Human serum activates CIDEB-mediated lipid droplet enlargement in hepatoma cells

International Nuclear Information System (INIS)

Singaravelu, Ragunath; Lyn, Rodney K.; Srinivasan, Prashanth; Delcorde, Julie; Steenbergen, Rineke H.; Tyrrell, D. Lorne; Pezacki, John P.

2013-01-01

Highlights: •Human serum induced differentiation of hepatoma cells increases cellular lipid droplet (LD) size. •The observed increase in LD size correlates with increased PGC-1α and CIDEB expression. •Induction of CIDEB expression correlates with rescue of VLDL secretion and loss of ADRP. •siRNA knockdown of CIDEB impairs the human serum mediated increase in LD size. •This system represents a cost-efficient model to study CIDEB’s role in lipid biology. -- Abstract: Human hepatocytes constitutively express the lipid droplet (LD) associated protein cell death-inducing DFFA-like effector B (CIDEB). CIDEB mediates LD fusion, as well as very-low-density lipoprotein (VLDL) maturation. However, there are limited cell culture models readily available to study CIDEB’s role in these biological processes, as hepatoma cell lines express negligible levels of CIDEB. Recent work has highlighted the ability of human serum to differentiate hepatoma cells. Herein, we demonstrate that culturing Huh7.5 cells in media supplemented with human serum activates CIDEB expression. This activation occurs through the induced expression of PGC-1α, a positive transcriptional regulator of CIDEB. Coherent anti-Stokes Raman scattering (CARS) microscopy revealed a correlation between CIDEB levels and LD size in human serum treated Huh7.5 cells. Human serum treatment also resulted in a rapid decrease in the levels of adipose differentiation-related protein (ADRP). Furthermore, individual overexpression of CIDEB was sufficient to down-regulate ADRP protein levels. siRNA knockdown of CIDEB revealed that the human serum mediated increase in LD size was CIDEB-dependent. Overall, our work highlights CIDEB’s role in LD fusion, and presents a new model system to study the PGC-1α/CIDEB pathway’s role in LD dynamics and the VLDL pathway

Fibronectin synthesized by a human hepatoma cell line

International Nuclear Information System (INIS)

Glasgow, J.E.; Colman, R.W.

1984-01-01

Fibronectin is a family of immunologically similar glycoproteins which mediate a variety of cell-cell and cell-substratum interactions. It is a constituent of the extracellular matrix of connective tissue and circulates in plasma. When suspension and adherent cultures of a human hepatoma cell line (SK-HEP-1) were incubated in serum-free medium, the resulting conditioned medium contained material which was specifically immunoprecipitated by antisera to human plasma fibronectin. By double immunodiffusion, a component in the conditioned culture medium was shown to form a line of identity with fibronectin in human plasma and to migrate as an alpha 2- to beta-globulin during immunoelectrophoresis. Human fibronectin was quantified in conditioned medium by electroimmunodiffusion, and was found to increase for at least three days at about 0.1 micrograms/10(6) cells/day. Adherent cultures of SK-HEP-1 cells were incubated with L-[ 35 S]methionine to label newly synthesized proteins. Labeled fibronectin in conditioned medium or in cell extracts comigrated with fibronectin in human plasma as shown by autoradiography following crossed-immunoelectrophoresis. Fibronectin was demonstrated in the extra-cellular matrix of adherent SK-HEP-1 cultures by immunofluorescence. It was shown previously that SK-HEP-1 cells synthesize alpha 1-protease inhibitor, one of the products of normal hepatocytes. The finding that these hepatoma cells also synthesize fibronectin supports the concept that the hepatocyte may be one source of circulating fibronectin, a possibility consistent with the established role of this cell type in blood plasma protein synthesis

Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells.

Directory of Open Access Journals (Sweden)

Hai-Shan Peng

Full Text Available OBJECTIVES: Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS: Hepatoma cell lines (BEL-7402 and SK-Hep1 were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS: Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS: We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression

Cellular- and micro-dosimetry of heterogeneously distributed tritium.

Science.gov (United States)

Chao, Tsi-Chian; Wang, Chun-Ching; Li, Junli; Li, Chunyan; Tung, Chuan-Jong

2012-01-01

The assessment of radiotoxicity for heterogeneously distributed tritium should be based on the subcellular dose and relative biological effectiveness (RBE) for cell nucleus. In the present work, geometry-dependent absorbed dose and RBE were calculated using Monte Carlo codes for tritium in the cell, cell surface, cytoplasm, or cell nucleus. Penelope (PENetration and Energy LOss of Positrins and Electrons) code was used to calculate the geometry-dependent absorbed dose, lineal energy, and electron fluence spectrum. RBE for the intestinal crypt regeneration was calculated using a lineal energy-dependent biological weighting function. RBE for the induction of DNA double strand breaks was estimated using a nucleotide-level map for clustered DNA lesions of the Monte Carlo damage simulation (MCDS) code. For a typical cell of 10 μm radius and 5 μm nuclear radius, tritium in the cell nucleus resulted in much higher RBE-weighted absorbed dose than tritium distributed uniformly. Conversely, tritium distributed on the cell surface led to trivial RBE-weighted absorbed dose due to irradiation geometry and great attenuation of beta particles in the cytoplasm. For tritium uniformly distributed in the cell, the RBE-weighted absorbed dose was larger compared to tritium uniformly distributed in the tissue. Cellular- and micro-dosimetry models were developed for the assessment of heterogeneously distributed tritium.

Quantitative image analysis of cellular heterogeneity in breast tumors complements genomic profiling.

Science.gov (United States)

Yuan, Yinyin; Failmezger, Henrik; Rueda, Oscar M; Ali, H Raza; Gräf, Stefan; Chin, Suet-Feung; Schwarz, Roland F; Curtis, Christina; Dunning, Mark J; Bardwell, Helen; Johnson, Nicola; Doyle, Sarah; Turashvili, Gulisa; Provenzano, Elena; Aparicio, Sam; Caldas, Carlos; Markowetz, Florian

2012-10-24

Solid tumors are heterogeneous tissues composed of a mixture of cancer and normal cells, which complicates the interpretation of their molecular profiles. Furthermore, tissue architecture is generally not reflected in molecular assays, rendering this rich information underused. To address these challenges, we developed a computational approach based on standard hematoxylin and eosin-stained tissue sections and demonstrated its power in a discovery and validation cohort of 323 and 241 breast tumors, respectively. To deconvolute cellular heterogeneity and detect subtle genomic aberrations, we introduced an algorithm based on tumor cellularity to increase the comparability of copy number profiles between samples. We next devised a predictor for survival in estrogen receptor-negative breast cancer that integrated both image-based and gene expression analyses and significantly outperformed classifiers that use single data types, such as microarray expression signatures. Image processing also allowed us to describe and validate an independent prognostic factor based on quantitative analysis of spatial patterns between stromal cells, which are not detectable by molecular assays. Our quantitative, image-based method could benefit any large-scale cancer study by refining and complementing molecular assays of tumor samples.

I-123-insulin: A new marker for hepatoma

International Nuclear Information System (INIS)

Sodoyez, J.C.; Goffaux, F.S.; Fallais, C.; Bourgeois, P.

1984-01-01

Previous studies have demonstrated that carrier-free I-123-Tyr Al4 insulin was taken up by the liver (by a saturable mechanism) and by the kidneys (by a non saturable mechanism). Autoradiographs of rat liver after injection of I-125-insulin showed that binding specifically occurred at the plasma membrane of the hepatocytes. I-123-Insulin binding to the hepatocyte plasma membrane appeared mediated by specific receptors. Indeed it was blocked by antibodies to the insulin receptors and by an excess of native insulin. Futhermore insulin derivatives with low biological potency (proinsulin and desoctapeptide insulin) did not inhibit I-123-insulin binding to the hepatocytes. I-123-Insulin (1.3 mCi) was I.V. injected into a patient in whom the right liver lobe was normal (normal uptake of Tc-99m-colloid sulfur) but the left liver lobe was occupied by a voluminous hepatoma (no uptake of Tc-99m-colloid sulfur). Liver blood supply was also studied by Tc-99m-pyrophosphate-labeled red cells. Computer analysis of the data revealed that compared to the normal liver lobe, binding of I-123-insulin to the hepatoma was more precocious (vascularization through the hepatic artery and not the portal vein), more intense and more prolonged (half-lives were 6 min in the normal liver and 14 min in the hepatoma). These results are consistent with characteristics of hepatoma cells in culture in which high insulin binding capacity contrasts with a markedly decreased insulin degrading activity. It is concluded that I-123-insulin may be used as a specific marker of hepatoma in man

Effect of interleukin-17A on stemness of hepatoma cell lines

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LI Kexin

2017-06-01

Full Text Available ObjectiveTo investigate the effect of interleukin-17A (IL-17A on stemness of human hepatoma cell lines Hep 3B, MHCC97H, and MHCC97L and the association between IL-17A and the progression of liver cancer. MethodsHuman hepatoma cell lines Hep 3B, MHCC97H, and MHCC97L were selected, and in vitro 3D sphere formation assay was used to analyze the effect of IL-17A on sphere formation ability. The control group with common culture solution and the experimental group with 50 ng/ml IL-17A were established. Real-time cellular analysis was used to determine the effect of IL-17A on the proliferation and migration of hepatoma cells with enhanced sphere formation ability; quantitative real-time PCR was used to measure the changes in the mRNA expression of IL-17A receptors IL-17RA and IL-17RC and stemness-related genes SOX2, NANOG, OCT4, and BMI1 in hepatoma cells with enhanced sphere formation ability; Western blot was used to measure the expression of epithelial-mesenchymal transition-related proteins E-cadherin, N-cadherin, and vimentin. The t-test was used for comparison of continuous doota betwwen groups. ResultsWith the presence of 50 ng/ml IL-17A and 500 inoculated cells, Hep 3B cells had a significant increase in the number of spheres formed (113.0±10.3 vs 180.0±7.2, t=5.533, P＜0.001, while MHCC97H and MHCC97L cells showed no significant changes (t=1.087 and 0.279, P=0.325 and 0785. The analysis showed that IL-17A promoted the proliferation and migration of Hep 3B cells with an increased number of spheres formed. After the addition of 50 ng/ml IL-17A, there was an increase in the mRNA expression of IL-17A receptors IL-17RA and IL-17RC over the time of treatment; Hep 3B cells showed significant increases in the mRNA expression of stemness-related genes SOX2 (t=4.749, P=0.042, NANOG (t=19.600, P=0.003, OCT4 (t=37.310, P＜0.001, and BMI1 (t=16.810, P=0.004. Western blot showed no significant change in the expression of the epithelium

Acetyl-CoA carboxylase in Reuber hepatoma cells: variation in enzyme activity, insulin regulation, and cellular lipid content.

Science.gov (United States)

Bianchi, A; Evans, J L; Nordlund, A C; Watts, T D; Witters, L A

1992-01-01

Reuber hepatoma cells are useful cultured lines for the study of insulin action, lipid and lipoprotein metabolism, and the regulation of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid biosynthesis. During investigations in different clonal lines of these cells, we have uncovered marked intercellular variability in the activity, enzyme content, and insulin regulation of ACC paralleled by differences in cellular neutral lipid (triglyceride) content. Two contrasting clonal lines, Fao and H356A-1, have been studied in detail. Several features distinguish these two lines, including differences in ACC activity and enzyme kinetics, the content of the two major hepatic ACC isozymes (Mr 280,000 and 265,000 Da) and their heteroisozymic complex, the extent of ACC phosphorylation, and the ability of ACC to be activated on stimulation by insulin and insulinomimetic agonists. As studied by Nile Red staining and fluorescence-activated cell sorting, these two lines also display marked differences in neutral lipid content, which correlates with both basal levels of ACC activity and inhibition of ACC by the fatty acid analog, 5-(tetradecyloxy)-2-furoic acid (TOFA). These results emphasize the importance of characterization of any particular clonal line of Reuber cells for studies of enzyme regulation, substrate metabolism, and hormone action. With respect to ACC, studies in contrasting clonal lines of Reuber cells could provide valuable clues to understanding both the complex mechanisms of intracellular ACC regulation in the absence and presence of hormones and its regulatory role(s) in overall hepatic lipid metabolism.

Skeletal metastases from hepatoma: frequency, distribution, and radiographic features

International Nuclear Information System (INIS)

Kuhlman, J.E.; Fishman, E.K.; Leichner, P.K.; Magid, D.; Order, S.E.; Siegelman, S.S.

1986-01-01

Over the past 6 years, the authors evaluated 300 patients with hepatoma as part of phase 1 and 2 treatment protocol trials. Analysis of the available clinical data and radiographic studies revealed 22 patients (7.3%) with skeletal metastases demonstrated by radiography, computed tomography (CT), and/or nuclear scintigraphy. The plain film appearance of skeletal metastases from hepatoma was osteolytic in all cases. CT scanning best demonstrated the expansile, destructive nature of these metastases, which were often associated with large, bulky soft-tissue masses. Skeletal metastases from hepatomas demonstrated increased radiotracer uptake on standard bone scans and were gallium avid, similar to the hepatoma itself. In addition, they could be targeted therapeutically with I-131 antiferritin immunoglobulin. The most frequent sites of skeletal metastases were the ribs, spine, femur, pelvis, and humerus. An initial symptom in ten patients was skeletal pain corresponding to the osseous metastases. In five patients, pathologic fractures of the proximal femur or humerus developed and required total hip replacement or open-reduction internal fixation. Patients with long-standing cirrhosis or known hepatocellular carcinoma who also have skeletal symptoms should be evaluated for possible osseous metastases

Hydrogen sulfide (H{sub 2}S)/cystathionine γ-lyase (CSE) pathway contributes to the proliferation of hepatoma cells

Energy Technology Data Exchange (ETDEWEB)

Pan, Yan; Ye, Shuang; Yuan, Dexiao; Zhang, Jianghong; Bai, Yang; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

2014-05-15

Highlights: • Inhibition of H{sub 2}S/CSE pathway strongly stimulates cellular apoptosis. • Inhibition of H{sub 2}S/CSE pathway suppresses cell growth by blocking EGFR pathway. • H{sub 2}S/CSE pathway is critical for maintaining the proliferation of hepatoma cells. - Abstract: Hydrogen sulfide (H{sub 2}S)/cystathionine γ-lyase (CSE) pathway has been demonstrated to play vital roles in physiology and pathophysiology. However, its role in tumor cell proliferation remains largely unclear. Here we found that CSE over-expressed in hepatoma HepG2 and PLC/PRF/5 cells. Inhibition of endogenous H{sub 2}S/CSE pathway drastically decreased the proliferation of HepG2 and PLC/PRF/5 cells, and it also enhanced ROS production and mitochondrial disruption, pronounced DNA damage and increased apoptosis. Moreover, this increase of apoptosis was associated with the activation of p53 and p21 accompanied by a decreased ratio of Bcl-2/Bax and up-regulation of phosphorylated c-Jun N-terminal kinase (JNK) and caspase-3 activity. In addition, the negative regulation of cell proliferation by inhibition of H{sub 2}S/CSE system correlated with the blockage of cell mitogenic and survival signal transduction of epidermal growth factor receptor (EGFR) via down-regulating the extracellular-signal-regulated kinase 1/2 (ERK1/2) activation. These results demonstrate that H{sub 2}S/CSE and its downstream pathway contribute to the proliferation of hepatoma cells, and inhibition of this pathway strongly suppress the excessive growth of hepatoma cells by stimulating mitochondrial apoptosis and suppressing cell growth signal transduction.

Kinetic imaging of NPC1L1 and sterol trafficking between plasma membrane and recycling endosomes in hepatoma cells

DEFF Research Database (Denmark)

Hartwig Petersen, Nicole; Færgeman, Nils J; Yu, Liqing

2008-01-01

fluorescent protein (NPC1L1-EGFP) and cholesterol analogues in hepatoma cells. At steady state about 42% of NPC1L1 resided in the transferrin (Tf) positive, sterol enriched endocytic recycling compartment (ERC), while time-lapse microscopy demonstrated NPC1L1 traffic between plasma membrane and ERC...... the ERC to the plasma membrane. NPC1L1-EGFP facilitated transport of fluorescent sterols from the plasma membrane to the ERC. Insulin induced translocation of vesicles containing NPC1L1 and fluorescent sterol from the ERC to the cell membrane. Upon polarization of hepatoma cells NPC1L1 resided almost...... exclusively in the canalicular membrane, where the protein is highly mobile. Our study demonstrates dynamic trafficking of NPC1L1 between cell surface and intracellular compartments and suggests that this transport is involved in NPC1L1 mediated cellular sterol uptake....

Preparation of [[sup 131]I]lipiodol as a hepatoma therapeutic agent

Energy Technology Data Exchange (ETDEWEB)

Jiunnguang Lo; Aiyih Wang; Yuanyaw Wei (National Tsinghua Univ., Hsinchu (Taiwan). Inst. of Nuclear Science); Wingyiu Lui; Chinwen Chi (Taipei Veterans General Hospital, Taipei (Taiwan)); Wingkai Chan (Academia Sinica, Taipei (Taiwan). Inst. of Biomedical Sciences)

1992-12-01

An isotopic exchange method was used to label lipiodol with [sup 131]I. The labelling efficiency was > 92.5%, and the radiochemical purity of [[sup 131]I]lipiodol was above 98% as determined by ITLC. The influencing factors e.g. the heating temperature, reaction, pH and storage conditions were studied and the optimum conditions were determined. In a pilot study injecting [[sup 131]I]lipiodol for the treatment of hepatoma, about 70% of hepatoma patients had a response to the treatment with a reduction of [alpha]-fetoprotein and decrease of hepatoma sizes. The overall median survival was 9 months (range 2-17 months). (author).

Cell damage of hepatoma-22 cells exposed to continuous wave ultrasound.

Science.gov (United States)

Wang, Pan; Wang, Xiaobing; Liu, Quanhong

2012-01-01

The cellular response of hepatoma-22 cells to ultrasonic irradiation and the potential cause for the action were evaluated. Hepatoma-22 cells were subjected to ultrasound irradiation at a frequency of 2.17 MHz and a spatial average intensity of 1.6 W/cm2 for variable periods of time, and several biological parameters were analyzed. The terephthalic acid (TA) dosimetry method was used to evaluate the efficacies of irradiation parameters on the acoustic cavitation activity by monitoring hydroxyl radical (OH) production. Lactate dehydrogenase (LDH) leakage was assayed to investigate cell membrane integrity. The polarization value of fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was measured to monitor plasma membrane fluidity. The malonaldehyde content in cells was determined to reflect lipid peroxidation. Trypan blue exclusion was used to detect cell viability. Additionally, electron microscopy was used to observe morphological changes. The generation of intracellular reactive oxygen species, mitochondria swelling and the loss of mitochondria membrane potential were also investigated. The results showed that 1) the concentration of ·OH production by ultrasonic irradiation in air-saturated cell suspensions increased as ultrasound exposure time increased; 2) compared with control, lactate dehydrogenase leakage, the polarization value of 1,6-diphenyl-1,3,5-hexatriene, malonaldehyde content and cell lysis were significantly elevated when cells were treated by ultrasound for 60 s; 3) cytotoxicity by ultrasound irradiation was also accompanied by an increase in production of intracellular reactive oxygen species and dissipation of mitochondria membrane potential as well as by mitochondria swelling. Presently available information indicates that the plasma membrane and mitochondria are the main targets for ultrasound treatment, and free radicals formation such as ·OH due to ultrasound cavitation may play an important role in mediating these cellular response

Incidence and significance of pleural effusion after hepatoma surgery

International Nuclear Information System (INIS)

Song, Jae Uoo; Im, Jung Gi; Ahn, Joong Mo; Kim, Seung Cheol; Kim, Sam Soo; Kim, Seung Hoon; Yeon, Kyung Mo

1994-01-01

We performed this study to evaluate the clinical significance and temporal changes of pleural effusion developed after the resection of hepatoma. We reviewed retrospectively follow-up chest radiographs of 97 patients who had undergone operation for hepatoma and had no radiologically demonstrable postoperative complications. The duration of pleural effusion was classified into five groups and the amount of pleural effusion at one week after operation was graded into four groups. Statistical significance of the relationship between the duration, amount of pleural effusion and five factors, which are location and size of tumor, age of the patients, methods of operation, and preoperative liver function, was studied respectively. Pleural effusion was developed in 63.9% (62/97) and the mean duration was 2.5 weeks. In 92% (52/56), pleural effusion disappeared spontaneously within four weeks. Patients who had hepatoma in upper portion of the right lobe developed more frequent pleural effusion which persisted longer, and was larger in amount at one week after operation(p<0.05). There were no statistically significant differences between pleural effusion and the other four factors. Pleural effusion following hepatoma surgery should not be regarded as a sign of post-operative complication, as it invariably disappears spontaneously within four weeks. Development of pleural effusion is considered to be caused by local irritation and disturbance of lymphatic flow at the diaphragm

Liver regeneration in mice bearing a transplanted hepatoma.

Science.gov (United States)

Badran, A F; Moreno, F R; Echave Llanos, J M

1984-01-01

The hepatocyte mitotic index curve in hepatectomized hepatoma-bearing mice, rises earlier, has a greater amplitude and is less synchronized than that of normal hepatectomized mice. This indicates a stimulation (more mitosis in a shorter time period) produced by the presence of the tumors. The sinusoid litoral cells mitotic index curve in hepatectomized hepatoma-bearing mice appears earlier and is much less synchronized than that of normal hepatectomized mice. Nevertheless both curves have the same amplitude for the whole sampling period and the early stimulation is quickly compensated by lower values (apparent inhibition) appearing in the resting (light) period.

Various imaging methods in the detection of small hepatomas

International Nuclear Information System (INIS)

Nakatsuka, Haruki; Kaminou, Toshio; Takemoto, Kazumasa; Takashima, Sumio; Kobayashi, Nobuyuki; Nakamura, Kenji; Onoyama, Yasuto; Kurioka, Naruto

1985-01-01

Fifty-one patients with small hepatomas under 5 cm in diameter were studied to compare the detectability of various imaging methods. Positive finding was obtained in 50 % of the patients by scintigraphy, in 74 % by ultrasonography and in 79 % by CT during screening tests. Rate of detection in retrospective analysis, after the site of the tumor had been known, were 73 %, 93 % and 87 % respectively. Rate of detection was 92 % by celiac arteriography and 98 % by selective hepatic arteriography. In 21 patients, who had the tumor under 3 cm, the rate was 32 % for scintigraphy, 74 % for ultrasonography and 65 % for CT during screening, whereas it was 58 %, 84 % and 75 % retrospectively. By celiac arteriography, it was 85 %, and by hepatic arteriography, 95 %. Rate of detection of small hepatomas in screening tests differed remarkably from that in retrospective analysis. No single method of imaging can disclose reliably the presense of small hepatoma, therefore more than one method should be used in screening. (author)

On the area spectral efficiency improvement of heterogeneous network by exploiting the integration of macro-femto cellular networks

KAUST Repository

Shakir, Muhammad

2012-06-01

Heterogeneous networks are an attractive means of expanding mobile network capacity. A heterogeneous network is typically composed of multiple radio access technologies (RATs) where the base stations are transmitting with variable power. In this paper, we consider a Heterogeneous network where we complement the macrocell network with low-power low-cost user deployed nodes, such as femtocell base stations to increase the mean achievable capacity of the system. In this context, we integrate macro-femto cellular networks and derive the area spectral efficiency of the proposed two tier Heterogeneous network. We consider the deployment of femtocell base stations around the edge of the macrocell such that this configuration is referred to as femto-on-edge (FOE) configuration. Moreover, FOE configuration mandates reduction in intercell interference due to the mobile users which are located around the edge of the macrocell since these femtocell base stations are low-power nodes which has significantly lower transmission power than macrocell base stations. We present a mathematical analysis to calculate the instantaneous carrier to interference ratio (CIR) of the desired mobile user in macro and femto cellular networks and determine the total area spectral efficiency of the Heterogeneous network. Details of the simulation processes are included to support the analysis and show the efficacy of the proposed deployment. It has been shown that the proposed setup of the Heterogeneous network offers higher area spectral efficiency which aims to fulfill the expected demand of the future mobile users. © 2012 IEEE.

Serum concentration of alpha-1-fetoprotein suggestive of, or pathognomonic for hepatoma

International Nuclear Information System (INIS)

Polterauer, P.; Horak, W.; Legenstein, E.; Mueller, M.

1979-01-01

A short review of alpha-1-fetoprotein (AFP), is followed by a presentation of the serum AFP concentrations obtained in healthy subjects and in patients with hepatoma, cirrhosis of the liver or metastatic liver cancer, measured by radioimmunoassay (RIA). A calculation is made from these results of the upper limit of normal (9 ng/ml), a limit which is suggestive of hepatome (215 ng/ml) and a limit which is pathognomonic for hepatoma (7500 ng/ml). It is concluded that the quantitative determination of AFP by RIA represents a sensitive method which provides valuable clinical information for the early diagnosis of hepatoma. (author)

Recent advances in live cell imaging of hepatoma cells

Science.gov (United States)

2014-01-01

Live cell imaging enables the study of dynamic processes of living cells in real time by use of suitable reporter proteins and the staining of specific cellular structures and/or organelles. With the availability of advanced optical devices and improved cell culture protocols it has become a rapidly growing research methodology. The success of this technique relies mainly on the selection of suitable reporter proteins, construction of recombinant plasmids possessing cell type specific promoters as well as reliable methods of gene transfer. This review aims to provide an overview of the recent developments in the field of marker proteins (bioluminescence and fluorescent) and methodologies (fluorescent resonance energy transfer, fluorescent recovery after photobleaching and proximity ligation assay) employed as to achieve an improved imaging of biological processes in hepatoma cells. Moreover, different expression systems of marker proteins and the modes of gene transfer are discussed with emphasis on the study of lipid droplet formation in hepatocytes as an example. PMID:25005127

Retroviral-mediated gene transfer of human phenylalanine hydroxylase into NIH 3T3 and hepatoma cells

Energy Technology Data Exchange (ETDEWEB)

Ledley, F.D.; Grenett, H.E.; McGinnis-Shelnutt, M.; Woo, S.L.C.

1986-01-01

Phenylketonuria (PKU) is caused by deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). A full-length human PAH cDNA sequence has been inserted into pzip-neoSV(X), which is a retroviral vector containing the bacterial neo gene. The recombinant has been transfected into Psi2 cells, which provide synthesis of the retroviral capsid. Recombinant virus was detected in the culture medium of the transfected Psi2 cells, which is capable of transmitting the human PAH gene into mouse NIH 3T3 cells by infection leading to stable incorporation of the recombinant provirus. Infected cells express PAH mRNA, immunoreactive PAH protein, and exhibit pterin-dependent phenylaline hydroxylase activity. The recombinant virus is also capable of infecting a mouse hepatoma cell line that does not normal synthesize PAH. PAH activity is present in the cellular extracts and the entire hydroxylation system is reconstituted in the hepatoma cells infected with the recombinant viruses. Thus, recombinant viruses containing human PAH cDNA provide a means for introducing functional PAH into mammalian cells of hepatic origin and can potentially be introduced into whole animals as a model for somatic gene therapy for PKU.

HYPOLIPIDEMIC EFFECT OF ARGLABIN IN HEPATOMA TISSUE CULTURE

Directory of Open Access Journals (Sweden)

A. V. Ratkin

2015-01-01

Full Text Available Objective. Investigation of hypolipidemic effect of sesquiterpene γ-lactone Arglabin in hepatoma tissue culture (HTC.Materials and methods. In this study we’ve evaluated the effect of sesquiterpene γ-lactone Arglabin and gemfibrozil (reference drug on the lipid content in the hepatoma tissue culture (HTC which were incubated with a fat emulsion “Lipofundin” by fluorescent method with vital dye Nile Red. The cell viability was investigated using the MTT-test and staining by Trypan blue.Results. Cultivation of cell cultures of rat’s hepatoma cell line HTC with Arglabin and gemfibrozil in concentrations from 10 to 50 μmol and from 0.25 to 0.5 mmol, respectively, had no cytotoxic effect. HTC cell viability did not change compared with the corresponding rate in the control culture. Experimental hyperlipidemia in hepatoma culture was induced by the addition in the incubation medium of fat emulsion “Lipofundin” in a final concentration of 0.05 %. The fluorescence intensity of Nile Red in the cells was increased 4-fold (p < 0.05, which indicates a significant accumulation of lipids in the cytosol of cells. In these steady-state Arglabin and gemfibrozil at concentrations 75–100 μM and 0.25–1.0 mM, respectively, reduced the content of lipid in cells. Conclusion. In the model of hyperlipidemia induced by lipofundin, sesquiterpene γ-lactone Arglabin prevents the accumulation of lipids in the HTC cell line, as evidenced by a decrease in Nile Red fluorescence. However hypolipidemic effect of Arglabin is associated with cytotoxic effects, which is typical for anticancer drugs.

Intraspecies cellular fatty acids heterogeneity of Lactobacillus plantarum strains isolated from fermented foods in Ukraine.

Science.gov (United States)

Garmasheva, I; Vasyliuk, O; Kovalenko, N; Ostapchuk, A; Oleschenko, L

2015-09-01

The intraspecies heterogeneity of cellular fatty acids composition of Lactobacillus plantarum strains isolated from Ukrainian traditional fermented foods was examined. Seven cellular fatty acids were identified. All Lact. plantarum strains investigated contained C16:0 (from 7·54 to 49·83% of total fatty acids), cC18:1 (3·23-38·67% of total fatty acids) and cycC19:0 acids (9·03-67·68% of total fatty acids) as the major fatty acids. The tC18:1 acid made up 1·47-22·0% of the total fatty acids. The C14:0 and C16:1 acids were present in small amounts (0·22-6·96% and 0·66-7·42% respectively) in most Lact. plantarum strains. Differences in relative contents of some fatty acids between Lact. plantarum strains depending on the source isolation were found. Isolates of dairy origin contained slightly greater levels of the C16:0 and tC18:1 fatty acids and lower levels of the cC18:1 than strains obtained from fermented vegetables. The origin of Lact. plantarum strains affects their fatty acids composition, which in turn, appears to be related to their ability to growth under stress factors. Cellular fatty acids composition is an important chemotaxonomic characteristic of bacterial cells. At the same time cellular fatty acids play a key role in maintaining the viability of micro-organisms in different environmental conditions. In this study, intraspecies heterogeneity of cellular fatty acids composition of Lactobacillus plantarum strains was examined. This work provides novel and important information about a relationship between cellular fatty acids composition of Lact. plantarum strains and source of isolation or stress resistance profile. Our results showed that cellular fatty acids composition is quite diverse among Lact. plantarum strains derived from different sources and may reflect previous cell's history. Our findings should be considered in chemotaxonomic studies of lactic acid bacteria and its ecology. © 2015 The Society for Applied Microbiology.

Physical-layer Network Coding in Two-Way Heterogeneous Cellular Networks with Power Imbalance

OpenAIRE

Thampi, Ajay K; Liew, Soung Chang; Armour, Simon M D; Fan, Zhong; You, Lizhao; Kaleshi, Dritan

2016-01-01

The growing demand for high-speed data, quality of service (QoS) assurance and energy efficiency has triggered the evolution of 4G LTE-A networks to 5G and beyond. Interference is still a major performance bottleneck. This paper studies the application of physical-layer network coding (PNC), a technique that exploits interference, in heterogeneous cellular networks. In particular, we propose a rate-maximising relay selection algorithm for a single cell with multiple relays assuming the decode...

Computed tomographic evaluation of the portal vein in the hepatomas

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Lee, Kee Hyung; Lee, Seung Chul; Bae, Man Gil; Seo, Heung Suk; Kim, Soon Yong; Lee, Min Ho; Kee, Choon Suhk; Park, Kyung Nam [Hanyang University College of Medicine, Seoul (Korea, Republic of)

1986-10-15

Computed tomography and pornographic findings of 63 patients with hepatoma, undergone hepatic angiography and superior mesenteric pornography for evaluation of tumor and thrombosis of portal vein and determination of indication of transcatheter arterial embolization for palliative treatment of hepatoma from April, 85 to June, 86 in Hanyang university hospital, were reviewed. The results were as follows: 1. In 36 cases, portal vein thrombosis was detected during photography. Nineteen of 37 cases which revealed localized hepatoma in the right lobe of the liver showed portal vein thrombosis; 9 of 11 cases of the left lobe; 8 of 14 cases which were involved in entire liver revealed thrombosis. One case localized in the caudate lobe showed no evidence of invasion to portal vein. 2. Twenty-four of 34 cases with diffuse infiltrative hepatoma revealed portal vein thrombosis and the incidence of portal vein thrombosis in this type were higher than in the cases of the nodular type. 3. The portal vein thrombosis appeared as filling defects of low density in the lumen of the portal veins in CT and they did not reveal contrast enhancement. 4. CT revealed well the evidence of obstructions in the cases of portal vein thrombosis and the findings were well-corresponded to the findings of the superior mesenteric photography. 5. Five of the cases of the portal vein thrombosis were missed in the CT and the causes were considered as due to partial volume effect of enhanced portal vein with partial occlusion or arterioportal shunts. 6. Six of 13 cases with occlusion of main portal vein showed cavernous transformation and they were noted as multiple small enhanced vascularities around the porta hepatis in the CT. According to the results, we conclude that CT is a useful modality to detect the changes of the portal veins in the patients of the hepatoma.

Computed tomographic evaluation of the portal vein in the hepatomas

International Nuclear Information System (INIS)

Lee, Kee Hyung; Lee, Seung Chul; Bae, Man Gil; Seo, Heung Suk; Kim, Soon Yong; Lee, Min Ho; Kee, Choon Suhk; Park, Kyung Nam

1986-01-01

Computed tomography and pornographic findings of 63 patients with hepatoma, undergone hepatic angiography and superior mesenteric pornography for evaluation of tumor and thrombosis of portal vein and determination of indication of transcatheter arterial embolization for palliative treatment of hepatoma from April, 85 to June, 86 in Hanyang university hospital, were reviewed. The results were as follows: 1. In 36 cases, portal vein thrombosis was detected during photography. Nineteen of 37 cases which revealed localized hepatoma in the right lobe of the liver showed portal vein thrombosis; 9 of 11 cases of the left lobe; 8 of 14 cases which were involved in entire liver revealed thrombosis. One case localized in the caudate lobe showed no evidence of invasion to portal vein. 2. Twenty-four of 34 cases with diffuse infiltrative hepatoma revealed portal vein thrombosis and the incidence of portal vein thrombosis in this type were higher than in the cases of the nodular type. 3. The portal vein thrombosis appeared as filling defects of low density in the lumen of the portal veins in CT and they did not reveal contrast enhancement. 4. CT revealed well the evidence of obstructions in the cases of portal vein thrombosis and the findings were well-corresponded to the findings of the superior mesenteric photography. 5. Five of the cases of the portal vein thrombosis were missed in the CT and the causes were considered as due to partial volume effect of enhanced portal vein with partial occlusion or arterioportal shunts. 6. Six of 13 cases with occlusion of main portal vein showed cavernous transformation and they were noted as multiple small enhanced vascularities around the porta hepatis in the CT. According to the results, we conclude that CT is a useful modality to detect the changes of the portal veins in the patients of the hepatoma.

