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Sample records for mediates hepatocellular uptake

  1. The organic anion transport polypeptide 1d1 (Oatp1d1) mediates hepatocellular uptake of phalloidin and microcystin into skate liver.

    Science.gov (United States)

    Meier-Abt, F; Hammann-Hänni, A; Stieger, B; Ballatori, N; Boyer, J L

    2007-02-01

    Organic anion transporting polypeptides (rodent Oatp; human OATP) mediate cellular uptake of numerous organic compounds including xenobiotic toxins into mammalian hepatocytes. In the little skate Leucoraja erinacea a liver-specific Oatp (Oatp1d1, also called sOatp) has been identified and suggested to represent an evolutionarily ancient precursor of the mammalian liver OATP1B1 (human), Oatp1b2 (rat), and OATP1B3 (human). The present study tested whether Oatp1d1 shares functional transport activity of the xenobiotic oligopeptide toxins phalloidin and microcystin with the mammalian liver Oatps/OATPs. The phalloidin analogue [(3)H]-demethylphalloin was taken up into skate hepatocytes with high affinity (Km approximately 0.4 microM), and uptake could be inhibited by phalloidin and a variety of typical Oatp/OATP substrates such as bromosulfophthalein, bile salts, estrone-3-sulfate, cyclosporine A and high concentrations of microcystin-LR (Ki approximately 150 microM). When expressed in Xenopus laevis oocytes Oatp1d1 increased uptake of demethylphalloin (Km approximately 2.2 microM) and microcystin-LR (Km approximately 27 microM) 2- to 3-fold over water-injected oocytes, whereas the alternative skate liver organic anion transporter, the dimeric Ostalpha/beta, exhibited no phalloidin and only minor microcystin-LR transport. Also, the closest mammalian Oatp1d1 orthologue, the human brain and testis OATP1C1, did not show any phalloidin transport activity. These results demonstrate that the evolutionarily ancient Oatp1d1 is able to mediate uptake of cyclic oligopeptide toxins into skate liver. The findings support the notion that Oatp1d1 is a precursor of the liver-specific mammalian Oatps/OATPs and that its transport properties are closely associated with certain forms of toxic liver injury such as for example protein phosphatase inhibition by the water-borne toxin microcystin.

  2. The organic anion transport polypeptide 1d1 (Oatp1d1) mediates hepatocellular uptake of phalloidin and microcystin into skate liver

    International Nuclear Information System (INIS)

    Meier-Abt, F.; Hammann-Haenni, A.; Stieger, B.; Ballatori, N.; Boyer, J.L.

    2007-01-01

    Organic anion transporting polypeptides (rodent Oatp; human OATP) mediate cellular uptake of numerous organic compounds including xenobiotic toxins into mammalian hepatocytes. In the little skate Leucoraja erinacea a liver-specific Oatp (Oatp1d1, also called sOatp) has been identified and suggested to represent an evolutionarily ancient precursor of the mammalian liver OATP1B1 (human), Oatp1b2 (rat), and OATP1B3 (human). The present study tested whether Oatp1d1 shares functional transport activity of the xenobiotic oligopeptide toxins phalloidin and microcystin with the mammalian liver Oatps/OATPs. The phalloidin analogue [ 3 H]-demethylphalloin was taken up into skate hepatocytes with high affinity (Km ∼ 0.4 μM), and uptake could be inhibited by phalloidin and a variety of typical Oatp/OATP substrates such as bromosulfophthalein, bile salts, estrone-3-sulfate, cyclosporine A and high concentrations of microcystin-LR (Ki ∼ 150 μM). When expressed in Xenopus laevis oocytes Oatp1d1 increased uptake of demethylphalloin (Km ∼ 2.2 μM) and microcystin-LR (Km ∼ 27 μM) 2- to 3-fold over water-injected oocytes, whereas the alternative skate liver organic anion transporter, the dimeric Ostα/β, exhibited no phalloidin and only minor microcystin-LR transport. Also, the closest mammalian Oatp1d1 orthologue, the human brain and testis OATP1C1, did not show any phalloidin transport activity. These results demonstrate that the evolutionarily ancient Oatp1d1 is able to mediate uptake of cyclic oligopeptide toxins into skate liver. The findings support the notion that Oatp1d1 is a precursor of the liver-specific mammalian Oatps/OATPs and that its transport properties are closely associated with certain forms of toxic liver injury such as for example protein phosphatase inhibition by the water-borne toxin microcystin

  3. Diselenolane-mediated cellular uptake.

    Science.gov (United States)

    Chuard, Nicolas; Poblador-Bahamonde, Amalia I; Zong, Lili; Bartolami, Eline; Hildebrandt, Jana; Weigand, Wolfgang; Sakai, Naomi; Matile, Stefan

    2018-02-21

    The emerging power of thiol-mediated uptake with strained disulfides called for a move from sulfur to selenium. We report that according to results with fluorescent model substrates, cellular uptake with 1,2-diselenolanes exceeds uptake with 1,2-dithiolanes and epidithiodiketopiperazines with regard to efficiency as well as intracellular localization. The diselenide analog of lipoic acid performs best. This 1,2-diselenolane delivers fluorophores efficiently to the cytosol of HeLa Kyoto cells, without detectable endosomal capture as with 1,2-dithiolanes or dominant escape into the nucleus as with epidithiodiketopiperazines. Diselenolane-mediated cytosolic delivery is non-toxic (MTT assay), sensitive to temperature but insensitive to inhibitors of endocytosis (chlorpromazine, methyl-β-cyclodextrin, wortmannin, cytochalasin B) and conventional thiol-mediated uptake (Ellman's reagent), and to serum. Selenophilicity, the extreme CSeSeC dihedral angle of 0° and the high but different acidity of primary and secondary selenols might all contribute to uptake. Thiol-exchange affinity chromatography is introduced as operational mimic of thiol-mediated uptake that provides, in combination with rate enhancement of DTT oxidation, direct experimental evidence for existence and nature of the involved selenosulfides.

  4. Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma

    OpenAIRE

    Narita, Masato; Hatano, Etsuro; Arizono, Shigeki; Miyagawa-Hayashino, Aya; Isoda, Hiroyoshi; Kitamura, Koji; Yasuchika, Kentaro; Nitta, Takashi; Uemoto, Shinji

    2009-01-01

    Background: Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is an MRI contrast agent with perfusion and hepatoselective properties. The purpose of the study was to examine uptake of Gd-EOB-DTPA in the hepatobiliary phase in hepatocellular carcinoma (HCC). Methods: A retrospective analysis of 22 patients with HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI was performed. Enhancement ratios (ERs) and expression levels of the organic anion transporter (OATP) 1B3...

  5. Baseline Tumor Lipiodol Uptake after Transarterial Chemoembolization for Hepatocellular Carcinoma: Identification of a Threshold Value Predicting Tumor Recurrence.

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    Matsui, Yusuke; Horikawa, Masahiro; Jahangiri Noudeh, Younes; Kaufman, John A; Kolbeck, Kenneth J; Farsad, Khashayar

    2017-12-01

    The aim of the study was to evaluate the association between baseline Lipiodol uptake in hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with early tumor recurrence, and to identify a threshold baseline uptake value predicting tumor response. A single-institution retrospective database of HCC treated with Lipiodol-TACE was reviewed. Forty-six tumors in 30 patients treated with a Lipiodol-chemotherapy emulsion and no additional particle embolization were included. Baseline Lipiodol uptake was measured as the mean Hounsfield units (HU) on a CT within one week after TACE. Washout rate was calculated dividing the difference in HU between the baseline CT and follow-up CT by time (HU/month). Cox proportional hazard models were used to correlate baseline Lipiodol uptake and other variables with tumor response. A receiver operating characteristic (ROC) curve was used to identify the optimal threshold for baseline Lipiodol uptake predicting tumor response. During the follow-up period (mean 5.6 months), 19 (41.3%) tumors recurred (mean time to recurrence = 3.6 months). In a multivariate model, low baseline Lipiodol uptake and higher washout rate were significant predictors of early tumor recurrence ( P = 0.001 and Baseline Lipiodol uptake and washout rate on follow-up were independent predictors of early tumor recurrence. A threshold value of baseline Lipiodol uptake > 270.2 HU was highly sensitive and specific for tumor response. These findings may prove useful for determining subsequent treatment strategies after Lipiodol TACE.

  6. Hepatocellular carcinoma with marginal superparamagnetic iron oxide uptake on T2*-weighted magnetic resonance imaging: Histopathologic correlation

    International Nuclear Information System (INIS)

    Ishigami, Kousei; Tajima, Tsuyoshi; Fujita, Nobuhiro; Nishie, Akihiro; Asayama, Yoshiki; Kakihara, Daisuke; Nakayama, Tomohiro; Okamoto, Daisuke; Taketomi, Akinobu; Shirabe, Ken; Honda, Hiroshi

    2011-01-01

    Purpose: To evaluate the characteristics of hepatocellular carcinomas (HCCs) with marginal superparamagnetic iron oxide (SPIO) uptake on T2*-weighted MRI. Materials and methods: The study group consisted of 73 patients with 83 surgically resected HCCs. Preoperative SPIO-enhanced MRI studies were retrospectively reviewed. Marginal SPIO uptake was considered positive if a rim-like or band-like low intensity area was present on SPIO-enhanced T2*-weighted images. The prevalence of marginal SPIO uptake was evaluated. Pathological specimens with hematoxylin and eosin staining and immunohistochemical staining of CD68 were reviewed in HCCs with marginal SPIO uptake and 33 HCCs without marginal SPIO uptake (control group). Results: Ten of 83 (12%) HCCs showed marginal SPIO uptake. All HCCs were hypervascular, and only one nodule showed a nodule-in-nodule appearance on imaging findings. The pathology specimens suggested possible causes of marginal SPIO uptake, including marginal macrophage infiltration in moderately or poorly differentiated HCC (n = 4), residual normal hepatic tissue at the marginal area of confluent multinodular or single nodular with extranodular growth type HCC (n = 3), and a well-differentiated HCC component in nodule-in-nodule type HCC (n = 3). Marginal macrophage infiltration was not seen in the control group. Conclusion: SPIO-enhanced MRI may be able to demonstrate marginal macrophage infiltration in HCC.

  7. Characteristic Uptake Pattern of Bone Scintigraphy in Patients with Hepatocellular Carcinoma Following Treatment with High-Intensity Focused Ultrasound

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    Ma, Waihan; Ho, Waiyin; Lai, Andrew S. H.; Wong, Kwongkuen; Law, Martin [Queen Mary Hospital, Pokfulam (Hong Kong)

    2013-12-15

    This study retrospectively reviews the characteristic bone scintigraphic findings in 18 patients with hepatocellular carcinoma (HCC) following treatment with high-intensity focused ultrasound (HIFU). A potential complication of HIFU is damage to the tissues along the path of the ultrasound beam and structures superficial to the lesion of interest. Patients with hepatocellular carcinoma who underwent a bone scan between 1st December 2005 and 31st December 2011 were considered for this study. Among these patients, only those who had bone scans after the HIFU treatment were included. The time between HIFU treatment and bone scans, HIFU energy, HCC sites, tumour sizes and related radiological findings were evaluated. In total, 20 bone scans of 18 patients were reviewed. Of these scans, two patients were normal; three patients showed decreased uptake, four patients showed increased uptake and nine patients showed mixed uptakes of the bony tracer in their rib cages. The defects were located in the anterior, lateral, anterolateral or posterolateral aspects of the rib cage. The majority of those cold defects were in the right anterior rib cages. SPECT/CT was used to localise the decreased uptake in ribs. The magnetic resonance imaging in individual patients invariably showed ill-defined rim enhancement along the right chest wall, signifying chest wall injury. The results showed that tissue ablation using HIFU caused tissue injury along the pathway of high-intensity ultrasound beams. The harm to tissues is presented as photopenic area on the rib cages due to necrosis or hot spots due to rib fractures in the bone scan. Since these cold defects are subtle, they are easily overlooked or mistaken as aggressive bony metastasis.

  8. STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma.

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    Tai, Wei-Tien; Chu, Pei-Yi; Shiau, Chung-Wai; Chen, Yao-Li; Li, Yong-Shi; Hung, Man-Hsin; Chen, Li-Ju; Chen, Pei-Lung; Su, Jung-Chen; Lin, Ping-Yi; Yu, Hui-Chuan; Chen, Kuen-Feng

    2014-11-15

    Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC). HCC cell lines (PLC5, HepG2, Hep3B, SK-Hep1, and HA59T) were used to investigate the in vitro effect of regorafenib. Phosphatase activity was analyzed in HCC cells and purified SHP-1 proteins. PLC5-bearing mice were used to test the therapeutic efficiency of 20 and 40 mg/kg/d treatment with regorafenib ([Formula: see text] mice). The clinical relevance of STAT3 signaling was investigated with 142 tumor samples from different patients with HCC. Descriptive statistical analysis was used to compare the baseline characteristics of patients and the expression of p-STAT3. Regorafenib inhibited STAT3-related signaling in a dose-dependent manner and was a more potent inhibitor of STAT3 than sorafenib. Regorafenib increased SHP-1 phosphatase activity in purified SHP-1 protein directly. N-SH2 domain deletion and D61A mutants mimicking open-form SHP-1 partially abolished regorafenib-induced STAT3 inhibition and apoptosis. Importantly, a higher level of expression of STAT3 was found in patients with advanced clinical stages (P = 0.009) and poorly differentiated tumors (P = 0.035). Regorafenib induced significant tumor inhibition by relieving the autoinhibited N-SH2 domain of SHP-1 directly and inhibiting p-STAT3 signals. STAT3 may be suitable as a prognostic marker of HCC development, and may be a druggable target for HCC-targeted therapy using regorafenib. ©2014 American Association for Cancer Research.

  9. Channel-mediated and carrier-mediated uptake of K+ into cultured ovine oligodendrocytes

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    Hertz, L.; Soliven, B.; Hertz, E.; Szuchet, S.; Nelson, D.J. (Univ. of Saskatchewan, Saskatoon (Canada))

    1990-01-01

    Uptake of radioactive K+ by mature ovine oligodendrocytes (OLGs) maintained in primary culture was measured under steady-state conditions, i.e., in cells maintained in a normal tissue culture medium (5.4 mM K+), and in cells after depletion of intracellular K+ to less than 15% of its normal value by pre-incubation in K(+)-free medium. The latter value is dominated by an active, carrier-mediated uptake (although it may include some diffusional uptake), whereas the former, in addition to active uptake, also reflects passive K+ diffusion through ion selective channels and possible self-exchange between extracellular and intracellular K+, which may be carrier-mediated. The total uptake rate was 144 +/- 10 nmol/min/mg protein, and the uptake after K+ depletion was 60 +/- 2 nmol/min/mg protein, much lower rates than previously observed in astrocytes. The uptake into K(+)-depleted cells was inhibited by about 80% in the presence of ouabain (1 mM) and about 30% in the presence of furosemide (2 mM). Activators of protein kinase C (phorbol esters) and cAMP-dependent protein kinase (forskolin) have been shown to alter the myelinogenic metabolism as well as outward K+ current in cultured OLGs. The present study demonstrates that K+ homeostasis in OLGs is modulated through similar second messenger pathways. Active uptake was inhibited by about 60% in the presence of active phorbol esters (100 nM) but was not affected by forskolin (100 nM). Forskolin likewise had no effect on total uptake, whereas phorbol esters caused a much larger inhibition than expected from their effect on carrier-mediated uptake alone, suggesting that channel-mediated uptake was also reduced.

  10. FDG uptake on PET and enhancement on CT or MRI in hepatocellular carcinoma (HCC)

    International Nuclear Information System (INIS)

    Ko, K. H.; Yun, M.; Kim, M. J.; Ryu, Y. H.; Lee, J. D.

    2002-01-01

    To correlate between FDG PET and enhancement pattern on CT and MRI and assess the factors affecting FDG uptake in HCC. Thirty seven nontreated HCC from 34 pts (M:F=30:4, mean age 53) were enrolled. All cases were histologically diagnosed and classified according to Edmonson and Steiner's grading. Tumor FDG uptake was visually assessed on a scale of 0 to 3 compared to the adjacent liver. (0 liver and 3>>liver) and was semi-quantitatively analyzed using SUV. Enhancement pattern on CT and MRI was classified into 3 groups according to signal intensity or density in arterial and portal phase (GroupI: hyperintense-hypointense, GroupII: isointense-hypointense, GroupIII: hypointense-hypointense). Tumor FDG uptake was correlated with enhancement pattern, grade, size and serum aFP level. The tumor ranged from 1.5cm to 20cm. Of the 37 cases, 19(51%) had positive FDG uptake (2 or 3), while 18(49%) were negative (0 or 1). The correlation between FDG uptake and enhancement pattern was statistically insignificant. Lower FDG uptake was associated with lower tumor grade and/or smaller tumor size (P<0.005). FDG uptake of HCC seems to be useful in predicting the differentiation of the tumor and may be prognostic. Although the significance of dynamic enhancement pattern on CT or MRI is yet controversial, it has no specific correlation with FDG uptake and grade on the tumor in this study

  11. Pekinenin E Inhibits the Growth of Hepatocellular Carcinoma by Promoting Endoplasmic Reticulum Stress Mediated Cell Death

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    Lu Fan

    2017-06-01

    Full Text Available Hepatocellular carcinoma (HCC is a malignant primary liver cancer with poor prognosis. In the present study, we report that pekinenin E (PE, a casbane diterpenoid derived from the roots of Euphorbia pekinensis, has a strong antitumor activity against human HCC cells both in vitro and in vivo. PE suppressed the growth of human HCC cells Hep G2 and SMMC-7721. In addition, PE-mediated endoplasmic reticulum (ER stress caused increasing expressions of C/EBP homologous protein (CHOP, leading to apoptosis in HCC cells both in vitro and in vivo. Inhibition of ER stress with CHOP small interfering RNA or 4-phenyl-butyric acid partially reversed PE-induced cell death. Furthermore, PE induced S cell cycle arrest, which could also be partially reversed by CHOP knockdown. In all, these findings suggest that PE causes ER stress-associated cell death and cell cycle arrest, and it may serve as a potent agent for curing human HCC.

  12. Analysis of gene expression profiles of hepatocellular carcinomas with regard to 18F-fluorodeoxyglucose uptake pattern on positron emission tomography

    International Nuclear Information System (INIS)

    Lee, Jong Doo; Yun, Mijin; Lee, Jae Myun; Choi, Youjeong; Choi, Youn-Hee; Kim, Ji Su; Kim, Se Jong; Park, Jeon Han; Kim, Kyung Sik; Lee, Woo Jung; Yang, Woo Ick; Park, Young Nyun; Han, Kwang-Hyub; Yoo, Naechun; Lim, Sang Moo

    2004-01-01

    18 F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scan has been found to reflect tumour aggressiveness and prognosis in various types of cancer. In this study, the gene expression profiles of hepatocellular carcinomas (HCCs) were evaluated to determine whether HCCs with high 18 F-FDG uptake have more aggressive biological potential than those with low uptake. Surgical specimens were obtained from ten patients with HCC (six males and four females, age range 38-68 years). The tumour samples were divided into two groups based on the 18 F-FDG PET scan findings: high 18 F-FDG uptake (n=4) and low 18 F-FDG uptake (n=6). The pathological tumour grade was closely correlated with the 18 F-FDG uptake pattern: HCCs with high 18 F-FDG uptake were pathologically Edmondson-Steiner grade III, while those with low uptake were either grade II or grade II with a focal area of grade III. The total RNA was extracted from the frozen tissues of all HCCs (n=10) and adjacent non-cancerous tissue (n=7). The gene expression profiles were evaluated using an oligoDNA microarray. The HCCs with high 18 F-FDG uptake showed increased expression of 11 genes - including vascular cell adhesion molecule-1, vinexin beta and core 1 UDP-galactose: N-acetylgalactosamine-alpha-R-beta 1,3-galactosyltransferase and the natural killer cell inhibitory receptor - compared to those with low uptake (p 18 F-FDG uptake appear to have more aggressive biological properties than those with low uptake. (orig.)

  13. Ursolic acid attenuates oxidative stress-mediated hepatocellular carcinoma induction by diethylnitrosamine in male Wistar rats.

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    Gayathri, Renganathan; Priya, D Kalpana Deepa; Gunassekaran, G R; Sakthisekaran, Dhanapal

    2009-01-01

    Hepatocellular carcinoma is the most common primary cancer of the liver in Asian countries. For more than a decade natural dietary agents including fruits, vegetables and spices have drawn a great deal of attention in the prevention of diseases, preferably cancer. Ursolic acid is a natural triterpenoid widely found in food, medicinal herbs, apple peel and other products it has been extensively studied for its anticancer and antioxidant properties. The purpose of this study was to evaluate the effect of ursolic acid in diethylnitrosamine (DEN) induced and phenobarbital promoted hepatocarcinogenesis in male Wistar rats. Antioxidant status was assessed by alterations in level of lipid peroxides and protein carbonyls. Damage to plasma membranes was assessed by levels of membrane and tissue ATPases. Liver tissue was homogenized and utilized for estimation of lipid peroxides, protein carbonyls and glycoproteins. Anticoagulated blood was utilized for erythrocyte membrane isolation. Oral administration of UA 20 mg/kg bodyweight for 6 weeks decreased the levels of lipid peroxides and protein carbonyls at a significance of pmembrane and tissue ATPases returned to normal after UA administration. Levels of glycoproteins were also restored after treatment. Histopathological observations were recorded. The findings from the above study suggest the effectiveness of UA in reducing the oxidative stress mediated changes in liver of rats. Since UA has been found to be a potent antioxidant, it can be suggested as an excellent chemopreventive agent in overcoming diseases like cancer which are mediated by free radicals.

  14. Structural basis for alpha fetoprotein-mediated inhibition of caspase-3 activity in hepatocellular carcinoma cells.

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    Lin, Bo; Zhu, Mingyue; Wang, Wenting; Li, Wei; Dong, Xu; Chen, Yi; Lu, Yan; Guo, Junli; Li, Mengsen

    2017-10-01

    Alpha-fetoprotein (AFP) is an early serum growth factor in the foetal liver development and hepatic carcinogenesis; However, the precise biological role of cytoplasmic AFP remains elusive. Although we recently demonstrated that cytoplasmic AFP might interact with caspase-3 and inhibit the signal transduction of apoptosis in human hepatocellular carcinoma (HCC) cells, the details of this interaction are not clear. To reveal the molecular relationship between AFP and caspase-3, we performed molecular docking, co-immunoprecipitation (Co-IP), laser confocal microscopy, site-directed mutagenesis and functional experiments to analyse the key amino acid residues in the binding site of caspase-3. The results of Co-IP, laser confocal microscopy and functional analyses were consistent with the computational model. We also used the model to explain why AFP cannot bind to caspase-8. These results provide the molecular basis for the AFP-mediated inhibition of caspase-3 activity in HCC cells. Altogether, we found that AFP interacts with caspase-3 through precise amino acids, namely loop-4 residues Glu-248, Asp-253 and His-257. The results further demonstrated that AFP plays a critical role in the inhibition of the apoptotic signal transduction that mediated by caspase-3. Thus, AFP might represent a novel biotarget for the therapy of HCC patients. © 2017 UICC.

  15. {sup 18}F-fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment

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    Sung, Pil Soo; Yang, Keungmo; Hwang, Seawon; Song, Myeong Jun; Jang, Jeong Won; Choi, Jong Young; Yoon, Seung Kew; Bae, Si Hyun [The Catholic University of Korea, Division of Hepatology, Department of Internal Medicine, The Catholic University Liver Research Center, College of Medicine, Seoul (Korea, Republic of); Park, Hye Lim; Yoo, Ie Ryung [The Catholic University of Korea, Division of Nuclear Medicine, Department of Radiology, College of Medicine, Seoul (Korea, Republic of)

    2018-03-15

    Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed to evaluate the performance of {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG PET) for predicting tumour progression during sorafenib treatment. We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing {sup 18}F-FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured. Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio [HR] = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis. Pretreatment tumour metabolic activity assessed by {sup 18}F-FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment. (orig.)

  16. Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides.

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    Allred, Benjamin E; Rupert, Peter B; Gauny, Stacey S; An, Dahlia D; Ralston, Corie Y; Sturzbecher-Hoehne, Manuel; Strong, Roland K; Abergel, Rebecca J

    2015-08-18

    Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin-transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein-ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligand-based metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of two-stage biomimetic platforms for photoluminescence, separation, and transport applications.

  17. Butein activates p53 in hepatocellular carcinoma cells via blocking MDM2-mediated ubiquitination

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    Zhou Y

    2018-04-01

    Full Text Available Yuanfeng Zhou,1,2 Kuifeng Wang,2 Ni Zhou,2 Tingting Huang,2 Jiansheng Zhu,2 Jicheng Li1 1Institute of Cell Biology, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, People’s Republic of China Introduction: In this study, we aimed to investigate the effect of butein on p53 in hepatocellular carcinoma (HCC cells and the related molecular mechanisms by which p53 was activated. Methods: MTS assay and clonogenic survival assay were used to examine the antitumor activity of butein in vitro. Reporter gene assay was adopted to evaluate p53 transcriptional activity. Flow cytometry and western blotting were performed to study apoptosis induction and protein expression respectively. Xenograft model was applied to determine the in vivo efficacy and the expression of p53 in tumor tissue was detected by immunohistochemistry. Results: HCC cell proliferation and clonogenic survival were significantly inhibited after butein treatment. With the activation of cleaved-PARP and capsase-3, butein induced apoptosis in HCC cells in a dose-dependent manner. The transcriptional activity of p53 was substantially promoted by butein, and the expression of p53-targeted gene was increased accordingly. Mechanism studies demonstrated that the interaction between MDM2 and p53 was blocked by butein and MDM2-mediated p53 ubiquitination was substantially decreased. Short-hairpin RNA experiment results showed that the sensitivity of HCC cells to butein was substantially impaired after p53 was knocked down and butein-induced apoptosis was dramatically decreased. In vivo experiments validated substantial antitumor efficacy of butein against HepG2 xenograft growth, and the expression of p53 in butein-treated tumor tissue was significantly increased. Conclusion: Butein demonstrated potent antitumor activities in HCC by activating p53, and butein or its analogs had

  18. Caveolin-1 enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model

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    Yang Hui-ling

    2009-03-01

    Full Text Available Abstract Background Resveratrol (RES, an estrogen analog, is considered as a potential cancer chemo-preventive agent. However, it remains unclear how RES is transported into cells. In this study, we observed that Caveolin-1(CAV1 expression can increase the cytotoxic and pro-apoptotic activity of RES in a dose- and time-dependent manner both in vitro and in vivo in a Hepatocellular Carcinoma animal model. Methods High performance liquid chromatography (HPLC demonstrated that RES intra-cellular concentration is increased about 2-fold in cells stably expressing CAV1 or CAVM1 (a scaffolding domain (81-101AA-defective CAV1 mutant compared to the untransduced human Hepatoblastoma cell line (HepG2 or after transduction with the green fluorescent protein (GFP control vector. The increased intra-cellular transport of RES was abolished in cells stably expressing CAVM2 (a cholesterol shuttle domain (143-156AA-defective CAV1 mutant or CAVRNAi. In order to further characterize CAV1-dependent RES transport, we synthesized RES-dansyl chloride derivatives as fluorescent probes to visualize the transport process, which demonstrated a distribution consistent with that of CAV1 in HepG2 cells. Results In addition, RES endocytosis was not mediated by estrogen receptor (ER α and β, as suggested by lack of competitive inhibition by estrogen or Tamoxifen. Pathway analysis showed that RES can up-regulate the expression of endogenous CAV1; this activates further the MAPK pathway and caspase-3 expression. Discussion This study provides novel insights about the role played by CAV1 in modulating cellular sensitivity to RES through enhancement of its internalization and trafficking.

  19. Epidermal Growth Factor Enhances Cellular Uptake of Polystyrene Nanoparticles by Clathrin-Mediated Endocytosis.

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    Phuc, Le Thi Minh; Taniguchi, Akiyoshi

    2017-06-19

    The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies to assess the influence of cellular factors, such as growth factor responses, on the cellular uptake efficiency of nanoparticles. The aim of this study was to clarify the effects of epidermal growth factor (EGF) on the uptake efficiency of polystyrene nanoparticles (PS NPs) by A431 cells, a human carcinoma epithelial cell line. The results showed that EGF enhanced the uptake efficiency of A431 cells for PS NPs. In addition, inhibition and localization studies of PS NPs and EGF receptors (EGFRs) indicated that cellular uptake of PS NPs is related to the binding of EGF-EGFR complex and PS NPs. Different pathways are used to enter the cells depending on the presence or absence of EGF. In the presence of EGF, cellular uptake of PS NPs is via clathrin-mediated endocytosis, whereas, in the absence of EGF, uptake of PS NPs does not involve clathrin-mediated endocytosis. Our findings indicate that EGF enhances cellular uptake of PS NPs by clathrin-mediated endocytosis. This result could be important for developing safe nanoparticles and their safe use in medical applications.

  20. Epidermal Growth Factor Enhances Cellular Uptake of Polystyrene Nanoparticles by Clathrin-Mediated Endocytosis

    Directory of Open Access Journals (Sweden)

    Le Thi Minh Phuc

    2017-06-01

    Full Text Available The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies to assess the influence of cellular factors, such as growth factor responses, on the cellular uptake efficiency of nanoparticles. The aim of this study was to clarify the effects of epidermal growth factor (EGF on the uptake efficiency of polystyrene nanoparticles (PS NPs by A431 cells, a human carcinoma epithelial cell line. The results showed that EGF enhanced the uptake efficiency of A431 cells for PS NPs. In addition, inhibition and localization studies of PS NPs and EGF receptors (EGFRs indicated that cellular uptake of PS NPs is related to the binding of EGF–EGFR complex and PS NPs. Different pathways are used to enter the cells depending on the presence or absence of EGF. In the presence of EGF, cellular uptake of PS NPs is via clathrin-mediated endocytosis, whereas, in the absence of EGF, uptake of PS NPs does not involve clathrin-mediated endocytosis. Our findings indicate that EGF enhances cellular uptake of PS NPs by clathrin-mediated endocytosis. This result could be important for developing safe nanoparticles and their safe use in medical applications.

  1. TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells.

    Science.gov (United States)

    Li, Yang; Zhu, Danxi; Hou, Lidan; Hu, Bin; Xu, Min; Meng, Xiangjun

    2018-01-01

    Tribbles homolog 3 (TRB3), a type of pseudokinase that contains a consensus serine/threonine kinase catalytic core structure, is upregulated in hepatocellular carcinoma. However, the effect of TRB3 expression in hepatocellular carcinoma and the molecular mechanisms underlying TRB3-mediated effects on tumorigenesis in hepatocellular carcinoma have not been fully elucidated. The present study focused on the effect of TRB3 expression in MHCC97H hepatocellular carcinoma cells and investigated the underlying molecular mechanisms in MHCC97H cells. In the present study, it was revealed that TRB3 was significantly overexpressed in the MHCC97H hepatocellular carcinoma cell compared with L-02 normal hepatic cells. Under endoplasmic reticulum (ER) stress induced by thapsigargin and tunicamycin, the levels of TRB3, CCAAT/enhancer binding protein homologous protein (CHOP), protein kinase B (AKT) and phosphorylated (p)AKT expression were upregulated. Furthermore, when the expression of TRB3 was silenced by short hairpin (sh)RNA, the survival of MHCC97H hepatocellular carcinoma cells was increased. Notably, following transduction with lentiviral containing TRB3-shRNA, cell survival also increased after treatment with chemotherapy drug cisplatin. The present study demonstrated that knockdown of CHOP by shRNA was able to reduce TRB3 expression, and the knockdown of TRB3 markedly increased the level of pAKT. TRB3 was overexpressed in MHCC97H hepatocellular carcinoma cells, particularly under endoplasmic reticulum stress. Knockdown of TRB3 was able to increase cell survival. Therefore, TRB3 expression may induce apoptosis and reverse resistance to chemotherapy in MHCC97H hepatic carcinoma cells. The present study suggests that TRB3 is a key molecule that mediates the crosstalk between ER stress and AKT signal pathways. Furthermore, the present study may provide further insight into the cancer biology of hepatocellular carcinoma and the development of anticancer drugs targeting the ER

  2. Social Cognitive Mediators of Sociodemographic Differences in Colorectal Cancer Screening Uptake

    Directory of Open Access Journals (Sweden)

    Siu Hing Lo

    2015-01-01

    Full Text Available Background. This study examined if and how sociodemographic differences in colorectal cancer (CRC screening uptake can be explained by social cognitive factors. Methods. Face-to-face interviews were conducted with individuals aged 60–70 years (n=1309 living in England as part of a population-based omnibus survey. Results. There were differences in screening uptake by SES, marital status, ethnicity, and age but not by gender. Perceived barriers (stand. b=-0.40, p<0.001, social norms (stand. b=0.33, p<0.001, and screening knowledge (stand. b=0.17, p<0.001 had independent associations with uptake. SES differences in uptake were mediated through knowledge, social norms, and perceived barriers. Ethnic differences were mediated through knowledge. Differences in uptake by marital status were primarily mediated through social norms and to a lesser extent through knowledge. Age differences were largely unmediated, except for a small mediated effect via social norms. Conclusions. Sociodemographic differences in CRC screening uptake were largely mediated through social cognitive factors. Impact. Our findings suggest that multifaceted interventions might be needed to reduce socioeconomic inequalities. Ethnic differences might be reduced through improved screening knowledge. Normative interventions could emphasise screening as an activity endorsed by important others outside the immediate family to appeal to a wider audience.

  3. Silencing of Pokemon enhances caspase-dependent apoptosis via fas- and mitochondria-mediated pathways in hepatocellular carcinoma cells.

    Science.gov (United States)

    Zhang, Yu-Qin; Xiao, Chuan-Xing; Lin, Bi-Yun; Shi, Ying; Liu, Yun-Peng; Liu, Jing-Jing; Guleng, Bayasi; Ren, Jian-Lin

    2013-01-01

    The role of Pokemon (POK erythroid myeloid ontogenic actor), a recently identified POK transcription factor with proto-oncogenic activity, in hepatocellular carcinogenesis has only been assessed by a few studies. Our previous study revealed that Pokemon is overexpressed in hepatocellular carcinomas (HCC) and promotes HCC cell proliferation and migration via an AKT- and ERK- dependent manner. In the present study, we used the TUNEL assay and FACS analysis to demonstrate that oxaliplatin induced apoptosis was significantly increased in cells with silenced Pokemon. Western blots showed that p53 expression and phosphorylation were significantly increased in Pokemon defective cells, thereby initiating the mitochondria-mediated and death receptor-mediated apoptotic pathways. In the mitochondria-mediated pathway, expression of pro-apoptotic Bcl-2 family members (including Bad, Bid, Bim and Puma) as well as AIF was increased and decreasing the mitochondrial membrane potential resulted in cytochrome C released from mitochondrial in HepG2 si-Pokemon cells. In addition, upon oxaliplatin treatment of Pokemon-silenced cells, the FAS receptor, FADD and their downstream targets caspase-10 and caspase-8 were activated, causing increased release of caspase-8 active fragments p18 and p10. Increased activated caspase-8-mediated cleavage and activation of downstream effector caspases such as caspase-9 and caspase-3 was observed in HepG2 si-Pokemon cells as compared to control. Therefore, Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cells. Moreover, our findings suggest that Pokemon could be an attractive therapeutic target gene for human cancer therapy.

  4. Silencing of Pokemon enhances caspase-dependent apoptosis via fas- and mitochondria-mediated pathways in hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Yu-Qin Zhang

    Full Text Available The role of Pokemon (POK erythroid myeloid ontogenic actor, a recently identified POK transcription factor with proto-oncogenic activity, in hepatocellular carcinogenesis has only been assessed by a few studies. Our previous study revealed that Pokemon is overexpressed in hepatocellular carcinomas (HCC and promotes HCC cell proliferation and migration via an AKT- and ERK- dependent manner. In the present study, we used the TUNEL assay and FACS analysis to demonstrate that oxaliplatin induced apoptosis was significantly increased in cells with silenced Pokemon. Western blots showed that p53 expression and phosphorylation were significantly increased in Pokemon defective cells, thereby initiating the mitochondria-mediated and death receptor-mediated apoptotic pathways. In the mitochondria-mediated pathway, expression of pro-apoptotic Bcl-2 family members (including Bad, Bid, Bim and Puma as well as AIF was increased and decreasing the mitochondrial membrane potential resulted in cytochrome C released from mitochondrial in HepG2 si-Pokemon cells. In addition, upon oxaliplatin treatment of Pokemon-silenced cells, the FAS receptor, FADD and their downstream targets caspase-10 and caspase-8 were activated, causing increased release of caspase-8 active fragments p18 and p10. Increased activated caspase-8-mediated cleavage and activation of downstream effector caspases such as caspase-9 and caspase-3 was observed in HepG2 si-Pokemon cells as compared to control. Therefore, Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cells. Moreover, our findings suggest that Pokemon could be an attractive therapeutic target gene for human cancer therapy.

  5. Characterization of cesium uptake mediated by a potassium transport system of bacteria in a soil conditioner

    International Nuclear Information System (INIS)

    Zhang, Pengyao; Idota, Yoko; Yano, Kentaro; Negishi, Masayuki; Kawabata, Hideaki; Arakawa, Hiroshi; Ogihara, Takuo; Morimoto, Kaori; Tsuji, Akira

    2014-01-01

    We found that bacteria in a commercial soil conditioner sold in Ishinomaki, Miyagi, exhibited concentrative and saturable cesium ion (Cs + ) uptake in the natural range of pH and temperature. The concentration of intracellular Cs + could be condensed at least a few times higher compared with the outside medium of the cells. This uptake appeared to be mediated by a K + transport system, since Cs + uptake was dose-dependently inhibited by potassium ion (K + ). Eadie-Hofstee plot analysis indicated that the Cs + uptake involved a single saturable process. The maximum uptake amount (J max ) was the same in the presence and absence of K + , suggesting that Cs + and K + uptakes were competitive with respect to each other. These bacteria might be useful for bioremediation of cesium-contaminated soil. (author)

  6. Are metabolic signatures mediating the relationship between lifestyle factors and hepatocellular carcinoma risk?

    DEFF Research Database (Denmark)

    Assi, Nada; Thomas, Duncan C; Leitzman, Michael

    2018-01-01

    BACKGROUND: The "meeting-in-the-middle" (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case-control study of hepatocellular carcinoma (HCC) within EPIC where healthy lifestyle index (HLI) variables...

  7. Extracellular Electron Uptake: Among Autotrophs and Mediated by Surfaces

    DEFF Research Database (Denmark)

    Tremblay, Pier-Luc; Angenent, Largus T.; Zhang, Tian

    2017-01-01

    Autotrophic microbes can acquire electrons from solid donors such as steel, other microbial cells, or electrodes. Based on this feature, bioprocesses are being developed for the microbial electrosynthesis (MES) of useful products from the greenhouse gas CO2. Extracellular electron-transfer mechan......Autotrophic microbes can acquire electrons from solid donors such as steel, other microbial cells, or electrodes. Based on this feature, bioprocesses are being developed for the microbial electrosynthesis (MES) of useful products from the greenhouse gas CO2. Extracellular electron......; or (iii) mediator-generating enzymes detached from cells. This review explores the interactions of autotrophs with solid electron donors and their importance in nature and for biosustainable technologies....

  8. Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

    Science.gov (United States)

    Kraehling, Jan R.; Chidlow, John H.; Rajagopal, Chitra; Sugiyama, Michael G.; Fowler, Joseph W.; Lee, Monica Y.; Zhang, Xinbo; Ramírez, Cristina M.; Park, Eon Joo; Tao, Bo; Chen, Keyang; Kuruvilla, Leena; Larriveé, Bruno; Folta-Stogniew, Ewa; Ola, Roxana; Rotllan, Noemi; Zhou, Wenping; Nagle, Michael W.; Herz, Joachim; Williams, Kevin Jon; Eichmann, Anne; Lee, Warren L.; Fernández-Hernando, Carlos; Sessa, William C.

    2016-01-01

    In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL. PMID:27869117

  9. Phospholipase D1 mediates AMP-activated protein kinase signaling for glucose uptake.

    Directory of Open Access Journals (Sweden)

    Jong Hyun Kim

    2010-03-01

    Full Text Available Glucose homeostasis is maintained by a balance between hepatic glucose production and peripheral glucose utilization. In skeletal muscle cells, glucose utilization is primarily regulated by glucose uptake. Deprivation of cellular energy induces the activation of regulatory proteins and thus glucose uptake. AMP-activated protein kinase (AMPK is known to play a significant role in the regulation of energy balances. However, the mechanisms related to the AMPK-mediated control of glucose uptake have yet to be elucidated.Here, we found that AMPK-induced phospholipase D1 (PLD1 activation is required for (14C-glucose uptake in muscle cells under glucose deprivation conditions. PLD1 activity rather than PLD2 activity is significantly enhanced by glucose deprivation. AMPK-wild type (WT stimulates PLD activity, while AMPK-dominant negative (DN inhibits it. AMPK regulates PLD1 activity through phosphorylation of the Ser-505 and this phosphorylation is increased by the presence of AMP. Furthermore, PLD1-S505Q, a phosphorylation-deficient mutant, shows no changes in activity in response to glucose deprivation and does not show a significant increase in (14C-glucose uptake when compared to PLD1-WT. Taken together, these results suggest that phosphorylation of PLD1 is important for the regulation of (14C-glucose uptake. In addition, extracellular signal-regulated kinase (ERK is stimulated by AMPK-induced PLD1 activation through the formation of phosphatidic acid (PA, which is a product of PLD. An ERK pharmacological inhibitor, PD98059, and the PLD inhibitor, 1-BtOH, both attenuate (14C-glucose uptake in muscle cells. Finally, the extracellular stresses caused by glucose deprivation or aminoimidazole carboxamide ribonucleotide (AICAR; AMPK activator regulate (14C-glucose uptake and cell surface glucose transport (GLUT 4 through ERK stimulation by AMPK-mediated PLD1 activation.These results suggest that AMPK-mediated PLD1 activation is required for (14C

  10. TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling

    Directory of Open Access Journals (Sweden)

    Nigel Beaton

    2015-11-01

    Conclusions: Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans.

  11. Health-related quality of life in patients with hepatocellular carcinoma: the mediation effects of illness perceptions and coping.

    Science.gov (United States)

    Fan, Sheng-Yu; Eiser, Christine; Ho, Ming-Chih; Lin, Cheng-Yao

    2013-06-01

    The aims of this study were to explore health-related quality of life (HRQOL) in patients with hepatocellular carcinoma (HCC). We report the following: (1) differences in HRQOL between patients with HCC and the general population; (2) significant physical and psychological predictors of HRQOL; and (3) mediation effects of illness perceptions and coping on HRQOL. Patients with HCC (n = 286) from Taiwan completed standardized measures of HRQOL, illness perception (cognitive representations, emotional representations and illness comprehensibility) and coping (emotion-oriented and problem-orientation coping). Demographic and physical variables were also collected. Patients with HCC had worse global HRQOL, physical, role, cognitive and social functioning, but better emotional functioning than the general population. Physical variables and cognitive representation were significant predictors of global HRQOL, physical functioning and emotional functioning. Cognitive representation mediated the relationships between physical variables and global HRQOL, physical functioning and emotional functioning, but coping only mediated the relationship between cognitive representation and global HRQOL. The results suggest that physical variables have direct effects on global HRQOL and physical functioning, but there were also partial mediations through cognitive representation. The effect of physical variables on emotional functioning was mediated through cognitive and emotional representations. Patients with better performance status and positive illness perceptions tended to report better HRQOL, but those with negative illness perceptions and who used more emotion-oriented coping had worse HRQOL. Limitations of the work associated with use of theory and measures developed in Europe and the US are discussed, as are the clinical implications for patients with HCC. Copyright © 2012 John Wiley & Sons, Ltd.

  12. Intracellular cholesterol-binding proteins enhance HDL-mediated cholesterol uptake in cultured primary mouse hepatocytes.

    Science.gov (United States)

    Storey, Stephen M; McIntosh, Avery L; Huang, Huan; Landrock, Kerstin K; Martin, Gregory G; Landrock, Danilo; Payne, H Ross; Atshaves, Barbara P; Kier, Ann B; Schroeder, Friedhelm

    2012-04-15

    A major gap in our knowledge of rapid hepatic HDL cholesterol clearance is the role of key intracellular factors that influence this process. Although the reverse cholesterol transport pathway targets HDL to the liver for net elimination of free cholesterol from the body, molecular details governing cholesterol uptake into hepatocytes are not completely understood. Therefore, the effects of sterol carrier protein (SCP)-2 and liver fatty acid-binding protein (L-FABP), high-affinity cholesterol-binding proteins present in hepatocyte cytosol, on HDL-mediated free cholesterol uptake were examined using gene-targeted mouse models, cultured primary hepatocytes, and 22-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol). While SCP-2 overexpression enhanced NBD-cholesterol uptake, counterintuitively, SCP-2/SCP-x gene ablation also 1) enhanced the rapid molecular phase of free sterol uptake detectable in rate and maximal uptake of HDL free cholesterol and 2) differentially enhanced free cholesterol uptake mediated by the HDL3, rather than the HDL2, subfraction. The increased HDL free cholesterol uptake was not due to increased expression or distribution of the HDL receptor [scavenger receptor B1 (SRB1)], proteins regulating SRB1 [postsynaptic density protein (PSD-95)/Drosophila disk large tumor suppressor (dlg)/tight junction protein (ZO1) and 17-kDa membrane-associated protein], or other intracellular cholesterol trafficking proteins (steroidogenic acute response protein D, Niemann Pick C, and oxysterol-binding protein-related proteins). However, expression of L-FABP, the single most prevalent hepatic cytosolic protein that binds cholesterol, was upregulated twofold in SCP-2/SCP-x null hepatocytes. Double-immunogold electron microscopy detected L-FABP sufficiently close to SRB1 for direct interaction, similar to SCP-2. These data suggest a role for L-FABP in HDL cholesterol uptake, a finding confirmed with SCP-2/SCP-x/L-FABP null

  13. Arbuscular mycorrhizal fungi mediated uptake of 137Cs in leek and ryegrass

    International Nuclear Information System (INIS)

    Rosen, Klas; Weiliang, Zhong; Maertensson, Anna

    2005-01-01

    In a first experiment of soil contaminated with 137 Cs, inoculation with a mixture of arbuscular mycorrhizae enhanced the uptake of 137 Cs by leek under greenhouse conditions, while no effect on the uptake by ryegrass was observed. The mycorrhizal infection frequency in leek was independent of whether the 137 Cs-contaminated soil was inoculated with mycorrhizal spores or not. The lack of mycorrhizae-mediated uptake of 137 Cs in ryegrass could be due to the high root density, which was about four times that of leek, or due to a less well functioning mycorrhizal symbiosis than of leek. In a second experiment, ryegrass was grown for a period of four cuts. Additions of fungi enhanced 137 Cs uptake of all harvests, improved dry weight production in the first cut, and also improved the mycorrhizal infection frequencies in the roots. No differences were obtained between the two fungal inoculums investigated with respect to biomass production or 137 Cs uptake, but root colonization differed. We conclude that, under certain circumstances, mycorrhizae affect plant uptake of 137 Cs. There may be a potential for selecting fungal strains that stimulate 137 Cs accumulation in crops. The use of ryegrass seems to be rather ineffective for remediation of 137 Cs-contaminated soil

  14. Arbuscular mycorrhizal fungi mediated uptake of {sup 137}Cs in leek and ryegrass

    Energy Technology Data Exchange (ETDEWEB)

    Rosen, Klas; Weiliang, Zhong; Maertensson, Anna [Department of Soil Sciences, Swedish University of Agricultural Sciences P.O. Box 7014, SE-750 07 Uppsala (Sweden)

    2005-02-15

    In a first experiment of soil contaminated with {sup 137}Cs, inoculation with a mixture of arbuscular mycorrhizae enhanced the uptake of {sup 137}Cs by leek under greenhouse conditions, while no effect on the uptake by ryegrass was observed. The mycorrhizal infection frequency in leek was independent of whether the {sup 137}Cs-contaminated soil was inoculated with mycorrhizal spores or not. The lack of mycorrhizae-mediated uptake of {sup 137}Cs in ryegrass could be due to the high root density, which was about four times that of leek, or due to a less well functioning mycorrhizal symbiosis than of leek. In a second experiment, ryegrass was grown for a period of four cuts. Additions of fungi enhanced {sup 137}Cs uptake of all harvests, improved dry weight production in the first cut, and also improved the mycorrhizal infection frequencies in the roots. No differences were obtained between the two fungal inoculums investigated with respect to biomass production or {sup 137}Cs uptake, but root colonization differed. We conclude that, under certain circumstances, mycorrhizae affect plant uptake of {sup 137}Cs. There may be a potential for selecting fungal strains that stimulate {sup 137}Cs accumulation in crops. The use of ryegrass seems to be rather ineffective for remediation of {sup 137}Cs-contaminated soil.

  15. Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zuo, Chaohui, E-mail: zuochaohui@vip.sina.com [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Qiu, Xiaoxin [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Liu, Nianli; Yang, Darong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); Xia, Man [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL (United States); Liu, Jingshi [Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital & Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan Province (China); Wang, Xiaohong [Cancer Research Institute, University of South China, Hengyang, Hunan Province (China); and others

    2015-05-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. - Highlights: ●The cytotoxic effect of TRAIL on a developed HCC HLCZ01 cells infected with HBV. ●IFN-α and celecoxib induced apoptosis in HLCZ01 cells infected with HBV. ●The combined regime reduced the growth of xenotransplanted HCCs in nude mice model.

  16. Antagonizing SET augments the effects of radiotherapy in hepatocellular carcinoma through reactivating PP2A-mediated AKT downregulation.

    Science.gov (United States)

    Huang, Chao-Yuan; Hung, Man-Hsin; Shih, Chi-Ting; Hsieh, Feng-Shu; Kuo, Chiung-Wen; Tsai, Ming-Hsien; Chang, Shih-Shin; Hsiao, Yung-Jen; Chen, Li-Ju; Chao, Tzu-I; Chen, Kuen-Feng

    2018-06-18

    Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiotherapy (RT)-mediated anti-cancer effects has not yet been explored. Here, we investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assay, we found that RT-induced proliferative inhibition was critically associated with SET expression. Next, we tested a novel SET antagonist, EMQA, in combination with RT. We showed that additive use of EMQA significantly enhanced the effects of RT against HCC in vitro and in vivo. Notably, compared to mice receiving either RT or EMQA alone, the growth of PLC5 xenografted tumor in mice receiving RT plus EMQA was significantly reduced without compromising treatment tolerability. Furthermore, we proved that antagonizing SET to restore PP2A-mediated p-AKT downregulation was responsible for the synergism between EMQA and RT. Our data demonstrate a new oncogenic property of SET, and provide preclinical evidence that combining a SET antagonist and RT may be effective for treatment of HCC. Further investigation is warranted to validate the clinical relevance of this approach. The American Society for Pharmacology and Experimental Therapeutics.

  17. The value of paradoxical uptake of hepatocellular carcinoma on the hepatobiliary phase of gadoxetic acid-enhanced liver magnetic resonance imaging for the prediction of lipiodol uptake after transcatheter arterial chemoembolization

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jeong Woo, E-mail: pridebio@naver.com [Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Lee, Chang Hee, E-mail: chlee86@korea.ac.kr [Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Park, Yang Shin, E-mail: pys797979@naver.com [Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Seo, Tae Seok, E-mail: g1q1papa@korea.ac.kr [Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Song, Myung Gyu, E-mail: acube808@naver.com [Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Kim, Ji Hoon, E-mail: kjhhepar@naver.com [Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Kim, Kyeong Ah, E-mail: kahkim@korea.ac.kr [Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Park, Cheol Min, E-mail: radpic@hanmail.net [Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of)

    2017-04-15

    Highlights: • HCC{sub para} shows more frequent initial compact lipiodol uptake after TACE than HCC{sub def}. • HCC{sub para} demonstrates less frequent early local recurrence after TACE. • HCC{sub para} has larger mean size, lower AER, and more frequent capsule appearance. - Abstract: Purpose: To compare the response to transcatheter arterial chemoembolization (TACE) between hepatocellular carcinoma (HCC) with paradoxical uptake on the hepatobiliary phase (HBP) (HCC{sub para}) and HCC with defect on the HBP (HCC{sub def}), and to identify some imaging features that can differentiate between two groups. Materials and methods: Ninety-three HCCs from 54 patients who underwent gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) prior to TACE were included. HCCs were classified into two groups according to the signal intensity (SI) on the HBP: HCC{sub para} and HCC{sub def}. Using post-TACE computed tomography (CT) as a reference standard, initial compact lipiodol uptake was assessed and compared between groups. The arterial enhancement ratio (AER), SI ratios of the arterial phase and HBP, and presence of the capsule appearance were compared between groups. After initial response, local tumor recurrence within 6 and 18 months was evaluated based on follow-up CT or MRI. Results: Fifteen HCC{sub para} and 78 HCC{sub def} were included. Compared to HCC{sub def}, HCC{sub para} showed more frequent initial compact lipiodol uptake (p = 0.009), larger mean size (p = 0.019), lower AER (p = 0.005), higher SI ratio of the HBP (p < 0.0001), and more frequent capsule appearance (p < 0.0001). Local tumor recurrence rate within 6 months was also significantly lower in HCC{sub para} than in HCC{sub def} (p = 0.008). Conclusion: Despite larger size and lower AER, HCC{sub para} showed more frequent initial compact lipiodol uptake and lower early local recurrence rate after TACE than did HCC{sub def}.

  18. Diagnostic pharmaco-scintigraphy with hepatic intra-arterial technetium-99m macroaggregated albumin in the determination of tumour to non-tumour uptake ratio in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Lau, W.Y.; Leung, T.W.T.; Chan, M.; Leung, N.W.Y.; Metreweli, C.; Li, A.K.C.

    1994-01-01

    Between October 1990 and March 1993, 124 patients with hepatocellular carcinoma (HCC) underwent diagnostic pharmaco-scintigraphy with hepatic intraarterial technetium-99m macroaggregated albumin (TcMAA) to determine the tumorous to non-tumorous liver tissue uptake ratio (T/N ratio). There were 110 males and 14 females. Ages ranged from 16 to 73 with a median of 55 years. The range of T/N ratio was 0.7 to 19.3 with a median of 3.8. 12 patients with inoperable HCC were subsequently selected by predetermined criteria to undergo treatment with hepatic intraarterial yttrium-90 microspheres and the T/N ratios in these patients were validated by beta probe dosimetry and liquid scintillation count of multiple liver biopsies. The T/N ratio determined by preoperative diagnostic TcMAA scan corrected well with intraoperative beta probe dosimetry, with coefficient of correlation r = 0.82. Preoperative TcMAA scan also correlated well with liquid scintillation count of biopsy specimens. (author)

  19. miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect

    Directory of Open Access Journals (Sweden)

    Liu W

    2018-03-01

    Full Text Available Wenpeng Liu,1,* Lei Kang,2,* Juqiang Han,3 Yadong Wang,1 Chuan Shen,1 Zhifeng Yan,4 Yanhong Tai,5 Caiyan Zhao1 1Department of Infectious Diseases, Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China; 2Department of Nuclear Medicine, Peking University First Hospital, Beijing, China; 3Institute of Liver Disease, Beijing Military General Hospital, Beijing, China; 4Department of Gynecology and Obstetrics, PLA General Hospital, Beijing, China; 5Department of Pathology, Hospital of PLA, Beijing, China *These authors contributed equally to this work Background: Insulin-like growth factor-1 receptor (IGF-1R is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Materials and methods: Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. Results: In this study, we demonstrate that by directly targeting the 3’-UTR (3’-untranslated regions of IGF-1R, microRNA-342-3p (miR-342-3p suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation

  20. miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect.

    Science.gov (United States)

    Liu, Wenpeng; Kang, Lei; Han, Juqiang; Wang, Yadong; Shen, Chuan; Yan, Zhifeng; Tai, Yanhong; Zhao, Caiyan

    2018-01-01

    Insulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. In this study, we demonstrate that by directly targeting the 3'-UTR (3'-untranslated regions) of IGF-1R, microRNA-342-3p (miR-342-3p) suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation, ATP production, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in hepatoma cells. Importantly, glycolysis regulated by miR-342-3p is critical for its regulating HCC growth both in vitro and in vivo. Our findings provide clues regarding the role of miR-342-3p as a tumor suppressor in liver cancer mainly through the inhibition of IGF-1R. Targeting IGF-1R by miR-342-3p could be a potential therapeutic strategy in liver cancer.

  1. Phosphate Uptake from Phytate Due to Hyphae-Mediated Phytase Activity by Arbuscular Mycorrhizal Maize.

    Science.gov (United States)

    Wang, Xin-Xin; Hoffland, Ellis; Feng, Gu; Kuyper, Thomas W

    2017-01-01

    Phytate is the most abundant form of soil organic phosphorus (P). Increased P nutrition of arbuscular mycorrhizal plants derived from phytate has been repeatedly reported. Earlier studies assessed acid phosphatase rather than phytase as an indication of mycorrhizal fungi-mediated phytate use. We investigated the effect of mycorrhizal hyphae-mediated phytase activity on P uptake by maize. Two maize ( Zea mays L.) cultivars, non-inoculated or inoculated with the arbuscular mycorrhizal fungi Funneliformis mosseae or Claroideoglomus etunicatum , were grown for 45 days in two-compartment rhizoboxes, containing a root compartment and a hyphal compartment. The soil in the hyphal compartment was supplemented with 20, 100, and 200 mg P kg -1 soil as calcium phytate. We measured activity of phytase and acid phosphatase in the hyphal compartment, hyphal length density, P uptake, and plant biomass. Our results showed: (1) phytate addition increased phytase and acid phosphatase activity, and resulted in larger P uptake and plant biomass; (2) increases in P uptake and biomass were correlated with phytase activity but not with acid phosphatase activity; (3) lower phytate addition rate increased, but higher addition rate decreased hyphal length density. We conclude that P from phytate can be taken up by arbuscular mycorrhizal plants and that phytase plays a more important role in mineralizing phytate than acid phosphatase.

  2. Lysosomal membrane protein SIDT2 mediates the direct uptake of DNA by lysosomes.

    Science.gov (United States)

    Aizawa, Shu; Contu, Viorica Raluca; Fujiwara, Yuuki; Hase, Katsunori; Kikuchi, Hisae; Kabuta, Chihana; Wada, Keiji; Kabuta, Tomohiro

    2017-01-02

    Lysosomes degrade macromolecules such as proteins and nucleic acids. We previously identified 2 novel types of autophagy, RNautophagy and DNautophagy, where lysosomes directly take up RNA and DNA, in an ATP-dependent manner, for degradation. We have also reported that SIDT2 (SID1 transmembrane family, member 2), an ortholog of the Caenorhabditis elegans putative RNA transporter SID-1 (systemic RNA interference defective-1), mediates RNA translocation during RNautophagy. In this addendum, we report that SIDT2 also mediates DNA translocation in the process of DNautophagy. These findings help elucidate the mechanisms underlying the direct uptake of nucleic acids by lysosomes and the physiological functions of DNautophagy.

  3. Polymer-Mediated Delivery of siRNAs to Hepatocellular Carcinoma: Variables Affecting Specificity and Effectiveness

    Directory of Open Access Journals (Sweden)

    Rossella Farra

    2018-03-01

    Full Text Available Despite the advances in anticancer therapies, their effectiveness for many human tumors is still far from being optimal. Significant improvements in treatment efficacy can come from the enhancement of drug specificity. This goal may be achieved by combining the use of therapeutic molecules with tumor specific effects and delivery carriers with tumor targeting ability. In this regard, nucleic acid-based drug (NABD and particularly small interfering RNAs (siRNAs, are attractive molecules due to the possibility to be engineered to target specific tumor genes. On the other hand, polymeric-based delivery systems are emerging as versatile carriers to generate tumor-targeted delivery systems. Here we will focus on the most recent findings in the selection of siRNA/polymeric targeted delivery systems for hepatocellular carcinoma (HCC, a human tumor for which currently available therapeutic approaches are poorly effective. In addition, we will discuss the most attracting and, in our opinion, promising siRNA-polymer combinations for HCC in relation to the biological features of HCC tissue. Attention will be also put on the mathematical description of the mechanisms ruling siRNA-carrier delivery, this being an important aspect to improve effectiveness reducing the experimental work.

  4. Pokemon siRNA Delivery Mediated by RGD-Modified HBV Core Protein Suppressed the Growth of Hepatocellular Carcinoma.

    Science.gov (United States)

    Kong, Jing; Liu, Xiaoping; Jia, Jianbo; Wu, Jinsheng; Wu, Ning; Chen, Jun; Fang, Fang

    2015-10-01

    Hepatocellular carcinoma (HCC) is a deadly human malignant tumor that is among the most common cancers in the world, especially in Asia. Hepatitis B virus (HBV) infection has been well established as a high risk factor for hepatic malignance. Studies have shown that Pokemon is a master oncogene for HCC growth, suggesting it as an ideal therapeutic target. However, efficient delivery system is still lacking for Pokemon targeting treatment. In this study, we used core proteins of HBV, which is modified with RGD peptides, to construct a biomimetic vector for the delivery of Pokemon siRNAs (namely, RGD-HBc-Pokemon siRNA). Quantitative PCR and Western blot assays revealed that RGD-HBc-Pokemon siRNA possessed the highest efficiency of Pokemon suppression in HCC cells. In vitro experiments further indicated that RGD-HBc-Pokemon-siRNA exerted a higher tumor suppressor activity on HCC cell lines, evidenced by reduced proliferation and attenuated invasiveness, than Pokemon-siRNA or RGD-HBc alone. Finally, animal studies demonstrated that RGD-HBc-Pokemon siRNA suppressed the growth of HCC xenografts in mice by a greater extent than Pokemon-siRNA or RGD-HBc alone. Based on the above results, Pokemon siRNA delivery mediated by RGD-modified HBV core protein was shown to be an effective strategy of HCC gene therapy.

  5. Nanocurcumin-Mediated Down-Regulation of Telomerase Via Stimulating TGFβ1 Signaling Pathway in Hepatocellular Carcinoma Cells

    Science.gov (United States)

    Shariati, Molood; Hajigholami, Samira; Veisi Malekshahi, Ziba; Entezari, Maliheh; Bodaghabadi, Narges; Sadeghizadeh, Majid

    2017-10-10

    Curcumin, extracted from turmeric, represents enormous potential to serve as an anticancer agent. Telomerase is viewed as a prominent molecular target of curcumin, and Transforming growth factor-β1 (TGFβ1) has proven to be a major inhibitory signaling pathway for telomerase activity. In the current study, we aimed to explore suppressive effects of nanocurcumin on telomerase expression through TGFβ1 pathway in a hepatocellular carcinoma cell line (Huh7). MTT assay was used to determine the effect of nonocurcumin on viability of Huh7 cells. RT-PCR was used to analyze the gene expression patterns. MTT assay revealed that nanocurcumin acts in a dose- and time-dependent manner to diminish the cell viability. RT-PCR analysis indicated that nanocurcumin results in augmentation of TGFβ1 72 hours post treatment and leads to the reduction of telomerase expression 48 and 72 hours post exposure. Also, up-regulation of Smad3 and E2F1 and down-regulation of Smad7 confirmed the effect of nanocurcumin on intermediate components of TGFβ1 pathway. Furthermore, transfection of the proximal promoter of telomerase triggered a significant reduction in luciferase activity. The data from the present study lead us to develop a deeper understanding of the mechanisms underlying nanocurcumin-mediated regulation of telomerase expression, thereby presenting a new perspective to the landscape of using nanocurcumin as a cancer-oriented therapeutic agent.

  6. Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist-mediated CD10 expression.

    Science.gov (United States)

    Chien, Ming-Hsien; Ho, Yung-Chuan; Yang, Shun-Fa; Yang, Yi-Chieh; Lai, Szu-Yu; Chen, Wan-Shen; Chen, Ming-Jenn; Yeh, Chao-Bin

    2018-02-26

    Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially, in eastern Asia, and its prognosis is poor once metastasis occurs. Niclosamide, a US Food and Drug Administration-approved antihelmintic drug, was shown to inhibit the growth of various cancers including HCC, but the effect of niclosamide on cell motility and the underlying mechanism have not yet been completely defined. The present study demonstrated that niclosamide, at 0-40 nM, concentration-dependently inhibited wound closure and the migratory/invasive capacities of human Huh7 and SK-Hep-1 HCC cells without exhibiting cytotoxicity. A protease array analysis showed that CD10 was dramatically downregulated in Huh7 cells after niclosamide treatment. Western blot and flow cytometric assays further demonstrated that CD10 expression was concentration-dependently downregulated in Huh7 and SK-Hep-1 cells after niclosamide treatment. Mechanistic investigations found that niclosamide suppressed Twist-mediated CD10 transactivation. Moreover, knockdown of CD10 expression by CD10 small interfering RNA in HCC cells suppressed cell migratory/invasive abilities and overexpression of CD10 relieved the migration inhibition induced by niclosamide. Taken together, our results indicated that niclosamide could be a potential agent for inhibiting metastasis of HCC, and CD10 is an important target of niclosamide for suppressing the motility of HCC cells. © 2018 Wiley Periodicals, Inc.

  7. Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans

    International Nuclear Information System (INIS)

    Baron, A.D.; Brechtel, G.; Wallace, P.; Edelman, S.V.

    1988-01-01

    In vivo glucose uptake can occur via two mechanisms, namely, insulin-mediated glucose uptake (IMGU) and non-insulin-mediated glucose uptake (NIMGU). Although the principal tissue sites for IMGU are skeletal muscle, the tissue sites for NIMGU at a given serum glucose concentration are not known. To examine this issue, rates of whole body glucose uptake (Rd) were measured at basal and during glucose clamp studies performed at euglycemia (approximately 90 mg/dl) and hyperglycemia (approximately 220 mg/dl) in six lean healthy men. Studies were performed during hyperinsulinemia (approximately 70 microU/ml) and during somatostatin-induced insulinopenia to measure IMGU and NIMGU, respectively. During each study, leg glucose balance (arteriovenous catheter technique) was also measured. With this approach, rates of whole body skeletal muscle IMGU and NIMGU can be estimated, and the difference between overall Rd and skeletal muscle glucose uptake represents non-skeletal muscle Rd. The results indicate that approximately 20% of basal Rd is into skeletal muscle. During insulinopenia approximately 86% of body NIMGU occurs in non-skeletal muscle tissues at euglycemia. When hyperglycemia was created, whole body NIMGU increased from 128 +/- 6 to 213 +/- 18 mg/min (P less than 0.01); NIMGU into non-skeletal muscle tissues was 134 +/- 11 and 111 +/- 6 mg/min at hyperglycemia and euglycemia, respectively, P = NS. Therefore, virtually all the hyperglycemia induced increment in NIMGU occurred in skeletal muscle. During hyperinsulinemia, IMGU in skeletal muscle represented 75 and 95% of body Rd, at euglycemia and hyperglycemia, respectively

  8. Radioiodine uptake of undifferentiated thyroid cancer cells by adenovirus-mediated Na+/ I- symporter gene transfer

    Energy Technology Data Exchange (ETDEWEB)

    So, Y.; Lee, Y. J.; Shin, J. H.; Oh, H. J.; Chung, J. K.; Lee, M. C.; Cho, B. Y. [College of Medicine, Univ. of Seoul National, Seoul (Korea, Republic of); Lee, K. H. [Samsung Medical Center, Seoul (Korea, Republic of)

    2003-07-01

    To increase radioiodine uptake on undifferentiated thyroid cancer cell (ARO cells) by adenovirus-mediated human Na+/I- symporter (hNIS) gene transfer. Recombinant adenovirus Ad-hNIS was manufactured successfully. After transfecting Ad-hNIS on ARO cells, in vitro I-125 uptake and efflux studies were performed. For in vivo studies, 1.510'8 p.f.u. (50 1) of Ad-hNIS was injected into xenograft ARO tumors on the R thigh of BALB/c nu/nu mice (n=12), and same amount of normal saline was injected into xenograft ARO tumors on the L thigh. Two, 3, 4 and 6 days after intratumoral injection of Ad-hNIS, I-131 images (3 mice per day) were taken and xenograft tumors on both thighs were all excised. Total RNA was extracted from each tumor tissue and RT-PCR was performed to confirm the hNIS expression of Ad-hNIS injected xenograft ARO tumors. I-125 uptake of Ad-hNIS transfected ARO cells was increased up to 233 folds at 120 minutes in vitro. I-125 efflux study revealed rapid washout of I-125 from Ad-hNIS transfected ARO cells. On dynamic image, I-131 uptake of Ad-hNIS injected ARO tumor was continuously increased until 60 minutes. Mean count ratios of xenograft ARO tumors (R/L) of 60 minutes I-131 images at 2, 3, 4 and 6 days after Ad-hNIS injection were 2.85, 2.54, 2.31, and 2.18, each. On RT-PCR, hNIS expression of Ad-hNIS transfected ARO xenograft tumors was confirmed. Radioiodine uptake was successfully increased in ARO cells by adenovirus-mediated hNIs gene transfer both in vitro and in vivo.

