    Shi, Haiyan; Lv, Longxian; Cao, Hongcui; Lu, Haifeng; Zhou, Ning; Yang, Jiezuan; Jiang, Haiyin; Dong, Huihui; Hu, Xinjun; Yu, Wei; Jiang, Xiawei; Zheng, Beiwen; Li, Lanjuan

    2017-01-01

    Bacterial translocation (BT) is thought to play an important role in the development of liver cirrhosis, but the mechanisms have not been fully explored. This study aims to investigate the distribution of Treg (CD3+CD4+CD25+Foxp3+), Th17 (CD3+CD4+IL-17+), and Th1 (CD3+CD4+IFN-γ+) cells in the intestinal lamina propria, liver and blood and to explore their relationships with BT. Cirrhotic rats with ascites were induced by CCl4. We found that there were lower levels of total protein and albumin, lower albumin/globulin ratio, lower body weight and higher spleen weight and ascites volume in cirrhotic rats with than without BT. We found that BT may cause increase of Treg cells in the proximal small intestine and decrease of Th17 cells in the whole intestine and blood in cirrhotic rats. It may also aggravate the CCl4-induced decrease in Th1 cells in the whole intestine, liver, caecum, and blood and the CCl4-induced increase in Th17 cells in the liver and Tregs in the distal small intestine, colon, and liver. Our data suggest that BT may aggravate liver injury and decrease liver function via an interaction with CD4+ T Cells. The results of this study may be helpful for the development of new treatments for liver cirrhosis. PMID:28134306

  15. Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine

    SciTech Connect

    Santra, Amal . E-mail: asantra2000@yahoo.co.in; Chowdhury, Abhijit; Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna

    2007-04-15

    Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects.

  16. Differential Sympathetic Vasomotor Activation Induced by Liver Cirrhosis in Rats

    PubMed Central

    Bergamaschi, Cássia T.; Campos, Ruy R.

    2016-01-01

    We tested the hypothesis that there is a topographical sympathetic activation in rats submitted to experimental cirrhosis. Baseline renal (rSNA) and splanchnic (sSNA) sympathetic nerve activities were evaluated in anesthetized rats. In addition, we evaluated main arterial pressure (MAP), heart rate (HR), and baroreceptor reflex sensitivity (BRS). Cirrhotic Wistar rats were obtained by bile duct ligation (BDL). MAP and HR were measured in conscious rats, and cardiac BRS was assessed by changes in blood pressure induced by increasing doses of phenylephrine or sodium nitroprusside. The BRS and baseline for the control of sSNA and rSNA were also evaluated in urethane-anesthetized rats. Cirrhotic rats had increased baseline sSNA (BDL, 102 vs control, 58 spikes/s; p<0.05), but no baseline changes in the rSNA compared to controls. These data were accompanied by increased splanchnic BRS (p<0.05) and decreased cardiac (p<0.05) and renal BRS (p<0.05). Furthermore, BDL rats had reduced basal MAP (BDL, 93 vs control, 101 mmHg; p<0.05) accompanied by increased HR (BDL, 378 vs control, 356; p<0.05). Our data have shown topographical sympathetic activation in rats submitted to experimental cirrhosis. The BDL group had increased baseline sSNA, independent of dysfunction in the BRS and no changes in baseline rSNA. However, an impairment of rSNA and HR control by arterial baroreceptor was noted. We suggest that arterial baroreceptor impairment of rSNA and HR is an early marker of cardiovascular dysfunction related to liver cirrhosis and probably a major mechanism leading to sympathoexcitation in decompensated phase. PMID:27055088

  17. Chronic Uridine Administration Induces Fatty Liver and Pre-Diabetic Conditions in Mice

    PubMed Central

    Urasaki, Yasuyo; Pizzorno, Giuseppe; Le, Thuc T.