Addressing population heterogeneity and distribution in epidemics models using a cellular automata approach.

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López, Leonardo; Burguerner, Germán; Giovanini, Leonardo

2014-04-12

The spread of an infectious disease is determined by biological and social factors. Models based on cellular automata are adequate to describe such natural systems consisting of a massive collection of simple interacting objects. They characterize the time evolution of the global system as the emergent behaviour resulting from the interaction of the objects, whose behaviour is defined through a set of simple rules that encode the individual behaviour and the transmission dynamic. An epidemic is characterized trough an individual-based-model built upon cellular automata. In the proposed model, each individual of the population is represented by a cell of the automata. This way of modeling an epidemic situation allows to individually define the characteristic of each individual, establish different scenarios and implement control strategies. A cellular automata model to study the time evolution of a heterogeneous populations through the various stages of disease was proposed, allowing the inclusion of individual heterogeneity, geographical characteristics and social factors that determine the dynamic of the desease. Different assumptions made to built the classical model were evaluated, leading to following results: i) for low contact rate (like in quarantine process or low density population areas) the number of infective individuals is lower than other areas where the contact rate is higher, and ii) for different initial spacial distributions of infected individuals different epidemic dynamics are obtained due to its influence on the transition rate and the reproductive ratio of disease. The contact rate and spatial distributions have a central role in the spread of a disease. For low density populations the spread is very low and the number of infected individuals is lower than in highly populated areas. The spacial distribution of the population and the disease focus as well as the geographical characteristic of the area play a central role in the dynamics of the

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.

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Yuki Haga

Full Text Available Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC. Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.The expression of molecules involved in the mitogen-activated protein kinase (MAPK signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun was measured.The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

Effects of Uptake of Hydroxyapatite Nanoparticles into Hepatoma Cells on Cell Adhesion and Proliferation

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Meizhen Yin

2014-01-01

Full Text Available Hydroxyapatite nanoparticles (nano-HAPs were prepared by homogeneous precipitation, and size distribution and morphology of these nanoparticles were determined by laser particle analysis and transmission electron microscopy, respectively. Nano-HAPs were uniformly distributed, with rod-like shapes sizes ranging from 44.6 to 86.8 nm. Attached overnight, suspended, and proliferating Bel-7402 cells were repeatedly incubated with nano-HAPs. Inverted microscopy, transmission electron microscopy, and fluorescence microscopy were used to observe the cell adhesion and growth, the culture medium containing nano-HAPs, the cell ultrastructure, and intracellular Ca2+ labeled with a fluo-3 calcium fluorescent probe. The results showed that nano-HAPs inhibited proliferation of Bel-7402 cells and, caused an obvious increase in the concentration of intracellular Ca2+, along with significant changes in the cell ultrastructure. Moreover, nano-HAPs led suspended cells and proliferating cells after trypsinized that did not attach to the bottom of the culture bottle died. Nano-HAPs continuously entered these cells. Attached, suspended, and proliferating cells endocytosed nano-HAPs, and nanoparticle-filled vesicles were in the cytoplasm. Therefore, hepatoma cellular uptake of nano-HAPs through endocytosis was very active and occurred continuously. Nano-HAPs affected proliferation and adhesion of hepatoma cells probably because uptake of nano-HAPs blocked integrin-mediated cell adhesion, which may have potential significance in inhibiting metastatic cancer cells to their target organ.

Role of ROS-mediated autophagy in radiation-induced bystander effect of hepatoma cells.

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Wang, Xiangdong; Zhang, Jianghong; Fu, Jiamei; Wang, Juan; Ye, Shuang; Liu, Weili; Shao, Chunlin

2015-05-01

Autophagy plays a crucial role in cellular response to ionizing radiation, but it is unclear whether autophagy can modulate radiation-induced bystander effect (RIBE). Here, we investigated the relationship between bystander damage and autophagy in human hepatoma cells of HepG2. HepG2 cells were treated with conditioned medium (CM) collected from 3 Gy γ-rays irradiated hepatoma HepG2 cells for 4, 12, or 24 h, followed by the measurement of micronuclei (MN), intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and protein expressions of microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 in the bystander HepG2 cells. In some experiments, the bystander HepG2 cells were respectively transfected with LC3 small interfering RNA (siRNA), Beclin-1 siRNA or treated with 1% dimethyl sulfoxide (DMSO). Additional MN and mitochondrial dysfunction coupled with ROS were induced in the bystander cells. The expressions of protein markers of autophagy, LC3-II/LC3-I and Beclin-1, increased in the bystander cells. The inductions of bystander MN and overexpressions of LC3 and Beclin-1 were significantly diminished by DMSO. However, when the bystander cells were transfected with LC3 siRNA or Beclin-1 siRNA, the yield of bystander MN was significantly enhanced. The elevated ROS have bi-functions in balancing the bystander effects. One is to cause MN and the other is to induce protective autophagy.

A case report of hepatoma with cystic calcification

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Jeon, Byung Hee; Choi, Sung Wook; Kim, Byung So [Busan National University College of Medicine, Busan (Korea, Republic of)

1974-10-15

A case of hepatoma with cystic calcification radiographically which confirmed by pathological examination, was reported. The patients was 19 years old boy who had abdominal mass and pain in left upper quadrant for 1 month. His family history was not contributary. The upper G-I series revealed slight posterior displacement of the fundus with a cyst like calcification, about 4.5 X 5 cm, in diameter at the left upper quadrant. Liver scanning showed normal concentration of 198{sup A}u on the right lobe but nonvisualization of the left lobe area. Biopsy specimen showed hepatoma cells invading the portal vein and intrahepatic blood vessels, and the cystic structure which was a blood vessel invaded by the tumor consisting of the organized thrombi.

Prostaglandin (PG) synthesis by hepatoma cells

International Nuclear Information System (INIS)

Cyran, J.; Lysz, T.W.; Lea, M.A.

1987-01-01

Proliferation of cultured HTC hepatoma cells was reported to be inhibited by indomethacin but synthesis of PG in these cells was no detected. The authors have found that omission of fetal calf serum from the medium permits detection of synthesis of 6-keto-PGF1 alpha, PFG2 alpha, PGE2 and TxB2 from labeled arachidonic acid. Two additional peaks were identified as metabolites of PGF2 alpha and PGE2 by retention times on HPLC. Indomethacin inhibited the formation of the PGs and the metabolites. When 3 H-PGE2 and 3 H-PGF2 alpha were added to the cultures, approximately 50% of the label was recovered as the PG metabolites after a 4 day incubation. Metabolism of 3 H-TxB2 was not detected. When HTC cells were grown in the presence of 100 μM flurbiprofen, a cyclooxygenase inhibitor, there was significant inhibition of both cell proliferation and 3 H-thymidine uptake. The authors data suggest that proliferation of hepatoma cells is facilitated by synthesis of PGs

Preliminary result in patients with primary hepatoma treated by stereotactic radiotherapy

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Kang, Ki Mun; Choi, Ihl Bohng; Kim, In Ah; Choi, Byung Ock; Kang, Young Nam; Han, Sung Tae; Chung, Gyu Won [College of Medicine, Catholic Univ., Seoul (Korea, Republic of); Chai, Gyu Young [College of Medicine, Gyeongsang National Univ., Chinju (Korea, Republic of)

2001-03-01

It is not common to evaluate the response of the fractionated stereotactic radiotherapy (SRT) to primary hepatoma as compared with conventional radiotherapy. The purpose of the study was to take the preliminary result on the clinical trial of primary hepatoma by SRT. From July 1999 to March 2000, thirty three patients were hospitalized in the St. Mary's Hospital, and treated with SRT for extracranial tumors. Among them, 13 patients were diagnosed to primary hepatoma and then applied by frameless SRT using 6 MV linac accelerator. There were 12 male and 1 female patients. They had the age of 44-66 year old (median: 59) and the tumor size of 10-825 cc (median: 185 cc). SRT was given to them 3-5 fractions a week (5 Gy/fraction, 90% isodose line) for 2-3 weeks. Median dose of SRT was 50 Gy and the range was 30-50 Gy. Follow-up period ranged from 3 months to 13 months with median of 8 months. After treating SRT to thirteen patients with primary hepatoma, the response of the tumor was examined by abdominal CT: they are classified by 1 complete regression (7.7%), 7 partial regression (53.8%), 4 minimal regression (30.8%), 1 stable disease (7.7%). The positive responses more than partial remission were 8 patients (61.5%) after the treatment. The level of serum alpha-fetoprotein (AFP) after the treatment as compared with pretreatment had been 92.3% decreased. There was no severe complication except dyspepsia 84.6%, mild nausea 69.2%, transient decreased of hepatic function 15.4% and fever 7.7%. SRT to the patients with primary hepatoma was potentially suggested to become the safe and more effective tool than the conventional radiotherapy even though there were relatively short duration of follow-up and small numbers to be tested.

Baicalein inhibits the migration and invasive properties of human hepatoma cells

International Nuclear Information System (INIS)

Chiu, Yung-Wei; Lin, Tseng-Hsi; Huang, Wen-Shih; Teng, Chun-Yuh; Liou, Yi-Sheng; Kuo, Wu-Hsien; Lin, Wea-Lung; Huang, Hai-I; Tung, Jai-Nien; Huang, Chih-Yang; Liu, Jer-Yuh; Wang, Wen-Hung; Hwang, Jin-Ming

2011-01-01

Flavonoids have been demonstrated to exert health benefits in humans. We investigated whether the flavonoid baicalein would inhibit the adhesion, migration, invasion, and growth of human hepatoma cell lines, and we also investigated its mechanism of action. The separate effects of baicalein and baicalin on the viability of HA22T/VGH and SK-Hep1 cells were investigated for 24 h. To evaluate their invasive properties, cells were incubated on matrigel-coated transwell membranes in the presence or absence of baicalein. We examined the effect of baicalein on the adhesion of cells, on the activation of matrix metalloproteinases (MMPs), protein kinase C (PKC), and p38 mitogen-activated protein kinase (MAPK), and on tumor growth in vivo. We observed that baicalein suppresses hepatoma cell growth by 55%, baicalein-treated cells showed lower levels of migration than untreated cells, and cell invasion was significantly reduced to 28%. Incubation of hepatoma cells with baicalein also significantly inhibited cell adhesion to matrigel, collagen I, and gelatin-coated substrate. Baicalein also decreased the gelatinolytic activities of the matrix metalloproteinases MMP-2, MMP-9, and uPA, decreased p50 and p65 nuclear translocation, and decreased phosphorylated I-kappa-B (IKB)-β. In addition, baicalein reduced the phosphorylation levels of PKCα and p38 proteins, which regulate invasion in poorly differentiated hepatoma cells. Finally, when SK-Hep1 cells were grown as xenografts in nude mice, intraperitoneal (i.p.) injection of baicalein induced a significant dose-dependent decrease in tumor growth. These results demonstrate the anticancer properties of baicalein, which include the inhibition of adhesion, invasion, migration, and proliferation of human hepatoma cells in vivo. - Highlight: → Baicalein inhibits several essential steps in the onset of metastasis.

Expression of 65-kDa oncofetal protein in experimental hepatoma after antivancer therapy

International Nuclear Information System (INIS)

Mirowski, M.; Rozalski, M.; Krajewska, U.; Wierbicki, R.; Hanausek, M.

1997-01-01

We have tested the expression of 65-kDa oncofetal protein (p65) after combined treatment with menadione and methotrexate in hamsters transplanted with Kirkman-Robbins hepatoma. The treatment of tumor-bearing animals with these compounds significantly inhibited both the tumor development and the expression of p65. This inhibition in tumor tissue was calculated from densitograms of Western blots. The inhibition of p65 was also confirmed in the serum of hepatoma bearing animals by using solid-phase radioimmunoassay (RIA) to quantify the specificity of polyclonal antibodies to fetal p65 molecules. Additionally, p65 was shown to localize both in cytoplasm an in the nuclear extracts prepared from hepatoma tissue. (author)

The concentration of cadmium in hepatoma among Filipinos

International Nuclear Information System (INIS)

Alejandrino, A.L.; Goze, C.B.; Paradero, R.R.

1977-08-01

The concentration of cadmium in liver hepatoma and in normal liver in Filipinos was determined by atomic absorption spectrophotometry. Using NBS Bovine Liver (SRM1577) as reference material, a value of 0.28+-0.025 ug/g dry weight was obtained for cadmium which is close to the certified NBS value of 0.27+-0.04 ug/g. The mean percentage recovery for cadmium determination by AAS was 98.38%. A mean value of 2.14+-1.58 ug Cd/g liver hepatoma was observed for the 12 cases investigated, showing decreased cadmium levels in the cancerous liver compared to the mean value of 12.62 ug Cd/g observed for normal liver obtained from 10 cases of accidental deaths. The values are expressed on a dry weight basis

Elemental trace analysis of hepatomas and normal tissues by proton induced x-ray emission spectroscopy

International Nuclear Information System (INIS)

Matsuzawa, Taiju; Shishido, Fumio; Sera, Koichiro; Sato, Tachio; Morita, Tasuku.

1977-01-01

Specimens taken from liver, brain, serum and ascites hepatoma 130 in rats, were bombarded with 3.5 MeV protons accelerated by a Van de graaff generator, and the induced x-ray fluorescence was analysed with a Si(Li) detector. Absolute concentrations were determined with reference to a known concentration of uranium in the specimen. Small amounts of Ga, Yb and Tl which are known as metals having tumor affinity were injected into rats implanted with ascites hepatoma and several of its derivatives. Twenty-four hours after injection, liver, brain, serum and hepatoma were removed from the rats and these specimens were analysed by the same method. Relative concentrations of Fe, Cu, Zn and Br in liver, brain, serum and hepatoma specimens showed characteristic patterns. Patterns of liver and ascites hepatoma were quite similar, but the total amount of metals in liver was greater. The serum contained a large quantity of Br. Each AH 130 tumor cell line and its derivatives showed a different accumulation rate for Ga, Yb and Tl. Tl accumulated peculiarly in the brain. There was excellent co-relation between the concentrations of the elements and the biological characteristics of the tumor. (Evans, J.)

Time lapse microscopy observation of cellular structural changes and image analysis of drug treated cancer cells to characterize the cellular heterogeneity.

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Vaiyapuri, Periasamy S; Ali, Alshatwi A; Mohammad, Akbarsha A; Kandhavelu, Jeyalakshmi; Kandhavelu, Meenakshisundaram

2015-01-01

The effect of Calotropis gigantea latex (CGLX) on human mammary carcinoma cells is not well established. We present the results of this drug activity at total population and single cell level. CGLX inhibited the growth of MCF7 cancer cells at lower IC50 concentration (17 µL/mL). Microscopy of IC50 drug treated cells at 24 hr confirming the appearance of morphological characteristics of apoptotic and necrotic cells, associated with 70% of DNA damage. FACS analysis confirmed that, 10 and 20% of the disruption of cellular mitochondrial nature by at 24 and 48 h, respectively. Microscopic image analysis of total population level proved that MMP changes were statistically significant with P values. The cell to cell variation was confirmed by functional heterogeneity analysis which proves that CGLX was able to induce the apoptosis without the contribution of mitochondria. We conclude that CGLX inhibits cell proliferation, survival, and heterogeneity of pathways in human mammary carcinoma cells. © 2014 Wiley Periodicals, Inc.

The involvement of splenic artery in the blood supply of hepatomas: its DSA findings and interventional treatment

International Nuclear Information System (INIS)

Duan Xuhua; Liang Huiming; Feng Gansheng; Zheng Chuangsheng; Ren Jianzhuang

2009-01-01

Objective: To investigate the DSA manifestations of the involvement of splenic artery in supplying blood to hepatomas and to assess the therapeutic value of super-selective interventional embolization. Methods: During the period of March 2005-June 2008, 897 patients with hepatoma underwent angiography and the involvement of splenic artery in the blood supply of hepatoma was confirmed in 7 cases. Splenic arteriography was performed by means of super-selective catheterization with 5 F Yashiro catheter together with 3 F SP catheter. The splenic arteries which supplied blood to hepatomas were embolized with hyper-liquid iodized-oil emulsion mixed with chemotherapy drug, which was followed by the injection of sufficient gelatin sponge or ethanol. The clinical results were analyzed. Results: Splenic arteriography revealed that the splenic artery was the main supplying vessel of the hepatoma in two cases, and was not the main supplying vessel of the hepatoma in five cases. The splenic supplying vessels were completely embolized in all 7 cases. After the procedure, AFP level was decreased over 50%, and in two patients it dropped to normal. CT checkup 4-6 weeks after the surgery revealed that the diameter of tumor decreased to 2.5 - 4.6 cm. Conclusion: The involvement of splenic artery in supplying blood to hepatomas is not common. Super-selective catheterization and sufficient embolization of the splenic supplying vessels are very important for improving the interventional effectiveness. (authors)

Diagnosis of hepatoma using grayscale and Doppler ultrasound in patients with chronic liver disease

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Idris S

2011-10-01

Full Text Available Wasim A Memon, Zishan Haider, Mirza Amanullah Beg, Muhammad Idris, Tanveer-ul-Haq, Waseem Akhtar, Sidra IdrisRadiology Department, Aga Khan University Hospital, Karachi, Pakistan Every author contributed equally to the workObjective: To determine the diagnostic accuracy of liver ultrasound for the detection of hepatoma in chronic liver disease (CLD patients by either taking histopathology or serum α-fetoprotein levels or a biphasic computed tomography (CT scan (whichever is available as the gold standard.Study design: Cross-sectional.Place and duration of study: Radiology Department, The Aga Khan University Hospital, Karachi, Pakistan, from January 2007 to January 2010.Methods: A total of 239 patients (156 males and 83 females with clinical suspicion or surveillance of hepatoma in CLD referred to the radiology department for ultrasound evaluation followed by either liver biopsy and histopathology or serum α-fetoprotein level or biphasic CT scan.Results: The sensitivity of ultrasound for hepatoma detection in CLD was 65%, specificity was 85%, and accuracy was 70%, and positive predictive value and negative predictive value were 92% and 45%, respectively.Conclusion: Ultrasound is a relatively quick, safe, reasonably accurate, and noninvasive imaging modality for the detection of hepatoma in CLD and can be complemented with clinical assessment of screening high-risk patients.Keywords: hepatoma, ultrasound, radiology, chronic liver disease

Repression of the albumin gene in Novikoff hepatoma cells

International Nuclear Information System (INIS)

Capetanaki, Y.G.; Flytzanis, C.N.; Alonso, A.

1982-01-01

Novikoff hepatoma cells have lost their capacity to synthesize albumin. As a first approach to study the mechanisms underlying this event, in vitro translation in a reticulocyte system was performed using total polyadenylated mRNA from rat liver and Novikoff hepatoma cells. Immunoprecipitation of the in vitro translation products with albumin-specific antibody revealed a total lack of albumin synthesis in Novikoff hepatoma, suggesting the absence of functional albumin mRNA in these cells. Titration experiments using as probe albumin cDNA cloned in pBR322 plasmid demonstrated the absence of albumin-specific sequences in both polysomal and nuclear polyadenylated and total RNA from Novikoff cells. This albumin recombinant plasmid was obtained by screening a rat liver cDNA library with albumin [/sup 32/P]cDNA reverse transcribed from immuno-precipitated mRNA. The presence of an albumin-specific gene insert was documented with translation assays as well as by restriction mapping. Repression of the albumin gene at the transcriptional level was further demonstrated by RNA blotting experiments using the cloned albumin cDNA probe. Genomic DNA blots using the cloned albumin cDNA as probe did not reveal any large-scale deletions, insertions, or rearrangements in the albumin gene, suggesting that the processes involved in the suppression of albumin mRNA synthesis do not involve extensive genomic rearrangements

Relationship between P53 and bystander effect induced by radiated hepatoma cells

International Nuclear Information System (INIS)

Zhao Meijia; Shen Bo; Yuan Dexiao; Cheng Honghong; Shao Chunlin

2009-01-01

The role of p53 in bystander responses on normal liver cells were investigated by co-culturing irradiated hepatoma cells with non-irradiated bystander Chang liver cells. It was found that radiosensitivity of the hepatoma cells was relative to p53. HepG2 cells with wtp53 had the highest radiosensitivity followed by PLC/PRF/5 cells with mtp53 and Hep3B cells with null-p53. The induction of bystander micronucleus(MN) was observed only in the Chang liver cells that had been co-cultured with HepG2 cells but not co-cultured with PLC/PRF/5 or Hep3B. Also, this bystander MN was relative to the irradiation dose and the cell co-culture rime. When the hepatoma cells were treated with pifithrin-α, a p53 inhibitor, their radiosensitivities were reduced, and the bystander effect was diminished. The results indicate that p53 could regulate not only the radiosensitivity but also the bystander response. (authors)

Magnetic nanoparticles for targeted therapeutic gene delivery and magnetic-inducing heating on hepatoma

International Nuclear Information System (INIS)

Yuan, Chenyan; Zhang, Jia; Li, Hongbo; Zhang, Hao; Wang, Ling; Zhang, Dongsheng; An, Yanli

2014-01-01

Gene therapy holds great promise for treating cancers, but their clinical applications are being hampered due to uncontrolled gene delivery and expression. To develop a targeted, safe and efficient tumor therapy system, we constructed a tissue-specific suicide gene delivery system by using magnetic nanoparticles (MNPs) as carriers for the combination of gene therapy and hyperthermia on hepatoma. The suicide gene was hepatoma-targeted and hypoxia-enhanced, and the MNPs possessed the ability to elevate temperature to the effective range for tumor hyperthermia as imposed on an alternating magnetic field (AMF). The tumoricidal effects of targeted gene therapy associated with hyperthermia were evaluated in vitro and in vivo. The experiment demonstrated that hyperthermia combined with a targeted gene therapy system proffer an effective tool for tumor therapy with high selectivity and the synergistic effect of hepatoma suppression. (paper)

Inhibitory effect of chitosan oligosaccharide on human hepatoma ...

African Journals Online (AJOL)

Background: Chitosan oligosaccharide, the degradation products of chitin, was reported to have a wide range of physiological functions and biological activities. In this study, we explored the inhibitory effect of Chitosan oligosaccharide on human hepatoma cells. Materials and Methods: MTT assay was applied to detect cell ...

Effects of a fish oil-based emulsion on rat hepatoma cell invasion in culture.

Science.gov (United States)

Hagi, Akifumi; Nakayama, Mitsuo; Miura, Yutaka; Yagasaki, Kazumi

2007-01-01

Total parenteral nutrition containing a lipid emulsion is often employed after surgical tumor resection. This study investigated the effects of a fish oil-based infusion on rat hepatoma cell invasion. Rat ascites hepatoma cell line AH109A was precultured with a fish oil-based or safflower oil-based emulsion for 48 h. Changes in membranous fatty acid composition were evaluated by gas chromatography. The invasiveness of hepatoma cells was assessed by coculturing with mesentery-derived mesothelial cells. To examine ex vivo effects of the fish oil-based infusion on hepatoma invasion, sera were prepared from rats infused with fish oil- or safflower oil-based emulsion and the effects of these sera were assessed. To clarify the mechanism of inhibition of invasion by the fish oil-based emulsion, the effects of prostaglandin (PG) E(2) and PGE(3) on invasion were examined. Pretreatment with the fish oil-based emulsion reduced invasiveness without affecting growth compared with the safflower oil-based emulsion. Pretreatment with the sera from rats infused with the fish oil-based emulsion also reduced invasiveness compared with the sera from rats infused with the safflower oil-based emulsion. The addition of PGE(2) eliminated the inhibitory effect of the fish oil-based emulsion, and the addition of PGE(3) reduced the invasiveness of hepatoma cells pretreated with the safflower oil-based emulsion. These results suggest that the fish oil-based emulsion may have anti-invasive effects. Changes in the membranous fatty acid composition and consequent changes in the prostaglandins produced may be involved in this inhibitory effect.

Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.

Science.gov (United States)

Choi, Joung-Woo; Kim, Hyun Ah; Nam, Kihoon; Na, Youjin; Yun, Chae-Ok; Kim, SungWan

2015-12-28

Despite adenovirus (Ad) vector's numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma. Copyright © 2015 Elsevier B.V. All rights reserved.

A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity.

Science.gov (United States)

Cerchiari, Alec E; Garbe, James C; Jee, Noel Y; Todhunter, Michael E; Broaders, Kyle E; Peehl, Donna M; Desai, Tejal A; LaBarge, Mark A; Thomson, Matthew; Gartner, Zev J

2015-02-17

Developing tissues contain motile populations of cells that can self-organize into spatially ordered tissues based on differences in their interfacial surface energies. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in the mammary gland, we reconstituted its self-organization from aggregates of primary cells in vitro. We find that self-organization is dominated by the interfacial energy of the tissue-ECM boundary, rather than by differential homo- and heterotypic energies of cell-cell interaction. Surprisingly, interactions with the tissue-ECM boundary are binary, in that only one cell type interacts appreciably with the boundary. Using mathematical modeling and cell-type-specific knockdown of key regulators of cell-cell cohesion, we show that this strategy of self-organization is robust to severe perturbations affecting cell-cell contact formation. We also find that this mechanism of self-organization is conserved in the human prostate. Therefore, a binary interfacial interaction with the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of two-component tissues that exhibit abundant heterogeneity and plasticity. Our model also predicts that mutations affecting binary cell-ECM interactions are catastrophic and could contribute to loss of tissue architecture in diseases such as breast cancer.

Percutaneous hepatic arterial catheterization for infusion chemotherapy in treatment of primary hepatoma

International Nuclear Information System (INIS)

Juhn, Jae Ryang; Chang, Jae Yong; Cha, Seong Sook; Han, Sang Suk; Bae, Cheol; Kim, Sung Rok; Chae, Yoo Soon

1984-01-01

Chemotherapy offers palliative treatment to patient with advanced nonresectable hepatoma. The usefulness of systemic chemotherapy is limited because of serious side reaction and low concentration of drug at tumor. But this problem may be overcome by intraarterial infusion. Nonsurgical percutaneous hepatic arterial catheterization was done in 21 patients with primary hepatoma, and infusion chemotherapy was done in 19 patients who were successful in catheterization. The results were as follows: 1. Selective catheterization of hepatic artery proper, common hepatic artery, and celiac artery were successful in 4, 9 and 4 patients respectively. The success rate of selective catheterization is 80.9% including celiac artery among 21 patients with hepatoma. 2. Simple catheterization method was applied in 14 patients, and catheter exchange and Loop methods were applied in 2 and 1 patient respectively. 3. Complication related to catheterization, such as infection and bleeding on punctured site, intimal injury and dislodgement of catheter were not serious. 4. Drugs were well tolerated without serious toxicity or complication. 5. 3 patients showed objective response and median survival time of treated patients is 2.5 months.

Influence of Nutrient Availability and Quorum Sensing on the Formation of Metabolically Inactive Microcolonies Within Structurally Heterogeneous Bacterial Biofilms: An Individual-Based 3D Cellular Automata Model.

Science.gov (United States)

Machineni, Lakshmi; Rajapantul, Anil; Nandamuri, Vandana; Pawar, Parag D

2017-03-01

The resistance of bacterial biofilms to antibiotic treatment has been attributed to the emergence of structurally heterogeneous microenvironments containing metabolically inactive cell populations. In this study, we use a three-dimensional individual-based cellular automata model to investigate the influence of nutrient availability and quorum sensing on microbial heterogeneity in growing biofilms. Mature biofilms exhibited at least three structurally distinct strata: a high-volume, homogeneous region sandwiched between two compact sections of high heterogeneity. Cell death occurred preferentially in layers in close proximity to the substratum, resulting in increased heterogeneity in this section of the biofilm; the thickness and heterogeneity of this lowermost layer increased with time, ultimately leading to sloughing. The model predicted the formation of metabolically dormant cellular microniches embedded within faster-growing cell clusters. Biofilms utilizing quorum sensing were more heterogeneous compared to their non-quorum sensing counterparts, and resisted sloughing, featuring a cell-devoid layer of EPS atop the substratum upon which the remainder of the biofilm developed. Overall, our study provides a computational framework to analyze metabolic diversity and heterogeneity of biofilm-associated microorganisms and may pave the way toward gaining further insights into the biophysical mechanisms of antibiotic resistance.

Studies on the Identification of Constituents in Ethanol Extract of Radix Glycyrrhizae and Their Anti-Primary Hepatoma Cell Susceptibility

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Jie Liu

2014-01-01

Full Text Available The objective of this paper is to study the chemical constituents of Radix Glycyrrhizae and to apply the resulting natural products in the study of drug susceptibility of hepatoma cells so as to provide a scientific basis for quality standards and clinical application of medicinal Radix Glycyrrhizae. Chromatographic materials were used for isolation and purification; structural identification was performed based on physicochemical properties and spectral data. MTT colorimetry was used to detect the proliferation inhibition rate against primary hepatoma cells by natural products, and flow cytometry was used to detect the changes in cell cycle progression. Five compounds were isolated and identified, namely, liquiritigenin (1, liquiritin (2, isoliquiritigenin (3, betulinic acid (4, and oleanolic acid (5. In the study, 5-FU (5-fluorouracil is used as a positive control to the hepatoma cells. Primary hepatoma cells were highly susceptible to 5-FU and liquiritigenin, both of which markedly inhibited the proliferation of hepatoma cells; flow cytometry results showed an increase in G0/G1 phase cells, a decrease in S phase cells, and a relative increase in G2/M phase cells. Primary hepatoma cells are highly susceptible to liquiritigenin, a natural product; the testing of tumor cell susceptibility is of important significance to the improvement of therapeutic effect of cancer.

Development of a formalism of movable cellular automaton method for numerical modeling of fracture of heterogeneous elastic-plastic materials

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S. Psakhie

2013-04-01

Full Text Available A general approach to realization of models of elasticity, plasticity and fracture of heterogeneous materials within the framework of particle-based numerical methods is proposed in the paper. It is based on building many-body forces of particle interaction, which provide response of particle ensemble correctly conforming to the response (including elastic-plastic behavior and fracture of simulated solids. Implementation of proposed approach within particle-based methods is demonstrated by the example of the movable cellular automaton (MCA method, which integrates the possibilities of particle-based discrete element method (DEM and cellular automaton methods. Emergent advantages of the developed approach to formulation of many-body interaction are discussed. Main of them are its applicability to various realizations of the concept of discrete elements and a possibility to realize various rheological models (including elastic-plastic or visco-elastic-plastic and models of fracture to study deformation and fracture of solid-phase materials and media. Capabilities of particle-based modeling of heterogeneous solids are demonstrated by the problem of simulation of deformation and fracture of particle-reinforced metal-ceramic composites.

NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation

International Nuclear Information System (INIS)

Pan, Tao; Zhang, Mei; Zhang, Fang; Yan, Guang; Ru, Yi; Wang, Qinhao; Zhang, Yao; Wei, Xuehui; Xu, Xinyuan; Shen, Lan; Zhang, Jian; Wu, Kaichun; Yao, Libo; Li, Xia

2017-01-01

Because of the high nutrient consumption and inadequate vascularization, solid tumor constantly undergoes metabolic stress during tumor development. Oncogenes and tumor suppressor genes participated in cancer cells' metabolic reprogramming. N-Myc downstream regulated gene 2 (NDRG2) is a recently identified tumor suppressor gene, but its function in cancer metabolism, particularly during metabolic stress, remains unclear. In this study, we found that NDRG2 overexpression significantly reduced hepatoma cell proliferation and enhanced cell apoptosis under glucose limitation. Moreover, NDRG2 overexpression aggravated energy imbalance and oxidative stress by decreasing the intracellular ATP and NADPH generation and increasing ROS levels. Strikingly, NDRG2 inhibited the activation of fatty acid oxidation (FAO), which preserves ATP and NADPH purveyance in the absence of glucose. Finally, mechanistic investigation showed that NDRG2 overexpression suppressed the glucose-deprivation induced AMPK/ACC pathway activation in hepatoma cells, whereas the expression of a constitutively active form of AMPK abrogated glucose-deprivation induced AMPK activation and cell apoptosis. Thus, as a negative regulator of AMPK, NDRG2 disturbs the induction of FAO genes by glucose limitation, leading to dysregulation of ATP and NADPH, and thus reduces the tolerance of hepatoma cells to glucose limitation. - Highlights: • NDRG2 overexpression reduces the tolerance of hepatoma cells to glucose limitation. • NDRG2 overexpression aggravates energy imbalance and oxidative stress under glucose deprivation. • NDRG2 overexpression disturbs the activation of FAO in hepatoma cells under glucose limitation. • NDRG2 overexpression inhibits the activation of AMPK/ACC pathway in hepatoma cells during glucose starvation.

Sampling strategies to capture single-cell heterogeneity

OpenAIRE

Satwik Rajaram; Louise E. Heinrich; John D. Gordan; Jayant Avva; Kathy M. Bonness; Agnieszka K. Witkiewicz; James S. Malter; Chloe E. Atreya; Robert S. Warren; Lani F. Wu; Steven J. Altschuler

2017-01-01

Advances in single-cell technologies have highlighted the prevalence and biological significance of cellular heterogeneity. A critical question is how to design experiments that faithfully capture the true range of heterogeneity from samples of cellular populations. Here, we develop a data-driven approach, illustrated in the context of image data, that estimates the sampling depth required for prospective investigations of single-cell heterogeneity from an existing collection of samples. ...

Cell death induced by Morarah and Khaltita in hepatoma cancer cells (Huh-7).

Science.gov (United States)

Baig, Saeeda; Alamgir, Mohiuddin

2009-10-01

To compare the combined and isolated growth inhibitory effects of Morarah and Khaltita (herbs) on hepatoma cell lines (Huh-7), through induction of apoptosis or necrosis. Comparative controlled in-vitro study. The Molecular Biology Laboratory, The Aga Khan University, Karachi, from June to December 2006. The growth of hepatoma cell lines (Huh-7) was checked by adding Khaltita and Morarah to the cells before culture in a 24 well plate. Six wells were selected and labeled for each of the four variables (controls, Khaltita, Morarah and mixture). After 2 days, cells were studied under an inverted phase contrast microscope and fields were recorded. Approximately four fields per slide of higher intensity were selected randomly to determine the dead cell density, and the procedure was repeated 10 or more times. Frequency and percentages were calculated for dead or alive cells in controls, Morarah, Khaltita and their mixture. Chi-square was used to compare the qualitative variables. P-values < 0.05 were considered significant. Morarah and Khaltita were found to induce statistically significant (p < 0.001) cell death in hepatoma cell lines (Huh-7). At a magnification of 40x, the controls showed 1% dead cells compared to 91% in Morarah, 83% in Khaltita and 73% in combined mixture of Khaltita and Morarah. At magnification of 20x, the controls showed 4% dead cells compared to 44% in Morarah, 47% in Khaltita and 49% in the combined mixture of Khaltita and Morarah. Morarah and Khaltita induced cell death in cultured hepatoma cells (Huh-7).