  9. Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Song Zhang

    Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

  10. Promoter hypermethylation mediated downregulation of FBP1 in human hepatocellular carcinoma and colon cancer.

    Directory of Open Access Journals (Sweden)

    Mingquan Chen

    Full Text Available FBP1, fructose-1,6-bisphosphatase-1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. The mechanism that it functions to antagonize glycolysis and was epigenetically inactivated through NF-kappaB pathway in gastric cancer has been reported. However, its role in the liver carcinogenesis still remains unknown. Here, we investigated the expression and DNA methylation of FBP1 in primary HCC and colon tumor. FBP1 was lowly expressed in 80% (8/10 human hepatocellular carcinoma, 66.7% (6/9 liver cancer cell lines and 100% (6/6 colon cancer cell lines, but was higher in paired adjacent non-tumor tissues and immortalized normal cell lines, which was well correlated with its promoter methylation status. Methylation was further detected in primary HCCs, gastric and colon tumor tissues, but none or occasionally in paired adjacent non-tumor tissues. Detailed methylation analysis of 29 CpG sites at a 327-bp promoter region by bisulfite genomic sequencing confirmed its methylation. FBP1 silencing could be reversed by chemical demethylation treatment with 5-aza-2'-deoxycytidine (Aza, indicating direct epigenetic silencing. Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest. Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS generation. In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer. FBP1 appears to be a functional tumor suppressor involved in the liver and colon carcinogenesis.

  11. HBV-specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell-mediated antitumor immunity.

    Science.gov (United States)

    Meng, Fanzhi; Zhen, Shoumei; Song, Bin

    2017-08-01

    In East Asia and sub-Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell-based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV-specific CD4 + cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV-specific cytotoxic CD4 + and CD8 + T cells were identified by HBV peptide pool stimulation. We found that in HBV-induced hepatocellular carcinoma patients, the HBV-specific cytotoxic CD4 + T cells and cytotoxic CD8 + T cells were present at similar numbers. But compared to the CD8 + cytotoxic T cells, the CD4 + cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4 + T cells suppressed the cytotoxicity mediated by CD8 + T cells, even when CD4 + CD25 + regulator T cells were absent. Interestingly, we found that interleukin 10 (IL-10)-secreting Tr1 cells were enriched in the cytotoxic CD4 + T cells. Neutralization of IL-10 abrogated the suppression of CD8 + T cells by CD4 + CD25 - T cells. Neither the frequency nor the absolute number of HBV-specific CD4 + cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV-related hepatocellular carcinoma, CD4 + T cell-mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties. © 2017 APMIS. Published by John Wiley & Sons Ltd.

  12. Characterization of GABA/sub A/ receptor-mediated 36chloride uptake in rat brain synaptoneurosomes

    International Nuclear Information System (INIS)

    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-01-01

    γ-Aminobutyric acid (GABA) receptor-mediated 36 chloride ( 36 Cl - ) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36 Cl - uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated 36 Cl - uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated 36 Cl - uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br - >Cl - ≥NO 3 - >I - ≥SCN - >>C 3 H 5 OO - ≥ClO 4 - >F - , consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl - channel. 43 references, 4 figures, 3 tables

  13. Receptor-mediated uptake of low density lipoprotein stimulates bile acid synthesis by cultured rat hepatocytes

    International Nuclear Information System (INIS)

    Junker, L.H.; Davis, R.A.

    1989-01-01

    The cellular mechanisms responsible for the lipoprotein-mediated stimulation of bile acid synthesis in cultured rat hepatocytes were investigated. Adding 280 micrograms/ml of cholesterol in the form of human or rat low density lipoprotein (LDL) to the culture medium increased bile acid synthesis by 1.8- and 1.6-fold, respectively. As a result of the uptake of LDL, the synthesis of [14C]cholesterol from [2-14C]acetate was decreased and cellular cholesteryl ester mass was increased. Further studies demonstrated that rat apoE-free LDL and apoE-rich high density lipoprotein (HDL) both stimulated bile acid synthesis 1.5-fold, as well as inhibited the formation of [14C]cholesterol from [2-14C]acetate. Reductive methylation of LDL blocked the inhibition of cholesterol synthesis, as well as the stimulation of bile acid synthesis, suggesting that these processes require receptor-mediated uptake. To identify the receptors responsible, competitive binding studies using 125I-labeled apoE-free LDL and 125I-labeled apoE-rich HDL were performed. Both apoE-free LDL and apoE-rich HDL displayed an equal ability to compete for binding of the other, suggesting that a receptor or a group of receptors that recognizes both apolipoproteins is involved. Additional studies show that hepatocytes from cholestyramine-treated rats displayed 2.2- and 3.4-fold increases in the binding of apoE-free LDL and apoE-rich HDL, respectively. These data show for the first time that receptor-mediated uptake of LDL by the liver is intimately linked to processes activating bile acid synthesis

  14. Uptake of apoptotic leukocytes by synovial lining macrophages inhibits immune complex-mediated arthritis.

    Science.gov (United States)

    van Lent, P L; Licht, R; Dijkman, H; Holthuysen, A E; Berden, J H; van den Berg, W B

    2001-11-01

    Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimental immune complex-mediated arthritis (ICA). During joint inflammation, many leukocytes undergo apoptosis, and removal of leukocytes by SLMs may regulate resolution of inflammation. In this study we investigated binding and uptake of apoptotic leukocytes by SLMs and its impact on the onset of murine experimental arthritis. We used an in vitro model to evaluate phagocytosis of apoptotic cells on chemotaxis. Phagocytosis of apoptotic thymocytes resulted in a significant decrease (58%) of chemotactic activity for polymorphonuclear neutrophils (PMNs). If apoptotic cells were injected directly into a normal murine knee joint, SLMs resulted in a prominent uptake of cells. After ICA induction, electron micrographs showed that apoptotic leukocytes were evidently present in SLMs on days 1 and 2. Injection of apoptotic leukocytes into the knee joint 1 h before induction of ICA significantly inhibited PMN infiltration into the knee joint at 24 h (61% decrease). This study indicates that uptake of apoptotic leukocytes by SLM reduces chemotactic activity and inhibits the onset of experimental arthritis. These findings indicate an important mechanism in the resolution of joint inflammation.

  15. Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

    Science.gov (United States)

    2016-01-01

    Mycobacterium tuberculosis requires iron for normal growth but faces a limitation of the metal ion due to its low solubility at biological pH and the withholding of iron by the mammalian host. The pathogen expresses the Fe3+-specific siderophores mycobactin and carboxymycobactin to chelate the metal ion from insoluble iron and the host proteins transferrin, lactoferrin, and ferritin. Siderophore-mediated iron uptake is essential for the survival of M. tuberculosis, as knockout mutants, which were defective in siderophore synthesis or uptake, failed to survive in low-iron medium and inside macrophages. But as excess iron is toxic due to its catalytic role in the generation of free radicals, regulation of iron uptake is necessary to maintain optimal levels of intracellular iron. The focus of this review is to present a comprehensive overview of iron homeostasis in M. tuberculosis that is discussed in the context of mycobactin biosynthesis, transport of iron across the mycobacterial cell envelope, and storage of excess iron. The clinical significance of the serum iron status and the expression of the iron-regulated protein HupB in tuberculosis (TB) patients is presented here, highlighting the potential of HupB as a marker, notably in extrapulmonary TB cases. PMID:27402628

  16. Cysteine- and glutathione-mediated uptake of lead and cadmium into Zea mays and Brassica napus roots

    International Nuclear Information System (INIS)

    Vadas, Timothy M.; Ahner, Beth A.

    2009-01-01

    This study examines a new mechanism for the uptake of Pb and Cd into Brassica napus and Zea mays roots. During hydroponic experiments, the uptake of Pb and Cd was enhanced in the presence of cysteine and glutathione, whereas no or very low uptake was observed in EDTA and penicillamine controls. Uptake rates were also enhanced after pre-exposure to cysteine or glutathione and inhibited in the presence of vanadate, suggesting a biological mechanism of uptake. Increasing concentrations of glutathione in solution resulted in decreasing Pb uptake rates, indicating competition for transport between free-glutathione and Pb-glutathione species. Pb uptake in the presence of increasing cysteine concentrations resulted in decreased uptake initially but linearly increasing uptake at higher concentrations. Experimentation showed concentration dependent Pb uptake rates. We speculate that there are specific transporters for these thiol ligands and describe what barriers remain for application of this novel transport mechanism in chelator-assisted phytoremediation. - Cysteine and glutathione mediate the transport of lead and cadmium into plant roots.

  17. Cysteine- and glutathione-mediated uptake of lead and cadmium into Zea mays and Brassica napus roots

    Energy Technology Data Exchange (ETDEWEB)

    Vadas, Timothy M., E-mail: tvadas@umbc.ed [Department of Biological and Environmental Engineering, Cornell University, 320 Riley-Robb Hall, Ithaca, NY 14853 (United States); Ahner, Beth A., E-mail: baa7@cornell.ed [Department of Biological and Environmental Engineering, Cornell University, 320 Riley-Robb Hall, Ithaca, NY 14853 (United States)

    2009-08-15

    This study examines a new mechanism for the uptake of Pb and Cd into Brassica napus and Zea mays roots. During hydroponic experiments, the uptake of Pb and Cd was enhanced in the presence of cysteine and glutathione, whereas no or very low uptake was observed in EDTA and penicillamine controls. Uptake rates were also enhanced after pre-exposure to cysteine or glutathione and inhibited in the presence of vanadate, suggesting a biological mechanism of uptake. Increasing concentrations of glutathione in solution resulted in decreasing Pb uptake rates, indicating competition for transport between free-glutathione and Pb-glutathione species. Pb uptake in the presence of increasing cysteine concentrations resulted in decreased uptake initially but linearly increasing uptake at higher concentrations. Experimentation showed concentration dependent Pb uptake rates. We speculate that there are specific transporters for these thiol ligands and describe what barriers remain for application of this novel transport mechanism in chelator-assisted phytoremediation. - Cysteine and glutathione mediate the transport of lead and cadmium into plant roots.

  18. Inhibition of calcium uptake during hypoxia in developing zebrafish is mediated by hypoxia-inducible factor.

    Science.gov (United States)

    Kwong, Raymond W M; Kumai, Yusuke; Tzaneva, Velislava; Azzi, Estelle; Hochhold, Nina; Robertson, Cayleih; Pelster, Bernd; Perry, Steve F

    2016-12-15

    The present study investigated the potential role of hypoxia-inducible factor (HIF) in calcium homeostasis in developing zebrafish (Danio rerio). It was demonstrated that zebrafish raised in hypoxic water (30 mmHg; control, 155 mmHg P O 2 ) until 4 days post-fertilization exhibited a substantial reduction in whole-body Ca 2+ levels and Ca 2+ uptake. Ca 2+ uptake in hypoxia-treated fish did not return to pre-hypoxia (control) levels within 2 h of transfer back to normoxic water. Results from real-time PCR showed that hypoxia decreased the whole-body mRNA expression levels of the epithelial Ca 2+ channel (ecac), but not plasma membrane Ca 2+ -ATPase (pmca2) or Na + /Ca 2+ -exchanger (ncx1b). Whole-mount in situ hybridization revealed that the number of ecac-expressing ionocytes was reduced in fish raised in hypoxic water. These findings suggested that hypoxic treatment suppressed the expression of ecac, thereby reducing Ca 2+ influx. To further evaluate the potential mechanisms for the effects of hypoxia on Ca 2+ regulation, a functional gene knockdown approach was employed to prevent the expression of HIF-1αb during hypoxic treatment. Consistent with a role for HIF-1αb in regulating Ca 2+ balance during hypoxia, the results demonstrated that the reduction of Ca 2+ uptake associated with hypoxic exposure was not observed in fish experiencing HIF-1αb knockdown. Additionally, the effects of hypoxia on reducing the number of ecac-expressing ionocytes was less pronounced in HIF-1αb-deficient fish. Overall, the current study revealed that hypoxic exposure inhibited Ca 2+ uptake in developing zebrafish, probably owing to HIF-1αb-mediated suppression of ecac expression. © 2016. Published by The Company of Biologists Ltd.

  19. Environmental and cortisol-mediated control of Ca(2+) uptake in tilapia (Oreochromis mossambicus).

    Science.gov (United States)

    Lin, Chia-Hao; Kuan, Wei-Chun; Liao, Bo-Kai; Deng, Ang-Ni; Tseng, Deng-Yu; Hwang, Pung-Pung

    2016-04-01

    Ca(2+) is a vital element for many physiological processes in vertebrates, including teleosts, which live in aquatic environments and acquire Ca(2+) from their surroundings. Ionocytes within the adult gills or larval skin are critical sites for transcellular Ca(2+) uptake in teleosts. The ionocytes of zebrafish were found to contain transcellular Ca(2+) transporters, epithelial Ca(2+) channel (ECaC), plasma membrane Ca(2+)-ATPase 2 (PMCA2), and Na(+)/Ca(2+) exchanger 1b (NCX1b), providing information about the molecular mechanism of transcellular Ca(2+) transports mediated by ionocytes in fish. However, more evidence is required to establish whether or not a similar mechanism of transcellular Ca(2+) transport also exists in others teleosts. In the present study, ecac, pmca2, and ncx1 were found to be expressed in the branchial ionocytes of tilapia, thereby providing further support for the mechanism of transcellular Ca(2+) transport through ionocytes previously proposed for zebrafish. In addition, we also reveal that low Ca(2+) water treatment of tilapia stimulates Ca(2+) uptake and expression of ecac and cyp11b (the latter encodes a cortisol-synthesis enzyme). Treatment of tilapia with exogenous cortisol (20 mg/l) enhanced both Ca(2+) influx and ecac expression. Therefore, increased cyp11b expression is suggested to enhance Ca(2+) uptake capacity in tilapia exposed to low Ca(2+) water. Furthermore, the application of cortisol receptor antagonists revealed that cortisol may regulate Ca(2+) uptake through glucocorticoid and/or mineralocorticoid receptor (GR and/or MR) in tilapia. Taken together, the data suggest that cortisol may activate GR and/or MR to execute its hypercalcemic action by stimulating ecac expression in tilapia.

  20. Quantitative therapy response assessment by volumetric iodine-uptake measurement: Initial experience in patients with advanced hepatocellular carcinoma treated with sorafenib

    International Nuclear Information System (INIS)

    Dai, Xu; Schlemmer, Heinz-Peter; Schmidt, Bernhard; Höh, Karolin; Xu, Ke; Ganten, Tom M.; Ganten, Maria-Katharina

    2013-01-01

    Objectives: To investigate the volumetric iodine-uptake (VIU) changes by dual-energy CT (DECT) in assessing the response to sorafenib treated hepatocellular carcinoma (HCC) patients, compared with AASLD (American Association for the Study of Liver Diseases) and Choi criteria. Materials and methods: Fifteen patients with HCC receiving sorafenib, monitored with contrast-enhanced DECT scans at baseline and a minimum of one follow-up (8–12 weeks) were retrospectively evaluated. 30 target lesions in total were analyzed for tumor response according to VIU and adapted Choi criteria and compared with the standard AASLD. Results: According to AASLD criteria, 67% target lesions showed disease control: partial response (PR) in 3% and stable disease (SD) in 63%. 33% lesions progressed (PD). Disease control rate presented by VIU (60%) was similar to AASLD (67%) and Choi (63%) (P > 0.05). For disease control group, change in mean VIU was from 149.5 ± 338.3 mg to 108.5 ± 284.1 mg (decreased 19.1 ± 42.9%); and for progressive disease group, change in mean VIU was from 163.7 ± 346.7 mg to 263.9 ± 537.2 mg (increased 230.5 ± 253.1%). Compared to AASLD (PR, 3%), VIU and Choi presented more PR (33% and 30%, respectively) in disease control group (P < 0.05). VIU has moderate consistency with both AASLD (kappa = 0.714; P < 0.005) and Choi (kappa = 0.648; P < 0.005), while VIU showed a better consistency and correlation with AASLD (kappa = 0.714; P < 0.005; r = 0.666, P < 0.005) than Choi with AASLD (kappa = 0.634, P < 0.005; r = 0.102, P = 0.296). Conclusion: VIU measurements by DECT can evaluate the disease control consistent with the current standard AASLD. Measurements are semi-automatic and therefore easy and robust to apply. As VIU reflects vital tumor burden in HCC, it is likely to be an optimal tumor response biomarker in HCC

  1. HAb18G/CD147 regulates vinculin-mediated focal adhesion and cytoskeleton organization in cultured human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Qiang Liang

    Full Text Available Focal adhesions (FAs, integrin-mediated macromolecular complexes located at the cell membrane extracellular interface, have been shown to regulate cell adhesion and migration. Our previous studies have indicated that HAb18G/CD147 (CD147 is involved in cytoskeleton reorganization and FA formation in human hepatocellular carcinoma (HCC cells. However, the precise mechanisms underlying these processes remain unclear. In the current study, we determined that CD147 was involved in vinculin-mediated FA focal adhesion formation in HCC cells. We also found that deletion of CD147 led to reduced vinculin-mediated FA areas (P<0.0001, length/width ratios (P<0.0001, and mean intensities (P<0.0001. CD147 promoted lamellipodia formation by localizing Arp2/3 to the leading edge of the cell. Deletion of CD147 significantly reduced the fluorescence (t1/2 recovery times (22.7±3.3 s of vinculin-mediated focal adhesions (P<0.0001. In cell-spreading assays, CD147 was found to be essential for dynamic focal adhesion enlargement and disassembly. Furthermore, the current data showed that CD147 reduced tyrosine phosphorylation in vinculin-mediated focal adhesions, and enhanced the accumulation of the acidic phospholipid phosphatidylinositol-4, 5-bisphosphate (PIP2. Together, these results revealed that CD147 is involved in vinculin-mediated focal adhesion formation, which subsequently promotes cytoskeleton reorganization to facilitate invasion and migration of human HCC cells.

  2. Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells.

    Science.gov (United States)

    Wang, Bin; Chen, Linfeng; Ni, Zhenhong; Dai, Xufang; Qin, Liyan; Wu, Yaran; Li, Xinzhe; Xu, Liang; Lian, Jiqin; He, Fengtian

    2014-11-01

    Natural BH3-memitic (-)-gossypol shows promising antitumor efficacy in several kinds of cancer. However, our previous studies have demonstrated that protective autophagy decreases the drug sensitivities of Bcl-2 inhibitors in hepatocellular carcinoma (HCC) cells. In the present study, we are the first to report that Hsp90 inhibitor 17-AAG enhanced (-)-gossypol-induced apoptosis via suppressing (-)-gossypol-triggered protective autophagy and Mcl-1 accumulation. The suppression effect of 17-AAG on autophagy was mediated by inhibiting ERK-mediated Bcl-2 phosphorylation while was not related to Beclin1 or LC3 protein instability. Meanwhile, 17-AAG downregulated (-)-gossypol-triggered Mcl-1 accumulation by suppressing Mcl-1(Thr163) phosphorylation and promoting protein degradation. Collectively, our study indicates that Hsp90 plays an important role in tumor maintenance and inhibition of Hsp90 may become a new strategy for sensitizing Bcl-2-targeted chemotherapies in HCC cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms.

    Directory of Open Access Journals (Sweden)

    Farnaz Fekri

    Full Text Available Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR, and distinct mechanism(s that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may

  4. Autophagy‑mediated adaptation of hepatocellular carcinoma cells to hypoxia‑mimicking conditions constitutes an attractive therapeutic target.

    Science.gov (United States)

    Owada, Satoshi; Endo, Hitoshi; Shida, Yukari; Okada, Chisa; Ito, Kanako; Nezu, Takahiro; Tatemichi, Masayuki

    2018-04-01

    Hepatocellular carcinoma has extremely poor prognosis. In cancerous liver tissues, aberrant proliferation of cancer cells leads to the creation of an area where an immature vascular network is formed. Since oxygen is supplied to cancer tissues through the bloodstream, a part of the tumor is exposed to hypoxic conditions. As hypoxia is known to severely reduce the effectiveness of existing anticancer agents, novel valid therapeutic targets must be identified for the treatment of hepatocellular carcinoma. Generally, autophagy has been reported to play an important role in the adaptation of cancer cells to hypoxia. However, the exact role and significance of this process vary depending on the cancer type, requiring detailed analysis in individual primary tumors and cell lines. In the present study, we examined autophagy induced by cobalt chloride, a hypoxia‑mimicking agent, in hepatocellular carcinoma cells with the aim to evaluate the validity of this process as a potential therapeutic target. We observed that treatment with cobalt chloride induced autophagy, including the intracellular quality control mechanism, in an AMPK‑dependent manner. Furthermore, treatment with autophagy inhibitors (bafilomycin and LY294002) resulted in significant, highly‑selective cytotoxicity and apoptosis activation under hypoxia‑mimicking conditions. The knockdown of AMPK also revealed significant cytotoxicity in hypoxia‑mimicking conditions. These results clearly demonstrated that autophagy, especially mitophagy, was induced by the AMPK pathway when hepatocellular carcinoma cells were subjected to hypoxic conditions and played an important role in the adaptation of these cells to such conditions. Thus, autophagy may constitute an attractive therapeutic target for the treatment of hepatocellular carcinoma.

  5. Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharide-sensitive carrier-mediated process

    Science.gov (United States)

    Ghosal, Abhisek; Sekar, Thillai V.

    2014-01-01

    Biotin is essential for the normal function of pancreatic beta cells. These cells obtain biotin from their surroundings via transport across their cell membrane. Little is known about the uptake mechanism involved, how it is regulated, and how it is affected by internal and external factors. We addressed these issues using the mouse-derived pancreatic beta-TC-6 cells and freshly isolated mouse and human primary pancreatic beta cells as models. The results showed biotin uptake by pancreatic beta-TC-6 cells occurs via a Na+-dependent, carrier-mediated process, that is sensitive to desthiobiotin, as well as to pantothenic acid and lipoate; the process is also saturable as a function of concentration (apparent Km = 22.24 ± 5.5 μM). These cells express the sodium-dependent multivitamin transporter (SMVT), whose knockdown (with doxycycline-inducible shRNA) led to a sever inhibition in biotin uptake. Similarly, uptake of biotin by mouse and human primary pancreatic islets is Na+-dependent and carrier-mediated, and both cell types express SMVT. Biotin uptake by pancreatic beta-TC-6 cells is also adaptively regulated (via transcriptional mechanism) by extracellular substrate level. Chronic treatment of pancreatic beta-TC-6 cells with bacterial lipopolysaccharides (LPS) leads to inhibition in biotin uptake. This inhibition is mediated via a Toll-Like receptor 4-mediated process and involves a decrease in membrane expression of SMVT. These findings show, for the first time, that pancreatic beta cells/islets take up biotin via a specific and regulated carrier-mediated process, and that the process is sensitive to the effect of LPS. PMID:24904078

  6. Kinetics of cellular uptake of viruses and nanoparticles via clathrin-mediated endocytosis

    Science.gov (United States)

    Banerjee, Anand; Berezhkovskii, Alexander; Nossal, Ralph

    2016-02-01

    Several viruses exploit clathrin-mediated endocytosis to gain entry into host cells. This process is also used extensively in biomedical applications to deliver nanoparticles (NPs) to diseased cells. The internalization of these nano-objects is controlled by the assembly of a clathrin-containing protein coat on the cytoplasmic side of the plasma membrane, which drives the invagination of the membrane and the formation of a cargo-containing endocytic vesicle. Current theoretical models of receptor-mediated endocytosis of viruses and NPs do not explicitly take coat assembly into consideration. In this paper we study cellular uptake of viruses and NPs with a focus on coat assembly. We characterize the internalization process by the mean time between the binding of a particle to the membrane and its entry into the cell. Using a coarse-grained model which maps the stochastic dynamics of coat formation onto a one-dimensional random walk, we derive an analytical formula for this quantity. A study of the dependence of the mean internalization time on NP size shows that there is an upper bound above which this time becomes extremely large, and an optimal size at which it attains a minimum. Our estimates of these sizes compare well with experimental data. We also study the sensitivity of the obtained results on coat parameters to identify factors which significantly affect the internalization kinetics.

  7. Dual role for myosin II in GLUT4-mediated glucose uptake in 3T3-L1 adipocytes

    International Nuclear Information System (INIS)

    Fulcher, F. Kent; Smith, Bethany T.; Russ, Misty; Patel, Yashomati M.

    2008-01-01

    Insulin-stimulated glucose uptake requires the activation of several signaling pathways to mediate the translocation and fusion of GLUT4 vesicles to the plasma membrane. Our previous studies demonstrated that GLUT4-mediated glucose uptake is a myosin II-dependent process in adipocytes. The experiments described in this report are the first to show a dual role for the myosin IIA isoform specifically in regulating insulin-stimulated glucose uptake in adipocytes. We demonstrate that inhibition of MLCK but not RhoK results in impaired insulin-stimulated glucose uptake. Furthermore, our studies show that insulin specifically stimulates the phosphorylation of the RLC associated with the myosin IIA isoform via MLCK. In time course experiments, we determined that GLUT4 translocates to the plasma membrane prior to myosin IIA recruitment. We further show that recruitment of myosin IIA to the plasma membrane requires that myosin IIA be activated via phosphorylation of the RLC by MLCK. Our findings also reveal that myosin II is required for proper GLUT4-vesicle fusion at the plasma membrane. We show that once at the plasma membrane, myosin II is involved in regulating the intrinsic activity of GLUT4 after insulin stimulation. Collectively, our results are the first to reveal that myosin IIA plays a critical role in mediating insulin-stimulated glucose uptake in 3T3-LI adipocytes, via both GLUT4 vesicle fusion at the plasma membrane and GLUT4 activity

  8. Uptake of oleate by isolated rat adipocytes is mediated by a 40-kDa plasma membrane fatty acid binding protein closely related to that in liver and gut

    International Nuclear Information System (INIS)

    Schwieterman, W.; Sorrentino, D.; Potter, B.J.; Rand, J.; Kiang, C.L.; Stump, D.; Berk, P.D.

    1988-01-01

    A portion of the hepatocellular uptake of nonesterified long-chain fatty acids is mediated by a specific 40-kDa plasma membrane fatty acid binding protein, which has also been isolated from the gut. To investigate whether a similar transport process exists in other tissues with high transmembrane fatty acid fluxes, initial rates (V/sub O/) of [ 3 H]-oleate uptake into isolated rat adipocytes were studied as a function of the concentration of unbound [ 3 H]oleate in the medium. V/sub O/ reached a maximum as the concentration of unbound oleate was increased and was significantly inhibited both by phloretin and by prior incubation of the cells with Pronase. A rabbit antibody to the rat liver plasma membrane fatty acid binding protein inhibited adipocyte fatty acid uptake by up to 63% in dose-dependent fashion. Inhibition was noncompetitive; at an immunoglobulin concentration of 250 μg/ml V/sub max/ was reduced from 2480 /plus minus/ 160 to 1870 /plus minus/ 80 pmol/min per 5 /times/ 10 4 adipocytes, with no change in K/sub m/. A basic kDa adipocyte plasma membrane fatty acid binding protein, isolated from crude adipocyte plasma membrane fractions, reacted strongly in both agar gel diffusion and electrophoretic blots with the antibody raised against the corresponding hepatic plasma membrane protein. These data indicate that the uptake of oleate by rat adipocytes is mediated by a 40-kDa plasma membrane fatty acid binding protein closely related to that in liver and gut

  9. Adolescent Attitudes toward Influenza Vaccination and Vaccine Uptake in a School-Based Influenza Vaccination Intervention: A Mediation Analysis

    Science.gov (United States)

    Painter, Julia E.; Sales, Jessica M.; Pazol, Karen; Wingood, Gina M.; Windle, Michael; Orenstein, Walter A.; DiClemente, Ralph J.

    2011-01-01

    Background: School-based vaccination programs may provide an effective strategy to immunize adolescents against influenza. This study examined whether adolescent attitudes toward influenza vaccination mediated the relationship between receipt of a school-based influenza vaccination intervention and vaccine uptake. Methods: Participants were…

  10. Usage of adenovirus expressing thymidine kinase mediated hepatocellular damage for enabling mouse liver repopulation with allogenic or xenogenic hepatocytes.

    Directory of Open Access Journals (Sweden)

    Daniel Moreno

    Full Text Available It has been shown that the liver of immunodeficient mice can be efficiently repopulated with human hepatocytes when subjected to chronic hepatocellular damage. Mice with such chimeric livers represent useful reagents for medical and clinical studies. However all previously reported models of humanized livers are difficult to implement as they involve cross-breeding of immunodeficient mice with mice exhibiting genetic alterations causing sustained hepatic injury. In this paper we attempted to create chimeric livers by inducing persistent hepatocellular damage in immunodeficient Rag2(-/- γc(-/- mice using an adenovirus encoding herpes virus thymidine kinase (AdTk and two consecutive doses of ganciclovir (GCV. We found that this treatment resulted in hepatocellular damage persisting for at least 10 weeks and enabled efficient engraftment and proliferation within the liver of either human or allogenic hepatocytes. Interestingly, while the nodules generated from the transplanted mouse hepatocytes were well vascularized, the human hepatocytes experienced progressive depolarization and exhibited reduced numbers of murine endothelial cells inside the nodules. In conclusion, AdTk/GCV-induced liver damage licenses the liver of immunodeficient mice for allogenic and xenogenic hepatocyte repopulation. This approach represents a simple alternative strategy for chimeric liver generation using immunodeficient mice without additional genetic manipulation of the germ line.

  11. Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin.

    Science.gov (United States)

    Okuda, Yu; Kushida, Masahiko; Kikumoto, Hiroko; Nakamura, Yoshimasa; Higuchi, Hashihiro; Kawamura, Satoshi; Cohen, Samuel M; Lake, Brian G; Yamada, Tomoya

    2017-01-01

    High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 µM) and a major metabolite Z-CMCA (5-1,000 µM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative DNA synthesis in rat and human hepatocytes. However, while NaPB and momfluorothrin increased replicative DNA synthesis in rat hepatocytes, NaPB, momfluorothrin and Z-CMCA did not increase replicative DNA synthesis in human hepatocytes. NaPB, momfluorothrin and Z-CMCA increased CYP2B1/2 mRNA levels in rat hepatocytes. NaPB and momfluorothrin also increased CYP2B6 mRNA levels in human hepatocytes. Overall, while momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative DNA synthesis was not increased in human hepatocytes of chimeric mice treated with momfluorothrin or its close structural analogue metofluthrin. As human hepatocytes are refractory to the mitogenic effects of momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for momfluorothrin-induced rat liver tumor formation is not relevant for humans.

  12. Opioid receptor subtypes mediating the noise-induced decreases in high-affinity choline uptake in the rat brain.

    Science.gov (United States)

    Lai, H; Carino, M A

    1992-07-01

    Acute (20 min) exposure to 100-dB white noise elicits a naltrexone-sensitive decrease in sodium-dependent high-affinity choline uptake in the frontal cortex and hippocampus of the rat. In the present study, the subtypes of opioid receptors involved were investigated by pretreating rats with microinjection of specific opioid-receptor antagonists into the lateral cerebroventricle before noise exposure. We found that the noise-induced decrease in high-affinity choline uptake in the hippocampus was blocked by pretreatment with either mu-, delta-, or kappa-opioid-receptor antagonists, whereas the effect of noise on frontal cortical high-affinity choline uptake was blocked by a mu- and delta- but not by a kappa-antagonist. These data further confirm the role of endogenous opioids in mediating the effects of noise on central cholinergic activity and indicate that different neural mechanisms are involved in the effects of noise on the frontal cortical and hippocampal cholinergic systems.

  13. Further characterization of cadmium uptake by rat liver sinusoidal plasma membrane vesicles as a carrier mediated process

    International Nuclear Information System (INIS)

    Eastman, H.B.; Frazier, J.M.

    1990-01-01

    Previously we have reported that cadmium (Cd) transport by rat hepatic sinusoidal plasma membrane vesicles (SPMV's) occurs by both carrier mediated process and simple diffusion. This study was undertaken in order to further characterize the carrier mediated component of Cd transport as a carrier mediated process. Efflux of Cd from SPMV's was measured by first loading the vesicles with 1 μM Cd, containing 109 Cd (Amersham, 0.25 mCi/ml, carrier free) as a tracer, and then diluting the vesicles 1 to 5 into efflux buffer containing 0.25 M sucrose, 150 mM NaCl and 50 mM Tris/HCl (pH 7.4). Under standard conditions, no efflux of Cd from the vesicles was observed. However, the presence of 4mM CdCl 2 or 4.0% BSA in the efflux buffer was able to release 109 Cd from the vesicles. When the vesicles were lysed with 0.1% Triton X-100, approximately 75% of the internalized Cd could be released from the vesicles. Efflux of Cd from the vesicles was also determined to be a temperature dependent process. At 0 C the efflux of Cd from the vesicles, in the presence of a 4 mM CdCl 2 or 4.0% BSA chase, was blocked. The specificity of the carrier mediated component of Cd transport for Cd was investigated by determining whether other metals could compete for Cd uptake. Zinc was a competitive inhibitor of the carrier mediated component of Cd uptake while calcium had no effect on Cd uptake. Using this system, we have demonstrated that one component of Cd transport exhibits the basic characteristics of a carrier mediated process: saturation, reversibility, specificity and temperature dependence

  14. A multiple mediator analysis approach to quantify the effects of the ADH1B and ALDH2 genes on hepatocellular carcinoma risk.

    Science.gov (United States)

    Shih, Stephannie; Huang, Yen-Tsung; Yang, Hwai-I

    2018-06-01

    Previous work suggested a genetic component affecting the risk of hepatocellular carcinoma (HCC) and mediation analyses have elucidated potential indirect pathways of these genetic effects. Specifically, the effects of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase (ALDH2) genes on HCC risk vary based on alcohol consumption habits. However, alcohol consumption may not be the only mediator in the identified pathway: factors related to alcohol consumption may contribute to the same indirect pathway. Thus, we developed a multimediator model to quantify the genetic effects on HCC risk through sequential dichotomous mediators under the counterfactual framework. Our method provided a closed form formula for the mediation effects through different indirect paths, which requires no assumption for the rarity of outcome. In simulation studies of a finite sample, we presented the utility of the method with the variance of the effects estimated using the delta method and bootstrapping. We applied our method to data from participants in Taiwan (580 cases and 3,207 controls) and quantified the mediation effects of single nucleotide polymorphisms (SNPs) in the ADH1B and ALDH2 genes on HCC through alcohol consumption (yes/no) and high alanine transaminase (ALT) levels (greater than or equal to 45 U/L or below 45 U/L). Assuming a dominant risk model, we identified that the SNPs' effects through alcohol consumption is more significant than through ALT levels on HCC risk. This new method provides insight to the magnitude of various casual mechanisms as a closed form solution and can be readily applied in other genomic studies. © 2018 WILEY PERIODICALS, INC.

  15. Superparamagnetic poly(methyl methacrylate) nanoparticles surface modified with folic acid presenting cell uptake mediated by endocytosis

    Energy Technology Data Exchange (ETDEWEB)

    Feuser, Paulo Emilio [Federal University of Santa Catarina, Department of Chemical Engineering and Food Engineering (Brazil); Jacques, Amanda Virtuoso [Federal University of Santa Catarina, Department of Clinical Analyses (Brazil); Arévalo, Juan Marcelo Carpio; Rocha, Maria Eliane Merlin [Federal University of Paraná, Department of Biochemistry and Molecular Biology (Brazil); Santos-Silva, Maria Claudia dos [Federal University of Santa Catarina, Department of Clinical Analyses (Brazil); Sayer, Claudia; Araújo, Pedro H. Hermes de, E-mail: pedro.h.araujo@ufsc.br [Federal University of Santa Catarina, Department of Chemical Engineering and Food Engineering (Brazil)

    2016-04-15

    The encapsulation of superparamagnetic nanoparticles (MNPs) in polymeric nanoparticles (NPs) with modified surfaces can improve targeted delivery and induce cell death by hyperthermia. The goals of this study were to synthesize and characterize surface modified superparamagnetic poly(methyl methacrylate) with folic acid (FA) prepared by miniemulsion polymerization (MNPsPMMA-FA) and to evaluate their in vitro cytotoxicity and cellular uptake in non-tumor cells, murine fibroblast (L929) cells and tumor cells that overexpressed folate receptor (FR) β, and chronic myeloid leukemia cells in blast crisis (K562). Lastly, hemolysis assays were performed on human red blood cells. MNPsPMMA-FA presented an average mean diameter of 135 nm and a saturation magnetization (Ms) value of 37 emu/g of iron oxide, as well as superparamagnetic behavior. The MNPsPMMA-FA did not present cytotoxicity in L929 and K562 cells. Cellular uptake assays showed a higher uptake of MNPsPMMA-FA than MNPsPMMA in K562 cells when incubated at 37 °C. On the other hand, MNPsPMMA-FA showed a low uptake when endocytosis mechanisms were blocked at low temperature (4 °C), suggesting that the MNPsPMMA-FA uptake was mediated by endocytosis. High concentrations of MNPsPMMA-FA showed hemocompatibility when incubated for 24 h in human red blood cells. Therefore, our results suggest that these carrier systems can be an excellent alternative in targeted drug delivery via FR.

  16. Superparamagnetic poly(methyl methacrylate) nanoparticles surface modified with folic acid presenting cell uptake mediated by endocytosis

    International Nuclear Information System (INIS)

    Feuser, Paulo Emilio; Jacques, Amanda Virtuoso; Arévalo, Juan Marcelo Carpio; Rocha, Maria Eliane Merlin; Santos-Silva, Maria Claudia dos; Sayer, Claudia; Araújo, Pedro H. Hermes de

    2016-01-01

    The encapsulation of superparamagnetic nanoparticles (MNPs) in polymeric nanoparticles (NPs) with modified surfaces can improve targeted delivery and induce cell death by hyperthermia. The goals of this study were to synthesize and characterize surface modified superparamagnetic poly(methyl methacrylate) with folic acid (FA) prepared by miniemulsion polymerization (MNPsPMMA-FA) and to evaluate their in vitro cytotoxicity and cellular uptake in non-tumor cells, murine fibroblast (L929) cells and tumor cells that overexpressed folate receptor (FR) β, and chronic myeloid leukemia cells in blast crisis (K562). Lastly, hemolysis assays were performed on human red blood cells. MNPsPMMA-FA presented an average mean diameter of 135 nm and a saturation magnetization (Ms) value of 37 emu/g of iron oxide, as well as superparamagnetic behavior. The MNPsPMMA-FA did not present cytotoxicity in L929 and K562 cells. Cellular uptake assays showed a higher uptake of MNPsPMMA-FA than MNPsPMMA in K562 cells when incubated at 37 °C. On the other hand, MNPsPMMA-FA showed a low uptake when endocytosis mechanisms were blocked at low temperature (4 °C), suggesting that the MNPsPMMA-FA uptake was mediated by endocytosis. High concentrations of MNPsPMMA-FA showed hemocompatibility when incubated for 24 h in human red blood cells. Therefore, our results suggest that these carrier systems can be an excellent alternative in targeted drug delivery via FR.

  17. Superparamagnetic poly(methyl methacrylate) nanoparticles surface modified with folic acid presenting cell uptake mediated by endocytosis

    Science.gov (United States)

    Feuser, Paulo Emilio; Jacques, Amanda Virtuoso; Arévalo, Juan Marcelo Carpio; Rocha, Maria Eliane Merlin; dos Santos-Silva, Maria Claudia; Sayer, Claudia; de Araújo, Pedro H. Hermes

    2016-04-01

    The encapsulation of superparamagnetic nanoparticles (MNPs) in polymeric nanoparticles (NPs) with modified surfaces can improve targeted delivery and induce cell death by hyperthermia. The goals of this study were to synthesize and characterize surface modified superparamagnetic poly(methyl methacrylate) with folic acid (FA) prepared by miniemulsion polymerization (MNPsPMMA-FA) and to evaluate their in vitro cytotoxicity and cellular uptake in non-tumor cells, murine fibroblast (L929) cells and tumor cells that overexpressed folate receptor (FR) β, and chronic myeloid leukemia cells in blast crisis (K562). Lastly, hemolysis assays were performed on human red blood cells. MNPsPMMA-FA presented an average mean diameter of 135 nm and a saturation magnetization (Ms) value of 37 emu/g of iron oxide, as well as superparamagnetic behavior. The MNPsPMMA-FA did not present cytotoxicity in L929 and K562 cells. Cellular uptake assays showed a higher uptake of MNPsPMMA-FA than MNPsPMMA in K562 cells when incubated at 37 °C. On the other hand, MNPsPMMA-FA showed a low uptake when endocytosis mechanisms were blocked at low temperature (4 °C), suggesting that the MNPsPMMA-FA uptake was mediated by endocytosis. High concentrations of MNPsPMMA-FA showed hemocompatibility when incubated for 24 h in human red blood cells. Therefore, our results suggest that these carrier systems can be an excellent alternative in targeted drug delivery via FR.

  18. Siderophores mediate reduced and increased uptake of cadmium by Streptomyces tendae F4 and sunflower (Helianthus annuus), respectively.

    Science.gov (United States)

    Dimkpa, C O; Merten, D; Svatos, A; Büchel, G; Kothe, E

    2009-11-01

    As a toxic metal, cadmium (Cd) affects microbial and plant metabolic processes, thereby potentially reducing the efficiency of microbe or plant-mediated remediation of Cd-polluted soil. The role of siderophores produced by Streptomyces tendae F4 in the uptake of Cd by bacteria and plant was investigated to gain insight into the influence of siderophores on Cd availability to micro-organisms and plants. The bacterium was cultured under siderophore-inducing conditions in the presence of Cd. The kinetics of siderophore production and identification of the siderophores and their metal-bound forms were performed using electrospray ionization mass spectrometry. Inductively coupled plasma spectroscopy was used to measure iron (Fe) and Cd contents in the bacterium and in sunflower plant grown in Cd-amended soil. Siderophores significantly reduced the Cd uptake by the bacterium, while supplying it with iron. Bacterial culture filtrates containing three hydroxamate siderophores secreted by S. tendae F4 significantly promoted plant growth and enhanced uptake of Cd and Fe by the plant, relative to the control. Furthermore, application of siderophores caused slightly more Cd, but similar Fe uptake, compared with EDTA. Bioinoculation with Streptomyces caused a dramatic increase in plant Fe content, but resulted only in slight increase in plant Cd content. It is concluded that siderophores can help reduce toxic metal uptake in bacteria, while simultaneously facilitating the uptake of such metals by plants. Also, EDTA is not superior to hydroxamate siderophores in terms of metal solubilization for plant uptake. The study showed that microbial processes could indirectly influence the availability and amount of toxic metals taken up from the rhizosphere of plants. Furthermore, although EDTA is used for chelator-enhanced phytoremediation, microbial siderophores would be ideal for this purpose.

  19. Downstream mechanisms of nitric oxide-mediated skeletal muscle glucose uptake during contraction.

    Science.gov (United States)

    Merry, Troy L; Lynch, Gordon S; McConell, Glenn K

    2010-12-01

    There is evidence that nitric oxide (NO) is required for the normal increases in skeletal muscle glucose uptake during contraction, but the mechanisms involved have not been elucidated. We examined whether NO regulates glucose uptake during skeletal muscle contractions via cGMP-dependent or cGMP-independent pathways. Isolated extensor digitorum longus (EDL) muscles from mice were stimulated to contract ex vivo, and potential NO signaling pathways were blocked by the addition of inhibitors to the incubation medium. Contraction increased (P contraction by ∼50% (P contraction; however, DTT attenuated (P contraction-stimulated glucose uptake (by 70%). NOS inhibition and antioxidant treatment reduced contraction-stimulated increases in protein S-glutathionylation and tyrosine nitration (P skeletal muscle glucose uptake during ex vivo contractions via a cGMP/PKG-, AMPK-, and p38 MAPK-independent pathway. In addition, it appears that NO and ROS may regulate skeletal muscle glucose uptake during contraction through a similar pathway.

  20. Hepatocellular calcification

    DEFF Research Database (Denmark)

    Ladefoged, Claus; Frifelt, J J

    1987-01-01

    Autopsy of a twenty year old girl dying from complications of renal and cardiac failure demonstrated severe hepatocellular calcification, a rare finding. The pathogenesis is thought to be a combination of dystrophic calcification caused by severe centrilobular necrosis and metastatic calcificatio...

  1. miR2Pathway: A Novel Analytical Method to Discover MicroRNA-mediated Dysregulated Pathways Involved in Hepatocellular Carcinoma.

    Science.gov (United States)

    Li, Chaoxing; Dinu, Valentin

    2018-03-22

    MicroRNAs (miRNAs) are small, non-coding RNAs involved in the regulation of gene expression at a post-transcriptional level. Recent studies have shown miRNAs as key regulators of a variety of biological processes, such as proliferation, differentiation, apoptosis, metabolism, etc. Aberrantly expressed miRNAs influence individual gene expression level, but rewired miRNA-mRNA connections can influence the activity of biological pathways. Here, we define rewired miRNA-mRNA connections as the differential (rewiring) effects on the activity of biological pathways between hepatocellular carcinoma (HCC) and normal phenotypes. Our work presented here uses a PageRank-based approach to measure the degree of miRNA-mediated dysregulation of biological pathways between HCC and normal samples based on rewired miRNA-mRNA connections. In our study, we regard the degree of miRNA-mediated dysregulation of biological pathways as disease risk of biological pathways. Therefore, we propose a new method, miR2Pathway, to measure and rank the degree of miRNA-mediated dysregulation of biological pathways by measuring the total differential influence of miRNAs on the activity of pathways between HCC and normal states. miR2Pathway proposed here systematically shows the first evidence for a mechanism of biological pathways being dysregulated by rewired miRNA-mRNA connections, and provides new insight into exploring mechanisms behind HCC. Thus, miR2Pathway is a novel method to identify and rank miRNA-dysregulated pathways in HCC. Copyright © 2018. Published by Elsevier Inc.

  2. Are Metabolic Signatures Mediating the Relationship between Lifestyle Factors and Hepatocellular Carcinoma Risk? Results from a Nested Case-Control Study in EPIC.

    Science.gov (United States)

    Assi, Nada; Thomas, Duncan C; Leitzmann, Michael; Stepien, Magdalena; Chajès, Véronique; Philip, Thierry; Vineis, Paolo; Bamia, Christina; Boutron-Ruault, Marie-Christine; Sandanger, Torkjel M; Molinuevo, Amaia; Boshuizen, Hendriek C; Sundkvist, Anneli; Kühn, Tilman; Travis, Ruth C; Overvad, Kim; Riboli, Elio; Gunter, Marc J; Scalbert, Augustin; Jenab, Mazda; Ferrari, Pietro; Viallon, Vivian

    2018-05-01

    Background: The "meeting-in-the-middle" (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case-control study of hepatocellular carcinoma (HCC) within European Prospective Investigation into Cancer and Nutrition (EPIC), where healthy lifestyle index (HLI) variables were related to targeted serum metabolites. Methods: Lifestyle and targeted metabolomic data were available from 147 incident HCC cases and 147 matched controls. Partial least squares analysis related 7 lifestyle variables from a modified HLI to a set of 132 serum-measured metabolites and a liver function score. Mediation analysis evaluated whether metabolic profiles mediated the relationship between each lifestyle exposure and HCC risk. Results: Exposure-related metabolic signatures were identified. Particularly, the body mass index (BMI)-associated metabolic component was positively related to glutamic acid, tyrosine, PC aaC38:3, and liver function score and negatively to lysoPC aC17:0 and aC18:2. The lifetime alcohol-specific signature had negative loadings on sphingomyelins (SM C16:1, C18:1, SM(OH) C14:1, C16:1 and C22:2). Both exposures were associated with increased HCC with total effects (TE) = 1.23 (95% confidence interval = 0.93-1.62) and 1.40 (1.14-1.72), respectively, for BMI and alcohol consumption. Both metabolic signatures mediated the association between BMI and lifetime alcohol consumption and HCC with natural indirect effects, respectively, equal to 1.56 (1.24-1.96) and 1.09 (1.03-1.15), accounting for a proportion mediated of 100% and 24%. Conclusions: In a refined MITM framework, relevant metabolic signatures were identified as mediators in the relationship between lifestyle exposures and HCC risk. Impact: The understanding of the biological basis for the relationship between modifiable exposures and cancer would pave avenues for clinical and public health interventions on metabolic mediators

  3. The anti-hepatocellular carcinoma activity of Mel-P15 is mediated by natural killer cells.

    Science.gov (United States)

    Xu, Tao; Cui, Tongxing; Peng, Lipan; Kong, Shuai; Zou, Jianqiang; Tian, Xingsong

    2017-12-01

    Mel-P15 is a peptide derived from melittin, the main toxic component in the venom of the European honeybee Apis mellifera . In the present study, the antitumor effects of Mel-P15 and the underlying molecular mechanisms of these effects in vivo were investigated. Mel-P15 directly stimulated natural killer (NK) cell cytotoxicity in vitro , which was increased to 55.45% at a 4 µg/ml dose of Mel-P15. In the mouse liver cancer (H22) xenograft mice model, Mel-P15 suppressed tumor growth in vivo ; the tumor inhibitory rate was 61.15% following treatment with 2 mg/kg Mel-P15. In addition, the immune response was activated following Mel-P15 treatment. Mel-P15 treatment increased the spleen and thymus indices, promoted splenocyte proliferation, stimulated NK cytotoxicity and upregulated the secretion of cytokines, including interleukin-2, interferon-γ and tumor necrosis factor-α. In addition, the tumor inhibitory effect of Mel-P15 on BEL-7402-bearing nude mice was abrogated by the selective depletion of NK cells via the intraperitoneal injection of an anti-asialo GM-1 antibody. The results suggest that Mel-P15 inhibits tumor growth in vivo by promoting NK cell cytotoxicity. Mel-P15 may therefore be a potential immunotherapy candidate for the treatment of hepatocellular carcinoma.

  4. Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture

    DEFF Research Database (Denmark)

    Benrick, Anna; Kokosar, Milana; Hu, Min

    2017-01-01

    was higher after EA in controls and women with PCOS. Plasma serotonin levels and homovanillic acid, markers of vagal activity, decreased in both controls and patients with PCOS. Adipose tissue expression of pro-nerve growth factor (proNGF) decreased, and the mature NGF/proNGF ratio increased after EA in PCOS...... of EA increases whole-body glucose uptake by activation of the sympathetic and partly the parasympathetic nervous systems, which could have important clinical implications for the treatment of insulin resistance.-Benrick, A., Kokosar, M., Hu, M., Larsson, M., Maliqueo, M., Marcondes, R. R., Soligo, M......., Protto, V., Jerlhag, E., Sazonova, A., Behre, C. J., Højlund, K., Thorén, P., Stener-Victorin, E. Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture....

  5. The Nitric Oxide Prodrug JS-K Induces Ca(2+)-Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells.

    Science.gov (United States)

    Liu, Ling; Wang, Dongmei; Wang, Jiangang; Wang, Shuying

    2016-04-01

    Hepatocellular carcinoma is one of the most common and deadly forms of human malignancies. JS-K, O(2)-(2, 4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1, 2-diolate, has the ability to induce apoptosis of tumor cell lines. In the present study, JS-K inhibited the proliferation of HepG2 cells in a time- and concentration-dependent manner and significantly induced apoptosis. JS-K enhanced the ratio of Bax-to-Bcl-2, released of cytochrome c (Cyt c) from mitochondria and the activated caspase-9/3. JS-K caused an increasing cytosolic Ca(2+) and the loss of mitochondrial membrane potential. Carboxy-PTIO (a NO scavenger) and BAPTA-AM (an intracellular Ca(2+) chelator) significantly blocked an increasing cytosolic Ca(2+) in JS-K-induced HepG2 cells apoptosis, especially Carboxy-PTIO. Meanwhile, Carboxy-PTIO and BAPTA-AM treatment both attenuate JS-K-induced apoptosis through upregulation of Bcl-2, downregulation of Bax, reduction of Cyt c release from mitochondria to cytoplasm and inactivation of caspase-9/3. In summary, JS-K induced HepG2 cells apoptosis via Ca(2+)/caspase-3-mediated mitochondrial pathway. © 2015 Wiley Periodicals, Inc.

  6. An Evaluation on Transfection Efficiency of pHRE-Egr1-EGFP in Hepatocellular Carcinoma Cells Bel-7402 Mediated by PEI-MZF-NPs

    Directory of Open Access Journals (Sweden)

    Mei Lin

    2011-01-01

    Full Text Available To improve transfection and expression efficiency of target gene, especially under cancer anoxic microenvironment, we have developed pHRE-Egr1-EGFP/PEI-MZF-NPs nanosystem, in which pHRE-Egr1-EGFP, eukaryotic gene expression plasmid, is constructed by combining radiation promoter Egr1 with anoxia induction components (HRE, forming anoxic radiation double sensitive HRE/Egr1 promoter to activate reporter gene EGFP expression. MZF-NPs (Mn0.5 Zn0.5 Fe2O4 magnetic nanoparticles, obtained by coprecipitation method, are coated with cation poly(ethylenimine (PEI. We transferred pHRE-Egr1-EGFP into hepatocellular carcinoma Bel-7402 cells, using PEI-MZF-NPs as the carrier and tested some relevant efficacy. The results show that PEI-MZF-NPs have good DNA-binding ability, protection ability, release ability, little toxicity, and high transfection efficiency, obviously superior to those of the liposome method and electricity perforation method. Moreover, the expression level of EGFP gene induced by anoxia and radiation was significantly higher than that of single radiation activation. It is therefore concluded that HRE/Egr1 can induce and improve target gene expression efficiency in cancer anoxic microenvironment, and that PEI-MZF-NPs can be used as a novel nonviral gene vector which offers a viable approach to the mediated radiation gene therapy of cancer.

  7. C/EBPα Short-Activating RNA Suppresses Metastasis of Hepatocellular Carcinoma through Inhibiting EGFR/β-Catenin Signaling Mediated EMT.

    Directory of Open Access Journals (Sweden)

    Hongbo Huan

    Full Text Available Hepatocellular carcinoma is associated with high mortality, and tumor metastasis is an important reason for poor prognosis. However, metastasis has not been effectively prevented in clinical therapy and the mechanisms underlying metastasis have not been fully characterized. CCAAT/enhancer-binding protein-α (C/EBPα is a transcriptional regulator with an essential role in tumor metastasis. We used short-activating RNAs (saRNA to enhance expression of C/EBPα. Intravenous injection of C/EBPα-saRNA in a nude mouse liver orthotopic xenograft tumor model inhibited intrahepatic and distant metastasis. C/EBPα-saRNA-treated mice showed increased serum levels of albumin and decreased alanine aminotransferase (ALT, glutamic-oxalacetic transaminase (AST, indicating a role of C/EBPα in improving liver function. Migration and invasion were inhibited in hepatoma cell lines transfected with C/EBPα-saRNA. We also observed an inhibition of epithelial-mesenchymal transition (EMT and suppression of epidermal growth factor receptor (EGFR, EGFR phosphorylation, and β-catenin in C/EBPa-saRNA-transfected cells. Our results suggested that C/EBPα-saRNA successfully inhibited HCC metastasis by inhibiting EGFR/β-catenin signaling pathway mediated EMT in vitro and in vivo.

  8. Native low-density lipoprotein uptake by macrophage colony-stimulating factor-differentiated human macrophages is mediated by macropinocytosis and micropinocytosis.

    Science.gov (United States)

    Anzinger, Joshua J; Chang, Janet; Xu, Qing; Buono, Chiara; Li, Yifu; Leyva, Francisco J; Park, Bum-Chan; Greene, Lois E; Kruth, Howard S

    2010-10-01

    To examine the pinocytotic pathways mediating native low-density lipoprotein (LDL) uptake by human macrophage colony-stimulating factor-differentiated macrophages (the predominant macrophage phenotype in human atherosclerotic plaques). We identified the kinase inhibitor SU6656 and the Rho GTPase inhibitor toxin B as inhibitors of macrophage fluid-phase pinocytosis of LDL. Assessment of macropinocytosis by time-lapse microscopy revealed that both drugs almost completely inhibited macropinocytosis, although LDL uptake and cholesterol accumulation by macrophages were only partially inhibited (approximately 40%) by these agents. Therefore, we investigated the role of micropinocytosis in mediating LDL uptake in macrophages and identified bafilomycin A1 as an additional partial inhibitor (approximately 40%) of macrophage LDL uptake that targeted micropinocytosis. When macrophages were incubated with both bafilomycin A1 and SU6656, inhibition of LDL uptake was additive (reaching 80%), showing that these inhibitors target different pathways. Microscopic analysis of fluid-phase uptake pathways in these macrophages confirmed that LDL uptake occurs through both macropinocytosis and micropinocytosis. Our findings show that human macrophage colony-stimulating factor-differentiated macrophages take up native LDL by macropinocytosis and micropinocytosis, underscoring the importance of both pathways in mediating LDL uptake by these cells.

  9. Vesicular (liposomal and nanoparticulated delivery of curcumin: a comparative study on carbon tetrachloride–mediated oxidative hepatocellular damage in rat model

    Directory of Open Access Journals (Sweden)

    Choudhury ST

    2016-05-01

    -induced oxidative stress–mediated hepatocellular damage and thereby can be considered as an effective therapeutic strategy. Keywords: reactive oxygen species, mitochondria, apoptosis, antioxidants, histopathology, Western blot

  10. Contraction-mediated glucose uptake is increased in men with impaired glucose tolerance

    DEFF Research Database (Denmark)

    Skov-Jensen, Camilla; Skovbro, Mette; Flint, Anne

    2007-01-01

    stimulation alone and with superimposed exercise. Patients with type 2 diabetes, subjects with impaired glucose tolerance (IGT), healthy controls, and endurance-trained subjects were studied. The groups were matched for age and lean body mass (LBM), and differed in peak oxygen uptake (VO2 peak), body fat...

  11. How Does Silicon Mediate Plant Water Uptake and Loss Under Water Deficiency?

    Directory of Open Access Journals (Sweden)

    Daoqian Chen

    2018-03-01

    Full Text Available In plants, water deficiency can result from a deficit of water from the soil, an obstacle to the uptake of water or the excess water loss; in these cases, the similar consequence is the limitation of plant growth and crop yield. Silicon (Si has been widely reported to alleviate the plant water status and water balance under variant stress conditions in both monocot and dicot plants, especially under drought and salt stresses. However, the underlying mechanism is unclear. In addition to the regulation of leaf transpiration, recently, Si application was found to be involved in the adjustment of root hydraulic conductance by up-regulating aquaporin gene expression and concentrating K in the xylem sap. Therefore, this review discusses the potential effects of Si on both leaf transpiration and root water absorption, especially focusing on how Si modulates the root hydraulic conductance. A growing number of studies support the conclusion that Si application improves plant water status by increasing root water uptake, rather than by decreasing their water loss under conditions of water deficiency. The enhancement of plant water uptake by Si is achievable through the activation of osmotic adjustment, improving aquaporin activity and increasing the root/shoot ratio. The underlying mechanisms of the Si on improving plant water uptake under water deficiency conditions are discussed.

  12. Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy.

    Science.gov (United States)

    Chatterjee, Moumita; Ben-Josef, Edgar; Robb, Ryan; Vedaie, Marall; Seum, Star; Thirumoorthy, Krishnan; Palanichamy, Kamalakannan; Harbrecht, Matthew; Chakravarti, Arnab; Williams, Terence M

    2017-11-01

    Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for transendothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above that respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells, where Cav-1 was attenuated, exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs. Cancer Res; 77(21); 5925-37. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. Earthworm-mediated synthesis of silver nanoparticles: A potent tool against hepatocellular carcinoma, Plasmodium falciparum parasites and malaria mosquitoes.

    Science.gov (United States)

    Jaganathan, Anitha; Murugan, Kadarkarai; Panneerselvam, Chellasamy; Madhiyazhagan, Pari; Dinesh, Devakumar; Vadivalagan, Chithravel; Aziz, Al Thabiani; Chandramohan, Balamurugan; Suresh, Udaiyan; Rajaganesh, Rajapandian; Subramaniam, Jayapal; Nicoletti, Marcello; Higuchi, Akon; Alarfaj, Abdullah A; Munusamy, Murugan A; Kumar, Suresh; Benelli, Giovanni

    2016-06-01

    The development of parasites and pathogens resistant to synthetic drugs highlighted the needing of novel, eco-friendly and effective control approaches. Recently, metal nanoparticles have been proposed as highly effective tools towards cancer cells and Plasmodium parasites. In this study, we synthesized silver nanoparticles (EW-AgNP) using Eudrilus eugeniae earthworms as reducing and stabilizing agents. EW-AgNP showed plasmon resonance reduction in UV-vis spectrophotometry, the functional groups involved in the reduction were studied by FTIR spectroscopy, while particle size and shape was analyzed by FESEM. The effect of EW-AgNP on in vitro HepG2 cell proliferation was measured using MTT assays. Apoptosis assessed by flow cytometry showed diminished endurance of HepG2 cells and cytotoxicity in a dose-dependent manner. EW-AgNP were toxic to Anopheles stephensi larvae and pupae, LC(50) were 4.8 ppm (I), 5.8 ppm (II), 6.9 ppm (III), 8.5 ppm (IV), and 15.5 ppm (pupae). The antiplasmodial activity of EW-AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. EW-AgNP IC(50) were 49.3 μg/ml (CQ-s) and 55.5 μg/ml (CQ-r), while chloroquine IC(50) were 81.5 μg/ml (CQ-s) and 86.5 μg/ml (CQ-r). EW-AgNP showed a valuable antibiotic potential against important pathogenic bacteria and fungi. Concerning non-target effects of EW-AgNP against mosquito natural enemies, the predation efficiency of the mosquitofish Gambusia affinis towards the II and II instar larvae of A. stephensi was 68.50% (II) and 47.00% (III), respectively. In EW-AgNP-contaminated environments, predation was boosted to 89.25% (II) and 70.75% (III), respectively. Overall, this research highlighted the EW-AgNP potential against hepatocellular carcinoma, Plasmodium parasites and mosquito vectors, with little detrimental effects on mosquito natural enemies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Human SR-BII mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Irina N Baranova

    Full Text Available Serum amyloid A (SAA is an acute phase protein with cytokine-like and chemotactic properties, that is markedly up-regulated during various inflammatory conditions. Several receptors, including FPRL-1, TLR2, TLR4, RAGE, class B scavenger receptors, SR-BI and CD36, have been identified as SAA receptors. This study provides new evidence that SR-BII, splice variant of SR-BI, could function as an SAA receptor mediating its uptake and pro-inflammatory signaling. The uptake of Alexa Fluor488 SAA was markedly (~3 fold increased in hSR-BII-expressing HeLa cells when compared with mock-transfected cells. The levels of SAA-induced interleukin-8 secretion by hSR-BII-expressing HEK293 cells were also significantly (~3-3.5 fold higher than those detected in control cells. Moderately enhanced levels of phosphorylation of all three mitogen-activated protein kinases, ERK1/2, and p38 and JNK, were observed in hSR-BII-expressing cells following SAA stimulation when compared with control wild type cells. Transgenic mice with pLiv-11-directed liver/kidney overexpression of hSR-BI or hSR-BII were used to assess the in vivo role of each receptor in SAA-induced pro-inflammatory response in these organs. Six hours after intraperitoneal SAA injection both groups of transgenic mice demonstrated markedly higher (~2-5-fold expression levels of inflammatory mediators in the liver and kidney compared to wild type mice. Histological examinations of hepatic and renal tissue from SAA-treated mice revealed moderate level of damage in the liver of both transgenic but not in the wild type mice. Activities of plasma transaminases, biomarkers of liver injury, were also moderately higher in hSR-B transgenic mice when compared to wild type mice. Our findings identify hSR-BII as a functional SAA receptor that mediates SAA uptake and contributes to its pro-inflammatory signaling via the MAPKs-mediated signaling pathways.

  15. Potassium Uptake Mediated by Trk1 Is Crucial for Candida glabrata Growth and Fitness

    Czech Academy of Sciences Publication Activity Database

    Llopis-Torregrosa, Vincent; Hušeková, Barbora; Sychrová, Hana

    2016-01-01

    Roč. 11, č. 4 (2016), e0153374 E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GAP302/12/1151; GA ČR(CZ) GA16-03398S EU Projects: European Commission(XE) 606786 - ImResFun Institutional support: RVO:67985823 Keywords : Candida glabrata * potassium uptake * Trk1 protein Subject RIV: EE - Microbiology, Virology Impact factor: 2.806, year: 2016

  16. GLUT2-mediated glucose uptake and availability are required for embryonic brain development in zebrafish.

    Science.gov (United States)

    Marín-Juez, Rubén; Rovira, Mireia; Crespo, Diego; van der Vaart, Michiel; Spaink, Herman P; Planas, Josep V

    2015-01-01

    Glucose transporter 2 (GLUT2; gene name SLC2A2) has a key role in the regulation of glucose dynamics in organs central to metabolism. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, its role in the brain is not well understood. To decipher the role of GLUT2 in brain development, we knocked down slc2a2 (glut2), the functional ortholog of human GLUT2, in zebrafish. Abrogation of glut2 led to defective brain organogenesis, reduced glucose uptake and increased programmed cell death in the brain. Coinciding with the observed localization of glut2 expression in the zebrafish hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a but not those expressing neurod. Specificity of the morphant phenotype was demonstrated by the restoration of brain organogenesis, whole-embryo glucose uptake, brain apoptosis, and expression of proneural markers in rescue experiments. These results indicate that glut2 has an essential role during brain development by facilitating the uptake and availability of glucose and support the involvement of glut2 in brain glucose sensing.

  17. Dependence of Brown Adipose Tissue Function on CD36-Mediated Coenzyme Q Uptake

    Directory of Open Access Journals (Sweden)

    Courtney M. Anderson

    2015-02-01

    Full Text Available Brown adipose tissue (BAT possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ. While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for patients with CoQ deficiency. However, which tissues depend on exogenous CoQ uptake as well as the mechanism by which CoQ is taken up by cells and the role of this process in BAT function are not well understood. Here, we report that the scavenger receptor CD36 drives the uptake of CoQ by BAT and is required for normal BAT function. BAT from mice lacking CD36 displays CoQ deficiency, impaired CoQ uptake, hypertrophy, altered lipid metabolism, mitochondrial dysfunction, and defective nonshivering thermogenesis. Together, these data reveal an important new role for the systemic transport of CoQ to BAT and its function in thermogenesis.

  18. Hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Farooqi, J.I.; Farooqi, R.J.

    2001-01-01

    Hepatocellular carcinoma (HCC) is a common cause of cancer mortality. Hepatitis B and C viruses, aflatoxin and alga toxin in the contaminated drinking water are the major etiological factors. Rapidly progressing medical imaging has resulted in the improved treatment results. Surgical resection has a major role for influencing prognosis of HCC. Local cancer therapies based on the advances in early diagnosis are progressing rapidly. Multimodality combination and sequential treatment has proved effective, unfortunately systemic chemotherapy for HCC remains disappointed. All of these have resulted in the improved prognosis of HCC. (author)

  19. Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress.

    Directory of Open Access Journals (Sweden)

    Scott M Thompson

    Full Text Available Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC, but lesions larger than 2-3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC. Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K/mammalian target of rapamycin (mTOR dependent-protein kinase B (AKT survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primary human HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3 and prognosis (AKT1. Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin.

  20. Lipsome-mediated uptake of exogenous DNA by Sahiwal cattle spermatozoa

    Directory of Open Access Journals (Sweden)

    Thomas V. Babu

    Full Text Available Aim: To investigate the influence of lipofection treatment and exogenous DNA uptake on the quality of sahiwal cattle spermatozoa. Materials and Methods: Semen collected from sahiwal bulls (n=7 were evaluated separately for color, volume, mass activity, concentration, motility and viability using standard procedures. Pooled sperm samples from selected bulls (n=3 were transfected with a model gene construct enhanced green fluorescent protein (p-EGFP via lipofection method and confirmed the genome integration by PCR technique. Furthermore the effect of transfection on spermatozoa was assessed based on apotosis, viability and motility. Results: In the current investigation sahiwal bulls were selected based on their breeding records and better semen characteristics. Although the transfected sperm samples failed to show florescence under fluorescence microscope, PCR studies confirmed the successful uptake of the p-EGFP gene in to the host sperm cell genome. Moreover transfected samples showed a significant reduction in the viability and motility without causing any DNA damage induced apoptosis as demonstrated by DNA Ladder assay. [Vet World 2012; 5(10.000: 621-627

  1. Uptake of the proteins HTRA1 and HTRA2 by cells mediated by calcium phosphate nanoparticles

    Directory of Open Access Journals (Sweden)

    Olga Rotan

    2017-02-01

    Full Text Available The efficient intracellular delivery of (biomolecules into living cells remains a challenge in biomedicine. Many biomolecules and synthetic drugs are not able to cross the cell membrane, which is a problem if an intracellular mode of action is desired, for example, with a nuclear receptor. Calcium phosphate nanoparticles can serve as carriers for small and large biomolecules as well as for synthetic compounds. The nanoparticles were prepared and colloidally stabilized with either polyethyleneimine (PEI; cationic nanoparticles or carboxymethyl cellulose (CMC; anionic nanoparticles and loaded with defined amounts of the fluorescently labelled proteins HTRA1, HTRA2, and BSA. The nanoparticles were purified by ultracentrifugation and characterized by dynamic light scattering and scanning electron microscopy. Various cell types (HeLa, MG-63, THP-1, and hMSC were incubated with fluorescently labelled proteins alone or with protein-loaded cationic and anionic nanoparticles. The cellular uptake was followed by light and fluorescence microscopy, confocal laser scanning microscopy (CLSM, and flow cytometry. All proteins were readily transported into the cells by cationic calcium phosphate nanoparticles. Notably, only HTRA1 was able to penetrate the cell membrane of MG-63 cells in dissolved form. However, the application of endocytosis inhibitors revealed that the uptake pathway was different for dissolved HTRA1 and HTRA1-loaded nanoparticles.