    2016-01-01

    Uridine is a pyrimidine nucleoside that exerts restorative functions in tissues under stress. Short-term co-administration of uridine with multiple unrelated drugs prevents drug-induced liver lipid accumulation. Uridine has the ability to modulate liver metabolism; however, the precise mechanism has not been delineated. In this study, long-term effects of uridine on liver metabolism were examined in both HepG2 cell cultures and C57BL/6J mice. We report that uridine administration was associated with O-GlcNAc modification of FOXO1, increased gluconeogenesis, reduced insulin signaling activity, and reduced expression of a liver-specific fatty acid binding protein FABP1. Long-term uridine feeding induced systemic glucose intolerance and severe liver lipid accumulation in mice. Our findings suggest that the therapeutic potentials of uridine should be designed for short-term acute administration. PMID:26789264

  18. Is Liver Enzyme Release Really Associated with Cell Necrosis Induced by Oxidant Stress?

    PubMed Central

    Contreras-Zentella, Martha Lucinda; Hernández-Muñoz, Rolando

    2016-01-01

    Hepatic diseases are a major concern worldwide. Increased specific plasma enzyme activities are considered diagnostic features for liver diseases, since enzymes are released into the blood compartment following the deterioration of the organ. Release of liver mitochondrial enzymes is considered strong evidence for hepatic necrosis, which is associated with an increased production of ROS, often leading to greater hepatic lipid peroxidation. Lipotoxic mediators and intracellular signals activated Kupffer cells, which provides evidence strongly suggesting the participation of oxidant stress in acute liver damage, inducing the progression of liver injury to chronic liver damage. Elevated transaminase activities are considered as an index marker of hepatotoxicity, linked to oxidant stress. However, a drastic increase of serum activities of liver enzyme markers ought not necessarily to reflect liver cell death. In fact, increased serum levels of cytoplasmic enzymes have readily been observed after partial hepatectomy (PH) in the regenerating liver of rats. In this regard, we are now showing that in vitro modifications of the oxidant status affect differentially the release of liver enzymes, indicating that this release is a strictly controlled event and not directly related to the onset of oxidant stress of the liver. PMID:26798419

  19. 78 FR 11895 - Prospective Grant of Exclusive License: Development of MUC-1 Tumor Associated Antigens as Cancer...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-20

    ..., Gastric Cancer, Kidney Cancer, Liver Cancer, Lung Cancer, Ovarian Cancer, Prostate Cancer and Pancreatic..., gastric cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer and...

  20. A case of amoxicillin-induced hepatocellular liver injury with bile-duct damage.

    PubMed

    Kim, Ju Seung; Jang, Young Rock; Lee, Ji Won; Kim, Jin Yong; Jung, Young Kul; Chung, Dong Hae; Kwon, Oh Sang; Kim, Yun Soo; Choi, Duck Joo; Kim, Ju Hyun

    2011-09-01

    Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin-induced cholestatic hepatitis. When amoxicillin was discontinued, the patient's symptoms improved and her liver enzyme levels reduced to near to the normal range.

  1. Drug-induced Liver Injury Associated with Mosapride Citrate: A Report of Two Cases

    PubMed Central

    Sako, Ayaka; Bae, Sung Kwan; Gushima, Toshifumi; Motoshita, Junichi; Bekki, Shigemune; Abiru, Seigo; Komori, Atsumasa; Shimoda, Shinji; Ito, Masahiro; Yatsuhashi, Hiroshi; Takahashi, Kazuhiro

    2017-01-01

    We herein report two cases of drug-induced liver injury (DILI) due to mosapride. Case 1: A 78-year-old man was admitted with elevated transaminase levels. The cessation of mosapride led to the improvement of elevated liver enzyme levels. Case 2: A 54-year-old man was admitted with jaundice. Mosapride was discontinued immediately, and methylprednisolone was administered for acute liver failure. The patient's data showed improvement, and he was discharged on Day 32. In both cases, mosapride gave a positive response to a drug-induced lymphocyte stimulation test (DLST), and the patient's score based on the criteria for DILI was “highly probable”. PMID:28049998