Trichloroethylene toxicity in a human hepatoma cell line

Energy Technology Data Exchange (ETDEWEB)

Thevenin, E.; McMillian, J. [Medical Univ. of Charleston South Carolina, SC (United States)

1994-12-31

The experiments conducted in this study were designed to determine the usefullness of hepatocyte cultures and a human hepatoma cell line as model systems for assessing human susceptibility to hepatocellular carcinoma due to exposure to trichloroethylene. The results from these studies will then be analyzed to determine if human cell lines can be used to conduct future experiments of this nature.

microRNA-mediated resistance to hypoglycemia in the HepG2 human hepatoma cell line

International Nuclear Information System (INIS)

Ueki, Satomi; Murakami, Yuko; Yamada, Shoji; Kimura, Masaki; Saito, Yoshimasa; Saito, Hidetsugu

2016-01-01

It is generally accepted that the energy resources of cancer cells rely on anaerobic metabolism or the glycolytic system, even if they have sufficient oxygen. This is known as the Warburg effect. The cells skillfully survive under hypoglycemic conditions when their circumstances change, which probably at least partly involves microRNA (miRNA)-mediated regulation. To determine how cancer cells exploit miRNA-mediated epigenetic mechanisms to survive in hypoglycemic conditions, we used DNA microarray analysis to comprehensively and simultaneously compare the expression of miRNAs and mRNAs in the HepG2 human hepatoma cell line and in cultured normal human hepatocytes. The hypoglycemic condition decreased the expression of miRNA-17-5p and -20a-5p in hepatoma cells and consequently upregulated the expression of their target gene p21. These regulations were also confirmed by using antisense inhibitors of these miRNAs. In addition to this change, the hypoglycemic condition led to upregulated expression of heat shock proteins and increased resistance to caspase-3-induced apoptosis. However, we could not identify miRNA-mediated regulations, despite using comprehensive detection. Several interesting genes were also found to be upregulated in the hypoglycemic condition by the microarray analysis, probably because of responding to this cellular stress. These results suggest that cancer cells skillfully survive in hypoglycemic conditions, which frequently occur in malignancies, and that some of the gene regulation of this process is manipulated by miRNAs. The online version of this article (doi:10.1186/s12885-016-2762-7) contains supplementary material, which is available to authorized users

Dosimetric considerations in radioimmunotherapy of patients with hepatoma

International Nuclear Information System (INIS)

Leichner, P.K.; Klein, J.L.; Order, S.E.

1986-01-01

Dosimetric studies of I-131 labeled antiferritin have provided the foundation for preparative and administrative aspects of radiolabeled antibody treatment of patients with hepatoma. Tumor response to I-131 labeled antiferritin IgG was encouraging and radioimmunotherapy with Y-90 labeled antiferritin IgG was recently initiated. For these patients, In-111 labeled antiferritin IgG was used as the imaging agent, with administered activities ranging from 0.8 - 7 mCi. Serial gamma camera imaging from 30 minutes to 6 days post injection demonstrated that 5-30% of the administered activity localized in hepatomas (8/12 patients). The mean value of the effective half-life in the tumor and liver was 2.8 d. Disappearance curves for the blood circulation, spleen, and other normal tissues were biphasic such that 50% of the activity disappeared within 24 hours post injection. The eight patients who demonstrated sufficient tumor localization where subsequently treated with Y-90 labeled antiferritin IgG. Administered activities were dependent on tumor volume and uptake of radiolabeled IgG and ranged from 8 - 20 mCi. The remaining patients were treated under other existing protocols. 10 references

Degradation and repair of DNA from rat hepatoma cells after treatments with γ-rays and N-methyl-N-nitrosourea

International Nuclear Information System (INIS)

Zakrzhevskaya, D.G.; Kulagina, T.P.; Petrov, S.I.; Fomenko, L.A.; Gaziev, A.I.

1977-01-01

It has been shown, that DNA single-strand breaks induced in the cells of ascite hepatoma with γ-rays and metylnitrosourea (MNM) are effectively repaired. DNA two-strand breaks of hepatoma cells, treated with MNM are effectively repaired in situ as well. Only insignificant part of two-strand gamma-induced breaks in DNA of these cells is repaired during postirradiation period. Under combined effect of gamma rays and MNM on hepatoma cells a delay of DNA reparation and its further degradation as well as inhibition of nonplanned DNA synthesis and the suppression of DNA-polymerase 1 activity are observed

Hepatitis C virus NS2 protein activates cellular cyclic AMP-dependent pathways

International Nuclear Information System (INIS)

Kim, Kyoung Mi; Kwon, Shi-Nae; Kang, Ju-Il; Lee, Song Hee; Jang, Sung Key; Ahn, Byung-Yoon; Kim, Yoon Ki

2007-01-01

Chronic infection of the hepatitis C virus (HCV) leads to liver cirrhosis and cancer. The mechanism leading to viral persistence and hepatocellular carcinoma, however, has not been fully understood. In this study, we show that the HCV infection activates cellular cAMP-dependent pathways. Expression of a luciferase reporter gene controlled by a basic promoter with the cAMP response element (CRE) was significantly elevated in human hepatoma Huh-7 cells infected with the HCV JFH1. Analysis with viral subgenomic replicons indicated that the HCV NS2 protein is responsible for the effect. Furthermore, the level of cellular transcripts whose stability is known to be regulated by cAMP was specifically reduced in cells harboring NS2-expressing replicons. These results allude to the HCV NS2 protein having a novel function of regulating cellular gene expression and proliferation through the cAMP-dependent pathway

Total Saponin from Root of Actinidia valvata Dunn Inhibits Hepatoma 22 Growth and Metastasis In Vivo by Suppression Angiogenesis

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Guo-Yin Zheng

2012-01-01

Full Text Available The root of Actinidia valvata dunn has been widely used in the treatment of hepatocellular carcinoma (HCC, proved to be beneficial for a longer and better life in China. In present work, total saponin from root of Actinidia valvata Dunn (TSAVD was extracted, and its effects on hepatoma H22-based mouse in vivo were observed. Primarily transplanted hypodermal hepatoma H22-based mice were used to observe TSAVD effect on tumor growth. The microvessel density (MVD, vascular endothelial growth factor (VEGF, basic fibroblast growth factor (bFGF are characterized factors of angiogenesis, which were compared between TSAVD-treated and control groups. Antimetastasis effect on experimental pulmonary metastasis hepatoma mice was also observed in the study. The results demonstrated that TSAVD can effectively inhibit HCC growth and metastasis in vivo, inhibit the formation of microvessel, downregulate expressions of VEGF and bFGF, and retrain angiogenesis of hepatoma 22 which could be one of the reasons.

Anti-hepatoma activity of a novel compound glaucocalyxin H in vivo and in vitro.

Science.gov (United States)

Hai, Guangfan; Zhang, Chong; Jia, Yanlong; Bai, Suping; Han, Jinfen; Guo, Lanqing; Cui, Taizhen; Niu, Bingxuan; Huang, Feng; Song, Yu

2015-06-01

Glaucocalyxin H (GLH) is a new compound isolated from a traditional Chinese medical herb Isodon japonica var. glaucocalyx which has been used for folk medicine. This study was carried out for the first time to investigate the potential role of GLH in anti-hepatoma activity and underlying mechanisms in it. GLH could inhibit the growth of tumor in mice and induce HepG2 cells to death as assessed by the tumor reduction assay, toxic assay, morphological change, and survival rate assay. Many antitumor drugs originated from plants could inhibit the growth of tumor by inducing cells to apoptosis. The morphological changes of HepG2 cells treated with different concentrations of GLH under fluorescence and electron microscope and apoptotic rates were detected to verify its effect on apoptosis. As shown in the study, GLH could induce HepG2 cells to apoptosis in a dose-dependent manner. Bcl2 and Bax proteins played important roles in apoptosis and the disequilibrium between Bcl2 and Bax might result in apoptosis. The expression of Bax protein was upregulated and Bcl2 protein was downregulated in HepG2 cells treated with GLH assessed by Western blotting, and they were in a dose-dependent manner. Taken together, GLH can inhibit the growth of hepatoma cells in vivo and in vitro by inducing cell apoptosis due to the decreased Bcl2 and increased Bax proteins suggesting that GLH could be a potential candidate as an anti-hepatoma agent for the therapeutic treatment of hepatoma.

Enhancement of 1,3-bis(2-chloroethyl)-1-nitrosourea resistance by gamma-irradiation or drug pretreatment in rat hepatoma cells

International Nuclear Information System (INIS)

Habraken, Y.; Laval, F.

1991-01-01

Treatment of rat hepatoma cells (H4 cells) with various DNA-damaging agents increases the number of O6-methylguanine-DNA-methyltransferase (transferase) molecules per cell. Because the cellular resistance to chloroethylnitrosoureas depends on the number of transferase molecules, we studied the influence of pretreatment with gamma-irradiation, cis-dichlorodiammineplatinum(II), or 2-methyl-9-hydroxyellipticinium on the sensitivity of H4 cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The BCNU resistance depends on the gamma-ray dose and increases with time after irradiation: it is maximum when the drug is added 48 h after irradiation, which corresponds to the maximum enhancement of the transferase activity in the cells. Pretreatment with a single dose of cis-dichlorodiammineplatinum(II) or 2-methyl-9-hydroxyellipticinium also increases the cellular resistance to BCNU. This resistance is not due to a modification of the alkylation of the cellular DNA in the pretreated cells but is related to the increased transferase activity, as it is no longer observed when this activity is depleted by incubating the pretreated cells with the free base O6-methylguanine before BCNU treatment. These results suggest that tumor cells surviving after gamma-irradiation or drug treatment may become resistant to chemotherapy with chloroethylnitrosoureas

Emerging understanding of multiscale tumor heterogeneity

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Michael J Gerdes

2014-12-01

Full Text Available Cancer is a multifaceted disease characterized by heterogeneous genetic alterations and cellular metabolism, at the organ, tissue, and cellular level. Key features of cancer heterogeneity are summarized by ten acquired capabilities, which govern malignant transformation and progression of invasive tumors. The relative contribution of these hallmark features to the disease process varies between cancers. At the DNA and cellular level, germ-line and somatic gene mutations are found across all cancer types, causing abnormal protein production, cell behavior, and growth. The tumor microenvironment and its individual components (immune cells, fibroblasts, collagen, and blood vessels can also facilitate or restrict tumor growth and metastasis. Oncology research is currently in the midst of a tremendous surge of comprehension of these disease mechanisms. This will lead not only to novel drug targets, but also to new challenges in drug discovery. Integrated, multi-omic, multiplexed technologies are essential tools in the quest to understand all of the various cellular changes involved in tumorigenesis. This review examines features of cancer heterogeneity and discusses how multiplexed technologies can facilitate a more comprehensive understanding of these features.

Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro

International Nuclear Information System (INIS)

Yang, Wei; Sun, Ting; Cao, Jianping; Liu, Fenju; Tian, Ye; Zhu, Wei

2012-01-01

Hypoxia is a common feature of solid tumors and an important contributor to tumor radioresistance. miR-210 is the most consistently and robustly induced microRNA under hypoxia in different types of tumor cells and normal cells. In the present study, to explore the feasibility of miR-210 as an effective therapeutic target, lentiviral-mediated anti-sense miR-210 gene transfer technique was employed to downregulate miR-210 expression in hypoxic human hepatoma SMMC-7721, HepG2 and HuH7 cells, and phenotypic changes of which were analyzed. Hypoxia led to an increased hypoxia inducible factor-1α (HIF-1α) and miR-210 expression and cell arrest in the G 0 /G 1 phase in all cell lines. miR-210 downregulation significantly suppressed cell viability, induced cell arrest in the G 0 /G 1 phase, increased apoptotic rate and enhanced radiosensitivity in hypoxic human hepatoma cells. Moreover, apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) was identified as a direct target gene of miR-210. AIFM3 downregulation by siRNA attenuated radiation induced apoptosis in miR-210 downregulated hypoxic human hepatoma cells. Taken together, these data suggest that miR-210 might be a potential therapeutic target and specific inhibition of miR-210 expression in combination with radiotherapy might be expected to exert strong anti-tumor effect on hypoxic human hepatoma cells. -- Highlights: ► miR-210 downregulation radiosensitized hypoxic hepatoma. ► AIFM3 was identified as a direct target gene of miR-210. ► miR-210 might be a therapeutic target to hypoxic hepatoma.

Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity.

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Miles Miller

Full Text Available Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of β-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for 'synthetic cellular heterogeneity' that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism, demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a 'phenotypic sensitivity analysis' method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in

Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity.

Science.gov (United States)

Miller, Miles; Hafner, Marc; Sontag, Eduardo; Davidsohn, Noah; Subramanian, Sairam; Purnick, Priscilla E M; Lauffenburger, Douglas; Weiss, Ron

2012-01-01

Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of β-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for 'synthetic cellular heterogeneity' that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a 'phenotypic sensitivity analysis' method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in isolation, and

Size-dependent cytotoxicity of Fe3O4 nanoparticles induced by biphasic regulation of oxidative stress in different human hepatoma cells

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Xie Y

2016-07-01

Full Text Available Yuexia Xie,1,2,* Dejun Liu,3,* Chenlei Cai,1,* Xiaojing Chen,1 Yan Zhou,1 Liangliang Wu,1 Yongwei Sun,3 Huili Dai,1,2 Xianming Kong,1,2 Peifeng Liu1,2 1Central Laboratory, 2State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, 3Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: The application of Fe3O4 nanoparticles (NPs has made great progress in the diagnosis of disease and in the drug delivery system for cancer therapy, but the relative mecha­nisms of potential toxicity induced by Fe3O4 have not kept pace with its development in the application, which has hampered its further clinical application. In this article, we used two kinds of human hepatoma cell lines, SK-Hep-1 and Hep3B, to investigate the cytotoxic effects and the involved mechanisms of small Fe3O4 NPs with different diameters (6 nm, 9 nm, and 14 nm. Results showed that the size of NPs effectively influences the cytotoxicity of hepatoma cells: 6 nm Fe3O4 NPs exhibited negligible cytotoxicity and 9 nm Fe3O4 NPs affected cytotoxicity via cellular mitochondrial dysfunction and by inducing necrosis mediated through the mitochondria-dependent intracellular reactive oxygen species generation. Meanwhile, 14 nm Fe3O4 NPs induced cytotoxicity by impairing the integrity of plasma membrane and promoting massive lactate dehydrogenase leakage. These results explain the detailed mechanism of different diameters of small Fe3O4 NPs-induced cytotoxicity. We anticipate that this study will provide different insights into the cytotoxicity mechanism of Fe3O4 NPs, so as to make them safer to use in clinical application. Keywords: hepatoma cells, nanoparticles, cytotoxicity, mechanism, oxidative stress

Niclosamide suppresses hepatoma cell proliferation via the Wnt pathway

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Tomizawa M

2013-11-01

Full Text Available Minoru Tomizawa,1 Fuminobu Shinozaki,2 Yasufumi Motoyoshi,3 Takao Sugiyama,4 Shigenori Yamamoto,5 Makoto Sueishi,4 Takanobu Yoshida6 1Department of Gastroenterology, 2Department of Radiology, 3Department of Neurology, 4Department of Rheumatology, 5Department of Pediatrics, 6Department of Internal Medicine, National Hospital Organization Shimoshizu Hospital, Yotsukaido City, Chiba, Japan Background: The Wnt pathway plays an important role in hepatocarcinogenesis. We analyzed the association of the Wnt pathway with the proliferation of hepatoma cells using Wnt3a and niclosamide, a drug used to treat tapeworm infection. Methods: We performed an MTS assay to determine whether Wnt3a stimulated proliferation of Huh-6 and Hep3B human hepatoma cell lines after 72 hours of incubation with Wnt3a in serum-free medium. The cells were subjected to hematoxylin and eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL after 48 hours of incubation. RNA was isolated 48 hours after addition of Wnt3a or niclosamide, and cyclin D1 expression levels were analyzed by real-time quantitative polymerase chain reaction. The promoter activity of T-cell factor was analyzed by luciferase assay 48 hours after transfection of TOPflash. Western blot analysis was performed with antibodies against β-catenin, dishevelled 2, and cyclin D1. Results: Cell proliferation increased with Wnt3a. Niclosamide suppressed proliferation with or without Wnt3a. Hematoxylin and eosin and TUNEL staining suggested that apoptosis occurred in cells with niclosamide. Cyclin D1 was upregulated in the presence of Wnt3a and downregulated with addition of niclosamide. The promoter activity of T-cell factor increased with Wnt3a, whereas T-cell factor promoter activity decreased with niclosamide. Western blot analysis showed that Wnt3a upregulated β-catenin, dishevelled 2, and cyclin D1, while niclosamide downregulated them. Conclusion: Niclosamide is a potential

Hepatitis B virus X protein accelerates the development of hepatoma

International Nuclear Information System (INIS)

Zhang, Xiao-Dong; Wang, Yuan; Ye, Li-Hong

2014-01-01

The chronic infection of hepatitis B virus (HBV) is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Accumulated evidence has shown that HBV X protein (HBx protein) is a multifunctional regulator with a crucial role in hepatocarcinogenesis. However, information on the mechanism by which HBV induces HCC is lacking. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can modulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transcription factor AP-2. Moreover, HBx can affect regulatory non-coding RNAs (ncRNAs) including microRNAs and long ncRNAs (lncRNAs), such as miRNA-205 and highly upregulated in liver cancer (HULC), respectively. HBx is also involved in epigenetic modification, including methylation and acetylation. HBx interacts with various signal-transduction pathways, such as protein kinase B/Akt, Wnt/β-catenin, signal transducer and activator of transcription, and NF-κB pathways. Moreover, HBx affects cellular fate by shifting the balance toward cell survival. HBx may lead to the loss of apoptotic functions or directly contributes to oncogenesis by achieving transforming functions, which induce hepatocarcinogenesis. Additionally, HBx can modulate apoptosis and immune response by direct or indirect interaction with host factors. We conclude that HBx hastens the development of hepatoma

[Ursodeoxycholic acid induced apoptosis of human hepatoma cells HepG2 and SMMC-7721 bymitochondrial-mediated pathway].

Science.gov (United States)

Wu, Duan; Zhou, Jianyin; Yin, Zhenyu; Liu, Pingguo; Zhao, Yilin; Liu, Jianming; Wang, Xiaomin

2014-12-02

To explore the effects and underlying mechanisms of ursodeoxycholic acid on human hepatoma cells. HepG2 and SMMC-7721 HCC cell lines were respectively treated with ursodeoxycholic acid. And cell proliferation, apoptosis and the expression of Bax/Bcl-2 gene were detected by methyl thiazolyl tetrazolium (MTT), inverted microscopy, fluorescent microscopy, flow cytometry and Western blot. Ursodeoxycholic acid significantly inhibited the proliferation of human hepatoma cells in a concentration- and time-dependent manner. The half maximal inhibitory concentrations (IC50) of HepG2 and SMMC-7721 were 397.3 and 387.7 µg/ml respectively after a 48-hour treatment of 400 µg /ml ursodeoxycholic acid. And it also induced the apoptosis of HepG2 and SMMC-7721 cells, up-regulated Bax gene and down-regulated Bcl-2 gene. Ursodeoxycholic acid inhibits the proliferation of hepatoma cells and induce apoptosis by mitochondrial-mediated pathway.

Mechanisms involved in growth inhibition induced by clofibrate in hepatoma cells

International Nuclear Information System (INIS)

Muzio, Giuliana; Maggiora, Marina; Trombetta, Antonella; Martinasso, Germana; Reffo, Patrizia; Colombatto, Sebastiano; Canuto, Rosa Angela

2003-01-01

Low concentrations of some peroxisome proliferators have been found to decrease apoptosis in rat liver cells, whereas higher but pharmacological concentrations have been found to inhibit cell proliferation or to induce apoptosis in human and rat hepatoma cells. The highly deviated JM2 rat hepatoma cell line was used to examine the mechanisms underlying the inhibitory effect on cell proliferation. Clofibrate chiefly inhibited cell proliferation in these cells. Parallel to the decrease in cell proliferation there was an increase of peroxisome proliferator activated receptor (PPAR) gamma and of protein phosphatase 2A, whose importance was confirmed, respectively, by using antisense oliginucleotides (AS-ODN) or okadaic acid. The increase of protein phosphatase 2A induced by PPARgamma caused a decrease of MAPK, an intracellular signaling transduction pathway, as shown by evaluation of Erk1,2 and c-myc. In light of these results, clofibrate, like conventional synthetic ligands of PPARgamma, may be regarded as a possible prototype anti-tumour drug

Clinicopathological study on the primary hepatoma of the atomic bomb survivors

Energy Technology Data Exchange (ETDEWEB)

Satoh, T; Takahara, O; Takahashi, N; Matsuo, K; Tsunoo, S [Nagasaki Atomic Bomb Hospital (Japan)

1978-09-01

Fifty-eight cases autopsied during 10 years from 1968 to 1977 were divided into (A) a non-exposed group, (B) a group exposed within 2 km of the center of explosion, and (C) a group exposed over 2 km from the center of explosion or a group who entered Nagasaki city after the explosion, and clinicopathological study on them was made in detail. These three groups were studied as to incidences according to age and sex, prognosis, histological types and hepatic lesion complicated by hepatoma in survival cases for more than one year, histological diagnosis, gross types, histological types, degree of atypia, hepatic lesion at sites not injured with hepatoma, and the detection rate of B-type virus hepatitis surface antigen (HBs-Ag). Pathohistologically, ordinary hematoxylin-eosin staining, van Gieson staining, silvering staining, iron staining were performed, and aldehyde-fuchsine staining was also performed HBs-Ag detection in a part of cases for.

Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro

Energy Technology Data Exchange (ETDEWEB)

Yang, Wei, E-mail: detachedy@yahoo.com.cn [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China); Sun, Ting [Brain and Nerve Research Laboratory, The First Affiliated Hospital, Soochow University, Suzhou (China); Cao, Jianping; Liu, Fenju [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China); Tian, Ye [Department of Radiotherapy and Oncology, The Second Affiliated Hospital, Soochow University, Suzhou (China); Zhu, Wei [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China)

2012-05-01

Hypoxia is a common feature of solid tumors and an important contributor to tumor radioresistance. miR-210 is the most consistently and robustly induced microRNA under hypoxia in different types of tumor cells and normal cells. In the present study, to explore the feasibility of miR-210 as an effective therapeutic target, lentiviral-mediated anti-sense miR-210 gene transfer technique was employed to downregulate miR-210 expression in hypoxic human hepatoma SMMC-7721, HepG2 and HuH7 cells, and phenotypic changes of which were analyzed. Hypoxia led to an increased hypoxia inducible factor-1{alpha} (HIF-1{alpha}) and miR-210 expression and cell arrest in the G{sub 0}/G{sub 1} phase in all cell lines. miR-210 downregulation significantly suppressed cell viability, induced cell arrest in the G{sub 0}/G{sub 1} phase, increased apoptotic rate and enhanced radiosensitivity in hypoxic human hepatoma cells. Moreover, apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) was identified as a direct target gene of miR-210. AIFM3 downregulation by siRNA attenuated radiation induced apoptosis in miR-210 downregulated hypoxic human hepatoma cells. Taken together, these data suggest that miR-210 might be a potential therapeutic target and specific inhibition of miR-210 expression in combination with radiotherapy might be expected to exert strong anti-tumor effect on hypoxic human hepatoma cells. -- Highlights: Black-Right-Pointing-Pointer miR-210 downregulation radiosensitized hypoxic hepatoma. Black-Right-Pointing-Pointer AIFM3 was identified as a direct target gene of miR-210. Black-Right-Pointing-Pointer miR-210 might be a therapeutic target to hypoxic hepatoma.

Pokemon Silencing Leads to Bim-Mediated Anoikis of Human Hepatoma Cell QGY7703

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Kun Liu

2012-05-01

Full Text Available Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA. Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer.

Pokemon silencing leads to Bim-mediated anoikis of human hepatoma cell QGY7703.

Science.gov (United States)

Liu, Kun; Liu, Feng; Zhang, Nannan; Liu, Shiying; Jiang, Yuyang

2012-01-01

Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer.

Localization of 131I-chTNT in a nude mice model with human hepatoma

International Nuclear Information System (INIS)

Chen Shaoliang; Sun Xiaoguang; Xiu Yan; Zhong Gaoren; Qiao Weiwei; Xu Lanwen; Li Wenzheng

1998-01-01

Purpose: In order to evaluate the targeting activity in the animal model with human hepatoma, the 131 I-chTNT radioimmunoimaging was explored. Methods: Radioimmunoimages were taken on different intervals after injection of 131 I-chTNT 5.55 MBq to the nude mice, and tissue distribution was measured. The results of 131 I-chTNT monoclonal antibody group were compared with that of 131 I control group. Results: The experimental group developed tumor positive images after one day of radio-labelled monoclonal antibodies injection and held on until the end of the experiment. The radioactivity in tumor mass was stable, and the half life of 131 I-chTNT in hepatoma mass was 6.0 +- 1.6 days. there was no special radioactivity accumulation in normal liver tissue in the nude mice and the radioactivity in it disappeared rapidly. Statistics indicated the tumor/liver ratio in 1, 2, 3, 5, 7 days were 1.03, 2.43, 5.71, 7.96, 10.67, respectively. Conclusions: The results suggest that 131 I-chTNT monoclonal antibody has a considerable targeting activity, and provide an evidence for that it can be used as a new radiopharmaceutical agent for the imaging and radio therapy of hepatoma

99Tcm pertechnetate uptake by hepatoma cells induced by tissue specific hNIS gene expression

International Nuclear Information System (INIS)

Chen Libo; Luo Quanyong; Yu Yongli; Yuan Zhibin; Lu Hankui; Zhu Ruisen; Guo Lihe

2007-01-01

Objective: Human sodium/iodide symporter (hNIS) gene could be used both as an ideal reporter gene and promising therapeutic gene. Rather than radioiodine, 99 Tc m pertechnetate has been proven to be a better radiopharmaceutical for tracing and imaging purposes. Herein, the authors investigated the feasibility of monitoring hNIS gene expression in hepatoma cells using 99 Tc m pertechnetate as a tracer. Methods: Hepatoma cells MH3924A were stably transfected with recombinant retroviral vector in which hNIS cDNA was driven by murine albumin enhancer/promoter (mAlb) and coupled to hygromycin resistance gene. The uptake and efflux of 99 Tc m pertechnetate by transfected hepatoma cells were tested with 99 Tc m pertechnetate (74 kBq) solution adulterated into the culture media and counted after media suspension discharge at different intervals. In further tests, 50 μmol/L NaClO 4 and 500 μmol/L Ouabain were added into the media for 99 Tc m inhibition tests. For in vive studies, five ACI rats bearing NIS transfected hepatoma xenografts were injected with 99 Tc m pertechnetate (15.8 MBq) and followed by dynamic acquisition (0.57 1, 2 and 4 h) with small gamma camera to semi-quantitatively analyze the radioactivity distribution. Results: In vitro tests, the peak uptake of 99 Tc m pertechnetate by cultured transfected MH3924A cells was up to 254 folds higher than that by the wild type cells. 99 Tc m uptake by transfected cells were significantly inhibited by NaClO 4 down to 2.44% (P 99 Tc m pertechnetate out of cultured transfected cells became rapid immediately after renewal of culture media (half life 99 Tc m accumulations by hNIS transfected tumor xenografts were obvious in early phases of the acquisition with peak uptake at 12 min and gradually declining later on. Conclusions: hNIS transfected hepatoma cells can avidly uptake 99 Tc m pertechnetate both in vitro and in vive. It is feasible to utilize 99 Tc m pertechnetate for monitoring and even quantitatively analyzing

Studies on Anti-Hepatoma Effect of Gan-Ai-Xiao Decoction | Yuan ...

African Journals Online (AJOL)

Purpose: To explore the anti-hepatoma effect of Gan-Ai-Xiao Decoction (GAXD), a folk remedy. Methods: High performance liquid chromatography (HPLC) was used to identify the major chemical components of GAXD ethanol extract (EE). The cytotoxic effect of GAXD EE against HepG2 cells was measured by methyl ...

Variables affecting the tumor localization of 131I-antiferritin in experimental hepatoma

International Nuclear Information System (INIS)

Rostock, R.A.; Klein, J.L.; Kopher, K.A.; Order, S.E.

1984-01-01

Ferritin is both a normal tissue- and tumor-associated protein. The in vivo localization of 131 I-radiolabeled antitumor ferritin and normal IgG antibodies in the H-4-II-E rat hepatoma model was investigated in both tumor and normal tissues over a dose range of 0.67 micrograms to 5 mg of normal and antiferritin IgG and at labeling ratios (microCi 131 I per micrograms IgG) of 15:1, 5:1, and 1:10. The total dose from nonpenetrating radiation in rads was calculated and demonstrated a maximum of 2.9 times greater dose deposition (rads) of antiferritin than normal IgG in hepatoma without specific increase in binding in normal tissues. The maximum tumor targeting achieved was dependent on the amount of injected IgG and not on the labeling ratio or procedure. The binding in tumor could be inhibited by unlabeled antiferritin but not by unlabeled normal rabbit IgG and demonstrated the requirement of specificity for tumor binding. Normal tissues did not target with antiferritin. Most normal tissues have a capacity to bind normal and antiferritin IgG nonspecifically that is linear in relationship to the amount of injected IgG. The results demonstrate that 131 I-antiferritin selectively targets ferritin-secreting hepatoma over normal tissues and that the amount of targeting is dependent on the amount of antiferritin injected. The physiologic reasons for such selective localization is not known, but the term ''biologic window'' has been used to describe the differential availability of tumor ferritin for binding

Alpha-feto protein radioimmunoassay and its values for the diagnosis of hepatoma among normal Japanese population and those with chronic schistosomiasis

International Nuclear Information System (INIS)

Lio, Masahiro; Yamada, Hideo; Luchi, Masahiko

1972-01-01

Since its first report made by Ablevet al., α-feto protein which appears both in fetal serum and serum in the cases with hepatoma drew attention of hepatologist in order to establish an qualitative method to diagnose the presence of hepatoma. Since conventional liver scintigraphy is not able to make the diagnosis of the nature of lesion which appears as space occupying lesion need for the more qualitative method facilitated the establishment of the method to detect the presence of α-feto protein in serum. α-feto protein in the serum of hepatoma cases was reported to be identical to fetal α-feto protein by the immunological method. At first, assay of the α-feto protein was performed using the precipitation reaction in agar gel and became quite popular among clinical hepatologist. Detection sensitivity of this conventional method, however, is approximately 10 μgr/ml and α-feto protein was detected in 80% of hepatoma patient. However detection percentage of the hepatoma cases associated with chronic schistosomiasis was found to be as poor as 30% which was measured by our group at Kofu municipal Hospital. Because of the frequent incidences of deformed and small liver by scintigraphy among cases with chronic schistosomiasis and these abnormal liver scintigraphy easily lead one to middiagnose the presence of hepatoma, establishment of more sensitive assay method is needed. After the success of purification and crystallization of the α-feto protein by the group of Univ. of Hokkaido, the radioimmunoassay technique was developed in Japan and α-feto-125 Kit is now became available commercially. Initial trial of this new promising and this double antibody technique enabled us to measure 2 mμgr/ml of α-feto protein which was almost 500-1,000 times more sensitive than those of the conventional method.

Study on the damage effect of 131I-iodinated oil internal radiation in SMMC-7721 hepatoma model in rat

International Nuclear Information System (INIS)

Wu Shuyan; Zhang Xuguang; Wang Xiangying; Li Su'an; Mao Dihua

2004-01-01

Objective: To investigate the damage effect of 131 I-iodinated oil internal radiation in hepatoma. Methods: SMMC-7721 rat hepatoma model was used to evaluate the damage of 131 I-iodinated oil internal radiation in carcinoma. 131 I-iodinated oil was injected sector-shapely into tumor model of SMMC-7721 hepatoma with arc-needle, matched with routine straight-needle injection. Tumor damage induced by 131 I-iodinated oil intralesion radiation in the carcinoma models are recorded through survival time, weight of rat, local carcinoma, pathology, electron microscopy. Results: Arc-needle injection 131 I-iodinated oil in SMMC-7721 hepatoma at subcutis could increase rat's survival time, the body weight kept less descent, the lumps necrosed wholly. Pathology and ultrastructure detection revealed cell necrosis and collapse, sever nuclear damage was observed in the death cells. The early characteristics of necrosis such as margination of heterochromatin was also found in some tumor cells. Besides, well differentiated tumor cells, degenerative tumor cells and some lymphocytes were seen. Conclusion: Arc-needle injection 131 I-iodinated oil step-by step sector-shapely into tumor is a better method and necrosis is the major effect of 131 I-iodinated oil internal radiation in carcinoma at the level of treated dosage

Radiosensitizing effects of 9401 on mice bearing H22 hepatoma

International Nuclear Information System (INIS)

Liu Xiaoqiu; Wang Qin; Zhou Zewei; Han Ying; Wang Dezhi; Shen Xiu

2013-01-01

Objective: To investigate the radiosensitizing effects of 9401 on mice bearing H22 hepatoma. Methods: Mouse model bearing H22 hepatoma cells were established. Mice were randomly divided into six groups, the control group,the radiation group and four treatment groups including 9401 at high, medium and low dosages and nicotinamide combined with radiation. After irradiated, the growth of tumor was observed, the time of tumor growth was recorded, the delay time of tumor growth and enhancement factor (EF) were calculated. After 28 days, the mice were killed, the tumors were stripped and inhibition rate was calculated. Results: Groups of 9401 combined with radiation could postpone tumor growth. The difference was statistically significant between 9401 groups at high, medium dosages combined with radiation and nicotinamide combined with radiation group (t=24.7 and 7.5, both P<0.01). Compared with radiation alone group, groups of 9401 combined with radiation had significant radiosensitizing effect. The enhancement factor of 9401 combined with radiation groups at high and medium dosages were 2.13 and 1.73 respectively, they were significant higher than nicotinamide combined with radiation group (t=2.26 and 9.04, both P<0.05). The inhibition rate of 9401 groups at high, medium and low dosages combined with radiation were 64.5%, 50.9% and 42.6% respectively. The inhibition rate of nicotinamide group combined radiation was 53.2%. The inhibition rate of 9401 at high dosage combined with radiation had significant difference with nicotinamide combined radiation (t =2.8, P<0.05). Nicotinamide combined with radiation group, 9401 combined with radiation groups could significant inhibit the growth of tumors compared with radiation alone group (t=5.7, 4.0 and 2.2, all P<0.05). Conclusion: 9401 can inhibit the tumor growth and the inhibition effect increases gradually with the drug dose increasing. It also has radiosensitizing effects on mice bearing H22 hepatoma and present broadly

Analysis of the cytotoxicity of carbon-based nanoparticles, diamond and graphite, in human glioblastoma and hepatoma cell lines

DEFF Research Database (Denmark)

Zakrzewska, Karolina Ewa; Samluk, Anna; Wierzbicki, Mateusz

2015-01-01

carbon based nanoparticles, diamond and graphite, on glioblastoma and hepatoma cells were compared. First, we confirmed previous results that diamond nanoparticles are practically nontoxic. Second, graphite nanoparticles exhibited a negative impact on glioblastoma, but not on hepatoma cells. The studied...... carbon nanoparticles could be a potentially useful tool for therapeutics delivery to the brain tissue with minimal side effects on the hepatocytes. Furthermore, we showed the influence of the nanoparticles on the stable, fluorescently labeled tumor cell lines and concluded that the labeled cells...