  2. Phosphate uptake from phytate due to hyphae-mediated phytase activity by arbuscular mycorrhizal maize

    NARCIS (Netherlands)

    Wang, Xinxin; Hoffland, Ellis; Feng, Gu; Kuijper, Thomas

    2017-01-01

    Phytate is the most abundant form of soil organic phosphorus (P). Increased P nutrition of arbuscular mycorrhizal plants derived from phytate has been repeatedly reported. Earlier studies assessed acid phosphatase rather than phytase as an indication of mycorrhizal fungi-mediated phytate use. We

  3. Secreted protein eco-corona mediates uptake and impacts of polystyrene nanoparticles on Daphnia magna.

    Science.gov (United States)

    Nasser, Fatima; Lynch, Iseult

    2016-03-30

    Nanoparticles (NPs) are defined as having at least one external dimension between 1 and 100 nm. Due to their small size, NPs have a large surface area to volume ratio giving them unique characteristics that differ from bulk material of the same chemical composition. As a result these novel materials have found numerous applications in medical and industrial fields with the result that environmental exposure to NPs is increasingly likely. Similarly, increased reliance on plastic, which degrades extremely slowly in the environment, is resulting in increased accumulation of micro-/nano-plastics in fresh and marine waters, whose ecotoxicological impacts are as yet poorly understood. Although NPs are well known to adsorb macromolecules from their environment, forming a biomolecule corona which changes the NP identity and how it interacts with organisms, significantly less research has been performed on the ecological corona (eco-corona). Secretion of biomolecules is a well established predator-prey response in aquatic food chains, raising the question of whether NPs interact with secreted proteins, and the impact of such interaction on NP uptake and ecotoxicity. We report here initial studies, including optimisation of protocols using carboxylic-acid and amino modified spherical polystyrene NPs, to assess interaction of NPs with biomolecules secreted by Daphnia magna and the impact of these interactions on NP uptake, retention and toxicity towards Daphnia magna. Daphnia magna are an important environmental indicator species who may be especially sensitive to nanoparticles (NPs) as a result of being filter-feeders. This paper demonstrates for the first time that proteins released by Daphnia magna create an eco-corona around polystyrene NPs which causes heightened uptake of the NPs and consequently increases toxicity. The secreted protein eco-corona also causes the NPs to be less efficiently removed from the gut of D. magna and NPs remaining in the gut of D. magna

  4. Determination of Unbound Partition Coefficient and in Vitro-in Vivo Extrapolation for SLC13A Transporter-Mediated Uptake.

    Science.gov (United States)

    Riccardi, Keith; Li, Zhenhong; Brown, Janice A; Gorgoglione, Matthew F; Niosi, Mark; Gosset, James; Huard, Kim; Erion, Derek M; Di, Li

    2016-10-01

    Unbound partition coefficient (Kpuu) is important to an understanding of the asymmetric free drug distribution of a compound between cells and medium in vitro, as well as between tissue and plasma in vivo, especially for transporter-mediated processes. Kpuu was determined for a set of compounds from the SLC13A family that are inhibitors and substrates of transporters in hepatocytes and transporter-transfected cell lines. Enantioselectivity was observed, with (R)-enantiomers achieving much higher Kpuu (>4) than the (S)-enantiomers (<1) in human hepatocytes and SLC13A5-transfected human embryonic 293 cells. The intracellular free drug concentration correlated directly with in vitro pharmacological activity rather than the nominal concentration in the assay because of the high Kpuu mediated by SLC13A5 transporter uptake. Delivery of the diacid PF-06649298 directly or via hydrolysis of the ethyl ester prodrug PF-06757303 resulted in quite different Kpuu values in human hepatocytes (Kpuu of 3 for diacid versus 59 for prodrug), which was successfully modeled on the basis of passive diffusion, active uptake, and conversion rate from ester to diacid using a compartmental model. Kpuu values changed with drug concentrations; lower values were observed at higher concentrations possibly owing to a saturation of transporters. Michaelis-Menten constant (Km) of SLC13A5 was estimated to be 24 μM for PF-06649298 in human hepatocytes. In vitro Kpuu obtained from rat suspension hepatocytes supplemented with 4% fatty acid free bovine serum albumin showed good correlation with in vivo Kpuu of liver-to-plasma, illustrating the potential of this approach to predict in vivo Kpuu from in vitro systems. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  5. Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Weiwei Guo

    Full Text Available Heat shock protein 90 (HSP90 inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70 family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.

  6. Stimulation of mast cells leads to cholesterol accumulation in macrophages in vitro by a mast cell granule-mediated uptake of low density lipoprotein

    International Nuclear Information System (INIS)

    Kokkonen, J.O.; Kovanen, P.T.

    1987-01-01

    The uptake of low density lipoprotein (LDL) by cultured mouse macrophages was markedly promoted by isolated rat mast cell granules present in the culture medium. The granule-mediated uptake of 125 I-LDL enhanced the rate of cholesteryl ester synthesis in the macrophages, the result being accumulation of cholesteryl esters in these cells. Binding of LDL to the granules was essential for the granule-mediated uptake of LDL by macrophages, for the uptake process was prevented by treating the granules with avidin or protamine chloride or by treating LDL with 1,2-cyclohexanedione, all of which inhibit the binding of LDL to the granules. Inhibition of granule phagocytosis by the macrophages with cytochalasin B also abolished the granule-mediated uptake of LDL. Finally, mouse macrophage monolayers and LDL were incubated in the presence of isolated rat serosal mast cells. Stimulation of the mast cells with compound 48/80, a degranulating agent, resulted in dose-dependent release of secretory granules from the mast cells and a parallel increase in 14 C cholesteryl ester synthesis in the macrophages. The results show that, in this in vitro model, the sequence of events leading to accumulation of cholesteryl esters in macrophages involves initial stimulation of mast cells, subsequent release of their secretory granules, binding of LDL to the exocytosed granules, and, finally, phagocytosis of the LDL-containing granules by macrophages

  7. Restriction-modification mediated barriers to exogenous DNA uptake and incorporation employed by Prevotella intermedia.

    Science.gov (United States)

    Johnston, Christopher D; Skeete, Chelsey A; Fomenkov, Alexey; Roberts, Richard J; Rittling, Susan R

    2017-01-01

    Prevotella intermedia, a major periodontal pathogen, is increasingly implicated in human respiratory tract and cystic fibrosis lung infections. Nevertheless, the specific mechanisms employed by this pathogen remain only partially characterized and poorly understood, largely due to its total lack of genetic accessibility. Here, using Single Molecule, Real-Time (SMRT) genome and methylome sequencing, bisulfite sequencing, in addition to cloning and restriction analysis, we define the specific genetic barriers to exogenous DNA present in two of the most widespread laboratory strains, P. intermedia ATCC 25611 and P. intermedia Strain 17. We identified and characterized multiple restriction-modification (R-M) systems, some of which are considerably divergent between the two strains. We propose that these R-M systems are the root cause of the P. intermedia transformation barrier. Additionally, we note the presence of conserved Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) systems in both strains, which could provide a further barrier to exogenous DNA uptake and incorporation. This work will provide a valuable resource during the development of a genetic system for P. intermedia, which will be required for fundamental investigation of this organism's physiology, metabolism, and pathogenesis in human disease.

  8. Liver (Hepatocellular) Cancer Screening

    Science.gov (United States)

    ... 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 ...

  9. Therapeutic efficacy of improved α-fetoprotein promoter-mediated tBid delivered by folate-PEI600-cyclodextrin nanopolymer vector in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hu, Bao-guang; Liu, Li-ping; Chen, George G.; Ye, Cai Guo; Leung, Kevin K.C.; Ho, Rocky L.K.; Lin, Marie C.; Lai, Paul B.S.

    2014-01-01

    SNPs in human AFP promoter are associated with serum AFP levels in hepatocellular carcinoma (HCC), suggesting that AFP promoter variants may generate better transcriptional activities while retaining high specificity to AFP-producing cells. We sequenced human AFP promoters, cloned 15 different genotype promoters and tested their reporter activities in AFP-producing and non-producing cells. Among various AFP variant fragments tested, EA4D exhibited the highest reporter activity and thus was selected for the further study. EA4D was fused with tBid and coupled with nano-particle vector (H1) to form pGL3-EA4D-tBid/H1. pGL3-EA4D-tBid/H1 could express a high level of tBid while retain the specificity to AFP-producing cells. In a HCC tumor model, application of pGL3-EA4D-tBid/H1 significantly inhibited the growth of AFP-producing-implanted tumors with minimal side-effects, but had no effect on non-AFP-producing tumors. Furthermore, pGL3-EA4D-tBid/H1 could significantly sensitize HCC cells to sorafenib, an approved anti-HCC agent. Collectively, pGL3-EA4D-tBid/H1, a construct with the AFP promoter EA4D and the novel H1 delivery system, can specifically target and effectively suppress the AFP-producing HCC. This new therapeutic tool shows little toxicity in vitro and in vivo and it should thus be safe for further clinical tests. - Highlights: • The nano-particle vector H1 has advantages in mediating gene therapy construct pGL3-EA4D-tBid for HCC treatment. • pGL3-EA4D-tBid/H1, a construct with the AFP promoter EA4D, can specifically target the AFP-producing HCC. • pGL3-EA4D-tBid/H1effectively suppresses the proliferation and growth of AFP-producing HCC. • This novel pGL3-EA4D-tBid/H1 therapeutic tool shows little toxicity in vitro and in vivo

  10. Structure-based analysis of CysZ-mediated cellular uptake of sulfate

    Science.gov (United States)

    Assur Sanghai, Zahra; Liu, Qun; Clarke, Oliver B; Belcher-Dufrisne, Meagan; Wiriyasermkul, Pattama; Giese, M Hunter; Leal-Pinto, Edgar; Kloss, Brian; Tabuso, Shantelle; Love, James; Punta, Marco; Banerjee, Surajit; Rajashankar, Kanagalaghatta R; Rost, Burkhard; Logothetis, Diomedes; Quick, Matthias; Hendrickson, Wayne A

    2018-01-01

    Sulfur, most abundantly found in the environment as sulfate (SO42-), is an essential element in metabolites required by all living cells, including amino acids, co-factors and vitamins. However, current understanding of the cellular delivery of SO42- at the molecular level is limited. CysZ has been described as a SO42- permease, but its sequence family is without known structural precedent. Based on crystallographic structure information, SO42- binding and flux experiments, we provide insight into the molecular mechanism of CysZ-mediated translocation of SO42- across membranes. CysZ structures from three different bacterial species display a hitherto unknown fold and have subunits organized with inverted transmembrane topology. CysZ from Pseudomonas denitrificans assembles as a trimer of antiparallel dimers and the CysZ structures from two other species recapitulate dimers from this assembly. Mutational studies highlight the functional relevance of conserved CysZ residues. PMID:29792261

  11. Lipopolysaccharide inhibits colonic biotin uptake via interference with membrane expression of its transporter: a role for a casein kinase 2-mediated pathway.

    Science.gov (United States)

    Lakhan, Ram; Said, Hamid M

    2017-04-01

    Biotin (vitamin B7), an essential micronutrient for normal cellular functions, is obtained from both dietary sources as well as gut microbiota. Absorption of biotin in both the small and large intestine is via a carrier-mediated process that involves the sodium-dependent multivitamin transporter (SMVT). Although different physiological and molecular aspects of intestinal biotin uptake have been delineated, nothing is known about the effect of LPS on the process. We addressed this issue using in vitro (human colonic epithelial NCM460 cells) and in vivo (mice) models of LPS exposure. Treating NCM460 cells with LPS was found to lead to a significant inhibition in carrier-mediated biotin uptake. Similarly, administration of LPS to mice led to a significant inhibition in biotin uptake by native colonic tissue. Although no changes in total cellular SMVT protein and mRNA levels were observed, LPS caused a decrease in the fraction of SMVT expressed at the cell surface. A role for casein kinase 2 (CK2) (whose activity was also inhibited by LPS) in mediating the endotoxin effects on biotin uptake and on membrane expression of SMVT was suggested by findings that specific inhibitors of CK2, as well as mutating the putative CK2 phosphorylation site (Thr 78 Ala) in the SMVT protein, led to inhibition in biotin uptake and membrane expression of SMVT. This study shows for the first time that LPS inhibits colonic biotin uptake via decreasing membrane expression of its transporter and that these effects likely involve a CK2-mediated pathway.

  12. Are metabolic signatures mediating the relationship between lifestyle factors and hepatocellular carcinoma risk? Results from a nested case-control study in EPIC.

    NARCIS (Netherlands)

    Assi, Nada; Thomas, Duncan C; Leitzman, Michael; Stepien, Magdalena; Chajes, Veronique; Philip, Thierry; Vineis, Paolo; Bamia, Christina; Boutron-Ruault, Marie-Christine; Sandanger, Torkjel M; Molinuevo, Amaia; Boshuizen, Hendriek C; Sundkvist, Anneli; Kühn, Tilman; Travis, Ruth C; Overvad, Kim; Riboli, Elio; Gunter, Marc J; Scalbert, Augustin; Jenab, Mazda; Ferrari, Pietro; Viallon, Vivian

    2018-01-01

    The "meeting-in-the-middle" (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case-control study of hepatocellular carcinoma (HCC) within EPIC where healthy lifestyle index (HLI) variables were related to

  13. Further studies on the nature of postsynaptic dopamine uptake and metabolism in rat striatum: sodium dependency and investigation of a possible role for carrier-mediated uptake into serotonin neurons

    Energy Technology Data Exchange (ETDEWEB)

    Schoepp, D.D.; Azzaro, A.J.

    1985-06-01

    The nature of postsynaptic sites involved in the uptake and metabolism of striatal 3,4-dihydroxyphenylethylamine (dopamine, DA) was investigated. The accumulation of (/sup 3/H)DA (10(-7) M) into slices of rat striatum was found to be greatly dependent on the presence of sodium ion in the incubation medium. However, the formation of the (/sup 3/H)dihydroxyphenylacetic acid (DOPAC) and (/sup 3/H)homovanillic acid (HVA) was only partially reduced in the absence of sodium. Inhibition of carrier-mediated DA neuronal uptake with nomifensine significantly decreased DA accumulation (18% of control) and (/sup 3/H)DOPAC formation (62% of control), but enhanced (/sup 3/H)HVA production (143% of control). Inhibition of the 5-hydroxytryptamine (5-HT, serotonin) neuronal uptake system with fluoxetine (10(-6) M) or selective 5-HT neuronal lesions with 5,7-dihydroxytryptamine (5,7-DHT) had no effect on (/sup 3/H)DOPAC or (/sup 3/H)HVA formed from (/sup 3/H)DA in the presence or absence of nomifensine. These results demonstrate that the uptake and subsequent metabolism of striatal DA to DOPAC and HVA is only partially dependent on carrier-mediated uptake mechanism(s) requiring sodium ion. These data support our previous findings suggesting a significant role for synaptic glial cell deamination and O-methylation of striatal DA. Further, experiments with fluoxetine or 5,7-DHT suggest that 5-HT neurons do not significantly contribute in the synaptic uptake and metabolism of striatal DA.

  14. Resveratrol self-emulsifying system increases the uptake by endothelial cells and improves protection against oxidative stress-mediated death.

    Science.gov (United States)

    Amri, Ahmed; Le Clanche, Solenn; Thérond, Patrice; Bonnefont-Rousselot, Dominique; Borderie, Didier; Lai-Kuen, René; Chaumeil, Jean-Claude; Sfar, Souad; Charrueau, Christine

    2014-04-01

    The aim of the present study was to develop and characterize a resveratrol self-emulsifying drug delivery system (Res-SEDDS), and to compare the uptake of resveratrol by bovine aortic endothelial cells (BAECs), and the protection of these cells against hydrogen peroxide-mediated cell death, versus a control resveratrol ethanolic solution. Three Res-SEDDSs were prepared and evaluated. The in vitro self-emulsification properties of these formulations, the droplet size and the zeta potential of the nanoemulsions formed on adding them to water under mild agitation conditions were studied, together with their toxicity on BAECs. An optimal atoxic formulation (20% Miglyol® 812, 70% Montanox® 80, 10% ethanol 96% v/v) was selected and further studied. Pre-incubation of BAECs for 180 min with 25 μM resveratrol in the nanoemulsion obtained from the selected SEDDS significantly increased the membrane and intracellular concentrations of resveratrol (for example, 0.076±0.015 vs. ethanolic solution 0.041±0.016 nmol/mg of protein after 60 min incubation, p<0.05). Resveratrol intracellular localization was confirmed by fluorescence confocal microscopy. Resveratrol nanoemulsion significantly improved the endothelial cell protection from H2O2-induced injury (750, 1000 and 1500 μM H2O2) in comparison with incubation with the control resveratrol ethanolic solution (for example, 55±6% vs. 38±5% viability after 1500 μM H2O2 challenge, p<0.05). In conclusion, formulation of resveratrol as a SEDDS significantly improved its cellular uptake and potentiated its antioxidant properties on BAECs. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Neuronal nitric oxide synthase mediates insulin- and oxidative stress-induced glucose uptake in skeletal muscle myotubes.

    Science.gov (United States)

    Kellogg, Dean L; McCammon, Karen M; Hinchee-Rodriguez, Kathryn S; Adamo, Martin L; Roman, Linda J

    2017-09-01

    Previously published studies strongly suggested that insulin- and exercise-induced skeletal muscle glucose uptake require nitric oxide (NO) production. However, the signal transduction mechanisms by which insulin and contraction regulated NO production and subsequent glucose transport are not known. In the present study, we utilized the myotube cell lines treated with insulin or hydrogen peroxide, the latter to mimic contraction-induced oxidative stress, to characterize these mechanisms. We found that insulin stimulation of neuronal nitric oxide synthase (nNOS) phosphorylation, NO production, and GLUT4 translocation were all significantly reduced by inhibition of either nNOS or Akt2. Hydrogen peroxide (H 2 O 2 ) induced phosphorylation of nNOS at the same residue as did insulin, and also stimulated NO production and GLUT4 translocation. nNOS inhibition prevented H 2 O 2 -induced GLUT4 translocation. AMP activated protein kinase (AMPK) inhibition prevented H 2 O 2 activation and phosphorylation of nNOS, leading to reduced NO production and significantly attenuated GLUT4 translocation. We conclude that nNOS phosphorylation and subsequently increased NO production are required for both insulin- and H 2 O 2 -stimulated glucose transport. Although the two stimuli result in phosphorylation of the same residue on nNOS, they do so through distinct protein kinases. Thus, insulin and H 2 O 2 -activated signaling pathways converge on nNOS, which is a common mediator of glucose uptake in both pathways. However, the fact that different kinases are utilized provides a basis for the use of exercise to activate glucose transport in the face of insulin resistance. Copyright © 2017. Published by Elsevier Inc.

  16. Organic cation transporter-mediated ergothioneine uptake in mouse neural progenitor cells suppresses proliferation and promotes differentiation into neurons.

    Directory of Open Access Journals (Sweden)

    Takahiro Ishimoto

    Full Text Available The aim of the present study is to clarify the functional expression and physiological role in neural progenitor cells (NPCs of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO as a substrate in vivo. Real-time PCR analysis revealed that mRNA expression of OCTN1 was much higher than that of other organic cation transporters in mouse cultured cortical NPCs. Immunocytochemical analysis showed colocalization of OCTN1 with the NPC marker nestin in cultured NPCs and mouse embryonic carcinoma P19 cells differentiated into neural progenitor-like cells (P19-NPCs. These cells exhibited time-dependent [(3H]ERGO uptake. These results demonstrate that OCTN1 is functionally expressed in murine NPCs. Cultured NPCs and P19-NPCs formed neurospheres from clusters of proliferating cells in a culture time-dependent manner. Exposure of cultured NPCs to ERGO or other antioxidants (edaravone and ascorbic acid led to a significant decrease in the area of neurospheres with concomitant elimination of intracellular reactive oxygen species. Transfection of P19-NPCs with small interfering RNA for OCTN1 markedly promoted formation of neurospheres with a concomitant decrease of [(3H]ERGO uptake. On the other hand, exposure of cultured NPCs to ERGO markedly increased the number of cells immunoreactive for the neuronal marker βIII-tubulin, but decreased the number immunoreactive for the astroglial marker glial fibrillary acidic protein (GFAP, with concomitant up-regulation of neuronal differentiation activator gene Math1. Interestingly, edaravone and ascorbic acid did not affect such differentiation of NPCs, in contrast to the case of proliferation. Knockdown of OCTN1 increased the number of cells immunoreactive for GFAP, but decreased the number immunoreactive for βIII-tubulin, with concomitant down-regulation of Math1 in P19-NPCs. Thus, OCTN1-mediated uptake of ERGO in NPCs inhibits

  17. Lysosomal putative RNA transporter SIDT2 mediates direct uptake of RNA by lysosomes.

    Science.gov (United States)

    Aizawa, Shu; Fujiwara, Yuuki; Contu, Viorica Raluca; Hase, Katsunori; Takahashi, Masayuki; Kikuchi, Hisae; Kabuta, Chihana; Wada, Keiji; Kabuta, Tomohiro

    2016-01-01

    Lysosomes are thought to be the major intracellular compartment for the degradation of macromolecules. We recently identified a novel type of autophagy, RNautophagy, where RNA is directly taken up by lysosomes in an ATP-dependent manner and degraded. However, the mechanism of RNA translocation across the lysosomal membrane and the physiological role of RNautophagy remain unclear. In the present study, we performed gain- and loss-of-function studies with isolated lysosomes, and found that SIDT2 (SID1 transmembrane family, member 2), an ortholog of the Caenorhabditis elegans putative RNA transporter SID-1 (systemic RNA interference deficient-1), mediates RNA translocation during RNautophagy. We also observed that SIDT2 is a transmembrane protein, which predominantly localizes to lysosomes. Strikingly, knockdown of Sidt2 inhibited up to ˜50% of total RNA degradation at the cellular level, independently of macroautophagy. Moreover, we showed that this impairment is mainly due to inhibition of lysosomal RNA degradation, strongly suggesting that RNautophagy plays a significant role in constitutive cellular RNA degradation. Our results provide a novel insight into the mechanisms of RNA metabolism, intracellular RNA transport, and atypical types of autophagy.

  18. CD36 mediates both cellular uptake of very long chain fatty acids and their intestinal absorption in mice.

    Science.gov (United States)

    Drover, Victor A; Nguyen, David V; Bastie, Claire C; Darlington, Yolanda F; Abumrad, Nada A; Pessin, Jeffrey E; London, Erwin; Sahoo, Daisy; Phillips, Michael C

    2008-05-09

    The intestine has an extraordinary capacity for fatty acid (FA) absorption. Numerous candidates for a protein-mediated mechanism of dietary FA absorption have been proposed, but firm evidence for this process has remained elusive. Here we show that the scavenger receptor CD36 is required both for the uptake of very long chain FAs (VLCFAs) in cultured cells and the absorption of dietary VLCFAs in mice. We found that the fraction of CD36-dependent saturated fatty acid association/absorption in these model systems is proportional to the FA chain length and specific for fatty acids and fatty alcohols containing very long saturated acyl chains. Moreover, intestinal VLCFA absorption is completely abolished in CD36-null mice fed a high fat diet, illustrating that the predominant mechanism for VLCFA absorption is CD36-dependent. Together, these findings represent the first direct evidence for protein-facilitated FA absorption in the intestine and identify a novel therapeutic target for the treatment of diseases characterized by elevated VLCFA levels.

  19. Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis

    International Nuclear Information System (INIS)

    Black, J.D.; Dolly, J.O.

    1986-01-01

    Using pharmacological and autoradiographic techniques it has been shown that botulinum neurotoxin (BoNT) is translocated across the motor nerve terminal membrane to reach a postulated intraterminal target. In the present study, the nature of this uptake process was investigated using electron microscopic autoradiography. It was found that internalization is acceptor-mediated and that binding to specific cell surface acceptors involves the heavier chain of the toxin. In addition, uptake was shown to be energy and temperature-dependent and to be accelerated by nerve stimulation, a treatment which also shortens the time course of the toxin-induced neuroparalysis. These results, together with the observation that silver grains were often associated with endocytic structures within the nerve terminal, suggested that acceptor-mediated endocytosis is responsible for toxin uptake. Possible recycling of BoNT acceptors (an important aspect of acceptor-mediated endocytosis of toxins) at motor nerve terminals was indicated by comparing the extent of labeling in the presence and absence of metabolic inhibitors. On the basis of these collective results, it is concluded that BoNT is internalized by acceptor-mediated endocytosis and, hence, the data support the proposal that this toxin inhibits release of acetylcholine by interaction with an intracellular target

  20. Gene replacement therapy for genetic hepatocellular jaundice.

    Science.gov (United States)

    van Dijk, Remco; Beuers, Ulrich; Bosma, Piter J

    2015-06-01

    Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy.

  1. Tracking of cell nuclei for assessment of in vitro uptake kinetics in ultrasound-mediated drug delivery using fibered confocal fluorescence microscopy.

    Science.gov (United States)

    Derieppe, Marc; de Senneville, Baudouin Denis; Kuijf, Hugo; Moonen, Chrit; Bos, Clemens

    2014-10-01

    Previously, we demonstrated the feasibility to monitor ultrasound-mediated uptake of a cell-impermeable model drug in real time with fibered confocal fluorescence microscopy. Here, we present a complete post-processing methodology, which corrects for cell displacements, to improve the accuracy of pharmacokinetic parameter estimation. Nucleus detection was performed based on the radial symmetry transform algorithm. Cell tracking used an iterative closest point approach. Pharmacokinetic parameters were calculated by fitting a two-compartment model to the time-intensity curves of individual cells. Cells were tracked successfully, improving time-intensity curve accuracy and pharmacokinetic parameter estimation. With tracking, 93 % of the 370 nuclei showed a fluorescence signal variation that was well-described by a two-compartment model. In addition, parameter distributions were narrower, thus increasing precision. Dedicated image analysis was implemented and enabled studying ultrasound-mediated model drug uptake kinetics in hundreds of cells per experiment, using fiber-based confocal fluorescence microscopy.

  2. Drosophila lipophorin receptors mediate the uptake of neutral lipids in oocytes and imaginal disc cells by an endocytosis-independent mechanism.

    Directory of Open Access Journals (Sweden)

    Esmeralda Parra-Peralbo

    2011-02-01

    Full Text Available Lipids are constantly shuttled through the body to redistribute energy and metabolites between sites of absorption, storage, and catabolism in a complex homeostatic equilibrium. In Drosophila, lipids are transported through the hemolymph in the form of lipoprotein particles, known as lipophorins. The mechanisms by which cells interact with circulating lipophorins and acquire their lipidic cargo are poorly understood. We have found that lipophorin receptor 1 and 2 (lpr1 and lpr2, two partially redundant genes belonging to the Low Density Lipoprotein Receptor (LDLR family, are essential for the efficient uptake and accumulation of neutral lipids by oocytes and cells of the imaginal discs. Females lacking the lpr2 gene lay eggs with low lipid content and have reduced fertility, revealing a central role for lpr2 in mediating Drosophila vitellogenesis. lpr1 and lpr2 are transcribed into multiple isoforms. Interestingly, only a subset of these isoforms containing a particular LDLR type A module mediate neutral lipid uptake. Expression of these isoforms induces the extracellular stabilization of lipophorins. Furthermore, our data indicate that endocytosis of the lipophorin receptors is not required to mediate the uptake of neutral lipids. These findings suggest a model where lipophorin receptors promote the extracellular lipolysis of lipophorins. This model is reminiscent of the lipolytic processing of triglyceride-rich lipoproteins that occurs at the mammalian capillary endothelium, suggesting an ancient role for LDLR-like proteins in this process.

  3. Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1.

    Science.gov (United States)

    Svensson, Katrin J; Christianson, Helena C; Wittrup, Anders; Bourseau-Guilmain, Erika; Lindqvist, Eva; Svensson, Lena M; Mörgelin, Matthias; Belting, Mattias

    2013-06-14

    The role of exosomes in cancer can be inferred from the observation that they transfer tumor cell derived genetic material and signaling proteins, resulting in e.g. increased tumor angiogenesis and metastasis. However, the membrane transport mechanisms and the signaling events involved in the uptake of these virus-like particles remain ill-defined. We now report that internalization of exosomes derived from glioblastoma (GBM) cells involves nonclassical, lipid raft-dependent endocytosis. Importantly, we show that the lipid raft-associated protein caveolin-1 (CAV1), in analogy with its previously described role in virus uptake, negatively regulates the uptake of exosomes. We find that exosomes induce the phosphorylation of several downstream targets known to associate with lipid rafts as signaling and sorting platforms, such as extracellular signal-regulated kinase-1/2 (ERK1/2) and heat shock protein 27 (HSP27). Interestingly, exosome uptake appears dependent on unperturbed ERK1/2-HSP27 signaling, and ERK1/2 phosphorylation is under negative influence by CAV1 during internalization of exosomes. These findings significantly advance our general understanding of exosome-mediated uptake and offer potential strategies for how this pathway may be targeted through modulation of CAV1 expression and ERK1/2 signaling.

  4. The Impact of Homophobia and HIV Stigma on HIV Testing Uptake Among Chinese Men Who Have Sex With Men: a Mediation Analysis.

    Science.gov (United States)

    Wei, Chongyi; Cheung, Doug H; Yan, Hongjing; Li, Jianjun; Shi, Ling-en; Raymond, Henry F

    2016-01-01

    Gay and HIV-related stigma and discrimination are major barriers to accessing HIV prevention services among Men Who Have Sex with Men (MSM) worldwide. We aimed to identify modifiable factors that mediate the relationships between gay and HIV-related stigma and discrimination and HIV testing uptake among Chinese MSM. We conducted a cross-sectional survey study of 523 HIV-uninfected or unknown HIV status MSM in Jiangsu Province, China between November 2013 and January 2014. Multivariable analyses were conducted to examine the associations among experienced homophobia, HIV stigma, and recent HIV testing. Causal mediation parametric analyses were conducted to assess whether depression and social norms mediated hypothesized associations. Stronger subjective norms toward testing was associated with higher odds of recent HIV testing (adjusted odds ratio [AOR]: 1.10, 95% confidence interval [CI]: 1.01 to 1.21), whereas increasing levels of depression and HIV stigma were both associated with lower odds of recent testing (AOR: 0.96, 95% CI: 0.92 to 0.99; and AOR: 0.91, 95% CI: 0.84 to 0.99, respectively). There was an indirect relationship (natural indirect effect [NIE]) of experienced homophobia on recent testing (ORNIE: 0.96, 95% CI: 0.93 to 0.98) mediated (35.0%) through depression. Furthermore, there was an indirect relationship of HIV stigma on recent testing (ORNIE: 0.98, 95% CI: 0.95 to 0.99) mediated (19.2%) through subjective norms. Depression and social norms are important mediators of HIV testing uptake among stigmatized Chinese MSM. Therefore, in addition to advocacy efforts and policies that address social-level stigma and discrimination, HIV prevention programs should also address mental health issues and incorporate community-based approaches to changing social norms toward HIV testing.

  5. Angiopoietin-like 4 mediates PPAR delta effect on lipoprotein lipase-dependent fatty acid uptake but not on beta-oxidation in myotubes.

    Directory of Open Access Journals (Sweden)

    Marius R Robciuc

    Full Text Available Peroxisome proliferator-activated receptor (PPAR delta is an important regulator of fatty acid (FA metabolism. Angiopoietin-like 4 (Angptl4, a multifunctional protein, is one of the major targets of PPAR delta in skeletal muscle cells. Here we investigated the regulation of Angptl4 and its role in mediating PPAR delta functions using human, rat and mouse myotubes. Expression of Angptl4 was upregulated during myotubes differentiation and by oleic acid, insulin and PPAR delta agonist GW501516. Treatment with GW501516 or Angptl4 overexpression inhibited both lipoprotein lipase (LPL activity and LPL-dependent uptake of FAs whereas uptake of BSA-bound FAs was not affected by either treatment. Activation of retinoic X receptor (RXR, PPAR delta functional partner, using bexarotene upregulated Angptl4 expression and inhibited LPL activity in a PPAR delta dependent fashion. Silencing of Angptl4 blocked the effect of GW501516 and bexarotene on LPL activity. Treatment with GW501516 but not Angptl4 overexpression significantly increased palmitate oxidation. Furthermore, Angptl4 overexpression did not affect the capacity of GW501516 to increase palmitate oxidation. Basal and insulin stimulated glucose uptake, glycogen synthesis and glucose oxidation were not significantly modulated by Angptl4 overexpression. Our findings suggest that FAs-PPARdelta/RXR-Angptl4 axis controls the LPL-dependent uptake of FAs in myotubes, whereas the effect of PPAR delta activation on beta-oxidation is independent of Angptl4.

  6. Fungal inoculation and elevated CO2 mediate growth of Lolium mutiforum and Phytolacca americana, metal uptake, and metal bioavailability in metal-contaminated soil: evidence from DGT measurement.

    Science.gov (United States)

    Song, Ningning; Wang, Fangli; Zhang, Changbo; Tang, Shirong; Guo, Junkang; Ju, Xuehai; Smith, Donald L

    2013-01-01

    Fungal inoculation and elevated CO2 may mediate plant growth and uptake of heavy metals, but little evidence from Diffusive Gradients in Thin-films (DGT) measurement has been obtained to characterize the process. Lolium mutiforum and Phytolacca americana were grown at ambient and elevated CO2 on naturally Cd and Pb contaminated soils inoculated with and without Trichoderma asperellum strain C3 or Penicillium chrysogenum strain D4, to investigate plant growth, metal uptake, and metal bioavailability responses. Fungal inoculation increased plant biomass and shoot/root Cd and Pb concentrations. Elevated CO2 significantly increased plants biomass, but decreased Cd and Pb concentrations in shoot/root to various extents, leading to a metal dilution phenomenon. Total Cd and Pb uptake by plants, and DGT-measured Cd and Pb concentrations in rhizosphere soils, were higher in all fungal inoculation and elevated CO2 treatments than control treatments, with the combined treatments having more influence than either treatment alone. Metal dilution phenomenon occurred because the increase in DGT-measured bioavailable metal pools in plant rhizosphere due to elevated CO2 was unable to match the increase in requirement for plant uptake of metals due to plant biomass increase.

  7. Long non-coding RNA CCAT2 is associated with poor prognosis in hepatocellular carcinoma and promotes tumor metastasis by regulating Snail2-mediated epithelial–mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Xu Y

    2017-02-01

    Full Text Available Yongfu Xu,* Binfeng Wang,* Fabiao Zhang, Aidong Wang, Xuefeng Du, Peng Hu, Yu Zhu, Zheping Fang Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, People’s Republic of China *These authors contributed equally to this work Abstract: Increasing evidence has demonstrated that aberrant expressions of long non-coding RNAs (lncRNAs are involved in various malignancies, including hepatocellular carcinoma (HCC. This study aimed to investigate the role of lncRNA colon cancer-associated transcript 2 (CCAT2 in the progression of HCC. Quantitative real-time polymerase chain reaction analysis confirmed that CCAT2 was upregulated in HCC cell lines and cancerous tissues compared with normal liver cell line and adjacent normal tissue samples. The level of CCAT2 was positively associated with tumor–node–metastasis stages and vessel invasion. Survival analyses revealed that high CCAT2 expression predicted poor prognostic outcomes, serving as an independent prognostic factor for HCC patients. Patients with high CCAT2 expression had a 1.849-fold increased risk of death compared with those with low CCAT2 expression. Moreover, we also found that knockdown of CCAT2 expression reduced cell migration and invasion in vitro. We further demonstrated that CCAT2 played a key role in enhancing the epithelial–mesenchymal transition (EMT through the regulation of vimentin, E-cadherin and transcription factor snail2 expression. Taken together, our findings showed that high CCAT2 expression is associated with poor survival in HCC patients. CCAT2 promotes HCC progression by regulating Snail2-induced EMT. CCAT2 may be a prognostic biomarker and therapeutic target for HCC. Keywords: long non-coding RNA, CCAT2, hepatocellular carcinoma, epithelial–mesenchymal transition, survival

  8. The Cytochrome P450-Mediated Metabolism Alternation of Four Effective Lignans From Schisandra chinensis in Carbon Tetrachloride-Intoxicated Rats and Patients With Advanced Hepatocellular Carcinoma.

    Science.gov (United States)

    Wu, Rongrong; Xiao, Zhiyong; Zhang, Xiaorui; Liu, Feng; Zhou, Wenxia; Zhang, Yongxiang

    2018-01-01

    It is highly valuable to study the pharmacokinetics of herbal components under the pathological condition of liver dysfunction for safe and rational use of herbal medicines. In this study, the pharmacokinetic profiles of four effective lignans from Schisandra chinensis (SC) , schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, were investigated in carbon tetrachloride (CCl 4 )-intoxicated rats. The metabolism of the four lignans was also studied using microsomes from patients with advanced hepatocellular carcinoma. In situ intestinal and hepatic perfusions were conducted to clarify the contributions from impairments of gut and liver on the pharmacokinetics of the four schisandra lignans in CCl 4 -intoxicated rats. The metabolism in rat and human liver microsomes and transport in Caco-2 monolayer cell model were studied to reveal the key factors for the in vivo disposition of the four lignans. When SC alcoholic extract was orally administrated to CCl 4 -intoxicated rat for a short term (4 days), the pharmacokinetics of four active SC lignans was significantly changed while its hepatotherapeutic effect was not obviously observed. The plasma concentrations of the four schisandra lignans were dramatically elevated compared with the control. The Cmax, AUC and MRT were all increased or prolonged significantly while parameter CLz/F was obviously reduced in rat pretreated with CCl 4 . In hepatic perfusion study and liver microsomes incubation, it was found that the hepatic metabolism of the four lignans was markedly decreased mainly due to the activity reduction of multiple CYP450 isoenzymes involved the metabolism, which, eventually, might lead to the alternation of their pharmacokinetic profiles in CCl 4 -intoxicated rats or patients with advanced hepatocellular carcinoma. The pharmacokinetic studies of SC components in pathological situation of liver dysfunction are expected to provide useful data for rational and safe application of SC preparations in

  9. Effects of divalent cations, EDTA and chitosan on the uptake and photoinactivation of Escherichia coli mediated by cationic and anionic porphyrins.

    Science.gov (United States)

    Gsponer, Natalia S; Spesia, Mariana B; Durantini, Edgardo N

    2015-03-01

    The effect of divalent cations, EDTA and chitosan (CS) on the uptake and photoinactivation of Escherichia coli produced by 5,10,15,20-tetrakis(4-N,N,N-trimethylammoniumphenyl)porphyrin (TMAP(4+)), 5,10-di(4-methylphenyl)-15,20-di(4-N,N,N-trimethylammoniumphenyl)porphyrin (MPAP(2+)) and 5,10,15,20-tetra(4-sulphonatophenyl)porphyrin (TPPS(4-)) were examined under different conditions. These porphyrins were rapidly bound to E. coli cells (TMAP(4+), MPAP(2+) and TPPS(4-), respectively. The addition of Ca(2+) or Mg(2+) to the cultures enhanced the uptake of MPAP(2+) and TPPS(4-) by cells. In contrast, the amount of TMAP(4+) bound to cells was decreased. The presence of EDTA produced an increase in the uptake of porphyrins by cells, while CS mainly enhanced the amount of TPPS(4-) bound to E. coli. The photoinactivation of E. coli cells mediated by TMAP(4+) was highly effective even at low concentration (1μM) and short irradiation period (5min). However, a reduction in the phototoxicity was found for TMAP(4+) in presence of Ca(2+) and Mg(2+). In contrast, the phototoxic activity mediated by MPAP(2+) and TPPS(4-) was increased. Addition of EDTA did not show effect on the photoinactivation induced by cationic porphyrins, while a small enhance was found for TPPS(4-). Moreover, inactivation of E. coli cells was achieved in the presence CS. This cationic polymer was antimicrobial by itself in the dark. Using a slightly toxic CS concentration, the phototoxic activity induced by TMAP(4+) was diminished. This effect was mainly observed at lower concentration of TMAP(4+) (0.5-1μM). In contrast, an increase in E. coli photoinactivation was obtained for MPAP(2+) and TPPS(4-) in presence of CS. Thus, this natural polymeric destabilizer agent mainly benefited the photoinactivation mediated by TPPS(4-). Copyright © 2014 Elsevier B.V. All rights reserved.

  10. An ATP Binding Cassette Transporter Mediates the Uptake of α-(1,6)-Linked Dietary Oligosaccharides in Bifidobacterium and Correlates with Competitive Growth on These Substrates

    DEFF Research Database (Denmark)

    Hansen, Morten Ejby; Fredslund, Folmer; Andersen, Joakim Mark

    2016-01-01

    that the dominant HGM commensal Bacteroides ovatus was out-competed by B. animalis subsp. lactis Bl-04 in mixed cultures growing on raffinose, the preferred ligand for the BlG16BP. By comparison, B. ovatus mono-cultures grew very efficiently on this trisaccharide. These findings suggest that the ABC-mediated uptake...... of raffinose provides an important competitive advantage, particularly against dominant Bacteroides that lack glycan-specific ABC-transporters. This novel insight highlights the role of glycan transport in defining the metabolic specialization of gut bacteria....

  11. Hypoxia-inducible factor-1α mediates the toll-like receptor 4 signaling pathway leading to anti-tumor effects in human hepatocellular carcinoma cells under hypoxic conditions.

    Science.gov (United States)

    Zhang, Xiaoyu; Li, Shuchen; Li, Mingrong; Huang, Haiying; Li, Jingyuan; Zhou, Changwei

    2016-08-01

    Hypoxia-inducible factor-1α (HIF-1α) and toll-like receptor 4 (TLR4) are involved in numerous mechanisms of cancer biology, including cell proliferation and survival; however the interaction of the two factors under hypoxic conditions remains unclear. The present study investigated the in vitro mechanism that results in the suppression of tumor cell growth and cellular functions when HIF-1α is silenced. In the present study, the human hepatocellular carcinoma HepG2 cell line was transfected with short hairpin RNA (shRNA) against HIF-1α and cultured under hypoxic conditions (1% O 2 for 24 h). The expression of HIF-1α and various growth factors, including epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), were examined using quantitative polymerase chain reaction and immunoblotting. Tumor growth was measured using a Cell Counting Kit-8 assay and tumor activity was measured using tumor cell invasion and migration assays. Lipopolysaccharide and TAK-242 were used to activate and inhibit TLR4, respectively, to observe the role of TLR4 in the HIF-1α silenced tumor cells. The expression of TLR4 signaling pathway associates, including myeloid differentiation primary response gene 88 (MyD88), apoptosis signal-regulating kinase 1 (ASK1), p38 mitogen-activated protein kinases and HIF-1α, were analyzed by western blot assay. Under hypoxic conditions, silencing of HIF-1α expression suppressed tumor cell growth and regulated the expression of tumor growth-associated genes, including EGF, HGF, VEGF and FG2. Suppression of tumor cell invasion and migration was also observed in the HIF-1α silenced HepG2 cell line. In addition, TLR4 was identified to be involved in HIF-1α and MyD88 accumulation, and activation of ASK1 and p38 were demonstrated to be critical for TLR4-mediated HIF-1α pathway. In conclusion, silencing of HIF-1α expression may induce anti-tumor effects under hypoxic

  12. CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma.

    Science.gov (United States)

    Wadkin, James C R; Patten, Daniel A; Kamarajah, Sivesh K; Shepherd, Emma L; Novitskaya, Vera; Berditchevski, Fedor; Adams, David H; Weston, Chris J; Shetty, Shishir

    2017-08-01

    CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention. NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated

  13. Iron metabolism in BeWo chorion carcinoma cells. Transferrin-mediated uptake and release of iron

    NARCIS (Netherlands)

    van der Ende, A.; du Maine, A.; Simmons, C. F.; Schwartz, A. L.; Strous, G. J.

    1987-01-01

    Growing human choriocarcinoma BeWo b24 cells contain 1.5 X 10(6) functional cell surface transferrin binding sites and 2.0 X 10(6) intracellular binding sites. These cells rapidly accumulate iron at a rate of 360,000 iron atoms/min/cell. During iron uptake the transferrin and its receptor recycle at

  14. Radiosensitivity of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hennequin, C.; Quero, L.; Rivera, S.

    2011-01-01

    The frequency of hepatocellular carcinoma (HCC) is increasing in the western world and the role of radiotherapy is more and more discussed. Classically, hepatocellular carcinoma was considered as a radioresistant tumour: in fact, modern radio-biologic studies, performed on cell lines directly established from patients, showed that hepatocellular carcinoma has the same radiosensitivity than the other epithelial tumours. From clinical studies, its α/β ratio has been estimated to be around 15 Gy. Radiosensitivity of normal hepatic parenchyma is now well evaluated and some accurate NTCP models are available to guide hepatic irradiation. The biology of hepatocellular carcinoma is also better described: the combination of radiotherapy and targeted therapies will be a promising approach in the near future. (authors)

  15. Cryotherapy for hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Awad, Tahany; Thorlund, Kristian; Gluud, Christian

    2009-01-01

    BACKGROUND: Hepatocellular carcinoma is the most common primary malignant cancer of the liver. Evidence for the role of cryotherapy in the treatment of hepatocellular carcinoma is controversial. OBJECTIVES: The aim of this review is to evaluate the potential benefits and harms of cryotherapy...... for the treatment of hepatocellular carcinoma. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS until June 2009. We identified further studies by searching...... of benefit but included for the assessment of harm. Both severe and non-severe adverse events were reported, but the true nature and extent of harm was difficult to asses. AUTHORS' CONCLUSIONS: At present, there is no evidence to recommend or refute cryotherapy for patients with hepatocellular carcinoma...

  16. Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma

    Science.gov (United States)

    Baglioni, Michele; Fornari, Francesca; Giannone, Ferdinando; Ravaioli, Matteo; Cescon, Matteo; Chieco, Pasquale; Bolondi, Luigi; Gramantieri, Laura

    2014-01-01

    To successfully target Notch receptors as part of a multidrug anticancer strategy, it will be essential to fully characterize the factors that are modulated by Notch signaling. We recently reported that Notch3 silencing in HCC results in p53 up-regulation in vitro and, therefore, we focused on the mechanisms that associate Notch3 to p53 protein expression. We explored the regulation of p53 by Notch3 signalling in three HCC cell lines HepG2, SNU398 and Hep3B.We found that Notch3 regulates p53 at post-transcriptional level controlling both Cyclin G1 expression and the feed-forward circuit involving p53, miR-221 and MDM2. Moreover, our results were validated in human HCCs and in a rat model of HCC treated with Notch3 siRNAs. Our findings are becoming an exciting area for further in-depth research toward targeted inactivation of Notch3 receptor as a novel therapeutic approach for increasing the drug-sensitivity, and thereby improving the treatment outcome of patients affected by HCC. Indeed, we proved that Notch3 silencing strongly increases the effects of Nutilin-3. With regard to therapeutic implications, Notch3-specific drugs could represent a valuable strategy to limit Notch signaling in the context of hepatocellular carcinoma over-expressing this receptor. PMID:25431954

  17. Essential Oil Derived From Eupatorium adenophorum Spreng. Mediates Anticancer Effect by Inhibiting STAT3 and AKT Activation to Induce Apoptosis in Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Hao Chen

    2018-05-01

    Full Text Available Eupatorium adenophorum Spreng. (EA is a well-known noxious invasive species. Gas chromatography-mass spectrometry (GC-MS analysis revealed that the essential oil derived from EA (EAEO is mainly composed of sesquiterpenes. However, the pharmacological value of EAEO in hepatocellular carcinoma (HCC remains largely unexplored. Herein, we investigated the anti-HCC activities of EAEO, and explored the potential mechanisms of EAEO-induced apoptosis. An MTT assay showed that EAEO inhibited HCC cell proliferation with little toxicity on normal liver cells. Wound healing and FACS assays revealed that EAEO suppressed HCC cell migration and arrested cell cycle, respectively. Moreover, EAEO promoted in vitro HCC cell apoptosis, and EAEO treatment inhibited HepG2 xenografts growth and enhanced apoptotic nucleus of xenografts in HepG2-bearing nude mice. Mechanistically, EAEO significantly decreased the ratio of Bcl-2/Bax and resulted in the activation of caspase-9 and -3. EAEO also reduced the expression of Grp78, which in turn relieved the inhibition of caspase-12 and -7. Meanwhile, EAEO suppressed the phosphorylation of STAT3 and AKT, indicative of its anti-HCC potential. In summary, we determined that EAEO treatment promoted HCC apoptosis via activation of the apoptotic signaling pathway in mitochondria and endoplasmic reticulum, as well as repressed the activity of STAT3 and AKT in HCC cells.

  18. Ubiquitin specific peptidase 5 mediates Histidine-rich protein Hpn induced cell apoptosis in hepatocellular carcinoma through P14-P53 signaling.

    Science.gov (United States)

    Liu, Yi; Wang, Wei-Mao; Zou, Li-Yi; Li, Li; Feng, Lu; Pan, Ming-Zhu; Lv, Min-Yi; Cao, Ying; Wang, Hua; Kung, Hsiang-Fu; Pang, Jian-Xin; Fu, Wei-Ming; Zhang, Jin-Fang

    2017-06-01

    Hpn is a small histidine-rich cytoplasmic protein from Helicobacter pylori and has been recognized as a high-risk factor for several cancers including gastric cancer, colorectal cancer, and MALT lymphoma. However, the relationship between Hpn and cancers remains elusive. In this study, we discovered that Hpn protein effectively suppressed cell growth and induced apoptosis in hepatocellular carcinoma (HCC). A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics was performed to find the molecular targets of Hpn in HCC cells. It was identified that twelve proteins were differentially expressed, with USP5 being one of the most significantly downregulated protein. The P14 ARF -P53 signaling was activated by USP5 knockdown in HCC cells. Furthermore, USP5 overexpression significantly rescued the suppressive effect of Hpn on the viability of HCC cells. In conclusion, our study suggests that Hpn plays apoptosis-inducing roles through suppressing USP5 expression and activating the P14 ARF -P53 signaling. Therefore, Hpn may be a potential candidate for developing novel anti-HCC drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Specific diagnosis of hepatocellular carcinoma by delayed hepatobiliary imaging

    International Nuclear Information System (INIS)

    Hasegawa, Y.; Nakano, S.; Ibuka, K.

    1986-01-01

    For assessment of the value of delayed hepatobiliary imaging with technetium 99m (/sup 99m/Tc)-(Sn)-N-pyridoxyl-5-methyltryptophan (/sup 99m/Tc-PMT) for specific diagnosis of hepatocellular carcinoma, 88 patients with various malignant and benign liver diseases (49 with hepatocellular carcinoma, 4 with cholangiocellular carcinoma, 10 with metastatic liver carcinoma, 2 with liver cysts, 2 with liver hemangioma, 1 with liver abscess, 2 with intrahepatic lithiasis, 12 with liver cirrhosis, and 6 with chronic hepatitis) were studied. In 20 (41%) of the 49 patients with hepatocellular carcinoma, greater uptake of /sup 99m/Tc-PMT by the tumor than by the surrounding liver tissue was seen in delayed hepatobiliary images, whereas in eight patients (16%), equilibrated uptake was seen. No increased uptake of the radioisotope by hepatic lesions was seen in 21 patients with localized liver diseases other than hepatoma. Moreover, in 18 patients with diffuse liver diseases, no focal accumulation of the radioisotope was seen in delayed /sup 99m/Tc-PMT images. In addition, of 28 patients with hepatocellular carcinoma in whom the serum alpha-fetoprotein level showed little or no increase, 12 showed increased uptake of /sup 99m/Tc-PMT by the tumor. In assessing delayed /sup 99m/Tc-PMT images, however, it was necessary to consider following complications: accumulation of tracer in obstructed and dilated biliary trees; retention of radioactivity in nonneoplastic liver tissues; difficulties in evaluating /sup 99m/Tc-PMT uptake by small hepatic tumors; overlapping of radioactivity in the gut and gallbladder in delayed /sup 99m/Tc-PMT images of tumors. This study indicates that delayed /sup 99m/Tc-PMT images can be useful in the diagnosis of hepatocellular carcinoma

  20. Heat shock protein 27 mediates the effect of 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone on mitochondrial apoptosis in hepatocellular carcinoma.

    Science.gov (United States)

    Fu, Wei-ming; Zhang, Jin-fang; Wang, Hua; Xi, Zhi-chao; Wang, Wei-mao; Zhuang, Peng; Zhu, Xiao; Chen, Shih-chi; Chan, Tak-ming; Leung, Kwong-Sak; Lu, Gang; Xu, Hong-Xi; Kung, Hsiang-fu

    2012-08-03

    Hepatocellular carcinoma (HCC) is a global public health problem which causes approximately 500,000 deaths annually. Considering that the limited therapeutic options for HCC, novel therapeutic targets and drugs are urgently needed. In this study, we discovered that 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP), isolated from the traditional Chinese medicinal herb, Garcinia oblongifolia, effectively inhibited cell growth and induced the caspase-dependent mitochondrial apoptosis in HCC. A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics were performed to find the molecular targets of TDP in HCC cells. Eighteen proteins were identified as differently expressed, with Hsp27 protein being one of the most significantly down-regulated proteins induced by TDP. In addition, the following gain- and loss-of-function studies indicated that Hsp27 mediates mitochondrial apoptosis induced by TDP. Furthermore, a nude mice model also demonstrated the suppressive effect of TDP on HCC. Our study suggests that TDP plays apoptosis-inducing roles by strongly suppressing the Hsp27 expression that is specifically associated with the mitochondrial death of the caspase-dependent pathway. In conclusion, TDP may be a potential anti-cancer drug candidate, especially to cancers with an abnormally high expression of Hsp27. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. RbsB (NTHI_0632) mediates quorum signal uptake in nontypeable Haemophilus influenzae strain 86-028NP.

    Science.gov (United States)

    Armbruster, Chelsie E; Pang, Bing; Murrah, Kyle; Juneau, Richard A; Perez, Antonia C; Weimer, Kristin E D; Swords, W Edward

    2011-11-01

    Nontypeable Haemophilus influenzae (NTHI) is a respiratory commensal and opportunistic pathogen, which persists within biofilms on airway mucosal surfaces. For many species, biofilm formation is impacted by quorum signalling. Our prior work shows that production of autoinducer-2 (AI-2) promotes biofilm development and persistence for NTHI 86-028NP. NTHI 86-028NP encodes an ABC transporter annotated as a ribose transport system that includes a protein (RbsB) with similarity to the Escherichia coli LsrB and Aggregatibacter actinomycetemcomitans RbsB proteins that bind AI-2. In this study, inactivation of rbsB significantly reduced uptake of AI-2 and the AI-2 precursor dihydroxypentanedione (DPD) by NTHI 86-028NP. Moreover, DPD uptake was not competitively inhibited by ribose or other pentose sugars. Transcript levels of rbsB increased in response to DPD and as bacteria approached stationary-phase growth. The NTHI 86-028NP rbsB mutant also formed biofilms with significantly reduced thickness and total biomass and reduced surface phosphorylcholine, similar to a luxS mutant. Infection studies revealed that loss of rbsB impaired bacterial persistence in the chinchilla middle ear, similar to our previous results with luxS mutants. Based on these data, we conclude that in NTHI 86-028NP, RbsB is a LuxS/AI-2 regulated protein that is required for uptake of and response to AI-2. © 2011 Blackwell Publishing Ltd.

  2. Studies on the mechanism of pyrophosphate-mediated uptake of iron from transferrin by isolated rat-liver mitochondria

    International Nuclear Information System (INIS)

    Konopka, K.; Romslo, I.; Bergen Univ.

    1981-01-01

    1. Respiring rat liver mitochondria accumulate iron released from transferrin by pyrophosphate. The amount of iron accumulated is 1-1.5 nmol mg protein -1 h -1 , or approximately 60% of the amount of iron mobilized from transferrin. 2. The uptake declines if respiration is inhibited, substrate is depleted, or the experiments are run under anaerobic conditions. Substrate, depletion and respiratory inhibitors are less inhibitory under anaerobic conditions. 3. More than 80% of the amount of iron accumulated by aerobic, actively respiring mitochondria can be chelated by bathophenanthroline sulphonate, and with deuteroporphyrin included, up to 30% of the amount of iron accumulated is recovered as deuteroheme. Iron accumulated by respiration-inhibited mitochondria under aerobic conditions is not available for heme synthesis. 4. With time the uptake of iron increases eightfold relative to the uptake of pyrophosphate. 5. The results are compatible with a model in which ferric iron is mobilized from transferrin by pyrophosphate, ferric iron pyrophosphate is bound to the mitochondria, iron is reduced, dissociates from pyrophosphate and is taken up by the mitochondria. Ferrous irons thus formed is available for heme synthesis. (orig.) [de

  3. Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.

    Science.gov (United States)

    Chung, Chih-Ling; Wang, Shih-Wei; Sun, Wei-Chih; Shu, Chih-Wen; Kao, Yu-Chen; Shiao, Meng-Shin; Chen, Chun-Lin

    2018-04-18

    Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Superparamagnetic iron oxide nanoparticles mediated 131I-hVEGF siRNA inhibits hepatocellular carcinoma tumor growth in nude mice

    International Nuclear Information System (INIS)

    Chen, Jing; Zhu, Shu; Tong, Liangqian; Li, Jiansha; Chen, Fei; Han, Yunfeng; Zhao, Ming; Xiong, Wei

    2014-01-01

    Hepatocellular carcinoma (HCC) is a primary liver tumor and is the most difficult human malignancy to treat. In this study, we sought to develop an integrative approach in which real-time tumor monitoring, gene therapy, and internal radiotherapy can be performed simultaneously. This was achieved through targeting HCC with superparamagnetic iron oxide nanoparticles (SPIOs) carrying small interfering RNA with radiolabled iodine 131 ( 131 I) against the human vascular endothelial growth factor (hVEGF). hVEGF siRNA was labeled with 131 I by the Bolton-Hunter method and conjugated to SilenceMag, a type of SPIOs. 131 I-hVEGF siRNA/SilenceMag was then subcutaneously injected into nude mice with HCC tumors exposed to an external magnetic field (EMF). The biodistribution and cytotoxicity of 131 I-hVEGF siRNA/SilenceMag was assessed by SPECT (Single-Photon Emission Computed Tomography) and MRI (Magnetic Resonance Imaging) studies and blood kinetics analysis. The body weight and tumor size of nude mice bearing HCC were measured daily for the 4-week duration of the experiment. 131 I-hVEGF siRNA/SilenceMag was successfully labeled; with a satisfactory radiochemical purity (>80%) and biological activity in vitro. External application of an EMF successfully attracted and retained more 131 I-hVEGF siRNA/SilenceMag in HCC tumors as shown by SPECT, MRI and biodistribution studies. The tumors treated with 131 I-hVEGF siRNA/SilenceMag grew nearly 50% slower in the presence of EMF than those without EMF and the control. Immunohistochemical assay confirmed that the tumor targeted by 131 I-hVEGF siRNA/SilenceMag guided by an EMF had a lower VEGF protein level compared to that without EMF exposure and the control. EMF-guided 131 I-hVEGF siRNA/SilenceMag exhibited an antitumor effect. The synergic therapy of 131 I-hVEGF siRNA/SilenceMag might be a promising future treatment option against HCC with the dual functional properties of tumor therapy and imaging

  5. Uptake of 131I-FIAU in BMSCs infected by adenovirus vector-mediated HSV1-TK

    International Nuclear Information System (INIS)

    Zhang Binqing; Wu Tao; Sun Xun; An Rui

    2010-01-01

    Report gene HSV1-TK and therapy gene were connected by IRES, and recombinant adenovirus vector Ad5-TK-IRES-BDNF-EGFP was constructed and infected with BMSCs at MOI of 0, 50, 100, 150, 200 and 250, with the control recombinant adenovirus vector of Ad5-EGFP. Green fluorescence cell positive rate was observed under the microscopy. MTT assay was used to determine the cell proliferation. bFGF and EGF were used to induce the BMSCs, and RQ-PCR to determine target gene expression in infection BMSCs. Uptake of 131 I-FIAU was assessed by gamma counter. The data were processed by SPSS11.code. Recombinant adenovirus at MOI 150 had high infectionefficiency and low toxic in BMSCs. There was a strong relation between the mRNA expression of TK and BDNF in infection BMSCs. The significance between the infection BMSCs and control BMSCs for uptake of 131 I-FIAU at all the time points was t=23.06-173.83 and P 131 I-FIAU. This suggests a suitable gene vector for tracing genetically modified stem cells. (authors)

  6. Quantitative analysis of receptor-mediated uptake and pro-apoptotic activity of mistletoe lectin-1 by high content imaging.

    Science.gov (United States)

    Beztsinna, N; de Matos, M B C; Walther, J; Heyder, C; Hildebrandt, E; Leneweit, G; Mastrobattista, E; Kok, R J

    2018-02-09

    Ribosome inactivating proteins (RIPs) are highly potent cytotoxins that have potential as anticancer therapeutics. Mistletoe lectin 1 (ML1) is a heterodimeric cytotoxic protein isolated from European Mistletoe and belongs to RIP class II. The aim of this project was to systematically study ML1 cell binding, endocytosis pathway(s), subcellular processing and apoptosis activation. For this purpose, state of the art cell imaging equipment and automated image analysis algorithms were used. ML1 displayed very fast binding to sugar residues on the membrane and energy-dependent uptake in CT26 cells. The co-staining with specific antibodies and uptake blocking experiments revealed involvement of both clathrin-dependent and -independent pathways in ML1 endocytosis. Co-localization studies demonstrated the toxin transport from early endocytic vesicles to Golgi network; a retrograde road to the endoplasmic reticulum. The pro-apoptotic and antiproliferative activity of ML1 were shown in time lapse movies and subsequently quantified. ML1 cytotoxicity was less affected in multidrug resistant tumor cell line 4T1 in contrast to commonly used chemotherapeutic drug (ML1 resistance index 6.9 vs 13.4 for doxorubicin; IC 50 : ML1 1.4 ng/ml vs doxorubicin 24000 ng/ml). This opens new opportunities for the use of ML1 as an alternative treatment in multidrug resistant cancers.

  7. Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent.

    Science.gov (United States)

    Sutera, Flavia Maria; Giannola, Libero Italo; Murgia, Denise; De Caro, Viviana

    2017-12-01

    The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate. The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) - a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-mediated metabolism of drug-like molecules. Wistar rats, subjected to two different behavioural studies in which DA-Phen was intraperitoneally administrated at a dose equal to 0.03mmol/kg, were sacrificed after the experimental protocols and their major organs were analysed to quantify the drug uptake. The data obtained were integrated with in silico prediction of potential metabolites of DA-Phen using the SmartCYP predictive tool. DA-Phen reached quantitatively the Central Nervous System and the results showed that the amide bond of the DA-Phen is scarcely hydrolysed as it was found intact in analyzed organs. As a consequence, it is possible to assume that DA-Phen acts as dopaminergic modulator per se and not as a Dopamine prodrug, thus avoiding peripheral release and toxic side effects due to the endogenous neurotransmitter. Furthermore the identification of potential metabolites related to biotransformation of the drug candidate leads to a more careful evaluation of the appropriate route of administration for future intended therapeutic aims and potential translation into clinical studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. An ATP Binding Cassette Transporter Mediates the Uptake of α-(1,6)-Linked Dietary Oligosaccharides in Bifidobacterium and Correlates with Competitive Growth on These Substrates.

    Science.gov (United States)

    Ejby, Morten; Fredslund, Folmer; Andersen, Joakim Mark; Vujičić Žagar, Andreja; Henriksen, Jonas Rosager; Andersen, Thomas Lars; Svensson, Birte; Slotboom, Dirk Jan; Abou Hachem, Maher

    2016-09-16

    The molecular details and impact of oligosaccharide uptake by distinct human gut microbiota (HGM) are currently not well understood. Non-digestible dietary galacto- and gluco-α-(1,6)-oligosaccharides from legumes and starch, respectively, are preferentially fermented by mainly bifidobacteria and lactobacilli in the human gut. Here we show that the solute binding protein (BlG16BP) associated with an ATP binding cassette (ABC) transporter from the probiotic Bifidobacterium animalis subsp. lactis Bl-04 binds α-(1,6)-linked glucosides and galactosides of varying size, linkage, and monosaccharide composition with preference for the trisaccharides raffinose and panose. This preference is also reflected in the α-(1,6)-galactoside uptake profile of the bacterium. Structures of BlG16BP in complex with raffinose and panose revealed the basis for the remarkable ligand binding plasticity of BlG16BP, which recognizes the non-reducing α-(1,6)-diglycoside in its ligands. BlG16BP homologues occur predominantly in bifidobacteria and a few Firmicutes but lack in other HGMs. Among seven bifidobacterial taxa, only those possessing this transporter displayed growth on α-(1,6)-glycosides. Competition assays revealed that the dominant HGM commensal Bacteroides ovatus was out-competed by B. animalis subsp. lactis Bl-04 in mixed cultures growing on raffinose, the preferred ligand for the BlG16BP. By comparison, B. ovatus mono-cultures grew very efficiently on this trisaccharide. These findings suggest that the ABC-mediated uptake of raffinose provides an important competitive advantage, particularly against dominant Bacteroides that lack glycan-specific ABC-transporters. This novel insight highlights the role of glycan transport in defining the metabolic specialization of gut bacteria. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Onset of lipoprotein-supported steroidogenesis in differentiating granulosa cells of rats: cellular events involved in mediating FSH-enhanced uptake of low-density lipoproteins

    International Nuclear Information System (INIS)

    Foster, J.D.

    1987-01-01

    Luteal cells use lipoproteins as the main source of cholesterol in steroidogenesis. However, little is known about the mechanisms underlying hormonal control of lipoprotein uptake. Thus, the authors tested the hypothesis that FSH and androgens regulate low density lipoprotein (LDL)-supported steroidogenesis in maturing granulosa cells by affecting receptor-mediated endocytosis of LDL at a cellular level. For this, immature ovarian granulosa cells were cultured with or without hormones, compactin (de novo synthesis inhibitor), or unlabeled or labeled ( 125 I or gold particles) LDL. Nonhormone-treated cultures produced little progestin; FSH and FSH/androstenedione stimulated steroid secretion. Progestin production by hormone-, but not nonhormone-, treated cultures was decreased by compactin, suggesting that de novo synthesis provided sterol for steroidogenesis. EM quantitation of cells exposed to gold-LDL at 37 0 C revealed that, compared to nonhormone-treated cells, FSH-treated cells (1) bound and internalized more gold-LDL, (2) had a smaller percentage of gold-LDL at their surfaces, (3) displayed a faster apparent rate of LDL internalization and delivery to lysosomes, and (4) contained more gold-labeled lysosomes. Data from biochemical studies in which 125 I-LDL was used supported the morphological findings. In conclusion, this study demonstrates that FSH has important effects at the cellular level on LDL uptake, which seem to underlie the striking increase in progestin production accompanying granulosa cell differentiation

  10. Neuroactivity of detonation nanodiamonds: dose-dependent changes in transporter-mediated uptake and ambient level of excitatory/inhibitory neurotransmitters in brain nerve terminals.

    Science.gov (United States)

    Pozdnyakova, Natalia; Pastukhov, Artem; Dudarenko, Marina; Galkin, Maxim; Borysov, Arsenii; Borisova, Tatiana

    2016-03-31

    Nanodiamonds are one of the most perspective nano-sized particles with superb physical and chemical properties, which are mainly composed of carbon sp(3) structures in the core with sp(2) and disorder/defect carbons on the surface. The research team recently demonstrated neuromodulatory properties of carbon nanodots with other than nanodiamonds hybridization types, i.e., sp(2) hybridized graphene islands and diamond-like sp(3) hybridized elements. In this study, neuroactive properties of uncoated nanodiamonds produced by detonation synthesis were assessed basing on their effects on transporter-mediated uptake and the ambient level of excitatory and inhibitory neurotransmitters, glutamate and γ-aminobutyric acid (GABA), in isolated rat brain nerve terminals. It was shown that nanodiamonds in a dose-dependent manner attenuated the initial velocity of Na(+)-dependent transporter-mediated uptake and accumulation of L-[(14)C]glutamate and [(3)H]GABA by nerve terminals and increased the ambient level of these neurotransmitters. Also, nanodiamonds caused a weak reduction in acidification of synaptic vesicles and depolarization of the plasma membrane of nerve terminals. Therefore, despite different types of hybridization in nanodiamonds and carbon dots, they exhibit very similar effects on glutamate and GABA transport in nerve terminals and this common feature of both nanoparticles is presumably associated with their nanoscale size. Observed neuroactive properties of pure nanodiamonds can be used in neurotheranostics for simultaneous labeling/visualization of nerve terminals and modulation of key processes of glutamate- and GABAergic neurotransmission. In comparison with carbon dots, wider medical application involving hypo/hyperthermia, external magnetic fields, and radiolabel techniques can be perspective for nanodiamonds.

  11. Effects of Endogenous Androgens and Abdominal Fat Distribution on the Interrelationship Between Insulin and Non-Insulin-Mediated Glucose Uptake in Females

    Science.gov (United States)

    Ezeh, Uche; Pall, Marita; Mathur, Ruchi; Dey, Damini; Berman, Daniel; Chen, Ida Y.; Dumesic, Daniel A.