  2. Pretreatment with wortmannin alleviates lipopolysaccharide/d-galactosamine-induced acute liver injury.

    PubMed

    Li, Yan; Wang, Xiaoyan; Wei, Zengtao; Mao, Hongju; Gao, Meng; Liu, Yanping; Ma, Yanyan; Liu, Xingli; Guo, Chun; Zhang, Lining; Wang, Xiaoyan

    2014-12-12

    Intestinal endotoxemia-induced liver injury is a common clinical disease which leads to liver failure and death. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, could be used for suppressing autophagy in vitro and in vivo. Autophagy is an evolutionarily conserved and lysosome dependent protein degradation pathway, which participates in various physiological and pathological processes. The present study aims to explore the effect of pretreatment with wortmannin on acute liver injury and the autophagy in acute liver injury. We demonstrated that wortmannin could downregulate the expression of phosphorylated extracellular regulated protein kinase and p65, decrease the production and release of hepatic inflammatory cytokines, and then reduce hepatocytes apoptosis and necrosis. More importantly, we found that autophagy was induced to increase in LPS/D-GalN-induced acute liver injury, and pretreatment with wortmannin could effectively inhibit increased autophagy in acute liver injury. In conclusion, these results indicate that wortmannin plays a protective role in LPS/D-GalN induced hepatocytotoxity maybe by inhibiting autophagy and could be acted as a target for the treatment of acute liver injury.

  3. Pathological response after neoadjuvant bevacizumab- or cetuximab-based chemotherapy in resected colorectal cancer liver metastases.

    PubMed

    Pietrantonio, Filippo; Mazzaferro, Vincenzo; Miceli, Rosalba; Cotsoglou, Christian; Melotti, Flavia; Fanetti, Giuseppe; Perrone, Federica; Biondani, Pamela; Muscarà, Cecilia; Di Bartolomeo, Maria; Coppa, Jorgelina; Maggi, Claudia; Milione, Massimo; Tamborini, Elena; de Braud, Filippo

    2015-07-01

    Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.

  4. The nanomechanical signature of liver cancer tissues and its molecular origin.

    PubMed

    Tian, Mengxin; Li, Yiran; Liu, Weiren; Jin, Lei; Jiang, Xifei; Wang, Xinyan; Ding, Zhenbin; Peng, Yuanfei; Zhou, Jian; Fan, Jia; Cao, Yi; Wang, Wei; Shi, Yinghong

    2015-08-14

    Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the "gold standard" in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus distribution of surgically removed liver cancer tissues can serve as a mechanical fingerprint to evaluate the malignancy of liver cancer. Cirrhotic tissues shared the same LEP as normal tissues. However, a noticeable downward shift in the LEP was detected when the cirrhotic tissues progressed to a malignant state, making the tumor tissues more prone to microvascular invasion. Cell-level mechanistic studies revealed that the expression level of a Rho-family effector (mDia1) was consistent with the mechanical trend exhibited by the tissue. Our findings indicate that the mechanical profiles of liver cancer tissues directly varied with tumor progression, providing an additional platform for the future diagnosis of HCC.

  5. An updated dose–response meta-analysis of coffee consumption and liver cancer risk

    PubMed Central

    Yu, Chengbo; Cao, Qing; Chen, Ping; Yang, Shigui; Deng, Min; Wang, Yugang; Li, Lanjuan

    2016-01-01

    Prospective cohort studies of the relationship between coffee consumption and liver cancer risk have drawn different conclusions. Therefore, a dose-response meta-analysis of prospective cohort studies was performed to disentangle this causal relationship. Prospective cohort studies of the association between coffee consumption and liver cancer risk published prior to Jan 9, 2016 were identified by searching in the PubMed and EMBASE databases. Extracted data were analyzed using a random-effects model. Of the 2892 records identified using the search strategy, a total of twenty cohort studies from ten publications were included in the final meta-analysis. The pooled estimate of relative risk (RR) with 95% confidence interval (CI) for highest vs. non/occasional coffee drinkers was 0.55(0.44–0.67). No evidence of publication bias was observed (p for Egger’s test = 0.229). Sensitivity analysis indicated the results were robust. Dose-response analysis revealed a significant linear dose-response relationship between coffee consumption and liver cancer risk (p = 0.36). Subgroup analyses stratified by pre-specified variables (gender, geographic region, and adjusted factors) indicated similar results within individual subgroups. Our meta-analysis suggested that coffee consumption is inversely associated with liver cancer risk. PMID:27910873

  6. [A case of liver metastasis from sigmoid colon cancer treated effectively by second-line chemotherapy].