Hepatitis B virus X protein mutant HBxΔ127 promotes proliferation of hepatoma cells through up-regulating miR-215 targeting PTPRT

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Liu, Fabao [Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071 (China); Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071 (China); You, Xiaona [Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071 (China); Chi, Xiumei [Department of Hepatology, The First Hospital, Jilin University, Changchun 130021 (China); Wang, Tao [Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071 (China); Ye, Lihong [Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071 (China); Niu, Junqi, E-mail: junqiniu@yahoo.com.cn [Department of Hepatology, The First Hospital, Jilin University, Changchun 130021 (China); Zhang, Xiaodong, E-mail: zhangxd@nankai.edu.cn [Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071 (China)

2014-02-07

Highlights: • Relative to wild type HBx, HBX mutant HBxΔ127 strongly enhances cell proliferation. • Relative to wild type HBx, HBxΔ127 remarkably up-regulates miR-215 in hepatoma cells. • HBxΔ127-elevated miR-215 promotes cell proliferation via targeting PTPRT mRNA. - Abstract: The mutant of virus is a frequent event. Hepatitis B virus X protein (HBx) plays a vital role in the development of hepatocellular carcinoma (HCC). Therefore, the identification of potent mutant of HBx in hepatocarcinogenesis is significant. Previously, we identified a natural mutant of the HBx gene (termed HBxΔ127). Relative to wild type HBx, HBxΔ127 strongly enhanced cell proliferation and migration in HCC. In this study, we aim to explore the mechanism of HBxΔ127 in promotion of proliferation of hepatoma cells. Our data showed that both wild type HBx and HBxΔ127 could increase the expression of miR-215 in hepatoma HepG2 and H7402 cells. However, HBxΔ127 was able to significantly increase miR-215 expression relative to wild type HBx in the cells. We identified that protein tyrosine phosphatase, receptor type T (PTPRT) was one of the target genes of miR-215 through targeting 3′UTR of PTPRT mRNA. In function, miR-215 was able to promote the proliferation of hepatoma cells. Meanwhile anti-miR-215 could partially abolish the enhancement of cell proliferation mediated by HBxΔ127 in vitro. Knockdown of PTPRT by siRNA could distinctly suppress the decrease of cell proliferation mediated by anti-miR-215 in HepG2-XΔ127/H7402-XΔ127 cells. Moreover, we found that anti-miR-215 remarkably inhibited the tumor growth of hepatoma cells in nude mice. Collectively, relative to wild type HBx, HBxΔ127 strongly enhances proliferation of hepatoma cells through up-regulating miR-215 targeting PTPRT. Our finding provides new insights into the mechanism of HBx mutant HBxΔ127 in promotion of proliferation of hepatoma cells.

Internal Disequilibria and Phenotypic Diversification during Replication of Hepatitis C Virus in a Noncoevolving Cellular Environment.

Science.gov (United States)

Moreno, Elena; Gallego, Isabel; Gregori, Josep; Lucía-Sanz, Adriana; Soria, María Eugenia; Castro, Victoria; Beach, Nathan M; Manrubia, Susanna; Quer, Josep; Esteban, Juan Ignacio; Rice, Charles M; Gómez, Jordi; Gastaminza, Pablo; Domingo, Esteban; Perales, Celia

2017-05-15

Viral quasispecies evolution upon long-term virus replication in a noncoevolving cellular environment raises relevant general issues, such as the attainment of population equilibrium, compliance with the molecular-clock hypothesis, or stability of the phenotypic profile. Here, we evaluate the adaptation, mutant spectrum dynamics, and phenotypic diversification of hepatitis C virus (HCV) in the course of 200 passages in human hepatoma cells in an experimental design that precluded coevolution of the cells with the virus. Adaptation to the cells was evidenced by increase in progeny production. The rate of accumulation of mutations in the genomic consensus sequence deviated slightly from linearity, and mutant spectrum analyses revealed a complex dynamic of mutational waves, which was sustained beyond passage 100. The virus underwent several phenotypic changes, some of which impacted the virus-host relationship, such as enhanced cell killing, a shift toward higher virion density, and increased shutoff of host cell protein synthesis. Fluctuations in progeny production and failure to reach population equilibrium at the genomic level suggest internal instabilities that anticipate an unpredictable HCV evolution in the complex liver environment. IMPORTANCE Long-term virus evolution in an unperturbed cellular environment can reveal features of virus evolution that cannot be explained by comparing natural viral isolates. In the present study, we investigate genetic and phenotypic changes that occur upon prolonged passage of hepatitis C virus (HCV) in human hepatoma cells in an experimental design in which host cell evolutionary change is prevented. Despite replication in a noncoevolving cellular environment, the virus exhibited internal population disequilibria that did not decline with increased adaptation to the host cells. The diversification of phenotypic traits suggests that disequilibria inherent to viral populations may provide a selective advantage to viruses that can

Viral-Cellular DNA Junctions as Molecular Markers for Assessing Intra-Tumor Heterogeneity in Cervical Cancer and for the Detection of Circulating Tumor DNA

Directory of Open Access Journals (Sweden)

Katrin Carow

2017-09-01

Full Text Available The development of cervical cancer is frequently accompanied by the integration of human papillomaviruses (HPV DNA into the host genome. Viral-cellular junction sequences, which arise in consequence, are highly tumor specific. By using these fragments as markers for tumor cell origin, we examined cervical cancer clonality in the context of intra-tumor heterogeneity. Moreover, we assessed the potential of these fragments as molecular tumor markers and analyzed their suitability for the detection of circulating tumor DNA in sera of cervical cancer patients. For intra-tumor heterogeneity analyses tumors of 8 patients with up to 5 integration sites per tumor were included. Tumor islands were micro-dissected from cryosections of several tissue blocks representing different regions of the tumor. Each micro-dissected tumor area served as template for a single junction-specific PCR. For the detection of circulating tumor-DNA (ctDNA junction-specific PCR-assays were applied to sera of 21 patients. Samples were collected preoperatively and during the course of disease. In 7 of 8 tumors the integration site(s were shown to be homogenously distributed throughout different tumor regions. Only one tumor displayed intra-tumor heterogeneity. In 5 of 21 analyzed preoperative serum samples we specifically detected junction fragments. Junction-based detection of ctDNA was significantly associated with reduced recurrence-free survival. Our study provides evidence that HPV-DNA integration is as an early step in cervical carcinogenesis. Clonality with respect to HPV integration opens new perspectives for the application of viral-cellular junction sites as molecular biomarkers in a clinical setting such as disease monitoring.

Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells

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Elodie Jouan

2016-12-01

Full Text Available Human hepatoma cells may represent a valuable alternative to the use of human hepatocytes for studying hepatic drug transporters, which is now a regulatory issue during drug development. In the present work, we have characterized hepatic drug transporter expression, activity and regulation in human hepatoma HuH-7 cells, in order to determine the potential relevance of these cells for drug transport assays. HuH-7 cells displayed notable multidrug resistance-associated protein (MRP activity, presumed to reflect expression of various hepatic MRPs, including MRP2. By contrast, they failed to display functional activities of the uptake transporters sodium taurocholate co-transporting polypeptide (NTCP, organic anion-transporting polypeptides (OATPs and organic cation transporter 1 (OCT1, and of the canalicular transporters P-glycoprotein and breast cancer resistance protein (BCRP. Concomitantly, mRNA expressions of various sinusoidal and canalicular hepatic drug transporters were not detected (NTCP, OATP1B1, organic anion transporter 2 (OAT2, OCT1 and bile salt export pump or were found to be lower (OATP1B3, OATP2B1, multidrug and toxin extrusion protein 1, BCRP and MRP3 in hepatoma HuH-7 cells than those found in human hepatocytes, whereas other transporters such as OAT7, MRP4 and MRP5 were up-regulated. HuH-7 cells additionally exhibited farnesoid X receptor (FXR- and nuclear factor erythroid 2-related factor 2 (Nrf2-related up-regulation of some transporters. Such data indicate that HuH-7 cells, although expressing rather poorly some main hepatic drug transporters, may be useful for investigating interactions of drugs with MRPs, notably MRP2, and for studying FXR- or Nrf2-mediated gene regulation.

Expression of rat class I major histocompatibility complex (MHC) alloantigens and hepatocytes and hepatoma cells

International Nuclear Information System (INIS)

Hunt, J.M.; Desai, P.A.; Chakraborty, S.

1986-01-01

Altered expression of Class I MHC alloantigens has been reported for murine tumors, and may be associated with the tumorigenic phenotype of tumor cells. To characterize MHC Class I alloantigen expression on a chemically-induced transplantable rat hepatoma cell line, 17X, derived from a (WF x F344) F 1 rat, polyvalent anti-F344 and anti-WF rat alloantisera were first used to immunoprecipitate the rat RT1.A Class I MHC alloantigens expressed on primary (WF x F344) F 1 hepatocyptes in short-term monolayer cultures. Two-dimensional isoelectric focusing and SDS-PAGE of immunoprecipitates from 35 S-methionine-labeled (WF x F344) F 1 hepatocytes clearly resolved the RT1.A/sup u/ (WF) and RT1.A/sup LvI/ (F344) parental alloantigens. Identical radiolabeling and immunoprecipitation failed to detect either parental alloantigen on the 17X hepatoma cells. However, indirect immunofluorescence and immunoblot analyses demonstrated the presence of parental alloantigens on the 17X cells. Immunization of F344 rats but not of WF rats with 17X cells resulted in antibodies cytotoxic for normal (WF X F344) F 1 spleen cells in the presence of complement. These findings indicate that a combination of detection techniques will be necessary to characterize altered alloantigen expression on rat hepatoma cells

miR-150-5p inhibits hepatoma cell migration and invasion by targeting MMP14.

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Tao Li

Full Text Available Hepatocellular carcinoma (HCC is one of the leading causes of cancer-related mortality worldwide. Despite progress in diagnostics and treatment of HCC, its prognosis remains poor because the molecular mechanisms underlying hepatocarcinogenesis are not well understood. In the study, we focused on identifying the role of miRNAs in HCC progression. miRNA microarray was used to analyze the differentially expressed miRNAs, and the results were validated by qPCR. We found that the miR-150-5p expression is down-regulated in HCC tissues compared with pair non-tumor tissues. miR-150-5p expression is also decreased in metastatic cancer tissues compared with pair primary tissues, indicating that miR-150-5p may be involved in HCC metastasis. Functionally, miR-150-5p inhibition significantly promotes hepatoma cell migration and invasion, whereas miR-150-5p overexpression suppresses cancer cell migration and invasion in vitro. The matrix metalloproteinase 14 (MMP14 is identified as a new target gene of miR-150-5p. miR-150-5p markedly inhibits MMP14 expression in hepatoma cells, and miR-150-5p expression is negative correlation with MMP14 expression in vivo. More important, re-expression of MMP14 in hepatoma cells partially reverses the effect of miR-150-5p in inhibiting cell invasion.

188Re-SSS lipiodol: radiolabelling and biodistribution following injection into the hepatic artery of rats bearing hepatoma.

Science.gov (United States)

Garin, Etienne; Denizot, Benoit; Noiret, Nicolas; Lepareur, Nicolas; Roux, Jerome; Moreau, Myriam; Herry, Jean-Yves; Bourguet, Patrick; Benoit, Jean-Pierre; Lejeune, Jean-Jacques

2004-10-01

Although intra-arterial radiation therapy with 131I-lipiodol is a useful therapeutic approach to the treatment of hepatocellular carcinoma, various disadvantages limit its use. To describe the development of a method for the labelling of lipiodol with 188Re-SSS (188Re (S2CPh)(S3CPh)2 complex) and to investigate its biodistribution after injection into the hepatic artery of rats with hepatoma. 188Re-SSS lipiodol was obtained after dissolving a chelating agent, previously labelled with 188Re, in cold lipiodol. The radiochemical purity (RCP) of labelling was checked immediately. The 188Re-SSS lipiodol was injected into the hepatic artery of nine rats with a Novikoff hepatoma. They were sacrificed 1, 24 and 48 h after injection, and used for ex vivo counting. Labelling of 188Re-SSS lipiodol was achieved with a yield of 97.3+/-2.1%. The immediate RCP was 94.1+/-1.7%. Ex vivo counting confirmed a predominantly hepatic uptake, with a good tumoral retention of 188Re-SSS lipiodol, a weak pulmonary uptake and a very faint digestive uptake. The 'tumour/non-tumoral liver' ratio was high at 1, 24 and 48 h after injection (2.9+/-1.5, 4.1+/-/4.1 and 4.1+/-0.7, respectively). Using the method described here, 188Re-SSS lipiodol can be obtained with a very high yield and a satisfactory RCP. The biodistribution in rats with hepatoma indicates a good tumoral retention of 188Re-SSS lipiodol associated with a predominant hepatic uptake, a weak pulmonary uptake and a very faint digestive uptake. This product should be considered for intra-arterial radiation therapy in human hepatoma.

Preparation of a radioactive boron compound (B-I-131-lipiodol) for neutron capture therapy of hepatoma

International Nuclear Information System (INIS)

Chou, F.I.; Chung, H.P.; Chung, R.J.; Wen, H.W.; Wei, Y.Y.; Kai, J.J.; Lui, W.Y.; Chi, C.W.

2000-01-01

In our research, a radioactive boron compound, B-I-131-lipiodol, that can be selectively retained in hepatoma cells was prepared. Combining the effect of α particles produced by boron neutron capture reaction with the β particles released by radionuclides in the radioactive boron compounds will produce a synergistic killing effect on cancer cells. Human hepatoma HepG2 cell cultures were used to examine the stability and the intracellular distribution of the radioactive boron drug. Microscopes were used to examine the interaction and retention of B-I-131-lipiodol globules in the individual hepatoma cell. Moreover, ICP-AES and NaI scintillation counter were performed to determine boron concentrations and I-131 radioactivity, respectively. Results showed that B-I-131-lipiodol with a boron concentration and a specific radioactivity ranged from 500-2000 ppm and 0.05-10 mCi/mL respectively was stably retained in serum. The radiochemical purity of B-I-131-lipiodol was 98%. After supplement with a medium containing B-I-131-lipiodol, the HepG2 cells had intracellular B-I-131-lipiodol globules in the cytoplasm as seen by inverted light microscope, the I-131 and boron can be stably retained in HepG2 cells. (author)

pH-Responsive Hyaluronic Acid-Based Mixed Micelles for the Hepatoma-Targeting Delivery of Doxorubicin

Directory of Open Access Journals (Sweden)

Jing-Liang Wu

2016-03-01

Full Text Available The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid–glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA–GA/HA–His were prepared through ultrasonic dispersion. The formation and characterization of the mixed micelles were confirmed via 1H-NMR, particle size, and ζ potential measurements. The in vitro cellular uptake of the micelles was evaluated using human liver carcinoma (HepG2 cells. The antitumor effect of doxorubicin (DOX-loaded micelles was investigated in vitro and in vivo. Results indicated that the DOX-loaded HA–GA/HA–His micelles showed a pH-dependent controlled release and were remarkably absorbed by HepG2 cells. Compared with free DOX, the DOX-loaded HA–GA/HA–His micelles showed a higher cytotoxicity to HepG2 cells. Moreover, the micelles effectively inhibited tumor growth in H22 cell-bearing mice. These results suggest that the HA–GA/HA–His mixed micelles are a good candidate for drug delivery in the prevention and treatment of hepatocarcinoma.

The diagnostic application of Ga-67 scintigraphy in primary lung cancer, hepatoma and abdominal abscess

International Nuclear Information System (INIS)

Oshiumi, Yoshihiko

1983-01-01

It is difficult to detect tumor lesions by 67 Gascintigraphy, though it is named as a tumor scintigraphy. Recently, 67 Ga-scintigraphy is well used in the detection of inflammatic lesions. This paper is to discuss the detectability of lesions and diagnostic limitation on operability by 67 Ga-scintigraphy to primary lung cancer, minute hepatoma and abdominal absccess. Primary lung cancer: In detecting metastatic hilar lymph nodes, the sensitivity is 54%, and the specificity is 78%. In detecting metastatic mediastinal lymph nodes, the sensitivity is 32% and the specificity is 89%. Minute hepatoma : The detectability depended on the size of the lesion. It is hard to detect lesions with under 2 cm by 67 Ga-scintigraphy. Abdominal abscess : The sensitivity is 88%, and the specificity is 92%. (author)

Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors

International Nuclear Information System (INIS)

Zhao Lanjuan; Wang Lu; Ren Hao; Cao Jie; Li Li; Ke Jinshan; Qi Zhongtian

2005-01-01

Dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways by various viruses has been shown to be responsible for viral pathogenicity. The molecular mechanism by which hepatitis C virus (HCV) infection caused human liver diseases has been investigated on the basis of abnormal intracellular signal events. Current data are very limited involved in transmembrane signal transduction triggered by HCV E2 protein. Here we explored regulation of the MAPK/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway by E2 expressed in Chinese hamster oval cells. In human hepatoma Huh-7 cells, E2 specifically activated the MAPK/ERK pathway including downstream transcription factor ATF-2 and greatly promoted cell proliferation. CD81 and low density lipoprotein receptor (LDLR) on the cell surface mediated binding of E2 to Huh-7 cells. The MAPK/ERK activation and cell proliferation driven by E2 were suppressed by blockage of CD81 as well as LDLR. Furthermore, pretreatment with an upstream kinase MEK1/2 inhibitor U0126 also impaired the MAPK/ERK activation and cell proliferation induced by E2. Our results suggest that the MAPK/ERK signaling pathway triggered by HCV E2 via its receptors maintains survival and growth of target cells

Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity.

Science.gov (United States)

Sailem, Heba; Bousgouni, Vicky; Cooper, Sam; Bakal, Chris

2014-01-22

One goal of cell biology is to understand how cells adopt different shapes in response to varying environmental and cellular conditions. Achieving a comprehensive understanding of the relationship between cell shape and environment requires a systems-level understanding of the signalling networks that respond to external cues and regulate the cytoskeleton. Classical biochemical and genetic approaches have identified thousands of individual components that contribute to cell shape, but it remains difficult to predict how cell shape is generated by the activity of these components using bottom-up approaches because of the complex nature of their interactions in space and time. Here, we describe the regulation of cellular shape by signalling systems using a top-down approach. We first exploit the shape diversity generated by systematic RNAi screening and comprehensively define the shape space a migratory cell explores. We suggest a simple Boolean model involving the activation of Rac and Rho GTPases in two compartments to explain the basis for all cell shapes in the dataset. Critically, we also generate a probabilistic graphical model to show how cells explore this space in a deterministic, rather than a stochastic, fashion. We validate the predictions made by our model using live-cell imaging. Our work explains how cross-talk between Rho and Rac can generate different cell shapes, and thus morphological heterogeneity, in genetically identical populations.

In vivo PET imaging with 18F-FHBG of hepatoma cancer gene therapy using herpes simplex virus thymidine kinase and ganciclovir

International Nuclear Information System (INIS)

Lee, TaeSup; Kim, JunYoup; Moon, ByungSeok; Kang, JooHyun; Song, Inho; Kwon, HeeChung; Kim, KyungMin; Cheon, GiJeong; Choi, ChangWoon; Lim, SangMoo

2007-01-01

Monitoring gene expression in vivo to evaluate the gene therapy efficacy is a critical issue for scientists and physicians. Non-invasive nuclear imaging can offer information regarding the level of gene expression and its location when an appropriate reporter gene is constructed in the therapeutic gene therapy. Herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) is the most common reporter gene and is used in cancer gene therapy by activating relatively nontoxic compounds, such as acyclovir or ganciclovir (GCV), to induce cell death. In this study, we investigate the feasibility of monitoring cancer gene therapy using retroviral vector transduced HSV1-tk and GCV, in vitro cellular uptake and in vivo animal studies, including biodistribution and small animal positron emission tomography (PET) imaging, were performed in HSV1-tk and luciferase (Luc)-transduced MCA-TK/Luc and enhanced green fluorescent protein (eGFP)-transduced MCA-eGFP hepatoma cell lines

GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells.

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ZhenZhen Hu

Full Text Available BACKGROUND: Epidermal growth factor (EGF signaling is implicated in the invasion and metastasis of hepatoma cells. However, the signaling pathways for EGF-induced motility of hepatoma cells remain undefined. METHODOLOGY/PRINCIPAL FINDINGS: We found that EGF dose-dependently stimulated the migration of human hepatoma cells HepG2, with the maximal effect at 10 ng/mL. Additionally, EGF increased Arf6 activity, and ectopic expression of Arf6 T27N, a dominant negative Arf6 mutant, largely abolish EGF-induced cell migration. Blocking GEP100 with GEP100 siRNA or GEP100-△PH, a pleckstrin homology (PH domain deletion mutant of GEP100, blocked EGF-induced Arf6 activity and cell migration. EGF also increased ERK and Rac1 activity. Ectopic expression GEP100 siRNA, GEP100-△PH, or Arf6-T27N suppressed EGF-induced ERK and Rac1 activity. Furthermore, blocking ERK signaling with its inhibitor U0126 remarkably inhibited both EGF-induced Rac1 activation as well as cell migration, and ectopic expression of inactive mutant form of Rac1 (Rac1-T17N also largely abolished EGF-induced cell migration. CONCLUSIONS/SIGNIFICANCE: Taken together, this study highlights the function of the PH domain of GEP100 and its regulated Arf6/ERK/Rac1 signaling cascade in EGF-induced hepatoma cell migration. These findings could provide a rationale for designing new therapy based on inhibition of hepatoma metastasis.

Proof-of-Concept of a Millimeter-Wave Integrated Heterogeneous Network for 5G Cellular.

Science.gov (United States)

Okasaka, Shozo; Weiler, Richard J; Keusgen, Wilhelm; Pudeyev, Andrey; Maltsev, Alexander; Karls, Ingolf; Sakaguchi, Kei

2016-08-25

The fifth-generation mobile networks (5G) will not only enhance mobile broadband services, but also enable connectivity for a massive number of Internet-of-Things devices, such as wireless sensors, meters or actuators. Thus, 5G is expected to achieve a 1000-fold or more increase in capacity over 4G. The use of the millimeter-wave (mmWave) spectrum is a key enabler to allowing 5G to achieve such enhancement in capacity. To fully utilize the mmWave spectrum, 5G is expected to adopt a heterogeneous network (HetNet) architecture, wherein mmWave small cells are overlaid onto a conventional macro-cellular network. In the mmWave-integrated HetNet, splitting of the control plane (CP) and user plane (UP) will allow continuous connectivity and increase the capacity of the mmWave small cells. mmWave communication can be used not only for access linking, but also for wireless backhaul linking, which will facilitate the installation of mmWave small cells. In this study, a proof-of-concept (PoC) was conducted to demonstrate the practicality of a prototype mmWave-integrated HetNet, using mmWave technologies for both backhaul and access.

Cellular responses to environmental DNA damage

Energy Technology Data Exchange (ETDEWEB)

1994-08-01

This volume contains the proceedings of the conference entitled Cellular Responses to Environmental DNA Damage held in Banff,Alberta December 1--6, 1991. The conference addresses various aspects of DNA repair in sessions titled DNA repair; Basic Mechanisms; Lesions; Systems; Inducible Responses; Mutagenesis; Human Population Response Heterogeneity; Intragenomic DNA Repair Heterogeneity; DNA Repair Gene Cloning; Aging; Human Genetic Disease; and Carcinogenesis. Individual papers are represented as abstracts of about one page in length.

Species-specific differences in peroxisome proliferation, catalase, and SOD2 upregulation as well as toxicity in human, mouse, and rat hepatoma cells induced by the explosive and environmental pollutant 2,4,6-trinitrotoluene.

Science.gov (United States)

Naumenko, Ekaterina Anatolevna; Ahlemeyer, Barbara; Baumgart-Vogt, Eveline

2017-03-01

2,4,6-Trinitrotoluene (TNT) has been widely used as an explosive substance and its toxicity is still of interest as it persisted in polluted areas. TNT is metabolized in hepatocytes which are prone to its toxicity. Since analysis of the human liver or hepatocytes is restricted due to ethical reasons, we investigated the effects of TNT on cell viability, reactive oxygen species (ROS) production, peroxisome proliferation, and antioxidative enzymes in human (HepG2), mouse (Hepa 1-6), and rat (H4IIEC3) hepatoma cell lines. Under control conditions, hepatoma cells of all three species were highly comparable exhibiting identical proliferation rates and distribution of their cell cycle phases. However, we found strong differences in TNT toxicity with the lowest IC 50 values (highest cell death rate) for rat cells, whereas human and mouse cells were three to sevenfold less sensitive. Moreover, a strong decrease in cellular dehydrogenase activity (MTT assay) and increased ROS levels were noted. TNT caused peroxisome proliferation with rat hepatoma cells being most responsive followed by those from mouse and human. Under control conditions, rat cells contained fivefold higher peroxisomal catalase and mitochondrial SOD2 activities and a twofold higher capacity to reduce MTT than human and mouse cells. TNT treatment caused an increase in catalase and SOD2 mRNA and protein levels in human and mouse, but not in rat cells. Similarly, human and mouse cells upregulated SOD2 activity, whereas rat cells failed therein. We conclude that TNT induced oxidative stress, peroxisome proliferation and mitochondrial damage which are highest in rat cells rendering them most susceptible toward TNT. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 989-1006, 2017. © 2016 Wiley Periodicals, Inc.

Diagnostic application of Ga-67 scintigraphy in primary lung cancer, hepatoma and abdominal abscess. On surgical operation

Energy Technology Data Exchange (ETDEWEB)

Oshiumi, Yoshihiko (National Central Hospital of Fukuoka (Japan))

1983-05-01

It is difficult to detect tumor lesions by /sup 67/Ga-scintigraphy, though it is named as a tumor scintigraphy. Recently, /sup 67/Ga-scintigraphy is well used in the detection of inflammatic lesions. This paper is to discuss the detectability of lesions and diagnostic limitation on operability by /sup 67/Ga-scintigraphy to primary lung cancer, minute hepatoma and abdominal abscess. Primary lung cancer: In detecting metastatic hilar lymph nodes, the sensitivity is 54%, and the specificity is 78%. In detecting metastatic mediastinal lymph nodes, the sensitivity is 32% and the specificity is 89%. Minute hepatoma : The detectability depended on the size of the lesion. It is hard to detect lesions with under 2 cm by /sup 67/Ga-scintigraphy. Abdominal abscess : The sensitivity is 88%, and the specificity is 92%.

Synergistic effect of intervention of glypican-3 gene transcription combined with antitumor drugs in inhibiting hepatoma cell proliferation

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YANG Jie

2016-12-01

Full Text Available ObjectiveTo investigate the inhibitory effect of intervention of glypican-3 (GPC3 gene transcription combined with antitumor drugs on hepatoma cell proliferation. MethodsFour types of GPC3-shRNA plasmids were established and transfected into HepG2 hepatoma cells. Quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression of GPC3 to analyze its association with hepatoma cell proliferation and apoptosis. The independent samples t-test was used for comparison of continuous data between any two groups, and a one-way analysis of variance was used for comparison between multiple groups. ResultsAmong these four plasmids, shRNA1 had a transfection efficiency of ＞85% in the transfection of HepG2 cells and a silence efficiency of 89.3% at the mRNA level, and the protein expression of GPC3 was significantly inhibited(P＜0.01）. At 72 hours, the GPC3-shRNA1 co-intervention group had an HepG2 cell inhibition rate of 71.1%, significantly different from that in the negative group (t=18.092, P＜0.001, an inhibition rate of migration of 89.1%, significantly lower than that in the negative group (t=8.326, P＜0.001, and inhibition rates of HepG2 cell movement and invasion of 53.6% and 60.1%, which were significantly different from those in the negative group (t=52.400 and 48.245, both P＜0.001. The GPC3-shRNA1 co-intervention group had a β-catenin mRNA inhibition rate of 46.9% and a Gli1 mRNA upregulation rate of 7.4%, significantly different from those in the negative group (t=30.108 and -3.551, P＜0.001 and P=0.009. At 24 hours, 10 μmol/L sorafenib combined with shRNA1 had an inhibition rate of tumor cells of 52.6% and 100 μmol/L sorafenib combined with shRNA1 had an inhibition rate of tumor cells of 79.5%, which were significantly different from that in the control group (t=23.314 and 50.352, both P＜0.001. The half-maximal inhibitory concentrations of sorafenib, rapamycin, and erlotinib for HepG2 were 4.67±1

Radiation induced bystander effect on hepatoma HepG2 cells under hypoxia condition

International Nuclear Information System (INIS)

Zhang Jianghong; Jin Yizun; Shao Chunlin; Prise KM

2009-01-01

Objective: To investigate radiation induced bystander effect and its mechanism on hepatoma HepG2 cells under hypoxia condition. Methods: Non-irradiated bystander hepatoma cells were co-cultured with irradiated cells or treated with the conditioned medium (CM) from irradiated cells, then micronuclei (MN) were measured for both irradiated cells and bystander cells. Results: The MN yield of irradiated HepG2 cells under hypoxic condition was significantly lower than that under normoxia, the oxygen enhancement ratio of HepG2 cells of MN was 1.6. For both hypoxic and normoxic condition, the MN yield of bystander cells were obviously enhanced to a similar high level after co-culturing with irradiated cells or with CM treatment, and it also correlated with the irradiation dose. When the hypoxic HepG2 cells were treated with either DMSO, a scavenger of reactive oxygen species (ROS), or aminoguanidine, an iNOS inhibitor, the yield of bystander MN was partly diminished, and the reducing rate of DMSO was 42.2%-46.7%, the reducing rate of aminoguanidine was 42% . Conclusion: ROS, NO and their downstream signal factors are involved in the radiation induced bystander effect of hypoxic HepG2 cells. (authors)

Recent advances and opportunities in proteomic analyses of tumour heterogeneity.

Science.gov (United States)

Bateman, Nicholas W; Conrads, Thomas P

2018-04-01

Solid tumour malignancies comprise a highly variable admixture of tumour and non-tumour cellular populations, forming a complex cellular ecosystem and tumour microenvironment. This tumour heterogeneity is not incidental, and is known to correlate with poor patient prognosis for many cancer types. Indeed, non-malignant cell populations, such as vascular endothelial and immune cells, are known to play key roles supporting and, in some cases, driving aggressive tumour biology, and represent targets of emerging therapeutics, such as antiangiogenesis and immune checkpoint inhibitors. The biochemical interplay between these cellular populations and how they contribute to molecular tumour heterogeneity remains enigmatic, particularly from the perspective of the tumour proteome. This review focuses on recent advances in proteomic methods, namely imaging mass spectrometry, single-cell proteomic techniques, and preanalytical sample processing, that are uniquely positioned to enable detailed analysis of discrete cellular populations within tumours to improve our understanding of tumour proteomic heterogeneity. This review further emphasizes the opportunity afforded by the application of these techniques to the analysis of tumour heterogeneity in formalin-fixed paraffin-embedded archival tumour tissues, as these represent an invaluable resource for retrospective analyses that is now routinely accessible, owing to recent technological and methodological advances in tumour tissue proteomics. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress.

Science.gov (United States)

Kim, Kiyoon; Kim, Hunsung; Jeong, Kwon; Jung, Min Hyung; Hahn, Bum-Soo; Yoon, Kyung-Sik; Jin, Byung Kwan; Jahng, Geon-Ho; Kang, Insug; Ha, Joohun; Choe, Wonchae

2012-08-01

Cyclophilin, a cytosolic receptor for the immunosuppressive drug cyclosporin A, plays a role in diverse pathophysiologies along with its receptor, CD147. Although the interaction between cyclophilin A and CD147 is well established in inflammatory disease, that of cyclophilin B (CypB) with CD147 has not been fully explored, especially in cancer cell biology, and the exact molecular mechanism underlying such an association is poorly understood. In this study, we first identified high expression levels of CypB in 54 % of hepatocellular carcinoma patient tissues but in only 12.5 % of normal liver tissues. Then, we demonstrated that CypB overexpression protects human hepatoma cells against oxidative stress through its binding to CD147; this protective effect depends on the peptidyl prolyl isomerase activity of CypB. siRNA-mediated knockdown of CypB expression rendered hepatoma cells more vulnerable to ROS-mediated apoptosis. Furthermore, we also determined that a direct interaction between secreted CypB and CD147 regulates the extracellular signal-regulated kinase intracellular signaling pathway and is indispensible for the protective functions of CypB. For the first time, we demonstrated that CypB has an essential function in protecting hepatoma cells against oxidative stress through binding to CD147 and regulating the ERK pathway.

Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors.

Science.gov (United States)

Yamamoto, Hideaki; Tonello, Jane Marie; Sambuichi, Takanori; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi

2018-01-01

New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver-enriched transcription factors that could be inducibly overexpressed-hepatocyte nuclear factor (HNF)1α, HNF1β, HNF3β [FOXA2], HNF4α, HNF6, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ and C/EBPγ-we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Proof-of-Concept of a Millimeter-Wave Integrated Heterogeneous Network for 5G Cellular

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Shozo Okasaka

2016-08-01

Full Text Available The fifth-generation mobile networks (5G will not only enhance mobile broadband services, but also enable connectivity for a massive number of Internet-of-Things devices, such as wireless sensors, meters or actuators. Thus, 5G is expected to achieve a 1000-fold or more increase in capacity over 4G. The use of the millimeter-wave (mmWave spectrum is a key enabler to allowing 5G to achieve such enhancement in capacity. To fully utilize the mmWave spectrum, 5G is expected to adopt a heterogeneous network (HetNet architecture, wherein mmWave small cells are overlaid onto a conventional macro-cellular network. In the mmWave-integrated HetNet, splitting of the control plane (CP and user plane (UP will allow continuous connectivity and increase the capacity of the mmWave small cells. mmWave communication can be used not only for access linking, but also for wireless backhaul linking, which will facilitate the installation of mmWave small cells. In this study, a proof-of-concept (PoC was conducted to demonstrate the practicality of a prototype mmWave-integrated HetNet, using mmWave technologies for both backhaul and access.

In vitro infectivity of irradiated Plasmodium berghei sporozoites to cultured hepatoma cells

International Nuclear Information System (INIS)

Sigler, C.I.; Leland, P.; Hollingdale, M.R.

1984-01-01

The invasion of gamma-irradiated Plasmodium berghei sporozoites into cultured hepatoma cells and their transformation into trophozoites was similar to invasion and transformation of non-irradiated sporozoites. However, trophozoites from irradiated sporozoites did not further develop into schizonts, but persisted within the cells for up to 3 days. Sporozoite surface protective antigen was present in trophozoites from irradiated and non-irradiated sporozoites, suggesting that hepatocyte antigen processing may contribute to the induction of anti-malarial immunity

Up-regulation of ALG-2 in hepatomas and lung cancer tissue

DEFF Research Database (Denmark)

la Cour, Jonas Marstrand; Mollerup, Jens; Winding, Pernille

2003-01-01

, a result confirmed by immunohistochemical analysis. Staining of four different lung cancer tissue microarrays including specimens of 263 patients showed that ALG-2 is mainly localized to epithelial cells and significantly up-regulated in small-cell lung cancers and in non-small-cell lung cancers. Our...... using Western blot analysis and immunohistochemistry. Western blot analysis of 15 different adult mouse tissues demonstrated that ALG-2 is ubiquitously expressed. We found that ALG-2 was more than threefold overexpressed in rat liver hepatoma compared to normal rat liver using Western blot analysis...