    2013-01-01

    Background: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance. Glucose disposal occurs via noninsulin-mediated glucose uptake (NIMGU) and insulin-mediated glucose uptake (IMGU). It is unknown whether in PCOS NIMGU increases to compensate for declining IMGU and whether androgens and fat distribution influence this relationship. Objectives: The objective of the study was to compare in women with PCOS and controls the interrelationship between NIMGU [ie, glucose effectiveness (Sg)] and IMGU [ie, the insulin sensitivity index (Si)] and the role of androgens and fat distribution. Participants: Twenty-eight PCOS (by National Institutes of Health 1990 criteria) and 28 control (age, race, and body mass index matched) women were prospectively studied. A subset of 16 PCOS subjects and 16 matched controls also underwent abdominal computed tomography. Main Outcome Measures: Glucose disposal (by a frequently sampled iv glucose tolerance test), circulating androgens, and abdominal fat distribution [by waist to hip ratio and visceral (VAT) and sc (SAT) adipose tissue content] were measured. Results: PCOS women had lower mean Si and similar Sg and abdominal fat distribution compared with controls. PCOS women with Si below the PCOS median (more insulin resistant) had a lower mean Sg than controls with Si above the control median (more insulin sensitive). In PCOS only, body mass index, free T, modified Ferriman-Gallwey score, and waist to hip ratio independently predicted Sg, whereas Si did not. In PCOS, VAT and SAT independently and negatively predicted Si and Sg, respectively. Conclusion: The decreased IMGU in PCOS is not accompanied by a compensatory increase in NIMGU or associated with excessive VAT accumulation. Increased general obesity, SAT, and hyperandrogenism are primary predictors of the deterioration of NIMGU in PCOS. PMID:23450052

  12. Study on the enhanced cellular uptake effect of daunorubicin on leukemia cells mediated via functionalized nickel nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Guo Dadong; Wu Chunhui; Hu Hongli; Wang Xuemei [State Key Lab of Bioelectronics (Chien-Shiung Wu Lab), Southeast University, Nanjing 210096 (China); Li Xiaomao [Department of Physics, University of Saarland, D-66041 Saarbruecken (Germany); Chen Baoan, E-mail: xuewang@seu.edu.c [Zhongda Hospital, School of Clinical Medical, Southeast University, Nanjing 210096 (China)

    2009-04-15

    The success of cancer chemotherapy is largely dependent on the efficient anticancer drug accumulation in target tumor tissues and cells so as to inhibit the proliferation of the cancer cells. Recently, some biocompatible nanomaterials have been utilized as drug target delivery systems and have shown the great potential to effectively afford the sustained drug delivery for the target cancer cells. In this study, we have explored the possibility for the bio-application of the functionalized nickel (Ni) nanoparticles and the efficiency of the functionalized Ni nanoparticles on drug permeability, and cellular uptake of leukemia K562 cells in vitro has been probed via atomic force microscopy, inverted fluorescence microscopy and confocal microscopy, electrochemical study and MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide) assay. It is observed that the presence of relevant Ni nanoparticles could induce the membrane structure change of target cells and efficiently improve the permeability of the cell membrane so that the combination of these Ni nanoparticles with anticancer drug daunorubicin could have a synergistic effect on the efficient cytotoxicity suppression in leukemia cancer cells. These observations indicate the great potential of Ni nanoparticles in the future biomedical application including target cancer diagnosis and chemotherapy.

  13. EphA2 modulates radiosensitive of hepatocellular carcinoma cells via p38/mitogen-activated protein kinase-mediated signal pathways

    Directory of Open Access Journals (Sweden)

    Qiao Jin

    2015-10-01

    Full Text Available This experiment was conducted to investigate the role of EPH receptor A2 (EphA2 in the modulation of radiosensitivity of hepatic cellular cancer (HCC cells and to determine whether p38/mitogen-activated protein kinase (p38MAPK signaling mediated EphA2 function in this respect. The protein expressions of EphA2 and phosphorylated p38MAPK were tested in HCC and normal hepatic tissues. In HCC 97H cells, EphA2 was overexpressed and knocked out by transfection with EphA2 expression vector and EphA2-ShRNA, respectively, prior to cell exposure to low-dose irradiation. Significantly upregulated EphA2 and phosphorylated p38MAPK were observed in HCC tissues, compared with those in normal hepatic tissues. Low-dose irradiation (1 Gy only caused minor damage to HCC 97H cells, as assessed by alterations in cell viability, apoptosis rate, and cell healing capacity (p = 0.072, p = 0.078, and p = 0.069 respectively. However, EphA2 knock-out in HCC 97H cells induced significant reduction in cell viability and cell healing capacity after these cells were subjected to low-dose irradiation. Apoptosis rate underwent dramatic increase (p < 0.01. By contrast, EphA2 overexpression in HCC 97H cells reversed these effects and enhanced cell colony formation rate, thus displaying remarkable attenuation of radiosensitivity of HCC 97H cells. Further, SB203580, a specific inhibitor of p38MAPK, was added to HCC 97H cells over-expressing EphA2. The effect of EphA2 overexpression on the radiosensitivity of HCC 97H cells was abrogated. Thus, the present study indicates that EphA2 have the ability to negatively regulate the radiosensitivity of HCC 97H cells, which mainly depends on 38MAPK-mediated signal pathways.

  14. Mediatization

    DEFF Research Database (Denmark)

    Hjarvard, Stig

    2017-01-01

    Mediatization research shares media effects studies' ambition of answering the difficult questions with regard to whether and how media matter and influence contemporary culture and society. The two approaches nevertheless differ fundamentally in that mediatization research seeks answers...... to these general questions by distinguishing between two concepts: mediation and mediatization. The media effects tradition generally considers the effects of the media to be a result of individuals being exposed to media content, i.e. effects are seen as an outcome of mediated communication. Mediatization...... research is concerned with long-term structural changes involving media, culture, and society, i.e. the influences of the media are understood in relation to how media are implicated in social and cultural changes and how these processes come to create new conditions for human communication and interaction...

  15. Inoculation with Bacillus subtilis and Azospirillum brasilense produces abscisic acid that reduces IRT1-mediated cadmium uptake of roots.

    Science.gov (United States)

    Xu, Qianru; Pan, Wei; Zhang, Ranran; Lu, Qi; Xue, Wanlei; Wu, Cainan; Song, Bixiu; Du, Shaoting

    2018-05-08

    Cadmium (Cd) contamination of agricultural soils represents a serious risk to crop safety. A new strategy using abscisic acid (ABA)-generating bacteria, Bacillus subtilis or Azospirillum brasilense, was developed to reduce the Cd accumulation in plants grown in Cd-contaminated soil. Inoculation with either bacterium resulted in a pronounced increase in the ABA level in wild-type Arabidopsis Col-0 plants, accompanied by a decrease in Cd levels in plant tissues, which mitigated the Cd toxicity. As a consequence, the growth of plants exposed to Cd was improved. Nevertheless, B. subtilis and A. brasilense inoculation had little effect on Cd levels and toxicity in the ABA-insensitive mutant snrk 2.2/2.3, indicating that the action of ABA is required for these bacteria to reduce Cd accumulation in plants. Furthermore, inoculation with either B. subtilis or A. brasilense down-regulated the expression of IRT1 (IRON-REGULATED TRANSPORTER 1) in the roots of wild-type plants and had little effect on Cd levels in the IRT1-knockout mutants irt1-1 and irt1-2. In summary, we conclude that B. subtilis and A. brasilense can reduce Cd levels in plants via an IRT1-dependent ABA-mediated mechanism.

  16. Dynamic CT of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Nobuyuki; Shirato, Hiroki; Shinohara, Masahiro; Miyasaka, Kazuo; Morita, Yutaka; Irie, Goro

    1983-03-01

    We performed dynamic CT in 30 cases of hepatocellular carcinoma, and concluded as below. Detecting the stain in the early phase of the dynamic series, it is possible to make a diagnosis of hepatocellular carcinoma. The dynamic CT is effective in a case of small hepatocellular carcinoma in which it is difficult to gain an accurate diagnosis in the routine CT study. The dynamic CT is also effective in the differential diagnosis of hepatic lesions, as other hepatic lesions such as hemangioma and metastatic liver cancer show different patterns compared with hepatocellular carcinoma.

  17. Dynamic CT of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Fujita, Nobuyuki; Shirato, Hiroki; Shinohara, Masahiro; Miyasaka, Kazuo; Morita, Yutaka; Irie, Goro

    1983-01-01

    We performed dynamic CT in 30 cases of hepatocellular carcinoma, and concluded as below. 1 Decting the stain in the early phase of the dynamic series, it is possible to make a diagnosis of hepatocellular carcinoma. 2 The dinamic CT is effective in a case of small hepatocellular carcinoma in which it is difficult to gain an accurate diagnosis in the routine CT study. 3 The dynamic CT is also effective in the differential diagnosis of hepatic lesions, as other hepatic lesions such as hemangioma and metastatic liver cancer show different patterns compared with hepatocellular carcinoma. (author)

  18. Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.

    Science.gov (United States)

    Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L

    2016-02-01

    The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1, and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about 2 times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a 9 times-enhanced apparent permeability (P(app)) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (P(eff)) in mice, 6.32 ± 3.12 and 5.20 ± 2.81 × 10(-5) cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val, seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  19. Receptor-independent, vacuolar ATPase-mediated cellular uptake of histamine receptor-1 ligands: Possible origin of pharmacological distortions and side effects

    International Nuclear Information System (INIS)

    Morissette, Guillaume; Lodge, Robert; Bouthillier, Johanne; Marceau, Francois

    2008-01-01

    The aims of this study were to investigate whether several histamine receptor agonists and antagonists are subjected to receptor-independent ion trapping into acidic organelles, and whether this sequestration influences their pharmacological or toxicological properties. Vacuolar (V)-ATPase-dependent intracellular sequestration of agonists was recognized as morphological alterations (large fluid-filled vacuoles for betahistine and 1-methylhistamine, granular uptake for fluorescent BODIPY FL histamine) prevented by the specific V-ATPase inhibitor bafilomycin A1 in rabbit vascular smooth muscle cells. Lipophilicity was the major determinant of these cellular effects (order of potency: BODIPY FL histamine > betahistine > 1-methylhistamine > histamine) that occurred at high concentrations. This ranking was dissociable from the potency order for H 1 receptor-mediated contraction of the rabbit aorta, a response uninfluenced by bafilomycin. Antihistamines are inherently more lipophilic and caused vacuolization of a proportion of cells at 5-500 μM. Agonist or antagonist-induced vacuoles were of macroautophagic nature (labeled with GFP-conjugated LC3, Rab7 and CD63; detection of LC3 II). Further, the 2 most lipophilic antihistamines tested, astemizole and terfenadine, were potentiated by V-ATPase blockade in the aortic contractility assay (13- and 3.6-fold more potent, respectively, pA 2 scale), suggesting that V-ATPase-mediated cation trapping sequesters these antagonists from the vicinity of H 1 receptors in the therapeutic concentration range. This potentiation did not apply to less lipophilic antagonists (pyrilamine, diphenhydramine). While some agonists and all tested antagonists of the histamine H 1 receptors induce the V-ATPase-dependent vacuolar and autophagic cytopathology, sequestration affects the pharmacology of only the most lipophilic antagonists, the ones prone to off-target arrhythmogenic side effects

  20. Protein phosphatase 2A mediates JS-K-induced apoptosis by affecting Bcl-2 family proteins in human hepatocellular carcinoma HepG2 cells.

    Science.gov (United States)

    Liu, Ling; Huang, Zile; Chen, Jingjing; Wang, Jiangang; Wang, Shuying

    2018-04-25

    Protein phosphatase 2A (PP2A) is an important enzyme within various signal transduction pathways. The present study was investigated PP2A mediates JS-K-induced apoptosis by affecting Bcl-2 family protein. JS-K showed diverse inhibitory effects in five HCC cell lines, especially HepG2 cells. JS-K caused a dose- and time-dependent reduction in cell viability and increased in levels of LDH release. Meanwhile, JS-K- induced apoptosis was characterized by mitochondrial membrane potential reduction, Hoechst 33342 + /PI + dual staining, release of cytochrome c (Cyt c), and activation of cleaved caspase-9/3. Moreover, JS-K-treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C), decrease of anti-apoptotic Bcl-2 family-protein expression including p-Bcl-2 (Ser70), Bcl-2, Bcl-xL, and Mcl-1 as well as the increase of pro-apoptosis Bcl-2 family-protein including Bim, Bad, Bax, and Bak. Furthermore, JS-K caused a marked increase of intracellular NO levels while pre-treatment with Carboxy-PTIO (a NO scavenger) reduced the cytotoxicity effects and the apoptosis rate. Meanwhile, pre-treatment with Carboxy-PTIO attenuated the JS-K-induced up-regulation of PP2A, Cyt c, and cleaved-caspase-9/3 activation. The silencing PP2A-C by siRNA could abolish the activation of PP2A-C, down-regulation of anti-apoptotic Bcl-2 family-protein (p-Bcl-2, Bcl-2, Bcl-xL, and Mcl-1), increase of pro-apoptosis Bcl-2 family-protein (Bim, Bad, Bax, and Bak) and apoptotic-related protein (Cyt c, cleaved caspase-9/3) that were caused by JS-K in HepG2 cells. In addition, pre-treatment with OA (a PP2A inhibitor) also attenuated the above effects induced by JS-K. In summary, NO release from JS-K induces apoptosis through PP2A activation, which contributed to the regulation of Bcl-2 family proteins. © 2018 Wiley Periodicals, Inc.

  1. Megalin-mediated specific uptake of chitosan/siRNA nanoparticles in mouse kidney proximal tubule epithelial cells enables AQP1 gene silencing.

    Science.gov (United States)

    Gao, Shan; Hein, San; Dagnæs-Hansen, Frederik; Weyer, Kathrin; Yang, Chuanxu; Nielsen, Rikke; Christensen, Erik I; Fenton, Robert A; Kjems, Jørgen

    2014-01-01

    RNAi-based strategies provide a great therapeutic potential for treatment of various human diseases including kidney disorders, but face the challenge of in vivo delivery and specific targeting. The chitosan delivery system has previously been shown to target siRNA specifically to the kidneys in mice when administered intravenously. Here we confirm by 2D and 3D bioimaging that chitosan formulated siRNA is retained in the kidney for more than 48 hours where it accumulates in proximal tubule epithelial cells (PTECs), a process that was strongly dependent on the molecular weight of chitosan. Chitosan/siRNA nanoparticles, administered to chimeric mice with conditional knockout of the megalin gene, distributed almost exclusively in cells that expressed megalin, implying that the chitosan/siRNA particle uptake was mediated by a megalin-dependent endocytotic pathway. Knockdown of the water channel aquaporin 1 (AQP1) by up to 50% in PTECs was achieved utilizing the systemic i.v. delivery of chitosan/AQP1 siRNA in mice. In conclusion, specific targeting PTECs with the chitosan nanoparticle system may prove to be a useful strategy for knockdown of specific genes in PTECs, and provides a potential therapeutic strategy for treating various kidney diseases.

  2. Viral hepatitis and hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Juei-Low, Sung [ed.; National Taiwan University College of Medicine, Taipei (Republic of China Taiwan). Department of Internal Medicine; Ding-Shinn, Chen [ed.; National Taiwan University College of Medicine, Taipei (Republic of China Taiwan). Hepatitis Research Center National Taiwan University College of Medicine, Taipei (Republic of China Taiwan). Graduate Institute of Clinical Medicine

    1990-01-01

    Two papers in this volume are in INIS scope, respectively dealing with MRI in the study of viral hepatitis and hepatocellular carcinoma, and The use of {sup 131}I-labeled Lipidol in the diagnosis of hepato-cellular carcinoma. (H.W.). refs.; figs.; tabs.

  3. Viral hepatitis and hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Sung Juei-Low; Chen Ding-Shinn

    1990-01-01

    Two papers in this volume are in INIS scope, respectively dealing with MRI in the study of viral hepatitis and hepatocellular carcinoma, and The use of 131 I-labeled Lipidol in the diagnosis of hepato-cellular carcinoma. (H.W.). refs.; figs.; tabs

  4. Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716 in hepatocellular carcinoma xenograft models

    Directory of Open Access Journals (Sweden)

    Braidwood L

    2014-10-01

    Full Text Available Lynne Braidwood, Kirsty Learmonth, Alex Graham, Joe Conner Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK Abstract: Oncolytic herpes simplex virus (HSV1716, lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies of glioma, melanoma, head and neck squamous cell carcinoma, pediatric non-central nervous system solid tumors, and malignant pleural mesothelioma. To date, 88 patients have received HSV1716 and the virus is well tolerated, with selective replication in tumor cells and no spread to surrounding normal tissue. We assessed the potential value of HSV1716 in preclinical studies with two human hepatocellular carcinoma cell lines, HuH7 and HepG2-luc. HSV1716 displayed excellent replication kinetics in vitro in HepG2-luc cells, a cell line engineered to express luciferase, and virus-mediated cell killing correlated with loss of light emissions from the cells. In vivo, the HepG2-luc cells readily formed light-emitting xenografts that were easily visualized by an in vivo imaging system and efficiently eliminated by HSV1716 oncolysis after intratumoral injection. HSV1716 also demonstrated strong efficacy signals in subcutaneous HuH7 xenografts in nude mice after intravenous administration of virus. In the HuH7 model, the intravenously injected virus replicated prolifically immediately after efficient tumor localization, resulting in highly significant reductions in tumor growth and enhanced survival. Our preclinical results demonstrate excellent tumor uptake of HSV1716, with prolific replication and potent oncolysis. These observations warrant a clinical study of HSV1716 in hepatocellular carcinoma. Keywords: oncolytic herpes simplex virus, HSV1716, hepatocellular carcinoma, xenografts, efficacy 

  5. Skeletal metastases from primary hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Kim, So Sun; Huh, Jin Do; Kim, Ho Joon; Chun, Byung Hee; Joh, Young Duk; Chang, Hee Kyung; Huh, Man Ha

    1988-01-01

    In order to detect and to evaluate the frequency, the distribution, and the radiological findings of skeletal metastases from hepatocellular carcinoma, the authors retrospectively analyzed radiographic, scintigraphic, and CT findings of 257 patients with hepatocellular carcinoma. The results were as follows: 1. Skeletal metastases were demonstrated in 21 patients (8.2%). 2. Frequent symptoms were pain, limitation of motion, paralysis, and mass. In nine of them the initial symptoms were due to skeletal metastases. 3. The common sites of metastases were spine (13 cases), ribs (8 cases), pelvis (8 cases) and femur (6 cases). Humerus, skull and sternum were also frequently involved. 4. Plain film findings were purely osteolytic in all cases and pathologic fractures were noted in 5 cases. 5. The lesions appear expansible in 7 cases, and 4 of them showed associated soft tissue masses on CT scans. 6. Bone scans were performed in 13 cases of them and showed increased radiotracer uptake in all. 7. Angiographic studies of 3 cases showed hypervascularity of the metastatic lesions as well as the primary hepatic tumor.

  6. Clinical utility of imaging for evaluation of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Murakami T

    2014-07-01

    Full Text Available Takamichi Murakami,1 Masakatsu Tsurusaki,1 Tomoko Hyodo,1 Yasuharu Imai2 1Department of Radiology, Kinki University Faculty of Medicine, 2Department of Hepatology and Gastroenterology, Ikeda Municipal Hospital, Osaka, Japan Abstract: The hemodynamics of a hepatocellular nodule is the most important imaging parameter used to characterize various hepatocellular nodules in liver cirrhosis, because sequential changes occur in the feeding vessels and hemodynamic status during hepatocarcinogenesis. Therefore, the imaging criteria for hepatocellular carcinoma (HCC are also usually based on vascular findings, eg, early arterial uptake followed by washout in the portal venous and equilibrium phases. Contrast-enhanced ultrasonography, dynamic multidetector-row computed tomography (MDCT, and dynamic magnetic resonance (MR imaging with gadopentetate dimeglumine (Gd-DTPA are useful for detecting hypervascular HCC on the basis of vascular criteria but are not as useful for hypovascular HCC. Contrast-enhanced MR imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA, a hepatocyte-specific MR contrast agent, is superior to dynamic MDCT and dynamic MR imaging with Gd-DTPA in detecting both hypervascular and hypovascular HCC. Moreover, Gd-EOB-DTPA-enhanced MR imaging can display each histologically differentiated HCC as hypointense relative to the liver parenchyma. 18F-fluorodeoxyglucose positron emission tomography imaging might not be suitable for the screening and detection of HCC, given its lower diagnostic performance. However, this technique plays an important role in determining whether HCC has spread beyond the liver. Keywords: hepatocellular carcinoma, evaluation, imaging, clinical utility

  7. Ultrasound manifestation of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, M S; Yoo, H S; Park, C Y; Choi, H J; Moon, Y M; Lee, S I [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    1982-06-15

    With the advent of gray scale ultrasonographic equipment, the parenchymal disease of liver is more easily evaluated. Ultrasonography is a non-invasive technique, different from angiography, and performed without discomfort to patient. And also ultrasonography can be used in assessing the liver in cases showing equivocal scintigraphy and in differentiation of solid and cystic masses, first detected on scintigrams. Therefore, the complementary use of ultrasonography, Tc-99m-sulfur colloid scan and angiography provides better diagnostic accuracy for the detection of hepatocellular carcinoma, and moreover, sequential ultrasonographic studies in the same patient are valuable of following the course of hepatocellular carcinoma and monitoring the effectiveness of therapy for hepatocellular carcinoma. In thirty patients with histologically proven hepatocellular carcinoma, an analysis of ultrasound manifestation is made and the results are as follows; 1. Ultrasound manifestation of hepatocellular carcinoma by gray scale showed four different sonographic patterns including discrete echo free, discrete echogenic, ill defined echogenic and mixed patterns. 2. The size of hepatocellular carcinoma by ultrasonographic measurement was larger than 5 cm in diameter in 28 cases. 3. In 7 cases performed with angiography, all echogenicities of hepatocellualr carcinoma were correlated with the findings of vascularity of angiography. 4. In cases combined with liver cirrhosis, the sonographic pattern of hepatocellular carcinoma appeared to be discrete or ill defined echogenic patterns.

  8. Ultrasound manifestation of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hwang, M. S.; Yoo, H. S.; Park, C. Y.; Choi, H. J.; Moon, Y. M.; Lee, S. I.

    1982-01-01

    With the advent of gray scale ultrasonographic equipment, the parenchymal disease of liver is more easily evaluated. Ultrasonography is a non-invasive technique, different from angiography, and performed without discomfort to patient. And also ultrasonography can be used in assessing the liver in cases showing equivocal scintigraphy and in differentiation of solid and cystic masses, first detected on scintigrams. Therefore, the complementary use of ultrasonography, Tc-99m-sulfur colloid scan and angiography provides better diagnostic accuracy for the detection of hepatocellular carcinoma, and moreover, sequential ultrasonographic studies in the same patient are valuable of following the course of hepatocellular carcinoma and monitoring the effectiveness of therapy for hepatocellular carcinoma. In thirty patients with histologically proven hepatocellular carcinoma, an analysis of ultrasound manifestation is made and the results are as follows; 1. Ultrasound manifestation of hepatocellular carcinoma by gray scale showed four different sonographic patterns including discrete echo free, discrete echogenic, ill defined echogenic and mixed patterns. 2. The size of hepatocellular carcinoma by ultrasonographic measurement was larger than 5 cm in diameter in 28 cases. 3. In 7 cases performed with angiography, all echogenicities of hepatocellualr carcinoma were correlated with the findings of vascularity of angiography. 4. In cases combined with liver cirrhosis, the sonographic pattern of hepatocellular carcinoma appeared to be discrete or ill defined echogenic patterns

  9. CT of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, H; Tanaka, T; Sai, H; Kawamoto, S; Morimoto, K [Osaka Univ. (Japan). Faculty of Medicine

    1982-06-01

    CT was investigated in 125 cases of hepatocelluar carcinoma and 47 cases of metastatic hepatic neoplasm. The entire contour of each tumor was traced and the average CT value in the tumor was estimated. As a result, the CT value for hepatocellular carcinoma tended to be higher on plain CT and also after contrast enhancement. The CT findings seen frequently were as follows: capsule in 76 cases (60.8%) and septum in 67 cases (53.6%); tumor thrombus in portal vein in 39 cases (31.2%) and that in inferior vena cava in 3 cases (2.4%); localized enlargement of hepatic bile duct in 24 cases (19.2%). These findings were rarely seen in the cases of metastatic hepatic neoplasm. As a relatively outstanding feature of hepatic metastases, a double contour, like concentric circles or contour lines, with a relatively large inner circle or contour line, was found in 21 cases (44.7%). By paying attention to the change of CT value on contrast enhancement and the characteristic image of each case, hepatocellular carcinoma could be differentiated from metastatic hepatic neoplasm with high probability.

  10. Histopathology of hepatocellular carcinoma.

    Science.gov (United States)

    Schlageter, Manuel; Terracciano, Luigi Maria; D'Angelo, Salvatore; Sorrentino, Paolo

    2014-11-21

    Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.

  11. Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice.

    Science.gov (United States)

    Slijepcevic, Davor; Roscam Abbing, Reinout L P; Katafuchi, Takeshi; Blank, Antje; Donkers, Joanne M; van Hoppe, Stéphanie; de Waart, Dirk R; Tolenaars, Dagmar; van der Meer, Jonathan H M; Wildenberg, Manon; Beuers, Ulrich; Oude Elferink, Ronald P J; Schinkel, Alfred H; van de Graaf, Stan F J

    2017-11-01

    The Na + -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B-treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte-models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631-1643).

  12. Morphologic Subtypes of Hepatocellular Carcinoma.

    Science.gov (United States)

    Torbenson, Michael S

    2017-06-01

    Hepatocellular carcinomas can be further divided into distinct subtypes that provide important clinical information and biological insights. These subtypes are distinct from growth patterns and are on based on morphologic and molecular findings. There are 12 reasonably well-defined subtypes as well as 6 provisional subtypes, together making up 35% of all hepatocellular carcinomas. These subtypes are discussed, with an emphasis on their definitions and the key morphologic findings. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Proton-coupled organic cation antiporter-mediated uptake of apomorphine enantiomers in human brain capillary endothelial cell line hCMEC/D3.

    Science.gov (United States)

    Okura, Takashi; Higuchi, Kei; Kitamura, Atsushi; Deguchi, Yoshiharu

    2014-01-01

    R(-)-Apomorphine is a dopamine agonist used for rescue management of motor function impairment associated with levodopa therapy in Parkinson's disease patients. The aim of this study was to examine the role of proton-coupled organic cation antiporter in uptake of R(-)-apomorphine and its S-enantiomer in human brain, using human endothelial cell line hCMEC/D3 as a model. Uptake of R(-)- or S(+)-apomorphine into hCMEC/D3 cells was measured under various conditions to evaluate its time-, concentration-, energy- and ion-dependency. Inhibition by selected organic cations was also examined. Uptakes of both R(-)- and S(+)-apomorphine increased with time. The initial uptake velocities of R(-)- and S(+)-apomorphine were concentration-dependent, with similar Km and Vmax values. The cell-to-medium (C/M) ratio of R(-)-apomorphine was significantly reduced by pretreatment with sodium azide, but was not affected by replacement of extracellular sodium ion with N-methylglucamine or potassium. Intracellular alkalization markedly reduced the uptake, while intracellular acidification increased it, suggesting that the uptake is driven by an oppositely directed proton gradient. The C/M ratio was significantly decreased by amantadine, verapamil, pyrilamine and diphenhydramine (substrates or inhibitors of proton-coupled organic cation antiporter), while tetraethylammonium (substrate of organic cation transporters (OCTs)) and carnitine (substrate of carnitine/organic cation transporter 2; (OCTN2)) had no effect. R(-)-Apomorphine uptake was competitively inhibited by diphenhydramine. Our results indicate that R(-)-apomorphine transport in human blood-brain barrier (BBB) model cells is similar to S(+)-apomorphine uptake. The transport was dependent on an oppositely directed proton gradient, but was sodium- or membrane potential-independent. The transport characteristics were consistent with involvement of the previously reported proton-coupled organic cation antiporter.

  14. Rottlerin upregulates DDX3 expression in hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Zhong; Shen, Gen-Hai; Xie, Jia-Ming; Li, Bin; Gao, Quan-Gen

    2018-01-01

    Rottlerin has been reported to exert its anti-tumor activity in various types of human cancers. However, the underlying molecular mechanism has not been fully elucidated. In the current study, we explored whether rottlerin exhibits its tumor suppressive function in hepatocellular carcinoma cells. Our MTT assay results showed that rottlerin inhibited cell growth in hepatocellular carcinoma cells. Moreover, we found that rottlerin induced cell apoptosis and caused cell cycle arrest at G1 phase. Furthermore, our wound healing assay result demonstrated that rottlerin retarded cell migration in hepatocellular carcinoma cells. Additionally, rottlerin suppressed cell migration and invasion. Notably, we found that rottlerin upregulated DDX3 expression and subsequently downregulated Cyclin D1 expression and increased p21 level. Importantly, down-regulation of DDX3 abrogated the rottlerin-mediated tumor suppressive function, whereas overexpression of DDX3 promoted the anti-tumor activity of rottlerin. Our study suggests that rottlerin exhibits its anti-cancer activity partly due to upregulation of DDX3 in hepatocellular carcinoma cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Hepatocellular carcinoma: a review

    Directory of Open Access Journals (Sweden)

    Balogh J

    2016-10-01

    Full Text Available Julius Balogh,1,2 David Victor III,1,3,4 Emad H Asham,1,2 Sherilyn Gordon Burroughs,1,2 Maha Boktour,1,2 Ashish Saharia,1,2 Xian Li,1,2 R Mark Ghobrial,1,2 Howard P Monsour Jr,1,3,4 1Sherrie and Alan Conover Center for Liver Disease and Transplantation, 2Division of Transplantation, Department of Surgery, 3Department of Gastroenterology and Transplant Hepatology, 4Department of Medicine, Houston Methodist Hospital, Houston, TX, USA Abstract: Hepatocellular carcinoma (HCC is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an

  16. Delayed hepatobiliary imaging in the diagnosis of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Chen, S.; Ma, Z.; Tang, Z.

    2000-01-01

    In recent years, the use of ultrasonography (US), X-CT and MRI has reduced the employment of isotopic explorations in the detection of hepatocellular carcinoma (HCC). But sometime the results of US, X-CT or MRI were different and diagnosis was very difficult. This present investigation was aimed to assess the usefulness of delayed hepatobiliary imaging in the diagnosis of HCC in these patients. Forty-eight patients consisting of 33 males and 15 females were entered into the research protocol. The mean age was 46 yr old (range 12-71 yr old). All of the patients were performed by surgery and verified histologically after nuclear examination. The subject was in a supine position under a gamma camera (Elscint, Apex Ap-6) and 555 MBq of Tc-99m-PMT were injected intravenously. The initial scinphotos obtained within 1 min after injection were used to image the blood pool phase. Subsequently, hepatic scans were obtained at 5 min, 1,2 and 5 hr. Anterior, right lateral and posterior hepatic images were recorded. According to the radioactive uptake by the lesion in delayed phase, the negative (no or minor uptake), positive (equal or greater uptake) or very strong positive (almost equal to the activity, of gallbladder) were judged. The positive were considered as diagnostic of HCC. And the very strong positive, were considered as diagnostic of benign hepatoma, such as adenoma or FNH. Thirty-seven of the forty-eight patients were HCC based on histology. Delayed imaging revealed increased or equilibrated uptake of radioactivity by the tumors in 22 of 37 patients with hepatocellular carcinoma. The sensitivity was 59.5%. One patient final diagnosis based on histology was focal nodular regenerative hyperplasia, and only the diagnosis with delayed hepatobiliary imaging before surgery was correct. Compared with US, X-CT and MRI, delayed hepatobiliary imaging had the highest specificity for diagnosis of hepatocellular carcinoma. In recent group, the specificity of Tc-99m-PMT delayed

  17. Investigating the Effects of Mass Media Exposure on the Uptake of Preventive Measures by Hong Kong Residents during the 2015 MERS Outbreak: The Mediating Role of Interpersonal Communication and the Perception of Concern.

    Science.gov (United States)

    Ludolph, Ramona; Schulz, Peter J; Chen, Ling

    2018-01-01

    In 2015, South Korea experienced the largest outbreak to date of the Middle East Respiratory Syndrome (MERS-CoV) outside the Middle East. Fears related to a potential spread of the disease led to an increased alert level as well as heightened media coverage in the neighboring Hong Kong. A cross-sectional survey (N = 533) among residents of Hong Kong was conducted to assess the relationships between the effects of outbreak-related mass media coverage, interpersonal communication, the perceived level of concern in one's close environment, and the uptake of preventive measures. A serial multiple mediator model finds that interpersonal communication and higher perceived concern indirectly influence the effects of media coverage on the engagement in preventive actions. These results expand previous research on the mediating role of interpersonal communication and support assumptions about a modified two-step flow of communication in the context of a public health emergency.

  18. An ATP Binding Cassette Transporter Mediates the Uptake of alpha-(1,6)-Linked Dietary Oligosaccharides in Bifidobacterium and Correlates with Competitive Growth on These Substrates

    NARCIS (Netherlands)

    Ejby, Morten; Fredslund, Folmer; Andersen, Joakim Mark; Zagar, Andreja Vujicic; Henriksen, Jonas Rosager; Andersen, Thomas Lars; Svensson, Birte; Slotboom, Dirk Jan; Abou Hachem, Maher

    2016-01-01

    The molecular details and impact of oligosaccharide uptake by distinct human gut microbiota (HGM) are currently not well understood. Non-digestible dietary galacto- and gluco--(1,6)-oligosaccharides from legumes and starch, respectively, are preferentially fermented by mainly bifidobacteria and

  19. Radioembolization of hepatocellular carcinoma.

    Science.gov (United States)

    Van de Wiele, Christophe

    2010-12-01

    In this review paper, available data on radioembolization of unresectable hepatocellular carcinoma (HCC) using commercially available radiopharmaceuticals, respectively (131)I-Lipiodol, Therasphere (glass-microspheres) and SIRspheres (resin-microspheres) are reviewed. In the palliative setting, (131)I-Lipiodol was shown to yield response rates of 17-92% which in patients with portal vein thrombosis (PVT) translate into a survival benefit as evidenced by a phase III randomized trial. Furthermore, in terms of efficacy, (131)I-Lipiodol is as efficacious as trans-arterial chemoembolization (TACE) but far better tolerated. In the adjuvant setting, improved recurrence-free and overall survival when compared to surgery alone have been reported but these results warrant confirmation by randomized prospective trials. Similar to (131)I-Lipiodol, when administered in a palliative setting, radioembolization using (90)Y microspheres was proven effective for selected cases of non-resectable HCC and well tolerated. Available data suggest that Therasphere treatment outperforms TACE both in terms of response as in terms of event-free survival in unresectable HCC. However, this finding needs confirmation by randomized prospective trials. Therasphere treatment was also shown to limit progression of HCC allowing potential candidates for orthotopic liver transplantation (OLT) more time to wait for donor organs as well as to downstage the HCC disease to such an extent that patients that were initially not, as yet become eligible for OLT with a gain in survival. Finally, Therasphere was shown to be safe and efficacious in HCC patients presenting with PVT, reason for which approval was granted for this indication by the FDA.

  20. Maltitol inhibits small intestinal glucose absorption and increases insulin mediated muscle glucose uptake ex vivo but not in normal and type 2 diabetic rats.

    Science.gov (United States)

    Chukwuma, Chika Ifeanyi; Ibrahim, Mohammed Auwal; Islam, Md Shahidul

    2017-02-01

    This study investigated the effects of maltitol on intestinal glucose absorption and muscle glucose uptake using ex vivo and in vivo experimental models. The ex vivo experiment was conducted in isolated jejunum and psoas muscle from normal rats. The in vivo study investigated the effects of a single bolus dose of maltitol on gastric emptying, intestinal glucose absorption and digesta transit in normal and type 2 diabetic rats. Maltitol inhibited glucose absorption in isolated rat jejunum and increased glucose uptake in isolated rat psoas muscle in the presence of insulin but not in the absence of insulin. In contrast, maltitol did not significantly (p > 0.05) alter small intestinal glucose absorption or blood glucose levels as well as gastric emptying and digesta transit in normal or type 2 diabetic rats. The results suggest that maltitol may not be a suitable dietary supplement for anti-diabetic food and food products to improve glycemic control.

  1. Hepatocellular carcinoma in Danish patients

    DEFF Research Database (Denmark)

    Stefansdottir, Jenna; Christensen, Erik; Schiødt, Frank Vinholt

    2017-01-01

    OBJECTIVE: Hepatocellular carcinoma (HCC) is a common cause of cancer, and most HCC patients have underlying cirrhosis. Retrospectively, we aimed to characterize patients with newly diagnosed HCC at a Danish hospital and to investigate survival and identify predictive factors for survival. METHODS...

  2. Glutathione treatment of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Dalhoff, K; Ranek, L; Mantoni, M

    1992-01-01

    This prospective study was undertaken to substantiate observations that glutathione (GSH) inhibits or reverses tumor growth in humans with hepatocellular carcinoma (HCC), a neoplasm with an extremely poor prognosis. Eight patients with biopsy-proven HCC not amenable to surgery were given 5 g of GSH...

  3. Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling

    Science.gov (United States)

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients. PMID:26560447

  4. Thymostimulin in advanced hepatocellular carcinoma: A phase II trial

    Directory of Open Access Journals (Sweden)

    Behl Susanne

    2008-03-01

    Full Text Available Abstract Background Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. Methods 44 patients (84 % male, median age 69 years not suitable or refractory to conventional therapy received thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. Results Median survival was 11.5 months (95% CI 7.9–15.0 with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01, a low score in the Okuda- and CLIP-classification (p Conclusion Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage in addition to response to thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept. Trial registration Current Controlled Trials ISRCTN29319366.

  5. Reduced intracellular drug accumulation in drug-resistant leukemia cells is not solely due to MDR-mediated efflux but also to decreased uptake

    Directory of Open Access Journals (Sweden)

    Angela Oliveira Pisco

    2014-10-01

    Full Text Available Expression of ABC family transporter proteins that promote drug efflux from cancer cells is a widely observed mechanism of multi-drug resistance of cancer cells. Cell adaptation in long-term culture of HL60 leukemic cells in the presence of chemotherapy leads to induction and maintenance of the ABC transporters expression, preventing further accumulation of drugs. However, we found that decreased accumulation of drugs and fluorescent dyes was also contributed by a reduced uptake by the resistant cells. Confocal time-lapse microscopy and flow cytometry revealed that fluid-phase endocytosis was diminished in drug-resistant cells compared to drug-sensitive cells. Drug uptake was increased by insulin co-treatment when cells were grown in methylcellulose and monitored under the microscope, but not when cultured in suspension. We propose that multi-drug resistance is not solely achieved by enhanced efflux capacity but also by supressed intake of the drug offering an alternative target to overcome drug resistance or potentiate chemotherapy.

  6. Isoviolanthin Extracted from Dendrobium officinale Reverses TGF-β1-Mediated Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma Cells via Deactivating the TGF-β/Smad and PI3K/Akt/mTOR Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Shangping Xing

    2018-05-01

    Full Text Available Dendrobium officinale is a precious medicinal herb and health food, and its pharmacological actions have been studied and proved. However, the mechanisms by which its active flavonoid glycosides affect epithelial–mesenchymal transition (EMT in hepatocellular carcinoma (HCC cells, such as HepG2 and Bel-7402 cells, have not been previously investigated. Therefore, we investigated whether isoviolanthin extracted from the leaves of Dendrobium officinale inhibits transforming growth factor (TGF-β1-induced EMT in HCC cells. In this study, the physicochemical properties and structure of isoviolanthin were identified by HPLC, UV, ESIMS, and NMR and were compared with literature data. HCC cells were pretreated with 10 ng/mL TGF-β1 to induce EMT and then treated with isoviolanthin. Herein, we found that isoviolanthin exhibited no cytotoxic effects on normal liver LO2 cells but notably reduced the migratory and invasive capacities of TGF-β1-treated HCC cells. Additionally, isoviolanthin treatment decreased matrix metalloproteinase (MMP-2 and -9 levels, and remarkably altered the expression of EMT markers via regulating the TGF-β/Smad and PI3K/Akt/mTOR signaling pathways; Western blot analysis confirmed that the effects of the inhibitors SB431542 and LY294002 were consistent with those of isoviolanthin. These findings demonstrate the potential of isoviolanthin as a therapeutic agent for the treatment of advanced-stage metastatic HCC.

  7. GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets 1

    DEFF Research Database (Denmark)

    Guan, Xinfu; Stoll, Barbara; Lu, Xiaofeng

    2003-01-01

    (n = 8) received consecutive intravenous infusions of saline, GLP-2, and GLP-2 plus N(G)-Nitro-L-arginine methyl ester (L-NAME, 50 micromol x kg(-1) x hour(-1)) for 4 hours each. RESULTS: GLP-2 acutely increased portal-drained visceral (PDV) blood flow rate (+25%) and intestinal blood volume (+51......%) in TPN-fed piglets. GLP-2 also increased intestinal constitutive nitric oxide synthase (NOS) activity and endothelial NOS protein abundance. GLP-2 acutely increased PDV glucose uptake (+90%) and net lactate production (+79%). Co-infusion of GLP-2 plus L-NAME did not increase either PDV blood flow rate......, and this response is nitric oxide-dependent. These findings suggest that GLP-2 may play an important physiological role in the regulation of intestinal blood flow and that nitric oxide is involved in GLP-2 receptor function....

  8. Aquaporin-mediated increase in root hydraulic conductance is involved in silicon-induced improved root water uptake under osmotic stress in Sorghum bicolor L.

    Science.gov (United States)

    Liu, Peng; Yin, Lina; Deng, Xiping; Wang, Shiwen; Tanaka, Kiyoshi; Zhang, Suiqi

    2014-09-01

    The fact that silicon application alleviates water deficit stress has been widely reported, but the underlying mechanism remains unclear. Here the effects of silicon on water uptake and transport of sorghum seedlings (Sorghum bicolor L.) growing under polyethylene glycol-simulated osmotic stress in hydroponic culture and water deficit stress in sand culture were investigated. Osmotic stress dramatically decreased dry weight, photosynthetic rate, transpiration rate, stomatal conductance, and leaf water content, but silicon application reduced these stress-induced decreases. Although silicon application had no effect on stem water transport capacity, whole-plant hydraulic conductance (Kplant) and root hydraulic conductance (Lp) were higher in silicon-treated seedlings than in those without silicon treatment under osmotic stress. Furthermore, the extent of changes in transpiration rate was similar to the changes in Kplant and Lp. The contribution of aquaporin to Lp was characterized using the aquaporin inhibitor mercury. Under osmotic stress, the exogenous application of HgCl2 decreased the transpiration rates of seedlings with and without silicon to the same level; after recovery induced by dithiothreitol (DTT), however, the transpiration rate was higher in silicon-treated seedlings than in untreated seedlings. In addition, transcription levels of several root aquaporin genes were increased by silicon application under osmotic stress. These results indicate that the silicon-induced up-regulation of aquaporin, which was thought to increase Lp, was involved in improving root water uptake under osmotic stress. This study also suggests that silicon plays a modulating role in improving plant resistance to osmotic stress in addition to its role as a mere physical barrier. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  9. Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells.

    Science.gov (United States)

    Zhang, Yafei; Zhang, Bicheng; Zhang, Anran; Zhao, Yong; Zhao, Jie; Liu, Jian; Gao, Jianfei; Fang, Dianchun; Rao, Zhiguo

    2012-09-01

    Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients

  10. An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Yan; Fang, Lin; Zhang, Quan'an; Zheng, Qin; Tong, Jinlong; Fu, Xiaohui; Jiang, Xiaoqing; Su, Changqing; Zheng, Junnian

    2013-06-01

    Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  11. Follicle-stimulating hormone receptor-mediated uptake of 45Ca2+ by cultured rat Sertoli cells does not require activation of cholera toxin- or pertussis toxin-sensitive guanine nucleotide binding proteins or adenylate cyclase

    International Nuclear Information System (INIS)

    Grasso, P.; Reichert, L.E. Jr.

    1990-01-01

    We have previously reported that FSH stimulates flux of 45Ca2+ into cultured Sertoli cells from immature rats via voltage-sensitive and voltage-independent calcium channels. In the present study, we show that this effect of FSH does not require cholera toxin (CT)- or pertussis toxin (PT)-sensitive guanine nucleotide binding (G) protein or activation of adenylate cyclase (AC). Significant stimulation of 45Ca2+ influx was observed within 1 min, and maximal response (3.2-fold over basal levels) was achieved within 2 min after exposure to FSH. FSH-stimulated elevations in cellular cAMP paralleled increases in 45Ca2+ uptake, suggesting a possible coupling of AC activation to 45Ca2+ influx. (Bu)2cAMP, however, was not able to enhance 45Ca2+ uptake over basal levels at a final concentration of 1000 microM, although a concentration-related increase in androstenedione conversion to estradiol was evident. Exposure of Sertoli cells to CT (10 ng/ml) consistently stimulated basal levels of androstenedione conversion to estradiol but had no effect on basal levels of 45Ca2+ uptake. Similarly, CT had no effect on FSH-induced 45Ca2+ uptake, but potentiated FSH-stimulated estradiol synthesis. PT (10 ng/ml) augmented basal and FSH-stimulated estradiol secretion without affecting 45Ca2+ influx. The adenosine analog N6-phenylisopropyladenosine, which binds to Gi-coupled adenosine receptors on Sertoli cells, inhibited FSH-stimulated androgen conversion to estradiol in a dose-related (1-1000 nM) manner, but FSH-stimulated 45Ca2+ influx remained unchanged. Our results show that in contrast to FSH-stimulated estradiol synthesis, the flux of 45Ca2+ into Sertoli cells in response to FSH is not mediated either directly or indirectly by CT- or PT-sensitive G protein, nor does it require activation of AC. Our data further suggest that the FSH receptor itself may function as a calcium channel

  12. Follicle-stimulating hormone receptor-mediated uptake of sup 45 Ca sup 2+ by cultured rat Sertoli cells does not require activation of cholera toxin- or pertussis toxin-sensitive guanine nucleotide binding proteins or adenylate cyclase

    Energy Technology Data Exchange (ETDEWEB)

    Grasso, P.; Reichert, L.E. Jr. (Albany Medical College, NY (USA))

    1990-08-01

    We have previously reported that FSH stimulates flux of 45Ca2+ into cultured Sertoli cells from immature rats via voltage-sensitive and voltage-independent calcium channels. In the present study, we show that this effect of FSH does not require cholera toxin (CT)- or pertussis toxin (PT)-sensitive guanine nucleotide binding (G) protein or activation of adenylate cyclase (AC). Significant stimulation of 45Ca2+ influx was observed within 1 min, and maximal response (3.2-fold over basal levels) was achieved within 2 min after exposure to FSH. FSH-stimulated elevations in cellular cAMP paralleled increases in 45Ca2+ uptake, suggesting a possible coupling of AC activation to 45Ca2+ influx. (Bu)2cAMP, however, was not able to enhance 45Ca2+ uptake over basal levels at a final concentration of 1000 microM, although a concentration-related increase in androstenedione conversion to estradiol was evident. Exposure of Sertoli cells to CT (10 ng/ml) consistently stimulated basal levels of androstenedione conversion to estradiol but had no effect on basal levels of 45Ca2+ uptake. Similarly, CT had no effect on FSH-induced 45Ca2+ uptake, but potentiated FSH-stimulated estradiol synthesis. PT (10 ng/ml) augmented basal and FSH-stimulated estradiol secretion without affecting 45Ca2+ influx. The adenosine analog N6-phenylisopropyladenosine, which binds to Gi-coupled adenosine receptors on Sertoli cells, inhibited FSH-stimulated androgen conversion to estradiol in a dose-related (1-1000 nM) manner, but FSH-stimulated 45Ca2+ influx remained unchanged. Our results show that in contrast to FSH-stimulated estradiol synthesis, the flux of 45Ca2+ into Sertoli cells in response to FSH is not mediated either directly or indirectly by CT- or PT-sensitive G protein, nor does it require activation of AC. Our data further suggest that the FSH receptor itself may function as a calcium channel.

  13. Protective effect of the poly(ADP-ribose polymerase inhibitor PJ34 on mitochondrial depolarization-mediated cell death in hepatocellular carcinoma cells involves attenuation of c-Jun N-terminal kinase-2 and protein kinase B/Akt activation

    Directory of Open Access Journals (Sweden)

    Radnai Balazs

    2012-05-01

    Full Text Available Abstract Background 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11 was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose-polymerase (PARP, protein kinase B/Akt and mitogen activated protein kinase (MAPK activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy. Results We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase. At higher concentrations, IK11 induced reactive oxygen species (ROS production, mitochondrial membrane depolarization, activation of c-Jun N-terminal kinase 2 (JNK2, and substantial loss of HepG2 cells. ROS production appeared marginal in mediating the cytotoxicity of IK11 since N-acetyl cysteine was unable to prevent it. However, the PARP inhibitor PJ34, although not a ROS scavenger, strongly inhibited both IK11-induced ROS production and cell death. JNK2 activation seemed to be a major mediator of the effect of IK11 since inhibition of JNK resulted in a substantial cytoprotection while inhibitors of the other kinases failed to do so. Inhibition of Akt slightly diminished the effect of IK11, while the JNK and Akt inhibitor and ROS scavenger trans-resveratrol completely protected against it. Conclusions These results indicate significant involvement of PARP, a marginal role of ROS and a pro-apoptotic role of Akt in this system, and raise attention to a novel mechanism that should be considered when cancer therapy is augmented with PARP-inhibition, namely the cytoprotection by inhibition of JNK2.

  14. [Primary study on fluro [ 19F] berberine derivative for human hepatocellular carcinoma targetting in vitro].

    Science.gov (United States)

    Zhang, Tong; Wu, Xiaoai; Cai, Huawei; Liang, Meng; Fan, Chengzhong

    2017-04-01

    [ 18 F]HX-01, a Fluorine-18 labeled berberine derivative, is a potential positron emission tomography (PET) tumor imaging agent, while [ 19 F]HX-01 is a nonradioactive reference substance with different energy state and has the same physical and chemical properties. In order to collect data for further study of [ 18 F]HX-01 PET imaging of hepatocellular carcinoma in vivo , this study compared the uptake of [ 19 F]HX-01 by human hepatocellular carcinoma and normal hepatocytes in vitro . The target compound, [ 19 F]HX-01, was synthesized in one step using berberrubine and 3-fluoropropyl 4-methylbenzenesulfonate. Cellular uptake and localization of [ 19 F]HX-01 were performed by a fluorescence microscope in human hepatocellular carcinoma HepG2, SMMC-7721 and human normal hepatocyte HL-7702. Cellular proliferation inhibition and cell cytotoxicity assay of the [ 19 F]HX-01 were conducted using cell counting kit-8 (CCK-8) on HepG2, SMMC-7721 and HL-7702 cells. Fluorescent microscopy showed that the combining ability of [ 19 F]HX-01 to the carcinoma SMMC-7721 and HepG2 was higher than that to the normal HL-7702. Cellular proliferation inhibition assay demonstrated that [ 19 F]HX-01 leaded to a dose-dependent inhibition on SMMC-7721, HepG2, and HL-7702 proliferation. Cell cytotoxicity assay presented that the cytotoxicity of [ 19 F]HX-01 to SMMC-7721 and HepG2 was obviously higher than that to HL-7702. This in vitro study showed that [ 19 F]HX-01 had a higher selectivity on human hepatocellular carcinoma cells (SMMC-7721, HepG2) but has less toxicity to normal hepatocytes (HL-7702). This could set up the idea that the radioactive reference substance [ 18 F]HX-01 may be worthy of further development as a potential molecular probe targeting human hepatocellular carcinoma using PET.

  15. Ion Exchangers NHX1 and NHX2 Mediate Active Potassium Uptake into Vacuoles to Regulate Cell Turgor and Stomatal Function in Arabidopsis[W][OA

    Science.gov (United States)

    Barragán, Verónica; Leidi, Eduardo O.; Andrés, Zaida; Rubio, Lourdes; De Luca, Anna; Fernández, José A.; Cubero, Beatriz; Pardo, José M.

    2012-01-01

    Intracellular NHX proteins are Na+,K+/H+ antiporters involved in K+ homeostasis, endosomal pH regulation, and salt tolerance. Proteins NHX1 and NHX2 are the two major tonoplast-localized NHX isoforms. Here, we show that NHX1 and NHX2 have similar expression patterns and identical biochemical activity, and together they account for a significant amount of the Na+,K+/H+ antiport activity in tonoplast vesicles. Reverse genetics showed functional redundancy of NHX1 and NHX2 genes. Growth of the double mutant nhx1 nhx2 was severely impaired, and plants were extremely sensitive to external K+. By contrast, nhx1 nhx2 mutants showed similar sensitivity to salinity stress and even greater rates of Na+ sequestration than the wild type. Double mutants had reduced ability to create the vacuolar K+ pool, which in turn provoked greater K+ retention in the cytosol, impaired osmoregulation, and compromised turgor generation for cell expansion. Genes NHX1 and NHX2 were highly expressed in guard cells, and stomatal function was defective in mutant plants, further compromising their ability to regulate water relations. Together, these results show that tonoplast-localized NHX proteins are essential for active K+ uptake at the tonoplast, for turgor regulation, and for stomatal function. PMID:22438021

  16. [3H]uridine uptake by target monolayers as a terminal label in an in vitro cell-mediated cytotoxicity assay

    International Nuclear Information System (INIS)

    Smith, G.; Nicklin, S.

    1979-01-01

    A terminal labelling method is described for measuring cell-mediated cytotoxicity based on the ability of surviving target cells to incorporate [ 3 H]uridine into their RNA precursor pools. Parameters of the system were examined using whole and damaged embryonic mouse fibroblast monolayers. This assay is less laborious than direct cell counting and gives increased sensitivity at low target to effector cell ratios. The labelling time is short and, unlike similar techniques, it allows target cell monolayers to remain intact after completion of the radioassay and available for histological examination. This is important where heterogeneous target populations are employed since it allows assessment of differential cell killing and eliminates the need for duplicate cultures. The assay was used in conjunction with a well defined mouse popliteal lymph node assay to investigate the appearance of cytotoxic cells during a localised graft versus host response. Results showed a direct correlation between proliferative index and the development of highly specific cell-mediated cytotoxicity. (Auth.)

  17. l-Arginine Uptake by Cationic Amino Acid Transporter Promotes Intra-Macrophage Survival of Leishmania donovani by Enhancing Arginase-Mediated Polyamine Synthesis

    Directory of Open Access Journals (Sweden)

    Abhishek Mandal

    2017-07-01

    Full Text Available The survival of intracellular protozoan parasite, Leishmania donovani, the causative agent of Indian visceral leishmaniasis (VL, depends on the activation status of macrophages. l-Arginine, a semi-essential amino acid plays a crucial regulatory role for activation of macrophages. However, the role of l-arginine transport in VL still remains elusive. In this study, we demonstrated that intra-macrophage survival of L. donovani depends on the availability of extracellular l-arginine. Infection of THP-1-derived macrophage/human monocyte-derived macrophage (hMDM with Leishmania, resulted in upregulation of l-arginine transport. While investigating the involvement of the transporters, we observed that Leishmania survival was greatly impaired when the transporters were blocked either using inhibitor or siRNA-mediated downregulation. CAT-2 was found to be the main isoform associated with l-arginine transport in L. donovani-infected macrophages. l-arginine availability and its transport regulated the host arginase in Leishmania infection. Arginase and inducible nitric oxide synthase (iNOS expression were reciprocally regulated when assayed using specific inhibitors and siRNA-mediated downregulation. Interestingly, induction of iNOS expression and nitric oxide production were observed in case of inhibition of arginase in infected macrophages. Furthermore, inhibition of l-arginine transport as well as arginase resulted in decreased polyamine production, limiting parasite survival inside macrophages. l-arginine availability and transport regulated Th1/Th2 cytokine levels in case of Leishmania infection. Upregulation of l-arginine transport, induction of host arginase, and enhanced polyamine production were correlated with increased level of IL-10 and decreased level of IL-12 and TNF-α in L. donovani-infected macrophages. Our findings provide clear evidence for targeting the metabolism of l-arginine and l-arginine-metabolizing enzymes as an important

  18. Current management of hepatocellular carcinoma

    Science.gov (United States)

    Tabrizian, Parissa; Roayaie, Sasan; Schwartz, Myron E

    2014-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and leading cause of death among patients with cirrhosis. Treatment guidelines are based according to the Barcelona Clinic Liver Cancer staging system. The choice among therapeutic options that include liver resection, liver transplantation, locoregional, and systemic treatments must be individualized for each patient. The aim of this paper is to review the outcomes that can be achieved in the treatment of HCC with the heterogeneous therapeutic options currently available in clinical practice. PMID:25132740

  19. Transhemangioma Ablation of Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Pua, Uei

    2012-01-01

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  20. Transhemangioma Ablation of Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Pua, Uei, E-mail: druei@yahoo.com [Tan Tock Seng Hospital, Department of Diagnostic Radiology (Singapore)

    2012-12-15

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  1. How to detect hepatocellular carcinoma in cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Ward, Janice; Robinson, Philip J. [Department of Clinical Radiology, St. James' s University Hospital, Beckett Street, Leeds LS9 7TF (United Kingdom)

    2002-09-01

    Cirrhosis predisposes to hepatocellular carcinoma (HCC) which develops by sequential steps of de-differentiation of hepatocytes from regenerative nodules via borderline (dysplastic) nodules to frankly malignant HCC. Effective treatment depends on early recognition of HCC, so the key tasks for imaging are firstly recognising the presence of a suspicious lesion, and secondly differentiating between benign, borderline and malignant nodules. Screening of high-risk cirrhotic patients with sonography and measurement of alpha fetoprotein (AFP) is helpful but will not reliably differentiate small HCC from benign or dysplastic nodules. Large HCCs can usually be recognised by their characteristic morphology on imaging, but the appearances of smaller benign and malignant nodules show considerable overlap on unenhanced sonography, CT and MRI. Increasing degrees of histological malignancy are associated with increasing arterialisation and loss of portal blood supply, so the recognition of HCC requires the use of dynamic imaging with contrast-enhanced CT or T1-weighted MRI with gadolinium enhancement. Sonography with microbubble contrast media now offers another method for detecting arterialised nodules; however, some non-malignant nodules show arterial hypervascularity and a minority of HCCs are hypovascular, so the assessment of perfusion does not conclusively distinguish benign from malignant lesions. Kupffer cell function is another attribute of liver tissue which can be explored using MRI with superparamagnetic iron oxide particles (SPIO). Experience thus far suggests that uptake of SPIO is an effective discriminator between benign and malignant nodules. The combination of SPIO with gadolinium-enhanced MRI offers the opportunity for imaging characterisation of cirrhotic nodules by cellular function as well as by blood supply, and this approach is now proposed as the examination of choice for detecting HCC in cirrhosis. (orig.)

  2. Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling.

    Science.gov (United States)

    Watanabe, Marina; Hisatake, Mitsuhiro; Fujimori, Ko

    2015-05-27

    3,7,3',4'-Tetrahydroxyflavone (fisetin) is a flavonoid found in vegetables and fruits having broad biological activities. Here the effects of fisetin on adipogenesis and its regulatory mechanism in mouse adipocytic 3T3-L1 cells are studied. Fisetin inhibited the accumulation of intracellular lipids and lowered the expression of adipogenic genes such as peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein (C/EBP) α and fatty acid-binding protein 4 (aP2) during adipogenesis. Moreover, the mRNA levels of genes such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase involved in the fatty acid biosynthesis (lipogenesis) were reduced by the treatment with fisetin. The expression level of the glucose transporter 4 (GLUT4) gene was also decreased by fisetin, resulting in down-regulation of glucose uptake. Furthermore, fisetin inhibited the phosphorylation of the mammalian target of rapamycin (mTOR) and that of p70 ribosomal S6 kinase, a target of the mTOR complex, the inhibition of which was followed by a decreased mRNA level of the C/EBPα gene. The results obtained from a chromatin immunoprecipitation assay demonstrated that the ability of C/EBPα to bind to the GLUT4 gene promoter was reduced by the treatment with fisetin, which agreed well with those obtained when 3T3-L1 cells were allowed to differentiate into adipocytes in medium in the presence of rapamycin, an inhibitor for mTOR. These results indicate that fisetin suppressed the accumulation of intracellular lipids by inhibiting GLUT4-mediated glucose uptake through inhibition of the mTOR-C/EBPα signaling in 3T3-L1 cells.

  3. Ultrasonographic finding of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Han Soo; Woo, Seong Ku; Lim, Jae Hoon; Ko, Young Tae; Kim, Ho Kyun; Kim, Soon Yong [Kyung Hee University Hospital, Seoul (Korea, Republic of)

    1983-12-15

    With the development of gray scale ultrasonography, detection and evaluation of hepatic parenchymal disease including space occupying lesion are easily performed and frequently used in the world. Thrity five cases of histopathologically proven and ultrasonographically suggested hepatocellular carcinoma are retrospectively studied. The results were as follows; 1. Ultrasonographic findings of hepatocellular carcinoma show hyperechoic pattern in 22 cases (63%), hypoechoic pattern in 2 cases (6%), and mixed pattern in 11 cases (31%). 2. The margin of tumor is ill-defined in 19 cases (54%) and well defined in16 cases (46%). 3. The size of tumor by sonographic measurement was large than 5 cm in diameter in 33 cases (94%). 4. The number of tumor is solitary in 19 cases and multiple in 16 cases. The sites of involved lobe were right lobe in 22 cases (63%), left lobe in 2 cases (6%), and both lobes in 11 cases (31%). 5. Associated sonographic findings were hepatomegaly with focal contour change in 25 cases (71%), splenomegaly in 16 cases (46%), cirrhosis of liver in 15 cases (43%), ascites in 11 cases (31%) and tumoral thrombosis in portal vein in 8 cases (23%). 6. The sex ratio is 6 : 1 male predominence and the age ranges from 32 to 76 years with highest incidence in 5th and 6th decades.

  4. Synchronous gastric neuroendocrine carcinoma and hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Ewertsen, Caroline; Henriksen, Birthe Merete; Hansen, Carsten Palnæs

    2009-01-01

    of synchronous gastric NEC and hepatocellular carcinoma in a patient with several other precancerous lesions is presented. The patient had anaemia, and a gastric tumour and two duodenal polyps were identified on upper endoscopy. A CT scan of the abdomen revealed several lesions in the liver. The lesions were...... invisible on B-mode sonography and real-time sonography fused with CT was used to identify and biopsy one of the lesions. Histology showed hepatocellular carcinoma. A literature search showed that only one case of a hepatocellular carcinoma synchronous with a gastric NEC has been reported previously. TRIAL...

  5. Grp78 promotes the invasion of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Li Hongdan

    2010-01-01

    RhoA-GTP level, and Grp78 siRNA knockdown rescued RhoA-GTP level in Grp78 overexpressing cells, indicating Grp78 inhibited RhoA activity in hepatocellular carcinoma cells. Furthermore, overexpression of Grp78 in SMMC7721 cells increased phospho-p190RhoGAP level. FAK siRNA knockdown in Grp78 overexpressing cells reversed phospho-p190RhoGAP level. These data suggested that Grp78 inhibited RhoA activity by up-regulated phospho-p190RhoGAP level and Grp78 mediated p190RhoGAP phosphorylation is FAK dependent. Conclusion Grp78 promoted the invasion of hepatocellular carcinoma both in vitro and in vivo. Overexpression of Grp78 in hepatocellular carcinoma cells enhanced the activation and activity of FAK which negatively regulated Rock kinase activity by promoting the phosphorylation of p190RhoGAP.

  6. Grp78 promotes the invasion of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Su, Rongjian; Li, Zhen; Li, Hongdan; Song, Huijuan; Bao, Cuifen; Wei, Jia; Cheng, Liufang

    2010-01-01

    A-GTP level in Grp78 overexpressing cells, indicating Grp78 inhibited RhoA activity in hepatocellular carcinoma cells. Furthermore, overexpression of Grp78 in SMMC7721 cells increased phospho-p190RhoGAP level. FAK siRNA knockdown in Grp78 overexpressing cells reversed phospho-p190RhoGAP level. These data suggested that Grp78 inhibited RhoA activity by up-regulated phospho-p190RhoGAP level and Grp78 mediated p190RhoGAP phosphorylation is FAK dependent. Grp78 promoted the invasion of hepatocellular carcinoma both in vitro and in vivo. Overexpression of Grp78 in hepatocellular carcinoma cells enhanced the activation and activity of FAK which negatively regulated Rock kinase activity by promoting the phosphorylation of p190RhoGAP

  7. Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model.

    Science.gov (United States)

    Sia, Kian Chuan; Huynh, Hung; Chung, Alexander Yaw Fui; Ooi, London Lucien Peng Jin; Lim, Kiat Hon; Hui, Kam Man; Lam, Paula Yeng Po

    2013-08-01

    Gene regulation of many key cell-cycle players in S-, G(2) phase, and mitosis results from transcriptional repression in their respective promoter regions during the G(0) and G(1) phases of cell cycle. Within these promoter regions are phylogenetically conserved sequences known as the cell-cycle-dependent element (CDE) and cell-cycle genes homology regions (CHR) sites. Thus, we hypothesize that transcriptional regulation of cell-cycle regulation via the CDE/CHR region together with liver-specific apolipoprotein E (apoE)-hAAT promoter could bring about a selective transgene expression in proliferating human hepatocellular carcinoma. We show that the newly generated vector AH-6CC-L2C could mediate hepatocyte-targeted luciferase gene expression in tumor cells and freshly isolated short-term hepatocellular carcinoma cultures from patient biopsy. In contrast, normal murine and human hepatocytes infected with AH-6CC-L2C expressed minimal or low luciferase activities. In the presence of prodrug 5-fluorocytosine (5-FC), AH-6CC-L2C effectively suppressed the growth of orthotopic hepatocellular carcinoma patient-derived xenograft mouse model via the expression of yeast cytosine deaminase (yCD) that converts 5-FC to anticancer metabolite 5-fluoruracil. More importantly, we show that combination treatment of AH-6CC-L2C with an EZH2 inhibitor, DZNep, that targets EpCAM-positive hepatocellular carcinoma, can bring about a greater therapeutic efficacy compared with a single treatment of virus or inhibitor. Our study showed that targeting proliferating human hepatocellular carcinoma cells through the transcriptional control of therapeutic gene could represent a feasible approach against hepatocellular carcinoma.

  8. Impact of UV-B (290-320 nm) radiation on photosynthesis-mediated uptake of 15N-ammonia and 15N-nitrate of several marine diatoms

    International Nuclear Information System (INIS)

    Doehler, G.; Stolter, H.

    1986-01-01

    The marine diatoms Ditylum brigthwellii, Lithodesmium variabile, Odontella sinensis, Synedra planctonica and Thalassiosira rotula grown at 18 0 C under normal air conditions (0.035 vol.% CO 2 ) were exposed to different levels (439 and 717 J m -2 d -1 , weighted) of UV-B radiation for 2 d (5 h/d). Pigmentation, protein and total nitrogen content were reduced linearly to the dose of UV-B radiation. Photosynthesis-mediated uptake of 15 N-ammonia was more affected by UV-B irradiance in all tested diatoms than that of 15 N-nitrate. A species-dependent behavior in the assimilation of inorganic nitrogenous compounds has been observed: Synedra was a very sensitive species to UV-B radiation whereas the same UV-B doses had no effect on the assimilation rate of ammonia and nitrate of the Lithodesmium cells. The results were discussed with reference to the inhibition of the enzymes of the nitrogen metabolism. (author)

  9. Risks of Liver (Hepatocellular) Cancer Screening

    Science.gov (United States)

    ... cancer. Having hepatitis or cirrhosis can increase the risk of developing liver cancer. Anything that increases the ... clinical trials is available from the NCI website . Risks of Liver (Hepatocellular) Cancer Screening Key Points Screening ...

  10. Computed tomographic findings of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Jo, In Su; Jong, Woo Yung; Lee, Jong Yul; Choi, Han Yong; Kim, Bong Ki

    1987-01-01

    With Development of Computed Tomography, detection of the Hepatocellular Carcinoma are easily performed and frequently used in the world. During 15 months, from December 1985 to February 1987, 59 patients with hepatocellular carcinoma were evaluated with computed tomography in department of radiology at Wallace Memorial Baptist Hospital. The results were as follow: 1. The most prevalent age group was 5th to 7th decades, male to female ratio was 4.9:1. 2. Classification with incidence of computed tomographic appearance of the hepatocellular carcinoma were solitary type 28 cases (48%), multinodular type 24 cases (40%), and diffuse type 7 cases (12%), Association with liver cirrhosis was noted in 22 cases (38%). 3. Inhomogenous internal consistency of hepatocellular carcinoma due to central necrosis were 35 cases (60%). Portal vein invasion by hepatocellular carcinoma was noted in 15 cases (25%), and particularly most common in diffuse type 4 cases (55%). 4. On precontrast scan, all hepatocellular carcinoma were seen as area of low density except for 3 cases(0.5%) of near isodensity which turned out to be remarkable low density on postcontrast scan. 5. In solitary type, posterior segment of right lobe was most common site of involvement 12 cases (43%). In diffuse type, bilobar involvement was most common, 6 cases (85%)

  11. Percutaneous cryoablation for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Kyoung Doo Song

    2016-12-01

    Full Text Available Local ablation therapy is considered as a conventional treatment option for patients with early stage hepatocellular carcinoma (HCC. Although radiofrequency (RF ablation is widely used for HCC, the use of cryoablation has been increasing as newer and safer cryoablation systems have developed. The thermodynamic mechanism of freezing and thawing used in cryoablation is the Joule-Thomson effect. Cryoablation destroys tissue via direct tissue destruction and vascular-related injury. A few recent comparative studies have shown that percutaneous cryoablation for HCCs is comparable to percutaneous RF ablation in terms of long term therapeutic outcomes and complications. Cryoablation has several advantages over RF ablation such as well visualization of iceball, no causation of severe pain, and lack of severe damage to great vessels and gallbladder. It is important to know the advantages and disadvantages of cryoablation compared with RF ablation for improvement of therapeutic efficacy and safety.