    PubMed

    Gokita, Kentaro; Ami, Katsunori; Matsunaga, Yutaro; Fujiya, Keiichi; Ohshima, Nana; Amagasa, Hidetoshi; Ganno, Hideaki; Imai, Kenichiro; Fukuda, Akira; Nagahama, Takeshi; Ando, Masayuki; Akita, Hidetaka; Tei, Shikofumi; Okada, Youichi; Arai, Kuniyoshi

    2014-11-01

    A case of successful chemotherapy for a metachronous liver metastasis following resection for sigmoid colon cancer is presented. A 51-year-old man underwent sigmoidectomy, ileocecal resection, and descending colon colostomy for sigmoid colon cancer with ileum invasion. Six courses of FOLFOX4 were performed as adjuvant chemotherapy. One year after sigmoidectomy, a liver metastasis was detected on computed tomography (CT) examination. Chemotherapy with FOLFOX+bevacizumab was restarted. Three courses were administered, but hepatic dysfunction occurred after the second and third courses, and FOLFOX was discontinued. Subsequent chemotherapy was reinitiated with FOLFIRI+bevacizumab. After 9 courses, the carcinoembryonic antigen level was normalized and appeared to be decreased by imaging studies. Upon the patient's request, only oral S-1 was administered. After 2 courses, CT revealed that the diameter of the tumor had increased by 2 cm. Therefore, right lobectomy of the liver, colostomy closure, and anastomosis were performed. During these procedures, a nodule was found in the omentum and was removed. Rapid intra-operative diagnosis revealed peritoneal dissemination. The pathological diagnosis was liver metastasis of sigmoid colon cancer, with necrosis and fibrosis seen in approximately one-half of specimens. The surgical margins were negative. Neither metastatic cancer nor dissemination were found in the resected greater omentum.

  7. Comparison of percutaneous microwave ablation and laparoscopic resection in the prognosis of liver cancer.

    PubMed

    Xu, Juan; Zhao, Ye

    2015-01-01

    The effect of percutaneous microwave ablation and laparoscopic resection on the prognosis of liver cancer was investigated. Ninety patients with liver cancer treated at our hospital from March 2010 to March 2012 were divided into group A and group B (n=45) by using a random number table, and the surgical conditions and the prognosis were compared. The surgical conditions of patients in group A were significantly better than those in group B (P<0.05). The incidence of complications in group A was 6.67%, which was obviously lower than that of group B (P<0.05). The local recurrence rate of group A was 20.00%, and that of group B was 8.89%, which showed a significant difference (P<0.05). The two groups did not differ significantly in terms of either total recurrence rate (P>0.05) or 1-year, 2-year and 3-year survival (P>0.05). Both percutaneous microwave ablation and laparoscopic resection had a good long-term efficacy in liver cancer. However, percutaneous microwave ablation was superior as it caused less invasiveness, reduced the incidence of complications and improved prognosis of liver cancer.

  8. CUDR promotes liver cancer stem cell growth through upregulating TERT and C-Myc

    PubMed Central

    Pu, Hu; Zheng, Qidi; Li, Haiyan; Wu, Mengying; An, Jiahui; Gui, Xin; Li, Tianming; Lu, Dongdong