Magnetic targeting of iron-oxide-labeled fluorescent hepatoma cells to the liver

International Nuclear Information System (INIS)

Luciani, Alain; Wilhelm, Claire; Gazeau, Florence; Bruneval, Patrick; Cunin, Patrick; Autret, Gwennhael; Clement, Olivier; Rahmouni, Alain

2009-01-01

The purpose of this study was to determine whether an external magnet field can induce preferential trafficking of magnetically labeled Huh7 hepatoma cells to the liver following liver cell transplantation. Huh7 hepatoma cells were labeled with anionic magnetic nanoparticles (AMNP) and tagged with a fluorescent membrane marker (PKH67). Iron-uptake was measured by magnetophoresis. Twenty C57Bl6 mice received an intrasplenic injection of 2 x 10 6 labeled cells. An external magnet (0.29 T; 25 T/m) was placed over the liver of 13 randomly selected animals (magnet group), while the remaining 7 animals served as controls. MRI (1.5 T) and confocal fluorescence microscopy (CFM) were performed 10 days post-transplantation. The presence and location of labeled cells within the livers were compared in the magnet group and controls, and confronted with histological analysis representing the standard of reference. Mean iron content per cell was 6 pg. Based on histology, labeled cells were more frequently present within recipient livers in the magnet group (p < 0.01) where their distribution was preferentially peri-vascular (p<0.05). MRI and CFM gave similar results for the overall detection of transplanted cells (kappa=0.828) and for the identification of peri-vascular cells (kappa=0.78). Application of an external magnet can modify the trafficking of transplanted cells, especially by promoting the formation of perivascular aggregates. (orig.)

Uptake of 153Sm-DTPA-bis-biotin and 99mTc-DTPA-bis-biotin in rat as-30D-hepatoma cells

International Nuclear Information System (INIS)

Correa-Gonzalez, Luis; Arteaga de Murphy, Consuelo; Ferro-Flores, Guillermina; Pedraza-Lopez, Martha; Murphy-Stack, Eduardo; Mino-Leon, Dolores; Perez-Villasenor, Graciela; Diaz-Torres, Yaneth; Munoz-Olvera, Rodrigo

2003-01-01

Labeled biotin has been used mainly for pretargeted therapy, an approach for increasing the amount of radioactivity delivered to a cancer cell. The aim of this investigation was to prepare 153 Sm-DTPA-bis-biotin and 99m Tc-DTPA-bis-biotin in order to study their in vitro and in vivo uptake in rat AS-30D hepatoma cells found in ascites and in implanted tumor. DTPA-bis-biotin (pH 8) was 153 Sm labeled with 153 SmCl 3 and 99m Tc-DTPA-bis-biotin was prepared via SnCl 2 reduction. Radiochemical purity was >98% in both cases. AS-30D hepatoma cells were obtained from ascites of a rat with hepatoma and were propagated in the peritoneum cavity of normal rats. In vitro ascites cell 153 Sm-DTPA-bis-biotin uptake was compared with 153 SmCl 3 cell uptake. The ratio cell 153 Sm-DTPA-bis-biotin/ 153 SmCl 3 was 39.6 and when avidin was added it increased to 50. The ratio 99m Tc-DTPA-bis-biotin/TcO 4 Na was 8.7. Concentration of 153 Sm-DTPA-bis-biotin in tumor 2, 3 and 24 h after administration, was 5, 15 and 3 times higher than in normal muscle (T/nT). Biodistribution in a 0.083-24 h time period showed that 153 Sm-DTPA-bis-biotin was taken up only by ascites tumor cells and hepatoma cells. Two and 3 h ratio ascites/liver (As/Lv) was 6.4 and 6.0. For 99m Tc-DTPA-bis-biotin 2 and 3 h T/nT was 15.7 and 4.7 and 2 h As/Lv was 1.4. In conclusion, both radiopharmaceuticals show high uptake in rat AS-30D hepatoma cells in ascites and in implanted tumor. Since lung, thyroid, kidney, liver or pancreas carcinomas are ascites producing cancers 153 Sm-DTPA-bis-biotin would be an adequate therapeutic radiopharmaceutical for these patients whose life quality would be enhanced with control of ascites, and a reduction of the primary tumor and its metastases

Case of double cancer of the liver (hepatoma and cholangioma) caused by accumulation of thorotrast

Energy Technology Data Exchange (ETDEWEB)

Masai, K; Watanabe, T [Yanai-Byoin National Sanatorium, (Japan)

1977-03-01

Fairly many cases of delayed disorders caused by thorotrast have been reported. The authors experienced a case of a 65 year old male who had received an infusion of thorotrast solution at the old army hospital 38 years ago and died from liver cirrhosis and hepatic cancer (double cancer of hepatoma and cholangiocarcinoma). By the biopsy after his death, alpha rays were demonstrated in granules of foreign body in hepatic tissues, and in corporation with its contrast, it was certified that a chain of abnormal shadows mainly seen in the liver and the spleen, on the scout film of the abdomen before death, was caused by thorotrast. From pathological findings in hepatic cancers, hepatoma was recognized in the right lobe and cholangioma, in the left lobe, and there was no pathological relationship between the two cancers. Namely, it was double cancer within the same organ. Case of double cancer in the liver such as this case were thought to be very rare in Japan, and a few literature considerations were also reported.

Molecular dynamics study of lipid bilayers modeling the plasma membranes of mouse hepatocytes and hepatomas.

Science.gov (United States)

Andoh, Yoshimichi; Aoki, Noriyuki; Okazaki, Susumu

2016-02-28

Molecular dynamics (MD) calculations of lipid bilayers modeling the plasma membranes of normal mouse hepatocytes and hepatomas in water have been performed under physiological isothermal-isobaric conditions (310.15 K and 1 atm). The changes in the membrane properties induced by hepatic canceration were investigated and were compared with previous MD calculations included in our previous study of the changes in membrane properties induced by murine thymic canceration. The calculated model membranes for normal hepatocytes and hepatomas comprised 23 and 24 kinds of lipids, respectively. These included phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, lysophospholipids, and cholesterol. We referred to previously published experimental values for the mole fraction of the lipids adopted in the present calculations. The calculated structural and dynamic properties of the membranes such as lateral structure, order parameters, lateral self-diffusion constants, and rotational correlation times all showed that hepatic canceration causes plasma membranes to become more ordered laterally and less fluid. Interestingly, this finding contrasts with the less ordered structure and increased fluidity of plasma membranes induced by thymic canceration observed in our previous MD study.

Molecular switch of Cre/loxP for radiation modulated gene therapy on hepatoma

Energy Technology Data Exchange (ETDEWEB)

Hsieh, Y.-J. [Institute of Radiological Sciences, National Yang-Ming University, Taiwan (China); Chen, Fu-Du [Institute of Radiological Sciences, National Yang-Ming University, Taiwan (China); Institute of Radiological Sciences, Central Taiwan University of Science and Technology, Taiwan (China); Wang, F.H. [National Yang-Ming University Medical School, Taiwan (China); Ke, C.C. [National PET/Cyclotron Center, Taipei Veterans General Hospital, Taiwan (China); Wang, H.-E. [Institute of Radiological Sciences, National Yang-Ming University, Taiwan (China); Liu, R.-S. [Institute of Radiological Sciences, National Yang-Ming University, Taiwan (China) and National Yang-Ming University Medical School, Taiwan (China) and National PET/Cyclotron Center, Taipei Veterans General Hospital, Taiwan (China)]. E-mail: maimai5010@yahoo.com.tw

2007-02-01

For the purpose of enhancement of AFP promoter for the use of radiation modulated gene therapy for hepatocellular carcinoma (HCC), we combined hepatitis B virus (HBV) enhancer II with AFP promoter which shows the selectivity to the target cells to control the Cre/loxP system. Different gene constructs, pE4luc, pE4Tk, EIIAPA-Cre, E4CMV-STOP-Tk and chimeric promoters combined with HBV enhancer were constructed and transfected into HepG2, HeLa and NIH-3T3 cell lines. Cell experiments revealed that E4 enhancer responses to radiation best after 60 h irradiation at a dose range of 5-7 Gy in HepG2 stable clone. The EIIAPA promoter provided high specificity to hepatoma and activated the Cre downstream and removed the stop cassette only in hepatoma cells. After removal of the stop cassette, the E4 response to radiation could encode more Tk protein and kill more tumor cells. In summary, the chimeric EIIAPA promoter can stringently control the expression of Cre recombinase only in HCC. The radiation effect of the EIIAPA-Cre and E4CMV-STOP-Tk system shows promising results in terms of cell survival of HCC.

Molecular switch of Cre/loxP for radiation modulated gene therapy on hepatoma

International Nuclear Information System (INIS)

Hsieh, Y.-J.; Chen, Fu-Du; Wang, F.H.; Ke, C.C.; Wang, H.-E.; Liu, R.-S.

2007-01-01

For the purpose of enhancement of AFP promoter for the use of radiation modulated gene therapy for hepatocellular carcinoma (HCC), we combined hepatitis B virus (HBV) enhancer II with AFP promoter which shows the selectivity to the target cells to control the Cre/loxP system. Different gene constructs, pE4luc, pE4Tk, EIIAPA-Cre, E4CMV-STOP-Tk and chimeric promoters combined with HBV enhancer were constructed and transfected into HepG2, HeLa and NIH-3T3 cell lines. Cell experiments revealed that E4 enhancer responses to radiation best after 60 h irradiation at a dose range of 5-7 Gy in HepG2 stable clone. The EIIAPA promoter provided high specificity to hepatoma and activated the Cre downstream and removed the stop cassette only in hepatoma cells. After removal of the stop cassette, the E4 response to radiation could encode more Tk protein and kill more tumor cells. In summary, the chimeric EIIAPA promoter can stringently control the expression of Cre recombinase only in HCC. The radiation effect of the EIIAPA-Cre and E4CMV-STOP-Tk system shows promising results in terms of cell survival of HCC

Synthesis of PBAD-lipiodol nanoparticles for combination treatment with boric acid in boron neutron capture therapy for hepatoma in-vitro

International Nuclear Information System (INIS)

Chou, F.I.; Chung, H.P.; Liu, H.M.; Wen, H.W.; Chi, C.W.; Lin, Shanyang; Lui, W.Y.; Kai, J.J.

2006-01-01

This study attempted to increase BNCT efficiency for hepatoma by a combined treatment of phenylboric acid derivative entrapped lipiodol nanoparticles (PBAD-L nanoparticles) with boric acid. The size of PBAD-L nanoparticles were 400-750 nm at the boron concentrations of 0.3-2.7 mg/ml. After 24 hours the boron concentration in PBAD-L nanoparticles treated human hepatoma HepG2 cells was 112 ppm, while that in rat liver Clone 9 cells was 52 ppm. With the use of 25 μg B/ml boric acid, after 6 hours the boron concentration in HepG2 and Clone 9 cells were 75 ppm and 40 ppm, respectively. In a combined treatment, boron concentration in HepG2 cells which were treated with PBAD-L nanoparticles for 18 hours and then combined with boric acid for 6 hours was 158 ppm. After neutron irradiation, the surviving fraction of HepG2 cells treated with PBAD-L nanoparticles was 12.6%, while that in the ones with a combined treatment was 1.3%. In conclusion, the combined treatment provided a higher boron concentration in HepG2 cells than treatments with either PBAD-L nanoparticles or boric acid, resulting in a higher therapeutic efficacy of BNCT in hepatoma cells. (author)

Bioactive chemical constituents of Curcuma longa L. rhizomes extract inhibit the growth of human hepatoma cell line (HepG2).

Science.gov (United States)

Abdel-Lateef, Ezzat; Mahmoud, Faten; Hammam, Olfat; El-Ahwany, Eman; El-Wakil, Eman; Kandil, Sherihan; Abu Taleb, Hoda; El-Sayed, Mortada; Hassenein, Hanaa

2016-09-01

The present study was designed to identify the chemical constituents of the methanolic extract of Curcuma longa L. rhizomes and their inhibitory effect on a hepatoma cell line. The methanolic extract was subjected to GC-MS analysis to identify the volatile constituents and the other part of the same extract was subjected to liquid column chromatographic separation to isolate curcumin. The inhibition of cell growth in the hepatoma cell line and the cytopathological changes were studied. GC-MS analysis showed the presence of fifty compounds in the methanolic extract of C. longa. The major compounds were ar-turmerone (20.50 %), β-sesquiphellandrene (5.20 %) and curcumenol (5.11 %). Curcumin was identified using IR, 1H and 13C NMR. The inhibition of cell growth by curcumin (IC50 = 41.69 ± 2.87 μg mL-1) was much more effective than that of methanolic extract (IC50 = 196.12 ± 5.25 μg mL-1). Degenerative and apoptotic changes were more evident in curcumin- treated hepatoma cells than in those treated with the methanol extract. Antitumor potential of the methanolic extract may be attributed to the presence of sesquiterpenes and phenolic constituents including curcumin (0.051 %, 511.39 μg g-1 dried methanol extract) in C. longa rhizomes.

Value of an hepatobiliary imaging agent for diagnosing hepatoma. Example of diethyl-IDA

Energy Technology Data Exchange (ETDEWEB)

Bourguet, P; Estable, P; Herry, J Y

1985-01-01

A comparative study was performed using two hepatic tracers, a Tc 99m labelled colloid and an hepatobiliary agent Tc 99m labelled diethyl-IDA. In some patients with isolated primary hepatocarcinoma the uptake of the hepatobiliary agent was observed but the colloid was not taken up. In the contrary, the hepatobiliary agent has proved to be of limited value for the diagnosis of hepatomas coexisting with cirrhosis and for the detection of secondary hepatocarcinoma.

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Directory of Open Access Journals (Sweden)

Fanyun Kong

2016-11-01

Full Text Available Abstract Background Interleukin-7 receptor (IL-7R is involved in the abnormal function of solid tumors, but the role and regulatory mechanisms of IL-7R in HBV-related hepatocellular carcinoma (HCC are still unclear. Methods Gene and protein expression levels of IL-7R were examined in hepatoma cells transfected with hepatitis B virus (HBV plasmids and in hepatoma cells transfected with the multifunctional nonstructural protein X (HBX. The expression of HBX and IL-7R was measured by immunohistochemical analysis in HBV-related HCC tissues. The role of NF-κB and Notch1 pathways in HBX-mediated expression of IL-7R in hepatoma cells was examined. Activation of IL-7R downstream of intracellular signaling proteins AKT, JNK, STAT5, and the associated molecules CyclinD1 and matrix metalloproteinase-9 (MMP-9, was assessed in HBX-positive cells with or without treatment with IL-7R short hairpin RNA (shRNA. Additionally, the role of IL-7R in HBX-mediated proliferation and migration of hepatoma cells was investigated. Results The expression of IL-7R was increased in hepatoma cells transfected with HBV plasmids; HBX was responsible for the HBV-mediated upregulation of IL-7R. Compared to adjacent tissues, the expression of HBX and IL-7R was increased in HBV-related HCC tissues. Additionally, the relative expression levels of HBX were associated with IL-7R in HBV-related HCC tissues. The activation of NF-κB pathways and expression of Notch1 were increased in hepatoma cells transfected with HBX, and inhibition of NF-κB and Notch1 pathways significantly decreased HBX-mediated expression of IL-7R. The activation of AKT and JNK and the expression of CyclinD1 and MMP-9 were increased in HBX-positive cells. When cells were treated with IL-7R shRNA, the activation of AKT and JNK, as well as the expression of CyclinD1 and MMP-9, were significantly inhibited. Additionally, IL-7R was responsible for HBX-induced proliferation and migration ability of hepatoma cells

Characterization of Cellular and Molecular Heterogeneity of Bone Marrow Stromal Cells

DEFF Research Database (Denmark)

Elsafadi, Mona; Manikandan, Muthurangan; Atteya, Muhammad

2016-01-01

and osteoblast differentiation genes which included several homeobox genes: TBX15, HOXA2 and HOXA10, and IGF1, FGFR3, BMP6, MCAM, ITGA10, IGFBP5, and ALP. siRNA-based downregulation of the ALP gene in CL1 impaired osteoblastic and adipocytic differentiation. Our studies demonstrate the existence of molecular......Human bone marrow-derived stromal stem cells (hBMSC) exhibit multiple functions, including differentiation into skeletal cells (progenitor function), hematopoiesis support, and immune regulation (nonprogenitor function). We have previously demonstrated the presence of morphological and functional...... and functional heterogeneity in cultured hBMSC. ALP can be employed to identify osteoblastic and adipocytic progenitor cells in the heterogeneous hBMSC cultures...

Value of an hepatobiliary imaging agent for diagnosing hepatoma. Example of diethyl-IDA

International Nuclear Information System (INIS)

Bourguet, P.; Estable, P.; Herry, J.Y.

1985-01-01

A comparative study was performed using two hepatic tracers, a Tc 99m labelled colloid and an hepatobiliary agent Tc 99m labelled diethyl-IDA. In some patients with isolated primary hepatocarcinoma the uptake of the hepatobiliary agent was observed but the colloid was not taken up. In the contrary, the hepatobiliary agent has proved to be of limited value for the diagnosis of hepatomas coexisting with cirrhosis and for the detection of secondary hepatocarcinoma [fr

Magnetic targeting of iron-oxide-labeled fluorescent hepatoma cells to the liver

Energy Technology Data Exchange (ETDEWEB)

Luciani, Alain [Universite Rene Descartes, Hopital Europeen Georges Pompidou, Laboratoire de Recherche en Imagerie, EA 4062, Paris (France); Imagerie Medicale, Faculte de Medecine Paris XII, CHU Henri Mondor, Creteil cedex (France); Wilhelm, Claire; Gazeau, Florence [Universite Paris Diderot, Batiment Condorcet, Laboratoire Matiere et Systemes Complexes, CNRS-UMR 7057, Paris Cedex (France); Bruneval, Patrick [Anatomopathologie, Hopital Europeen Georges Pompidou, Paris (France); Cunin, Patrick [Unite de Recherche Clinique, Faculte de Medecine Paris XII, CHU Henri Mondor, Creteil cedex (France); Autret, Gwennhael; Clement, Olivier [Universite Rene Descartes, Hopital Europeen Georges Pompidou, Laboratoire de Recherche en Imagerie, EA 4062, Paris (France); Rahmouni, Alain [Imagerie Medicale, Faculte de Medecine Paris XII, CHU Henri Mondor, Creteil cedex (France)

2009-05-15

The purpose of this study was to determine whether an external magnet field can induce preferential trafficking of magnetically labeled Huh7 hepatoma cells to the liver following liver cell transplantation. Huh7 hepatoma cells were labeled with anionic magnetic nanoparticles (AMNP) and tagged with a fluorescent membrane marker (PKH67). Iron-uptake was measured by magnetophoresis. Twenty C57Bl6 mice received an intrasplenic injection of 2 x 10{sup 6} labeled cells. An external magnet (0.29 T; 25 T/m) was placed over the liver of 13 randomly selected animals (magnet group), while the remaining 7 animals served as controls. MRI (1.5 T) and confocal fluorescence microscopy (CFM) were performed 10 days post-transplantation. The presence and location of labeled cells within the livers were compared in the magnet group and controls, and confronted with histological analysis representing the standard of reference. Mean iron content per cell was 6 pg. Based on histology, labeled cells were more frequently present within recipient livers in the magnet group (p < 0.01) where their distribution was preferentially peri-vascular (p<0.05). MRI and CFM gave similar results for the overall detection of transplanted cells (kappa=0.828) and for the identification of peri-vascular cells (kappa=0.78). Application of an external magnet can modify the trafficking of transplanted cells, especially by promoting the formation of perivascular aggregates. (orig.)

Glyco-nanoparticles with sheddable saccharide shells: A unique and potent platform for hepatoma-targeting delivery of anticancer drugs

NARCIS (Netherlands)

Chen, Wei; Zou, Yan; Meng, Fenghua; Cheng, Ru; Deng, Chao; Feijen, Jan; Zhong, Zhiyuan

2014-01-01

Reduction-sensitive shell-sheddable glyco-nanoparticles were designed and developed based on poly(ε-caprolactone)-graft-SS-lactobionic acid (PCL-g-SS-LBA) copolymer for efficient hepatoma-targeting delivery of doxorubicin (DOX). PCL-g-SS-LBA was prepared by ring-opening copolymerization of

A case of double cancer of the liver (hepatoma and cholangioma) caused by accumulation of thorotrast

International Nuclear Information System (INIS)

Masai, Kenji; Watanabe, Tadashi

1977-01-01

Fairly many cases of delayed disorders caused by thorotrast have been reported. The authors experienced a case of 65 year old male who had received an infusion of thorotrast solution at the old army hospital 38 years ago and died for liver cirrhosis and hepatic cancer (double cancer of hepatoma and cholangiocarcinoma). By the biopsy after his death, alpha ray was proved in granules of foreign body in hepatic tissues, and in corporation with its contrast, it was certified that a chain of abnormal shadows mainly seen in the liver and the spleen, on the scout film of the abdomen before death, was caused by thorotrast. From pathological findings in hepatic cancers, hepatoma was recognized in the right lobe and cholangioma, in the left lobe, and there was no pathological relationship between two cancers. Namely, it was double cancer within the same organ. Case of double cancer in the liver such as this case was thought to be very rare in Japan, and a few literature considerations were also reported. (Tsunoda, M.)

Inhibitory effects of α-pinene on hepatoma carcinoma cell proliferation.

Science.gov (United States)

Chen, Wei-Qiang; Xu, Bin; Mao, Jian-Wen; Wei, Feng-Xiang; Li, Ming; Liu, Tao; Jin, Xiao-Bao; Zhang, Li-Rong

2014-01-01

Pine needle oil from crude extract of pine needles has anti-tumor effects, but the effective component is not known. In the present study, compounds from a steam distillation extract of pine needles were isolated and characterized. Alpha-pinene was identified as an active anti-proliferative compound on hepatoma carcinoma BEL-7402 cells using the MTT assay. Further experiments showed that α-pinene inhibited BEL-7402 cells by arresting cell growth in the G2/M phase of the cell cycle, downregulating Cdc25C mRNA and protein expression, and reducing cycle dependence on kinase 1(CDK1) activity. Taken together, these findings indicate that α-pinene may be useful as a potential anti-tumor drug.

Glucocorticoid-regulated and constitutive trafficking of proteolytically processed cell surface-associated glycoproteins in wild type and variant rat hepatoma cells

International Nuclear Information System (INIS)

Amacher, S.L.; Goodman, L.J.; Bravo, D.A.; Wong, K.Y.; Goldfine, I.D.; Hawley, D.M.; Firestone, G.L.

1989-01-01

Glucocorticoids regulate the trafficking of mouse mammary tumor virus (MMTV) glycoproteins to the cell surface in the rat hepatoma cell line M1.54, but not in the immunoselected sorting variant CR4. To compare the localization of MMTV glycoproteins to another proteolytically processed glycoprotein, both wild type M1.54 cells and variant CR4 cells were transfected with a human insulin receptor (hIR) expression vector, pRSVhIR. The production of cell surface hIR was monitored in dexamethasone-treated and -untreated wild type M1.54 and variant CR4 cells by indirect immunofluorescence, direct plasma membrane immunoprecipitation, and by [125I] insulin binding. In both wild type and variant rat hepatoma cells, hIR were localized at the cell surface in the presence or in the absence of 1 microM dexamethasone. In contrast, the glucocorticoid-regulated trafficking of cell surface MMTV glycoproteins occurred only in wild type M1.54 cells. We conclude that the hIR, which undergoes posttranslational processing reactions similar to MMTV glycoproteins, does not require glucocorticoids to be transported to the plasma membrane and is representative of a subset of cell surface glycoproteins whose trafficking is constitutive in rat hepatoma cells. Thus, MMTV glycoproteins and hIR provide specific cell surface markers to characterize the glucocorticoid-regulated and constitutive sorting pathways

Radiosensitization by inhibiting survivin in human hepatoma HepG2 cells to high-LET radiation

International Nuclear Information System (INIS)

Jin Xiaodong; Li Qiang; Wu Qingfeng; Li Ping; Gong Li; Hao Jifang; Dai Zhongying; Matsumoto, Yoshitaka; Furusawa, Yoshiya

2011-01-01

In this study, whether survivin plays a direct role in mediating high-linear energy transfer (LET) radiation resistance in human hepatoma cells was investigated. Small interfering RNA (siRNA) targeting survivin mRNA was designed and transfected into human hepatoma HepG2 cells. Real-time polymerase chain reaction (PCR) and western blotting analyses revealed that survivin expression in HepG2 cells decreased at both transcriptional and post-transcriptional levels after treatment with survivin-specific siRNA. Caspase-3 activity was determined with a microplate reader assay as well. Following exposure to high-LET carbon ions, a reduced clonogenic survival effect, increased apoptotic rates and caspase-3 activity were observed in the cells treated with the siRNA compared to those untreated with the siRNA. The cells with transfection of the survivin-specific siRNA also increased the level of G 2 /M arrest. These results suggest that survivin definitely plays a role in mediating the resistance of HepG2 cells to high-LET radiation and depressing survivin expression might be useful to improve the therapeutic efficacy of heavy ions for radioresistant solid tumors. (author)

Clinical impact of leukemic blast heterogeneity at diagnosis in cytogenetic intermediate-risk acute myeloid leukemia

DEFF Research Database (Denmark)

Hoffmann, Marianne Hutchings; Klausen, Tobias Wirenfeldt; Boegsted, Martin

2012-01-01

Individual cellular heterogeneity within the acute myeloid leukemia (AML) bone marrow samples can be observed by multi parametric flow cytometry analysis (MFC) indicating that immunophenotypic screening for leukemic blast subsets may have prognostic impact.......Individual cellular heterogeneity within the acute myeloid leukemia (AML) bone marrow samples can be observed by multi parametric flow cytometry analysis (MFC) indicating that immunophenotypic screening for leukemic blast subsets may have prognostic impact....

Cellular automaton for surface reactions

Energy Technology Data Exchange (ETDEWEB)

Pechatnikov, E L [AN SSSR, Chernogolovka (Russian Federation). Otdelenie Inst. Khimicheskoj Fiziki; Frankowicz, A; Danielak, R [Uniwersytet Jagiellonski, Cracow (Poland)

1994-06-01

A new algorithm which overcomes some specific difficulties arising in modeling of heterogeneous catalytic processes by cellular automata (CA) technique is proposed. The algorithm was tested with scheme introduced by Ziff, Gulari and Barshad and showed a good agreement with their results. The problem of the physical adequacy and interpretation of the algorithm was discussed. (author). 10 refs, 4 figs.

Folate-targeted paclitaxel-conjugated polymeric micelles inhibits pulmonary metastatic hepatoma in experimental murine H22 metastasis models

Directory of Open Access Journals (Sweden)

Zhang Y

2014-04-01

Full Text Available Yan Zhang,1 Hui Zhang,2 Wenbin Wu,2 Fuhong Zhang,3,4 Shi Liu,3 Rui Wang,3 Yingchun Sun,1 Ti Tong,1 Xiabin Jing3 1Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China; 2Department of Thoracic Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, People's Republic of China; 3State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China; 4Department of Otolaryngology, The First Hospital of Lanzhou University, Lanzhou, Gansu, People's Republic of China Abstract: Hepatocellular carcinoma shows low response to most conventional chemotherapies; additionally, extrahepatic metastasis from hepatoma is considered refractory to conventional systemic chemotherapy. Target therapy is a promising strategy for advanced hepatoma; however, targeted accumulation and controlled release of therapeutic agents into the metastatic site is still a great challenge. Folic acid (FA and paclitaxel (PTX containing composite micelles (FA-M[PTX] were prepared by coassembling the FA polymer conjugate and PTX polymer conjugate. The main purpose of this study is to investigate the inhibitory efficacy of FA-M(PTX on the pulmonary metastasis of intravenously injected murine hepatoma 22 (H22 on BALB/c mice models. The lung metastatic burden of H22 were measured and tissues were analyzed by immunohistochemistry and histology (hematoxylin and eosin stain, followed by survival analysis. The results indicated that FA-M(PTX prevented pulmonary metastasis of H22, and the efficacy was stronger than pure PTX and simple PTX-conjugated micelles. In particular, the formation of lung metastasis colonies in mice was evidently inhibited, which was paralleled with the downregulated expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, the mice bearing pulmonary metastatic hepatoma in the FA

INVESTIGATION OF HYPOLIPIDEMIC EFFECT OF SESQUITERPENE Γ-LACTONE AHILLIN IN HEPATOMA TISSUE CULTURE (HTC CELLS

Directory of Open Access Journals (Sweden)

V. V. Ivanov

2014-01-01

Full Text Available Objective. Investigation of hypolipidemic effect of sesquiterpene γ-lactone ahillin in hepatoma tissue culture (HTC cells.Material and methods. In this study we’ve evaluated the effect of γ-lactone sesquiterpene aсhillin and gemfibrozil (comparator drug on the lipid content in the hepatoma tissue culture (HTC cell which were incubated with a fat emulsion lipofundin by fluorescent method with vital dye Nile Redand staining the cells with the dye Oil Red O. The cell viability was investigated using the MTT-test and staining with Trypan blue.Results. Cultivation cells HTC with aсhillin and gemfibrozilat concentrations ranging from 0.5 to1.5 mM and from0.25 mM to0.5 mM, respectively, resulted in dose-dependent decrease of the fluorescence’s intensity Nile Red. It reflects a decrease in lipid content in the cells. At these concentrations the drugs didn’t have cytotoxic effect and the cell viability didn’t change compared to the control culture.An experimental hyperlipidemia in the hepatoma culture cells was induced by adding to the incubation medium a fat emulsion lipofundin at a final concentration 0.05%. The intensity of fluorescence Nile Red in the cells was increased 4 fold (p < 0.05. This result suggests the significant accumulation of lipids in the cell’s cytosol and confirmed by microscopy after staining neutral lipids with the dye Oil Red O. Under these conditions aсhillin and gemfibrozil reduced lipid content in cells and hadthe effect at concentrations of0.5 mM and0.25 mM respectively.Conclusion. In the lipofundin-mediated model of hyperlipidemia the sesquiterpene lactone aсhillin prevents the lipid accumulation in cells. It confirms by decrease of fluorescence Nile Red and reduction lipid drops which were stained with Oil Red O in cytosol. To establish the molecular targets of aсhillin’saction on lipid metabolism in cell culture HTC we need to investigate a gene expression of key enzymes of lipid metabolism.

Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

International Nuclear Information System (INIS)

Inda, Maria-del-Mar; Bonavia, Rudy; Seoane, Joan

2014-01-01

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape

Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

Energy Technology Data Exchange (ETDEWEB)

Inda, Maria-del-Mar, E-mail: mminda@vhio.net; Bonavia, Rudy [Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 119-129 Passeig Vall d’Hebron, Barcelona 08035 (Spain); Seoane, Joan [Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 119-129 Passeig Vall d’Hebron, Barcelona 08035 (Spain); Catalan Institution of Research and Advanced Studies (ICREA), Barcelona 08035 (Spain)

2014-01-27

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

Directory of Open Access Journals (Sweden)

Maria-del-Mar Inda

2014-01-01

Full Text Available Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM, the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

Glioblastoma multiforme: a look inside its heterogeneous nature.

Science.gov (United States)

Inda, Maria-Del-Mar; Bonavia, Rudy; Seoane, Joan

2014-01-27

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

Hepatoscintiangiography of normal liver and its alteration in hepatomas and liver abscess

International Nuclear Information System (INIS)

Bahk, Y.W.; Chung, S.K.

1984-01-01

This study was performed to establish normal hepatoscintiangiographic (HSA) pattern of hepatic blood flow and to investigate differential HSA findings of primary and metastatic carcinomas and abscess of the liver. HSA was carried out after intravenous bolus injection of l0 mCi of Tc-99m-phytate by obtaining sequential anterior images of 1-second exposure for 16 seconds. Observations included (1) baseline study of normal hepatic blood flow patterns by correlating with contrast angiogram, (2) time-sequence phasing of normal HSA, and (3) analysis of altered patterns in primary and metastatic carcinomas and abscess of the liver. Results were: (1) Normal HSA demonstrated 3 distinct phases of arterialization (AP), arterial hepatrogram (AHP), and portal venous hepatogram (PVHP). The means of each phase were 5.3, 6.3, and 8.3 seconds, respectively. Portal vein could be seen in all but one of 20 normal subjects. (2) Pattern changes in disease groups were early start of AP in carcinomas and very early start of AP in abscess. AP became prolonged in all disease groups. (3) Distinction between AHP and PVHP was sharp in metastasis and abscess but was unsharp in primary hepatoma. Cold area or areas became vascularized in primary hepatoma but not in abscess. Cold areas of metastasis were inhomogenously vascularized in late AP and throughout AHP and became relatively avascular as PVHP began. The cold area of abscess showed rim enhancement during AH and APH. These differences in HSA pattern were very useful in differential diagnosis of the diseases studied

Chylomicron remnant-vitamin A metabolism by the human hepatoma cell line HepG2

International Nuclear Information System (INIS)

Lenich, C.M.

1985-01-01

The binding and metabolism of [ 3 H] vitamin A-containing chylomicron remnants (CMR) by the human hepatoma cell line Hep G2 was studied. Mesenteric lymph chylomicrons (CM) were collected from [ 3 H] retinol-fed rats and incubated with lipoprotein-lipase to obtain CMR. At 4 0 C, specific CMR binding was inhibited by excess unlabeled CMR. Specific binding predominated at low concentrations and approached saturation while total binding continued to increase over an extensive concentration range (0.45-32 μg triglyceride/ml). CMR uptake at 37 0 C was greater than that of CM and at least 100 times more efficient than the fluid-phase pinocytosis of sucrose. CMR binding increased as the extent of lipolysis obtained by incubation with lipoprotein-lipase increased. Addition of human apolipoprotein E enhanced both CMR and CM binding. After internalization, Hep G2 cells hydrolyzed CMR-[ 3 H]retinyl esters and radiolabeled metabolites accumulated as a function of time and temperature. As a function of the concentration of [ 3 H] VA initially cell-bound, retinol and retinyl esters accumulated as the major cell-associated metabolites. By contrast, retinol was the major metabolite in the medium only at low VA concentrations as other more polar metabolites accumulated at higher concentrations (> 110 pmol VA/mg cell protein). The accumulation of CMR-VA metabolites in the medium was reduced when cells were preincubated in retinol-supplemented media. Also, the specific activity of retinol in the medium closely resembled that in the cell indicating that CMR-VA mixed with the cellular store prior to its secretion

The interaction of HAb18G/CD147 with integrin α6β1 and its implications for the invasion potential of human hepatoma cells

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Tang Juan

2009-09-01

Full Text Available Abstract Background HAb18G/CD147 plays pivotal roles in invasion by hepatoma cells, but the underlying mechanism remains unclear. Our previous study demonstrated that overexpression of HAb18G/CD147 promotes invasion by interacting with integrin α3β1. However, it has never been investigated whether α3β1 is solely responsible for this process or if other integrin family members also interact with HAb18G/CD147 in human hepatoma cells. Methods Human SMMC-7721 and FHCC98 cells were cultured and transfected with siRNA fragments against HAb18G/CD147. The expression levels of HAb18G/CD147 and integrin α6β1 were determined by immunofluorescent double-staining and confocal imaging analysis. Co-immunoprecipitation and Western blot analyses were performed to examine the native conformations of HAb18G/CD147 and integrin α6β1. Invasion potential was evaluated with an invasion assay and gelatin zymography. Results We found that integrin α6β1 co-localizes and interacts with HAb18G/CD147 in human hepatoma cells. The enhancing effects of HAb18G/CD147 on invasion capacity and secretion of matrix metalloproteinases (MMPs were partially blocked by integrin α6β1 antibodies (P 2+ mobilization, significantly reduced cell invasion potential and secretion of MMPs in human hepatoma cells (P Conclusion These results suggest that α6β1 interacts with HAb18G/CD147 to mediate tumor invasion and metastatic processes through the PI3K pathway.