  12. Medical treatment of hepatocellular carcinoma.

    Science.gov (United States)

    Granito, Alessandro; Bolondi, Luigi

    2009-12-16

    Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and the third leading cause of cancer-related deaths worldwide. Cirrhosis, most often due to viral hepatitis, is the predominant risk factors for HCC and geographical differences in both risk factors and incidence are largely due to epidemiological variations in hepatitis B and C infection. Hepatic function is a relevant parameter in selecting therapy in HCC. The current clinical classification of HCC split patients into 5 stages, with a specific treatment schedule for any stage. As patients with early stages can receive curative treatments, such as surgical resection, liver transplantation or local ablation, surveillance program in high-risk populations has become mandatory. Sorafenib, a multikinase inhibitor, has recently shown survival benefits in patients at advanced stage of disease. Hopefully, new molecular targeted therapies and their combination with sorafenib or interventional and surgical procedures, should expand the therapeutic armamentarium against HCC.

  13. [Radiofrequency ablation of hepatocellular carcinoma].

    Science.gov (United States)

    Widmann, Gerlig; Schullian, Peter; Bale, Reto

    2013-03-01

    Percutaneous radiofrequency ablation (RFA) is well established in the treatment of hepatocellular carcinoma (HCC). Due to its curative potential, it is the method of choice for non resectable BCLC (Barcelona Liver Clinic) 0 and A. RFA challenges surgical resection for small HCC and is the method of choice in bridging for transplantation and recurrence after resection or transplantation. The technical feasibility of RFA depends on the size and location of the HCC and the availability of ablation techniques (one needle techniques, multi-needle techniques). More recently, stereotactic multi-needle techniques with 3D trajectory planning and guided needle placement substantially improve the spectrum of treatable lesions including large volume tumors. Treatment success depends on the realization of ablations with large intentional margins of tumor free tissue (A0 ablation in analogy to R0 resection), which has to be documented by fusion of post- with pre-ablation images, and confirmed during follow-up imaging.

  14. Gene mutations in hepatocellular adenomas

    DEFF Research Database (Denmark)

    Raft, Marie B; Jørgensen, Ernö N; Vainer, Ben

    2015-01-01

    is associated with bi-allelic mutations in the TCF1 gene and morphologically has marked steatosis. β-catenin activating HCA has increased activity of the Wnt/β-catenin pathway and is associated with possible malignant transformation. Inflammatory HCA is characterized by an oncogene-induced inflammation due...... to alterations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In the diagnostic setting, sub classification of HCA is based primarily on immunohistochemical analyzes, and has had an increasing impact on choice of treatment and individual prognostic assessment....... This review offers an overview of the reported gene mutations associated with hepatocellular adenomas together with a discussion of the diagnostic and prognostic value....

  15. Angiographic findings of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Han, Man Chung; Cho, Byung Jae; Huh, Seung Jae; Bae, Sang Hoon; Kim, Ung Jin; Kim, Chung Yong; Kim, Noe Kyeong [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    1985-12-15

    From March 1977 to July 1979, 69 cases of angiograms of hepatocellular carcinoma were observed in Seoul National University Hospital. The findings of selective celiac and/or hepatic arteriography in total 69 cases of confirmed hepatocellular carcinoma, with clinical and laboratory findings, were analyzed. The summarized results are as follows; 1. Among 69 cases od hepatoma, 62 were male and 7 were female with sex ratio of 8.9 : 1. Peak incidence is 5th to 7th decades (72.5%). Epigastric pain, indigestion, and palpable mass in right upper quadrant were common symptoms and sign. Laboratory findings showed elevated serum alkaline phosphatase more than 5 Bodansky unit in 75.4%. Alpha-feto protein was positive in 65.2% of all the patients. 2 All 69 cases were classified into 31 cases of massive type, 22 cases of diffuse type, and 16 cases of nodular type, in accordance with angiographic gross anatomy. The frequency of angiographic findings were hypervascularities and tumor vessels (100%), tumor stainings (98.5%), arteriovenous shunt (71.0%), displacement of intrahepatic arteries (66.7%), vascular lakes and channel (59.4%). Encasement of hepatic artery and portal vein regurgitation was respectively 4 cases. Tumor mass in portal vein were 6 cases and tumor mass in hepatic vein was 1 case. 3. Intraarterial infusion of 5-FU was performed in 15 hepatoma patients, and the results were that angiographic improvement was demonstrated in 3 cases, no improvement in 8 cases, and incomplete infusion in 4 cases. 4. The selective celiac and/or hepatic angiograms are excellent diagnostic tools as well as therapeutic management for intraarterial infusion of anticancerous drugs.

  16. Angiographic findings of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Han, Man Chung; Cho, Byung Jae; Huh, Seung Jae; Bae, Sang Hoon; Kim, Ung Jin; Kim, Chung Yong; Kim, Noe Kyeong

    1985-01-01

    From March 1977 to July 1979, 69 cases of angiograms of hepatocellular carcinoma were observed in Seoul National University Hospital. The findings of selective celiac and/or hepatic arteriography in total 69 cases of confirmed hepatocellular carcinoma, with clinical and laboratory findings, were analyzed. The summarized results are as follows; 1. Among 69 cases od hepatoma, 62 were male and 7 were female with sex ratio of 8.9 : 1. Peak incidence is 5th to 7th decades (72.5%). Epigastric pain, indigestion, and palpable mass in right upper quadrant were common symptoms and sign. Laboratory findings showed elevated serum alkaline phosphatase more than 5 Bodansky unit in 75.4%. Alpha-feto protein was positive in 65.2% of all the patients. 2 All 69 cases were classified into 31 cases of massive type, 22 cases of diffuse type, and 16 cases of nodular type, in accordance with angiographic gross anatomy. The frequency of angiographic findings were hypervascularities and tumor vessels (100%), tumor stainings (98.5%), arteriovenous shunt (71.0%), displacement of intrahepatic arteries (66.7%), vascular lakes and channel (59.4%). Encasement of hepatic artery and portal vein regurgitation was respectively 4 cases. Tumor mass in portal vein were 6 cases and tumor mass in hepatic vein was 1 case. 3. Intraarterial infusion of 5-FU was performed in 15 hepatoma patients, and the results were that angiographic improvement was demonstrated in 3 cases, no improvement in 8 cases, and incomplete infusion in 4 cases. 4. The selective celiac and/or hepatic angiograms are excellent diagnostic tools as well as therapeutic management for intraarterial infusion of anticancerous drugs.

  17. Role of suppressed hepatocellular regeneration and Ca2+ in chlordecone-potentiated CCl4 hepatotoxicity

    International Nuclear Information System (INIS)

    Bell, A.N.

    1987-01-01

    The mechanism by which the chlorinated pesticide chlordecone (CD; Kepone) potentiates CCl 4 -induced hepatotoxicity and lethality was investigated. It was hypothesized that perturbations in Ca 2+ homeostasis, greater than those observed with a low dose of CCl 4 alone, in concert with a suppression of hepatocellular regeneration induced by CD alone or by CD + CCl 4 are responsible, at least in part, for CD-potentiated CCl 4 hepatotoxicity. Ca 2+ homeostasis was evaluated by measuring total cell Ca 2+ and 45 Ca 2+ uptake in viable isolated hepatocyte suspension obtained from normal and CD-pretreated rats receiving CCl 4 in vivo. In the normal rats in vivo CCL challenge did not affect 45 Ca 2+ uptake by viable isolated hepatocytes. In contrast, 45 Ca 2+ uptake was inhibited in viable isolated hepatocytes obtained from rats exposed to CD + CCl 4

  18. 18F-FDG PET/CT in detection of gynecomastia in patients with hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Hsin-Yi; Jeng, Long-Bin; Lin, Ming-Chia; Chao, Chih-Hao; Lin, Wan-Yu; Kao, Chia-Hung

    2013-01-01

    We retrospectively investigate the prevalence of gynecomastia as false-positive 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging in patients with hepatocellular carcinoma (HCC). Among the 127 male HCC patients who underwent 18F-FDG PET/CT scan, the 18FDG uptakes at the bilateral breasts in 9 patients with gynecomastia were recorded as standard uptake value (SUVmax) and the visual interpretation in both early and delayed images. The mean early SUVmax was 1.58/1.57 (right/left breast) in nine gynecomastia patients. The three patients with early visual score of 3 had higher early SUVmaxs. Gynecomastia is a possible cause of false-positive uptake on 18F-FDG PET/CT images. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Upregulation of MiR-212 Inhibits Migration and Tumorigenicity and Inactivates Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma.

    Science.gov (United States)

    Jia, Pengbo; Wei, Guangbing; Zhou, Cancan; Gao, Qi; Wu, Yunhua; Sun, Xuejun; Li, Xuqi

    2018-01-01

    MicroRNAs are involved in hepatocellular carcinoma metastasis, a principal cause of hepatocellular carcinoma-related death in patients worldwide. MiR-212 is a microRNA that has been identified in several types of cancers and is postulated to influence cell signaling and subsequent malignant pathogenesis. Despite emerging reports suggesting that miR-212 plays a significant role in the onset, progression, and migration of these types of malignant tumors, its involvement in the development of hepatocellular carcinoma has not been fully elucidated. Quantitative reverse transcription polymerase chain reaction, wound healing, transwell migration and invasion assays, Western blotting, and xenograft tumor growth models were performed to test the expression levels and functions of miR-212 in hepatocellular carcinoma. Luciferase reporter assay, quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry were used to identify and verify the target of miR-212. In this study, we identify significant repression of miR-212 in hepatocellular carcinoma and demonstrate that overexpression of miR-212 inhibits the migration of hepatocellular carcinoma cells in vitro and in vivo. Furthermore, we identify forkhead box M1, whose expression is inversely related to that of miR-212, as a direct target of miR-212. Additionally, reexpression of forkhead box M1 rescues the miR-212-mediated inhibition of cell migration. We observed that inhibition of miR-212 activates forkhead box M1 but inhibits the Wnt/β-catenin pathway by suppressing Wnt, LEF-1, c-Myc, and nuclear β-catenin. Finally, in vivo studies confirmed the inhibitory effect of miR-212 on hepatocellular carcinoma growth. Our present findings indicate that miR-212 is a potential prognostic biomarker of hepatocellular carcinoma and that the miR-212/forkhead box M1 regulatory axis may represent a new therapeutic objective for hepatocellular carcinoma treatment.

  20. CYCLOOXYGENASE-2 AND HEPATOCELLULAR CARCINOMA: THE PROTEOMICS OF ASSOCIATION

    Directory of Open Access Journals (Sweden)

    Jaya Gandhi

    2011-12-01

    Full Text Available Hepatocellular carcinoma represents one of the most common malignancies worldwide with a rising incidence in western countries. Chronic inflammation is recognised as a threat factor for cancer progression. Cyclooxygenase-2 is the major mediator of inflammation. Various studies on Cox-2 suggest its possible association with HCC differentiation. Sufficient genetic and pharmacologic evidences implicate its crucial role in neoplasia and it is also now clear that Cox-2 plays a crucial role in tumor progression. Cox-2 overexpression is associated with maintaining tumor microenvironment and has crucial implication for angiogenesis. Cox-2 operates in multifactorial fashion. Cox-2 selective inhibition has been reported as a successful tool in suppressing angiogenesis and metastasis. The pharmacological suppression of Cox-2 represents a bright future as a therapeutic tool for treatment of various malignancies. This review is an attempt to discuss the critical issue of overexpression of Cox-2 and its role in the development of HCC in particular and cancer in general.

  1. Surgical management of spontaneous ruptured hepatocellular adenoma

    Directory of Open Access Journals (Sweden)

    Marcelo Augusto Fontenelle Ribeiro Junior

    2009-01-01

    Full Text Available AIMS: Spontaneous ruptured hepatocellular adenoma (SRHA is a rare life-threatening condition that may require surgical treatment to control hemorrhaging and also stabilize the patient. We report a series of emergency surgeries performed at our institution for this condition. METHODS: We reviewed medical records and radiology files of 28 patients (from 1989 to 2006 with a proven diagnosis of hepatocellular adenoma (HA. Three (10.7% of 28 patients had spontaneous ruptured hepatocellular adenoma, two of which were associated with intrahepatic hemorrhage while one had intraperitoneal bleeding. Two patients were female and one was male. Both female patients had a background history of oral contraceptive use. Sudden abdominal pain associated with hemodynamic instability occurred in all patients who suffered from spontaneous ruptured hepatocellular adenoma. The mean age was 41.6 years old. The preoperative assessment included liver function tests, ultrasonography and computed tomography. RESULTS: The surgical approaches were as follows: right hemihepatectomy for controlling intraperitoneal bleeding, and right extended hepatectomy and non-anatomic resection of the liver for intrahepatic hemorrhage. There were no deaths, and the postoperative complications were bile leakage and wound infection (re-operation, as well as intraperitoneal abscess (re-operation and pleural effusion. CONCLUSION: Spontaneous ruptured hepatocellular adenoma may be treated by surgery for controlling hemorrhages and stabilizing the patient, and the decision to operate depends upon both the patient's condition and the expertise of the surgical team.

  2. Uptake of proline by the scutellum of germinating barley grain

    International Nuclear Information System (INIS)

    Vaeisaenen, E.; Sopanen, T.

    1986-01-01

    Scutella separated from germinating grains of barley (Hordeum vulgare L. cv Himalaya) took up 1 millimolar L-[ 14 C]proline at an initial rate of about 6.5 micromoles gram -1 fresh weight hour -1 (pH 5, 30 0 C). The uptake had a pH optimum at 5. The bulk of the uptake (93%) was via carrier-mediated active transport. All of the 19 L-amino acids tested at 10 millimolar concentration inhibited the mediated uptake of 1 millimolar proline, the inhibitions varying from 18 to 76%. By studying how large a fraction of the mediated uptake was inhibitable by asparagine, alanine, glutamine, and leucine, the mediated uptake was shown to be due to three components. Two of these are most probably attributable to the two nonspecific uptake systems proposed earlier to act in the uptake of glutamine and leucine. The third component was not inhibited by glutamine, asparagine, or alanine, but was inhibited by unlabeled proline and leucine. The uptake by this system was apparently carrier-mediated active transport. D-Proline inhibited this system as strongly as L-proline. Nine of the 16 L-amino tested at 50 millimolar concentrations did not inhibit the uptake of 1 millimolar proline by this system. Valine, leucine, isoleucine, and the basic amino acids were inhibitory, but in spite of this, they did not appear to be taken up by this system. It seems therefore that in addition to two nonspecific amino acid uptake systems the scutella have an uptake system which is specific for proline. It is likely that this proline-specific system accounts for the bulk of proline uptake in a germinating grain

  3. Giant hepatocellular adenoma; case report

    Energy Technology Data Exchange (ETDEWEB)

    Pitella, F.A.; Coutinho, A.M.N.; Coura Filho, G.B.; Costa, P.L.A.; Ono, C.R.; Watanabe, T.; Sapienza, M.T.; Hironaka, F.; Cerri, G.G.; Buchpiguel, C.A. [Universidade de Sao Paulo (FM/USP), SP (Brazil). Inst. de Radiologia. Servico de Medicina Nuclear

    2008-07-01

    Full text: Introduction: Hepatocellular adenoma is a benign hepatic tumor identified mainly in women during fertility age, with estimated incidence of 4/1000 inhabitants. It is usually unique, well circumscribed, with or without a capsule, size varying from 1 to 30 cm, with possible central areas of necrosis and hemorrhage. Case Report: A 37-year-old female patient presenting with no comorbities, use of hormonal birth control pills for 18 years, a condition of reduction in the consistency of feces, increase in number of daily defecations, abdominal cramps, and a stuffed sensation after meals for two years. A palpable abdominal mass extending from the right hypochondriac to the right iliac fossa was noticed four months ago. A computerized tomography (CT) showed an extensive hepatic mass on the right which was considered, within the diagnostic hypotheses, hepatic adenomatosis, without ruling out secondary lesions. A hepatic scintillography with {sup 99m}Tc-DISIDA showed an extensive exophytic area from segment V to the right iliac fossa with arterialized blood flow and hepatocytic activity, as well as a hepatic nodule in segment VII with hepatocytic activity consistent with the hepatic adenomas hypothesis. The biopsy confirmed the hepatic adenoma diagnosis and the patient was submitted to a partial hepatectomy and cholecystectomy with good clinical evolution. Conclusion: Nuclear Medicine may supplement the assessment of hepatic nodules, including giant masses, thus suggesting new hypotheses and direction to therapeutic conduct. (author)

  4. Treatment options for hepatocellular carcinoma.

    Science.gov (United States)

    Sandhu, Dalbir S; Tharayil, Vivek S; Lai, Jin-Ping; Roberts, Lewis R

    2008-02-01

    Hepatocellular carcinoma (HCC) is frequently diagnosed at advanced stages and has a high mortality rate. With improved survival of patients with cirrhotic liver disease and increased prevalence of chronic hepatitis C viral infections, a rise in the number of HCC cases is being reported worldwide. Early diagnosis and treatment can significantly improve the prognosis of patients with HCC. Although surgical resection is an important potentially curative therapy for liver tumors, in appropriately selected patients, liver transplantation has been shown to achieve excellent survival rates for a solid tumor. Locally ablative and locoregional therapies in the form of percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization and transcatheter arterial radioembolization (TheraSphere) are viable options in patients with unresectable HCC. Unfortunately, the role of systemic therapy has been very limited in the treatment of these patients. Novel treatment options based on an improved understanding of the molecular pathogenesis of HCC are being explored. These targeted molecular therapies are aimed at growth factors and their receptors, intracellular signal transduction and cell cycle control. A substantial improvement in outcomes of intermediate and advanced stage HCC is expected with the advent of these targeted therapies, used in combination with surgical or locoregional therapies. Recent positive results from a large Phase III study of the receptor tyrosine kinase inhibitor, sorafenib, hold great promise in the treatment of HCC.

  5. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... for a thyroid scan is 30 minutes or less. Thyroid Uptake You will be given radioactive iodine ( ... for each thyroid uptake is five minutes or less. top of page What will I experience during ...

  6. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... uptake measurements are obtained at different times. For example, you may have uptake measurements at four to ... medicine procedures can be time consuming. It can take several hours to days for the radiotracer to ...

  7. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... Scan and Uptake Thyroid scan and uptake uses small amounts of radioactive materials called radiotracers, a special ... is a branch of medical imaging that uses small amounts of radioactive material to diagnose and determine ...

  8. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... radioactive iodine uptake test (RAIU) is also known as a thyroid uptake. It is a measurement of ... potential to identify disease in its earliest stages as well as a patient’s immediate response to therapeutic ...

  9. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... known as a thyroid uptake. It is a measurement of thyroid function, but does not involve imaging. ... eating can affect the accuracy of the uptake measurement. Jewelry and other metallic accessories should be left ...

  10. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... Uptake? A thyroid scan is a type of nuclear medicine imaging. The radioactive iodine uptake test (RAIU) ... of thyroid function, but does not involve imaging. Nuclear medicine is a branch of medical imaging that ...

  11. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... for a thyroid scan is 30 minutes or less. Thyroid Uptake You will be given radioactive iodine (I-123 or I-131) in liquid or capsule form to swallow. The thyroid uptake will begin several hours to 24 hours later. Often, two separate uptake ...

  12. Current radiologic interventions in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Masoud, I.; Naeem, M.Q.T.; Saeed, F.; Mirza, S.A.M.; Khan, A.; Bhatti, M.A.

    2006-01-01

    With the rising incidence of chronic liver disease caused by viral hepatitis, hepatocellular carcinoma is showing a corresponding rise worldwide. Surgery remains the mainstay of treatment, but patients unfit for surgery or liver transplantation form the bulk of those presenting with this disease. Palliative treatments are being used to treat those and radiological modalities form the mainstay of the treatment. Radiology plays a major role in the diagnosis, treatment and follow-up of hepatocellular carcinoma. Current radiological treatment modalities include percutaneous ethanol ablation, radiofrequency ablation and trans-arterial chemoembolization. This update highlights the recent advancements in the field and compares their relative merits and demerits. (author)

  13. Multiphasic helical CT of hepatocellular carcinoma. Evaluation after chemo embolization

    International Nuclear Information System (INIS)

    Catalano, O.; Esposito, M.; Sandomenico, F.; Siani, A.; Nunziata, A.

    2000-01-01

    The main purpose of this work is to report the personal experience with addition of contrast-enhanced multiphase helical CT to unenhanced CT (Lipiodol CT) in the evaluation of patients with hepatocellular carcinoma treated with chemoembolization and to analyze the present role of oily agent CT. It has been retrospectively reviewed the examinations of 42 consecutive patients submitted to globla chemoembolization over a 2-year period. CT was performed 18-30 days after the treatment. The Lipiodol CT study was carried out with volume acquisitions. It has been considered as nodules all well-defined areas with dense oily agent uptake; uptake itself was classified as: 0=absent, I=lower tha 10% of the tumor volume; II=lower than 50%, III=50%, IV=homogeneous. Contrast-enhanced helical CT was performed with the 2-phase technique in 28 patients and with the 3-phase technique in 14; it has been considered as nodules all well-defined and relatively homogeneous areas with hyperattenuation in the arterial phase and hypo-isoattenuation in the portal and/or delayed phase, or with hypo-isoattenuation in the arterial phase and in the portal and/or delayed phase. Lipiodol CT permitted to recognize 65 nodules (1-5/patient, mean 1.5), namely 15 grade I, 21 grade II, 20 grade III and 9 grade IV. Multiphase CT identified 6 additional nodules in 5 patients, 5 hypervascular and 1 hypovascular, and better assessed the correct morphology and volume of grade I nodules. Only 4 of 6 nodules missed on Lipiodol CT showed oily agent uptake after a new chemoembolization session. Moreover after retreatment, carried out in 6 of 9 patients with grade I uptake (11 nodules in all), it has been found persistence of the grade I pattern in 5 nodules, grade II in 5, and grade III in 1. Lipiodol CT may miss liver nodules and underestimate the volume of nodules with poor uptake. Though Lipiodol CT should still be considered slightly more sensitive than multiphase CT, in the general opinion this technique has

  14. Selective killing of hepatocellular carcinoma HepG2 cells by three-dimensional nanographene nanoparticles based on triptycene

    Science.gov (United States)

    Xiong, Xiaoqin; Gan, Lu; Liu, Ying; Zhang, Chun; Yong, Tuying; Wang, Ziyi; Xu, Huibi; Yang, Xiangliang

    2015-03-01

    Carbon-based materials have been widely used in the biomedical fields including drug delivery and cancer therapies. In this paper, a recently synthesized three-dimensional nanographene (NG) based on triptycene self-assembles into nanoparticles which selectively kill human hepatocellular carcinoma HepG2 cells as compared to human normal liver HL7702 cells. Obvious differences in cellular accumulation, the endocytic pathway and intracellular trafficking of NG nanoparticles are observed in HepG2 cells and HL7702 cells. Further studies reveal that NG nanoparticles significantly increase the levels of reactive oxygen species (ROS) in HepG2 cells, but not in HL7702 cells. NG nanoparticle-induced ROS result in apoptosis induction and the decrease in mitochondrial membrane potential in HepG2 cells. Moreover, IKK/nuclear factor-κB (NF-κB) signaling is found to be activated by NG nanoparticle-induced ROS and serves to antagonize NG nanoparticle-induced apoptosis in HepG2 cells. Our studies show that the distinct behaviors of cellular uptake and ROS-mediated cytotoxicity are responsible for the selective killing of HepG2 cells. This study provides a foundation for understanding the mechanism of selective induction of apoptosis in cancer cells by NG nanoparticles and designing more effective chemotherapeutical agents.Carbon-based materials have been widely used in the biomedical fields including drug delivery and cancer therapies. In this paper, a recently synthesized three-dimensional nanographene (NG) based on triptycene self-assembles into nanoparticles which selectively kill human hepatocellular carcinoma HepG2 cells as compared to human normal liver HL7702 cells. Obvious differences in cellular accumulation, the endocytic pathway and intracellular trafficking of NG nanoparticles are observed in HepG2 cells and HL7702 cells. Further studies reveal that NG nanoparticles significantly increase the levels of reactive oxygen species (ROS) in HepG2 cells, but not in HL7702

  15. Surgical Treatment of Hepatocellular Carcinoma

    Science.gov (United States)

    Zamora-Valdes, Daniel; Taner, Timucin; Nagorney, David M.

    2017-01-01

    Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. In select patients, surgical treatment in the form of either resection or transplantation offers a curative option. The aims of this review are to (1) review the current American Association for the Study of Liver Diseases/European Association for the Study of the Liver guidelines on the surgical management of HCC and (2) review the proposed changes to these guidelines and analyze the strength of evidence underlying these proposals. Three authors identified the most relevant publications in the literature on liver resection and transplantation for HCC and analyzed the strength of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. In the United States, the liver allocation system provides priority for liver transplantation to patients with HCC within the Milan criteria. Current evidence suggests that liver transplantation may also be indicated in certain patient groups beyond Milan criteria, such as pediatric patients with large tumor burden or adult patients who are successfully downstaged. Patients with no underlying liver disease may also benefit from liver transplantation if the HCC is unresectable. In patients with no or minimal (compensated) liver disease and solitary HCC ≥2 cm, liver resection is warranted. If liver transplantation is not available or contraindicated, liver resection can be offered to patients with multinodular HCC, provided that the underlying liver disease is not decompensated. Many patients may benefit from surgical strategies adapted to local resources and policies (hepatitis B prevalence, organ availability, etc). Although current low-quality evidence shows better overall survival with aggressive surgical strategies, this approach is limited to select patients. Larger and well-designed prospective studies are needed to better define the benefits and limits of such approach. PMID:28975836

  16. New advances in hepatocellular carcinoma

    Science.gov (United States)

    Pascual, Sonia; Herrera, Iván; Irurzun, Javier

    2016-01-01

    Hepatocellular carcinoma (HCC) is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths. Most HCC are associated with well known underlying risk factors, in fact, HCC arise in cirrhotic patients in up to 90% of cases, mainly due to chronic viral hepatitis and alcohol abuse. The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients. HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified. The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient at-risk for developing HCC. The diagnosis of HCC can be based on non-invasive criteria (only in cirrhotic patient) or pathology. Accurately staging patients is essential to oncology practice. The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function. Treatment allocation is based on several factors: Liver function, size and number of tumours, macrovascular invasion or extrahepatic spread. The recommendations in terms of selection for different treatment strategies must be based on evidence-based data. Resection, liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates. Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment. Finally, in patients with advanced HCC with preserved liver function, sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients. PMID:27028578

  17. Efficient uptake of blood-borne BK and JC polyomavirus-like particles in endothelial cells of liver sinusoids and renal vasa recta.

    Directory of Open Access Journals (Sweden)

    Jaione Simon-Santamaria

    Full Text Available Liver sinusoidal endothelial cells (LSECs are specialized scavenger cells that mediate high-capacity clearance of soluble waste macromolecules and colloid material, including blood-borne adenovirus. To explore if LSECs function as a sink for other viruses in blood, we studied the fate of virus-like particles (VLPs of two ubiquitous human DNA viruses, BK and JC polyomavirus, in mice. Like complete virions, VLPs specifically bind to receptors and enter cells, but unlike complete virions, they cannot replicate. 125I-labeled VLPs were used to assess blood decay, organ-, and hepatocellular distribution of ligand, and non-labeled VLPs to examine cellular uptake by immunohisto- and -cytochemistry. BK- and JC-VLPs rapidly distributed to liver, with lesser uptake in kidney and spleen. Liver uptake was predominantly in LSECs. Blood half-life (∼1 min, and tissue distribution of JC-VLPs and two JC-VLP-mutants (L55F and S269F that lack sialic acid binding affinity, were similar, indicating involvement of non-sialic acid receptors in cellular uptake. Liver uptake was not mediated by scavenger receptors. In spleen, the VLPs localized to the red pulp marginal zone reticuloendothelium, and in kidney to the endothelial lining of vasa recta segments, and the transitional epithelium of renal pelvis. Most VLP-positive vessels in renal medulla did not express PV-1/Meca 32, suggesting location to the non-fenestrated part of vasa recta. The endothelial cells of these vessels also efficiently endocytosed a scavenger receptor ligand, formaldehyde-denatured albumin, suggesting high endocytic activity compared to other renal endothelia. We conclude that LSECs very effectively cleared a large fraction of blood-borne BK- and JC-VLPs, indicating a central role of these cells in early removal of polyomavirus from the circulation. In addition, we report the novel finding that a subpopulation of endothelial cells in kidney, the main organ of polyomavirus persistence, showed

  18. Hyperkalaemia after radiofrequency ablation of hepatocellular carcinoma

    NARCIS (Netherlands)

    Verhoevena, BH; Haagsma, EB; Appeltans, BMG; Slooff, MJH; de Jong, KP

    Radiofrequency ablation of liver tumours is a useful therapy for otherwise unresectable tumours. The complication rate is said to be low. In this case report we describe hyperkalaemia after radiofrequency ablation of a hepatocellular carcinoma in a patient with end-stage renal insufficiency. (C)

  19. Radioembolisation for treatment of pediatric hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, Clifford Matthew; Kukreja, Kamlesh [Cincinnati Children' s Hospital Medical Center, Department of Radiology, Cincinnati, OH (United States); Geller, James I. [Cincinnati Children' s Hospital Medical Center, Department of Hematology/Oncology, Cincinnati, OH (United States); Schatzman, Carmen; Ristagno, Ross [University of Cincinnati, UC Health, Department of Radiology, Division of Interventional Radiology, Cincinnati, OH (United States)

    2013-07-15

    Transarterial radioembolisation with yttrium-90 (TARE-Y90), a catheter-directed therapy, has been used extensively in adults to treat primary and secondary hepatic malignancies. To our knowledge, the use of this palliative technique has not been described in children. We present two children with unresectable hepatocellular carcinoma (HCC) treated with TARE-Y90. (orig.)

  20. Small hepatocellular carcinoma versus small cavernous hemangioma

    International Nuclear Information System (INIS)

    Choi, B.I.; Park, H.W.; Kim, S.H.; Han, M.C.; Kim, C.W.

    1989-01-01

    To determine the optimal pulse sequence for detection and differential diagnosis of small hepatocellular carcinomas and cavernous hemangiomas less than 5 cm in diameter, the authors have analyzed spin-echo (SE) images of 15 small hepatocellular carcinomas and 31 small cavernous hemangiomas obtained at 2.0 T. Pulse sequences used included repetition times (TRs) of 500 and 2,000 msec and echo times (TEs) of 30,60,90,120,150, and 180 msec. Mean tumor-liver contrast-to-noise ratios on the SE 2,000/60 (TR msec/TE msec) sequence were 23.90 ± 16.33 and 62.10 ± 25.94 for small hepatocellular carcinomas and hemangiomas, respectively, and were significantly greater than for all other pulse sequences. Mean tumor-liver signal intensity ratios on the SE 2,000/150 sequence were 2.34 ± 1.72 and 6.04 ± 2.72 for small hepatocellular carcinomas and hemangiomas, respectively, and were significantly greater than for all other pulse sequences in hemangiomas

  1. Liver transplantation in patients with hepatocellular carcinoma

    NARCIS (Netherlands)

    Polak, Wojciech G.; Soyama, Akihiko; Slooff, Maarten J. H.

    2008-01-01

    Liver transplantation has a definitive place in the treatment of patients with hepatocellular carcinoma (HCC) in a cirrhotic liver. Patients with a tumor load within the Milan criteria have excellent survival comparable to survival in patients with benign indications. When tumor load exceeds the

  2. Delayed presentation and diagnosis of metastatic hepatocellular ...

    African Journals Online (AJOL)

    Hepatocellular carcinoma (HCC) is rarely diagnosed in women of reproductive age. ... an adverse effect on HCC, and that high levels of oestrogen associated with pregnancy may ... A 30-year-old pregnant woman presented at 23 weeks' gestation and was diagnosed as HIV-infected, with anaemia. She was initiated on.

  3. Hepatocellular carcinoma: risk groups, surveillance and outcome

    NARCIS (Netherlands)

    van Meer, S

    2016-01-01

    The burden of hepatocellular carcinoma (HCC) has changed in the past few decades. Although the majority of HCC cases develops in East Asia and Sub-Saharan Africa, HCC has become an increasing problem in Western countries such as the Netherlands. Surveillance for HCC is controversial because of

  4. O-GlcNAcylation of RACK1 promotes hepatocellular carcinogenesis.

    Science.gov (United States)

    Duan, Fangfang; Wu, Hao; Jia, Dongwei; Wu, Weicheng; Ren, Shifang; Wang, Lan; Song, Shushu; Guo, Xinying; Liu, Fenglin; Ruan, Yuanyuan; Gu, Jianxin

    2018-06-01

    Aberrant oncogenic mRNA translation and protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) are general features during tumorigenesis. Nevertheless, whether and how these two pathways are interlinked remain unknown. Our previous study indicated that ribosomal receptor for activated C-kinase 1 (RACK1) promoted chemoresistance and growth in hepatocellular carcinoma (HCC). The aim of this study is to examine the role of RACK1 O-GlcNAcylation in oncogene translation and HCC carcinogenesis. The site(s) of RACK1 for O-GlcNAcylation was mapped by mass spectrometry analysis. HCC cell lines were employed to examine the effects of RACK1 O-GlcNAcylation on the translation of oncogenic factors and behaviors of tumor cells in vitro. Transgenic knock-in mice were used to detect the role of RACK1 O-GlcNAcylation in modulating HCC tumorigenesis in vivo. The correlation of RACK1 O-GlcNAcylation with tumor progression and relapse were analyzed in clinical HCC samples. We found that ribosomal RACK1 was highly modified by O-GlcNAc at Ser122. O-GlcNAcylation of RACK1 enhanced its protein stability, ribosome binding and interaction with PKCβII (PRKCB), leading to increased eukaryotic translation initiation factor 4E phosphorylation and translation of potent oncogenes in HCC cells. Genetic ablation of RACK1 O-GlcNAcylation at Ser122 dramatically suppressed tumorigenesis, angiogenesis, and metastasis in vitro and in diethylnitrosamine (DEN)-induced HCC mouse model. Increased RACK1 O-GlcNAcylation was also observed in HCC patient samples and correlated with tumor development and recurrence after chemotherapy. These findings demonstrate that RACK1 acts as key mediator linking O-GlcNAc metabolism to cap-dependent translation during HCC tumorigenesis. Targeting RACK1 O-GlcNAcylation provides promising options for HCC treatment. O-GlcNAcylation of ribosomal receptor for activated C-kinase 1 at the amino acid serine122 promotes its stability, ribosome localization and interaction

  5. Hepatocellular carcinoma: a clinico pathological study

    International Nuclear Information System (INIS)

    Abbasi, A.; Butt, N.; Bhutto, A.R.; Gulzar, K.; Munir, S.M.

    2010-01-01

    To describe the clinico-pathological and radiological profile of hepatocellular carcinoma. All consecutive patients suspected of having hepatocellular carcinoma (HCC), were admitted and included in this study. Diagnosis of HCC was established by clinical, biochemical, ultrasonographic and histopathologic findings. Patients with primary carcinoma elsewhere in the body, metastatic in the liver, fibrolamellar carcinoma and benign tumours were excluded from the study. At ultrasonography, the details of tumour size and number, portal vein thrombosis and presence of ascites were recorded. Patients were staged according to Okuda staging system. Results were described in mean and percentage values. There were 82 patients with hepatocellular carcinoma including 58 males and 24 females, with male to female ratio of 2.8:1. The mean age of patients was 56.24 +- 13.65 years. Right hypochondrial pain was the main symptom in 52 (63.4%) patients. The duration of symptoms varied from 1 month to 2 years. Tumour size was larger than 50% of liver size in 42 (51.2%) with portal vein thrombosis in 10 (12.19%). Anti HCV was positive in 44 (53.7%), HBsAg in 26 (31.7%) and both were found positive in 2 (2.44%) patients. Ten patients (12.2/%) found negative both for anti-HCV and HBsAg. According to Okuda staging system 18 patients had stage 1, 50 had stage 2 and 14 had stage 3 hepatocellular carcinoma. The mean age of presentation of hepatocellular carcinoma was younger as compared to western countries with potentially large non-resectable lesions. Chronic hepatitis C and B was found to be the major known factors. Patients with chronic hepatitis C and B should undergo vigorous HCC surveillance to detect early, potentially respectable HCC. (author)

  6. Arsenic uptake in bacterial calcite

    Science.gov (United States)

    Catelani, Tiziano; Perito, Brunella; Bellucci, Francesco; Lee, Sang Soo; Fenter, Paul; Newville, Matthew; Rimondi, Valentina; Pratesi, Giovanni; Costagliola, Pilario

    2018-02-01

    Bio-mediated processes for arsenic (As) uptake in calcite were investigated by means of X-ray Diffraction (XRD) and X-ray Absorption Spectroscopy (XAS) coupled with X-ray Fluorescence measurements. The environmental bacterial strain Bacillus licheniformis BD5, sampled at the Bullicame Hot Springs (Viterbo, Central Italy), was used to synthesize calcite from As-enriched growth media. Both liquid and solid cultures were applied to simulate planktonic and biofilm community environments, respectively. Bacterial calcite samples cultured in liquid media had an As enrichment factor (Kd) 50 times higher than that from solid media. The XRD analysis revealed an elongation of the crystal lattice along the c axis (by 0.03 Å) for biogenic calcite, which likely resulted from the substitution of larger arsenate for carbonate in the crystal. The XAS data also showed a clear difference in the oxidation state of sorbed As between bacterial and abiotic calcite. Abiotic chemical processes yielded predominantly As(V) uptake whereas bacterial precipitation processes led to the uptake of both As(III) and As(V). The presence of As(III) in bacterial calcite is proposed to result from subsequent reduction of arsenate to arsenite by bacterial activities. To the best of our knowledge, this is the first experimental observation of the incorporation of As(III) in the calcite crystal lattice, revealing a critical role of biochemical processes for the As cycling in nature.

  7. Arsenic uptake in bacterial calcite

    Energy Technology Data Exchange (ETDEWEB)

    Catelani, Tiziano; Perito, Brunella; Bellucci, Francesco; Lee, Sang Soo; Fenter, Paul; Newville, Matthew G.; Rimondi, Valentina; Pratesi, Giovanni; Costagliola, Pilario

    2018-02-01

    Bio-mediated processes for arsenic (As) uptake in calcite were investigated by means of X-ray Diffraction (XRD) and Xray Absorption Spectroscopy (XAS) coupled with X-ray Fluorescence measurements. The environmental bacterial strain Bacillus licheniformis BD5, sampled at the Bullicame Hot Springs (Viterbo, Central Italy), was used to synthesize calcite from As-enriched growth media. Both liquid and solid cultures were applied to simulate planktonic and biofilm community environments, respectively. Bacterial calcite samples cultured in liquid media had an As enrichment factor (Kd) 50 times higher than that from solid media. The XRD analysis revealed an elongation of the crystal lattice along the c axis (by 0.03Å) for biogenic calcite, which likely resulted from the substitution of larger arsenate for carbonate in the crystal. The XAS data also showed a clear difference in the oxidation state of sorbed As between bacterial and abiotic calcite. Abiotic chemical processes yielded predominantly As(V) uptake whereas bacterial precipitation processes led to the uptake of both As(III) and As(V). The presence of As(III) in bacterial calcite is proposed to result from subsequent reduction of arsenate to arsenite by bacterial activities. To the best of our knowledge, this is the first experimental observation of the incorporation of As(III) in the calcite crystal lattice, revealing a critical role of biochemical processes for the As cycling in nature.

  8. Silver Nanoparticles Induce HePG-2 Cells Apoptosis Through ROS-Mediated Signaling Pathways

    Science.gov (United States)

    Zhu, Bing; Li, Yinghua; Lin, Zhengfang; Zhao, Mingqi; Xu, Tiantian; Wang, Changbing; Deng, Ning

    2016-04-01

    Recently, silver nanoparticles (AgNPs) have been shown to provide a novel approach to overcome tumors, especially those of hepatocarcinoma. However, the anticancer mechanism of silver nanoparticles is unclear. Thus, the purpose of this study was to estimate the effect of AgNPs on proliferation and activation of ROS-mediated signaling pathway on human hepatocellular carcinoma HePG-2 cells. A simple chemical method for preparing AgNPs with superior anticancer activity has been showed in this study. AgNPs were detected by transmission electronic microscopy (TEM) and energy dispersive X-ray (EDX). The size distribution and zeta potential of silver nanoparticles were detected by Zetasizer Nano. The average size of AgNPs (2 nm) observably increased the cellular uptake by endocytosis. AgNPs markedly inhibited the proliferation of HePG-2 cells through induction of apoptosis with caspase-3 activation and PARP cleavage. AgNPs with dose-dependent manner significantly increased the apoptotic cell population (sub-G1). Furthermore, AgNP-induced apoptosis was found dependent on the overproduction of reactive oxygen species (ROS) and affecting of MAPKs and AKT signaling and DNA damage-mediated p53 phosphorylation to advance HePG-2 cells apoptosis. Therefore, our results show that the mechanism of ROS-mediated signaling pathways may provide useful information in AgNP-induced HePG-2 cell apoptosis.

  9. File list: Unc.Liv.05.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Liv.05.AllAg.Carcinoma,_Hepatocellular mm9 Unclassified Liver Carcinoma, Hepato...cellular http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Unc.Liv.05.AllAg.Carcinoma,_Hepatocellular.bed ...

  10. File list: His.Liv.10.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Liv.10.AllAg.Carcinoma,_Hepatocellular mm9 Histone Liver Carcinoma, Hepatocellu...lar http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Liv.10.AllAg.Carcinoma,_Hepatocellular.bed ...

  11. Thyroid uptake test

    International Nuclear Information System (INIS)

    Ganatra, R.D.

    1992-01-01

    The uptake of radioiodine by the thyroid gland is altered by the iodine content of diet or drugs. American diet has a high iodine content because each slice of the white bread contains nearly 150μg of iodine due to the bleaching process employed in the production of the bread. This carrier content of iodine reduces the uptake so much, that the normal American uptakes are usually three to four times lower than the uptakes in the developing countries. The other drawback of the thyroid uptake test is that it is affected by the iodine containing drugs. Anti-diarrhoea medications are quire common in the developing countries and many of them contain iodine moiety. Without a reliable drug history, a low thyroid uptake value may lead to a misleading conclusion

  12. Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion

    International Nuclear Information System (INIS)

    Wu Xiaofeng; Fan Jia; Wang Xiaoying; Zhou Jian; Qiu Shuangjian; Yu Yao; Liu Yinkun; Tang Zhaoyou

    2007-01-01

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

  13. Clinical experience of 123I-IMP scintigraphy in detecting vertebral bone metastases of hepatocellular carcinoma. A comparison with bone scintigraphy with 99mTc-MDP

    International Nuclear Information System (INIS)

    Suto, Y.; Iwamiya, T.; Tanigawa, N.; Shabana, M.; Ohta, Y.

    1994-01-01

    123 I-IMP and bone scintigraphy with 99m Tc-MDP were consecutively performed in patients with vertebral bone metastases from hepatocellular carcinoma and lumbar spondylosis deformans in a 7-day interval or shorter. The intensity of uptake was compared. Eighteen of the 20 metastatic lesions (90%) were classified as increased uptake areas in 123 I-IMP scintigraphy. MDP-scintigraphy disclosed 16 metastatic lesions (80%), 9 as ''hot'' lesions (56%) and 7 as ''cold'' lesions (44%). 123 I-IMP scintigraphy was negative in all 12 lesions of lumbar spondylosis deformans. Compared to MDP-scintigraphy, 123 I-IMP scintigraphy was more sensitive in detecting vertebral bone metastases of hepatocellular carcinoma with smaller rates of false-positive and false-negative findings. (orig./MG)

  14. Peritoneal carcinomatosis: an unusual presentation of fibrolamellar hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Vicente, R.; Garcia-Gutierrez, J. A.; Fernandez, A.; Santalla, F.

    2001-01-01

    Fibrolamellar hepatocellular carcinoma is an uncommon malignant tumor with characteristic clinical, radiological and histopathological features that is usually associated with a more favorable natural course and greater survival than more common variants of hepatocellular carcinoma. We describe an atypical case of a fibrolamellar hepatocellular carcinomas sowing aggressive behaviour in a 20-year-old woman. The lesion presented with massive ascites, and imaging studies revealed extensive peritoneal metastatic spread. (Author) 8 refs

  15. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

    Science.gov (United States)

    Wilson, C. L.; Jurk, D.; Fullard, N.; Banks, P.; Page, A.; Luli, S.; Elsharkawy, A. M.; Gieling, R. G.; Chakraborty, J. Bagchi; Fox, C.; Richardson, C.; Callaghan, K.; Blair, G. E.; Fox, N.; Lagnado, A.; Passos, J. F.; Moore, A. J.; Smith, G. R.; Tiniakos, D. G.; Mann, J.; Oakley, F.; Mann, D. A.

    2015-04-01

    Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1S340A/S340Amice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC.

  16. In vivo image of radioiodinated IVDU and IVFRU in HSV-TK gene tranduced hepatocellular carcinoma bearing buffalo rat

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Tae Sup; Choi, T. H.; Ahn, S. H.; Woo, K. S.; Chung, W. S.; Lee, S. J.; Choi, C. W. [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    2000-07-01

    The extent of gene delivery and expression in gene therapy with suicide genes such as herpes simplex virus thymidine kinase (HSV-tk) is assessed with measurement of selective localization of radioiodinated HSV-tk substrates in HSV-tk expressing tumor. We compared n vitro uptake of {sup 125}I-IVDU, IVFRU and in vivo image of HSV-tk gene tranduced hepatocellular carcinoma model. Using H{sub 2}O{sub 2}(hydrogen peroxide), IVDU and IVFRU was radiolabeled as carrier free form. The uptake of {sup 125}I-IVDU IVFRU was determined with increasing incubation periods in MCA-tk and MCA cell line (1X10{sup 6}cell/flask). The cell harvested and counted after incubation of 15, 30, 60, 120, 240, 480 minutes. For estimating accumulation of radiolabelled IVDU, IVFRU in HSV-tk expressing tumor, MCA-tk cells (1 X 10{sup 6}/100 {mu}l) injected intramuscularly into right thigh of buffalo rats. To determine selective localization of radiolabelled IVDU, IVFRU in HSV-tk expressing hepatocellular carcinoma bearing buffalo rats, MCA-tk cells (1X 10{sup 7} cell/100 {mu}l) were injected subcutaneously into both shoulders of buffalo rats. Established tumor mass implanted into liver of buffalo rats using intra-hepatic tumor injection. Two weeks later, {sup 123}I labelled IVDU, IVFRU(7.4 X 10{sup 7}Bq/200 {mu}l) injected intravenously into tail veins of each buffalo rats. Gamma camera used as revealing localization of {sup 123}I-IVDU, IVFRU in MCA-tk cells grafts rats and in vivo image was taken 2 hrs, 24 hrs after injection. radioiodinated IVDU, IVFRU were radiolabeled with {sup 123}I as labeling yield 70%, {sup 125}I as 84%. Two compounds showed minimal uptake in MCA cell line, but in MCA-tk cell line, increased uptake was observed. The ratio of MCA-tk to MCA was up to 116-fold in {sup 125}I-IVDU, up to 37-fold in {sup 125}I-IVFRU at 480 min. The uptake of IVDU was 4 times higher than IVFRU in MCA-tk cells. Gamma camera images of HSV-tk gene tranduced MCA tumor showed accumulation of {sup 123}I

  17. Diagnostic Approaches to Metastatic Hepatocellular Carcinoma of the Orbit.

    Science.gov (United States)

    Geske, Michael J; Bloomer, Michele M; Kersten, Robert C; Vagefi, M Reza

    Orbital metastasis of hepatocellular carcinoma is exceedingly rare and caries a grave prognosis. Three cases of metastatic orbital hepatocellular carcinoma in which the primary tumor was initially unknown and the diagnostic challenges encountered are presented. With hepatocellular carcinoma, open biopsy and palliative tumor debulking has an increased bleeding risk due to the highly vascular nature of the tumor and coagulopathy associated with chronic liver disease. As an alternative, fine needle aspiration biopsy should be considered for hepatocellular carcinoma with a readily accessible mass and the availability of an experienced cytopathologist.

  18. Research progress of vascular change after TACE in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Kang Zhen; Xiao Enhua

    2013-01-01

    Mortality rate of hepatocellular carcinoma is high. The majority of the patients are diagnosed in advanced stage and lose surgical opportunities. Many studies have reported transcatheter arterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma, and recommended TACE as a standard treatment for hepatocellular carcinoma of Barcelona Clinical Liver Cancer staging (BCLC staging) B. However, TACE can hardly fully embolize tumor blood supply, TACE postoperative hemodynamics and angiogenesis can induce tumor recurrence and metastasis. This paper reviewed characteristics of vascular changes, mechanisms, diagnosis and treatment methods, new progress in the field of hepatocellular carcinoma after TACE. (authors)

  19. Computed tomography diagnosis of hepatocellular carcinoma rupture haemorrhage

    International Nuclear Information System (INIS)

    Zhi Weike; Jiang Bin; Liu Jinquan; Li Sixia; Zhu Zhichang

    2004-01-01

    Objective: To evaluate the diagnostic value of hepatocellular carcinoma rupture hemorrhage using Computed Tomography. Methods: Six cases diagnosed hepatocellular carcinoma rupture hemorrhage were analyzed by morphic and histologic method and investigated the key point of scan in diagnosis. Result: The correct rate of hepatocellular carcinoma rupture hemorrhage by Computed Tomography is above 83 percent, it characteristic representation is strip and would high-density shadow after enhancement. Conclusion: The characteristic representation of hepatocellular carcinoma rupture hemorrhage is attain by Computed Tomography, which provides effective operation evidences for clinical operation. (authors)

  20. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available Toggle navigation Test/Treatment Patient Type Screening/Wellness Disease/Condition Safety En Español More Info Images/Videos About Us News Physician ... of nuclear medicine imaging. The radioactive iodine uptake test (RAIU) is also known as a thyroid uptake. ...

  1. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available Toggle navigation Test/Treatment Patient Type Screening/Wellness Disease/Condition Safety En Español More Info Images/Videos About Us News Physician Resources Professions Site Index A-Z Thyroid Scan and Uptake Thyroid scan and uptake uses ...

  2. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Gokhan Yildiz

    Full Text Available Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal" by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15

  3. Radio-embolization for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Raoul, J.L.; Edeline, J.; Pracht, M.; Boucher, E.; Rolland, Y.; Garin, E.

    2011-01-01

    Hepatocellular carcinoma is now a major public health concern. In intermediate stages (one third of hepatocellular carcinoma patients), chemo-embolization is the standard of care despite a poor tolerance and a moderate efficacy. Moreover, despite recent improvements, this technique seems in a dead end. Radio-embolization could be an excellent tool for such patients. Currently 131 I-Lipiodol, 188 Re-Lipiodol, 90 Y-glass or resin microspheres are available. More recent and promising data come from microspheres, but phase II and III studies are needed before drawing any conclusion. In the future, the combination of radio-embolization with systemic chemotherapy or targeted agents (particularly anti-angiogenic drugs) seems very promising. (authors)

  4. Uptake by J774 macrophages of very-low-density lipoproteins isolated from apoE-deficient mice is mediated by a distinct receptor and stimulated by lipoprotein lipase

    NARCIS (Netherlands)

    Hendriks, W.L.; Sman van der - Beer, F. de; Vlijmen, B.J.M. van; Vark, L.C. van; Hofker, M.H.; Havekes, L.M.

    1997-01-01

    Apolipoprotein (apo) E-deficient mice display marked accumulation in the plasma of VLDL deficient in both apoE and apoBl00 but containing apoB48, apoA-1, apoCs, and apoA-IV. Since apoE-deficient mice develop severe atherosclerotic lesions with lipid-laden macrophages, we reasoned that the uptake of

  5. Serum immunoreactive calcitonin concentration in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Dugard, J; Kew, M C; Da Fonseca, M; Levin, J [University of the Witwatersrand, Johannesburg (South Africa)

    1982-08-21

    Having found raised serum calcitonin concentrations in 94% of patients with hepatocellular carcinoma when using a dextran-coated-charcoal radio-immunoassay, we have now repeated the study, using a double-antibody radio-immunoassay, in 102 further patients with hepatocellular carcinoma and 35 matched controls. Serum immunoreactive calcitonin concentrations (iCT) in the controls ranged from 10 to 310 pg/ml (mean 154,6 pg/ml). Values in the tumour patients ranged from 10 to 1,650 pg/ml (mean 302,6 pg/ml). The mean figures were significantly higher in the tumour patients (P smaller than 0,001), 35.5% of them having values above 310 pg/ml. In 65 of the patients serum iCT concentrations were also determined by dextran-coated-charcoal radio-immunoassay. Values ranged from 10 to 10780 pg/ml (mean 2,179 pg/ml). If 1,000 pg/ml is taken as the upper limit of normal, 69% of the patients had raised iCT concentrations. There was a good correlation (r=0,67; P smaller than 0,001) between serum iCT values measured with both methods in 50 patients. If measured by the double-antibody radio-immunoassay method, the serum calcitonin value is not useful as a marker for hepatocellular carcinoma.

  6. Serum immunoreactive calcitonin concentration in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Dugard, J.; Kew, M.C.; Da Fonseca, M.; Levin, J.

    1982-01-01

    Having found raised serum calcitonin concentrations is 94% of patients with hepatocellular carcinoma when using a dextran-coated-charcoal radio-immunoassay, we have now repeated the study, using a double-antibody radio-immunoassay, in 102 further patients with hepatocellular carcinoma and 35 matched controls. Serum immunoreactive calcitonin concentrations (iCT) in the controls ranged from 10 to 310 pg/ml (mean 154,6 pg/ml). Values in the tumour patients ranged from 10 to 1 650 pg/ml (mean 302,6 pg/ml). The mean figures were significantly higher in the tumour patients (P smaller than 0,001), 35,5% of them having values above 310 pg/ml. In 65 of the patients serum iCT concentrations were also determined by dextran-coated-charcoal radio-immunoassay. Values ranged from 10 to 10780 pg/ml (mean 2 179 pg/ml). If 1 000 pg/ml is taken as the upper limit of normal, 69% of the patients had raised iCT concentrations. There was a good correlation (r=0,67; P smaller than 0,001) between serum iCT values measured with both methods in 50 patients. If measured by the double-antibody radio-immunoassay method, the serum calcitonin value is not useful as a marker for hepatocellular carcinoma

  7. Citrate and succinate uptake by potato mitochondria

    International Nuclear Information System (INIS)

    Jung, D.W.; Laties, G.G.

    1979-01-01

    Potato mitochondria, in the absence of respiration, have a very low capacity for uptake by exchange with endogenous anions, taking up only 2.4 nanomoles citrate and 2.0 nanomoles succinate per milligram protein. Maximum citrate uptake of over 17 nanomoles per milligram protein occurs in the presence of inorganic phosphate, a dicarboxylic acid, and an external energy source (NADH), conditions where net anion accumulation proceeds, mediated by the interlinking of the inorganic phosphate, dicarboxylate, and tricarboxylate carriers. Maximum succinate uptake in the absence of respiratory inhibitors requires only added inorganic phosphate. Compounds which inhibit respiration (antimycin), the exchange carriers (mersalyl and benzylmalonate), or the establishment of the membrane proton motive force (uncouplers) reduce substrate accumulation. A potent inhibitor of the citrate carrier in animal mitochondria, 1,2,3-benzenetricarboxylic acid, does not inhibit citrate uptake in potato mitochondria. Citrate uptake is reduced by concurrent ADP phosphorylation and this reduction is sensitive to oligomycin. The initiation of state 3 after a 3-minute substrate state results in a reduction of the steady-state of citrate uptake by approximately 50%. Accumulation of succinate initially is inhibited by increasing sucrose concentration in the reaction medium from 50 to 400 millimolar. Limited substrate uptake is one of the factors responsible for the often observed depressed initial state 3 respiration rates in many mitochondrial preparations. Since nonlimiting levels of substrate in the matrix cannot be attained by energy-independent exchange, a dependence on respiration for adequate uptake results. Substrate limitation therefore occurs in the matrix for the period of time needed for energy-dependent accumulation of nonlimiting levels

  8. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

    International Nuclear Information System (INIS)

    Seo, J.M.; Lee, S.J.; Kim, S.H.; Park, C.K.; Ha, S.Y.

    2012-01-01

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  9. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

    Energy Technology Data Exchange (ETDEWEB)

    Seo, J.M. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, S.J., E-mail: lucia@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, S.H. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, C.K.; Ha, S.Y. [Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  10. Dysregulated hepatic expression of glucose transporters in chronic disease: contribution of semicarbazide-sensitive amine oxidase to hepatic glucose uptake.

    Science.gov (United States)

    Karim, Sumera; Liaskou, Evaggelia; Fear, Janine; Garg, Abhilok; Reynolds, Gary; Claridge, Lee; Adams, David H; Newsome, Philip N; Lalor, Patricia F

    2014-12-15

    Insulin resistance is common in patients with chronic liver disease (CLD). Serum levels of soluble vascular adhesion protein-1 (VAP-1) are also increased in these patients. The amine oxidase activity of VAP-1 stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. We aimed to document human hepatocellular expression of glucose transporters (GLUTs) and to determine if VAP-1 activity influences receptor expression and hepatic glucose uptake. Quantitative PCR and immunocytochemistry were used to study human liver tissue and cultured cells. We also used tissue slices from humans and VAP-1-deficient mice to assay glucose uptake and measure hepatocellular responses to stimulation. We report upregulation of GLUT1, -3, -5, -6, -7, -8, -9, -10, -11, -12, and -13 in CLD. VAP-1 expression and enzyme activity increased in disease, and provision of substrate to hepatic VAP-1 drives hepatic glucose uptake. This effect was sensitive to inhibition of VAP-1 and could be recapitulated by H2O2. VAP-1 activity also altered expression and subcellular localization of GLUT2, -4, -9, -10, and -13. Therefore, we show, for the first time, alterations in hepatocellular expression of glucose and fructose transporters in CLD and provide evidence that the semicarbazide-sensitive amine oxidase activity of VAP-1 modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease. Copyright © 2014 the American Physiological Society.

  11. Tumor necrosis factor-α attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells

    International Nuclear Information System (INIS)

    Kou, Xingrui; Zhao, Qiudong; Zhao, Xue; Li, Rong; Wei, Lixin; Wu, Mengchao; Jing, Yingying; Deng, Weijie; Sun, Kai; Han, Zhipeng; Ye, Fei; Yu, Guofeng; Fan, Qingmin; Gao, Lu

    2013-01-01

    Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-α, which is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types. The basic objective of this study was to investigate the effects of TNF-α on the cell viability and apoptosis of hepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved. For this purpose, five different concentrations of TNF-α and two different serum settings (serum-cultured and serum-deprived) were used to investigate the effects of TNF-α on the cell viability and apoptosis of Hep3B and SMMC-7721 cells. TNF-α (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and autophagy conferred this process. BAY11-7082, a specific inhibitor of NF-κB, reversed the suppression of serum starvation-induced apoptosis by TNF-α. Moreover, TNF-α-induced NF-κB transactivation was suppressed by autophagy inhibitor 3-MA. In addition, TNF-α up-regulated Ferritin heavy chain (FHC) transiently by NF-κB activation and FHC levels were correlated with the TNF-α-induced protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation. Our findings suggested that autophagy conferred the TNF-α protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of the TNF-α/ NF-κB /FHC signaling pathway

  12. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Oliveri, Roberto S; Wetterslev, Jørn; Gluud, Christian

    2011-01-01

    Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC.......Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC....

  13. Selective angiography in fifty patients with primary hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Shou-Zhong, Wang; Xing-Rong, Chen; Gong-Xian, Wang

    1983-06-01

    Selective angiography is of great importance in the diagnosis of primary hepatocellular carcinoma. It offers information on the findings, multicentricity, localisation, extension, and type of growth. This paper discusses angiography from the methodical point of view, the findings to be obtained, the types of hepatocellular carcinoma, and the diagnostic efficiency of selective angiography in the evaluation of this type of tumour.

  14. Orbital Metastasis of Hepatocellular Carcinoma: A Case Report ...

    African Journals Online (AJOL)

    Background: Hepatocellular carcinoma is one of the commonest malignancies in Nigeria, however metastasis to the orbit is a rare presentation. Objective: To present a rare case of orbital metastasis of hepatocellular carcinoma. Case Report: A 25-year-old man presented with a 3-month history of pain, progressive swelling ...

  15. Follicle-stimulating hormone receptor-mediated uptake of 45Ca2+ by proteoliposomes and cultured rat sertoli cells: Evidence for involvement of voltage-activated and voltage-independent calcium channels

    International Nuclear Information System (INIS)

    Grasso, P.; Reichert, L.E. Jr.

    1989-01-01

    We have previously reported incorporation into liposomes of Triton X-100-solubilized FSH receptor-G-protein complexes derived from purified bovine calf testis membranes. In the present study we have used this model system to show that FSH induces flux of 45Ca2+ into such proteoliposomes in a hormone-specific concentration-dependent manner. FSH, inactivated by boiling, had no stimulatory effect on 45Ca2+ flux, nor did isolated alpha- or beta-subunits of FSH. Addition of GTP (or its analogs 5'-guanylylimidodiphosphate and guanosine-5'-O-[3-thiotriphosphate]) or sodium fluoride (in the presence or absence of GTP or its analogs) failed to induce 45Ca2+ flux into proteoliposomes, suggesting that the uptake of 45Ca2+ was receptor, and not G-protein, related. Voltage-independent (ruthenium red and gadolinium chloride) and voltage-activated (methyoxyverapamil and nifedipine) calcium channel-blocking agents reduced FSH-stimulated 45Ca2+ flux into proteoliposomes to control levels. FSH also induced uptake of 45Ca2+ by cultured rat Sertoli cells. Ruthenium red and gadolinium chloride had no effect on basal levels of 45Ca2+ uptake or estradiol secretion by cultured rat Sertoli cells, nor did methoxyverapamil or nifedipine. All four calcium channel blockers, however, were able to reduce FSH-induced 45Ca2+ uptake to basal levels and FSH-stimulated conversion of androstenedione to estradiol by up to 50%, indicating an involvement of Ca2+ in FSH-stimulated steroidogenesis. Our results suggest that the well documented changes in intracellular calcium levels consequent to FSH binding may be due, at least in part, to an influx of calcium through FSH receptor-regulated calcium channels

  16. Routes and mechanisms of extracellular vesicle uptake

    Directory of Open Access Journals (Sweden)

    Laura Ann Mulcahy

    2014-08-01

    Full Text Available Extracellular vesicles (EVs are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft–mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells.

  17. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... information about your thyroid’s size, shape, position and function that is often unattainable using other imaging procedures. ... thyroid uptake. It is a measurement of thyroid function, but does not involve imaging. Nuclear medicine is ...

  18. Thyroid Scan and Uptake

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    Full Text Available ... which are encased in metal and plastic and most often shaped like a box, attached to a ... will I experience during and after the procedure? Most thyroid scan and thyroid uptake procedures are painless. ...

  19. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... eat for several hours before your exam because eating can affect the accuracy of the uptake measurement. ... often unattainable using other imaging procedures. For many diseases, nuclear medicine scans yield the most useful information ...

  20. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... A thyroid scan is a type of nuclear medicine imaging. The radioactive iodine uptake test (RAIU) is ... thyroid function, but does not involve imaging. Nuclear medicine is a branch of medical imaging that uses ...

  1. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... Because nuclear medicine procedures are able to pinpoint molecular activity within the body, they offer the potential ... or imaging device that produces pictures and provides molecular information. The thyroid scan and thyroid uptake provide ...

  2. Thyroid Scan and Uptake

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    Full Text Available ... Actual scanning time for each thyroid uptake is five minutes or less. top of page What will ... diagnostic procedures have been used for more than five decades, and there are no known long-term ...

  3. Thyroid Scan and Uptake

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    Full Text Available ... top of page Additional Information and Resources RTAnswers.org Radiation Therapy for Head and Neck Cancer top ... Scan and Uptake Sponsored by Please note RadiologyInfo.org is not a medical facility. Please contact your ...

  4. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... When radiotracer is taken by mouth, in either liquid or capsule form, it is typically swallowed up ... radioactive iodine (I-123 or I-131) in liquid or capsule form to swallow. The thyroid uptake ...

  5. Thyroid Scan and Uptake

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    Full Text Available ... RAIU) is also known as a thyroid uptake. It is a measurement of thyroid function, but does ... they offer the potential to identify disease in its earliest stages as well as a patient’s immediate ...

  6. Thyroid Scan and Uptake

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    Full Text Available ... for several hours before your exam because eating can affect the accuracy of the uptake measurement. Jewelry ... small hand-held device resembling a microphone that can detect and measure the amount of the radiotracer ...

  7. Thyroid Scan and Uptake

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    Full Text Available ... of page What will I experience during and after the procedure? Most thyroid scan and thyroid uptake ... you otherwise, you may resume your normal activities after your nuclear medicine scan. If any special instructions ...

  8. Thyroid Scan and Uptake

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    Full Text Available ... scan and thyroid uptake provide information about the structure and function of the thyroid. The thyroid is ... computer, create pictures offering details on both the structure and function of organs and tissues in your ...

  9. Thyroid Scan and Uptake

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    Full Text Available ... eat for several hours before your exam because eating can affect the accuracy of the uptake measurement. ... its radioactivity over time. It may also pass out of your body through your urine or stool ...

  10. Thyroid Scan and Uptake

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    Full Text Available ... procedures within the last two months that used iodine-based contrast material. Your doctor will instruct you ... a type of nuclear medicine imaging. The radioactive iodine uptake test (RAIU) is also known as a ...

  11. Metastases of Hepatocellular Carcinoma Misdiagnosed as Isolated Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    Greco, Assunta; De Masi, Roberto; Orlando, Stefania; Metrangolo, Antonio; Zecca, Vittorio; Morciano, Giancarlo; De Donno, Antonella; Bagordo, Francesco; Piccinni, Giancarlo

    At present, cardiac metastasis of hepatocellular carcinoma is rarely mentioned in the literature. We report a hepatocellular carcinoma patient with cardiac metastasis misdiagnosed as hypertrophic cardiomyopathy in 2011. Two years later, on presentation of syncope, an abnormal ventricular septal size was recorded by ultrasound scan, and was subsequently shown by magnetic resonance imaging to be a tumour lesion. A myocardial biopsy confirmed infiltration of hepatocellular carcinoma. This observation underlines the risk of hepatocellular carcinoma cardiac metastasis, manifested in its infiltrative form as hypertrophic cardiomyopathy. In conclusion, we suggest that the ultrasound appearance of hypertrophic cardiomyopathy in hepatocellular carcinoma patients should be seen as a "red flag" and recommend the introduction of magnetic resonance imaging assessment of transplant candidates.

  12. Lipid-coated iron oxide nanoparticles for dual-modal imaging of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Liang J

    2017-03-01

    Full Text Available Jinying Liang,1–3 Xinxin Zhang,2 Yunqiu Miao,2 Juan Li,1 Yong Gan2 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China; 3School of Pharmacy, Xinxiang Medical University, Xinxiang, People’s Republic of China Abstract: The development of noninvasive imaging techniques for the accurate diagnosis of progressive hepatocellular carcinoma (HCC is of great clinical significance and has always been desired. Herein, a hepatocellular carcinoma cell-targeting fluorescent magnetic nanoparticle (NP was obtained by conjugating near-infrared fluorescence to the surface of Fe3O4 (NIRF-Fe3O4 NPs, followed by coating the lipids consisting of tumoral hepatocytes-targeting polymer (Gal-P123. This magnetic NP (GPC@NIRF-Fe3O4 with superparamagnetic behavior showed high stability and safety in physiological conditions. In addition, GPC@NIRF-Fe3O4 achieved more specific uptake of human liver cancer cells than free Fe3O4 NPs. Importantly, with superparamagnetic iron oxide and strong NIR absorbance, GPC@NIRF-Fe3O4 NPs demonstrate prominent tumor-contrasted imaging performance both on fluorescent and T2-weighted magnetic resonance (MR imaging modalities in a living body. The relative MR signal enhancement of GPC@NIRF-Fe3O4 NPs achieved 5.4-fold improvement compared with NIR-Fe3O4 NPs. Therefore, GPC@NIRF-Fe3O4 NPs may be potentially used as a candidate for dual-modal imaging of tumors with information covalidated and directly compared by combining fluorescence and MR imaging. Keywords: dual-imaging, magnetic resonance imaging, hepatocellular carcinoma, tumor-targeting

  13. Elevated serum levels of Chromogranin A in hepatocellular carcinoma.

    Science.gov (United States)

    Biondi, Antonio; Malaguarnera, Giulia; Vacante, Marco; Berretta, Massimiliano; D'Agata, Velia; Malaguarnera, Michele; Basile, Francesco; Drago, Filippo; Bertino, Gaetano

    2012-01-01

    During the past three decades, the incidence of hepatocellular carcinoma in the United States has tripled. The neuroendocrine character has been observed in some tumor cells within some hepatocellular carcinoma nodules and elevated serum chromogranin A also been reported in patients with hepatocellular carcinoma. The aim of this work was to investigate the role of serum concentration of chromogranin A in patients with hepatocellular carcinoma at different stages. The study population consisted of 96 patients (63 males and 33 females age range 52-84) at their first hospital admission for hepatocellular carcinoma. The control group consisted of 35 volunteers (20 males and 15 females age range 50-80). The hepatocellular carcinoma patients were stratified according the Barcelona-Clinic Liver Cancer classification. Venous blood samples were collected before treatment from each patients before surgery, centrifuged to obtain serum samples and stored at -80° C until assayed. The chromogranin A serum levels were elevated (> 100 ng/ml) in 72/96 patients with hepatocellular carcinoma. The serum levels of chromogranin A were significantly correlated (p<0.05) with alpha-fetoprotein. In comparison with controls, the hepatocellular carcinoma patients showed a significant increase (p<0.001) vs controls. The chromogranin A levels in the Barcelona staging of hepatocellular carcinoma was higher in stage D compared to stage C (p<0.01), to stage B (p<0.001), and to stage A (p<0.001). Molecular markers, such as chromogranin A, could be very useful tools for hepatocellular carcinoma diagnosis. However the molecular classification should be incorporated into a staging scheme, which effectively separated patients into groups with homogeneous prognosis and response to treatment, and thus serves to aid in the selection of appropriate therapy.