    2015-01-01

    Cancer up-regulated drug resistant (CUDR) is a novel non-coding RNA gene. Herein, we demonstrate excessive CUDR cooperates with excessive CyclinD1 or PTEN depletion to accelerate liver cancer stem cells growth and liver stem cell malignant transformation in vitro and in vivo. Mechanistically, we reveal the decrease of PTEN in cells may lead to increase binding capacity of CUDR to CyclinD1. Therefore, CUDR-CyclinD1 complex loads onto the long noncoding RNA H19 promoter region that may lead to reduce the DNA methylation on H19 promoter region and then to enhance the H19 expression. Strikingly, the overexpression of H19 increases the binding of TERT to TERC and reduces the interplay between TERT with TERRA, thus enhancing the cell telomerase activity and extending the telomere length. On the other hand, insulator CTCF recruits the CUDR-CyclinD1 complx to form the composite CUDR-CyclinD1-insulator CTCF complex which occupancied on the C-myc gene promoter region, increasing the outcome of oncogene C-myc. Ultimately, excessive TERT and C-myc lead to liver cancer stem cell and hepatocyte-like stem cell malignant proliferation. To understand the novel functions of long noncoding RNA CUDR will help in the development of new liver cancer therapeutic and diagnostic approaches. PMID:26513297

  9. Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis.

    PubMed

    Hisamochi, Akiko; Kage, Masayoshi; Arinaga, Teruko; Ide, Tatsuya; Miyajima, Ichiro; Ogata, Kei; Kuwahara, Reiichiro; Koga, Yuriko; Kumashiro, Ryukichi; Sata, Michio

    2013-04-01

    Agaricus blazei Murill (ABM) is one of the most popular complementary alternative medicines (CAM). We experienced a case of a 60-year-old woman with severe hepatitis associated with extract of ABM and extract of Ganoderma lucidum, and a case of a 75-year-old man with drug-induced liver injury (DILI) associated with extract of ABM and fucoidan. Their clinical courses from the start of CAM until the onset of DILI were observed unexpectedly, because they were under observation for stable malignant neoplasms: stage III malignant thymoma and stage IV lung cancer, respectively. However, they did not talk about taking CAM with their physicians. There were two common points between these two cases. First, they were diagnosed as compatible with DILI by using an international diagnostic scale, the Roussel Uclaf Causality Assessment Method. The second point was that histological findings of the liver were very similar to autoimmune hepatitis (AIH). In addition, serum immunoglobulin G and zinc sulfate turbidity tests gradually increased from the start of CAM to the onset of DILI. Their clinical course and liver histology suggested that the immunostimulating action of ABM caused liver injury which was very similar to that seen in AIH.

  10. Inflammasomes in Inflammation-Induced Cancer

    PubMed Central

    Lin, Chu; Zhang, Jun

    2017-01-01

    The inflammasome is an important multiprotein complex that functions during inflammatory immune responses. The activation of inflammasome will lead to the autoactivation of caspase-1 and subsequent cleavage of proIL-1β and proIL-18, which are key sources of inflammatory manifestations. Recently, the roles of inflammasomes in cancers have been extensively explored, especially in inflammation-induced cancers. In different and specific contexts, inflammasomes exhibit distinct and even contrasting effects in cancer development. In some cases, inflammasomes initiate carcinogenesis through the extrinsic pathway and maintain the malignant cancer microenvironment through the intrinsic pathway. On the contrary, inflammasomes also exert anticancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions. The phases and compartments in which inflammasomes are activated strongly influence the final immune effects. We systemically summarize the functions of inflammasomes in inflammation-induced cancers, especially in gastrointestinal and skin cancers. Besides, information about the current therapeutic use of inflammasome-related products and potential future developing directions are also introduced. PMID:28360909

  11. Transplacental arsenic plus postnatal 12-O-teradecanoyl phorbol-13-acetate exposures associated with hepatocarcinogenesis induce similar aberrant gene expression patterns in male and female mouse liver

    SciTech Connect

    Liu Jie . E-mail: Liu6@niehs.nih.gov; Xie Yaxiong; Merrick, B. Alex; Shen Jun; Ducharme, Danica M.K.; Collins, Jennifer; Diwan, Bhalchandra A.; Logsdon, Daniel; Waalkes, Michael P.