Hepatoma-derived growth factor and nucleolin exist in the same ribonucleoprotein complex

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Bremer Stephanie

2013-01-01

Full Text Available Abstract Background Hepatoma-derived growth factor (HDGF is a protein which is highly expressed in a variety of tumours. HDGF has mitogenic, angiogenic, neurotrophic and antiapoptotic activity but the molecular mechanisms by which it exerts these activities are largely unknown nor has its biological function in tumours been elucidated. Mass spectrometry was performed to analyse the HDGFStrep-tag interactome. By Pull–down-experiments using different protein and nucleic acid constructs the interaction of HDGF and nucleolin was investigated further. Results A number of HDGFStrep-tag copurifying proteins were identified which interact with RNA or are involved in the cellular DNA repair machinery. The most abundant protein, however, copurifying with HDGF in this approach was nucleolin. Therefore we focus on the characterization of the interaction of HDGF and nucleolin in this study. We show that expression of a cytosolic variant of HDGF causes a redistribution of nucleolin into the cytoplasm. Furthermore, formation of HDGF/nucleolin complexes depends on bcl-2 mRNA. Overexpression of full length bcl-2 mRNA increases the number of HDGF/nucleolin complexes whereas expression of only the bcl-2 coding sequence abolishes interaction completely. Further examination reveals that the coding sequence of bcl-2 mRNA together with either the 5′ or 3′ UTR is sufficient for formation of HDGF/nucleolin complexes. When bcl-2 coding sequence within the full length cDNA is replaced by a sequence coding for secretory alkaline phosphatase complex formation is not enhanced. Conclusion The results provide evidence for the existence of HDGF and nucleolin containing nucleoprotein complexes which formation depends on the presence of specific mRNAs. The nature of these RNAs and other components of the complexes should be investigated in future.

A study on the thermochemotherapy effect of nanosized As2O3/MZF thermosensitive magnetoliposomes on experimental hepatoma in vitro and in vivo

Science.gov (United States)

Wang, Li; Zhang, Jia; An, Yanli; Wang, Ziyu; Liu, Jing; Li, Yutao; Zhang, Dongsheng

2011-08-01

In this paper, we describe the synthesis and characterization of a nanosized, thermosensitive magnetoliposome encapsulating magnetic nanoparticles (MZFs) and antitumor drugs (As2O3). The nanoliposomes were spherical and mostly single volume, with an average diameter of 128.2 nm. Differential scanning calorimetry (DSC) showed a liposome phase transition temperature of 42.71 °C. After that, we studied the liposomes' anti-hepatoma effect in vitro and in vivo. The antitumor effect of the nanoliposomes on human hepatoma cells, SMMC-7721, and changes in expression of apoptosis-related proteins were examined in vitro. The results show that As2O3/MZF thermosensitive magnetoliposomes combined with hyperthermia had a great impact on the Bax/Bcl-2 ratio, which increased to 1.914 and exhibited a rapid response to induce apoptosis of tumor cells. An in situ rabbit liver tumor model was established and used to evaluate the antitumor effect of combined hyperthermia and chemotherapy following transcatheter arterial embolization with As2O3/MZF thermosensitive magnetoliposomes. The results demonstrated a strong anti-hepatoma effect, with a tumor volume inhibition rate of up to 85.22%. Thus, As2O3/MZF thermosensitive magnetoliposomes may play a great role in the treatment of hepatocarcinoma.

Retroperitoneal Cellular Angiofibroma: A Rare Gynecological Entity

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Ana Brandão

2017-12-01

Full Text Available Cellular angiofibroma is a mesenchymal tumor, described in 1997, without gender preference, that usually appears at age 40. The vulvovaginal area is the most common site in women, mimicking vulvar benign tumors, like Bartholin gland cyst. However, there are a few described cases of a deep or extra-pelvic angiofibroma. Excision is the treatment of choice and the recurrence rate appears to be low. We present the case of a woman with a heterogeneous tumor in the right adnexial region. At the surgery, a retroperitoneal tumor was excised and the histopathological tissue analysis revealed a cellular angiofibroma.

Elimination of Cancer Stem-Like “Side Population” Cells in Hepatoma Cell Lines by Chinese Herbal Mixture “Tien-Hsien Liquid”

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Chih-Jung Yao

2012-01-01

Full Text Available There are increasing pieces of evidence suggesting that the recurrence of cancer may result from a small subpopulation of cancer stem cells, which are resistant to the conventional chemotherapy and radiotherapy. We investigated the effects of Chinese herbal mixture Tien-Hsien Liquid (THL on the cancer stem-like side population (SP cells isolated from human hepatoma cells. After sorting and subsequent culture, the SP cells from Huh7 hepatoma cells appear to have higher clonogenicity and mRNA expressions of stemness genes such as SMO, ABCG2, CD133, β-catenin, and Oct-4 than those of non-SP cells. At dose of 2 mg/mL, THL reduced the proportion of SP cells in HepG2, Hep3B, and Huh7 cells from 1.33% to 0.49%, 1.55% to 0.43%, and 1.69% to 0.27%, respectively. The viability and colony formation of Huh7 SP cells were effectively suppressed by THL dose-dependently, accompanied with the inhibition of stemness genes, e.g., ABCG2, CD133, and SMO. The tumorigenicity of THL-treated Huh7 SP cells in NOD/SCID mice was also diminished. Moreover, combination with THL could synergize the effect of doxorubicin against Huh7 SP cells. Our data indicate that THL may act as a cancer stem cell targeting therapeutics and be regarded as complementary and integrative medicine in the treatment of hepatoma.

Comparison of the effect of interferon on two human hepatoma cell lines

Energy Technology Data Exchange (ETDEWEB)

Crespi, M; Schoub, B D; Lyons, S F; Chiu, M N [University of the Witwatersrand, Johannesburg (South Africa). Dept. of Virology

1985-06-01

Two human hepatoma cell lines, the PLC/PRF/5 and the Mahlavu cells, which differ in their production of the hepatitis B surface antigen (HBsAg), responded differently to interferon (IFN). After IFN treatment both cell lines were able to inhibit Sindbis virus replication. Oligo A synthetase (E enzyme) could be activated in the PLC/PRF/5 cells although they were not sensitive to exogenous 2 - 5 oligoadenylic acid (2 - 5 A). In contrast, the Mahlavu cells were sensitive to exogenous 2 - 5 A, but unable to activate the E enzyme. Both cell lines were unable to stimulate phosphorylation of the exogenous initiator factor eIF-2.

Stimulation of Hepatoma Cell Invasiveness and Metastatic Potential by Proteins Secreted From Irradiated Nonparenchymal Cells

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Zhou Leyuan [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai (China); Wang Zhiming [Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai (China); Gao Yabo [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai (China); Wang Lingyan [Experimental Research Center, Zhongshan Hospital, Fudan University, Shanghai (China); Zeng Zhaochong, E-mail: zeng.zhaochong@zs-hospital.sh.cn [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai (China)

2012-11-01

Purpose: To determine whether factors secreted by irradiated liver nonparenchymal cells (NPCs) may influence invasiveness and/or metastatic potential of hepatocellular carcinoma (HCC) cells and to elucidate a possible mechanism for such effect. Methods and Materials: Primary rat NPCs were cultured and divided into irradiated (10-Gy X-ray) and nonirradiated groups. Forty-eight hours after irradiation, conditioned medium from irradiated (SR) or nonirradiated (SnonR) cultures were collected and added to sublethally irradiated cultures of the hepatoma McA-RH7777 cell line. Then, hepatoma cells were continuously passaged for eight generations (RH10Gy-SR and RH10Gy-SnonR). The invasiveness and metastatic potential of McA-RH7777, RH10Gy-SnonR, and RH10Gy-SR cells were evaluated using an in vitro gelatinous protein (Matrigel) invasion and an in vivo metastasis assay. In addition, SR and SnonR were tested using rat cytokine antibody arrays and enzyme-linked immunosorbent assay (ELISA). Results: In vitro gelatinous protein invasion assay indicated that the numbers of invading cells was significantly higher in RH10Gy-SR (40 {+-} 4.74) than in RH10Gy-SnonR (30.6 {+-} 3.85) cells, and lowest in McA-RH7777 (11.4 {+-} 3.56) cells. The same pattern was observed in vivo in a lung metastasis assay, as evaluated by number of metastatic lung nodules seen with RH10Gy-SR (28.83 {+-} 5.38), RH10Gy-SnonR (22.17 {+-} 4.26), and McA-RH7777 (8.3 {+-} 3.8) cells. Rat cytokine antibody arrays and ELISA demonstrated that metastasis-promoting cytokines (tumor necrosis factor-{alpha} and interleukin-6), circulating growth factors (vascular endothelial growth factor and epidermal growth factor), and metalloproteinases (MMP-2 and MMP-9) were upregulated in SR compared with SnonR. Conclusions: Radiation can increase invasiveness and metastatic potential of sublethally irradiated hepatoma cells, and soluble mediators released from irradiated NPCs promote this potential. Increased secretion of

Heterogeneity and weak coupling may explain the synchronization characteristics of cells in the arterial wall

DEFF Research Database (Denmark)

Jacobsen, Jens Christian Brings; Aalkjær, Christian; Matchkov, Vladimir

2008-01-01

development of force known as vasomotion. We present experimental data showing a considerable heterogeneity in cellular calcium dynamics in the vascular wall. In stimulated vessels, some SMCs remain quiescent, whereas others display waves of variable frequency. At the onset of vasomotion, all SMCs...... are enrolled into synchronized oscillation.Simulations of coupled SMCs show that the experimentally observed cellular recruitment, the presence of quiescent cells and the variation in oscillation frequency may arise if the cell population is phenotypically heterogeneous. In this case, quiescent cells can...

Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2

International Nuclear Information System (INIS)

Niklas, Jens; Noor, Fozia; Heinzle, Elmar

2009-01-01

Commonly used cytotoxicity assays assess the toxicity of a compound by measuring certain parameters which directly or indirectly correlate to the viability of the cells. However, the effects of a given compound at concentrations considerably below EC 50 values are usually not evaluated. These subtoxic effects are difficult to identify but may eventually cause severe and costly long term problems such as idiosyncratic hepatotoxicity. We determined the toxicity of three hepatotoxic compounds, namely amiodarone, diclofenac and tacrine on the human hepatoma cell line Hep G2 using an online kinetic respiration assay and analysed the effects of subtoxic concentrations of these drugs on the cellular metabolism by using metabolic flux analysis. Several changes in the metabolism could be detected upon exposure to subtoxic concentrations of the test compounds. Upon exposure to diclofenac and tacrine an increase in the TCA-cycle activity was observed which could be a signature of an uncoupling of the oxidative phosphorylation. The results indicate that metabolic flux analysis could serve as an invaluable novel tool for the investigation of the effects of drugs. The described methodology enables tracking the toxicity of compounds dynamically using the respiration assay in a range of concentrations and the metabolic flux analysis permits interesting insights into the changes in the central metabolism of the cell upon exposure to drugs.

Induction of DNA double-strand breaks in hepatoma cell SMMC-7721 by accelerated carbon ion 12C6+

International Nuclear Information System (INIS)

Lei Suwen; Su Xu; Wang Jufang; Zhao Jing; Li Wenjian

2004-01-01

DNA lesions, especially DNA double-strand breaks (dsbs), are looked upon as the dominant molecular effect of radiation action. Dsbs mark the beginning of a cascade of cellular processes that either results in complete repair of the DNA damage or lead to deleterious stages such as mutation, transformation or even cell death. Changing the radiation quality can influence the radiosensitivity of cells in culture. Accelerated particles provide an excellent means of varying the ionization density of the test radiation. With ion beams, the molecular mechanisms underlying the biological consequences of high linear energy transfer (LET) irradiation can be studied and describing radiation action with biophysical models can be tested. In this paper, radiation-induced DNA double-strand breaks (dsbs) were measured in hepatoma SMMC-7721 cells by means of an experimental approach involving pulsed-field gel electrophoresis and densitometric scanning of ethidium bromide stained gels. With this set-up, the induction of dsbs was investigated in SMMC-7721 cells after irradiation with accelerated carbon ions with specific LET 70 keV/μm. The fraction of DNA retained was taken as quantitative measure to calculate absolute yields of induced DNA dsbs. Experimental data shows that the induction of DNA dsbs increasing with the dose of irradiation. Data are compared with published results on dsbs induction in mammalian cells by radiations of comparable LET

Intratumoral heterogeneity as a confounding factor in clonogenic assays for tumour radioresponsiveness

International Nuclear Information System (INIS)

Britten, R.A.; Evans, A.J.; Allalunis-Turner, M.J.; Franko, A.J.; Pearcey, R.G.

1996-01-01

The level of intra-tumoral heterogeneity of cellular radiosensitivity within primary cultures of three carcinomas of the cervix has been established. All three cultures contained clones that varied by as much as 3-fold in their clinically relevant radiosensitivity (SF 2 ). The level of intra-tumoral heterogeneity observed in these cervical tumour cultures was sufficient to be a major confounding factor to the use of pre-treatment assessments of radiosensitivity to predict for clinical radioresponsiveness. Mathematical modeling of the relative elimination of the tumour clones during fractionated radiotherapy indicates that, in two of the three biopsy samples, the use of pre-treatment derived SF 2 values from the heterogeneous tumour sample would significantly overestimate radioresponsiveness. We conclude that assays of cellular radiosensitivity that identify the radiosensitivity of the most radioresistant clones and measure their relative abundance could potentially increase the effectiveness of SF 2 values as a predictive marker of radioresponsiveness

A coarse-grained model for the simulations of biomolecular interactions in cellular environments

International Nuclear Information System (INIS)

Xie, Zhong-Ru; Chen, Jiawen; Wu, Yinghao

2014-01-01

The interactions of bio-molecules constitute the key steps of cellular functions. However, in vivo binding properties differ significantly from their in vitro measurements due to the heterogeneity of cellular environments. Here we introduce a coarse-grained model based on rigid-body representation to study how factors such as cellular crowding and membrane confinement affect molecular binding. The macroscopic parameters such as the equilibrium constant and the kinetic rate constant are calibrated by adjusting the microscopic coefficients used in the numerical simulations. By changing these model parameters that are experimentally approachable, we are able to study the kinetic and thermodynamic properties of molecular binding, as well as the effects caused by specific cellular environments. We investigate the volumetric effects of crowded intracellular space on bio-molecular diffusion and diffusion-limited reactions. Furthermore, the binding constants of membrane proteins are currently difficult to measure. We provide quantitative estimations about how the binding of membrane proteins deviates from soluble proteins under different degrees of membrane confinements. The simulation results provide biological insights to the functions of membrane receptors on cell surfaces. Overall, our studies establish a connection between the details of molecular interactions and the heterogeneity of cellular environments

The correlation between apparent diffusion coefficient and tumor cellularity in patients: a meta-analysis.

Science.gov (United States)

Chen, Lihua; Liu, Min; Bao, Jing; Xia, Yunbao; Zhang, Jiuquan; Zhang, Lin; Huang, Xuequan; Wang, Jian

2013-01-01

To perform a meta-analysis exploring the correlation between the apparent diffusion coefficient (ADC) and tumor cellularity in patients. We searched medical and scientific literature databases for studies discussing the correlation between the ADC and tumor cellularity in patients. Only studies that were published in English or Chinese prior to November 2012 were considered for inclusion. Summary correlation coefficient (r) values were extracted from each study, and 95% confidence intervals (CIs) were calculated. Sensitivity and subgroup analyses were performed to investigate potential heterogeneity. Of 189 studies, 28 were included in the meta-analysis, comprising 729 patients. The pooled r for all studies was -0.57 (95% CI: -0.62, -0.52), indicating notable heterogeneity (Pcorrelation between the ADC and cellularity for brain tumors. There was no notable evidence of publication bias. There is a strong negative correlation between the ADC and tumor cellularity in patients, particularly in the brain. However, larger, prospective studies are warranted to validate these findings in other cancer types.

Up-regulation of hepatoma-derived growth factor facilitates tumor progression in malignant melanoma [corrected].

Directory of Open Access Journals (Sweden)

Han-En Tsai

Full Text Available Cutaneous malignant melanoma is the fastest increasing malignancy in humans. Hepatoma-derived growth factor (HDGF is a novel growth factor identified from human hepatoma cell line. HDGF overexpression is correlated with poor prognosis in various types of cancer including melanoma. However, the underlying mechanism of HDGF overexpression in developing melanoma remains unclear. In this study, human melanoma cell lines (A375, A2058, MEL-RM and MM200 showed higher levels of HDGF gene expression, whereas human epidermal melanocytes (HEMn expressed less. Exogenous application of HDGF stimulated colony formation and invasion of human melanoma cells. Moreover, HDGF overexpression stimulated the degree of invasion and colony formation of B16-F10 melanoma cells whereas HDGF knockdown exerted opposite effects in vitro. To evaluate the effects of HDGF on tumour growth and metastasis in vivo, syngeneic mouse melanoma and metastatic melanoma models were performed by manipulating the gene expression of HDGF in melanoma cells. It was found that mice injected with HDGF-overexpressing melanoma cells had greater tumour growth and higher metastatic capability. In contrast, mice implanted with HDGF-depleted melanoma cells exhibited reduced tumor burden and lung metastasis. Histological analysis of excised tumors revealed higher degree of cell proliferation and neovascularization in HDGF-overexpressing melanoma. The present study provides evidence that HDGF promotes tumor progression of melanoma and targeting HDGF may constitute a novel strategy for the treatment of melanoma.

Thyroid hormone receptor inhibits hepatoma cell migration through transcriptional activation of Dickkopf 4

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Chi, Hsiang-Cheng; Liao, Chen-Hsin [Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC (China); Huang, Ya-Hui [Medical Research Central, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, ROC (China); Wu, Sheng-Ming; Tsai, Chung-Ying; Liao, Chia-Jung; Tseng, Yi-Hsin; Lin, Yang-Hsiang; Chen, Cheng-Yi; Chung, I-Hsiao; Wu, Tzu-I [Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC (China); Chen, Wei-Jan [First Cardiovascular Division, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, ROC (China); Lin, Kwang-Huei, E-mail: khlin@mail.cgu.edu.tw [Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC (China)

2013-09-13

Highlights: •T{sub 3} affects DKK4 mRNA and protein expression in HepG2-TR cells. •Regulation of DKK4 by T{sub 3} is at transcriptional level. •DKK4 overexpression suppresses hepatoma cell metastasis. -- Abstract: Triiodothyronine (T{sub 3}) is a potent form of thyroid hormone mediates several physiological processes including cellular growth, development, and differentiation via binding to the nuclear thyroid hormone receptor (TR). Recent studies have demonstrated critical roles of T{sub 3}/TR in tumor progression. Moreover, long-term hypothyroidism appears to be associated with the incidence of human hepatocellular carcinoma (HCC), independent of other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein that antagonizes the canonical Wnt signaling pathway, is induced by T{sub 3} at both mRNA and protein levels in HCC cell lines. However, the mechanism underlying T{sub 3}-mediated regulation of DKK4 remains unknown. In the present study, the 5′ promoter region of DKK4 was serially deleted, and the reporter assay performed to localize the T{sub 3} response element (TRE). Consequently, we identified an atypical direct repeat TRE between nucleotides −1645 and −1629 conferring T{sub 3} responsiveness to the DKK4 gene. This region was further validated using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). Stable DKK4 overexpression in SK-Hep-1 cells suppressed cell invasion and metastatic potential, both in vivo andin vitro, via reduction of matrix metalloproteinase-2 (MMP-2) expression. Our findings collectively suggest that DKK4 upregulated by T{sub 3}/TR antagonizes the Wnt signal pathway to suppress tumor cell progression, thus providing new insights into the molecular mechanism underlying thyroid hormone activity in HCC.

Response of Hepatoma 9618a and Normal Liver to Host Carbogen and Carbon Monoxide Breathing

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Simon P. Robinson

1999-12-01

Full Text Available The effects of hyperoxia (induced by host carbogen 95% oxygen/5% carbon dioxide breathing. and hypoxia (induced by host carbon monoxide CO at 660 ppm. breathing were compared by using noninvasive magnetic resonance (MR methods to gain simultaneous information on blood flow/oxygenation and the bioenergetic status of rat Morris H9618a hepatomas. Both carbogen and CO breathing induced a 1.5- to 2-fold increase in signal intensity in blood oxygenation level dependent (BOLD MR images. This was due to a decrease in deoxyhemoglobin (deoxyHb, which acts as an endogenous contrast agent, caused either by formation of oxyhemoglobin in the case of carbogen breathing, or carboxyhemoglobin with CO breathing. The results were confirmed by observation of similar changes in deoxyHb in arterial blood samples examined ex vivo after carbogen or CO breathing. There was no change in nucleoside triphosphates (NTP/PI in either tumor or liver after CO breathing, whereas NTP/Pl increased twofold in the hepatoma (but not in the liver after carbogen breathing. No changes in tumor intracellular pH were seen after either treatment, whereas extracellular pH became more alkaline after CO breathing and more acid after carbogen breathing, respectively. This tumor type and the liver are unaffected by CO breathing at 660 ppm, which implies an adequate oxygen supply.

Percutaneous Ethanol Injection of Unresectable Medium-to-Large-Sized Hepatomas Using a Multipronged Needle: Efficacy and Safety

International Nuclear Information System (INIS)

Ho, C.S.; Kachura, J.R.; Gallinger, S.; Grant, D.; Greig, P.; McGilvray, I.; Knox, J.; Sherman, M.; Wong, F.; Wong, D.

2007-01-01

Fine needles with an end hole or multiple side holes have traditionally been used for percutaneous ethanol injection (PEI) of hepatomas. This study retrospectively evaluates the safety and efficacy of PEI of unresectable medium-to-large (3.5-9 cm) hepatomas using a multipronged needle and with conscious sedation. Twelve patients, eight men and four women (age 51-77 years; mean: 69) received PEI for hepatomas, mostly subcapsular or exophytic in location with average tumor size of 5.6 cm (range: 3.5-9.0 cm). Patients were consciously sedated and an 18G retractable multipronged needle (Quadrafuse needle; Rex Medical, Philadelphia, PA) was used for injection under real-time ultrasound guidance. By varying the length of the prongs and rotating the needle, the alcohol was widely distributed within the tumor. The progress of ablation was monitored by contrast-enhanced ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) after each weekly injection and within a month after the final (third) injection and 3 months thereafter. An average total of 63 mL (range: 20-154 ml) of alcohol was injected per patient in an average of 2.3 sessions. Contrast-enhanced CT, ultrasound, or MRI was used to determine the degree of necrosis. Complete necrosis was noted in eight patients (67%), near-complete necrosis (90-99%) in two (16.7%), and partial success (50-89%) in two (16.7%). Follow-up in the first 9 months showed local recurrence in two patients and new lesions in another. There was no mortality. One patient developed renal failure, liver failure, and localized perforation of the stomach. He responded to medical treatment and surgery was not required for the perforation. One patient had severe postprocedural abdominal pain and fever, and another had transient hyperbilirubinemia; both recovered with conservative treatment. PEI with a multipronged needle is a new, safe, and efficacious method in treating medium-to-large-sized hepatocellular carcinoma under conscious

A study on the thermochemotherapy effect of nanosized As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes on experimental hepatoma in vitro and in vivo

Energy Technology Data Exchange (ETDEWEB)

Wang Li; Zhang Jia; Wang Ziyu; Liu Jing; Li Yutao; Zhang Dongsheng [School of Medicine, Southeast University, NO. 87 Ding jia qiao, Nanjing 210009 (China); An Yanli, E-mail: wangli040418@163.com, E-mail: zdszds1222@163.com [Affiliated Zhong-Da Hospital of Southeast University, Nanjing 210009 (China)

2011-08-05

In this paper, we describe the synthesis and characterization of a nanosized, thermosensitive magnetoliposome encapsulating magnetic nanoparticles (MZFs) and antitumor drugs (As{sub 2}O{sub 3}). The nanoliposomes were spherical and mostly single volume, with an average diameter of 128.2 nm. Differential scanning calorimetry (DSC) showed a liposome phase transition temperature of 42.71 deg. C. After that, we studied the liposomes' anti-hepatoma effect in vitro and in vivo. The antitumor effect of the nanoliposomes on human hepatoma cells, SMMC-7721, and changes in expression of apoptosis-related proteins were examined in vitro. The results show that As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes combined with hyperthermia had a great impact on the Bax/Bcl-2 ratio, which increased to 1.914 and exhibited a rapid response to induce apoptosis of tumor cells. An in situ rabbit liver tumor model was established and used to evaluate the antitumor effect of combined hyperthermia and chemotherapy following transcatheter arterial embolization with As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes. The results demonstrated a strong anti-hepatoma effect, with a tumor volume inhibition rate of up to 85.22%. Thus, As{sub 2}O{sub 3}/MZF thermosensitive magnetoliposomes may play a great role in the treatment of hepatocarcinoma.

A dynamic cellular vertex model of growing epithelial tissues

Science.gov (United States)

Lin, Shao-Zhen; Li, Bo; Feng, Xi-Qiao

2017-04-01

Intercellular interactions play a significant role in a wide range of biological functions and processes at both the cellular and tissue scales, for example, embryogenesis, organogenesis, and cancer invasion. In this paper, a dynamic cellular vertex model is presented to study the morphomechanics of a growing epithelial monolayer. The regulating role of stresses in soft tissue growth is revealed. It is found that the cells originating from the same parent cell in the monolayer can orchestrate into clustering patterns as the tissue grows. Collective cell migration exhibits a feature of spatial correlation across multiple cells. Dynamic intercellular interactions can engender a variety of distinct tissue behaviors in a social context. Uniform cell proliferation may render high and heterogeneous residual compressive stresses, while stress-regulated proliferation can effectively release the stresses, reducing the stress heterogeneity in the tissue. The results highlight the critical role of mechanical factors in the growth and morphogenesis of epithelial tissues and help understand the development and invasion of epithelial tumors.

Comparative study on lysosomal accumulation of 67Ga and 111In in Morris hepatoma 7316A

International Nuclear Information System (INIS)

Takeda, S.; Uchida, T.; Matsuzawa, T.

1977-01-01

Intracellular localization of 67 Ga and 111 In was investigated in Morris hepatoma 7316A and in normal Buffalo rat liver cells by a cell fractionation method at 48 hr after an intraperitoneal injection of the nuclides. Lysosomal fractions of the tumor and normal liver cells had the highest relative specific radioactivities of the nuclides (p 67 Ga (p 67 Ga seemed to indicate that 67 Ga determines lysosomal functions of tumor cells more precisely than 111 In

Evidence for ligand and/or receptor-specific mechanisms of internalization and processing in cultured H35 hepatoma cells

International Nuclear Information System (INIS)

Goldberg, R.I.; Smith, R.M.; Jarett, L.

1987-01-01

Total cell associated (TC) and intracellularly accumulated (IC) 125 I-labeled insulin (INS) or α-2-macroglobulin (α2M) were assessed in cultured H35 hepatoma cells which were preincubated with various agents. Cytochalasin D or sodium azide, which affect microfilament- or energy-dependent receptor internalization, had no significant effects on INS TC or IC but each decreased α2M TC and IC to 50-75% of control. Monensin and chloroquine, acidotrophic agents, each increased INS TC and IC to 150-300% of control yet decreased TC and IC of α2M to 20-50% of control. Only leupeptin, a lysosomal protease inhibitor, caused an increase in both INS and α2M TC and IC. These data suggest significant differences exist in the biochemical regulation or structural routes of INS and α2M receptors and/or receptor-ligand complexes in their (1) internalization, (2) processing in acidic organelles, (3) recycling to the cell surface or in combinations of the above. Biochemical and ultrastructural studies are being performed on the H35 hepatoma cell which will characterize the processing of INS and α2M receptors and provide an explanation for the differences observed

Dynamic heterogeneity and DNA methylation in embryonic stem cells.

KAUST Repository

Singer, Zakary S

2014-07-01

Cell populations can be strikingly heterogeneous, composed of multiple cellular states, each exhibiting stochastic noise in its gene expression. A major challenge is to disentangle these two types of variability and to understand the dynamic processes and mechanisms that control them. Embryonic stem cells (ESCs) provide an ideal model system to address this issue because they exhibit heterogeneous and dynamic expression of functionally important regulatory factors. We analyzed gene expression in individual ESCs using single-molecule RNA-FISH and quantitative time-lapse movies. These data discriminated stochastic switching between two coherent (correlated) gene expression states and burst-like transcriptional noise. We further showed that the "2i" signaling pathway inhibitors modulate both types of variation. Finally, we found that DNA methylation plays a key role in maintaining these metastable states. Together, these results show how ESC gene expression states and dynamics arise from a combination of intrinsic noise, coherent cellular states, and epigenetic regulation.

Identifying and quantifying heterogeneity in high content analysis: application of heterogeneity indices to drug discovery.

Directory of Open Access Journals (Sweden)

Albert H Gough

Full Text Available One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology.

The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells.

Science.gov (United States)

Shi, Hui; Fang, Runping; Li, Yinghui; Li, Leilei; Zhang, Weiying; Wang, Huawei; Chen, Fuquan; Zhang, Shuqin; Zhang, Xiaodong; Ye, Lihong

2016-11-28

Hepatitis B X-interacting protein (HBXIP) as an oncoprotein plays crucial roles in the development of cancer, involving glucose metabolism reprogramming. In this study, we are interested in whether the oncoprotein HBXIP is involved in the modulation of gluconeogenesis in liver cancer. Here, we showed that the expression level of phosphoenolpyruvate carboxykinase (PCK1), a key enzyme of gluconeogenesis, was lower in clinical hepatocellular carcinoma (HCC) tissues than that in normal tissues. Mechanistically, HBXIP inhibited the expression of PCK1 through down-regulating transcription factor FOXO1 in hepatoma cells, and up-regulated miR-135a targeting the 3'UTR of FOXO1 mRNA in the cells. In addition, HBXIP increased the phosphorylation levels of FOXO1 protein by activating PI3K/Akt pathway, leading to the export of FOXO1 from nucleus to cytoplasm. Strikingly, over-expression of PCK1 could abolish the HBXIP-promoted growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP is able to depress the gluconeogenesis through suppressing PCK1 to promote hepatocarcinogenesis, involving miR-135a/FOXO1 axis and PI3K/Akt/p-FOXO1 pathway. Our finding provides new insights into the mechanism by which oncoprotein HBXIP modulates glucose metabolism reprogramming in HCC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Expression of Hepatoma-derived growth factor family members in the adult central nervous system

Directory of Open Access Journals (Sweden)

Abouzied Mekky M

2006-01-01

Full Text Available Abstract Background Hepatoma-derived growth factor (HDGF belongs to a polypeptide family containing five additional members called HDGF related proteins 1–4 (HRP-1 to -4 and Lens epithelial derived growth factor. Whereas some family members such as HDGF and HRP-2 are expressed in a wide range of tissues, the expression of others is very restricted. HRP-1 and -4 are only expressed in testis, HRP-3 only in the nervous system. Here we investigated the expression of HDGF, HRP-2 and HRP-3 in the central nervous system of adult mice on the cellular level by immunohistochemistry. In addition we performed Western blot analysis of various brain regions as well as neuronal and glial cell cultures. Results HDGF was rather evenly expressed throughout all brain regions tested with the lowest expression in the substantia nigra. HRP-2 was strongly expressed in the thalamus, prefrontal and parietal cortex, neurohypophysis, and the cerebellum, HRP-3 in the bulbus olfactorius, piriform cortex and amygdala complex. HDGF and HRP-2 were found to be expressed by neurons, astrocytes and oligodendrocytes. In contrast, strong expression of HRP-3 in the adult nervous system is restricted to neurons, except for very weak expression in oligodendrocytes in the brain stem. Although the majority of neurons are HRP-3 positive, some like cerebellar granule cells are negative. Conclusion The coexpression of HDGF and HRP-2 in glia and neurons as well as the coexpression of all three proteins in many neurons suggests different functions of members of the HDGF protein family in cells of the central nervous system that might include proliferation as well as cell survival. In addition the restricted expression of HRP-3 point to a special function of this family member for neuronal cells.

Differential Cytotoxicity of Acetaminophen in Mouse Macrophage J774.2 and Human Hepatoma HepG2 Cells: Protection by Diallyl Sulfide.

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Haider Raza

Full Text Available Non-steroidal anti-inflammatory drugs (NSAIDs, including acetaminophen (APAP, have been reported to induce cytotoxicity in cancer and non-cancerous cells. Overdose of acetaminophen (APAP causes liver injury in humans and animals. Hepatic glutathione (GSH depletion followed by oxidative stress and mitochondrial dysfunction are believed to be the main causes of APAP toxicity. The precise molecular mechanism of APAP toxicity in different cellular systems is, however, not clearly understood. Our previous studies on mouse macrophage J774.2 cells treated with APAP strongly suggest induction of apoptosis associated with mitochondrial dysfunction and oxidative stress. In the present study, using human hepatoma HepG2 cells, we have further demonstrated that macrophages are a more sensitive target for APAP-induced toxicity than HepG2 cells. Using similar dose- and time-point studies, a marked increase in apoptosis and DNA fragmentation were seen in macrophages compared to HepG2 cells. Differential effects of APAP on mitochondrial respiratory functions and oxidative stress were observed in the two cell lines which are presumably dependent on the varying degree of drug metabolism by the different cytochrome P450s and detoxification by glutathione S-transferase enzyme systems. Our results demonstrate a marked increase in the activity and expression of glutathione transferase (GST and multidrug resistance (MDR1 proteins in APAP-treated HepG2 cells compared to macrophages. This may explain the apparent resistance of HepG2 cells to APAP toxicity. However, treatment of these cells with diallyl sulfide (DAS, 200 μM, a known chemopreventive agent from garlic extract, 24 h prior to APAP (10 μmol/ml for 18h exhibited comparable cytoprotective effects in the two cell lines. These results may help in better understanding the mechanism of cytotoxicity caused by APAP and cytoprotection by chemopreventive agents in cancer and non-cancerous cellular systems.