  14. CT diagnosis of rare histological variant of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Li Huaibo; Feng Zhipeng; Duan Shaoyin; Zhaugn Xiangrong

    2009-01-01

    Objective: To explore and understand the CT findings of 5 rare histological variants of hepatocellular carcinoma. Methods: CT findings of 31 cases of rare histological variants confirmed by surgery and pathology were analyzed retrospectively. Results: 13 cases were clear cell hepatocellular carcinoma. 3 cases of them showed patchy fat density in plain scans. Enhanced CT showed features of 'fast in fast out' which was similar to the common hepatocellular carcinoma. 4 cases belonged to sclerosis hepatocellular carcinoma. They appeared as heterogeneous, slowly enhancement on arterial phase images, and delay enhancement on portal venous phase and delay phase images. 9 cases belonged to mixed hepatocellular carcinoma. 5 cases of them showed inhomogeneous enhancement and 4 without enhancement during arterial phase, 3 cases showed delay enhancement and 4 without during portal venous and delay phase. 3 cases were fibrolamellar hepatocellular carcinoma. All showed obvious and fastly enhancement on arterial phase images, subsided slowly on the portal venous and delay phase images, showing features of 'fast in slow out', no enhancement was seen in the central scar. Shrinkage phenomenon on the surface of liver could be seen on the CT plain scans in sclerosis, mixed and fibrolamellar hepatocellular carcinoma. 2 cases were the type of dense hepatocellular carcinoma. The surrounding part in the 2 cases were slightly enhanced, while the most part of the center were not enhanced similar to necrosis. Conclusion: The CT findings of rate histological variant of hepatocellular carcinoma are characteristic. Analyzing the CT plain and enhancement finding is helpful to the diagnosis of these types of hepatocellular carcinoma. (authors)

  15. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

    Directory of Open Access Journals (Sweden)

    Stefanou Nikolaos

    2010-08-01

    Full Text Available Abstract Background Numerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC. The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT, a known mediator of cellular immortalization. Methods We investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3 and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes. Results We showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC. Conclusions We propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis.

  16. The multifaceted role of podoplanin expression in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Andreea Cioca

    2017-02-01

    Full Text Available The role of podoplanin in hepatocellular carcinoma (HCC is not clear yet. The aim of our study was to evaluate the expression of podoplanin in HCC and to determine its role in hepatocarcinogenesis. We performed immunohistochemistry with monoclonal D2-40 antibody, on paraffin-embedded tissue sections of 72 patients diagnosed with HCC. Lymphatic vessels density (LVD was increased in patients who had vascular invasion at the time of diagnosis (P=0.018 and in those with associated cirrhosis (P=0.006. Tumor cells showing podoplanin expression were correlated with histological grade (P=0.040. Podoplanin-expressing cancer associated fibroblasts (CAFs were correlated with both LVD (P=0.019 and tumor cells (P=0.015. Our results sustain the dual role of podoplanin in HCC by its involvement in both HCC tumorigenesis, lymphatic neovascularization and tumor invasion invasiveness. A possible crosstalk between epithelial and stromal tumor cells in HCC tumor microenvironment may be mediated by podoplanin, but this hypothesis needs further studies to elucidate this interrelation.

  17. The multifaceted role of podoplanin expression in hepatocellular carcinoma.

    Science.gov (United States)

    Cioca, Andreea; Ceausu, Amalia R; Marin, Irina; Raica, Marius; Cimpean, Anca M

    2017-02-13

    The role of podoplanin in hepatocellular carcinoma (HCC) is not clear yet. The aim of our study was to evaluate the expression of podoplanin in HCC and to determine its role in hepatocarcinogenesis. We performed immunohistochemistry with monoclonal D2-40 antibody, on paraffin-embedded tissue sections of 72 patients diagnosed with HCC. Lymphatic vessels density (LVD) was increased in patients who had vascular invasion at the time of diagnosis (P=0.018) and in those with associated cirrhosis (P=0.006). Tumor cells showing podoplanin expression were correlated with histological grade (P=0.040). Podoplanin-expressing cancer associated fibroblasts (CAFs) were correlated with both LVD (P=0.019) and tumor cells (P=0.015). Our results sustain the dual role of podoplanin in HCC by its involvement in both HCC tumorigenesis, lymphatic neovascularization and tumor invasion invasiveness. A possible crosstalk between epithelial and stromal tumor cells in HCC tumor microenvironment may be mediated by podoplanin, but this hypothesis needs further studies to elucidate this interrelation.

  18. Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Yu-Chi Su

    Full Text Available Hepatocellular carcinoma (HCC is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells. Moreover, galectin-1 was found to induce autophagic flux in HCC cells. Inhibition of autophagy by inhibitors or knockdown of Atg5 cancels galectin-1-induced cisplatin resistance in HCC cells. Increase of mitophagy triggered by galectin-1 was found to reduce the mitochondrial potential loss and apoptosis induced by cisplatin treatment. Finally, using an in situ hepatoma mouse model, we clearly demonstrated that inhibition of galectin-1 by thiodigalactoside could significantly augment the anti-HCC effect of cisplatin. Taken together, our findings offer a new insight into the chemoresistance galectin-1 causes against cisplatin treatment, and points to a potential approach to improve the efficacy of cisplatin in the treatment of HCC patients.

  19. A qualitative signature for early diagnosis of hepatocellular carcinoma based on relative expression orderings.

    Science.gov (United States)

    Ao, Lu; Zhang, Zimei; Guan, Qingzhou; Guo, Yating; Guo, You; Zhang, Jiahui; Lv, Xingwei; Huang, Haiyan; Zhang, Huarong; Wang, Xianlong; Guo, Zheng

    2018-04-23

    Currently, using biopsy specimens to confirm suspicious liver lesions of early hepatocellular carcinoma are not entirely reliable because of insufficient sampling amount and inaccurate sampling location. It is necessary to develop a signature to aid early hepatocellular carcinoma diagnosis using biopsy specimens even when the sampling location is inaccurate. Based on the within-sample relative expression orderings of gene pairs, we identified a simple qualitative signature to distinguish both hepatocellular carcinoma and adjacent non-tumour tissues from cirrhosis tissues of non-hepatocellular carcinoma patients. A signature consisting of 19 gene pairs was identified in the training data sets and validated in 2 large collections of samples from biopsy and surgical resection specimens. For biopsy specimens, 95.7% of 141 hepatocellular carcinoma tissues and all (100%) of 108 cirrhosis tissues of non-hepatocellular carcinoma patients were correctly classified. Especially, all (100%) of 60 hepatocellular carcinoma adjacent normal tissues and 77.5% of 80 hepatocellular carcinoma adjacent cirrhosis tissues were classified to hepatocellular carcinoma. For surgical resection specimens, 99.7% of 733 hepatocellular carcinoma specimens were correctly classified to hepatocellular carcinoma, while 96.1% of 254 hepatocellular carcinoma adjacent cirrhosis tissues and 95.9% of 538 hepatocellular carcinoma adjacent normal tissues were classified to hepatocellular carcinoma. In contrast, 17.0% of 47 cirrhosis from non-hepatocellular carcinoma patients waiting for liver transplantation were classified to hepatocellular carcinoma, indicating that some patients with long-lasting cirrhosis could have already gained hepatocellular carcinoma characteristics. The signature can distinguish both hepatocellular carcinoma tissues and tumour-adjacent tissues from cirrhosis tissues of non-hepatocellular carcinoma patients even using inaccurately sampled biopsy specimens, which can aid early

  20. Hepatic Arterial Perfusion Scintigraphy with '99mTc-Macroaggregated Albumin in Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Kim, Gang Deuk; Sohn, Kwang Joon; Min, Kyung Yoon; Kwon, Young Mi; Kim, Chang Guhn; Noh, Byung Suk; Won, Jong Jin

    1994-01-01

    Hepatic arterial perfusion scintigraphy with '9 9m Tc macroggregated albumin (HAPS) study was carried out in 16 patients with hepatocellular carcinoma (HCC) and in six patients without liver tumor to evaluate HAPS findings of hepatocellular carcinoma and use fullness of HAPS. HAPS with planar and SPECT study were performed in 22 patients after conventional hepatic or celiac arteriography. For HAPS study, 4 5 mCi of MAA mixed with 2 ml of saline was injected into proper hepatic artery or its distal branches at the rate of approximately 1 ml/sec. We analysed 21 HCCs over 2 cm in diameter(average diameter: 6.4 cm) and 17 of 21 HCCs were over 4 cm in diameter. CT, sonography and angiography were performed within two week in all 16 patients and liver scan was performed in 12 patients. Three different pattern of tumor perfusion were observed in 16 patients with HCC. 1) diffuse increased perfusion in 16 of 21(76%) 2) increased peripheral perfusion in 4 of 21(19%) 3) diffuse decreased perfusion in 1 of 21 (5%) Arteriovenous shunt indicated by lung uptake of MAA were observed in 9 of 16 (56% ). In contrast, angiography demonstrates arteriovenous shunt in 2 of 16 (13%). There was no accumulation of radioactivity on RRC blood pool scan in all six patients with HCC examined. HAPS is useful study in evaluation of perfusion pattern or vascularity of HCC and in detection of arteriovenous shunt.

  1. Liposomes equipped with cell penetrating peptide BR2 enhances chemotherapeutic effects of cantharidin against hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Xue; Lin, Congcong; Lu, Aiping; Lin, Ge; Chen, Huoji; Liu, Qiang; Yang, Zhijun; Zhang, Hongqi

    2017-11-01

    A main hurdle for the success of tumor-specific liposomes is their inability to penetrate tumors efficiently. In this study, we incorporated a cell-penetrating peptide BR2 onto the surface of a liposome loaded with the anticancer drug cantharidin (CTD) to create a system targeting hepatocellular carcinoma (HCC) cells more efficiently and effectively. The in vitro cytotoxicity assay comparing the loaded liposomes' effects on hepatocellular cancer HepG2 and the control Miha cells showed that CTD-loaded liposomes had a stronger anticancer effect after BR2 modification. The cellular uptake results of HepG2 and Miha cells further confirmed the superior ability of BR2-modified liposomes to penetrate cancer cells. The colocalization study revealed that BR2-modified liposomes could enter tumor cells and subsequently release drugs. A higher efficiency of delivery by BR2 liposomes as compared to unmodified liposomes was evident by evaluation of the HepG2 tumor spheroids penetration and inhibition. The biodistribution studies and anticancer efficacy results in vivo showed the significant accumulation of BR2-modified liposomes into tumor sites and an enhanced tumor inhibition. In conclusion, BR2-modified liposomes improve the anticancer potency of drugs for HCC.

  2. Hepatocellular carcinoma: treatment with transcatheter arterial chemoembolization

    International Nuclear Information System (INIS)

    Acunas, Buelent; Rozanes, Izzet

    1999-01-01

    This article presents a review of the literature regarding the use of transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC). There have been two different approaches to the treatment: (a) percutaneous tumor ablation methods which can be divided into injectable and thermal methods; percutaneous ethanol injection (PEI) is the most widely used method, and (b) TACE. PEI is the treatment of choice for single HCCs smaller or equal to 3 cm in size. For patients with large HCCs combined TACE and PEI is probably the most effective nonsurgical treatment. In the presence of multiple HCC nodules, TACE remains the treatment of choice

  3. Hepatitis C Virus and Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Masao Omata

    2013-01-01

    Full Text Available Hepatitis C virus (HCV, a hepatotropic virus, is a single stranded-positive RNA virus of ~9,600 nt. length belonging to the Flaviviridae family. HCV infection causes acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC. It has been reported that HCV-coding proteins interact with host-cell factors that are involved in cell cycle regulation, transcriptional regulation, cell proliferation and apoptosis. Severe inflammation and advanced liver fibrosis in the liver background are also associated with the incidence of HCV-related HCC. In this review, we discuss the mechanism of hepatocarcinogenesis in HCV-related liver diseases.

  4. Hepatocellular carcinoma directly invading the duodenum

    International Nuclear Information System (INIS)

    Mohamed, Abdelrehman O.; Joshi, Sandhya; Czechowski, Janusz; Branicki, Frank

    2005-01-01

    Recurrent gastrointestinal bleeding from hepatocellular carcinoma (HCC) invading the duodenum is very rare. We present a case of 50-year-old male who was admitted with a history of recurrent upper gastrointestinal tract (UGIT) bleeding, weight loss and anemia. The patient was known to have a chronic hepatitis C. Endoscopic examination showed grade-2 non-bleeding esophageal varices, and a large ulcerated duodenal mass partially obstructing the duodenal bulb outlet and causing recurrent UGIT bleeding. Pathological evaluation of the mass revealed HCC. (author)

  5. Living donor liver transplantation for hepatocellular carcinoma achieves better outcomes.

    Science.gov (United States)

    Lin, Chih-Che; Chen, Chao-Long

    2016-10-01

    Liver transplantation (LT) for hepatocellular carcinoma (HCC) at Kaohsiung Chang Gung Memorial Hospital mainly relies on live donor LT (LDLT). Owing to taking the risk of LD, we are obligated to adopt strict selection criteria for HCC patients and optimize the pre-transplant conditions to ensure a high disease-free survival similar to those without HCC, even better than deceased donor LT (DDLT). Better outcomes are attributed to excellent surgical results and optimal patient selection. The hospital mortality of primary and salvage LDLT are lower than 2% in our center. Although Taiwan Health Insurance Policy extended the Milan to University of California, San Francisco (UCSF) criteria in 2006, selection criteria will not be consolidated to take into account only by the morphologic size/number of tumors but also by their biology. The criteria are divided into modifiable image morphology, alpha fetoprotein (AFP), and positron emission tomography (PET) scan with standard uptake value (SUV) and unmodifiable unfavorable pathology such as HCC combined with cholangiocarcinoma (CC), sarcomatoid type, and poor differentiation. Downstaging therapy is necessary for HCC patients beyond criteria to fit all modifiable standards. The upper limit of downstaging treatment seems to be extended by more effective drug eluting transarterial chemoembolization in cases without absolute contraindications. In contrast, the pitfall of unmodifiable tumor pathology should be excluded by the findings of pretransplant core biopsy/resection if possible. More recently, achieving complete tumor necrosis in explanted liver could almost predict no recurrence after transplant. Necrotizing therapy is advised if possible before transplant even the tumor status within criteria to minimize the possibility of tumor recurrence. LDLT with low surgical mortality in experienced centers provides the opportunities of optimizing the pre-transplant tumor conditions and timing of transplant to achieve better

  6. Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice

    Science.gov (United States)

    Liu, Hui; Xu, Hong-Wei; Zhang, Yu-Zhen; Huang, Ya; Han, Guo-Qing; Liang, Tie-Jun; Wei, Li-Li; Qin, Cheng-Yong; Qin, Cheng-Kun

    2015-01-01

    AIM: To evaluate the efficacy of ursodeoxycholic acid (UDCA) as a chemotherapeutic agent for the treatment of hepatocellular carcinoma (HCC). METHODS: BALB/c nude mice were randomized into four groups 24 h before subcutaneous injection of hepatocarcinoma BEL7402 cells suspended in phosphate buffered saline (PBS) into the right flank. The control group (n = 10) was fed a standard diet while treatment groups (n = 10 each) were fed a standard daily diet supplemented with different concentrations of UDCA (30, 50 and 70 mg/kg per day) for 21 d. Tumor growth was measured once each week, and tumor volume (V) was calculated with the following equation: V = (L × W2) × 0.52, where L is the length and W is the width of the xenograft. After 21 d, mice were killed under ether anesthesia, and tumors were excised and weighed. Apoptosis was evaluated through detection of DNA fragmentation with gel electrophoresis and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the expression of apoptosis-related proteins BAX, BCL2, APAF1, cleaved caspase-9, and cleaved caspase-3. RESULTS: UDCA suppressed tumor growth relative to controls. The mean tumor volumes were the following: control, 1090 ± 89 mm3; 30 mg/kg per day, 612 ± 46 mm3; 50 mg/kg per day, 563 ± 38 mm3; and 70 mg/kg per day, 221 ± 26 mm3. Decreased tumor volumes reached statistical significance relative to control xenografts (30 mg/kg per day, P < 0.05; 50 mg/kg per day, P < 0.05; 70 mg/kg per day, P < 0.01). Increasing concentrations of UDCA led to increased DNA fragmentation observed on gel electrophoresis and in the TUNEL assay (control, 1.6% ± 0.3%; 30 mg/kg per day, 2.9% ± 0.5%; 50 mg/kg per day, 3.15% ± 0.7%, and 70 mg/kg per day, 4.86% ± 0.9%). Western blot analysis revealed increased expression of BAX, APAF1, cleaved-caspase-9 and cleaved-caspase-3 proteins, which induce apoptosis, but decreased expression of BCL2

  7. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    Full Text Available Nan Jiang,1,* Rongtong Sun,2,* Qing Sun3 1Shandong University School of Medicine, Jinan, Shandong Province, People’s Republic of China; 2Weihai Municipal Hospital, Weihai, Shandong Province, People’s Republic of China; 3Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC, are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both

  8. Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice.

    Science.gov (United States)

    Liu, Hui; Xu, Hong-Wei; Zhang, Yu-Zhen; Huang, Ya; Han, Guo-Qing; Liang, Tie-Jun; Wei, Li-Li; Qin, Cheng-Yong; Qin, Cheng-Kun

    2015-09-28

    To evaluate the efficacy of ursodeoxycholic acid (UDCA) as a chemotherapeutic agent for the treatment of hepatocellular carcinoma (HCC). BALB/c nude mice were randomized into four groups 24 h before subcutaneous injection of hepatocarcinoma BEL7402 cells suspended in phosphate buffered saline (PBS) into the right flank. The control group (n = 10) was fed a standard diet while treatment groups (n = 10 each) were fed a standard daily diet supplemented with different concentrations of UDCA (30, 50 and 70 mg/kg per day) for 21 d. Tumor growth was measured once each week, and tumor volume (V) was calculated with the following equation: V = (L × W(2)) × 0.52, where L is the length and W is the width of the xenograft. After 21 d, mice were killed under ether anesthesia, and tumors were excised and weighed. Apoptosis was evaluated through detection of DNA fragmentation with gel electrophoresis and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the expression of apoptosis-related proteins BAX, BCL2, APAF1, cleaved caspase-9, and cleaved caspase-3. UDCA suppressed tumor growth relative to controls. The mean tumor volumes were the following: control, 1090 ± 89 mm(3); 30 mg/kg per day, 612 ± 46 mm(3); 50 mg/kg per day, 563 ± 38 mm(3); and 70 mg/kg per day, 221 ± 26 mm(3). Decreased tumor volumes reached statistical significance relative to control xenografts (30 mg/kg per day, P < 0.05; 50 mg/kg per day, P < 0.05; 70 mg/kg per day, P < 0.01). Increasing concentrations of UDCA led to increased DNA fragmentation observed on gel electrophoresis and in the TUNEL assay (control, 1.6% ± 0.3%; 30 mg/kg per day, 2.9% ± 0.5%; 50 mg/kg per day, 3.15% ± 0.7%, and 70 mg/kg per day, 4.86% ± 0.9%). Western blot analysis revealed increased expression of BAX, APAF1, cleaved-caspase-9 and cleaved-caspase-3 proteins, which induce apoptosis, but decreased expression of BCL2 protein, which

  9. Supplemental Transcatheter Arterial Chemoembolization Through a Collateral Omental Artery: Treatment for Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Won, Jong Yun; Lee, Do Yun; Lee, Jong Tae; Park, Sung Il; Kim, Myeong-Jin; Yoo, Hyung Sik; Suh, Sang-Hyun; Park, Sang Joon

    2003-01-01

    Purpose: To evaluate the therapeutic efficacy and safety of supplemental transcatheter arterialchemoembolization (TACE) through the extrahepatic collateral omentalartery (OA) for the treatment of hepatocellular carcinoma (HCC). Methods: We studied 21 patients with extrahepatic collaterals of the OA, among 1,512 patients with HCC who had undergone angiography. HCCs supplied by collateral OAs were located at: segment IV in seven, segment V in five, segment III in three, segment VI in three and segment VIII in three patients (Couinaud classification of segments). On preoperative CT scans, every HCC was abutting the liver surface. Adjacent omental infiltration or engorgement was noted in 11 patients. Celiac and hepatic arteriograms showed hypertrophy of the feeding OA in all patients. TACE of the OA was performed in 19 patients with an emulsion of iodized oil and doxorubicin hydrochloride.Embolization with gelatin sponge particles was added in five patients. Results: Collaterals of the OA to the HCC were found on the first to seventeenth sessions of TACE. On follow-up CT scans, five patients showed complete uptake of iodized oil in the tumor. Partial uptake of iodized oil was noted in 13 patients and no uptake in one patient. There was no serious complication that related to the omental embolization, such as omental or bowel ischemia. The cumulative survival rates from the time of the TACE of the OA were 81% at 6 months and 68% at 12 months. Conclusion: TACE of the OA is safe and has a potential therapeutic effect in the treatment of HCC

  10. The evolutionary scenario of hepatocellular carcinoma in Italy: an update.

    Science.gov (United States)

    Bucci, Laura; Garuti, Francesca; Lenzi, Barbara; Pecorelli, Anna; Farinati, Fabio; Giannini, Edoardo G; Granito, Alessandro; Ciccarese, Francesca; Rapaccini, Gian Lodovico; Di Marco, Maria; Caturelli, Eugenio; Zoli, Marco; Borzio, Franco; Sacco, Rodolfo; Cammà, Calogero; Virdone, Roberto; Marra, Fabio; Felder, Martina; Morisco, Filomena; Benvegnù, Luisa; Gasbarrini, Antonio; Svegliati-Baroni, Gianluca; Foschi, Francesco Giuseppe; Missale, Gabriele; Masotto, Alberto; Nardone, Gerardo; Colecchia, Antonio; Bernardi, Mauro; Trevisani, Franco

    2017-02-01

    Epidemiology of hepatocellular carcinoma is changing worldwide. This study aimed at evaluating the changing scenario of aetiology, presentation, management and prognosis of hepatocellular carcinoma in Italy during the last 15 years. Retrospective analysis of the ITA.LI.CA (Italian Liver Cancer) database including 5192 hepatocellular carcinoma patients managed in 24 centres from 2000 to 2014. Patients were divided into three groups according to the date of cancer diagnosis (2000-2004, 2005-2009 and 2010-2014). The main results were as follows: (i) progressive patient aging; (ii) progressive expansion of non-viral cases and, namely, of "metabolic" hepatocellular carcinomas; (iii) increasing proportion of hepatocellular carcinoma diagnosed during a correct (semi-annual) surveillance programme; (iv) favourable cancer stage migration; (v) increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; (vi) improved outcomes of ablative and transarterial treatments; (vii) improved overall survival (adjusted for the lead time in surveyed patients), particularly after 2009, of both viral and non-viral patients presenting with an early- or intermediate-stage hepatocellular carcinoma. During the last 15 years several aetiological and clinical features of hepatocellular carcinoma patients have changed, as their management. The observed improvement of overall survival was owing both to the wider use of semi-annual surveillance, expanding the proportion of tumours that qualified for curative treatments, and to the improved outcome of loco-regional treatments. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Ficus Deltoidea Enhance Glucose Uptake Activity in Cultured Muscle Cells

    International Nuclear Information System (INIS)

    Zainah Adam; Shafii Khamis; Amin Ismail; Muhajir Hamid

    2015-01-01

    Ficus deltoidea or locally known as Mas cotek is one of the common medicinal plants used in Malaysia. Our previous studies showed that this plant have blood glucose lowering effect. Glucose uptake into muscle and adipocytes cells is one of the known mechanisms of blood glucose lowering effect. This study was performed to evaluate the effect of Ficus deltoidea on glucose uptake activity into muscle cells. The cells were incubated with Ficus deltoidea extracts either alone or combination with insulin. Amount of glucose uptake by L6 myotubes was determined using glucose tracer, 2-deoxy-(1- 3 H 1 )-glucose. The results showed that Ficus deltoidea extracts at particular doses enhanced basal or insulin-mediated glucose uptake into muscle cells significantly. Hot aqueous extract enhanced glucose uptake at the low concentration (10 μg/ ml) whereas methanolic extract enhanced glucose uptake at low and high concentrations. Methanolic extract also mimicked insulin activity during enhancing glucose uptake into L^ muscle cells. Glucose uptake activity of Ficus deltoidea could be attributed by the phenolic compound presence in the plant. This study had shown that Ficus deltoidea has the ability to enhance glucose uptake into muscle cells which is partly contributed the antidiabetic activity of this plant. (author)

  12. Is there a strategy I iron uptake mechanism in maize?

    Science.gov (United States)

    Li, Suzhen; Zhou, Xiaojin; Chen, Jingtang; Chen, Rumei

    2018-04-03

    Iron is a metal micronutrient that is essential for plant growth and development. Graminaceous and nongraminaceous plants have evolved different mechanisms to mediate Fe uptake. Generally, strategy I is used by nongraminaceous plants like Arabidopsis, while graminaceous plants, such as rice, barley, and maize, are considered to use strategy II Fe uptake. Upon the functional characterization of OsIRT1 and OsIRT2 in rice, it was suggested that rice, as an exceptional graminaceous plant, utilizes both strategy I and strategy II Fe uptake systems. Similarly, ZmIRT1 and ZmZIP3 were identified as functional zinc and iron transporters in the maize genome, along with the determination of several genes encoding Zn and Fe transporters, raising the possibility that strategy I Fe uptake also occurs in maize. This mini-review integrates previous reports and recent evidence to obtain a better understanding of the mechanisms of Fe uptake in maize.

  13. Evaluation of transcatheter therapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Yamada, Toshihiko

    1990-01-01

    The author proposed improvement of the criteria for the effects of transcatheter therapy for hepatocellular carcinoma. 104 patients were treated by transcatheter therapy. Their responses were determined by the usual criteria. Next, they were classified and evaluated in 3 groups, with the area of lipiodol deposition on CT for over 4 weeks regarded as nacrosis. The result was determined, and its relationship to prognosis was studied in light of the repeated therapy. By the usual criteria, only 10% of patients were judged as PR, and there were no differences between therapies. Many of the NC cases had low AFP levels with therapy. At the initial therapy, the ratio of cases with low AFP levels was higher and the survival time was longer in the A group. So the A group was judged as most effective. Clinically, 10 patients were considered most benefitted by therapy. They were considered the A group, but all were judged as NC. Considering the effects of repeated therapy, 10 patients with NC were judged as the A-max group. Prognosis was poor in patients of the B-max and C-max groups. These results indicate that judgement by the usual criteria was inconsistent with clinical condition. It was improved by regarding the area of lipiodol deposition on CT for over 4 weeks as necrosis. Estimations of effects and prognosis were made more accurate by considering repeated therapy. Thus, the proposed improvement of the criteria by CT is more useful to estimate transcatheter therapy of the hepatocellular carcinoma. (author)

  14. Radiological imagings of small hepatocellular carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Miyake, Hidetoshi; Hayashi, Kuniaki; Futagawa, Sakae; Matsunaga, Naofumi; Maeda, Tohru [Nagasaki Univ. (Japan). School of Medicine

    1984-08-01

    Forty three cases of small hepatocellular carcinoma (measuring less than 3 cm in diameter on imaging modalities) were detected during a period of four years and two months. There were two cases in which hepatoma measured 1 cm in diameter, twenty four cases between 1 and 2 cm, and seventeen cases between 2 and 3 cm. The relative role of each modality and AFP value in the detection of these tumors was evaluated. The detection rate of small hepatocellular carcinoma by liver scintigraphy, ultrasonography (US), computed tomography (CT) and angiography was 8%, 74%, 70% and 95%, respectively. The sensitivity of serum AFP value was 67% (either measuring more than 200ng/ml or showing a tendency of steady rising even if below the level of 200ng/ml). Most hepatomas less than 2 cm in size were hypoechoic on US, and those above 2 cm in size were hyperechoic with peripheral sonolucency (halo). Almost all cases were described as low density area on both plain and enhancement CT. Angiography was the best method for detecting small hepatomas. It may be recommended to perform angiography on every patient with liver cirrhosis at the time of diagnosis of this disease. Periodic examinations by AFP, US and CT should be done if the angiography was negative. Evaluation by US in every three months and by CT in every twelve months may be appropriate.

  15. Imaging findings of mimickers of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Tae Kyoung Kim

    2015-12-01

    Full Text Available Radiological imaging plays a crucial role in the diagnosis of hepatocellular carcinoma (HCC as the noninvasive diagnosis of HCC in high-risk patients by typical imaging findings alone is widely adopted in major practice guidelines for HCC. While imaging techniques have markedly improved in detecting small liver lesions, they often detect incidental benign liver lesions and non-hepatocellular malignancy that can be misdiagnosed as HCC. The most common mimicker of HCC in cirrhotic liver is nontumorous arterioportal shunts that are seen as focal hypervascular liver lesions on dynamic contrast-enhanced cross-sectional imaging. Rapidly enhancing hemangiomas can be easily misdiagnosed as HCC especially on MR imaging with liver-specific contrast agent. Focal inflammatory liver lesions mimic HCC by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging. It is important to recognize the suggestive imaging findings for intrahepatic cholangiocarcinoma (CC as the management of CC is largely different from that of HCC. There are other benign mimickers of HCC such as angiomyolipomas and focal nodular hyperplasia-like nodules. Recognition of their typical imaging findings can reduce false-positive HCC diagnosis.

  16. Thyroid uptake software

    International Nuclear Information System (INIS)

    Alonso, Dolores; Arista, Eduardo

    2003-01-01

    The DETEC-PC software was developed as a complement to a measurement system (hardware) able to perform Iodine Thyroid Uptake studies. The software was designed according to the principles of Object oriented programming using C++ language. The software automatically fixes spectrometric measurement parameters and besides patient measurement also performs statistical analysis of a batch of samples. It possesses a PARADOX database with all information of measured patients and a help system with the system options and medical concepts related to the thyroid uptake study

  17. Metastatic hepatocellular carcinoma on the mandible: a case report

    International Nuclear Information System (INIS)

    Kim, Jin Soo; Kim, Jae Duk

    2005-01-01

    Hepatocellular carcinoma is one of the most common cancer worldwide, primarily affecting those in regions with a high prevalence of viral hepatitis. However, the metastasis of hepatocellular carcinoma to the oral cavity is a rare phenomenon. This report presents a case of metastatic hepatocellular carcinoma in the left mandibular angle and ramus region of a 62-year-old man. Panoramic radiograph revealed an ill-defined radiolucent lesion extending from the retained root of the mandibular left second molar into the ascending ramus. The lesion had irregular and ill-defined margins.

  18. Selected Phytochemicals and Culinary Plant Extracts Inhibit Fructose Uptake in Caco-2 Cells.

    Science.gov (United States)

    Lee, Yurim; Lim, Yeni; Kwon, Oran

    2015-09-18

    This study compared the ability of nine culinary plant extracts containing a wide array of phytochemicals to inhibit fructose uptake and then explored the involvement of intestinal fructose transporters and phytochemicals for selected samples. The chemical signature was characterized by high performance liquid chromatography with mass spectrometry. Inhibition of [(14)C]-fructose uptake was tested by using human intestinal Caco-2 cells. Then, the relative contribution of the two apical-facing intestinal fructose transporters, GLUT2 and GLUT5, and the signature components for fructose uptake inhibition was confirmed in naive, phloretin-treated and forskolin-treated Caco-2 cells. HPLC/MS analysis of the chemical signature revealed that guava leaf contained quercetin and catechin, and turmeric contained curcumin, bisdemethoxycurcumin and dimethoxycurcumin. Similar inhibition of fructose uptake (by ~50%) was observed with guava leaf and turmeric in Caco-2 cells, but with a higher contribution of GLUT2 for turmeric and that of GLUT5 for guava leaf. The data suggested that, in turmeric, demethoxycurcumin specifically contributed to GLUT2-mediated fructose uptake inhibition, and curcumin did the same to GLUT5-mediated fructose uptake inhibition, but GLUT2 inhibition was more potent. By contrast, in guava leaf, catechin specifically contributed to GLUT5-mediated fructose uptake inhibition, and quercetin affected both GLUT5- and GLUT2-mediated fructose uptake inhibition, resulting in the higher contribution of GLUT5. These results suggest that demethoxycurcumin is an important contributor to GLUT2-mediated fructose uptake inhibition for turmeric extract, and catechin is the same to GLUT5-mediated fructose uptake inhibition for guava leaf extract. Quercetin, curcumin and bisdemethoxycurcumin contributed to both GLUT5- and GLUT2-mediated fructose uptake inhibition, but the contribution to GLUT5 inhibition was higher than the contribution to GLUT2 inhibition.

  19. Uptake of gold nanoparticles in primary human endothelial cells

    DEFF Research Database (Denmark)

    Klingberg, Henrik; Oddershede, Lene B.; Löschner, Katrin

    2015-01-01

    Gold nanoparticles (AuNPs) are relevant in nanomedicine for drug delivery in the vascular system, where endothelial cells are the first point of contact. We investigated the uptake of 80 nm AuNPs in primary human umbilical vein endothelial cells (HUVECs) by flow cytometry, 3D confocal microscopy......–3 or more particles. Pre-treatment with chlorpromazine inhibited the AuNP-uptake in HUVECs, indicating that internalisation occurred mainly by clathrin-mediated endocytosis. Cell activation by exposure to tumour necrosis factor or lipopolysaccharide had a slight or no effect on the uptake of Au...

  20. Effect of different biochars on Nitrogen uptake in poplar trees

    Science.gov (United States)

    George, Elizabeth; Tonon, Giustino; Scandellari, Francesca

    2014-05-01

    Influence of biochar on soil nitrogen transformation and plant uptake has been reported. This paper presents preliminary results of plant N uptake in poplars by using 15N isotope tracer approach Two types of biochar were applied to two sets of pots containing only sand and each pot received a pre-rooted poplar cutting. Half of the pots were inoculated with commercial mycorrhizal gel and the other half were left without. It is intended to provide information on how biochar, mycorrhiza and root interaction mediate nitrogen uptake and organ allocation.

  1. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features

    OpenAIRE

    Wood, Laura D; Heaphy, Christopher M; Daniel, Hubert Darius-J; Naini, Bita V; Lassman, Charles R; Arroyo, May R; Kamel, Ihab R; Cosgrove, David P; Boitnott, John K; Meeker, Alan K; Torbenson, Michael S

    2013-01-01

    Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independen...

  2. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available Toggle navigation Test/Treatment Patient Type Screening/Wellness Disease/Condition Safety En Español More Info Images/Videos About Us News Physician Resources Professions Site Index A-Z Thyroid Scan and Uptake ...

  3. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... information. The thyroid scan and thyroid uptake provide information about the structure and function of the thyroid. The thyroid is a gland in the neck that controls metabolism , a chemical process that regulates the rate at which the body ...

  4. Radioactive uptake by plants

    Energy Technology Data Exchange (ETDEWEB)

    Horak, O

    1986-01-01

    The fundamentals of radionuclide uptake by plants, both by leaves and roots are presented. Iodine, cesium, strontium and ruthenium are considered and a table of the measured concentrations in several agricultural plants shortly after the Chernobyl accident is presented. Another table gives the Cs and Sr transfer factors soil plants for some plants. By using them estimates of future burden can be obtained.

  5. Thyroid Scan and Uptake

    Medline Plus

    Full Text Available ... type your comment or suggestion into the following text box: Comment: E-mail: Area code: Phone no: ... of a typical probe counter used for thyroid uptake exams. The patient sits with the camera directed at the neck for five minutes, and then the leg for ...

  6. Thyroid Scan and Uptake

    Science.gov (United States)

    ... type your comment or suggestion into the following text box: Comment: E-mail: Area code: Phone no: ... of a typical probe counter used for thyroid uptake exams. The patient sits with the camera directed at the neck for five minutes, and then the leg for ...

  7. Immunization With AFP + GM CSF Plasmid Prime and AFP Adenoviral Vector Boost in Patients With Hepatocellular Carcinoma

    Science.gov (United States)

    2015-12-01

    Hepatocellular Carcinoma; Hepatoma; Liver Cancer, Adult; Liver Cell Carcinoma; Liver Cell Carcinoma, Adult; Cancer of Liver; Cancer of the Liver; Cancer, Hepatocellular; Hepatic Cancer; Hepatic Neoplasms; Hepatocellular Cancer; Liver Cancer; Neoplasms, Hepatic; Neoplasms, Liver

  8. PGK1 Drives Hepatocellular Carcinoma Metastasis by Enhancing Metabolic Process.

    Science.gov (United States)

    Xie, Huijun; Tong, Guihui; Zhang, Yupei; Liang, Shu; Tang, Kairui; Yang, Qinhe

    2017-07-27

    During the proliferation and metastasis, the tumor cells prefer glycolysis (Warburg effect), but its exact mechanism remains largely unknown. In this study, we demonstrated that phosphoglycerate kinase 1 (PGK1) is an important enzyme in the pathway of metabolic glycolysis. We observed a significant overexpression of PGK1 in hepatocellular carcinoma tissues, and a correlation between PGK1 expression and poor survival of hepatocellular carcinoma patients. Also, the depletion of PGK1 dramatically reduced cancer cell proliferation and metastasis, indicating an oncogenic role of PGK1 in liver cancer progression. Further experiments showed that PGK1 played an important role in MYC -induced metabolic reprogramming, which led to an enhanced Warburg effect. Our results revealed a new effect of PGK1, which can provide a new treatment strategy for hepatocellular carcinoma, as PGK1 is used to indicate the prognosis of hepatocellular carcinoma (HCC).

  9. Spontaneous rupture of adrenal metastasis from hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Chae Hun; Kim, Hyun Jin; Park, Soo Youn; Hwang, Seong Su; Choi, Hyun Joo [St. Vincent Hospital, Suwon (Korea, Republic of)

    2007-03-15

    Rupture of adrenal tumor from various primary origins is a rather rare event. We report here on a ruptured adrenal metastasis from hepatocellular carcinoma, and this ruptured metastasis was observed at the time of the initial diagnosis.

  10. Imaging and embolization of hepatocellular carcinoma supplied by gonadal artery

    International Nuclear Information System (INIS)

    Wu Hongping; Wang Junjie; Lu Yang; You Kaizhi

    2010-01-01

    Objective: To evaluate radiology and embolization for hepatocellular carcinoma supplied by gonadal artery. Methods: The medical records of 3 patients with hepatocellular carcinoma supplied by gonadal artery from August 2002 to September 2008 were reviewed. The demography, gonadal artery location, modus operandi, imaging features of liver cancer and prognosis were retrospectively analyzed. Results: Anatomic variation of gonadal artery occurred with the gonadal artery arising from the upper abdominal aorta in 1 patient and from the middle suprarenal artery in 2 patients. The blood supply of the hepatocellular carcinoma derived from the gonadal artery in all 3 patients. No complications occurred in the 6-month follow-up after embolization. Conclusion: Hepatocellular carcinoma may be supplied by gonadal artery with anomalous origin. This anatomic variant can be readily demonstrated by imaging to guide embolization. (authors)

  11. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integratio...

  12. Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice.

    Science.gov (United States)

    Shi, Sally Yu; Luk, Cynthia T; Schroer, Stephanie A; Kim, Min Jeong; Dodington, David W; Sivasubramaniyam, Tharini; Lin, Lauren; Cai, Erica P; Lu, Shun-Yan; Wagner, Kay-Uwe; Bazinet, Richard P; Woo, Minna

    2017-03-03

    Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis per se promotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive. The Janus kinase signal transducers and activators of transcription (JAK-STAT) pathway mediates signal transduction by numerous cytokines that regulate inflammation and may contribute to hepatocarcinogenesis. Mice with hepatocyte-specific deletion of JAK2 (L-JAK2 KO) develop extensive fatty liver spontaneously. We show here that this simple steatosis was insufficient to drive carcinogenesis. In fact, L-JAK2 KO mice were markedly protected from chemically induced tumor formation. Using the methionine choline-deficient dietary model to induce steatohepatitis, we found that steatohepatitis development was completely arrested in L-JAK2 KO mice despite the presence of steatosis, suggesting that JAK2 is the critical factor required for inflammatory progression in the liver. In line with this, L-JAK2 KO mice exhibited attenuated inflammation after chemical carcinogen challenge. This was associated with increased hepatocyte apoptosis without elevated compensatory proliferation, thus thwarting expansion of transformed hepatocytes. Taken together, our findings identify an indispensable role of JAK2 in hepatocarcinogenesis through regulating critical inflammatory pathways. Targeting the JAK-STAT pathway may provide a novel therapeutic option for the treatment of hepatocellular carcinoma. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. The evaluation of p,p'-DDT exposure on cell adhesion of hepatocellular carcinoma.

    Science.gov (United States)

    Jin, Xiaoting; Chen, Meilan; Song, Li; Li, Hanqing; Li, Zhuoyu

    2014-08-01

    Many studies have found a positive association between the progression of hepatocellular carcinoma and DDT exposure. These studies mainly focus on the effect of DDT exposure on cell proliferation and epithelial to mesenchymal transition (EMT) promotion. However, the influence of DDT on cell adhesion of hepatocellular carcinoma remains to be unclear. The aim of our study was to determine the effect of p,p'-DDT on cell adhesion of hepatocellular carcinoma in vitro and in vivo. The data showed that p,p'-DDT, exposing HepG2 cells for 6 days, decreased cell-cell adhesion and elevated cell-matrix adhesion. Strikingly, p,p'-DDT increased reactive oxygen species (ROS) content, and this was accompanied by the activation of JAK/STAT3 pathway. Moreover, ROS inhibitor supplement reversed these effects significantly. However, the addition of ER inhibitor, ICI, had no effect on the p,p'-DDT-induced effects. p,p'-DDT altered the mRNA levels of related adhesion molecules, including inhibition of E-cadherin and promotion of N-cadherin along with CD29. Interestingly, the p,p'-DDT-altered adhesion molecules could be reversed with JAK inhibitor or STAT3 inhibitor. Likewise, p,p'-DDT stimulated the JAK/STAT3 pathway in nude mice, as well as altered the mRNA levels of E-cadherin, N-cadherin, and CD29. Taken together, these results indicate that p,p'-DDT profoundly promotes the adhesion process by decreasing cell-cell adhesion and inducing cell-matrix adhesion via the ROS-mediated JAK/STAT3 pathway. All these events account for the carcinogenic potential of p,p'-DDT in liver. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Diagnosis of small hepatocellular carcinoma by incremental dynamic CT

    International Nuclear Information System (INIS)

    Uchida, Masafumi; Kumabe, Tsutomu; Edamitsu, Osamu

    1993-01-01

    Thirty cases of pathologically confirmed small hepatocellular carcinoma were examined by Incremental Dynamic CT (ICT). ICT scanned the whole liver with single-breath-hold technique; therefore, effective early contrast enhancement could be obtained for diagnosis. Among the 30 tumors, 26 were detected. The detection rate was 87%. A high detection rate was obtained in tumors more than 20 mm in diameter. Twenty-two of 26 tumors could be diagnosed correctly. ICT examination was useful for detection of small hepatocellular carcinoma. (author)

  15. Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma

    OpenAIRE

    Saif, Muhammad W.; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N.

    2011-01-01

    Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. La...

  16. Haptocorrin as marker of disease progression in fibrolamellar hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Lildballe, Dorte Launholt; Nguyen, Khoa Tran; Poulsen, Steen Seier

    2011-01-01

    No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker.......No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker....

  17. Hepatocellular Carcinoma: An Unusual Complication of Longstanding Wilson Disease.

    Science.gov (United States)

    Gunjan, Deepak; Shalimar; Nadda, Neeti; Kedia, Saurabh; Nayak, Baibaswata; Paul, Shashi B; Gamanagatti, Shivanand Ramachandra; Acharya, Subrat K

    2017-06-01

    Wilson disease is caused by the accumulation of copper in the liver, brain or other organs, due to the mutation in ATP7B gene, which encodes protein that helps in excretion of copper in the bile canaliculus. Clinical presentation varies from asymptomatic elevation of transaminases to cirrhosis with decompensation. Hepatocellular carcinoma is a known complication of cirrhosis, but a rare occurrence in Wilson disease. We present a case of neurological Wilson disease, who later developed decompensated cirrhosis and hepatocellular carcinoma.

  18. Effect of smoking on survival of patients with hepatocellular carcinoma.

    Science.gov (United States)

    Kolly, Philippe; Knöpfli, Marina; Dufour, Jean-François

    2017-11-01

    Lifestyle factors such as smoking, obesity and physical activity have gained interest in the field of hepatocellular carcinoma. These factors play a significant role in the development of hepatocellular carcinoma. Several studies revealed the impact of tobacco consumption on the development of hepatocellular carcinoma and its synergistic effects with viral etiologies (hepatitis B and C). The effects of smoking on survival in patients with a diagnosed hepatocellular carcinoma have not yet been investigated in a Western cohort where hepatitis C infection is a major risk factor. Using data from a prospective cohort of patients with hepatocellular carcinoma who were followed at the University Hospital of Bern, Switzerland, survival was compared by Kaplan-Meier analysis in smokers and nonsmokers, and multivariate Cox regression was applied to control for confounding variables. Of 238 eligible hepatocellular carcinoma patients, 64 were smokers at the time of inclusion and 174 were nonsmokers. Smokers had a significant worse overall survival than nonsmokers (hazard ratio 1.77, 95% confidence interval: 1.22-2.58, P=.003). Analysis of patients according to their underlying liver disease, revealed that smoking, and not nonsmoking, affected survival of hepatitis B virus and C virus-infected patients only. In this subgroup, smoking was an independent predictor for survival (hazard ratio 2.99, 95% confidence interval: 1.7-5.23, Phepatocellular carcinoma. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma.

    Science.gov (United States)

    Burra, Patrizia; Zanetto, Alberto; Germani, Giacomo

    2018-02-09

    Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma.

  20. BIOCHEMICAL NUTRITIONAL PROFILE OF LIVER CIRRHOSIS PATIENTS WITH HEPATOCELLULAR CARCINOMA

    Directory of Open Access Journals (Sweden)

    Gabriela Zanatta PORT

    2014-03-01

    Full Text Available Context Liver cirrhosis patients with hepatocellular carcinoma present nutritional alterations and metabolic disorders that negatively impact the prognosis. Objective The objective is to identify alterations in the metabolism of macro and micronutrients among liver cirrhosis patients with and without hepatocellular carcinoma and their relation to the Child-Turcote-Pugh score and Barcelona Clinic Liver Cancer staging. Methods Analytical transversal study, with 31 hepatocellular carcinoma patients and 48 liver cirrhosis patients. Laboratorial exams were carried out. The existence of an association between the biochemical parameters and the disease severity as well as the presence of hepatocellular carcinoma was assessed. Results The metabolic-nutritional profile of liver cirrhosis patients caused by the hepatitis C virus and hepatocellular carcinoma showed alterations, specifically the lipid (total cholesterol, HDL and triglycerides, protein (albumin, creatinine and uric acid, iron (transferrin, iron and ferritin saturation, hematocrit and hemoglobin, zinc and B12 vitamin profiles. There is a relation between nutritional biochemical markers and the Child-Turcote-Pugh, as well as Barcelona Clinic Liver Cancer staging. Conclusions Considering the existence of alterations in the metabolism of nutrients in liver cirrhosis patients with and without hepatocellular carcinoma, and also that conventional nutritional assessment methods present limitations for this population, the biochemical laboratorial exams are valid to complement the diagnosis of the nutritional state in a quick and practical manner.

  1. Montelukast induced acute hepatocellular liver injury

    Directory of Open Access Journals (Sweden)

    Harugeri A

    2009-01-01

    Full Text Available A 46-year-old male with uncontrolled asthma on inhaled albuterol and formoterol with budesonide was commenced on montelukast. He developed abdominal pain and jaundice 48 days after initiating montelukast therapy. His liver tests showed an increase in serum total bilirubin, conjugated bilirubin, aspartate aminotranferase, alanine aminotranferase, and alkaline phosphatase. The patient was evaluated for possible non-drug related liver injury. Montelukast was discontinued suspecting montelukast induced hepatocellular liver injury. Liver tests began to improve and returned to normal 55 days after drug cessation. Causality of this adverse drug reaction by the Council for International Organizations of Medical Sciences or Roussel Uclaf Causality Assessment Method (CIOMS or RUCAM and Naranjo′s algorithm was ′probable′. Liver tests should be monitored in patients receiving montelukast and any early signs of liver injury should be investigated with a high index of suspicion for drug induced liver injury.

  2. Evaluation of CT in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Nakao, Norio; Miura, Yukio; Ohnishi, Mitsunori; Kamikon-ya, Norihiko; Sakamoto, Yoshisato; Miura, Takashi; Sakamoto, Kiyoshi; Takayasu, Yoshio

    1985-06-01

    In order to evaluate the diagnostic ability of CT in hepatocellular carcinoma, four kinds of CT images were comparatively studied by the accuracy and ROC (receiver operating characteristic) curve analysis. As a result, it was clarified that CT images were evaluated more objectively by ROC curve analysis than by accuracy. The diagnostic ability of existence and differentiation of tumor in the liver were higher in order of plain CT, contrast enhanced CT (CECT), bolus CT and CT arteriography (CTA). Therefore, in an usual CT examination intended to make differential diagnosis in space occupying liver disease, bolus CT seems to be indispensable, and also CTA is essential where diagnosis is difficult even by bolus CT.

  3. Models of Hepatocellular Carcinoma and Biomarker Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Bagi, Cedo M., E-mail: cedo.bagi@pfizer.com; Andresen, Catharine J. [Global Science & Technology, PGRD, Pfizer Inc, Groton, CT 06340 (United States)

    2010-07-07

    The overwhelming need to improve preclinical models in oncology has stimulated research efforts to refine and validate robust orthotopic models that closely mimic the disease population and therefore have the potential to better predict clinical outcome with novel therapies. Sophisticated technologies including bioluminescence, contrast enhanced ultrasound imaging, positron emission tomography, computed tomography and magnetic resonance imaging have been added to existing serum- and histology-based biomarkers to assist with patient selection and the design of clinical trials. The rationale for the use of human hepatocellular carcinoma (HCC) cell lines, implementation of xenograft and orthotopic animal models and utilization of available biomarkers have been discussed, providing guidelines to facilitate preclinical research for the development of treatments for HCC patients.

  4. Embolotherapy in the management of hepatocellular carcinoma.

    Science.gov (United States)

    Mojtahedi, Alireza; Yang, Xiaoming; Goswami, Gaurav K

    2008-09-01

    Hepatocellular carcinoma (HCC) ranks fifth in frequency of cancers worldwide. The incidence of HCC in the United States is rising, primarily due to the number of patients who were infected by hepatitis in the 1960s and 1970s coupled with the rising migrant population from Asia, where hepatitis is widely prevalent. Up to 80% of the patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the option of resection or liver transplantation. The dual blood supply (arterial and portal) to the liver with predominantly arterial supply to the tumor has made embolotherapy a cornerstone in the management of inoperable HCC. The techniques have become refined not only due to the development of microcatheter angiographic capabilities, but also in the ability to deliver a wide variety of therapeutic agents to these tumors. This article reviews the fundamental principles of bland embolization, chemoembolization, and radioembolization in the management of HCC.

  5. Hepatocellular carcinoma detected by iodized oil

    International Nuclear Information System (INIS)

    Yumoto, Y.; Jinno, K.; Tokuyama, K.

    1985-01-01

    This study assesses the diagnostic value of Lipiodol (iodized oil) and computed tomography (CT) in detecting hepatocellular carcinoma (HCC). Twenty-four patients who were suspected of having HCC received injections of a small amount of Lipiodol, along with an antitumor agent, in the hepatic artery following routine celiac angiography. CT scans obtained 7-10 days after Lipiodol administration demonstrated HCC in distinct contrast to the surrounding noncancerous parenchyma. In particular, the CT-Lipiodol procedure disclosed many small HCC lesions that were not shown by celiac angiography, scintigraphy, CT with an without contrast medium enhancement, and ultrasonography. Although this procedure may miss very small or highly fibrotic lesions, it is recommended for patients suspected of having HCC and for patients for whom hepatic resection is being considered

  6. Laparoscopic RFA with splenectomy for hepatocellular carcinoma.

    Science.gov (United States)

    Hu, Kunpeng; Lei, Purun; Yao, Zhicheng; Wang, Chenhu; Wang, Qingliang; Xu, Shilei; Xiong, Zhiyong; Huang, He; Xu, Ruiyun; Deng, Meihai; Liu, Bo

    2016-07-27

    The treatment of hepatocellular carcinoma (HCC) is complicated and challenging because of the frequent presence of cirrhosis. Therefore, we propose a novel surgical approach to minimize the invasiveness and risk in patients with HCC, hypersplenism, and esophagogastric varices. This was a retrospective study carried out in 25 patients with HCC and hypersplenism and who underwent simultaneous laparoscopic-guided radio-frequency ablation and laparoscopic splenectomy with endoscopic variceal ligation. Tumor size was restricted to a single nodule of splenectomy. Laparoscopic-guided radio-frequency ablation with laparoscopic splenectomy and endoscopic variceal ligation could be an available technique for patients with HCC <3 cm, hypersplenism, and esophagogastric varices. This approach may help to minimize the surgical risks and results in a fast increase in platelet counts with an acceptable rate of complications.

  7. Clinical experience of [sup 123]I-IMP scintigraphy in detecting vertebral bone metastases of hepatocellular carcinoma. A comparison with bone scintigraphy with [sup 99m]Tc-MDP

    Energy Technology Data Exchange (ETDEWEB)

    Suto, Y. (Dept. of Radiology, Tottori Univ. Faculty of Medicine, Yonago (Japan) Dept. of Radiology, Matsue City Hospital (Japan)); Iwamiya, T. (Dept. of Radiology, Tottori Univ. Faculty of Medicine, Yonago (Japan) Dept. of Radiology, Matsue City Hospital (Japan)); Tanigawa, N. (Dept. of Radiology, Tottori Univ. Faculty of Medicine, Yonago (Japan) Dept. of Radiology, Matsue City Hospital (Japan)); Shabana, M. (Dept. of Radiology, Tottori Univ. Faculty of Medicine, Yonago (Japan) Dept. of Radiology, Matsue City Hospital (Japan)); Ohta, Y. (Dept. of Radiology, Tottori Univ. Faculty of Medicine, Yonago (Japan) Dept. of Radiology, Matsue City Hospital (Japan))

    1994-03-01

    [sup 123]I-IMP and bone scintigraphy with [sup 99m]Tc-MDP were consecutively performed in patients with vertebral bone metastases from hepatocellular carcinoma and lumbar spondylosis deformans in a 7-day interval or shorter. The intensity of uptake was compared. Eighteen of the 20 metastatic lesions (90%) were classified as increased uptake areas in [sup 123]I-IMP scintigraphy. MDP-scintigraphy disclosed 16 metastatic lesions (80%), 9 as ''hot'' lesions (56%) and 7 as ''cold'' lesions (44%). [sup 123]I-IMP scintigraphy was negative in all 12 lesions of lumbar spondylosis deformans. Compared to MDP-scintigraphy, [sup 123]I-IMP scintigraphy was more sensitive in detecting vertebral bone metastases of hepatocellular carcinoma with smaller rates of false-positive and false-negative findings. (orig./MG).

  8. Computed tomographic findings of hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Eun, Chung Kie [Kyung Hee University College of Medicine, Seoul (Korea, Republic of)

    1982-09-15

    It is well known that CT is very useful in the evaluation of hepatocellular carcinoma. The computed tomographic findings of 56 patients diagnosed as hepatocellular carcinoma were reviewed and analyzed. The results were as follows: 1. The male to female ratio was 3 : 1 and the age ranged from 31 to 73 years with average age of 54 years. 2. Alpha-fetoprotein was positive in 19 out of 38 cases (50%). HBsAg was positive in 8 out of 33 cases (24%). 3. All lesions were seen as areas of low density except 1 case (0%) of isodensity, and 40 cases (72%) appeared to be solitary while 15 (26%) were multifocal. The low density was homogenous in 13 cases (24%) and inhomogenous in 42 cases (76%), and 18 cases out of 42 cases inhomogenous low density showed peripheal and/or central nodular enhancement. The additional findings were contour changes in 37 cases (66%), metastasis in 35 cases (63%), splenomegaly in 23 cases (42%) and ascities in 22 cases (39%). 4. In postcontrast scans, 41 cases (80%) out of 51 cases showed the change of density after contrast infusion. The presence and extent of tumors were better seen after contrast infusion in 30 cases (59%), better seen before contrast infusion in 11 cases (21%) and no significant difference before and after contrast infusion in 10 cases (20%). 5. The sites of involved lobe were right lobe in 38 cases (68%), left lobe in 5 cases (9%) and both lobes in 13 cases (23%). 6. 35 cases (63%) showed evidence of metastasis to regional lymph nodes, organ or tissues.

  9. Finger Millet Growth and Nutrient Uptake Is Improved in Intercropping With Pigeon Pea Through “Biofertilization” and “Bioirrigation” Mediated by Arbuscular Mycorrhizal Fungi and Plant Growth Promoting Rhizobacteria

    Directory of Open Access Journals (Sweden)

    Krishna Saharan

    2018-06-01

    Full Text Available Legume-cereal intercropping is well known in traditional dry land agriculture. Here, we tested whether finger millet, a shallow-rooted cereal, can profit from neighboring pigeon pea, a deep-rooted legume, in the presence of “biofertilization” with arbuscular mycorrhizal fungi (AMF and plant growth-promoting rhizobacteria (PGPR, under drought conditions. We conducted a greenhouse experiment using compartmented microcosms. Pigeon pea was grown in a deep compartment with access to a moist substrate layer at the bottom, whereas finger millet was grown in a neighboring shallow compartment, separated by 25-μm nylon mesh, without access to the moist substrate layer. In the presence of a common mycorrhizal network (CMN, with or without PGPR, a drought condition had little negative effect on the biomass production of the finger millet plant whereas in absence of biofertilization, finger millet biomass production was less than half compared to well-watered condition. Biofertilization strongly increased nitrogen and phosphorus uptake by both plants, both under well-watered and drought conditions. In the presence of AMF, both plants also acquired 15N and 33P, offered in a labeling compartment accessible to fungal hyphae but not to roots. Our results show that “biofertilization” with AMF alleviates the negative effects of drought condition on finger millet, indicating that the CMN connecting pigeon pea and finger millet exert clearly a positive influence in this simulated intercropping system.

  10. THE ROLE OF CYTOKINE NETWORK IN HEPATOCELLULAR DAMAGE CAUSED BY СHRONIC HEPATITIS C

    Directory of Open Access Journals (Sweden)

    L. Ph. Skljar

    2006-01-01

    Full Text Available Abstract. Hepatitis C virus (HCV is the leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Liver damage in chronic viral hepatitis C is caused by both direct cytopathic viral effects, and indirect immune-mediated mechanisms. The cytokines locally produced in the liver, as well as those circulating in the blood circulation, play an important role in the control of viral replication and sufficiently contribute to hepatocellular damage. The goal of present study was to investigate the contents of some cytokines in blood serum and their local levels, being in interrelation with indices of necrotic inflammatory changes in the liver tissue. Correlations established between systemic and local contents of studied cytokines, and morphological indices indicate that, among immunological tests checked, the contents of IL-4, IL-10, IL-12p70, and TNFα in blood serum and supernatants of liver biopsies were of the greatest significance for determining the stage of fibrosis. Quantitative assays of abovementioned cytokines in blood serum represent, therefore, an alternative approach in order to perform noninvasive screening of liver fibrosis.

  11. Regulation of human hepatocellular carcinoma cells by Spred2 and correlative studies on its mechanism

    International Nuclear Information System (INIS)

    Ma, Xiao-Ni; Liu, Xiao-Yun; Yang, Yue-Feng; Xiao, Feng-Jun; Li, Qing-Fang; Yan, Jun; Zhang, Qun-Wei; Wang, Li-Sheng; Li, Xue-Yan; Wang, Hua

    2011-01-01

    Highlights: → Hepatocellular carcinoma is inhibited by Spred2 through as yet unclear mechanisms. → We studied the overexpression of Spred2 in cell line and murine tumor models of HCC. → Spred2 inhibited cell proliferation and migration via attenuating ERK signaling. → Spred2 overexpression induced apoptosis via caspase-3 and downregulated Mcl-1. → A Spred2 knockdown markedly induced tumor growth in vivo. -- Abstract: Members of the Spred gene family are negative regulators of the Ras/Raf-1/ERK pathway, which has been associated with several features of the tumor malignancy. However, the effect of Spred genes on hepatocellular carcinoma (HCC) remains uninvestigated. In the present work, we analyzed the in vitro and in vivo effects of Spred2 expression on the hepatic carcinoma cell line, SMMC-7721. In addition to attenuated ERK activation, which inhibited the proliferation and migration of unstimulated and HGF-stimulated SMMC-7721 cells. Adenovirus-mediated Spred2 overexpression induced the activation of caspase-3 and apoptosis, as well as reduced the expression level of Mcl-1. Most importantly, the knockdown of Spred2 markedly enhanced tumor growth in vivo. In conclusion, these results suggest that Spred2 could qualify as a potential therapeutic target in HCC.

  12. Hepatitis C Virus Protein Interaction Network Analysis Based on Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Yuewen Han

    Full Text Available Epidemiological studies have validated the association between hepatitis C virus (HCV infection and hepatocellular carcinoma (HCC. An increasing number of studies show that protein-protein interactions (PPIs between HCV proteins and host proteins play a vital role in infection and mediate HCC progression. In this work, we collected all published interaction between HCV and human proteins, which include 455 unique human proteins participating in 524 HCV-human interactions. Then, we construct the HCV-human and HCV-HCC protein interaction networks, which display the biological knowledge regarding the mechanism of HCV pathogenesis, particularly with respect to pathogenesis of HCC. Through in-depth analysis of the HCV-HCC interaction network, we found that interactors are enriched in the JAK/STAT, p53, MAPK, TNF, Wnt, and cell cycle pathways. Using a random walk with restart algorithm, we predicted the importance of each protein in the HCV-HCC network and found that AKT1 may play a key role in the HCC progression. Moreover, we found that NS5A promotes HCC cells proliferation and metastasis by activating AKT/GSK3β/β-catenin pathway. This work provides a basis for a detailed map tracking new cellular interactions of HCV and identifying potential targets for HCV-related hepatocellular carcinoma treatment.

  13. Activation of CFTR by ASBT-mediated bile salt absorption

    NARCIS (Netherlands)

    Bijvelds, MJC; Jorna, H; Verkade, HJ; Bot, AGM; Hofmann, F; Agellon, LB; Sinaasappel, M; de Jonge, HR

    2005-01-01

    In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal

  14. Brain docosahexaenoic acid uptake and metabolism.

    Science.gov (United States)

    Lacombe, R J Scott; Chouinard-Watkins, Raphaël; Bazinet, Richard P

    2018-02-08

    Docosahexaenoic acid (DHA) is the most abundant n-3 polyunsaturated fatty acid in the brain where it serves to regulate several important processes and, in addition, serves as a precursor to bioactive mediators. Given that the capacity of the brain to synthesize DHA locally is appreciably low, the uptake of DHA from circulating lipid pools is essential to maintaining homeostatic levels. Although, several plasma pools have been proposed to supply the brain with DHA, recent evidence suggests non-esterified-DHA and lysophosphatidylcholine-DHA are the primary sources. The uptake of DHA into the brain appears to be regulated by a number of complementary pathways associated with the activation and metabolism of DHA, and may provide mechanisms for enrichment of DHA within the brain. Following entry into the brain, DHA is esterified into and recycled amongst membrane phospholipids contributing the distribution of DHA in brain phospholipids. During neurotransmission and following brain injury, DHA is released from membrane phospholipids and converted to bioactive mediators which regulate signaling pathways important to synaptogenesis, cell survival, and neuroinflammation, and may be relevant to treating neurological diseases. In the present review, we provide a comprehensive overview of brain DHA metabolism, encompassing many of the pathways and key enzymatic regulators governing brain DHA uptake and metabolism. In addition, we focus on the release of non-esterified DHA and subsequent production of bioactive mediators and the evidence of their proposed activity within the brain. We also provide a brief review of the evidence from post-mortem brain analyses investigating DHA levels in the context of neurological disease and mood disorder, highlighting the current disparities within the field. Copyright © 2017. Published by Elsevier Ltd.

  15. Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Lulu Fan

    Full Text Available BACKGROUND: Endoplasmic reticulum stress (ER stress is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone, is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti-neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress-induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of the endoplasmic reticulum (ER stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up-regulation of the pro-apoptotic transcription factor CHOP (GADD153 in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that Pae reverses ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP.

  16. Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow

    Energy Technology Data Exchange (ETDEWEB)

    Kogita, Sachiyo; Imai, Yasuharu; Fukuda, Kazuto; Igura, Takumi; Sawai, Yoshiyuki [Ikeda Municipal Hospital, Department of Gastroenterology, Osaka (Japan); Okada, Masahiro; Murakami, Takamichi [Kinki University, School of Medicine, Department of Radiology, Osaka (Japan); Kim, Tonsok; Onishi, Hiromitsu; Hori, Masatoshi [Osaka University, Graduate School of Medicine, Department of Radiology, Osaka (Japan); Takamura, Manabu [Ikeda Municipal Hospital, Department of Radiology, Osaka (Japan); Morimoto, Osakuni [Ikeda Municipal Hospital, Department of Surgery, Osaka (Japan); Nagano, Hiroaki [Osaka University, Graduate School of Medicine, Department of Surgery, Osaka (Japan); Wakasa, Kenichi [Osaka City University, Graduate School of Medicine, Department of Diagnostic Pathology, Osaka (Japan); Hayashi, Norio [Osaka University, Graduate School of Medicine, Department of Gastroenterology and Hepatology, Osaka (Japan)

    2010-10-15

    To retrospectively investigate enhancement patterns of hepatocellular carcinoma (HCC) and dysplastic nodule (DN) in the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced MRI in relation to histological grading and portal blood flow. Sixty-nine consecutive patients with 83 histologically proven HCCs and DNs were studied. To assess Gd-EOB-DTPA uptake, we calculated the EOB enhancement ratio, which is the ratio of the relative intensity of tumorous lesion to surrounding nontumorous area on hepatobiliary phase images (post-contrast EOB ratio) to that on unenhanced images (pre-contrast EOB ratio). Portal blood flow was evaluated by CT during arterial portography. Post-contrast EOB ratios significantly decreased as the degree of differentiation declined in DNs (1.00 {+-} 0.14) and well, moderately and poorly differentiated HCCs (0.79 {+-} 0.19, 0.60 {+-} 0.27, 0.49 {+-} 0.10 respectively). Gd-EOB-DTPA uptake, assessed by EOB enhancement ratios, deceased slightly in DNs and still more in HCCs, while there was no statistical difference in the decrease between different histological grades of HCC. Reductions in portal blood flow were observed less frequently than decreases in Gd-EOB-DTPA uptake in DNs and well-differentiated HCCs. Reduced Gd-EOB-DTPA uptake might be an early event of hepatocarcinogenesis, preceding portal blood flow reduction. The hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI may help estimate histological grading, although difficulties exist in differentiating HCCs from DNs. (orig.)

  17. Using the marker CD34 as tool to discriminate adenoma versus hepatocellular

    International Nuclear Information System (INIS)

    Mohs Alfaro, Monica

    2011-01-01

    The CD34 marker is used as immunohistochemistry technique to detect and differentiate between the hepatocellular adenoma of the hepatocellular carcinoma. The liver lesions are described. The hepatic angiogenesis is explained [es

  18. Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C

    DEFF Research Database (Denmark)

    Kimer, Nina; Dahl, Emilie Kristine; Gluud, Lise Lotte

    2012-01-01

    To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C.......To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C....

  19. Radiofrequency (thermal) ablation versus no intervention or other interventions for hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Weis, Sebastian; Franke, Annegret; Mössner, Joachim

    2013-01-01

    Hepatocellular carcinoma is the fifth most common cancer worldwide. Percutaneous interventional therapies, such as radiofrequency (thermal) ablation (RFA), have been developed for early hepatocellular carcinoma. RFA competes with other interventional techniques such as percutaneous ethanol...