    2006-06-15

    Our prior work shows that in utero arsenic exposure alone is a complete transplacental carcinogen, producing hepatocellular carcinoma in adult male offspring but not in females. In a follow-up study to potentially promote arsenic-initiated tumors, mice were exposed to arsenic (85 ppm) from gestation day 8 to 18 and then exposed to 12-O-teradecanoyl phorbol-13-acetate (TPA), a well-known tumor promoter after weaning. The dermal application of TPA (2 {mu}g/0.1 ml acetone, twice/week for 21 weeks) after transplacental arsenic did not further increase arsenic-induced liver tumor formation in adult males but significantly increased liver tumor formation in adult females. Thus, for comparison, liver tumors and normal liver samples taken from adult male and female mice at necropsy were analyzed for aberrant gene/protein expression by microarray, real-time RT-PCR and Western blot analysis. Arsenic/TPA treatment resulted in increased expression of {alpha}-fetoprotein, k-ras, c-myc, estrogen receptor-{alpha}, cyclin D1, cdk2na, plasminogen activator inhibitor-1, cytokeratin-8, cytokeratin-18, glutathione S-transferases and insulin-like growth factor binding proteins in liver and liver tumors from both male and female mice. Arsenic/TPA also decreased the expression of BRCA1, betaine-homocysteine methyltransferase, CYP7B1, CYP2F2 and insulin-like growth factor-1 in normal and cancerous livers. Alterations in these gene products were associated with arsenic/TPA-induced liver tumors, regardless of sex. Thus, transplacental arsenic plus postnatal TPA exposure induced similar aberrant gene expression patterns in male and female mouse liver, which are persistent and potentially important to the mechanism of arsenic initiation of hepatocarcinogenesis.

  12. Melatonin protects rat liver against irradiation-induced oxidative injury.

    PubMed

    Koc, Mehmet; Taysi, Seyithan; Buyukokuroglu, Mehmet Emin; Bakan, Nuri

    2003-09-01

    The aim of this study was to investigate the antioxidant roles of different doses of melatonin (5 and 10 mg x kg (-1) ) against gamma-irradiation-caused oxidative damage in liver tissue after total body irradiation (TBI) with a single dose of 6.0 Gy. Fifty adult rats were divided into 5 equal groups, 10 rats each. Groups I and II were injected with 5 and 10 mg x kg (-1) of melatonin, and group III was injected with an isotonic NaCl solution. Group IV was injected with only 5 mg x kg (-1) of melatonin. Group V was reserved as a sham control. Following a 30-min-period, 6.0 Gy TBI was given to groups 1, 2 and 3 in a single fraction. The liver malondialdehyde (MDA) levels, super oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were measured in all groups. TBI resulted in a significant increase in the liver tissue MDA levels and a decrease of SOD and GSH-Px activities. The results demonstrated that the liver tissue MDA levels in irradiated rats that were pretreated with melatonin (5 or 10 mg x kg (-1) ) were significantly decreased, while the SOD and GSH-Px activities were significantly increased. Decreasing the MDA levels by melatonin was dose dependent, but the liver tissue SOD and GSH activities were not. The data obtained in this study suggest that melatonin administration prior to irradiation may prevent liver damage by irradiation.

  13. Erythema, papules, and arthralgia associated with liver cancer: report of a rare case of multicentric reticulohistiocytosis

    PubMed Central

    Hu, Liang; Mei, Jun-Hua; Xia, Jin; Hao, Quan-Shui; Cheng, Li-Ping; Wu, Yao-Hua

    2015-01-01

    We report a rare case of multicentric reticulohistiocytosis (MRH) associated with liver carcinoma. A 36-year-old man who had been diagnosed as having liver carcinoma for 2 years presented with a 2-month history of multiple papulonodules on the face, ears, neck, and upper chest, accompanied by progressive polyarthralgia of the hands, wrists, elbows and knee joints without fever or chills. Skin histology revealed well defined dermal infiltrate consisting of multinucleated giant cells and macrophages having abundant eosinophilic finely granular cytoplasm with ground glass appearance. Further immunohistochemical studies characterized the lesions as positive for CD68, CD45 and Vimentin. A diagnosis of MRH that was associated with liver