EE-eICIC: Energy-Efficient Optimization of Joint User Association and ABS for eICIC in Heterogeneous Cellular Networks

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Jie Zheng

2017-01-01

Full Text Available The densification and expansion of heterogeneous cellular networks (HetNets pose new challenges on interference management and reduction of energy consumption. The 3GPP has proposed enhanced intercell interference coordination (eICIC by making a macrocell silent in almost blank subframes (ABSs to mitigate interference for low power base stations (BSs in HetNets. However, energy efficiency (EE is very crucial for the deployment of a large number of low power nodes as they consume a lot of energy. In this work, we develop a novel EE-eICIC algorithm to determine the amount of ABSs and user equipment (UE that should associate with picocells or macrocells from energy efficiency perspective. Due to the nonsmooth and mixed combinatorial features of this formulation, we focus on a suboptimal algorithm design. Using generalized fractional programming and the convex programming theory, we propose an iterative and relaxed-rounding algorithm to solve the problem. Numerical results illustrate that the proposed EE-eICIC algorithm achieves superior performance in comparison with state-of-the-art methods in terms of energy efficiency of both system and user.

Spatially resolved microrheology of heterogeneous biopolymer hydrogels using covalently bound microspheres

NARCIS (Netherlands)

Wong, L.H.; Kurniawan, Nicholas A.; Too, H.-P.; Rajagopalan, R.

2014-01-01

Characterization of the rheological properties of heterogeneous biopolymers is important not only to understand the effect of substrate elasticity on cell behaviors, but also to provide insights into mechanical changes during cellular remodeling of the environment. Conventional particle-tracking

Phosphorus NMR of isolated perfused morris hepatomas

International Nuclear Information System (INIS)

Graham, R.A.; Meyer, R.A.; Brown, T.R.; Sauer, L.A.

1986-01-01

The authors are developing techniques for the study of perfused solid tumors by NMR. Tissue-isolated solid hepatomas were grown to 1-2 cm diameter as described previously. The arterial supply was isolated and the tumors perfused (0.5 - 1.0 ml/min) in vitro at 25 C with a 15% suspension of red blood cells in Krebs-Henseliet solution. 31 P-NMR spectra were acquired at 162 MHz in a specially-designed NMR probe using a solenoidal coil. Intracellular pH (monitored from the chemical shift of inorganic phosphate) and ATP levels were stable for up to 6 hrs during perfusion. During 30 min of global ischemia, ATP decreased by 75% and pH fell from 7.0 to 6.7. These changes were reversed by 1 hr reperfusion. In addition to ATP and phosphate, the spectra included a large resonance due to phosphomonoesters, as well as peaks consistent with glycerylphosphocholine, glyceryl-phosphoethanolamine, phosphocreatine, NAD, and UDPG. However, the most novel feature of the spectra was the presence of an unidentified peak in the phosphonate region (+ 16.9 ppm). The peak was not present in spectra of muscle, liver, brain, kidney, or fat tissues excised from the same animals. They are presently attempting to identify the compound that gives rise to this peak and to establish its metabolic origin

Enhancement of Localization Accuracy in Cellular Networks via Cooperative AdHoc Links

DEFF Research Database (Denmark)

Lhomme, Edouard; Frattasi, Simone; Figueiras, Joao

2006-01-01

Positioning information enables new applications for cellular phones, personal communication systems, and specialized mobile radios. The network heterogeneity emerging in the fourth generation (4G) of mobile networks can be utilized for enhancements of the location estimation accuracy...

Plasmid Transfer of Plasminogen K1-5 Reduces Subcutaneous Hepatoma Growth by Affecting Inflammatory Factors

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Lea A. Koch

2014-01-01

Full Text Available There is evidence that plasminogen K1-5 (PlgK1-5 directly affects tumour cells and inflammation. Therefore, we analysed if PlgK1-5 has immediate effects on hepatoma cells and inflammatory factors in vitro and in vivo. In vitro, effects of plasmid encoding PlgK1-5 (pK1-5 on Hepa129, Hepa1-6, and HuH7 cell viability, apoptosis, and proliferation as well as VEGF and TNF-alpha expression and STAT3-phosphorylation were investigated. In vivo, tumour growth, proliferation, vessel density, and effects on vascular endothelial growth factor (VEGF and tumour necrosis factor alpha (TNF-alpha expression were examined following treatment with pK1-5. In vivo, pK1-5 halved cell viability; cell death was increased by up to 15% compared to the corresponding controls. Proliferation was not affected. VEGF, TNF-alpha, and STAT3-phosphorylation were affected following treatment with pK1-5. In vivo, ten days after treatment initiation, pK1-5 reduced subcutaneous tumour growth by 32% and mitosis by up to 77% compared to the controls. Vessel density was reduced by 50%. TNF-alpha levels in tumour and liver tissue were increased, whereas VEGF levels in tumours and livers were reduced after pK1-5 treatment. Taken together, plasmid gene transfer of PlgK1-5 inhibits hepatoma (cell growth not only by reducing vessel density but also by inducing apoptosis, inhibiting proliferation, and triggering inflammation.

Bystander effect in human hepatoma HepG2 cells caused by medium transfers at different times after high-LET carbon ion irradiation

International Nuclear Information System (INIS)

Wu Qingfeng; Li Qiang; Jin Xiaodong; Liu Xinguo; Dai Zhongying

2011-01-01

Although radiation-induced bystander effects have been well documented in a variety of biological systems, whether irradiated cells have the ability to generate bystander signaling persistently is still unclear and the clinical relevance of bystander effects in radiotherapy remains to be elucidated. This study examines tumor cellular bystander response to autologous medium from cell culture irradiated with high-linear energy transfer (LET) heavy ions at a therapeutically relevant dose in terms of clonogenic cell survival. In vitro experiments were performed using human hepatoma HepG2 cell line exposed to 100 keV/μm carbon ions at a dose of 2 Gy. Two different periods (2 and 12 h) after irradiation, irradiated cell conditioned medium (ICCM) and replenished fresh medium were harvested and then transferred to unirradiated bystander cells. Cellular bystander responses were measured with the different medium transfer protocols. Significant higher survival fractions of unirradiated cells receiving the media from the irradiated cultures at the different times post-irradiation than those of the control were observed. Even replenishing fresh medium for unirradiated cells which had been exposed to the ICCM for 12 h could not prevent the bystander cells from the increased survival fraction. These results suggest that the irradiated cells could release unidentified signal factor(s), which induced the increase in survival fraction for the unirradiated bystander cells, into the media sustainedly and the carbon ions triggered a cascade of signaling events in the irradiated cells rather than secreting the soluble signal factor(s) just at a short period after irradiation. Based on the observations in this study, the importance of bystander effect in clinical radiotherapy was discussed and incorporating the bystander effect into the current radiobiological models, which are applicable to heavy ion radiotherapy, is needed urgently.

Effects of JS-K, a novel anti-cancer nitric oxide prodrug, on gene expression in human hepatoma Hep3B cells.

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Dong, Ray; Wang, Xueqian; Wang, Huan; Liu, Zhengyun; Liu, Jie; Saavedra, Joseph E

2017-04-01

JS-K is a novel anticancer nitric oxide (NO) prodrug effective against a variety of cancer cells, including the inhibition of AM-1 hepatoma cell growth in rats. To further evaluate anticancer effects of JS-K, human hepatoma Hep3B cells were treated with JS-K and the compound control JS-43-126 at various concentrations (0-100μM) for 24h, and cytotoxicity was determined by the MTS assay. The compound control JS-43-126 was not cytotoxic to Hep3B cells at concentrations up to 100μM, while the LC 50 for JS-K was about 10μM. To examine the molecular mechanisms of antitumor effects of JS-K, Hep3B cells were treated with 1-10μM of JS-K for 24h, and then subjected to gene expression analysis via real time RT-PCR and protein immunostain via confocal images. JS-K is a GST-α targeting NO prodrug, and decreased immunostaining for GST-α was associated with JS-K treatment. JS-K activated apoptosis pathways in Hep3B cells, including induction of caspase-3, caspase-9, Bax, TNF-α, and IL-1β, and immunostaining for caspase-3 was intensified. The expressions of thrombospondin-1 (TSP-1) and the tissue inhibitors of metalloproteinase-1 (TIMP-1) were increased by JS-K at both transcript and protein levels. JS-K treatment also increased the expression of differentiation-related genes CD14 and CD11b, and depressed the expression of c-myc in Hep3B cells. Thus, multiple molecular events appear to be associated with anticancer effects of JS-K in human hepatoma Hep3B cells, including activation of genes related to apoptosis and induction of genes involved in antiangiogenesis and tumor cell migration. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Dynamic MR imaging of hepatoma treated by transcatheter arterial embolization therapy

International Nuclear Information System (INIS)

Yamashita, Y.; Yoshimatsu, S.; Sumi, M.; Harada, M.; Takahashi, M.

1993-01-01

The effect of transcatheter arterial chemo-embolization theory (TACE) for hepatoma was evaluated with dynamic MR imaging with Gd-DTPA in 37 patients (44 tumors). TACE was performed using Lipiodol/cis-platinum and gelatin sponge (or microspheres) as an embolic material. All patients were examined with dynamic CT and MR imaging before and after treatment. On conventional spin echo images, changes of signal intensity after treatment varied regardless of presence of Lipiodol. Dynamic MR imaging revealed changes of tumor vascularity before and after treatment. On histologic correlation, areas of persistent tumor enhancement on dynamic MR imaging corresponded to areas of viable tumor cells while areas of nonenhancement corresponded to areas of necrosis. Dynamic MR imaging was superior in contrast resolution and was not influenced by the presence of Lipiodol compared with dynamic CT, and therefore residual viable tumors were better defined by dynamic MR imaging. (orig.)

Contribution of ketone bodies to cholesterogenesis in Morris hepatoma 7777 cells

International Nuclear Information System (INIS)

Hilderbrandt, L.; Elson, C.; Shrago, E.

1990-01-01

Cholesterol synthesis in neoplastic tissues is typically measured in incubations of minced tissue or tissue slices with 10 mM concentrations of individual substrates. Carbon incorporation into cholesterol from [ 14 C] labelled substrates by freshly isolated hepatoma cells was measured after one hour incubation with 10 mm single substrates. These observations were extended by measuring cholesterol synthesis supported by [ 14 C] substrates in a media containing a mixture of substrates at physiological concentrations: 5.0 mM glucose, 1.3 mM D(-)-3-hydroxybutyrate, 0.5 mM acetoacetate, 0.3 mM acetate, 0.3 mM oleate, 0.3 mM palmitate, 0.65 mM glutamine, 1.4 mM lactate and 0.1 mM pyruvate in Eagle's modified essential medium. Under single substrate conditions, the ketone bodies contribute substantially to cholesterogenesis. Estimates of the quantitative contribution of each substrate to total cholesterol synthesis are reported

SinCHet: a MATLAB toolbox for single cell heterogeneity analysis in cancer.

Science.gov (United States)

Li, Jiannong; Smalley, Inna; Schell, Michael J; Smalley, Keiran S M; Chen, Y Ann

2017-09-15

Single-cell technologies allow characterization of transcriptomes and epigenomes for individual cells under different conditions and provide unprecedented resolution for researchers to investigate cellular heterogeneity in cancer. The SinCHet ( gle ell erogeneity) toolbox is developed in MATLAB and has a graphical user interface (GUI) for visualization and user interaction. It analyzes both continuous (e.g. mRNA expression) and binary omics data (e.g. discretized methylation data). The toolbox does not only quantify cellular heterogeneity using S hannon P rofile (SP) at different clonal resolutions but also detects heterogeneity differences using a D statistic between two populations. It is defined as the area under the P rofile of S hannon D ifference (PSD). This flexible tool provides a default clonal resolution using the change point of PSD detected by multivariate adaptive regression splines model; it also allows user-defined clonal resolutions for further investigation. This tool provides insights into emerging or disappearing clones between conditions, and enables the prioritization of biomarkers for follow-up experiments based on heterogeneity or marker differences between and/or within cell populations. The SinCHet software is freely available for non-profit academic use. The source code, example datasets, and the compiled package are available at http://labpages2.moffitt.org/chen/software/ . ann.chen@moffitt.org. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

Noise-Driven Phenotypic Heterogeneity with Finite Correlation Time in Clonal Populations.

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UnJin Lee

Full Text Available There has been increasing awareness in the wider biological community of the role of clonal phenotypic heterogeneity in playing key roles in phenomena such as cellular bet-hedging and decision making, as in the case of the phage-λ lysis/lysogeny and B. Subtilis competence/vegetative pathways. Here, we report on the effect of stochasticity in growth rate, cellular memory/intermittency, and its relation to phenotypic heterogeneity. We first present a linear stochastic differential model with finite auto-correlation time, where a randomly fluctuating growth rate with a negative average is shown to result in exponential growth for sufficiently large fluctuations in growth rate. We then present a non-linear stochastic self-regulation model where the loss of coherent self-regulation and an increase in noise can induce a shift from bounded to unbounded growth. An important consequence of these models is that while the average change in phenotype may not differ for various parameter sets, the variance of the resulting distributions may considerably change. This demonstrates the necessity of understanding the influence of variance and heterogeneity within seemingly identical clonal populations, while providing a mechanism for varying functional consequences of such heterogeneity. Our results highlight the importance of a paradigm shift from a deterministic to a probabilistic view of clonality in understanding selection as an optimization problem on noise-driven processes, resulting in a wide range of biological implications, from robustness to environmental stress to the development of drug resistance.

Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines

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Chen Lei

2011-06-01

Full Text Available Abstract Background Cancer stem cells (CSCs are regarded as the cause of tumor formation and recurrence. The isolation and identification of CSCs could help to develop novel therapeutic strategies specifically targeting CSCs. Methods Human hepatoma cell lines were plated in stem cell conditioned culture system allowed for sphere forming. To evaluate the stemness characteristics of spheres, the self-renewal, proliferation, chemoresistance, tumorigenicity of the PLC/PRF/5 sphere-forming cells, and the expression levels of stem cell related proteins in the PLC/PRF/5 sphere-forming cells were assessed, comparing with the parental cells. The stem cell RT-PCR array was performed to further explore the biological properties of liver CSCs. Results The PLC/PRF/5, MHCC97H and HepG2 cells could form clonal nonadherent 3-D spheres and be serially passaged. The PLC/PRF/5 sphere-forming cells possessed a key criteria that define CSCs: persistent self-renewal, extensive proliferation, drug resistance, overexpression of liver CSCs related proteins (Oct3/4, OV6, EpCAM, CD133 and CD44. Even 500 sphere-forming cells were able to form tumors in NOD/SCID mice, and the tumor initiating capability was not decreased when spheres were passaged. Besides, downstream proteins DTX1 and Ep300 of the CSL (CBF1 in humans, Suppressor of hairless in Drosophila and LAG1 in C. elegans -independent Notch signaling pathway were highly expressed in the spheres, and a gamma-secretase inhibitor MRK003 could significantly inhibit the sphere formation ability. Conclusions Nonadherent tumor spheres from hepatoma cell lines cultured in stem cell conditioned medium possess liver CSC properties, and the CSL-independent Notch signaling pathway may play a role in liver CSCs.

Image-based computational quantification and visualization of genetic alterations and tumour heterogeneity.

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Zhong, Qing; Rüschoff, Jan H; Guo, Tiannan; Gabrani, Maria; Schüffler, Peter J; Rechsteiner, Markus; Liu, Yansheng; Fuchs, Thomas J; Rupp, Niels J; Fankhauser, Christian; Buhmann, Joachim M; Perner, Sven; Poyet, Cédric; Blattner, Miriam; Soldini, Davide; Moch, Holger; Rubin, Mark A; Noske, Aurelia; Rüschoff, Josef; Haffner, Michael C; Jochum, Wolfram; Wild, Peter J

2016-04-07

Recent large-scale genome analyses of human tissue samples have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions (PTEN) and amplifications (19q12, HER2) in diverse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility.

Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: experience with cis-platinum-based chemoradiotherapy in 76 patients

International Nuclear Information System (INIS)

Abrams, Ross A.; Cardinale, Robert M.; Enger, Cheryl; Haulk, Thomas L.; Hurwitz, Herbert; Osterman, Floyd; Sitzmann, James V.

1997-01-01

Purpose: Internationally, hepatoma is a common cause of cancer death. Although the only curative therapy is surgical, most tumors are unresectable and cause death. The value of nonsurgical, antineoplastic therapy for such tumors is controversial. This study was undertaken to extend and confirm promising, but preliminary, treatment observations in the unresectable context. Methods and Materials: From 1988 to 1993, 76 patients with unresectable, biopsy proven, hepatoma underwent uniform pretreatment assessment followed by induction therapy with external beam radiotherapy (21 Gy/7 fractions/10 days) and intravenous Cisplatinum, 50 mg/m 2 . One month later patients began monthly intrahepatic artery Cisplatinum, 50 mg/m 2 . Clinical course and treatment outcomes were correlated with previously published prognostic factors and groupings (Nomura et al., Okuda et al., Stillwagon, et al.). Results: The toxicity of this therapy was modest and nonlimiting. Twenty-four patients (32%) progressed during induction and prior to receiving two cycles of intrahepatic artery Cisplatinum without evidence of benefit. Patients showing this early progression were more likely to be Stillwagon unfavorable than favorable (p = 0.013), Okuda Stage II than Stage I (p = 0.024), and slightly but not statistically more likely to be alpha-fetoprotein positive than alpha-fetoprotein negative (p = 0.098). The overall objective response rate was 43% (38% among AFP positive and 62% among AFP negative patients) (p = 0.15). Although 21 patients had evidence of extra hepatic metastases, survival for these patients did not differ from patients without metastases (p = 0.09) and patients with extra hepatic metastases were just as likely to show intrahepatic response (p = 0.84). Conclusion: The chemoradiotherapy program utilized produced objective response and minimal toxicity. One-third of patients progressed rapidly in spite of treatment. Among the remaining patients, response occurred frequently. This

A Metric and Workflow for Quality Control in the Analysis of Heterogeneity in Phenotypic Profiles and Screens

Science.gov (United States)

Gough, Albert; Shun, Tongying; Taylor, D. Lansing; Schurdak, Mark

2016-01-01

Heterogeneity is well recognized as a common property of cellular systems that impacts biomedical research and the development of therapeutics and diagnostics. Several studies have shown that analysis of heterogeneity: gives insight into mechanisms of action of perturbagens; can be used to predict optimal combination therapies; and to quantify heterogeneity in tumors where heterogeneity is believed to be associated with adaptation and resistance. Cytometry methods including high content screening (HCS), high throughput microscopy, flow cytometry, mass spec imaging and digital pathology capture cell level data for populations of cells. However it is often assumed that the population response is normally distributed and therefore that the average adequately describes the results. A deeper understanding of the results of the measurements and more effective comparison of perturbagen effects requires analysis that takes into account the distribution of the measurements, i.e. the heterogeneity. However, the reproducibility of heterogeneous data collected on different days, and in different plates/slides has not previously been evaluated. Here we show that conventional assay quality metrics alone are not adequate for quality control of the heterogeneity in the data. To address this need, we demonstrate the use of the Kolmogorov-Smirnov statistic as a metric for monitoring the reproducibility of heterogeneity in an SAR screen, describe a workflow for quality control in heterogeneity analysis. One major challenge in high throughput biology is the evaluation and interpretation of heterogeneity in thousands of samples, such as compounds in a cell-based screen. In this study we also demonstrate that three heterogeneity indices previously reported, capture the shapes of the distributions and provide a means to filter and browse big data sets of cellular distributions in order to compare and identify distributions of interest. These metrics and methods are presented as a

Actions of exogenous histones and other proteins on [3H]-thymidine incorporation into DNA of Novikoff hepatoma cells

International Nuclear Information System (INIS)

Barra, R.; Beres, B.; Koch, M.R.; Lea, M.A.

1976-01-01

The effects of exogenous proteins on the incorporation of [ 3 H]-thymidine into DNA was studied in Novikoff hepatoma ascites cells incubated in Eagle's minimal essential medium. A liver cytosol fraction (8 mg protein/ml) caused approximately 80% inhibition of isotope incorporation. The inhibitory activity of cytosol fractions from Morris hepatomas 9618A 2 , 5123C and 20 were inversely related to their growth rate. Under conditions in which there appeared to be a density dependent inhibition of growth, a mean 10 to 20% stimulation of isotope incorporation was observed after addition of total calf thymus histones and individual fractions in the concentration range of 100 to 400μg/ml. In experiments with lower cell concentrations, a 60% or greater increase in [ 3 H]-thymidine incorporation could be obtained with total calf thymus histone and with Fl and arginine-rich histones from rat liver. At concentrations of 1 to 2 mg/ml, histones inhibited DNA synthesis. Bovine serum albumin had little effect on DNA synthesis. Polylysine caused an 80 to 90% inhibition at a concentration of 1 mg/ml, but stimulatory effects were detected under certain conditions at 10μg/ml. The results suggest critical dependence on the ratio of cell and exogenous protein concentration in the action of proteins on DNA synthesis. (author)

Heterogeneity maintenance in glioblastoma: a social network.

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Bonavia, Rudy; Inda, Maria-del-Mar; Cavenee, Webster K; Furnari, Frank B

2011-06-15

Glioblastoma multiforme (GBM), the most common intracranial tumor in adults, is characterized by extensive heterogeneity at the cellular and molecular levels. This insidious feature arises inevitably in almost all cancers and has great significance for the general outcome of the malignancy, because it confounds our understanding of the disease and also intrinsically contributes to the tumor's aggressiveness and poses an obstacle to the design of effective therapies. The classic view that heterogeneity arises as the result of a tumor's "genetic chaos" and the more contemporary cancer stem cell (CSC) hypothesis tend to identify a single cell population as the therapeutic target: the prevailing clone over time in the first case and the CSC in the latter. However, there is growing evidence that the different tumor cell populations may not be simple bystanders. Rather, they can establish a complex network of interactions between each other and with the tumor microenvironment that eventually strengthens tumor growth and increases chances to escape therapy. These differing but complementary ideas about the origin and maintenance of tumor heterogeneity and its importance in GBM are reviewed here.

Immunoprecipitation assay of alpha-fetoprotein synthesis by cultured mouse hepatoma cells treated with estrogens and glucocorticoids.

Science.gov (United States)

Rosebrock, J A; Parker, C L; Kute, T E

1981-01-01

This investigation was to study the biosynthesis of 3H-labeled alpha-fetoprotein (AFP) by cultured mouse hepatoma (HEPA-2) cells. Both the function and regulation of this oncodevelopmental gene are unknown. However, evidence indicates that mechanisms controlling the expression of AFP involve aspects of both normal embryonic development and neoplastic transformation. the secretion of AFP was analyzed during different phases of the growth cycle to provide information on AFP production using standard culture conditions. The highest rate of secretion occurred during the stationary phase, followed by the late logarithmic and early logarithmic phases of growth, respectively. The production of AFP was then determined following the addition of glucocorticoids and estrogens in an attempt to understand hormonal factors that may be involved. Studies utilizing estradiol-17 beta indicated that the secretion of AFP did not appear to be sensitive to this steroid even though sucrose density gradient analysis of HEPA-2 cytosol, for estrogenic receptors, revealed competitive binding moieties on the 8S and 4S regions of the gradient. In contrast, the secretion of the total complement of proteins, including AFP, was significantly stimulated by the glucocorticoids, dexamethasone and corticosterone. Analysis of HEPA-2 cytosol for glucocorticoid receptors revealed binding components in the 7S and 3-4S regions of the gradient. The 3H-dexamethasone binding appeared to be stereospecific since nonlabeled dexamethasone, but not nonlabeled estradiol-17 beta, effectively displaced the bound radioactivity. The glucocorticoid-binding component in HEPA-2 therefore displayed characteristics reported for glucocorticoid receptors in normal liver and other hepatomas.

SirT1 confers hypoxia-induced radioresistance via the modulation of c-Myc stabilization on hepatoma cells

International Nuclear Information System (INIS)

Xie Yuexia; Zhang Jianghong; Shao Chunlin; Xu Yanwu

2012-01-01

Intratumoral hypoxia is an important contributory factor to tumor cell resistance to radiotherapy. SirT1, a nicotinamide adenine dinucleotide (NAD + )-dependent histone/protein deacetylase, has been linked to the decrease of radiation-induced DNA damage and seems to be critical for cancer therapy. The purpose of this study was to investigate the role of SirT1 in hypoxia-induced radiation response on hepatoma cells. It was found that the administration with resveratrol, a putative SirT1 activator, enhanced the resistance of HepG2 cells against radiation-induced DNA damage of MN formation under hypoxia condition; while nicotinamide, a well-known SirT1 inhibitor, sensitized this radiation damage. Nevertheless, pretreatment of cells with 10058-F4, a specific inhibitor of c-Myc, almost eliminated the nicotinamide-induced radiosensitive effect. Further studies revealed that resveratrol inhibited c-Myc protein accumulation via up-regulation of SirT1 expression and deacetylase activity, and this loss of c-Myc protein was abolished by inhibiting its degradation in the presence of MG132, a potent inhibitor of proteasome. In contrast, nicotinamide attenuated c-Myc protein degradation induced by radiation under hypoxia through inhibition of SirT1 deacetylase activity. Our findings suggest that SirT1 could serve as a novel potent target of radiation-induced DNA damage and thus as a potential strategy to advance the efficiency of radiation therapy in hepatoma entities. (author)

Significant Histological Features Differentiating Cellular Fibroadenoma from Phyllodes Tumor on Core Needle Biopsies

Science.gov (United States)

Yasir, Saba; Gamez, Roberto; Jenkins, Sarah; Visscher, Daniel W.; Nassar, Aziza

2015-01-01

Objectives Cellular fibroepithelial lesions (CFEL) are a heterogeneous group of tumors encompassing cellular fibroadenoma (CFA) and phyllodes tumor (PT). Distinction between the two is challenging on core needle biopsy (CNB). The objective of this study was to evaluate histological features that can help distinguish PT from CFA on CNB. Methods Records of all patients diagnosed with CFEL on CNB with follow-up excision between 2002 and 2012 were retrieved. Histopathological stromal features were evaluated on CNB including mitoses per 10 HPF, overgrowth, increased cellularity, fragmentation, adipose tissue infiltration, heterogeneity, subepithelial condensation, and nuclear pleomorphism. Results Twenty-seven of 64 (42.2%) were diagnosed as PT (24 BPT, 3 borderline PT) and 37 (57.8%) as CFA on excision. All features except for increased stromal cellularity were statistically significant. The average number of histologic features seen in PT and CFA was 3.9 and 1.4, respectively (OR 7.27; 95% CI: 2.44, 21.69; p= 0.0004). The average mitoses per 10 HPF was 3.0 for PT as compared to 0.8 for CFA (OR 2.14; 95% CI: 1.18, 3.86; p= 0.01). Conclusions The presence of mitosis (3 or more) and/or total histologic features of 3 or more on CNB were most helpful features in predicting PT on excision. PMID:25125627

Induction of appropriate Th-cell phenotypes: cellular decision-making in heterogeneous environments.

Science.gov (United States)

van den Ham, H-J; Andeweg, A C; de Boer, R J

2013-11-01

Helper T (Th)-cell differentiation is a key event in the development of the adaptive immune response. By the production of a range of cytokines, Th cells determine the type of immune response that is raised against an invading pathogen. Th cells can adopt many different phenotypes, and Th-cell phenotype decision-making is crucial in mounting effective host responses. This review discusses the different Th-cell phenotypes that have been identified and how Th cells adopt a particular phenotype. The regulation of Th-cell phenotypes has been studied extensively using mathematical models, which have explored the role of regulatory mechanisms such as autocrine cytokine signalling and cross-inhibition between self-activating transcription factors. At the single cell level, Th responses tend to be heterogeneous, but corrections can be made soon after T-cell activation. Although pathogens and the innate immune system provide signals that direct the induction of Th-cell phenotypes, these instructive mechanisms could be easily subverted by pathogens. We discuss that a model of success-driven feedback would select the most appropriate phenotype for clearing a pathogen. Given the heterogeneity in the induction phase of the Th response, such a success-driven feedback loop would allow the selection of effective Th-cell phenotypes while terminating incorrect responses. © 2013 John Wiley & Sons Ltd.

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

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Letellier, Mathieu; Park, Yun Kyung; Chater, Thomas E.; Chipman, Peter H.; Gautam, Sunita Ghimire; Oshima-Takago, Tomoko; Goda, Yukiko

2016-01-01

Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-d-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca2+ channels. Intracellular infusion of NMDARs or Ca2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocyte-dependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites. PMID:27118849

The chicken c-erbA alpha-product induces expression of thyroid hormone-responsive genes in 3,5,3'-triiodothyronine receptor-deficient rat hepatoma cells

DEFF Research Database (Denmark)

Muñoz, A; Höppner, W; Sap, J

1990-01-01

To determine the capacity of the chicken c-erbA (cTR-alpha) gene product in regulating expression of known thyroid hormone-responsive genes, both the cTR-alpha and the viral v-erbA genes were expressed in FAO cells, a rat hepatoma cell line defective for functional thyroid hormone receptors. Upon...

Analytical bounds on the area spectral efficiency of uplink heterogeneous networks over generalized fading channels

KAUST Repository

Shakir, Muhammad; Tabassum, Hina; Alouini, Mohamed-Slim

2014-01-01

Heterogeneous networks (HetNets) are envisioned to enable next-generation cellular networks by providing higher spectral and energy efficiency. A HetNet is typically composed of multiple radio access technologies where several low-power low

Cellular Kinetics of Perivascular MSC Precursors

Directory of Open Access Journals (Sweden)

William C. W. Chen

2013-01-01

Full Text Available Mesenchymal stem/stromal cells (MSCs and MSC-like multipotent stem/progenitor cells have been widely investigated for regenerative medicine and deemed promising in clinical applications. In order to further improve MSC-based stem cell therapeutics, it is important to understand the cellular kinetics and functional roles of MSCs in the dynamic regenerative processes. However, due to the heterogeneous nature of typical MSC cultures, their native identity and anatomical localization in the body have remained unclear, making it difficult to decipher the existence of distinct cell subsets within the MSC entity. Recent studies have shown that several blood-vessel-derived precursor cell populations, purified by flow cytometry from multiple human organs, give rise to bona fide MSCs, suggesting that the vasculature serves as a systemic reservoir of MSC-like stem/progenitor cells. Using individually purified MSC-like precursor cell subsets, we and other researchers have been able to investigate the differential phenotypes and regenerative capacities of these contributing cellular constituents in the MSC pool. In this review, we will discuss the identification and characterization of perivascular MSC precursors, including pericytes and adventitial cells, and focus on their cellular kinetics: cell adhesion, migration, engraftment, homing, and intercellular cross-talk during tissue repair and regeneration.

Analysis of the Decoupled Access for Downlink and Uplink in Wireless Heterogeneous Networks

DEFF Research Database (Denmark)

Smiljkovikj, K.; Popovski, Petar; Gavrilovska, L.

2015-01-01

Wireless cellular networks evolve towards a heterogeneous infrastructure, featuring multiple types of Base Stations (BSs), such as Femto BSs (FBSs) and Macro BSs (MBSs). A wireless device observes multiple points (BSs) through which it can access the infrastructure and it may choose to receive th...

Using cellular automata for parallel simulation of laser dynamics with dynamic load balancing

NARCIS (Netherlands)

Guisado, J.L.; Fernández de Vega, F.; Jiménez Morales, F.; Iskra, K.A.; Sloot, P.M.A.

2008-01-01

We present an analysis of the feasibility of executing a parallel bioinspired model of laser dynamics, based on cellular automata (CA), on the usual target platform of this kind of applications: a heterogeneous non-dedicated cluster. As this model employs a synchronous CA, using the single program,

UV-B component of sunlight causes measurable damage in field-grown maize (Zea mays L.): developmental and cellular heterogeneity of damage and repair

International Nuclear Information System (INIS)

Stapleton, A.E.; Thornber, C.S.; Walbot, V.

1997-01-01

Ultraviolet radiation has diverse morphogenetic and damaging effects on plants. The end point of damage is reduced plant growth, but in the short term UV radiation damages specific cellular components. We measured cyclobutane pyrimidine dimers in maize DNA from plants grown in natural solar radiation. Green maize tissues had detectable DNA damage, roots had less damage, and anthers had much more damage than green leaves. This heterogeneity in damage levels may reflect differences in dose received or in damage repair. The architecture of green tissues had no measurable effects on DNA damage levels, as leaf sheath and leaf blade were equivalent. We observed a slight increase in damage levels in plants sampled at the end of the day, but there was no accumulation of damage over the growing season. We measured photoreactivation, and found substantial levels of this light-dependent repair in both the epidermis and inner cell layers of leaves, and in all organelles that contain DNA – the nucleus, chloroplasts and mitochondria. We conclude that maize has efficient mechanisms for photo repair of daily UV-induced DNA damage that prevent accumulation

Evaluation of the stiffness characteristics of square pore CoCrMo cellular structures manufactured using laser melting technology for potential orthopaedic applications

International Nuclear Information System (INIS)

Hazlehurst, Kevin; Wang, Chang Jiang; Stanford, Mark

2013-01-01

Highlights: • The compressive properties of CoCrMo cellular structures were investigated. • CoCrMo cellular structures with bone like properties have been presented. • An expression has been proposed to predict the effective elastic modulus. • Structural variation and heterogeneities were modelled within a cellular structure. - Abstract: In order to improve the stress shielding characteristics of orthopaedic devices implants that mimic the mechanical behaviour of bone need to be considered. Additive layer manufacturing processes provide a capability to produce orthopaedic implants with tailored mechanical properties. In this work cobalt chrome molybdenum cellular structures have been designed and manufactured using selective laser melting, with volume based porosity ranging between 25% and 95%. The effective mechanical properties have been determined through uniaxial compression testing and compared to numerical and analytical predictions where differences were observed. Cellular structures have been presented that exhibit similar stiffness and strength characteristics when compared to cortical and cancellous bone in the human femur. An expression has been proposed to predict the effective elastic modulus of cobalt chrome molybdenum cellular structures with volumetric porosity of 65% and above. A finite element modelling technique has been used to demonstrate that structural variation and heterogeneities that are associated with the manufacture of cellular structures can significantly decrease the effective stiffness

Yeast endoribonuclease stimulated by Novikoff Hepatoma small nuclear RNAS U1 and U2

International Nuclear Information System (INIS)

Stevens, A.