  20. Mangafodipir trisodium-enhanced MRI of hepatocellular carcinoma: correlation with histological characteristics

    International Nuclear Information System (INIS)

    Kim, J.H.; Kim, M.-J.; Park, Y.N.; Lee, J.T.; Kim, B.R.; Chung, J.B.; Choi, J.S.; Kim, K.S.; Kim, K.W.

    2008-01-01

    Aim: To define histopathological factors related to the degree of mangafodipir trisodium (MnDPDP) uptake in hepatocellular carcinomas (HCCs) on magnetic resonance imaging (MRI). Materials and methods: In-phase and opposed-phase gradient-echo MRI images were obtained preoperatively in 37 patients with 38 HCCs before and 15-30 min after intravenous injection of MnDPDP. Subjective ratings of the enhancement degree, the signal-to-noise ratio (SNR) of the lesion and the liver, and the contrast enhancement ratios (CER) were compared with histopathological factors. Results: The mean SNR of HCCs increased from 59.6 to 95.0 (CER = 59.5%), whereas that of the liver increased from 75.1 to 108.7 (CER = 45.2%). Eight HCCs showed mild enhancement, 11 moderate enhancement, and 15 strong enhancement. There was no visually perceptible enhancement in four HCCs (10.3%). The degree of MnDPDP enhancement was significantly related with the cell density ratio (p < .05) and monoclonal hepatocyte antibody positivity (p < 0.005), but not with size, growth type, cell type, histological type, cytokeratin 7, or cytokeratin 19. Well-differentiated HCC showed higher MnDPDP enhancement compared with higher grade HCCs, but the differences were not statistically significant. Conclusion: The uptake of MnDPDP by HCC was correlated with hepatocyte antibody expression and the cellular density ratio. Well-differentiated HCC tended to show higher MnDPDP enhancement

  1. Replenishment and mobilization of intracellular nitrogen pools decouples wine yeast nitrogen uptake from growth

    OpenAIRE

    SANCHO FORNER, MARTA; Alicia Gutiérrez; BELTRAN CASELLAS, GEMMA; José Manuel Guillamon; Jonas Warringer

    2016-01-01

    Wine yeast capacity to take up nitrogen from the environment and catabolize it to support population growth, fermentation, and aroma production is critical to wine production. Under nitrogen restriction, yeast nitrogen uptake is believed to be intimately coupled to reproduction with nitrogen catabolite repression (NCR) suggested mediating this link. We provide a time- and strain-resolved view of nitrogen uptake, population growth, and NCR activity in wine yeasts. Nitrogen uptake was found to ...

  2. Uptake of DNA by cancer cells without a transfection reagent

    Directory of Open Access Journals (Sweden)

    Yanping Kong

    Full Text Available Abstract Background Cancer cells exhibit elevated levels of glucose uptake and may obtain pre-formed, diet-derived fatty acids from the bloodstream to boost their rapid growth; they may also use nucleic acid from their microenvironment. The study of processing nucleic acid by cancer cells will help improve the understanding of the metabolism of cancer. DNA is commonly packaged into a viral or lipid particle to be transferred into cells; this process is called transfection in laboratory. Cancer cells are known for having gene mutations and the evolving ability of endocytosis. Their uptake of DNAs might be different from normal cells; they may take in DNAs directly from the environment. In this report, we studied the uptake of DNAs in cancer cells without a transfection reagent. Methods A group of DNA fragments were prepared with PCR and labeled with isotope phosphorous-32 to test their uptake by Huh 7 (liver cancer and THLE3 (normal liver cells after incubation overnight by counting radioactivity of the cells’ genomic DNA. Multiple cell lines including breast cancer and lung cancer were tested with the same method. DNA molecules were also labeled with fluorescence to test the location in the cells using a kit of “label it fluorescence in situ hybridization (FISH” from Mirus (USA. Results The data demonstrated that hepatocellular carcinoma cells possess the ability to take in large DNA fragments directly without a transfection reagent whereas normal liver cells cannot. Huh7 and MDA-MB231 cells displayed a significantly higher Rhodamine density in the cytoplasmic phagosomes and this suggests that the mechanism of uptake of large DNA by cancer cells is likely endocytosis. The efficacy of uptake is related to the DNA’s size. Some cell lines of lung cancer and breast cancer also showed similar uptake of DNA. Conclusions In the present study, we have revealed the evidence that some cancer cells, but not nontumorigenic cells, can take DNA

  3. Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake

    NARCIS (Netherlands)

    Berghe, van den P.V.E; Folmer, D.E.; Malingré, H.E.M.; Beurden, van E.; Klomp, A.E.M.; Sluis, van de B.; Merkx, M.; Berger, R.J.; Klomp, L.W.J.

    2007-01-01

    High-affinity cellular copper uptake is mediated by the CTR (copper transporter) 1 family of proteins. The highly homologous hCTR (human CTR) 2 protein has been identified, but its function in copper uptake is currently unknown. To characterize the role of hCTR2 in copper homoeostasis,

  4. effect of adrenaline on glucose uptake by the canine large bowel

    African Journals Online (AJOL)

    lower metabolic activity in the colon. From the results we concluded that the colon is involved in glucose homeostasis and that the colonic increase in glucose uptake in response to adrenaline is mediated by alpha and beta adrenergic receptors. KEYWORDS: :Adrenaline, glucose uptake, colon, dog, adrenergic receptors.

  5. Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages

    Directory of Open Access Journals (Sweden)

    Dagmar A. Kuhn

    2014-09-01

    Full Text Available Precise knowledge regarding cellular uptake of nanoparticles is of great importance for future biomedical applications. Four different endocytotic uptake mechanisms, that is, phagocytosis, macropinocytosis, clathrin- and caveolin-mediated endocytosis, were investigated using a mouse macrophage (J774A.1 and a human alveolar epithelial type II cell line (A549. In order to deduce the involved pathway in nanoparticle uptake, selected inhibitors specific for one of the endocytotic pathways were optimized regarding concentration and incubation time in combination with fluorescently tagged marker proteins. Qualitative immunolocalization showed that J774A.1 cells highly expressed the lipid raft-related protein flotillin-1 and clathrin heavy chain, however, no caveolin-1. A549 cells expressed clathrin heavy chain and caveolin-1, but no flotillin-1 uptake-related proteins. Our data revealed an impeded uptake of 40 nm polystyrene nanoparticles by J774A.1 macrophages when actin polymerization and clathrin-coated pit formation was blocked. From this result, it is suggested that macropinocytosis and phagocytosis, as well as clathrin-mediated endocytosis, play a crucial role. The uptake of 40 nm nanoparticles in alveolar epithelial A549 cells was inhibited after depletion of cholesterol in the plasma membrane (preventing caveolin-mediated endocytosis and inhibition of clathrin-coated vesicles (preventing clathrin-mediated endocytosis. Our data showed that a combination of several distinguishable endocytotic uptake mechanisms are involved in the uptake of 40 nm polystyrene nanoparticles in both the macrophage and epithelial cell line.

  6. Exosomes: Mechanisms of Uptake

    Directory of Open Access Journals (Sweden)

    Kelly J. McKelvey

    2015-07-01

    Full Text Available Exosomes are 30–100 nm microvesicles which contain complex cellular signals of RNA, protein and lipids. Because of this, exosomes are implicated as having limitless therapeutic potential for the treatment of cancer, pregnancy complications, infections, and autoimmune diseases. To date we know a considerable amount about exosome biogenesis and secretion, but there is a paucity of data regarding the uptake of exosomes by immune and non-immune cell types (e.g., cancer cells and the internal signalling pathways by which these exosomes elicit a cellular response. Answering these questions is of paramount importance.

  7. Exosomes: Mechanisms of Uptake

    Directory of Open Access Journals (Sweden)

    Kelly J. McKelvey

    2015-07-01

    Full Text Available Exosomes are 30–100 nm microvesicles which contain complex cellular signals of RNA, protein and lipids. Because of this, exosomes are implicated as having limitless therapeutic potential for the treatment of cancer, pregnancy complications, infections, and autoimmune diseases. To date we know a considerable amount about exosome biogenesis and secretion, but there is a paucity of data regarding the uptake of exosomes by immune and non- immune cell types (e.g., cancer cells and the internal signalling pathways by which these exosomes elicit a cellular response. Answering these questions is of para‐ mount importance.

  8. Overexpression of Cullin7 is associated with hepatocellular carcinoma progression and pathogenesis.

    Science.gov (United States)

    An, Jun; Zhang, Zhigang; Liu, Zhiyong; Wang, Ruizhi; Hui, Dayang; Jin, Yi

    2017-12-06

    Overexpression of Cullin7 is associated with some types of malignancies. However, the part of Cullin7 in hepatocellular carcinoma remains unclear. The aim of this study was to investigate the role of Cullin7 in pathogenesis and the progression of hepatocellular carcinoma. In the present study, the expression of Cullin7 in hepatocellular carcinoma cell lines and five surgical hepatocellular carcinoma specimens was detected with quantitative reverse transcription PCR and western blotting. In addition, the protein expression of Cullin7 was examined in 162 cases of archived hepatocellular carcinoma using immunohistochemistry. We found elevated expression of both mRNA and protein levels of Cullin7 in hepatocellular carcinoma cell lines, and Cullin7 protein was significantly upregulated in hepatocellular carcinoma compared with paired normal hepatic tissues. The immunohistochemistry analysis revealed that overexpression of Cullin7 occurred in 69.1% of hepatocellular carcinoma samples, which was a significantly higher rate than that in adjacent normal hepatic tissue (P hepatocellular carcinoma HepG2 cells, we revealed that Cullin7 could significantly enhance cell proliferation, growth, migration and invasion. Conversely, knocking down Cullin7 expression with short hairpin RNAi in hepatocellular carcinoma HepG2 cells inhibited cell proliferation, growth, migration and invasion. Our studies provide evidence that overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management.

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  1. File list: Oth.Liv.20.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

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  3. Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

    Science.gov (United States)

    Li, Min; Zhang, Weiyue; Wang, Birong; Gao, Yang; Song, Zifang; Zheng, Qi Chang

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high morbidity and mortality worldwide. Chemotherapy is recommended to patients with intermediate or advanced stage cancer. However, the conventional chemotherapy yields low desired response rates due to multidrug resistance, fast clearance rate, nonspecific delivery, severe side effects, low drug concentration in cancer cells, and so on. Nanoparticle-mediated targeted drug delivery system can surmount the aforementioned obstacles through enhanced permeability and retention effect and active targeting as a novel approach of therapeutics for HCC in recent years. The active targeting is triggered by ligands on the delivery system, which recognize with and internalize into hepatoma cells with high specificity and efficiency. This review focuses on the latest targeted delivery systems for HCC and summarizes the ligands that can enhance the capacity of active targeting, to provide some insight into future research in nanomedicine for HCC. PMID:27920520

  4. Thyroid Uptake Measurement System

    International Nuclear Information System (INIS)

    Nguyen Duc Tuan; Nguyen Thi Bao My; Nguyen Van Sy

    2007-01-01

    The NED-UP.M7 is a complete thyroid uptake and analysis system specifically designed for nuclear medicine. Capable of performing a full range of studies this system provides fast, accurate results for Uptake Studies. The heart of the NED-UP.M7 is a microprocessor-controlled 2048 channel Compact Multi-Channel Analyzer, coupled to a 2 inch x 2 inch NaI(Tl) detector with a USB personal computer interface. The system offers simple, straight-forward operation using pre-programmed isotopes, and menudriven prompts to guide the user step by step through each procedure. The pre-programmed radionuclides include I-123, I-125, I-131, Tc-99m and Cs-137. The user-defined radionuclides also allow for isotope identification while the printer provides hard copy printouts for patient and department record keeping. The included software program running on PC (Windows XP-based) is a user friendly program with menudriven and graphic interface for easy controlling the system and managing measurement results of patient on Excel standard form. (author)

  5. Role of polyhydroxybutyrate in mitochondrial calcium uptake

    Science.gov (United States)

    Smithen, Matthew; Elustondo, Pia A.; Winkfein, Robert; Zakharian, Eleonora; Abramov, Andrey Y.; Pavlov, Evgeny

    2013-01-01

    Polyhydroxybutyrate (PHB) is a biological polymer which belongs to the class of polyesters and is ubiquitously present in all living organisms. Mammalian mitochondrial membranes contain PHB consisting of up to 120 hydroxybutyrate residues. Roles played by PHB in mammalian mitochondria remain obscure. It was previously demonstrated that PHB of the size similar to one found in mitochondria mediates calcium transport in lipid bilayer membranes. We hypothesized that the presence of PHB in mitochondrial membrane might play a significant role in mitochondrial calcium transport. To test this, we investigated how the induction of PHB hydrolysis affects mitochondrial calcium transport. Mitochondrial PHB was altered enzymatically by targeted expression of bacterial PHB hydrolyzing enzyme (PhaZ7) in mitochondria of mammalian cultured cells. The expression of PhaZ7 induced changes in mitochondrial metabolism resulting in decreased mitochondrial membrane potential in HepG2 but not in U87 and HeLa cells. Furthermore, it significantly inhibited mitochondrial calcium uptake in intact HepG2, U87 and HeLa cells stimulated by the ATP or by the application of increased concentrations of calcium to the digitonin permeabilized cells. Calcium uptake in PhaZ7 expressing cells was restored by mimicking calcium uniporter properties with natural electrogenic calcium ionophore - ferutinin. We propose that PHB is a previously unrecognized important component of the mitochondrial calcium uptake system. PMID:23702223

  6. Arsenic Uptake and Translocation in Plants.

    Science.gov (United States)

    Li, Nannan; Wang, Jingchao; Song, Won-Yong

    2016-01-01

    Arsenic (As) is a highly toxic metalloid that is classified as a non-threshold class-1 carcinogen. Millions of people worldwide suffer from As toxicity due to the intake of As-contaminated drinking water and food. Reducing the As concentration in drinking water and food is thus of critical importance. Phytoremediation of soil contaminated with As and the reduction of As contamination in food depend on a detailed understanding of As uptake and transport in plants. As transporters play essential roles in As uptake, translocation and accumulation in plant cells. In this review, we summarize the current understanding of As transport in plants, with an emphasis on As uptake, mechanisms of As resistance and the long-distance translocation of As, especially the accumulation of As in grains through phloem-mediated transport. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  7. Anti-tumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Qin JM

    2012-01-01

    Full Text Available Jian-Min Qin1, Pei-Hao Yin1, Qi Li1, Zhong-Qiu Sa1, Xia Sheng1, Lin Yang1, Tao Huang1, Min Zhang1, Ke-Pan Gao2, Qing-Hua Chen2, Jing-Wei Ma3, He-Bai Shen31Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 2National Pharmaceutical Engineering Research Center; Shanghai Institute of Pharmaceutical Industry, 3Department of Physical Chemistry, Shanghai Normal University, Shanghai, People's Republic of ChinaBackground: Hepatocellular carcinoma is difficult to diagnose early, and most patients are already in the late stages of the disease when they are admitted to hospital. The total 5-year survival rate is less than 5%. Recent studies have showed that brucine has a good anti-tumor effect, but high toxicity, poor water solubility, short half-life, narrow therapeutic window, and a toxic dose that is close to the therapeutic dose, which all limit its clinical application. This study evaluated the effects of brucine immuno-nanoparticles (BIN on hepatocellular carcinoma.Materials and methods: Anionic polymerization, chemical modification technology, and phacoemulsification technology were used to prepare a carboxylated polyethylene glycol-polylactic acid copolymer carrier material. Chemical coupling technology was utilized to develop anti-human AFP McAb-polyethylene glycol-polylactic acid copolymer BIN. The size, shape, zeta potential, drug loading, encapsulation efficiency, and release of these immune-nanoparticles were studied in vitro. The targeting, and growth, invasion, and metastasis inhibitory effects of this treatment on liver cancer SMMC-7721 cells were tested.Results: BIN were of uniform size with an average particle size of 249 ± 77 nm and zeta potential of -18.7 ± 4.19 mV. The encapsulation efficiency was 76.0% ± 2.3% and the drug load was 5.6% ± 0.2%. Complete uptake and even distribution around the liver cancer cell membrane were observed.Conclusion: BIN had even size distribution, was

  8. The evaluation of p,p′-DDT exposure on cell adhesion of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Jin, Xiaoting; Chen, Meilan; Song, Li; Li, Hanqing; Li, Zhuoyu

    2014-01-01

    Graphical abstract: - Highlights: • Low doses p,p′-DDT exposure disrupts cell–cell adhesion and cell–matrix adhesion in HepG2 cells. • Both oxidative stress and JAK/STAT3 pathway are activated in p,p′-DDT-treated HepG2 cells. • The stimulation of JAK/STAT3 pathway is mediated by oxidative stress. • p,p′-DDT regulates adhesion molecules via the JAK/STAT3 pathway. • p,p′-DDT stimulates JAK/STAT3 signal pathway and disrupts the expressions of cell adhesion molecules in nude mice models. - Abstract: Many studies have found a positive association between the progression of hepatocellular carcinoma and DDT exposure. These studies mainly focus on the effect of DDT exposure on cell proliferation and epithelial to mesenchymal transition (EMT) promotion. However, the influence of DDT on cell adhesion of hepatocellular carcinoma remains to be unclear. The aim of our study was to determine the effect of p,p′-DDT on cell adhesion of hepatocellular carcinoma in vitro and in vivo. The data showed that p,p′-DDT, exposing HepG2 cells for 6 days, decreased cell–cell adhesion and elevated cell–matrix adhesion. Strikingly, p,p′-DDT increased reactive oxygen species (ROS) content, and this was accompanied by the activation of JAK/STAT3 pathway. Moreover, ROS inhibitor supplement reversed these effects significantly. However, the addition of ER inhibitor, ICI, had no effect on the p,p′-DDT-induced effects. p,p′-DDT altered the mRNA levels of related adhesion molecules, including inhibition of E-cadherin and promotion of N-cadherin along with CD29. Interestingly, the p,p′-DDT-altered adhesion molecules could be reversed with JAK inhibitor or STAT3 inhibitor. Likewise, p,p′-DDT stimulated the JAK/STAT3 pathway in nude mice, as well as altered the mRNA levels of E-cadherin, N-cadherin, and CD29. Taken together, these results indicate that p,p′-DDT profoundly promotes the adhesion process by decreasing cell–cell adhesion and inducing cell

  9. Hepatocellular carcinomas supplied by inferior phrenic arteries.

    Science.gov (United States)

    Tanabe, N; Iwasaki, T; Chida, N; Suzuki, S; Akahane, T; Kobayashi, N; Ishii, M; Toyota, T

    1998-07-01

    To assess the arterial supply to hepatocellular carcinomas (HCCs) by inferior phrenic arteries (IPA). A total of 126 consecutive cases of HCC were studied by contract-enhanced CT and conventional arteriography. Blood supply from an IPA was suspected when the size of the HCC mass as seen on contrast-enhanced CT did not match the size of the tumor mass as seen on hepatic arteriography. Inferior phrenic arteriography was employed to confirm these findings. HCCs fed by the IPA were analyzed in terms of size, location, and history of prior treatment. In 14 (11%) of the 126 cases, the tumor was found to have a blood supply from an IPA. Eleven of these tumors were located in segments 2 and 7. Three tumors, which had not been treated previously, had a blood supply from an IPA. Six tumors were almost exclusively fed by an IPA and were located in segments 1, 1, and 4. HCCs located in segments which form the bare area of the liver (S1, S2, S7) can be supplied by an IPA. This should be suspected when a lesion or part of a lesion is identified on contrast-enhanced CT but not on hepatic arteriography.

  10. Diagnostic and therapeutic management of hepatocellular carcinoma

    Science.gov (United States)

    Bellissimo, Francesco; Pinzone, Marilia Rita; Cacopardo, Bruno; Nunnari, Giuseppe

    2015-01-01

    Hepatocellular carcinoma (HCC) is an increasing health problem, representing the second cause of cancer-related mortality worldwide. The major risk factor for HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemo-embolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines. PMID:26576088

  11. Updates in the Management of Hepatocellular Carcinoma

    Science.gov (United States)

    Frenette, Catherine

    2011-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, and its increasing incidence worldwide is a cause for concern. Fortunately, advances in diagnostic and therapeutic approaches have contributed to earlier detection and treatment. As cancer epidemiology studies continue to elucidate the natural history of liver diseases, greater understanding of HCC has led to improved risk stratification and earlier enrollment of high-risk patients in cancer screening and surveillance programs. Improved survival rates among HCC patients also reflect significant advances in available treatment options. Advances in surgical techniques are pushing the boundaries of resection for localized disease, and progress in the field of transplantation has led to refinements in listing criteria and improved post-transplantation outcomes. The evolving field of locoregional therapies—including percutaneous ablation and transarterial chemoembolization—continues to provide novel therapeutic options that can be used in place of, or in addition to, surgical approaches. Recent advances in systemic multikinase inhibitor therapies have also demonstrated significant benefits for advanced-stage disease, and these therapies also show promise as adjuvant treatments for earlier-stage disease. This article provides an update on the management of HCC, with a focus on revised guidelines for screening and an in-depth discussion of emerging novel therapies. PMID:21346848

  12. Genetic alterations in hepatocellular carcinoma: An update

    Science.gov (United States)

    Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

  13. Nonalcoholic fatty liver disease and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    LI Liangping

    2016-03-01

    Full Text Available As the etiology of hepatocellular carcinoma (HCC has been changing, the incidence of HCC related to nonalcoholic fatty liver disease (NAFLD is gradually increasing in developed countries in Europe and America and some countries in Asia. This article introduces the close association between NAFLD and HCC, risk factors, clinicopathological features, and prevention and screening, and points out that although the incidence of NAFLD is not as high as that of hepatitis B- or hepatitis C-related HCC, there are a large absolute number of NAFLD patients, especially the high-risk patients with diabetes and obesity, or liver fibrosis/cirrhosis, due to a huge base number of NAFLD patients. NAFLD-related HCC is commonly seen in the elderly with various comorbidities and a poor prognosis. This article also points out that the prevention should focus on the effective treatment of NAFLD. The strict screening of high-risk population is the strategy for the diagnosis of early-stage HCC. At present, the sensitivity of alpha-fetoprotein is relatively low, and imaging examinations including computed tomography are the main screening methods; however, there are no measures for early warning of NAFLD-related HCC.

  14. CT findings of exophytic hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sang Jin; Cho, June Sik; Kim, Hyung Lyul; Lee, Chung Keun; Kim, Dae Hong; Rhee, Byung Chull [Chungnam National University College of Medicine, Daejeon (Korea, Republic of)

    1993-11-15

    We retrospectively evaluated the characteristic computed tomographic(CT) findings in nine patients with exohepatic hepatocellular carcinoma(HCC) pathologically prove by surgery(n=2) or percutaneous needle biopsy(n=7). The CT findings of exphepatic HCC were correlated with clinical findings and compared with those of usual HCC. Lesions were in the left lobe(n=7) and right lobe(n=2) of the liver. All lesions showed a well-marginated hypodense mass with capsular enhancement on enhanced CT scan. The patterns of capsular enhancement were complete in five and partial in four case. The portal vein thrombosis was seen only in one case. There was no difference between exohepatic HCC and usual HCC in clinical findings such as increased {alpha}-fetoprotein({alpha}-FP), positive hepatitis B surface antigen(HBsAg), and underlying liver cirrhosis. In conclusion, the CT findings of exohepatic HCC were a well-defined hyperdense mass with complete or partial capsular enhancement and these findings may be useful in differentiation from the tumors of adjacent organs.

  15. Ectopic hepatocellular carcinoma in a dog.

    Science.gov (United States)

    Burton, I R; Limpus, K; Thompson, K G; Owen, M C; Worth, A J

    2005-12-01

    A 14-year-old neutered male Bearded Collie was presented with a history of recurrent, intermittent urinary incontinence of 7 years duration. A large, firm, non-painful mass was found in the mid-abdominal region on palpation. Ultrasonography of the mass revealed a compartmentalised structure with mixed echogenicity, and which did not appear to be associated with any of the abdominal organs. Ultrasound-guided fine needle aspirates contained several clusters of epithelial cells with cytological features of hepatocytes. At exploratory laparotomy, the mass was found in the gastrosplenic ligament within the greater omentum. PATHOLOGICAL FINDINGS AND DIAGNOSIS: Histopathologically, the mass consisted of sheets of hepatocytes, but without the characteristic hepatic architecture. The cells showed moderate variation in nuclear size and were sometimes binucleate. A diagnosis of hepatocellular carcinoma (HCC) in the mesentery was made. The presence of ectopic hepatic tissue has been reported rarely in man and cats, but not in the dog. Neoplastic transformation of ectopic hepatic tissue is seen in man. This is the first report of the presentation, clinical findings and treatment of a dog with ectopic HCC.

  16. In Utero Hepatocellular Transplantation in Rats

    Directory of Open Access Journals (Sweden)

    Emma Muñoz-Sáez

    2013-01-01

    Full Text Available This work represents a step forward in the experimental design of an in utero hepatocellular transplantation model in rats. We focused on the enrichment optimization of isolated fetal hepatocytes suspension, arranging the surgery methodology of in utero transplantation, monitoring the biodistribution of the transplanted hepatocytes, and assessing the success of the transplants. Rat fetuses have been transplanted at the 17th embryonic day (ED17 with fetal hepatocytes isolated from rats at the end of pregnancy (ED21. We assessed possible differences between lymphocyte population, CD4 positive, CD8 positive, double-positive T-cells, and anti-inflammatory cytokines interleukins 4 and 10 (IL4 and IL10 as well. Cellular viability reached the rates of 90–95%. Transplanted groups had a limited success. Transplanted hepatocytes were not able to pass through the hematoplacental barrier. The hepatocytes injected were primarily located in the liver. There was an upward trend in the whole amount of T CD4 and T CD8 cells. There was an increased IL4 in the transplanted groups observed in the pregnant rats. The possibility to induce tolerance in fetuses with a hepatocyte transplant in utero could be a key point to avoid the immunosuppression treatments which must be undergone by transplanted patients.

  17. Potentiality of immunotherapy against hepatocellular carcinoma

    Science.gov (United States)

    Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

    2015-01-01

    Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future. PMID:26420958

  18. Repeated proton beam therapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Hashimoto, Takayuki; Tokuuye, Koichi; Fukumitsu, Nobuyoshi; Igaki, Hiroshi; Hata, Masaharu; Kagei, Kenji; Sugahara, Shinji; Ohara, Kiyoshi; Matsuzaki, Yasushi; Akine, Yasuyuki

    2006-01-01

    Purpose: To retrospectively evaluate the safety and effectiveness of repeated proton beam therapy for newly developed or recurrent hepatocellular carcinoma (HCC). Methods and Materials: From June 1989 through July 2000, 225 patients with HCC underwent their first course of proton beam therapy at University of Tsukuba. Of them, 27 with 68 lesions who had undergone two or more courses were retrospectively reviewed in this study. Median interval between the first and second course was 24.5 months (range 3.3-79.8 months). Median total dose of 72 Gy in 16 fractions and 66 Gy in 16 fractions were given for the first course and the rest of the courses, respectively. Results: The 5-year survival rate and median survival period from the beginning of the first course for the 27 patients were 55.6% and 62.2 months, respectively. Five-year local control rate for the 68 lesions was 87.8%. Of the patients, 1 with Child-Pugh class B and another with class C before the last course suffered from acute hepatic failure. Conclusions: Repeated proton beam therapy for HCC is safe when the patient has a target in the peripheral region of the liver and liver function is Child-Pugh class A

  19. Hepatocellular carcinoma: a systems biology perspective

    Directory of Open Access Journals (Sweden)

    Lorenza Alice D'alessandro

    2013-02-01

    Full Text Available Hepatocellular carcinomas (HCC have different etiology and heterogenic genomic alterations lead to high complexity. The molecular features of HCC have largely been studied by gene expression and proteome profiling focusing on the correlations between the expression of specific markers and clinical data. Integration of the increasing amounts of data in databases has facilitated the link of genomic and proteomic profiles of HCC to disease state and clinical outcome. Despite the current knowledge, specific molecular markers remain to be identified and new strategies are required to establish novel targeted therapies. In the last years, mathematical models reconstructing gene and protein networks based on experimental data of HCC have been developed providing powerful tools to predict candidate interactions and potential targets for therapy. Furthermore, the combination of dynamic and logical mathematical models with quantitative data allows detailed mechanistic insights into system properties. To address effects at the organ level, mathematical models reconstructing the three-dimensional organization of liver lobules were developed. In the future, integration of different modeling approaches capturing the effects at the cellular up to the organ level is required to address the complex properties of HCC and to enable the discovery of new targets for HCC prevention or treatment.

  20. Hepatocellular carcinomas supplied by inferior phrenic arteries

    International Nuclear Information System (INIS)

    Tanabe, N.; Iwasaki, T.; Akahane, T.; Kobayashi, N.; Ishii, M.; Toyota, T.; Chida, N.; Suzuki, S.

    1998-01-01

    Purpose: To assess the arterial supply to hepatocellular carcinomas (HCCs) by inferior phrenic arteries (IPA). Material and Methods: A total of 126 consecutive cases of HCC were studied by contrast-enhanced CT and conventional arteriography. Blood supply from an IPA was suspected when the size of the HCC mass as seen on contrast-enhanced CT did not match the size of the tumor mass as seen on hepatic arteriography. Inferior phrenic arteriography was employed to confirm these findings. HCCs fed by the IPA were analyzed in terms of size, location, and history of prior treatment. Results: In 14 (11%) of the 126 cases, the tumor was found to have a blood supply from an IPA. Eleven of these tumors were located in segments 2 and 7. Three tumors, which had not been treated previously, had a blood supply from an IPA. Six tumors were almost exclusively fed by an IPA and were located in segments 7, 1, and 4. Conclusion: HCCs located in segments which form the bare area of the liver (S1, S2, S7) can be supplied by an IPA. This should be suspected when a lesion or part of a lesion is identified on contrast-enhanced CT but not on hepatic arteriography. (orig.)

  1. Infrequent widespread microsatellite instability in hepatocellular carcinomas.

    Science.gov (United States)

    Yamamoto, H; Itoh, F; Fukushima, H; Kaneto, H; Sasaki, S; Ohmura, T; Satoh, T; Karino, Y; Endo, T; Toyota, J; Imai, K

    2000-03-01

    Widespread or high-frequency microsatellite instability (MSI) due to the defective DNA mismatch repair (MMR) occurs in the majority of hereditary non-polyposis colorectal cancer and a subset of sporadic malignant tumors. The incidence of MSI and underlying DNA MMR defects have been well characterized in gastrointestinal carcinogenesis, but not in hepatocarcinogenesis. To address the issue, we analyzed 55 Japanese hepatocellular carcinomas using several indicators of DNA MMR defects, such as microsatellite analysis, loss of heterozygosity (LOH) and mutation analysis of MMR genes, methylation of hMLH1 promoter, and frameshift mutations of mononucleotide repeat sequences within possible target genes. Mutation of beta2-microglobulin gene, which is presumably involved in MSI-positive tumor cell escape from immune surveillance was also examined. Some of these analyses were also carried out in 9 human liver cancer cell lines. None of the 3 quasi-monomorphic mononucleotide markers sensitive for MSI, BAT26, BAT25, and BAT34C4 presented shortened unstable alleles in any of the carcinoma, cirrhosis, chronic hepatitis tissues, or cell lines. LOH at MMR genes was infrequent (4.4 approximately 7.1%), and no mutations were detected. Neither hMLH1 hypermethylation nor frameshift mutation in the target genes was detected. No mutations were found in beta2-microglobulin. Widespread MSI due to the defective DNA MMR appears to play little if any part in Japanese hepatocarcinogenesis.

  2. Hepatocellular carcinomas supplied by inferior phrenic arteries

    Energy Technology Data Exchange (ETDEWEB)

    Tanabe, N.; Iwasaki, T.; Akahane, T.; Kobayashi, N.; Ishii, M.; Toyota, T. [Tohoku Univ. School of Medicine (Japan). Third Dept. of Internal Medicine; Chida, N.; Suzuki, S. [National Sendai Hospital (Japan). Dept. of Gastroenterology

    1998-07-01

    Purpose: To assess the arterial supply to hepatocellular carcinomas (HCCs) by inferior phrenic arteries (IPA). Material and Methods: A total of 126 consecutive cases of HCC were studied by contrast-enhanced CT and conventional arteriography. Blood supply from an IPA was suspected when the size of the HCC mass as seen on contrast-enhanced CT did not match the size of the tumor mass as seen on hepatic arteriography. Inferior phrenic arteriography was employed to confirm these findings. HCCs fed by the IPA were analyzed in terms of size, location, and history of prior treatment. Results: In 14 (11%) of the 126 cases, the tumor was found to have a blood supply from an IPA. Eleven of these tumors were located in segments 2 and 7. Three tumors, which had not been treated previously, had a blood supply from an IPA. Six tumors were almost exclusively fed by an IPA and were located in segments 7, 1, and 4. Conclusion: HCCs located in segments which form the bare area of the liver (S1, S2, S7) can be supplied by an IPA. This should be suspected when a lesion or part of a lesion is identified on contrast-enhanced CT but not on hepatic arteriography. (orig.)

  3. Magnetic Resonance Imaging Finding of Metastatic Hepatocellular Carcinoma in Ovary: A Case Report

    International Nuclear Information System (INIS)

    Kwak, Soon Hyuk; Cho, Bum Sang; Kang, Min Ho; Lee, Seung Young; Han, Gi Seok; Cha, Sang Hoon; Park, Kil Sun; Kim, Sung Jin; Choi, Song Yi

    2011-01-01

    Hepatocellular carcinoma is the most common primary malignant tumor of liver. Metastasis of hepatocellular carcinoma occurs in various organs, but metastasis to the ovary is extremely rare. We report MRI finding of metastatic hepatocellular carcinoma of the ovary in a 37-year-old woman who was treated hepatocellular carcinoma transarterial chemoembolization and radiofrequency ablation a year ago. Pelvic MRI revealed a mass in pelvic cavity with heterogeneous signal intensity and centripetal enhancement. Surgical excision and pathologic examination confirmed metastatic hepatocellular carcinoma in the ovary.

  4. Preparation and Optimization Lipid Nanocapsules to Enhance the Antitumor Efficacy of Cisplatin in Hepatocellular Carcinoma HepG2 Cells.

    Science.gov (United States)

    Zhai, Qingqing; Li, Hailong; Song, Yanlin; Wu, Ruijiao; Tang, Chuanfang; Ma, Xiaodong; Liu, Zhihao; Peng, Jinyong; Zhang, Jianbin; Tang, Zeyao

    2018-04-20

    This work aimed to develop and optimize several lipid nanocapsule formulations (LNCs) to encapsulate cisplatin (CDDP) for treatment of hepatocellular carcinoma. By comparing the effect of oil/surfactant ratio, lecithin content, and oil/surfactant type on LNC characteristics, two LNCs were selected as optimal formulations: HS15-LNC (Solutol HS 15/MCT/lecithin, 54.5:42.5:3%, w/w) and EL-LNC (Cremophor EL/MCT/lecithin, 54.5:42.5:3%, w/w). Both LNCs could effectively encapsulate CDDP with the encapsulation efficiency of 73.48 and 78.84%. In vitro release study showed that both LNCs could sustain the release CDDP. Moreover, cellular uptake study showed that C6-labeled LNCs could be effectively internalized by HepG2 cells. Cellular cytotoxicity study revealed that both LNCs showed negligible cellular toxicity when their concentrations were below 313 μg/mL. Importantly, CDDP-loaded LNCs exhibited much stronger cell killing potency than free CDDP, with the IC50 values decreased from 17.93 to 3.53 and 5.16 μM after 72-h incubation. In addition, flow cytometric analysis showed that the percentage of apoptotic cells was significantly increased after treatment with LNCs. Therefore, the prepared LNC formulations exhibited promising anti-hepatocarcinoma effect, which could be beneficial to hepatocellular carcinoma therapy.

  5. CXXC5 suppresses hepatocellular carcinoma by promoting TGF-β-induced cell cycle arrest and apoptosis.

    Science.gov (United States)

    Yan, Xiaohua; Wu, Jingyi; Jiang, Quanlong; Cheng, Hao; Han, Jing-Dong J; Chen, Ye-Guang

    2018-02-01

    Evading TGF-β-mediated growth inhibition is often associated with tumorigenesis in liver, including hepatocellular carcinoma (HCC). To better understand the functions and the underlying molecular mechanisms of TGF-β in HCC initiation and progression, we carried out transcriptome sequencing (RNA-Seq) to identify the target genes of TGF-β. CXXC5, a member of the CXXC-type zinc finger domain-containing protein family, was identified as a novel TGF-β target gene in Hep3B HCC cells. Knockdown of CXXC5 attenuated the expression of a substantial portion of TGF-β target genes and ameliorated TGF-β-induced growth inhibition or apoptosis of Hep3B cells, suggesting that CXXC5 is required for TGF-β-mediated inhibition of HCC progression. Analysis of the TCGA database indicated that CXXC5 expression is reduced in the majority of HCC tissue samples in comparison to that in normal tissues. Furthermore, CXXC5 associates with the histone deacetylase HDAC1 and competes its interaction with Smad2/3, thereby abolishing the inhibitory effect of HDAC1 on TGF-β signaling. These observations together suggest that CXXC5 may act as a tumor suppressor by promoting TGF-β signaling via a positive feedback loop, and reveal a strategy for HCC to bypass TGF-β-mediated cytostasis by disrupting the positive feedback regulation. Our findings shed new light on TGF-β signaling regulation and demonstrate the function of CXXC5 in HCC development.

  6. Antagonism of Sorafenib and Regorafenib actions by platelet factors in hepatocellular carcinoma cell lines

    International Nuclear Information System (INIS)

    D’Alessandro, Rosalba; Refolo, Maria G; Lippolis, Catia; Giannuzzi, Grazia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian I

    2014-01-01

    Platelets are frequently altered in hepatocellular carcinoma (HCC) patients. Platelet lysates (hPL) can enhance HCC cell growth and decrease apoptosis. The aims were to evaluate whether hPL can modulate the actions of Sorafenib or Regorafenib, two clinical HCC multikinase antagonists. Several human HCC cell lines were grown in the presence and absence of Sorafenib or Regorafenib, with or without hPL. Growth was measured by MTT assay, apoptosis was assessed by Annexin V and by western blot, and autophagy and MAPK growth signaling were also measured by western blot, and migration and invasion were measured by standard in vitro assays. Both Sorafenib and Regorafenib-mediated inhibition of cell growth, migration and invasion were all antagonized by hPL. Drug-mediated apoptosis and decrease in phospho-ERK levels were both blocked by hPL, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-xL levels. Preliminary data, obtained with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), included in hPL, revealed that these factors were able to antagonized Sorafenib in a proliferation assay, in particular when used in combination. Platelet factors can antagonize Sorafenib or Regorafenib-mediated growth inhibition and apoptosis in HCC cells. The modulation of platelet activity or numbers has the potential to enhance multikinase drug actions

  7. SIRT1 sensitizes hepatocellular carcinoma cells expressing hepatitis B virus X protein to oxidative stress-induced apoptosis

    International Nuclear Information System (INIS)

    Srisuttee, Ratakorn; Koh, Sang Seok; Malilas, Waraporn; Moon, Jeong; Cho, Il-Rae; Jhun, Byung Hak; Horio, Yoshiyuki; Chung, Young-Hwa

    2012-01-01

    Highlights: ► Up-regulation of SIRT1 protein and activity sensitizes Hep3B-HBX cells to oxidative stress-induced apoptosis. ► Nuclear localization of SIRT1 is not required for oxidation-induced apoptosis. ► Ectopic expression and enhanced activity of SIRT1 attenuate JNK phosphorylation. ► Inhibition of SIRT1 activity restores resistance to oxidation-induced apoptosis through JNK activation. -- Abstract: We previously showed that SIRT1 deacetylase inhibits proliferation of hepatocellular carcinoma cells expressing hepatitis B virus (HBV) X protein (HBX), by destabilization of β-catenin. Here, we report another role for SIRT1 in HBX-mediated resistance to oxidative stress. Ectopic expression and enhanced activity of SIRT1 sensitize Hep3B cells stably expressing HBX to oxidative stress-induced apoptosis. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for sensitization of oxidation-mediated apoptosis. Furthermore, ectopic expression of SIRT1 and treatment with resveratrol (a SIRT1 activator) attenuated JNK phosphorylation, which is a prerequisite for resistance to oxidative stress-induced apoptosis. Conversely, suppression of SIRT1 activity with nicotinamide inhibited the effect of resveratrol on JNK phosphorylation, leading to restoration of resistance to oxidation-induced apoptosis. Taken together, these results suggest that up-regulation of SIRT1 under oxidative stress may be a therapeutic strategy for treatment of hepatocellular carcinoma cells related to HBV through inhibition of JNK activation.

  8. Epidemiology of hepatocellular carcinoma in India.

    Science.gov (United States)

    Acharya, Subrat K

    2014-08-01

    Indian data on epidemiology of HCC is not available. Cancer is not a reportable disease in India and the cancer registries in India are mostly urban. National cancer registry program of the Indian Council of Medical Research (ICMR) has been recently expanded to include 21 population based and 6 hospital based cancer registries. The last published registry data by ICMR available in the cancer registry website (www.ncrpindia.org) was in 2008 which provides information on various cancers from 2006 to 2008. The other source of information was the report published by International Agency for Research on Cancer (WHO). According to these available data the age adjusted incidence rate of hepatocellular carcinoma (HCC) in India for men ranges from 0.7 to 7.5 and for women 0.2 to 2.2 per 100,000 population per year. The male:female ratio for HCC in India is 4:1. The age of presentation varies from 40 to 70 years. According to a study conducted by verbal autopsy in 1.1 million homes representing the whole country, the age standardized mortality rate for HCC in India for men is 6.8/100,000 and for women is 5.1/100,000. According to another study the incidence of HCC in cirrhotics in India is 1.6% per year. The unpublished data from various tertiary care centers suggest that the incidence of HCC is increasing in India. There is a need for a multi-centric HCC registry under the aegis of INASL.

  9. Dichlorodiphenyltrichloroethane (DDT) and risk of hepatocellular carcinoma

    Science.gov (United States)

    Persson, E. Christina; Graubard, Barry I.; Evans, Alison A.; London, W. Thomas; Weber, Jean-Philippe; LeBlanc, Alain; Chen, Gang; Lin, Wenyao; McGlynn, Katherine A.

    2014-01-01

    Dichlorodiphenyltrichloroethane (p,p’-DDT), an organochlorine pesticide known to have deleterious health effects in humans, has been linked to hepatocellular carcinoma (HCC) in rodents. A recent study has reported that p,p’-DDT and its most persistent metabolite, dichlorodiphenyldichloroethylene (p,p’-DDE), may also be associated with HCC in humans. To examine whether there is an association between p,p’-DDT and/or p,p’-DDE in a population at high-risk of developing HCC. A nested case-control study was conducted within the 83,794 person Haimen City Cohort in China. Sera and questionnaire data were collected from all participants between 1992 and 1993. The current study included 473 persons who developed HCC and 492 who did not, frequency matched on sex, age and area of residence. p,p’-DDT and p,p’-DDE levels were determined by mass spectrometry. Hepatitis B viral infection status (based on hepatitis B virus surface antigen; HBsAg) was also determined. Adjusting for age, sex, area of residence, HBsAg, family history of HCC, history of acute hepatitis, smoking, alcohol, occupation (farmers) and levels of p,p’-DDT or p,p’-DDE, odds ratios (OR) and 95% confidence intervals (CI) were calculated via unconditional logistic regression, p,p’-DDT and/or p,p’-DDE serum levels were significantly associated with sex, area of residence, occupation, alcohol consumption and cigarette smoking. Overall, the highest quintile of p,p’-DDT was associated with an increased risk of HCC, OR= 2.96 95% CI; 1.19–7.40. There were no statistically significant associations with p,p’-DDE. Overall, these results suggest that recent exposure to p,p’-DDT may increase risk of HCC. PMID:22290210

  10. Targeting cancer stem cells in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    He AR

    2014-12-01

    Full Text Available Aiwu Ruth He,1 Daniel C Smith,1 Lopa Mishra2 1Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 2Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: The poor outcome of patients with hepatocellular carcinoma (HCC is attributed to recurrence of the disease after curative treatment and the resistance of HCC cells to conventional chemotherapy, which may be explained partly by the function of liver cancer stem cells (CSCs. Liver CSCs have emerged as an important therapeutic target against HCC. Numerous surface markers for liver CSCs have been identified, and include CD133, CD90, CD44, CD13, and epithelial cell adhesion molecules. These surface markers serve not only as tools for identifying and isolating liver CSCs but also as therapeutic targets for eradicating these cells. In studies of animal models and large-scale genomic analyses of human HCC samples, many signaling pathways observed in normal stem cells have been found to be altered in liver CSCs, which accounts for the stemness and aggressive behavior of these cells. Antibodies and small molecule inhibitors targeting the signaling pathways have been evaluated at different levels of preclinical and clinical development. Another strategy is to promote the differentiation of liver CSCs to less aggressive HCC that is sensitive to conventional chemotherapy. Disruption of the tumor niche essential for liver CSC homeostasis has become a novel strategy in cancer treatment. To overcome the challenges in developing treatment for liver CSCs, more research into the genetic makeup of patient tumors that respond to treatment may lead to more effective therapy. Standardization of HCC CSC tumor markers would be helpful for measuring the CSC response to these agents. Herein, we review the current strategies for developing treatment to eradicate liver CSCs and to improve the outcome for patients with

  11. Angiogenic Blockade and Radiotherapy in Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Chi, Kwan-Hwa; Liao, Chao-Sheng; Chang, Chih-Chia; Ko, Hui-Ling; Tsang, Yuk-Wah; Yang, Kuo-Ching; Mehta, Minesh P.

    2010-01-01

    Purpose: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC. Methods and Materials: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial α-fetoprotein (AFP) kinetics, and survival. Results: Of 23 evaluable patients, 60% had ≥2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenance sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had ≥50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had ≥Grade 2 elevation of liver enzymes, and 15 had ≥Grade 2 thrombocytopenia. Conclusions: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.

  12. Hemodynamic characteristics of early stage hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Kudo, Masatoshi; Tomita, Shusuke; Tochio, Hitoshi

    1992-01-01

    Hemodynamic characteristics were studied by using in vivo vascular imaging techniques in 17 resected early stage hepatocellular carcinoma (e-HCC) by comparing them with 49 resected advanced HCCs (ad-HCC) less than 3 cm in diameter. In this study, e-HCC was defined as the nodule being uniformly composed of well-differentiated HCC or adenomatous hyperplastic nodule containing well-differentiated HCC foci within the nodule. In vivo vascular imaging techniques are as follows; US angiography with intraarterial CO 2 microbubbles were performed to assess the tumor arterial vascularity, and CT during arterial portography (CTAP) was performed to assess the portal perfusion within the nodule. Of 17 e-HCC nodules 5 were hypervascular, 5 were isovascular, 4 were hypovascular, and 3 were vascular spot in hypovascular pattern in contrast to 49 ad-HCC nodules, 43 of which were hypervascular and 6 were isovascular. Of 14 e-HCCs, 9 nodules showed perfusion defect and 5 did not on CTAP, whereas all 37 ad-HCCs on which CTAP was performed, showed perfusion defect. Forty-one percent (7/17) of e-HCC showed fatty metamorphosis in contrast to 8% (4/49) of ad-HCC. In conclusion, hemodynamic characteristics of e-HCC are summarized as follows. (1) Arterial tumor neovascularization is relatively low. (2) Portal perfusion is present in some of e-HCC cases. (3) Hypoperfusion state both from arterial and portal supply is present in some of e-HCC cases. (4) Vascular spot in hypovascular pattern is characteristic arterial pattern in AH containing HCC foci. (5) Fatty metamorphosis may be related with hypoperfusion state of the nodule in e-HCC. (author)

  13. Clinical evaluation of sup(99m)Tc-N-pyridoxyl-5-methyltryptophan hepatobiliary scintigraphy in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kashiwagi, Toru; Azuma, Masayoshi; Matsuda, Hiroyuki; Yoshioka, Hiroaki; Ishizu, Hiroshi; Mitsutani, Natsuki; Koizumi, Takeo; Kobayashi, Yasushi

    1985-09-01

    We have assessed the diagnostic value of sup(99m)Tc-N-pyridoxyl-5-methyltryptophan (sup(99m)Tc-PMT) hepatobiliary scintigraphy in 28 patients with hepatocellular carcinoma (HCC) who had obvious filling defects on sup(99m)Tc-phytate liver scintigram. Uptake of sup(99m)Tc-PMT in obvious defects on sup(99m)Tc-phytate liver scintigram was observed in 16 out of 28 patients (57.1 %). Most of HCC with sup(99m)Tc-PMT uptake were histologically well-differenciated. However, well-differenciated HCC did not always take up sup(99m)Tc-PMT. No correlation was observed between sup(99m)Tc-PMT uptake in the tumor and levels of serum alpha-fetoprotein. Patients with high alpha-fetoprotein level (>3000 ng/ml) were only 9 patients (32.1 %) in our study. By the combined results of sup(99m)Tc-PMT hepatobiliary scintigraphy and alpha-fetoprotein level (>3000 ng/ml), diagnostic rate for HCC was markedly elevated up to 75 %. Therefore, it is considered that sup(99m)Tc-PMT hepatobiliary scintigraphy is clinically useful for specific diagnosis of HCC. Furthermore, it provides the information for invasion of HCC into the bile duct.

  14. Clinical evaluation of sup(99m)Tc-N-pyridoxyl-5-methyltryptophan hepatobiliary scintigraphy in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Kashiwagi, Toru; Azuma, Masayoshi; Matsuda, Hiroyuki; Yoshioka, Hiroaki; Ishizu, Hiroshi; Mitsutani, Natsuki; Koizumi, Takeo; Kobayashi, Yasushi

    1985-01-01

    We have assessed the diagnostic value of sup(99m)Tc-N-pyridoxyl-5-methyltryptophan (sup(99m)Tc-PMT) hepatobiliary scintigraphy in 28 patients with hepatocellular carcinoma (HCC) who had obvious filling defects on sup(99m)Tc-phytate liver scintigram. Uptake of sup(99m)Tc-PMT in obvious defects on sup(99m)Tc-phytate liver scintigram was observed in 16 out of 28 patients (57.1 %). Most of HCC with sup(99m)Tc-PMT uptake were histologically well-differenciated. However, well-differenciated HCC did not always take up sup(99m)Tc-PMT. No correlation was observed between sup(99m)Tc-PMT uptake in the tumor and levels of serum alpha-fetoprotein. Patients with high alpha-fetoprotein level (>3000 ng/ml) were only 9 patients (32.1 %) in our study. By the combined results of sup(99m)Tc-PMT hepatobiliary scintigraphy and alpha-fetoprotein level (>3000 ng/ml), diagnostic rate for HCC was markedly elevated up to 75 %. Therefore, it is considered that sup(99m)Tc-PMT hepatobiliary scintigraphy is clinically useful for specific diagnosis of HCC. Furthermore, it provides the information for invasion of HCC into the bile duct. (author)

  15. Radioiodine uptake measurements in thyroid

    International Nuclear Information System (INIS)

    Kadireshn, A.; Kapur, S.C.; Samuel, J.R.; Mahajan, M.K.

    1988-01-01

    Evaluation of thyroid function can be carried out by measuring the uptake of orally administered radioactive iodine. The results of the thyroid uptake measurements for the period 1982-1987 in Christian Medical College, Ludhiana are presented here. About 3000 patients were screened during the analysis period. (author)

  16. Aquaporins and root water uptake

    Science.gov (United States)

    Water is one of the most critical resources limiting plant growth and crop productivity, and root water uptake is an important aspect of plant physiology governing plant water use and stress tolerance. Pathways of root water uptake are complex and are affected by root structure and physiological res...

  17. Uptake of nuclides by plants

    International Nuclear Information System (INIS)

    Greger, Maria

    2004-04-01

    This review on plant uptake of elements has been prepared to demonstrate how plants take up different elements. The work discusses the nutrient elements, as well as the general uptake and translocation in plants, both via roots and by foliar absorption. Knowledge of the uptake by the various elements within the periodic system is then reviewed. The work also discusses transfer factors (TF) as well as difficulties using TF to understand the uptake by plants. The review also focuses on species differences. Knowledge necessary to understand and calculate plant influence on radionuclide recirculation in the environment is discussed, in which the plant uptake of a specific nuclide and the fate of that nuclide in the plant must be understood. Plants themselves determine the uptake, the soil/sediment determines the availability of the nuclides and the nuclides themselves can interact with each other, which also influences the uptake. Consequently, it is not possible to predict the nuclide uptake in plants by only analysing the nuclide concentration of the soil/substrate

  18. Uptake of nuclides by plants

    Energy Technology Data Exchange (ETDEWEB)

    Greger, Maria [Stockholm Univ. (Sweden). Dept. of Botany

    2004-04-01

    This review on plant uptake of elements has been prepared to demonstrate how plants take up different elements. The work discusses the nutrient elements, as well as the general uptake and translocation in plants, both via roots and by foliar absorption. Knowledge of the uptake by the various elements within the periodic system is then reviewed. The work also discusses transfer factors (TF) as well as difficulties using TF to understand the uptake by plants. The review also focuses on species differences. Knowledge necessary to understand and calculate plant influence on radionuclide recirculation in the environment is discussed, in which the plant uptake of a specific nuclide and the fate of that nuclide in the plant must be understood. Plants themselves determine the uptake, the soil/sediment determines the availability of the nuclides and the nuclides themselves can interact with each other, which also influences the uptake. Consequently, it is not possible to predict the nuclide uptake in plants by only analysing the nuclide concentration of the soil/substrate.

  19. Dose establishing a safety margin reduce local recurrence in subsegmental transarterial chemoembolization for small nodular hepatocellular carcinomas?

    International Nuclear Information System (INIS)

    Kang, Hyo Jin; Kim, Young Il; Kim, Hyo Cheol; Jae, Hwan Jun; Hur, Sae Beam; Chung, Jin Wook

    2015-01-01

    To test the hypothesis that a safety margin may affect local tumor recurrence (LTR) in subsegmental chemoembolization. In 101 patients with 128 hepatocellular carcinoma (HCC) nodules (1-3 cm in size and ≤ 3 in number), cone-beam CT-assisted subsegmental lipiodol chemoembolization was performed. Immediately thereafter, a non-contrast thin-section CT image was obtained to evaluate the presence or absence of intra-tumoral lipiodol uptake defect and safety margin. The effect of lipiodol uptake defect and safety margin on LTR was evaluated. Univariate and multivariate analyses were performed to indentify determinant factors of LTR. Of the 128 HCC nodules in 101 patients, 49 (38.3%) nodules in 40 patients showed LTR during follow-up period (median, 34.1 months). Cumulative 1- and 2-year LTR rates of nodules with lipiodol uptake defect (n = 27) and those without defect (n = 101) were 58.1% vs. 10.1% and 72.1% vs. 19.5%, respectively (p < 0.001). Among the 101 nodules without a defect, the 1- and 2-year cumulative LTR rates for nodules with complete safety margin (n = 52) and those with incomplete safety margin (n = 49) were 9.8% vs. 12.8% and 18.9% vs. 19.0% (p = 0.912). In multivariate analyses, ascites (p = 0.035), indistinct tumor margin on cone-beam CT (p = 0.039), heterogeneous lipiodol uptake (p = 0.023), and intra-tumoral lipiodol uptake defect (p < 0.001) were determinant factors of higher LTR. In lipiodol chemoembolization, the safety margin in completely lipiodolized nodule without defect will not affect LTR in small nodular HCCs

  20. Intercultural Mediation

    OpenAIRE

    Dragos Marian Radulescu; Denisa Mitrut

    2012-01-01

    The Intercultural Mediator facilitates exchanges between people of different socio-cultural backgrounds and acts as a bridge between immigrants and national and local associations, health organizations, services and offices in order to foster integration of every single individual. As the use mediation increases, mediators are more likely to be involved in cross-cultural mediation, but only the best mediators have the opportunity to mediate cross border business disputes or international poli...

  1. Cadmium uptake by plants

    Energy Technology Data Exchange (ETDEWEB)

    Haghiri, F.

    1973-01-01

    Absorption of /sup 115m/Cd by soybean (Gylcine max l.) plants via foliar and root systems and translocation into the seed was determined. The uptake of /sup 115m/Cd by soybeans via the root system was more efficient than that of the foliar placement. Growth and Cd concentrations of soybean and wheat (Triticum aestivum l.) tops were influenced by soil-applied Cd. In both crops, the Cd concentration of plant tops increased while yield decreased with increasing levels of applied Cd. Cadmium toxicitiy began to occur in both crops at the lowest level of soil applied Cd (2.5 ppM). With soybean plants, Cd toxicity symptoms resembled fe chlorosis. For wheat plants there were no visual symptoms other than the studied growth. The relative concentration of Cd found in several vegetable crops varied depending on the plant species. The relative Cd concentration in descending order for various vegetables was lettuce (Lactuca sativa l.) > radish top (Raphanus sativus l.) > celery stalk (Apium graveolens l.) > celery leaves greater than or equal to green pepper (Capsicum frutescens l.) > radish roots.

  2. Liver resection for non-cirrhotic hepatocellular carcinoma in south ...

    African Journals Online (AJOL)

    Background. We describe the clinicopathologic features and outcome of South African patients who have undergone hepatic resection for hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. Methods. We utilised the prospective liver resection database in the Surgical Gastroenterology Unit at Groote Schuur ...

  3. Scintigraphic demonstration of a metastasizing hepato-cellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Heintz, P; Gratz, K F; Schwarzrock, R; Schober, O; Neuhaus, P; Creutzig, H

    1986-01-01

    Adenomas and hepato cellular carcinomas cannot be differentiated by nuclear medicine: both exhibit masked radiodrug trapping at reduced perfusion. Two patients revealed specific accumulation in extrahepatic foci unknown before; hence, the diagnosis of a metastasizing hepatocellular carcinoma had to be verified. One case is demonstrated in full detail. (orig./SHA).

  4. Infection of hepatitis C virus genotypes in hepatocellular carcinoma ...

    African Journals Online (AJOL)

    The aim of this retrospective study was to investigate the infection of hepatitis C virus (HCV) genotypes in hepatocellular carcinoma (HCC) patients from rural areas of Faisalabad region. Among 179 HCC subjects, men and women were 51 and 49%, respectively. All samples positive for HCV RNA by qualitative PCR were ...

  5. Hepatitis viruses and hepatocellular carcinoma | Kew | South African ...

    African Journals Online (AJOL)

    Animal models - other members of the hepadnavirus family (to which HBV belongs) that also cause HCC in their respective animal hosts, and transgenic mice into which sequences of HBV DNA have been inserted - are proving useful in elucidating putative mechanisms of HBV-related hepatocellular carcinogenesis, but no ...

  6. Magnetic Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy

    DEFF Research Database (Denmark)

    Ungureanu, Bogdan Silviu; Teodorescu, Cristian-Mihail; Săftoiu, Adrian

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, ranking as the second most common cause of death from cancer worldwide. Magnetic nanoparticles (MNPs) have been used so far in tumor diagnosis and treatment, demonstrating great potential and promising results...

  7. Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

    NARCIS (Netherlands)

    Fages, Anne; Duarte-Salles, Talita; Stepien, Magdalena; Ferrari, Pietro; Fedirko, Veronika; Pontoizeau, Clement; Trichopoulou, Antonia; Aleksandrova, Krasimira; Tjonneland, Anne; Olsen, Anja; Clavel-Chapelon, Franoise; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Kaaks, Rudolf; Kuhn, Tilman; Floegel, Anna; Boeing, Heiner; Lagiou, Pagona; Bamia, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Vineis, Paolo; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.; Weiderpass, Elisabete; Agudo, Antonio; Molina-Montes, Esther; Maria Huerta, Jose; Ardanaz, Eva; Dorronsoro, Miren; Sjoberg, Klas; Ohlsson, Bodil; Khaw, Kay-Tee; Wareham, Nick; Travis, Ruth C.; Schmidt, Julie A.; Cross, Amanda; Gunter, Marc; Riboli, Elio; Scalbert, Augustin; Romieu, Isabelle; Elena-Herrmann, Benedicte; Jenab, Mazda

    2015-01-01

    Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is

  8. Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma.

    Science.gov (United States)

    Yahagi, Naoya; Shimano, Hitoshi; Hasegawa, Kiyoshi; Ohashi, Kenichi; Matsuzaka, Takashi; Najima, Yuho; Sekiya, Motohiro; Tomita, Sachiko; Okazaki, Hiroaki; Tamura, Yoshiaki; Iizuka, Yoko; Ohashi, Ken; Nagai, Ryozo; Ishibashi, Shun; Kadowaki, Takashi; Makuuchi, Masatoshi; Ohnishi, Shin; Osuga, Jun-ichi; Yamada, Nobuhiro

    2005-06-01

    Hepatocellular carcinoma is a very common neoplastic disease in countries where hepatitis viruses B and/or C are prevalent. Small hepatocellular carcinoma lesions detected by ultrasonography at an early stage are often hyperechoic because they are composed of well-differentiated cancer cells that are rich in triglyceride droplets. The triglyceride content of hepatocytes depends in part on the rate of lipogenesis. Key lipogenic enzymes, such as fatty acid synthase, are co-ordinately regulated at the transcriptional level. We therefore examined the mRNA expression of lipogenic enzymes in human hepatocellular carcinoma samples from 10 patients who had undergone surgical resection. All of the samples exhibited marked elevation of expression of mRNA for lipogenic enzymes, such as fatty acid synthase, acetyl-CoA carboxylase and ATP citrate lyase, compared with surrounding non-cancerous liver tissue. In contrast, the changes in mRNA expression of SREBP-1, a transcription factor that regulates a battery of lipogenic enzymes, did not show a consistent trend. In some cases where SREBP-1 was elevated, the main contributing isoform was SREBP-1c rather than SREBP-1a. Thus, lipogenic enzymes are markedly induced in hepatocellular carcinomas, and in some cases SREBP-1c is involved in this activation.

  9. Cutaneous features seen in primary liver cell (Hepatocellular ...

    African Journals Online (AJOL)

    Primary liver cell carcinoma (PLCC), predominantly hepatocellular carcinoma is a killer. In the southwestern region of Nigeria it occupies the second position, behind prostate cancer in males. Females account for about a third of diagnosed cases. Children are not spared. Over 80 % of PLCC cases present to the hospital at ...

  10. Chemopreventive effect of corosolic acid in human hepatocellular ...

    African Journals Online (AJOL)

    Anticancer effects of corosolic acid have been demonstrated earlier in human cervix adenocarcinoma and osteosarcoma cells, but the exact underlying molecular mechanisms have not been studied. Hence, an attempt was made to identify the anticancer mechanism of corosolic acid in human hepatocellular carcinoma cells ...

  11. Chronic hepatitis C presenting with a diagnosis of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Hallager, Sofie; Weis, Nina

    2014-01-01

    Chronic hepatitis C (CHC) affects around 16,000 individuals in Denmark of whom about 50% are diagnosed. In the presence of CHC and cirrhosis the annual risk of hepatocellular carcinoma (HCC) is 1-5%. We report on two patients who presented with disseminated HCC at the time of CHC diagnosis...

  12. Chronic Liver Disease and the Detection of Hepatocellular Carcinoma by [18F]fluorocholine PET/CT

    Directory of Open Access Journals (Sweden)

    Sandi A. Kwee

    2015-05-01

    Full Text Available Positron emission tomography (PET using the radiopharmaceutical tracer fluorine-18 fluorocholine (FCh can elucidate tumors based on differences in choline phospholipid metabolism between tumor and surrounding tissue. The feasibility of detecting hepatocellular carcinoma (HCC using FCh PET has been shown despite constitutively high parenchymal choline metabolism in the liver. Since HCC frequently develops in the setting of chronic liver disease, we comparatively evaluated FCh PET/CT between cirrhotic and non-cirrhotic patients with HCC to investigate the effects of hepatic dysfunction on tumor detection and the tumor-to-background ratio (TBR of FCh uptake. FCh PET/CT was performed prospectively in 22 consecutive patients with HCC (7 newly diagnosed, 15 previously treated. Of these 22 patients, 14 were cirrhotic and 8 non-cirrhotic. Standardized uptake value (SUV measurements were obtained by region of interest analysis of the PET images. Tumor FCh uptake and the TBR were compared between cirrhotic and non-cirrhotic patients. Liver lesions were confirmed to be HCC by biopsy in 10 patients and by Barcelona criteria in 4 patients. There was correspondingly increased liver tumor FCh uptake in 13/14 of those patients, and iso-intense tumor FCh uptake (TBR 0.94 in one non-cirrhotic patient with newly diagnosed HCC. FCh PET/CT also showed metastatic disease without local tumor recurrence in 2 previously treated patients, and was negative in 6 treated patients without tumor recurrence by radiographic and clinical follow-up. Tumor maximum SUV ranged from 6.4 to 15.3 (mean 12.1 and liver TBR ranged from 0.94 to 2.1 (mean 1.6, with no significant differences between cirrhotic and non-cirrhotic patients (SUVmax 11.9 vs. 12.2, p = 0.83; TBR 1.71 vs. 1.51, p = 0.29. Liver parenchyma mean SUV was significantly lower in cirrhotic patients (6.4 vs. 8.7, p < 0.05. This pilot study supports the general feasibility of HCC detection by FCh PET/CT. However, a broad

  13. Static magnetic field reduced exogenous oligonucleotide uptake by spermatozoa using magnetic nanoparticle gene delivery system

    Science.gov (United States)

    Katebi, Samira; Esmaeili, Abolghasem; Ghaedi, Kamran

    2016-03-01

    Spermatozoa could introduce exogenous oligonucleotides of interest to the oocyte. The most important reason of low efficiency of sperm mediated gene transfer (SMGT) is low uptake of exogenous DNA by spermatozoa. The aim of this study was to evaluate the effects of static magnetic field on exogenous oligonucleotide uptake of spermatozoa using magnetofection method. Magnetic nanoparticles (MNPs) associated with the labeled oligonucleotides were used to increase the efficiency of exogenous oligonucleotide uptake by rooster spermatozoa. We used high-field/high-gradient magnet (NdFeB) to enhance and accelerate exogenous DNA sedimentation at the spermatozoa surface. Flow cytometry analysis was performed to measure viability and percentage of exogenous oligonucleotide uptake by sperm. Flow cytometry analysis showed a significant increase in exogenous oligonucleotide uptake by rooster spermatozoa (Prooster spermatozoa; however unlike others studies, static magnetic field, was not only ineffective to enhance exogenous oligonucleotide uptake by rooster spermatozoa but also led to reduction in efficiency of magnetic nanoparticles in gene transfer.

  14. Screening for hepatocellular carcinoma by Egyptian physicians

    Institute of Scientific and Technical Information of China (English)

    Sahar; M; Hassany; Ehab; F; Abdou; Moustafa; Mohamed; El; Taher; Afaf; Adel; Abdeltwab; Hubert; E; Blum

    2015-01-01

    AIM: To assess the practice of Egyptian physicians in screening patients for hepatocellular carcinoma(HCC). METHODS: The study included 154 physicians from all over Egypt caring for patients at risk for HCC. The study was based on a questionnaire with 20 items. Each questionnaire consisted of two parts:(1) personal information regarding the physician(name, age, specialty and type of health care setting); and(2) professional experience in the care of patients at risk for HCC development(screening, knowledge about the cause and natural course of liver diseases and HCC risk). RESULTS: Sixty-eight percent of doctors with an MD degree, 48% of doctors with a master degree or a diploma and 40% of doctors with a Bachelor of Medicine, Bachelor of Surgery certificate considered the hepatitis C virus(HCV) genotype as risk factor for HCC development(P < 0.05). Ninety percent of physicians specialized in tropical medicine, internal medicine or gastroenterology and 67% of physicians in other specialties advise patients to undergo screening for HCV and hepatitis B virus infection as well as liver cirrhosis(P < 0.05). Eighty-six percent of doctors in University Hospitals and 69% of Ministry of Health(MOH) doctors consider HCV infection as the leading cause of HCC in Egypt(P < 0.05). Seventy-two percent of doctors with an MD degree, 55% of doctors with a master degree or a diploma, 56% of doctors with an MBBCH certificate, 74% of doctors in University Hospitals and 46% of MOH hospital doctors consider abdominal ultrasonography as the most important investigation in HCC screening(P < 0.05). Sixty-five percent of physicians in tropical medicine, internal medicine or gastroenterology and 37% of physicians in other specialties recommend as HCC screening interval of 3 mo(P < 0.05). Seventy-one percent of doctors with an MD degree, 50% of doctors with a master degree or diploma and 60% of doctors with an MBBCH certificate follow the same recommendation.CONCLUSION: In Egypt, physicians

  15. Uptake of magnetic nanoparticles into cells for cell tracking

    International Nuclear Information System (INIS)

    Becker, Christiane; Hodenius, Michael; Blendinger, Gitta; Sechi, Antonio; Hieronymus, Thomas; Mueller-Schulte, Detlef; Schmitz-Rode, Thomas; Zenke, Martin

    2007-01-01

    A challenge for future applications in nanotechnology is the functional integration of nano-sized materials into cellular structures. Here we investigated superparamagnetic Fe 3 O 4 iron oxide nanoparticles coated with a lipid bilayer for uptake into cells and for targeting subcellular compartments. It was found that magnetic nanoparticles (MNPs) are effectively taken up into cells and make cells acquire magnetic activity. Biotin-conjugated MNPs were further functionalized by binding of the fluorescent tag streptavidin-fluorescein isothiocyanate (FITC) and, following uptake into cells, shown to confer magnetic activity and fluorescence labeling. Such FITC-MNPs were localized in the lysosomal compartment of cells which suggests a receptor-mediated uptake mechanism

  16. In vivo prediction of anti-tumor effect of 3-bromopyruvate in hepatocellular carcinoma using Tc-99m labeled annexin-v imaging

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Won; Yoon, Jung Hwan; Kim, Chung Yang [Seoul National University College of Medicine, Seoul (Korea, Republic of); Cheon, Gi Jeoog; Lee, Tae Sup; Woo, Kwang Sun; Chung, Wee Sup [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2005-07-01

    We have recently demonstrated that hypoxia stimulates hepatocellular carcinoma (HCC) cell growth through hexokinase II induction, and its inhibition induces apoptotic cell death through activating mitochondrial apoptotic signaling cascades. In this study, we were apt to evaluate the antitumoral effect of 3-bromopyruvate (3-BP) on in vivo model of HCC by apoptotic imaging using Tc-99m labeled annexin V. In vivo model of HCC was established in C3H mice intradermally implanted with MH134 cells, a mouse HCC cell line, and 3-BP (0, 5, 10 mg/kg) was subsequently administered intraperitoneally. Tc-99m-HYNIC-annexin V (185 KBq) was injected via tail vein at one and three days after the 3-BP treatment, planar scan was acquired at a hour after the injection using gamma camera. The anti-tumor effect was evaluated by measuring tumor volumes and quantification of apoptotic cells using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Tumor volume was significantly reduced in mice treated with 3-BP in a dose-dependent manner (mean tumor volume 1.07 vs. 0.58 vs. 0.39 cm{sup 3} in 3-BP 0, 5, 10 mg/kg, respectively: p=0.047). The percentage of TUNEL staining-positive cells was significantly increased in 3-BP-treated mice (0.53 vs. 1.40 vs. 1.84% in 3-BP 0, 5, 10 mg/kg, respectively; p=0.018). On Tc-99m-HYNIC annexin V imaging, tumor-to-background uptake ratio (UR) was 1.92 at one day and 4.23 at three days after 3-BP treatment of 5 mg/kg (non-treated tumor showed UR of 2.93). Apoptosis-inducing anti-tumor effect of 3-BP was able to be demonstrated in in vivo model of HCC by apoptotic in vivo imaging using Tc-99m-HYNIC annexin V.

  17. In vivo prediction of anti-tumor effect of 3-bromopyruvate in hepatocellular carcinoma using Tc-99m labeled annexin-v imaging

    International Nuclear Information System (INIS)

    Kim, Won; Yoon, Jung Hwan; Kim, Chung Yang; Cheon, Gi Jeoog; Lee, Tae Sup; Woo, Kwang Sun; Chung, Wee Sup

    2005-01-01

    We have recently demonstrated that hypoxia stimulates hepatocellular carcinoma (HCC) cell growth through hexokinase II induction, and its inhibition induces apoptotic cell death through activating mitochondrial apoptotic signaling cascades. In this study, we were apt to evaluate the antitumoral effect of 3-bromopyruvate (3-BP) on in vivo model of HCC by apoptotic imaging using Tc-99m labeled annexin V. In vivo model of HCC was established in C3H mice intradermally implanted with MH134 cells, a mouse HCC cell line, and 3-BP (0, 5, 10 mg/kg) was subsequently administered intraperitoneally. Tc-99m-HYNIC-annexin V (185 KBq) was injected via tail vein at one and three days after the 3-BP treatment, planar scan was acquired at a hour after the injection using gamma camera. The anti-tumor effect was evaluated by measuring tumor volumes and quantification of apoptotic cells using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Tumor volume was significantly reduced in mice treated with 3-BP in a dose-dependent manner (mean tumor volume 1.07 vs. 0.58 vs. 0.39 cm 3 in 3-BP 0, 5, 10 mg/kg, respectively: p=0.047). The percentage of TUNEL staining-positive cells was significantly increased in 3-BP-treated mice (0.53 vs. 1.40 vs. 1.84% in 3-BP 0, 5, 10 mg/kg, respectively; p=0.018). On Tc-99m-HYNIC annexin V imaging, tumor-to-background uptake ratio (UR) was 1.92 at one day and 4.23 at three days after 3-BP treatment of 5 mg/kg (non-treated tumor showed UR of 2.93). Apoptosis-inducing anti-tumor effect of 3-BP was able to be demonstrated in in vivo model of HCC by apoptotic in vivo imaging using Tc-99m-HYNIC annexin V

  18. Static magnetic field reduced exogenous oligonucleotide uptake by spermatozoa using magnetic nanoparticle gene delivery system

    International Nuclear Information System (INIS)

    Katebi, Samira; Esmaeili, Abolghasem; Ghaedi, Kamran

    2016-01-01

    Spermatozoa could introduce exogenous oligonucleotides of interest to the oocyte. The most important reason of low efficiency of sperm mediated gene transfer (SMGT) is low uptake of exogenous DNA by spermatozoa. The aim of this study was to evaluate the effects of static magnetic field on exogenous oligonucleotide uptake of spermatozoa using magnetofection method. Magnetic nanoparticles (MNPs) associated with the labeled oligonucleotides were used to increase the efficiency of exogenous oligonucleotide uptake by rooster spermatozoa. We used high-field/high-gradient magnet (NdFeB) to enhance and accelerate exogenous DNA sedimentation at the spermatozoa surface. Flow cytometry analysis was performed to measure viability and percentage of exogenous oligonucleotide uptake by sperm. Flow cytometry analysis showed a significant increase in exogenous oligonucleotide uptake by rooster spermatozoa (P<0.001) when spermatozoa were incubated in exogenous oligonucleotide solution and MNPs. However, by applying static magnetic field during magnetofection method, a significant decrease in exogenous oligonucleotide uptake was observed (P<0.05). Findings of this study showed that MNPs were effective to increase exogenous oligonucleotide uptake by rooster spermatozoa; however unlike others studies, static magnetic field, was not only ineffective to enhance exogenous oligonucleotide uptake by rooster spermatozoa but also led to reduction in efficiency of magnetic nanoparticles in gene transfer. - Highlights: • Core/shell type Iron oxide nanoparticles were used as a novel and efficient method. • This method increases exogenous DNA uptake by rooster spermatozoa. • Static magnetic field decreased DNA uptake by rooster spermatozoa.

  19. Static magnetic field reduced exogenous oligonucleotide uptake by spermatozoa using magnetic nanoparticle gene delivery system

    Energy Technology Data Exchange (ETDEWEB)

    Katebi, Samira; Esmaeili, Abolghasem, E-mail: aesmaeili@sci.ui.ac.ir; Ghaedi, Kamran

    2016-03-15

    Spermatozoa could introduce exogenous oligonucleotides of interest to the oocyte. The most important reason of low efficiency of sperm mediated gene transfer (SMGT) is low uptake of exogenous DNA by spermatozoa. The aim of this study was to evaluate the effects of static magnetic field on exogenous oligonucleotide uptake of spermatozoa using magnetofection method. Magnetic nanoparticles (MNPs) associated with the labeled oligonucleotides were used to increase the efficiency of exogenous oligonucleotide uptake by rooster spermatozoa. We used high-field/high-gradient magnet (NdFeB) to enhance and accelerate exogenous DNA sedimentation at the spermatozoa surface. Flow cytometry analysis was performed to measure viability and percentage of exogenous oligonucleotide uptake by sperm. Flow cytometry analysis showed a significant increase in exogenous oligonucleotide uptake by rooster spermatozoa (P<0.001) when spermatozoa were incubated in exogenous oligonucleotide solution and MNPs. However, by applying static magnetic field during magnetofection method, a significant decrease in exogenous oligonucleotide uptake was observed (P<0.05). Findings of this study showed that MNPs were effective to increase exogenous oligonucleotide uptake by rooster spermatozoa; however unlike others studies, static magnetic field, was not only ineffective to enhance exogenous oligonucleotide uptake by rooster spermatozoa but also led to reduction in efficiency of magnetic nanoparticles in gene transfer. - Highlights: • Core/shell type Iron oxide nanoparticles were used as a novel and efficient method. • This method increases exogenous DNA uptake by rooster spermatozoa. • Static magnetic field decreased DNA uptake by rooster spermatozoa.

  20. Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma.

    Science.gov (United States)

    Ishizawa, Takeaki; Masuda, Koichi; Urano, Yasuteru; Kawaguchi, Yoshikuni; Satou, Shouichi; Kaneko, Junichi; Hasegawa, Kiyoshi; Shibahara, Junji; Fukayama, Masashi; Tsuji, Shingo; Midorikawa, Yutaka; Aburatani, Hiroyuki; Kokudo, Norihiro

    2014-02-01

    Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear. In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence). ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence. Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.

  1. Technetium uptake by Sinapis Alba

    International Nuclear Information System (INIS)

    Mueller, H.; Ter Meer-Bekk, Ch.

    1986-01-01

    Transfer factors for pertechnetate uptake was determined for Sinapis Alba cultured hydroponically. For the freshly harvested, undried plants transfer factors were found between 13 and 40 depending on the growth period. (author)

  2. Thallium-201 chloride per-rectal scintigraphy in primary hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Tonami, Norihisa; Nakajima, Kenichi; Hisada, Kinichi; Matsui, Osamu; Kadoya, Masumi; Takashima, Tsutomu

    1985-10-01

    The results of Thallium-201(Tl-201) per-rectal scintigraphy in 10 patients with primary hepatocellular carcinoma(HCC) were presented with other clinical findings of contrast hepatic angiography, computed tomography and ultrasonography. Tl-201 accumulation within the tumor was seen in 7 of 10 patients. This accumulation was thought to be due to Tl-201 supply not from the portal vein but from the hepatic artery since significant high heart to liver uptake ratio(H/L) from 0.71 to 1.21(mean 0.95) was observed. Clear visualization of the heart and kidneys indicated the presence of abundant portal-to-systemic shunting. Other 3 patients showed negative Tl-201 accumulation within the tumor and near-normal H/L from 0.32 to 0.47(mean 0.37)which indicates a little portal-to-systemic shunting. This finding reveals the evidence of the lack of Tl-201 supply to the tumor from the portal vein. The results support the idea that HCC does not receive any significant amount of blood flow from the portal system.

  3. Galactosylated nanostructured lipid carriers for delivery of 5-FU to hepatocellular carcinoma.

    Science.gov (United States)

    Varshosaz, Jaleh; Hassanzadeh, Farshid; Sadeghi, Hojjat; Khadem, Mostafa

    2012-09-01

    The aim of the present study was to design a targeted delivery system of 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). Lactobionic acid (LB) was conjugated to stearyl amine (SA) by a chemical reaction. The nanostructured lipid carriers (NLCs), containing LB conjugate, lecithin, glyceryl monostearate, oil [oleic acid (OA) or Labrafac 5 or 10%], and 5-FU, were dissolved in alcohol/acetone, the oil phase was added to the aqueous phase containing Tween 80 or Solutol(®) HS15 (0.25 or 0.5%), and NLCs were prepared by an emulsification-solvent diffusion method. Physical properties and drug release were studied in NLCs. The thiazolyl blue tetrazolium bromide assay was used to study the cytotoxicity of NLCs on HepG(2) cells, and the cellular uptake of NLCs was determined by flow cytometry. Fourier transform infrared spectroscopy and (1)H-NMR spectra confirmed the successful conjugation of LB and SA. The optimized NLCs consisted of 0.5% Solutol HS15 and 10% OA oil. The particle size of these nanoparticles was 139.2 nm, with a zeta potential of -18 mV, loading efficiency of 34.2%, release efficiency after 2 hours of the release test was 72.6%, and crystallinity was 0.63%. The galactosylated NLCs of 5-FU were cytotoxic on the HepG(2) cell line in a half concentration of 5-FU and seems promising in reducing 5-FU dose in HCC.

  4. Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma.

    Science.gov (United States)

    Malarvizhi, Giridharan Loghanathan; Retnakumari, Archana Payickattu; Nair, Shantikumar; Koyakutty, Manzoor

    2014-11-01

    Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer. Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Oldenlandia diffusa Promotes Antiproliferative and Apoptotic Effects in a Rat Hepatocellular Carcinoma with Liver Cirrhosis

    Directory of Open Access Journals (Sweden)

    Yun-Young Sunwoo

    2015-01-01

    Full Text Available Oldenlandia diffusa (OD is commonly used with various diseases such as cancer, arthritis, and autoimmune disease. Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC. Here, we show that the therapeutic effect of OD, which was investigated both in vitro and chemically, induced HCC model. OD significantly enhanced apoptosis and antiproliferative activity and reduced migration ability of HCC cells. In vivo, OD was treated twice a day for 28 days after confirmed HCC model through 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG imaging. The survival in OD treated groups was shown to have a greater therapeutic effect than the control group. 28 days after OD treatment, OD treated groups resulted in a significant reduction in tumor number, size, 18F-FDG uptake, and serum levels such as alanine transaminase, aspartate transaminase, and alkaline phosphate compared to the control group. Also, proliferated cells in tumor sites by OD were reduced compared to the control group. Furthermore, several rats in OD treated group survived over 60 days and liver morphology of these rats showed the difference between tumor mass and normal tissue. These results suggest that OD may have antiproliferative activity, inhibition of metastasis, and apoptotic effects in chemically induced HCC model and can have the potential use for clinical application as anticancer drug of the herbal extract.

  6. BAG3 elevation inhibits cell proliferation via direct interaction with G6PD in hepatocellular carcinomas.

    Science.gov (United States)

    Kong, De-Hui; Li, Si; Du, Zhen-Xian; Liu, Chuan; Liu, Bao-Qin; Li, Chao; Zong, Zhi-Hong; Wang, Hua-Qin

    2016-01-05

    Bcl-2 associated athanogene 3 (BAG3) contains multiple protein-binding motifs to mediate potential interactions with chaperons and/or other proteins, which is possibly ascribed to the multifaceted functions assigned to BAG3. The current study demonstrated that BAG3 directly interacted with glucose 6 phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). BAG3 suppressed the PPP flux, de novo DNA synthesis and cell growth in hepatocellular carcinomas (HCCs). The growth defect of HCCs with forced BAG3 expression can be rescued by enforced G6PD expression. However, BAG3 elevation did not cause a reduction in cellular NADPH concentrations, another main product of G6PD. In addition, supplement of nucleosides alone was sufficient to recover the growth defect mediated by BAG3 elevation. Collectively, the current study established a tumor suppressor-like function of BAG3 via direct interaction with G6PD in HCCs at the cellular level.

  7. Inhibitory effect of recombinant adenovirus carrying immunocaspase-3 on hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaohua [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China); Fan, Rui [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China); Zou, Xue [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China); Gao, Lin [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China); Jin, Haifeng [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China); Du, Rui [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China); Xia, Lin [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China); Fan, Daiming [State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, 17 Changle Western Road, Xi' an 710032 (China)

    2007-06-29

    Previously, Srinivasula devised a contiguous molecule (C-cp-3 or immunocaspase-3) containing the small and large subunits similar to that in the active form of caspas-3 and found C-cp-3 had similar cleavage activity to the active form of caspase-3. To search for a new clinical application of C-cp-3 to treat hepatocellular carcinoma, recombinant adenoviruses carrying the C-cp-3 and a-fetoprotein (AFP) promoter (Ad-rAFP-C-cp-3) were constructed through a bacterial homologous recombinant system. The efficiency of adenovirus-mediated gene transfer and the inhibitory effect of Ad-rAFP-C-cp-3 on the proliferation of hepatocarcinoma cells were determined by X-gal stain and MTT assay, respectively. The tumorigenicity of hepatocarcinoma cells transfected by Ad-rAFP-C-cp-3 and the antitumor effect of Ad-rAFP-C-cp-3 on transplanted tumor in nude mice were detected in vivo. The results suggested that Ad-rAFP-C-cp-3 can inhibit specifically proliferation of AFP-producing human hepatocarcinoma cells in vitro and in vivo and adenovirus-mediated C-cp-3 transfer could be used as a new method to treat human hepatocarcinoma.

  8. Inhibitory effect of recombinant adenovirus carrying immunocaspase-3 on hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Li, Xiaohua; Fan, Rui; Zou, Xue; Gao, Lin; Jin, Haifeng; Du, Rui; Xia, Lin; Fan, Daiming

    2007-01-01

    Previously, Srinivasula devised a contiguous molecule (C-cp-3 or immunocaspase-3) containing the small and large subunits similar to that in the active form of caspas-3 and found C-cp-3 had similar cleavage activity to the active form of caspase-3. To search for a new clinical application of C-cp-3 to treat hepatocellular carcinoma, recombinant adenoviruses carrying the C-cp-3 and a-fetoprotein (AFP) promoter (Ad-rAFP-C-cp-3) were constructed through a bacterial homologous recombinant system. The efficiency of adenovirus-mediated gene transfer and the inhibitory effect of Ad-rAFP-C-cp-3 on the proliferation of hepatocarcinoma cells were determined by X-gal stain and MTT assay, respectively. The tumorigenicity of hepatocarcinoma cells transfected by Ad-rAFP-C-cp-3 and the antitumor effect of Ad-rAFP-C-cp-3 on transplanted tumor in nude mice were detected in vivo. The results suggested that Ad-rAFP-C-cp-3 can inhibit specifically proliferation of AFP-producing human hepatocarcinoma cells in vitro and in vivo and adenovirus-mediated C-cp-3 transfer could be used as a new method to treat human hepatocarcinoma

  9. Fatty acid uptake in normal human myocardium

    International Nuclear Information System (INIS)

    Vyska, K.; Meyer, W.; Stremmel, W.; Notohamiprodjo, G.; Minami, K.; Machulla, H.J.; Gleichmann, U.; Meyer, H.; Koerfer, R.

    1991-01-01

    Fatty acid binding protein has been found in rat aortic endothelial cell membrane. It has been identified to be a 40-kDa protein that corresponds to a 40-kDa fatty acid binding protein with high affinity for a variety of long chain fatty acids isolated from rat heart myocytes. It is proposed that this endothelial membrane fatty acid binding protein might mediate the myocardial uptake of fatty acids. For evaluation of this hypothesis in vivo, influx kinetics of tracer-labeled fatty acids was examined in 15 normal subjects by scintigraphic techniques. Variation of the plasma fatty acid concentration and plasma perfusion rate has been achieved by modulation of nutrition state and exercise conditions. The clinical results suggest that the myocardial fatty acid influx rate is saturable by increasing fatty acid plasma concentration as well as by increasing plasma flow. For analysis of these data, functional relations describing fatty acid transport from plasma into myocardial tissue in the presence and absence of an unstirred layer were developed. The fitting of these relations to experimental data indicate that the free fatty acid influx into myocardial tissue reveals the criteria of a reaction on a capillary surface in the vicinity of flowing plasma but not of a reaction in extravascular space or in an unstirred layer and that the fatty acid influx into normal myocardium is a saturable process that is characterized by the quantity corresponding to the Michaelis-Menten constant, Km, and the maximal velocity, Vmax, 0.24 ± 0.024 mumol/g and 0.37 ± 0.013 mumol/g(g.min), respectively. These data are compatible with a nondiffusional uptake process mediated by the initial interaction of fatty acids with the 40-kDa membrane fatty acid binding protein of cardiac endothelial cells

  10. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

    Science.gov (United States)

    Wood, Laura D; Heaphy, Christopher M; Daniel, Hubert Darius-J; Naini, Bita V; Lassman, Charles R; Arroyo, May R; Kamel, Ihab R; Cosgrove, David P; Boitnott, John K; Meeker, Alan K; Torbenson, Michael S

    2013-12-01

    Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts--we designate this variant as 'chromophobe hepatocellular carcinoma with abrupt anaplasia'. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P=0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of

  11. A novel role for myosin II in insulin-stimulated glucose uptake in 3T3-L1 adipocytes

    International Nuclear Information System (INIS)

    Steimle, Paul A.; Kent Fulcher, F.; Patel, Yashomati M.

    2005-01-01

    Insulin-stimulated glucose uptake requires the activation of several signaling pathways to mediate the translocation and fusion of GLUT4 vesicles from an intracellular pool to the plasma membrane. The studies presented here show that inhibition of myosin II activity impairs GLUT4-mediated glucose uptake but not GLUT4 translocation to the plasma membrane. We also show that adipocytes express both myosin IIA and IIB isoforms, and that myosin IIA is recruited to the plasma membrane upon insulin stimulation. Taken together, the data presented here represent the first demonstration that GLUT4-mediated glucose uptake is a myosin II-dependent process in adipocytes. Based on our findings, we hypothesize that myosin II is activated upon insulin stimulation and recruited to the cell cortex to facilitate GLUT4 fusion with the plasma membrane. The identification of myosin II as a key component of GLUT4-mediated glucose uptake represents an important advance in our understanding of the mechanisms regulating glucose homeostasis

  12. SERUM LEPTIN LEVENS AND HEPATOCELLULAR CARCINOMA: REVIEW ARTICLE.

    Science.gov (United States)

    Andrighetto, Luiza Vitelo; Poziomyck, Aline Kirjner

    2016-01-01

    Hepatocellular carcinoma is one of the most frequent types of malignant tumors in the world. There is growing evidence of the relationship between it development and obesity. The mechanism that links obesity to cancer is still not fully understood; however, it is essential to the understanding the adipose tissue in metabolic changes related to obesity and hepatocellular carcinoma. To review the influence of serum leptin levels in patients with hepatocelular carcinoma. Systematic review of the literature based on the methodology of the Cochrane Institute. The search for articles was in the database: Science Direct, Scielo, Medline, Lilacs e Pubmed. The key words used were hepatocellular carcinoma, leptin, adipokine. After evaluation of individual studies, were selected seven studies. The results previously studied are still inconsistent and contradictory, and leptin can be effectively involved in the occurrence and development of hepatocellular carcinoma. Therefore, it is necessary to develop prospective, well-designed and conducted focusing on the role and specific mechanisms of this hormone in patients with hepatocellular carcinoma, so that new correlations can be properly supported. O carcinoma hepatocelular é um dos tipos mais frequentes de tumores malignos no mundo. Há crescentes evidências da relação entre o seu desenvolvimento e a obesidade. O mecanismo que os relaciona ainda não é completamente entendido. Entretanto é essencial a compreensão do tecido adiposo nas alterações metabólicas relacionadas à obesidade e ao câncer. Revisar a influência dos níveis séricos de leptina em pacientes com carcinoma hepatocelular. Trata-se de revisão bibliográfica baseada na metodologia do Instituto Cochrane; a busca de dados foi realizada na base de dados Science Direct, Scielo, Medline, Lilacs e Pubmed, empregando as seguintes descritores: hepatocellular carcinoma, leptin, adipokine. Após avaliação individual dos artigos selecionaram-se sete estudos

  13. Accumulation of phenanthrene by roots of intact wheat (Triticum acstivnm L. seedlings: passive or active uptake?

    Directory of Open Access Journals (Sweden)

    Jiang Ting-Hui

    2010-03-01

    Full Text Available Abstract Background Polycyclic aromatic hydrocarbons (PAHs are of particular concern due to their hydrophobic, recalcitrant, persistent, potentially carcinogenic, mutagenic and toxic properties, and their ubiquitous occurrence in the environment. Most of the PAHs in the environment are present in surface soil. Plants grown in PAH-contaminated soils or water can become contaminated with PAHs because of their uptake. Therefore, they may threaten human and animal health. However, the mechanism for PAHs uptake by crop roots is little understood. It is important to understand exactly how PAHs are transported into the plant root system and into the human food chain, since it is beneficial in governing crop contamination by PAHs, remedying soils or waters polluted by PAHs with plants, and modeling potential uptake for risk assessment. Results The possibility that plant roots may take up phenanthrene (PHE, a representative of PAHs, via active process was investigated using intact wheat (Triticum acstivnm L. seedlings in a series of hydroponic experiments. The time course for PHE uptake into wheat roots grown in Hoagland solution containing 5.62 μM PHE for 36 h could be separated into two periods: a fast uptake process during the initial 2 h and a slow uptake component thereafter. Concentration-dependent PHE uptake was characterized by a smooth, saturable curve with an apparent Km of 23.7 μM and a Vmax of 208 nmol g-1 fresh weight h-1, suggesting a carrier-mediated uptake system. Competition between PHE and naphthalene for their uptake by the roots further supported the carrier-mediated uptake system. Low temperature and 2,4-dinitrophenol (DNP could inhibit PHE uptake equally, indicating that metabolism plays a role in PHE uptake. The inhibitions by low temperature and DNP were strengthened with increasing concentration of PHE in external solution within PHE water solubility (7.3 μM. The contribution of active uptake to total absorption was almost 40

  14. Uptake of exogenous spermidine by rat lungs perfused in situ

    International Nuclear Information System (INIS)

    Rannels, D.E.; Addison, J.L.

    1987-01-01

    Uptake of the polyamine spermidine (SPD) from the pulmonary circulation was characterized by using ventilated rat lungs perfused in situ with Krebs-Henseleit-bicarbonate buffer containing 4.5% bovine serum albumin, 5.6 mM glucose, and 20 amino acids at plasma levels. [ 14 C]SPD was accumulated by the lungs in a time- and concentration-dependent manner. The pathway of SPD uptake exhibited saturation kinetics with an apparent K/sub m/ in the range of 1 μM and a V/sub max/ of 450-540 pmol/g lung min. SPD uptake was inhibited by the naturally occurring polyamines putrescine and spermine (SPM) and by the inhibitor of polyamine synthesis, methyglyoxal bis(guanylhydrazone) (MGBG). Inhibition of SPD uptake by SPM followed competitive kinetics; although MGBG was also a competitive inhibitor of SPD uptake, MGBG was less effective than SPM. These observations indicate that SPD is taken up from the pulmonary circulation by a carrier-mediated pathway that is inhibited by other natural polyamines and by MGBG and exhibits by other natural polyamines and by MGBG and exhibits substrate affinity in the range of plasma SPD concentrations

  15. Uptake of exogenous spermidine by rat lungs perfused in situ

    Energy Technology Data Exchange (ETDEWEB)

    Rannels, D.E.; Addison, J.L.

    1987-01-01

    Uptake of the polyamine spermidine (SPD) from the pulmonary circulation was characterized by using ventilated rat lungs perfused in situ with Krebs-Henseleit-bicarbonate buffer containing 4.5% bovine serum albumin, 5.6 mM glucose, and 20 amino acids at plasma levels. (/sup 14/C)SPD was accumulated by the lungs in a time- and concentration-dependent manner. The pathway of SPD uptake exhibited saturation kinetics with an apparent K/sub m/ in the range of 1 ..mu..M and a V/sub max/ of 450-540 pmol/g lung min. SPD uptake was inhibited by the naturally occurring polyamines putrescine and spermine (SPM) and by the inhibitor of polyamine synthesis, methyglyoxal bis(guanylhydrazone) (MGBG). Inhibition of SPD uptake by SPM followed competitive kinetics; although MGBG was also a competitive inhibitor of SPD uptake, MGBG was less effective than SPM. These observations indicate that SPD is taken up from the pulmonary circulation by a carrier-mediated pathway that is inhibited by other natural polyamines and by MGBG and exhibits by other natural polyamines and by MGBG and exhibits substrate affinity in the range of plasma SPD concentrations.

  16. Mediation Analysis with Multiple Mediators.

    Science.gov (United States)

    VanderWeele, T J; Vansteelandt, S

    2014-01-01

    Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects through other pathways. The approaches proposed here accommodate exposure-mediator interactions and, to a certain extent, mediator-mediator interactions as well. The methods handle binary or continuous mediators and binary, continuous or count outcomes. When the mediators affect one another, the strategy of trying to assess direct and indirect effects one mediator at a time will in general fail; the approach given in this paper can still be used. A characterization is moreover given as to when the sum of the mediated effects for multiple mediators considered separately will be equal to the mediated effect of all of the mediators considered jointly. The approach proposed in this paper is robust to unmeasured common causes of two or more mediators.

  17. Uptake and bioaccumulation of Cry toxins by an aphidophagous predator

    International Nuclear Information System (INIS)

    Paula, Débora P.; Andow, David A.

    2016-01-01

    Uptake of Cry toxins by insect natural enemies has rarely been considered and bioaccumulation has not yet been demonstrated. Uptake can be demonstrated by the continued presence of Cry toxin after exposure has stopped and gut contents eliminated. Bioaccumulation can be demonstrated by showing uptake and that the concentration of Cry toxin in the natural enemy exceeds that in its food. We exposed larvae of the aphidophagous predator, Harmonia axyridis, to Cry1Ac and Cry1F through uniform and constant tritrophic exposure via an aphid, Myzus persicae, and looked for toxin presence in the pupae. We repeated the experiment using only Cry1F and tested newly emerged adults. Both Cry toxins were detected in pupae, and Cry1F was detected in recently emerged, unfed adults. Cry1Ac was present 2.05 times and Cry1F 3.09 times higher in predator pupae than in the aphid prey. Uptake and bioaccumulation in the third trophic level might increase the persistence of Cry toxins in the food web and mediate new exposure routes to natural enemies. - Highlights: • Uptake and bioaccumulation of two Cry toxins by a larval coccinellid was tested. • Uptake was demonstrated by presence of the toxins in pupae and adults. • Bioaccumulation was shown by higher toxin concentration in pupae than prey. • Cry1Ac was present 2.05× and Cry1F 3.09× higher in predator pupae than prey. • This might increase persistence of Cry toxins in food webs with new exposure routes. - Immatures of the predaceous coccinellid Harmonia axyridis can uptake and bioaccumulate Cry toxins delivered via their aphid prey.

  18. Combination therapy and evaluation of therapeutic effect in hepatocellular carcinoma cell using triple reporter genes; containing for NIS, HSV1-sr39tk and GFP

    Energy Technology Data Exchange (ETDEWEB)

    Lee, You La; Lee, Yong Jin; Ahn, Sohn Joo; Ahn, Byeong Cheol; Lee, Sang Woo; Yoo, Jeong Soo; Lee, Jae Tae [Kyungpook National University, Daegu (Korea, Republic of)

    2007-07-01

    To identify therapeutic effect after combine Sodium Iodine Symporter (NIS) and Mutant Herpes-simplex virus type 1 sr39tk (HSV1-sr39tk) expression in hepatocellular carcinoma cell, we transfected triple gene and investigated the properties of these gene ability in hepatocellular carcinoma cell line. After making vector with gene encoding a fusion protein comprised of HSV1-sr39tk and green florescence protein (GFP), to make triple reporter genes NIS gene was further fused to the vector using IRES vector. The vector expressing triple reporter gene was transfected to the Huh-7 cell line using liposome. Functions of hNIS and HSV1-sr39tk expression were confirmed by radio iodine uptake with and without perchlorate and [3H]-penciclovir (3-H PCV) uptake, respectively. To evaluate therapeutic effect in vitro, GCV and I-131 was treated in Huh-7/NTG cell and dual therapy performed. An animal imaging acquired using Optix and microPET in vivo. I-125 uptake was increased up to 100-fold compare to that of non-transfected cells. The transfected cell accumulated H-3 PCV up to 53 times higher at 2 hour than that of non-transfected cells. With fluorescence microscopy, green fluorescence was detected in the transfected cell. In cytotoxic studies, the cell viability of Huh-7/NTG cell was decreased to 41 % of control cell at 10ug/ml GCV concentrations. The survival rate of the Huh-7/NTG cell treated with I-131 decreased up to 16%. In I-131 and GCV dual therapy, Huh-7/NTG cell survival rate decreased up to 4%. In animal studies, Huh-7/NTG tumors showed higher uptake of 18F-FHBG and I-124 than Huh-7 tumors. GFP signal is also higher in Huh-7/NTG tumor than control. We successfully constructed a vector with delivery two therapeutic genes and one reporter gene and transfected the vector to a Huh-7 cell. The hepatocellular carcinoma cell transfected with the vector can be treated with GCV and I-131. The effect of dual gene therapy could be easily assessed by the optical reporter gene imaging.

  19. Clinical and laboratory features of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Andrés Cárdenas

    2007-02-01

    Full Text Available

    The clinical presentation of hepatocellular carcinoma (HCC differs between patients in developing countries (African and Chinese populations from those in industrialized countries. In industrialized countries, HCC co-exists with symptomatic cirrhosis in 80% of cases and clinical manifestations are usually related to those of the underlying disease. On the other hand, patients from developing countries have HCC and cirrhosis in approximately 40% of cases. Underlying cirrhosis in many cases is not advanced and does not produce any symptoms or associated symptoms are masked by those of the tumor (right upper quadrant pain, mass in the upper abdomen, weight loss and weakness. In a subset of patients, there are no clinical manifestations as HCC may occur in the context of hepatitis B infection without cirrhosis.

    Clinical Manifestations

    In Western countries, nearly 35% percent of patients with HCC are asymptomatic. Some of the most common clinical manifestations include: abdominal pain (53-58% of patients, especially in epigastrium or right upper quadrant, abdominal mass (30%, weight loss, malaise, anorexia, cachexia, jaundice or fever.

    Physical Exam

    Physical findings vary with the stage of disease. The patient may exhibit slight or moderate wasting when first seen. In patients with cirrhosis, typical stigmata of chronic liver disease may be present. In advanced stages of HCC the liver may be enlarged and there is significant tenderness. An arterial bruit may be heard over the liver

  20. Diagnostic imaging and interventional radiology of hepatocellular carcinoma: A multicenter study on 290 cases

    International Nuclear Information System (INIS)

    Dalla Palma, Ludovico; Puzzi Mucelli, Roberto; Sponza, Massimo; De Santis, Mario; Gandini, Giovanni; Matricardi, Luigi; Rossi, Cristina

    1997-01-01

    The authors report of a multicenter study on the diagnosis and interventional therapy of hepatocellular carcinoma (HCC).The first aim -diagnostic - was to evaluate the sensitivity of 4 imaging techniques, namely ultrasonography (US), Computed Tomography (CT), digital arteriography (DSA) and Lipiodol CT (LCT), in hepatocellular carcinoma detection. The accuracy of these techniques was also investigated in tumor staging, which is important for treatment planning.The second aim - treatment - consisted in assessing the therapeutic efficacy of intraarterial chemoembolization (CEAT) versus percutaneous ethanol injection (PEI) in non advanced hepatocellular carcinoma and of intraarterial chemoembolization versus no treatment (NT) in advanced hepatocellular carcinoma. Treatment efficacy was evaluated with the following randomized protocols

  1. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    International Nuclear Information System (INIS)

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou

    2014-01-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals

  2. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances

    Science.gov (United States)

    Dhanasekaran, Renumathy; Bandoh, Salome; Roberts, Lewis R.

    2016-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development. PMID:27239288

  3. CTP synthase forms the cytoophidium in human hepatocellular carcinoma.

    Science.gov (United States)

    Chang, Chia-Chun; Jeng, Yung-Ming; Peng, Min; Keppeke, Gerson Dierley; Sung, Li-Ying; Liu, Ji-Long

    2017-12-15

    CTP synthase (CTPS) can aggregate into an intracellular macrostructure, the cytoophidium, in various organisms including human cells. Previous studies have shown that assembly of human CTPS cytoophidia may be correlated with the cellular metabolic status, and is able to promote the activity of CTPS. A correlation between the cytoophidium and cancer metabolism has been proposed but not yet been revealed. In the current study we provide clear evidence of the presence of CTPS cytoophidia in various human cancers and some non-cancerous tissues. Moreover, among 203 tissue samples of hepatocellular carcinoma, 56 (28%) samples exhibited many cytoophidia, whereas no cytoophidia were detected in adjacent non-cancerous hepatocytes for all samples. Our findings suggest that the CTPS cytoophidium may participate in the adaptive metabolism of human hepatocellular carcinoma. Copyright © 2017. Published by Elsevier Inc.

  4. Hepatocellular carcinoma: Implications for Asia-Pacific Oncology Nurses

    Directory of Open Access Journals (Sweden)

    Deborah A Boyle

    2017-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a prominent malignancy in the Asia-Pacific region. Despite considerable knowledge about it's scope and nature this malignancy remains incurable. This manuscript reviews the epidemiology of this cancer, its pathogenesis, risk factors, potential prevention, surveillance, treatment, and the oncology nurses' role relative to this malignancy. A literature search from the past decade was performed using the PubMed and CINAHL databases using the search terms “hepatocellular carcinoma,” “Asia,” and “nursing issues”. Themes such as etiology, prevention, treatment, and prognosis were included in this synthesis which has particular relevance to oncology nurses within the Asia-Pacific region.

  5. Serological diagnosis of hepatocellular carcinoma: challenges and opportunities

    Directory of Open Access Journals (Sweden)

    LU Fengmin

    2017-07-01

    Full Text Available Serological markers have the features of noninvasiveness and simple operation and thus have become a research hotspot in the diagnosis of hepatocellular carcinoma. This article briefly introduces the role of the conventional serological marker alpha-fetoprotein (AFP in assisting the diagnosis and predicting the prognosis of HBV-related liver cancer, as well as the clinical value of new markers such as alpha-fetoprotein-L3 and abnormal prothrombin/des-γ-carboxy prothrombin. Based on literature review, the possibility of serum Golgi protein 73 used for laboratory auxiliary diagnosis of hepatocellular carcinoma has been denied. The results of the author′s experiment suggest that serum GP73 measurement can be used as a laboratory diagnostic index for progressive liver fibrosis and liver cirrhosis.

  6. Efficacy of intrahepatic absolute alcohol in unrespectable hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Farooqi, J.I.; Hameed, K.; Khan, I.U.; Shah, S.

    2001-01-01

    To determine efficacy of intrahepatic absolute alcohol injection in researchable hepatocellular carcinoma. A randomized, controlled, experimental and interventional clinical trial. Gastroenterology Department, PGMI, Hayatabad Medical Complex, Peshawar during the period from June, 1998 to June, 2000. Thirty patients were treated by percutaneous, intrahepatic absolute alcohol injection sin repeated sessions, 33 patients were not given or treated with alcohol to serve as control. Both the groups were comparable for age, sex and other baseline characteristics. Absolute alcohol therapy significantly improved quality of life of patients, reduced the tumor size and mortality as well as showed significantly better results regarding survival (P< 0.05) than the patients of control group. We conclude that absolute alcohol is a beneficial and safe palliative treatment measure in advanced hepatocellular carcinoma (HCC). (author)

  7. Case report combined hepatocellular and cholangiocarcinoma with sarcomatous transformation.

    Science.gov (United States)

    Boonsakan, Paisarn; Thangnapakorn, Orathai; Tapaneeyakorn, Jiemjit; Kositchaiwat, Sawit; Bunyaratvej, Sukhum

    2007-03-01

    Combined hepatocellular and cholangiocarcinoma with sarcomatous transformation was first recognized in Ramathibodi Hospital in 2005. This variant of carcinoma has been increasingly reported particularly from Asian countries. Dedifferentiation of the epithelial component to various sarcomatous components is likely the underlying mechanism. The causative factors of hepatocarcinogenesis in Thailand include chronic viral hepatitis B or C, exposures to aflatoxin B1 and nitrosamine(s) and occasionally some certain nodular hepatocellular lesions due to arterial hyperperfusion. It is suggested that the recent change of the Thai peoples' life style to an increased consumption of fast foods containing food preservatives especially nitrate or nitrite, the nitrosamine precursor may allow heavy exposure(s) to the chemical carcinogen(s) i.e. nitrosamine(s) leading to sarcomatous transformation of the carcinoma.

  8. Cerebrovascular accidents associated with sorafenib in hepatocellular carcinoma.

    Science.gov (United States)

    Saif, Muhammad W; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N

    2011-01-01

    Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered.

  9. Simple Sugar Intake and Hepatocellular Carcinoma: Epidemiological and Mechanistic Insight

    Directory of Open Access Journals (Sweden)

    Juan Carlos Laguna

    2014-12-01

    Full Text Available Sugar intake has dramatically increased during the last few decades. Specifically, there has been a clear trend towards higher consumption of fructose and high fructose corn syrup, which are the most common added sugars in processed food, soft drinks and other sweetened beverages. Although still controversial, this rising trend in simple sugar consumption has been positively associated with weight gain and obesity, insulin resistance and type 2 diabetes mellitus and non-alcoholic fatty liver disease. Interestingly, all of these metabolic alterations have also been related to the development of hepatocellular carcinoma. The purpose of this review is to discuss the evidence coming from epidemiological studies and data from animal models relating the consumption of simple sugars, and specifically fructose, with an increased risk of hepatocellular carcinoma and to gain insight into the putative molecular mechanisms involved.

  10. Diaphragmatic Hernia After Radiofrequency Ablation for Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Yamagami, Takuji; Yoshimatsu, Rika; Matsushima, Shigenori; Tanaka, Osamu; Miura, Hiroshi; Nishimura, Tsunehiko

    2011-01-01

    We describe a 71-year-old woman with a hepatocellular carcinoma who underwent percutaneous radiofrequency ablation (RF) with a single internally cooled electrode under computed tomography (CT) fluoroscopic guidance. Nine months after the procedure, CT images showed herniation of the large intestine into the right pleural cavity. To our knowledge this complication of RF performed with a single internally cooled electrode under CT guidance has not been previously reported.

  11. The Multifaceted Role of Podoplanin Expression in Hepatocellular Carcinoma

    OpenAIRE

    Cioca, Andreea; Ceausu, Amalia R.; Marin, Irina; Raica, Marius; Cimpean, Anca Maria

    2017-01-01

    The role of podoplanin in hepatocellular carcinoma (HCC) is not clear yet. The aim of our study was to evaluate the expression of podoplanin in HCC and to determine its role in hepatocarcinogenesis. We performed immunohistochemistry with monoclonal D2-40 antibody, on paraffin-embedded tissue sections of 72 patients diagnosed with HCC. Lymphatic vessels density (LVD) was increased in patients who had vascular invasion at the time of diagnosis (P=0.018) and in those with associated cirrhosis (P...

  12. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

    OpenAIRE

    Roomi, M. Waheed; Roomi, Nusrath W.; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2012-01-01

    The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the e...

  13. Dose response relationship in local radiotherapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Park, Hee Chul; Seong, Jin Sil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Song, Jae Seok; Suh, Chang Ok

    2001-01-01

    In this study, it was investigated whether dose response relation existed or not in local radiotherapy for primary hepatocellular carcinoma. From January 1992 to March 2000, 158 patients were included in present study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child's class C, tumors occupying more than two thirds of the entire liver, and performance status on the ECOG scale of more than 3. Radiotherapy was given to the field including tumor with generous margin using 6, 10-MV X-ray. Mean tumor dose was 48.2±7.9 Gy in daily 1.8 Gy fractions. Tumor response was based on diagnostic radiologic examinations such as CT scan, MR imaging, hepatic artery angiography at 4-8 weeks following completion of treatment. Statistical analysis was done to investigate the existence of dose response relationship of local radiotherapy when it was applied to the treatment of primary hepatocellular carcinoma. An objective response was observed in 106 of 158 patients, giving a response rate of 67. 1%. Statistical analysis revealed that total dose was the most significant factor in relation to tumor response when local radiotherapy was applied to the treatment of primary hepatocellular carcinoma. Only 29.2% showed objective response in patients treated with dose less than 40 Gy, while 68.6% and 77.1 % showed major response in patients with 40-50 Gy and more than 50 Gy, respectively. Child-Pugh classification was significant factor in the development of ascites, overt radiation induced liver disease and gastroenteritis. Radiation dose was an important factor for development of radiation induced gastroduodenal ulcer. Present study showed the existence of dose response relationship in local radiotherapy for primary hepatocellular carcinoma. Only radiotherapy dose was a significant factor to predict the objective response. Further study is required to predict the maximal tolerance dose in consideration of liver function and non-irradiated liver

  14. N-linked glycosylation at Asn152 on CD147 affects protein folding and stability: promoting tumour metastasis in hepatocellular carcinoma.

    Science.gov (United States)

    Li, Jiang-Hua; Huang, Wan; Lin, Peng; Wu, Bo; Fu, Zhi-Guang; Shen, Hao-Miao; Jing, Lin; Liu, Zhen-Yu; Zhou, Yang; Meng, Yao; Xu, Bao-Qing; Chen, Zhi-Nan; Jiang, Jian-Li

    2016-11-21

    Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer, is a transmembrane glycoprotein that mediates oncogenic processes partly through N-glycosylation modifications. N-glycosylation has been demonstrated to be instrumental for the regulation of CD147 function during malignant transformation. However, the role that site-specific glycosylation of CD147 plays in its defective function in hepatocellular carcinomacells needs to be determined. Here, we demonstrate that the modification of N-glycosylation at Asn152 on CD147 strongly promotes hepatocellular carcinoma (HCC) invasion and migration. After the removal of N-glycans at Asn152, CD147 was more susceptible to degradation by ER-localized ubiquitin ligase-mediated endoplasmic reticulum-associated degradation (ERAD). Furthermore, N-linked glycans at Asn152 were required for CD147 to acquire and maintain proper folding in the ER. Moreover, N-linked glycans at Asn152 functioned as a recognition motif that was directly mediated by the CNX quality control system. Two phases in the retention-based ER chaperones system drove ER-localized CD147 trafficking to degradation. Deletion of N-linked glycosylation at Asn152 on CD147 significantly suppressed in situ tumour metastasis. These data could potentially shed light on the molecular regulation of CD147 through glycosylation and provide a valuable means of developing drugs that target N-glycans at Asn152 on CD147.

  15. Root uptake of transuranic elements

    International Nuclear Information System (INIS)

    Schulz, R.K.

    1977-01-01

    The uptake of elements by plant roots is one of the important pathways of entry of many elements into the food chain of man. Data are cited showing plutonium concentration ratios, plant/soil, ranging from 10 -10 to 10 -3 . Concentration ratios for americium range from 10 -7 to 10 +1 . Limited experiments with curium and neptunium indicate that root uptake of curium is similar to that of americium and that plant uptake of neptunium is substantially larger than that of curium and americium. The extreme ranges of concentration ratios cited for plutonium and americium are due to a number of causes. Experimental conditions such as very intensive cropping will lead to abnormally high concentration ratios. In some experiments, addition of chelating agents markedly increased plant root uptake of transuranic elements. Particle size and composition of the source material influenced uptake of the transuranics by plants. Translocation within the plant, and soil factors such as pH and organic matter content, all affect concentration ratios

  16. Radiofrequency ablation of hepatocellular carcinoma: Mono or multipolar?

    Science.gov (United States)

    Cartier, Victoire; Boursier, Jérôme; Lebigot, Jérôme; Oberti, Frédéric; Fouchard-Hubert, Isabelle; Aubé, Christophe

    2016-03-01

    Thermo-ablation by radiofrequency is recognized as a curative treatment for early-stage hepatocellular carcinoma. However, local recurrence may occur because of incomplete peripheral tumor destruction. Multipolar radiofrequency has been developed to increase the size of the maximal ablation zone. We aimed to compare the efficacy of monopolar and multipolar radiofrequency for the treatment of hepatocellular carcinoma and determine factors predicting failure. A total of 171 consecutive patients with 214 hepatocellular carcinomas were retrospectively included. One hundred fifty-eight tumors were treated with an expandable monopolar electrode and 56 with a multipolar technique using several linear bipolar electrodes. Imaging studies at 6 weeks after treatment, then every 3 months, assessed local effectiveness. Radiofrequency failure was defined as persistent residual tumor after two sessions (primary radiofrequency failure) or local tumor recurrence during follow-up. This study received institutional review board approval (number 2014/77). Imaging showed complete tumor ablation in 207 of 214 lesions after the first session of radiofrequency. After a second session, only two cases of residual viable tumor were observed. During follow-up, there were 46 local tumor recurrences. Thus, radiofrequency failure occurred in 48/214 (22.4%) cases. By multivariate analysis, technique (P radiofrequency failure. Failure rate was lower with the multipolar technique for tumors radiofrequency, multipolar radiofrequency improves tumor ablation with a subsequent lower rate of local tumor recurrence. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  17. Methyleugenol hepatocellular cancer initiating effects in rat liver.

    Science.gov (United States)

    Williams, Gary M; Iatropoulos, Michael J; Jeffrey, Alan M; Duan, Jian-Dong

    2013-03-01

    Methyleugenol (MEG), a constituent of plants used in the human diet, is hepatocarcinogenic in rodents. In an experiment to elucidate its mode of action in rat liver, male F344 rats were administered MEG intragastrically at 3 doses per week for up to 16 weeks in an initiation phase, after which half the rats were fed 500 ppm phenobarbital (PB) in the diet to promote liver neoplasia and the other half were maintained on control diet for 24 weeks. At 8 and 16 week interim terminations, (32)P-nucleotide postlabeling assay revealed 3 adducts in livers of all MEG groups. The hepatocellular replicating fractions, measured by proliferating cell nuclear antigen immunohistochemistry, were doubled or more in all MEG groups. Hepatocellular altered foci, detected by glutathione S-transferase-placental type (π) immunohistochemistry, were present beginning with the high dose group at 8 weeks and extending to all MEG groups at 16 weeks. At the end of maintenance/promotion phase, the incidences, multiplicity and size of foci was similar between control and low dose groups, while those of mid and high dose groups were increased. Hepatocellular adenomas occurred in the mid and high dose groups, attaining higher multiplicity and size with PB. Thus, MEG had rapid initiating activity, reflecting the formation of DNA adducts and possibly cell proliferation. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Hepatocellular carcinoma: computed tomography assessment after invasive treatment

    International Nuclear Information System (INIS)

    Kozima, Shigeru; Larranaga, Nebil; Wulfson, Gabriela; Eisele, Guillermo; Ridruejo, Ezequiel; Mando, Oscar; Perazzo, Florencia

    2008-01-01

    Objective: To show the computed tomography (CT) usefulness after treatment with transcatheter arterial quimioembolization and radiofrequency ablation of hepatocellular carcinoma. Material and methods: In a period between march 2006 to april 2008 a total of 90 patient presenting 148 nodular lesions with diagnosis of hepatocellular carcinoma were controlled with triphasic CT. All the lesions were treated with minimally invasive procedure. For the treatment, the patients were classified in two groups following Milan criteria. The first group, constituted by 75 patients with 109 nodules, was treated with quimioembolization. The second group, of 15 patients with 25 nodules, was treated with radiofrequency ablation. In our population, a subgroup of 10 patients was treated with both methods. Results: Of 90 patients after CT control on a month, 3 months and for each 3 months during 2 years, on 63 cases (70%) was observed homogeneous accumulation of iodized oil, partial defect without enhancement or absence of enhancement on treated lesions. In these patients a new treatment after initial one was not performed. The remaining 27 patients (30%) underwent new treatment because we founded partial defect or absence of iodized oil with enhancement or peripheral enhancement on arterial phase in treated lesions. In this last group, 16 treated patients (17.7%) had new nodular enhancement on the remaining hepatic parenquimal. Conclusion: The CT unenhanced and the arterial phase on a month and for each 3 months, allow monitoring the effectiveness, residual disease and/or relapse of hepatocellular carcinoma after minimally invasive treatment. (authors) [es

  19. Relevance of Peptide Uptake Systems to the Physiology and Virulence of Streptococcus agalactiae

    OpenAIRE

    Samen, Ulrike; Gottschalk, Birgit; Eikmanns, Bernhard J.; Reinscheid, Dieter J.

    2004-01-01

    Streptococcus agalactiae is a major cause of invasive infections in human newborns. To satisfy its growth requirements, S. agalactiae takes up 9 of the 20 proteinogenic amino acids from the environment. Defined S. agalactiae mutants in one or several of four putative peptide permease systems were constructed and tested for peptide uptake, growth in various media, and expression of virulence traits. Oligopeptide uptake by S. agalactiae was shown to be mediated by the ABC transporter OppA1-F, w...

  20. Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle

    DEFF Research Database (Denmark)

    Deshmukh, Atul S

    2016-01-01

    transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type...... 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle....

  1. Cellular uptake of nanoparticles as determined by particle properties, experimental conditions, and cell type.

    Science.gov (United States)

    Kettler, Katja; Veltman, Karin; van de Meent, Dik; van Wezel, Annemarie; Hendriks, A Jan

    2014-03-01

    The increased application of nanoparticles (NPs) is increasing the risk of their release into the environment. Although many toxicity studies have been conducted, the environmental risk is difficult to estimate, because uptake mechanisms are often not determined in toxicity studies. In the present study, the authors review dominant uptake mechanisms of NPs in cells, as well as the effect of NP properties, experimental conditions, and cell type on NP uptake. Knowledge of NP uptake is crucial for risk assessment and is essential to predict the behavior of NPs based on their physical-chemical properties. Important uptake mechanisms for eukaryotic cells are macropinocytosis, receptor-mediated endocytosis, and phagocytosis in specialized mammalian cells. The studies reviewed demonstrate that uptake into nonphagocytic cells depends strongly on NP size, with an uptake optimum at an NP diameter of approximately 50 nm. Increasing surface charges, either positive or negative, have been shown to increase particle uptake in comparison with uncharged NPs. Another important factor is the degree of (homo-) aggregation. Results regarding shape have been ambiguous. Difficulties in the production of NPs, with 1 property changed at a time, call for a full characterization of NP properties. Only then will it be possible to draw conclusions as to which property affected the uptake. © 2013 SETAC.

  2. Hepatitis infections, aflatoxin and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Pierre Hainaut

    2007-02-01

    Full Text Available

    The incidence rates of hepatocellular carcinoma (HCC show large geographic variations, globally reflecting the prevalence of two main aetiologic factors, hepatitis B (HBV and/or C (HCV virus infection and exposure to high levels of aflatoxin in the diet (Chen et al. 1997. The highest incidence rates are observed in regions where most of the population is exposed to both factors, such as in parts of eastern Asia and in sub-Saharan Africa (Parkin et al. 2001. These high incidences are consistent with the fact that HBV chronicity and exposure to aflatoxin have a multiplicative effect of risk for HCC. Depending on aetiology and geographic area, mutations in TP53 show striking differences in prevalence and pattern. In Europe and the US, where alcohol is a major risk factor in addition to viral infections, mutations occur in about 25% of HCC and show as much diversity in their type and codon position as in most other epithelial cancers. However, in high incidence areas such as Mozambique, Senegal, The Gambia (Africa and Qidong county (China, TP53 is mutated in over 50% of the cases and the vast majority of these mutations are a single missense, hotspot mutation at codon 249, AGG to AGT, resulting in the substitution of arginine into serine (249ser. This mutation is uncommon in regions where aflatoxin is not present at significant levels in the diet. In areas of intermediate exposure to aflatoxin, as for example in Thailand, the prevalence of the 249ser mutation is intermediate between high- and low-incidence areas. Thus, there is a dose-dependent relationship between exposure to aflatoxin, incidence of HCC and prevalence of 249ser mutation. Aflatoxins are toxic and carcinogenic metabolites produced by several varieties of molds, mainly Aspergillus flavus and Aspergillus parasiticum. These molds contaminate a wide range of traditional agricultural products in countries

  3. Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma.

    Science.gov (United States)

    Yoo, Byoung Kwon; Santhekadur, Prasanna K; Gredler, Rachel; Chen, Dong; Emdad, Luni; Bhutia, Sujit; Pannell, Lewis; Fisher, Paul B; Sarkar, Devanand

    2011-05-01

    There is virtually no effective treatment for advanced hepatocellular carcinoma (HCC) and novel targets need to be identified to develop effective treatment. We recently documented that the oncogene Astrocyte elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis. Employing yeast two-hybrid assay and coimmunoprecipitation followed by mass spectrometry, we identified staphylococcal nuclease domain containing 1 (SND1), a nuclease in the RNA-induced silencing complex (RISC) facilitating RNAi-mediated gene silencing, as an AEG-1 interacting protein. Coimmunoprecipitation and colocalization studies confirmed that AEG-1 is also a component of RISC and both AEG-1 and SND1 are required for optimum RISC activity facilitating small interfering RNA (siRNA) and micro RNA (miRNA)-mediated silencing of luciferase reporter gene. In 109 human HCC samples SND1 was overexpressed in ≈74% cases compared to normal liver. Correspondingly, significantly higher RISC activity was observed in human HCC cells compared to immortal normal hepatocytes. Increased RISC activity, conferred by AEG-1 or SND1, resulted in increased degradation of tumor suppressor messenger RNAs (mRNAs) that are target of oncomiRs. Inhibition of enzymatic activity of SND1 significantly inhibited proliferation of human HCC cells. As a corollary, stable overexpression of SND1 augmented and siRNA-mediated inhibition of SND1 abrogated growth of human HCC cells in vitro and in vivo, thus revealing a potential role of SND1 in hepatocarcinogenesis. We unravel a novel mechanism that overexpression of AEG-1 and SND1 leading to increased RISC activity might contribute to hepatocarcinogenesis. Targeted inhibition of SND1 enzymatic activity might be developed as an effective therapy for HCC. Copyright © 2011 American Association for the Study of Liver Diseases.

  4. Lactate, Glucose and Oxygen Uptake in Human Brain During Recovery from Maximal Exercise

    DEFF Research Database (Denmark)

    Kojiro, I.; Schmalbruch, I.K.; Quistorff, B.

    1999-01-01

    Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake......Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake...

  5. Modulatory Role of Surface Coating of Superparamagnetic Iron Oxide Nanoworms in Complement Opsonization and Leukocyte Uptake

    DEFF Research Database (Denmark)

    Inturi, Swetha; Wang, Guankui; Chen, Fangfang

    2015-01-01

    demonstrated that neutrophils, monocytes, lymphocytes and eosinophils took up SPIO NWs, and the uptake was prevented by EDTA (a general complement inhibitor) and by antiproperdin antibody (an inhibitor of the alternative pathway of the complement system). Cross-linking and hydrogelation of SPIO NWs surface...... by epichlorohydrin decreased C3 opsonization in mouse serum, and consequently reduced the uptake by mouse leukocytes by more than 70% in vivo. Remarkably, the cross-linked particles did not show a decrease in C3 opsonization in human serum, but showed a significant decrease (over 60%) of the uptake by human...... leukocytes. The residual uptake of cross-linked nanoparticles was completely blocked by EDTA. These findings demonstrate species differences in complement-mediated nanoparticle recognition and uptake by leukocytes, and further show that human hemocompatibility could be improved by inhibitors of complement...

  6. Mediation Analysis with Multiple Mediators

    OpenAIRE

    VanderWeele, T.J.; Vansteelandt, S.

    2014-01-01

    Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects throu...

  7. A mathematical model for investigating the effect of cluster roots on plant nutrient uptake

    KAUST Repository

    Zygalakis, K. C.

    2012-04-01

    Cluster roots are thought to play an important role in mediating nutrient uptake by plants. In this paper we develop a mathematical model for the transport and uptake of phosphate by a single root. Phosphate is assumed to diffuse in the soil fluid phase and can also solubilised due to citrate exudation. Using multiple scale homogenisation techniques we derive an effective model that accounts for the cumulative effect of citrate exudation and phosphate uptake by cluster roots whilst still retaining all the necessary information about the microscale geometry and effects. © 2012 EDP Sciences and Springer.

  8. The chemical form of plutonium in foodstuffs - its influence on gastro-intestinal uptake

    International Nuclear Information System (INIS)

    Cooper, J.R.

    1984-01-01

    A brief review is given of some studies of the chemical form of plutonium in food eaten by man and how this may influence gastrointestinal uptake. Phytate ligands, present in many foods, bind strongly to plutonium. High levels of enzyme phytase in rat intestines enhance the gastrointestinal uptake of plutonium phytate in rats compared to rabbits. Taking into account 1) the low levels of phytase in human intestine and 2) the possibility of competing precipitation reactions, it would seem unlikely that the phytate-mediated elevation of plutonium uptake seen in rats will apply to humans. (U.K.)

  9. Chemical form of plutonium in foodstuffs - its influence on gastro-intestinal uptake

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, J.R. (National Radiological Protection Board, Harwell (UK))

    1984-01-01

    A brief review is given of some studies of the chemical form of plutonium in food eaten by man and how this may influence gastrointestinal uptake. Phytate ligands, present in many foods, bind strongly to plutonium. High levels of enzyme phytase in rat intestines enhance the gastrointestinal uptake of plutonium phytate in rats compared to rabbits. Taking into account 1) the low levels of phytase in human intestine and 2) the possibility of competing precipitation reactions, it would seem unlikely that the phytate-mediated elevation of plutonium uptake seen in rats will apply to humans.

  10. Editor's Highlight: Mode of Action Analysis for Rat Hepatocellular Tumors Produced by the Synthetic Pyrethroid Momfluorothrin: Evidence for Activation of the Constitutive Androstane Receptor and Mitogenicity in Rat Hepatocytes.

    Science.gov (United States)

    Okuda, Yu; Kushida, Masahiko; Sumida, Kayo; Nagahori, Hirohisa; Nakamura, Yoshimasa; Higuchi, Hashihiro; Kawamura, Satoshi; Lake, Brian G; Cohen, Samuel M; Yamada, Tomoya

    2017-08-01

    High dietary levels of momfluorothrin, a nongenotoxic synthetic pyrethroid, induced hepatocellular tumors in male and female Wistar rats in a 2-year bioassay. The mode of action (MOA) for rat hepatocellular tumors was postulated to occur via activation of the constitutive androstane receptor (CAR), as momfluorothrin is a close structural analogue of the pyrethroid metofluthrin, which is known to produce rat liver tumors through a CAR-mediated MOA. To elucidate the MOA for rat hepatocellular tumor formation by momfluorothrin, this study was conducted to examine effects on key and associative events of the CAR-mediated MOA for phenobarbital based on the International Programme on Chemical Safety framework. A 2-week in vivo study in Wistar rats revealed that momfluorothrin induced CYP2B activities, increased liver weights, produced hepatocyte hypertrophy and increased hepatocyte replicative DNA synthesis. These effects correlated with the dose-response relationship for liver tumor formation and also showed reversibility upon cessation of treatment. Moreover, momfluorothrin did not increase CYP2B1/2 mRNA expression and hepatocyte replicative DNA synthesis in CAR knockout rats. Using cultured Wistar rat hepatocytes and the RNA interference technique, knockdown of CAR resulted in a suppression of induction of CYP2B1/2 mRNA levels by momfluorothrin. Alternative MOAs for liver tumor formation were excluded. A global gene expression profile analysis of the liver of male Wistar rats treated with momfluorothrin for 2 weeks also showed similarity to the prototypic CAR activator phenobarbital. Overall, these data strongly support that the postulated MOA for momfluorothrin-induced rat hepatocellular tumors as being mediated by CAR activation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Effect of Phenolic Compounds from Elderflowers on Glucose- and Fatty Acid Uptake in Human Myotubes and HepG2-Cells

    Directory of Open Access Journals (Sweden)

    Giang Thanh Thi Ho

    2017-01-01

    Full Text Available Type 2 diabetes (T2D is manifested by progressive metabolic impairments in tissues such as skeletal muscle and liver, and these tissues become less responsive to insulin, leading to hyperglycemia. In the present study, stimulation of glucose and oleic acid uptake by elderflower extracts, constituents and metabolites were tested in vitro using the HepG2 hepatocellular liver carcinoma cell line and human skeletal muscle cells. Among the crude extracts, the 96% EtOH extract showed the highest increase in glucose and oleic acid uptake in human skeletal muscle cells and HepG2-cells. The flavonoids and phenolic acids contained therein were potent stimulators of glucose and fatty acid uptake in a dose-dependent manner. Most of the phenolic constituents and several of the metabolites showed high antioxidant activity and showed considerably higher α-amylase and α-glucosidase inhibition than acarbose. Elderflower might therefore be valuable as a functional food against diabetes.

  12. Hook1 inhibits malignancy and epithelial-mesenchymal transition in hepatocellular carcinoma.

    Science.gov (United States)

    Sun, Xu; Zhang, Qi; Chen, Wei; Hu, Qida; Lou, Yu; Fu, Qi-Han; Zhang, Jing-Ying; Chen, Yi-Wen; Ye, Long-Yun; Wang, Yi; Xie, Shang-Zhi; Hu, Li-Qiang; Liang, Ting-Bo; Bai, Xue-Li

    2017-07-01

    Hook1 is a member of the hook family of coiled-coil proteins, which is recently found to be associated with malignant tumors. However, its biological function in hepatocellular carcinoma is yet unknown. Here, we evaluated the Hook1 levels in human hepatocellular carcinoma samples and matched peritumoral tissues by real-time polymerase chain reaction. Small interfering RNA knockdown and a transforming growth factor-β-induced epithelial-mesenchymal transition model were employed to investigate the biological effects of Hook1 in hepatocellular carcinoma. Our results indicated that Hook1 levels were significantly lower in hepatocellular carcinoma tissues than in the peritumoral tissues. In addition, Hook1 expression was significantly associated with hepatocellular carcinoma malignancy. Hook1 was downregulated after transforming growth factor-β-induced epithelial-mesenchymal transition. Moreover, Hook1 knockdown promoted epithelial-mesenchymal transition and attenuated the sensitivity of hepatocellular carcinoma cells to doxorubicin. In summary, our results indicate that downregulation of Hook1 plays a pivotal role in hepatocellular carcinoma progression via epithelial-mesenchymal transition. Hook1 may be used as a novel marker and therapeutic molecular target in hepatocellular carcinoma.

  13. Hepatocellular Carcinoma in Tyrosinemia Type 1 Without Clear Increase of AFP

    NARCIS (Netherlands)

    van Ginkel, Willem G.; Gouw, Annette S. H.; van der Jagt, Eric J.; de Jong, Koert P.; Verkade, Henkjan J.; van Spronsen, Francjan J.

    Patients with hereditary tyrosinemia type 1 have an elevated risk of developing hepatocellular carcinoma, especially if initiation of treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione is delayed. Hepatocellular carcinoma can usually be suspected when there are increased

  14. Detection of hepatocellular carcinoma with multi-slice spiral CT by ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-06-07

    Jun 7, 2010 ... The purpose of the study is to evaluate the effect of iodine concentration of contrast material on detection of hepatocellular carcinoma with multi-slice spiral computed tomography (CT) by using double-arterial phase and portal venous phase enhanced scanning. Ninety-four (94) patients with hepatocellular ...

  15. Hg uptake in ureteral obstructions

    International Nuclear Information System (INIS)

    Desgrez, J.P.; Bourguignon, M.; Raynaud, C.; CEA, 91 - Orsay

    1976-01-01

    In the presence of a total obstruction the results obtained with the Hg uptake test, as indeed with other functional tests, inform on the value of the kidney function at the time but have no prognostic value where repair possibilities are concerned. Some preliminary results seem to show however that very soon after the obstacle is removed, by the 10th or 15th day perhaps, quantitative functional tests may once more be used to evaluate the functional prognosis. This would mean that by waiting about two weeks after the disappearance of a total obstruction the Hg uptake test may again be used in all confidence. In order to check this deduction, which is based on slender evidence but which nevertheless has important practical implications, the measurement of the Hg uptake rate during the days following removal of the obstacle appears essential. In long-standing partial obstructions the Hg uptake rate gives an accurate assessment of the functional balance and helps considerably in the choice of therapy [fr

  16. Cellular uptake of metallated cobalamins

    DEFF Research Database (Denmark)

    Tran, Mai Thanh Quynh; Stürup, Stefan; Lambert, Ian Henry

    2016-01-01

    Cellular uptake of vitamin B12-cisplatin conjugates was estimated via detection of their metal constituents (Co, Pt, and Re) by inductively coupled plasma mass spectrometry (ICP-MS). Vitamin B12 (cyano-cob(iii)alamin) and aquo-cob(iii)alamin [Cbl-OH2](+), which differ in the β-axial ligands (CN...

  17. Tumor uptake of radioruthenium compounds

    International Nuclear Information System (INIS)

    Srivastava, S.C.; Richards, P.; Meinken, G.E.; Larson, S.M.; Grunbaum, Z.

    1980-01-01

    The use of ruthenium-97 as a scintigraphic agent, particularly for tumor localization, is investigated. The tumor uptake of ruthenium chloride and ruthenium-labelled transferrin is evaluated and their application as tumor-imagine agents is compared to gallium-67 citrate

  18. Octreotide Uptake in Parathyroid Adenoma

    Directory of Open Access Journals (Sweden)

    Seyhan Karaçavuş

    2012-08-01

    Full Text Available The patient with a history of bone pain and muscle weakness, was thought to have oncogenic osteomalacia as a result of biochemical investigations and directed to Nuclear Medicine Department for a whole-body bone scintigraphy and 111In-octreotide scintigraphy. There was no focal pathologic tracer uptake, but generalized marked increase in skeletal uptake on bone scintigraphy. Octreotide scintigraphy showed accumulation of octreotide in the region of the left lobe of the thyroid gland in the neck. Thereafter, parathyroid scintigraphy was performed with technetium-99m labeled metroxy-isobutyl-isonitryl (99mTc-MIB and MIBI scan demonstrated radiotracer uptake at the same location with octreotide scintigraphy. The patient underwent left inferior parathyroidectomy and histopathology confirmed a parathyroid adenoma. Somatostatin receptor positive parathyroid adenoma may show octreotide uptake. Octreotide scintigraphy may be promising and indicate a possibility of using somatostatin analogues for the medical treatment of somatostatin receptor positive parathyroid tumors. (MIRT 2012;21:77-79

  19. SIRT1 sensitizes hepatocellular carcinoma cells expressing hepatitis B virus X protein to oxidative stress-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Srisuttee, Ratakorn [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Koh, Sang Seok [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Malilas, Waraporn; Moon, Jeong; Cho, Il-Rae [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Jhun, Byung Hak [Department of Applied Nanoscience, Pusan National University, Busan 609-735 (Korea, Republic of); Horio, Yoshiyuki [Department of Pharmacology, Sapporo Medical University, Sa