1982-01-01

Using [ 3 H]m 7 Gppp[ 14 C]RNA-poly(A) from yeast as a substrate, an endoribonuclease has been detected in enzyme fractions derived from a high salt wash of ribonucleoprotein particles of Saccharomyces cerevisiae. The [ 3 H]m 7 Gppp[ 14 C]RNA-poly(A) seems to be a preferred substrate since other polyribonucleotides are hydrolyzed more slowly, if at all. The enzyme is inhibited by ethidium bromide, but fully double-stranded polyribonucleotides are not hydrolyzed. The hydrolysis of [ 3 H]m 7 Gppp[ 14 C]RNA-poly(A) is stimulated about 2.5-fold by the addition of small nuclear RNAs U1 and U2 of Novikoff hepatoma cells. Results show that the stimulation involves an interaction of the labeled RNA with the small nuclear RNA

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

Science.gov (United States)

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-01-01

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

Icaritin inhibits the expression of alpha-fetoprotein in hepatitis B virus-infected hepatoma cell lines through post-transcriptional regulation.

Science.gov (United States)

Zhang, Chao; Li, Hui; Jiang, Wei; Zhang, Xiaowei; Li, Gang

2016-12-13

Although it has showed that icaritin can apparently suppress growth of HCC by reducing the level of AFP, the intrinsic mechanism remains unclear. In this study, we explored the possible mechanism of miRNAs on post-transcriptional regulation of AFP gene, as well as the effects of HBV infection and icaritin in hepatoma cells. The results showed that miR-620, miR-1236 and miR-1270 could bind target sites in the range of 9-18 nt and 131-151 nt downstream of the stop codon in the AFP mRNA 3'-UTR to suppress the expression of AFP. Mutation of these target sites could reverse the effects of these miRNAs. Icaritin (10 μM) might reduce the stability and translational activity of AFP mRNA by increasing the expression levels of these mentioned miRNAs. HBV infection resulted in apparent decreases of these miRNAs and, consequently, increased AFP expression. The results indicated that miR-620, miR-1236 and miR-1270 are critical factors in the post-transcriptional regulation of AFP. Icaritin can counteract the effect of HBV. These findings will contribute to full understanding of the regulatory mechanism of AFP expression in hepatoma cells. And also it revealed a synergistic mechanism of HBV infection and elevation of AFP in the pathogenesis of HCC, as well as the potential clinical significance of icaritin on the therapy of HCC induced by HBV.

Significant histologic features differentiating cellular fibroadenoma from phyllodes tumor on core needle biopsy specimens.

Science.gov (United States)

Yasir, Saba; Gamez, Roberto; Jenkins, Sarah; Visscher, Daniel W; Nassar, Aziza

2014-09-01

Cellular fibroepithelial lesions (CFELs) are a heterogeneous group of tumors encompassing cellular fibroadenoma (CFA) and phyllodes tumor (PT). Distinction between the two is challenging on core needle biopsy (CNB) specimens. The objective of this study was to evaluate histologic features that can help distinguish PT from CFA on CNB specimens. Records of all patients diagnosed with CFELs on CNB specimens with follow-up excision between January 2002 and December 2012 were retrieved. Histopathologic stromal features were evaluated on CNB specimens, including mitoses per 10 high-power fields (hpf), overgrowth, increased cellularity, fragmentation, adipose tissue infiltration, heterogeneity, subepithelial condensation, and nuclear pleomorphism. Twenty-seven (42.2%) of 64 were diagnosed as PT (24 benign PTs and three borderline PTs) and 37 (57.8%) as CFA on excision. All features except for increased stromal cellularity were statistically significant. The average number of histologic features seen in PT and CFA was 3.9 and 1.4, respectively (odds ratio [OR], 7.27; 95% confidence interval [CI], 2.44-21.69; P = .0004). The average number of mitoses per 10 hpf was 3.0 for PT compared with 0.8 for CFA (OR, 2.14; 95% CI, 1.18-3.86; P = .01). The presence of mitoses (three or more) and/or total histologic features of three or more on CNB specimens were the most helpful features in predicting PT on excision. Copyright© by the American Society for Clinical Pathology.

In vitro uptakes of radiolabeled IVDU and IVFRU in herpes simplex virus type-1 thymidine kinase (HSV1-tk) gene transduced morris hepatoma cell line

Energy Technology Data Exchange (ETDEWEB)

Lee, Tae Sup; Choi, Tae Hyun; Ahn, Soon Hyuk; Woo, Kwang Sun; Jeong, Wee Sup; Kwon, Hee Chung; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Awh, Ok Doo [College of Health Sciences, Yonsei Univ., Wonju (Korea, Republic of)

2004-02-01

The herpes simplex virus type 1 thymidine kinase gene(HSV1-tk) is an attractive candidate as a reporter gene in noninvasive reporter gene monitoring system. The HSV1-tk gene was chosen as a reporter gene, because it has been extensively studied, and there are appropriate reporter probes, substrates of HSV1-tk gene product, to apply for HSV1-tk gene imaging. We used radiolabeled 5-iodovinyl-2'-deoxyuridine (IVDU) and 5-lodovinyl-2'-fluoro-2'-deoxyuridine (IVFRU) as reporter probes for HSV1-tk gene monitoring system. We prepared HSV1-tk gene transduced Morris hepatoma cell line using retroviral vector, MOLTEN containing HSV1-tk gene. And we confirmed the HSV1-tk gene expression by Northern blotting and Western blotting. We compared in vitro uptakes of radioiodinated IVDU and IVFRU to monitor HSV1-tk gene expression in Morris hepatoma cell line (MCA) and HSV1-tk gene tranduced MCA (MAC-tk) cells until 480 minutes. We also performed correlation analysis between percentage of HSV1-tk gene tranduced MCA cell % (MCA-tk%) and uptakes of radiolabeled IVDU or IVFRU. MCA-tk cell expressed HSV1-tk mRNA and HSV1-TK protein. Two compounds showed minimal uptake in MCA, but increased uptake was observed in MCA-tk. IVDU showed 4-fold higher accumulation than IVFRU at 480 min in MCA-tk (p<0.01). Both IVDU and IVFRU uptake were linearly correlated (R{sup 2}>0.96) with increasing MCA-tk%. The rediolabeld IVDU and IVFRU showed higher specific accumulation in retrovirally HSV1-tk gene transfected Morris hepatoma cell line. Both IVDU and IVFRU could be used as good substrates for evaluation of HSV1-tk gene expression.

The X protein of hepatitis B virus activates hepatoma cell proliferation through repressing melanoma inhibitory activity 2 gene

Energy Technology Data Exchange (ETDEWEB)

Xu, Yilin; Yang, Yang; Cai, Yanyan; Liu, Fang; Liu, Yingle; Zhu, Ying [State Key Laboratory of Virology, College of Life Sciences, and Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan 430072 (China); Wu, Jianguo, E-mail: jwu@whu.edu.cn [State Key Laboratory of Virology, College of Life Sciences, and Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan 430072 (China)

2011-12-16

Highlights: Black-Right-Pointing-Pointer We demonstrated that HBV represses MIA2 gene expression both invitro and in vivo. Black-Right-Pointing-Pointer The X protein of HBV plays a major role in such regulation. Black-Right-Pointing-Pointer Knock-down of MIA2 in HepG2 cells activates cell growth and proliferation. Black-Right-Pointing-Pointer HBx activates cell proliferation, over-expression of MIA2 impaired such regulation. Black-Right-Pointing-Pointer HBx activates hepatoma cell proliferation through repressing MIA2 expression. -- Abstract: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer deaths globally. Chronic hepatitis B virus (HBV) infection accounts for over 75% of all HCC cases; however, the molecular pathogenesis of HCC is not well understood. In this study, we found that the expression of the newly identified gene melanoma inhibitory activity 2 (MIA2) was reduced by HBV infection invitro and invivo, and that HBV X protein (HBx) plays a major role in this regulation. Recent studies have revealed that MIA2 is a potential tumor suppressor, and that, in most HCCs, MIA2 expression is down-regulated or lost. We found that the knock-down of MIA2 in HepG2 cells activated cell growth and proliferation, suggesting that MIA2 inhibits HCC cell growth and proliferation. In addition, the over-expression of HBx alone induced cell proliferation, whereas MIA2 over-expression impaired the HBx-mediated induction of proliferation. Taken together, our results suggest that HBx activates hepatoma cell growth and proliferation through repression of the potential tumor suppressor MIA2.

Heterogeneity and weak coupling may explain the synchronization characteristics of cells in the arterial wall

DEFF Research Database (Denmark)

Jacobsen, Jens Christian Brings; Aalkjær, Christian; Matchkov, Vladimir

2008-01-01

development of force known as vasomotion. We present experimental data showing a considerable heterogeneity in cellular calcium dynamics in the vascular wall. In stimulated vessels, some SMCs remain quiescent, whereas others display waves of variable frequency. At the onset of vasomotion, all SMCs...

Intra-voxel heterogeneity influences the dose prescription for dose-painting with radiotherapy: a modelling study

NARCIS (Netherlands)

Petit, S.F.; Dekker, A.L.A.J.; Seigneuric, R.; Murrer, L.H.P.; Riel, van N.A.W.; Nordsmark, M.; Overgaard, J.; Lambin, Ph.; Wouters, B.G.

2009-01-01

The purpose of this study was to increase the potential of dose redistribution by incorporating estimates of oxygen heterogeneity within imaging voxels for optimal dose determination. Cellular oxygen tension (pO2) distributions were estimated for imaging-size-based voxels by solving oxygen

Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis.

Science.gov (United States)

Choe, Sehyo Charley; Hamacher-Brady, Anne; Brady, Nathan Ryan

2015-08-08

determined by levels and spatial localization of autophagy capacity, and subcellular mitochondrial protein heterogeneities. Our model identifies mechanisms and conditions that alter the mitophagy decision within mitochondrial subpopulations to an extent sufficient to shape cellular outcome to apoptotic stimuli. Overall, our modeling approach provides means to suggest new experiments and implement findings at multiple scales in order to understand how network topologies and subcellular heterogeneities can influence signaling events at individual organelle level, and hence, determine the emergence of heterogeneity in cellular decisions due the actions of the collective intra-cellular population.

Tumor heterogeneity and progression: conceptual foundations for modeling.

Science.gov (United States)

Greller, L D; Tobin, F L; Poste, G

1996-01-01

A conceptual foundation for modeling tumor progression, growth, and heterogeneity is presented. The purpose of such models is to aid understanding, test ideas, formulate experiments, and to model cancer 'in machina' to address the dynamic features of tumor cell heterogeneity, progression, and growth. The descriptive capabilities of such an approach provides a consistent language for qualitatively reasoning about tumor behavior. This approach provides a schema for building conceptual models that combine three key phenomenological driving elements: growth, progression, and genetic instability. The growth element encompasses processes contributing to changes in tumor bulk and is distinct from progression per se. The progression element subsumes a broad collection of processes underlying phenotypic progression. The genetics elements represents heritable changes which potentially affect tumor character and behavior. Models, conceptual and mathematical, can be built for different tumor situations by drawing upon the interaction of these three distinct driving elements. These models can be used as tools to explore a diversity of hypotheses concerning dynamic changes in cellular populations during tumor progression, including the generation of intratumor heterogeneity. Such models can also serve to guide experimentation and to gain insight into dynamic aspects of complex tumor behavior.

The spleen can influence the metastasis of AH130 hepatoma cells in rats.

Science.gov (United States)

Toyonaga, M; Hiraoka, T; Tanaka, H; Miyauchi, Y

1993-06-01

The effect of pathophysiological conditions due to disturbance of the spleen is still unclear. We studied the effects of splenectomy in normal and methylcellulose-induced hypersplenic rats on the development of pulmonary metastases created by intravenous injection of ascites containing AH130 hepatoma cells from male Hos-Donryu rats. Growth of metastatic lesions in the lung was not affected by splenectomy in normal rats, but was increased by splenectomy in hypersplenic rats. Overall, there were fewer pulmonary metastases in rats with hypersplenism, but after splenectomy rats with hypersplenism had a significantly greater number of metastases than did normal rats. The metastases rate correlated somewhat with changes in the blood coagulation and T lymphocyte profile. There is a relationship between the spleen and formation of metastases in cancer. Formation of metastases in the lung was affected most by splenectomy in hypersplenism. To elucidate the mechanism by which metastases are formed in the lung under these pathologic conditions, further studies on the exact role of the spleen are required.

Regulation of low density lipoprotein receptor function in a human hepatoma cell line

International Nuclear Information System (INIS)

Leichtner, A.M.; Krieger, M.; Schwartz, A.L.

1984-01-01

Low density lipoprotein (LDL) processing was investigated in a human hepatoma-derived cell line, Hep G2. Hep G2 cells bound, internalized and degraded LDL via a saturable, high affinity pathway similar to that present in other mammalian cells. Although 80% of the uptake and degradation of 125 I-LDL was inhibited by 40-fold excess native LDL, the same concentration of methylated LDL, which cannot bind to LDL receptors, had virtually no effect on processing. When added at low concentrations, the lysosomotropic agent, chloroquine, inhibited degradation without affecting the rate of lipoprotein internalization. Receptor activity was decreased 60% by preincubation of the cells in medium containing a source of cholesterol (LDL or unesterified cholesterol) and increased 1.7-fold by preincubation with compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. The Hep G2 cell line may prove a useful system both for the further study of hepatic lipoprotein metabolism and for the evaluation of new antihypercholesterolemic agents

Case of radiation gastroduodenitis caused by /sup 60/Co-irradiation therapy for hepatoma

Energy Technology Data Exchange (ETDEWEB)

Nishikawa, H; Hayashi, N; Morise, K; Tunekawa, J; Kaneshiro, K [Nagoya Univ. (Japan). Faculty of Medicine

1981-02-01

A 56-year-old man with hepatoma, who had been treated with total 3,960 rad of /sup 60/Co-irradiation 2 months previously, was readmitted to the hospital because of fever and anemia. Following admission, he passed tarry stools every day. Barium meal examination revealed esophageal varices and erosive gastritis of the antrum. At endoscopy, many hemorrhagic erosions were found in the gastric antrum and the first part of duodenum, which were located in the irradiation area. Since repeated blood transfusion failed to improve anemia, a complete fasting with intravenous hyperalimentation and antacid therapy were started. Two months later, feeding was started and thereafter continued without any appreciable GI bleeding or worsening of anemia. Endoscopic examination at this time revealed only a few erosions scattered over the edematous antral mucosa as well as the proximal duodenum. IVH, antacids and abstinence from food seem to be an effective measure in the treatment of radiation injury of the gut.

A yeast endoribonuclease stimulated by Novikoff hepatoma small nuclear RNAs U1 and U2

International Nuclear Information System (INIS)

Stevens, A.

1982-01-01

Using [ 3 H]m 7 Gppp[ 14 C]RNA-poly(A) from yeast as a substrate, an endoribonuclease has been detected in enzyme fractions derived from a high salt wash of ribonucleoprotein particles of Saccharomyces cerevisiae. The [ 3 H]m 7 Gppp[ 14 C]RNA-poly(A) seems to be a preferred substrate since other polyribonucleotides are hydrolyzed more slowly, if at all. The enzyme is inhibited by ethidium bromide, but fully double-stranded polyribonucleotides are not hydrolyzed. The hydrolysis of [ 3 H]m 7 Gppp[ 14 C]RNA-poly(A) is stimulated about 2.5-fold by the addition of small nuclear RNAs U1 and U2 of Novikoff hepatoma cells. Results show that the stimulation involves an interaction of the labeled RNA with the small nuclear RNA

Firing rate dynamics in recurrent spiking neural networks with intrinsic and network heterogeneity.

Science.gov (United States)

Ly, Cheng

2015-12-01

Heterogeneity of neural attributes has recently gained a lot of attention and is increasing recognized as a crucial feature in neural processing. Despite its importance, this physiological feature has traditionally been neglected in theoretical studies of cortical neural networks. Thus, there is still a lot unknown about the consequences of cellular and circuit heterogeneity in spiking neural networks. In particular, combining network or synaptic heterogeneity and intrinsic heterogeneity has yet to be considered systematically despite the fact that both are known to exist and likely have significant roles in neural network dynamics. In a canonical recurrent spiking neural network model, we study how these two forms of heterogeneity lead to different distributions of excitatory firing rates. To analytically characterize how these types of heterogeneities affect the network, we employ a dimension reduction method that relies on a combination of Monte Carlo simulations and probability density function equations. We find that the relationship between intrinsic and network heterogeneity has a strong effect on the overall level of heterogeneity of the firing rates. Specifically, this relationship can lead to amplification or attenuation of firing rate heterogeneity, and these effects depend on whether the recurrent network is firing asynchronously or rhythmically firing. These observations are captured with the aforementioned reduction method, and furthermore simpler analytic descriptions based on this dimension reduction method are developed. The final analytic descriptions provide compact and descriptive formulas for how the relationship between intrinsic and network heterogeneity determines the firing rate heterogeneity dynamics in various settings.

Clinical and biological significance of hepatoma-derived growth factor in Ewing's sarcoma.

Science.gov (United States)

Yang, Yang; Li, Hui; Zhang, Fenfen; Shi, Huijuan; Zhen, Tiantian; Dai, Sujuan; Kang, Lili; Liang, Yingjie; Wang, Jin; Han, Anjia

2013-11-01

We sought to investigate the clinicopathological significance and biological function of hepatoma-derived growth factor (HDGF) in Ewing's sarcoma. Our results showed that HDGF expression is up-regulated in Ewing's sarcoma. Nuclear HDGF expression is significantly associated with tumour volume (p Ewing's sarcoma cell growth, proliferation and enhances tumourigenesis, both in vitro and in vivo. Meanwhile, HDGF knock-down causes cell cycle arrest and enhanced sensitization to serum starvation-induced apoptosis. Furthermore, recombinant HDGF promotes proliferation and colony formation of Ewing's sarcoma cells. Ninety-eight candidate HDGF downstream genes were identified in Ewing's sarcoma cells using cDNA microarray analysis. In addition, we found that HDGF knock-down inhibited FLI1 expression in Ewing's sarcoma cells at the mRNA and protein levels. Our findings suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewing's sarcoma. Targeting HDGF might be a potential therapeutic strategy for Ewing's sarcoma. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Energy management in wireless cellular and ad-hoc networks

CERN Document Server

Imran, Muhammad; Qaraqe, Khalid; Alouini, Mohamed-Slim; Vasilakos, Athanasios

2016-01-01

This book investigates energy management approaches for energy efficient or energy-centric system design and architecture and presents end-to-end energy management in the recent heterogeneous-type wireless network medium. It also considers energy management in wireless sensor and mesh networks by exploiting energy efficient transmission techniques and protocols. and explores energy management in emerging applications, services and engineering to be facilitated with 5G networks such as WBANs, VANETS and Cognitive networks. A special focus of the book is on the examination of the energy management practices in emerging wireless cellular and ad hoc networks. Considering the broad scope of energy management in wireless cellular and ad hoc networks, this book is organized into six sections covering range of Energy efficient systems and architectures; Energy efficient transmission and techniques; Energy efficient applications and services. .

Resource allocation for phantom cellular networks: Energy efficiency vs spectral efficiency

KAUST Repository

Abdelhady, Amr Mohamed Abdelaziz; Amin, Osama; Alouini, Mohamed-Slim

2016-01-01

Multi-tier heterogeneous networks have become an essential constituent for next generation cellular networks. Mean-while, energy efficiency (EE) has been considered a critical design criterion along with the traditional spectral efficiency (SE) metric. In this context, we study power and spectrum allocation for the recently proposed two-tier network architecture known as phantom cellular networks. The optimization framework includes both EE and SE, where we propose an algorithm that finds the SE and EE resource allocation strategies for phantom cellular networks. Then, we compare the performance of both design strategies versus the number of users, and phantom cells share of the total number of available resource blocks. We aim to investigate the effect of some system parameters to achieve improved SE performance at a non-significant loss in EE performance, or vice versa. It was found that increasing phantom cells share of resource blocks decreases the SE performance loss due to EE optimization when compared with the optimized SE performance. © 2016 IEEE.

Resource allocation for phantom cellular networks: Energy efficiency vs spectral efficiency

KAUST Repository

Abdelhady, Amr M.

2016-07-26

Multi-tier heterogeneous networks have become an essential constituent for next generation cellular networks. Mean-while, energy efficiency (EE) has been considered a critical design criterion along with the traditional spectral efficiency (SE) metric. In this context, we study power and spectrum allocation for the recently proposed two-tier network architecture known as phantom cellular networks. The optimization framework includes both EE and SE, where we propose an algorithm that finds the SE and EE resource allocation strategies for phantom cellular networks. Then, we compare the performance of both design strategies versus the number of users, and phantom cells share of the total number of available resource blocks. We aim to investigate the effect of some system parameters to achieve improved SE performance at a non-significant loss in EE performance, or vice versa. It was found that increasing phantom cells share of resource blocks decreases the SE performance loss due to EE optimization when compared with the optimized SE performance. © 2016 IEEE.

Sulphonated hypocrellin B sensitized photo damage to ascetic hepatoma cells

International Nuclear Information System (INIS)

Yue Jiachang; Wang Tiandun; Pang Suzhen; An Jingyi; Jiang Lijing

1994-01-01

The cellular uptake of sulphonated hypocrellin (S-HB), as well as photo damage on cellular viability, lipid peroxidation and intrinsic fluorescence quenching of membrane protein was studied. It was found that S-HB suitable dissolved in aqueous solution, its cellular uptake is slower than HB. The photo damage on cellular viability both photo sensitizers was close to each other, however the photo sensitizers were different in physical and chemical properties. The HB photo damage target of cells was membrane, but the sulphonated HB photo damage target of cells may be part of organelles, besides the membrane. the experiments showed the sulphonated HB would be suggested as a potential advantage for photodynamic therapy of tumor in clinical application

Biodistribution and SPECT imaging of 99Tcm labeling NGR peptide in nude mice bearing human HePG2 hepatoma

International Nuclear Information System (INIS)

Ma Wenhui; Wang Jing; Yang Weidong; Li Guiyu; Ma Xiaowei; Wang Zhe

2012-01-01

A peptide containing the Asn-Gly-Arg (NGR) sequence was radiolabeled by 99 Tc m and its radiochemical characteristics, biodistribution and SPECT imaging in nude mice bearing human HePG2 hepatoma were evaluated. 99 Tc m -NGR was prepared directly with a labeling yield higher than 90%, and the radiochemical purity (RCP) higher than 95%. Nude mice bearing human HePG2 hepatoma were randomly divided into 6 groups with 3 mice in each group. The control group mice were blocked by injecting 100 μg unlabeled NGR 0.5 h before 99 Tc m -NGR injection. The mice were sacrificed at 1, 2, 4, 8, 12 h after caudal intravenous injection of 7.4 MBq 99 Tc m -NGR. The uptakes of kidney and liver were very high. Tumor uptake was (2.52±0.62)% ID/g at 1 h, with the highest uptake of (7.26±2.71) %ID/g. At 12 h, the uptake was still (3.93±1.93) %ID/g. In comparison, the uptake of the blocked control group was (1.29±0.85) %ID/g. The SPECT static images of 3 mice and the tumor/muscle (T/NT) value were obtained. The highest T/NT value was 3.25 at 4 h. The xenografted tumor became visible at 1 h and the clearest image of the tumor was observed at 12 h. Results from this work shows that 99 Tc m -NGR can be efficiently prepared, can favorably target tumor angiogenesis, and should be a potential probe in tumor therapy. (authors)

Cellular dosimetry in nuclear medicine imaging: training

International Nuclear Information System (INIS)

Gardin, I.; Faraggi, M.; Stievenart, J.L.; Le Guludec, D.; Bok, B.

1998-01-01

The radionuclides used in nuclear medicine imaging emit not only diagnostically useful photons, but also energy electron emissions, responsible for dose heterogeneity at the cellular level. The mean dose delivered to the cell nucleus by electron emissions of 99m Tc, 123 I, 111 In, 67 Ga, and 201 Tl, has been calculated, for the cell nucleus, a cytoplasmic and a cell membrane distribution of radioactivity. This model takes into account both the self-dose which results from the radionuclide located in the target cell, and the cross-dose, which comes from the surrounding cells. The results obtained by cellular dosimetry (D cel ) have been compared with those obtained with conventional dosimetry (D conv ), by assuming the same amount of radioactivity per cell. Cellular dosimetry shows, for a cytoplasmic and a cell membrane distributions of radioactivity, that the main contribution to the dose to the cell nucleus, comes from the surrounding cells. On the other hand, for a cell nucleus distribution of radioactivity, the self-dose is not negligible and may be the main contribution. The comparison between cellular and conventional dosimetry shows that D cel /D conv ratio ranges from 0.61 and O.89, in case of a cytoplasmic and a cell membrane distributions of radioactivity, depending on the radionuclide and cell dimensions. Thus, conventional dosimetry slightly overestimates the mean dose to the cell nucleus. On the other hand, D cel /D conv ranges from 1.1 to 75, in case of a cell nucleus distribution of radioactivity. Conventional dosimetry may strongly underestimates the absorbed dose to the nucleus, when radioactivity is located in the nucleus. The study indicates that in nuclear medicine imaging, cellular dosimetry may lead to a better understanding of biological effects of radiopharmaceuticals. (authors)

Cellular automaton simulation examining progenitor hierarchy structure effects on mammary ductal carcinoma in situ.

Science.gov (United States)

Bankhead, Armand; Magnuson, Nancy S; Heckendorn, Robert B

2007-06-07

A computer simulation is used to model ductal carcinoma in situ, a form of non-invasive breast cancer. The simulation uses known histological morphology, cell types, and stochastic cell proliferation to evolve tumorous growth within a duct. The ductal simulation is based on a hybrid cellular automaton design using genetic rules to determine each cell's behavior. The genetic rules are a mutable abstraction that demonstrate genetic heterogeneity in a population. Our goal was to examine the role (if any) that recently discovered mammary stem cell hierarchies play in genetic heterogeneity, DCIS initiation and aggressiveness. Results show that simpler progenitor hierarchies result in greater genetic heterogeneity and evolve DCIS significantly faster. However, the more complex progenitor hierarchy structure was able to sustain the rapid reproduction of a cancer cell population for longer periods of time.

Clinical implications of heterogeneity of tumor response to radiation therapy

International Nuclear Information System (INIS)

Suit, H.; Skates, S.; Taghian, A.; Okunieff, P.; Efird, J.T.

1992-01-01

Heterogeneity of response of tumor tissue to radiation clearly exists. Major parameters include histopathologic type, size (number of tumor rescue units (TRUs)), hemoglobin concentration, cell proliferation kinetics and immune rejection reaction by host. Further, normal and presumably tumor tissue response is altered in certain genetic diseases, e.g. ataxia telangiectasia. Any assessment of response of tumor tissue to a new treatment method or the testing of a new clinical response predictor is optimally based upon a narrow strata, viz., uniform with respect to known parameters of response, e.g. size, histological type. Even among tumors of such a clinical defined narrow strata, there will be residual heterogeneity with respect to inherent cellular radiation sensitivity, distributions of pO 2 , (SH), cell proliferation, etc. (author). 39 refs., 7 figs., 3 tabs

Axial and Cellular Heterogeneity in Electrolyte Transport Pathways Along the Thick Ascending Limb

DEFF Research Database (Denmark)

Dimke, Henrik; Schnermann, Jürgen

2018-01-01

The thick ascending limb (TAL) extends from the border of the inner medulla to the renal cortex, thus ascending through regions with wide differences in tissue solute and electrolyte concentrations. Structural and functional differences between TAL cells in the medulla (mTAL) and the cortex (c......TAL, divergent axial and cellular expression of H+transport proteins in TAL have been documented. The reabsorption of the divalent cations Ca2+and Mg2+is highest in cTAL and paralleled by differences in divalent cation permeability and the expression of select claudins. Morphologically, two cell types...

Heterogeneous chromatin target model

International Nuclear Information System (INIS)

Watanabe, Makoto

1996-01-01

The higher order structure of the entangled chromatin fibers in a chromosome plays a key role in molecular control mechanism involved in chromosome mutation due to ionizing radiations or chemical mutagens. The condensed superstructure of chromatin is not so rigid and regular as has been postulated in general. We have proposed a rheological explanation for the flexible network system ('chromatin network') that consists of the fluctuating assembly of nucleosome clusters linked with supertwisting DNA in a chromatin fiber ('Supertwisting Particulate Model'). We have proposed a 'Heterosensitive Target Model' for cellular radiosensitivity that is a modification of 'Heterogeneous Target Model'. The heterogeneity of chromatin target is derived from the highly condensed organization of chromatin segments consist of unstable and fragile sites in the fluctuating assembly of nucleosome clusters, namely 'supranucleosomal particles' or 'superbeads'. The models have been principally supported by our electron microscopic experiments employing 'surface - spreading whole - mount technique' since 1967. However, some deformation and artifacts in the chromatin structure are inevitable with these electron microscopic procedures. On the contrary, the 'atomic force microscope (AFM)' can be operated in liquid as well as in the air. A living specimen can be examined without any preparative procedures. Micromanipulation of the isolated chromosome is also possible by the precise positional control of a cantilever on the nanometer scale. The living human chromosomes were submerged in a solution of culture medium and observed by AFM using a liquid immersion cell. The surface - spreading whole - mount technique was applicable for this observation. The particulate chromatin segments of nucleosome clusters were clearly observed within mitotic human chromosomes in a living hydrated condition. These findings support the heterogeneity of chromatin target in a living cell. (J.P.N.)

Arecoline inhibits the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1A1 activation in human hepatoma cells

International Nuclear Information System (INIS)

Chang, Eddy Essen; Miao Zhifeng; Lee, W.-J.; Chao, H.-R.; Li, Lih-Ann; Wang, Y.-F.; Ko, Y.-C.; Tsai, F.-Y.; Yeh, S.C.; Tsou, T.-C.

2007-01-01

In the present study, we investigated the effect of arecoline, a major areca nut alkaloid, on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of cytochrome P4501A1 (CYP1A1) in a human hepatoma cell line Huh-7. We treated Huh-7 cells with 10 nM TCDD in the presence of different concentrations of arecoline (50-300 μM). Our results indicated that arecoline attenuated the TCDD-induced CYP1A1 enzyme activation with an inhibitory effect on cell proliferation. By using real-time RT-PCR, we demonstrated that arecoline inhibited the TCDD-induced activations of CYP1A1 and AhR repressor (AhRR) mRNA expression in a similar pattern. Our results revealed that arecoline inhibited AhR mRNA expression with no direct effect on CYP1A1 enzyme activity. Therefore, in our present study, the observed inhibitory effect of arecoline on CYP1A1 activation was not due to the up-regulation of AhRR or direct inhibitory effect on CYP1A1. Taken together, here we have demonstrated that arecoline attenuates the TCDD-induced CYP1A1 activation mainly via down-regulation of AhR expression in human hepatoma cells, suggesting the possible involvement of arecoline in the AhR-mediated metabolism of environmental toxicants in liver

Modeling connected and autonomous vehicles in heterogeneous traffic flow

Science.gov (United States)

Ye, Lanhang; Yamamoto, Toshiyuki

2018-01-01

The objective of this study was to develop a heterogeneous traffic-flow model to study the possible impact of connected and autonomous vehicles (CAVs) on the traffic flow. Based on a recently proposed two-state safe-speed model (TSM), a two-lane cellular automaton (CA) model was developed, wherein both the CAVs and conventional vehicles were incorporated in the heterogeneous traffic flow. In particular, operation rules for CAVs are established considering the new characteristics of this emerging technology, including autonomous driving through the adaptive cruise control and inter-vehicle connection via short-range communication. Simulations were conducted under various CAV-penetration rates in the heterogeneous flow. The impact of CAVs on the road capacity was numerically investigated. The simulation results indicate that the road capacity increases with an increase in the CAV-penetration rate within the heterogeneous flow. Up to a CAV-penetration rate of 30%, the road capacity increases gradually; the effect of the difference in the CAV capability on the growth rate is insignificant. When the CAV-penetration rate exceeds 30%, the growth rate is largely decided by the capability of the CAV. The greater the capability, the higher the road-capacity growth rate. The relationship between the CAV-penetration rate and the road capacity is numerically analyzed, providing some insights into the possible impact of the CAVs on traffic systems.

Handoff Rate and Coverage Analysis in Multi-tier Heterogeneous Networks

OpenAIRE

Sadr, Sanam; Adve, Raviraj S.

2015-01-01

This paper analyzes the impact of user mobility in multi-tier heterogeneous networks. We begin by obtaining the handoff rate for a mobile user in an irregular cellular network with the access point locations modeled as a homogeneous Poisson point process. The received signal-to-interference-ratio (SIR) distribution along with a chosen SIR threshold is then used to obtain the probability of coverage. To capture potential connection failures due to mobility, we assume that a fraction of handoff...

MALDI-imaging guided microproteomics workflow for biomarker discovery of intra-tumor heterogeneity

OpenAIRE

Alberts, Deborah; Longuespée, Rémi; Smargiasso, Nicolas; Mazzucchelli, Gabriel; Baiwir, Dominique; DELVENNE, Philippe; Pamelard, Fabien; Picard de Meller, Gael; De Pauw, Edwin

2016-01-01

Introduction A single tumoral tissue can bear phenotypically different cell populations. This phenomenon called intra-tumor heterogeneity can lead to differential behaviors regarding metastasis seeding and therapy resistance [Zardavas et al., Nature Rev. Clin. Onc. 2015]. MALDI imaging has proven its efficiency for revealing hidden molecular features offering an insight into distinct cellular regions based on their molecular content. Further, proteomics applied to these regions could allo...

MPTCP Tunnel: An Architecture for Aggregating Bandwidth of Heterogeneous Access Networks

Directory of Open Access Journals (Sweden)

Xiaolan Liu

2018-01-01

Full Text Available Fixed and cellular networks are two typical access networks provided by operators. Fixed access network is widely employed; nevertheless, its bandwidth is sometimes not sufficient enough to meet user bandwidth requirements. Meanwhile, cellular access network owns unique advantages of wider coverage, faster increasing link speed, more flexible deployment, and so forth. Therefore, it is attractive for operators to mitigate the bandwidth shortage by bundling these two. Actually, there have been existing schemes proposed to aggregate the bandwidth of two access networks, whereas they all have their own problems, like packet reordering or extra latency overhead. To address this problem, we design new architecture, MPTCP Tunnel, to aggregate the bandwidth of multiple heterogeneous access networks from the perspective of operators. MPTCP Tunnel uses MPTCP, which solves the reordering problem essentially, to bundle multiple access networks. Besides, MPTCP Tunnel sets up only one MPTCP connection at play which adapts itself to multiple traffic types and TCP flows. Furthermore, MPTCP Tunnel forwards intact IP packets through access networks, maintaining the end-to-end TCP semantics. Experimental results manifest that MPTCP Tunnel can efficiently aggregate the bandwidth of multiple access networks and is more adaptable to the increasing heterogeneity of access networks than existing mechanisms.

Suppression of cytochrome P450 reductase (POR) expression in hepatoma cells replicates the hepatic lipidosis observed in hepatic POR-null mice.

Science.gov (United States)

Porter, Todd D; Banerjee, Subhashis; Stolarczyk, Elzbieta I; Zou, Ling

2011-06-01

Cytochrome P450 reductase (POR) is a microsomal electron transport protein essential to cytochrome P450-mediated drug metabolism and sterol and bile acid synthesis. The conditional deletion of hepatic POR gene expression in mice results in a marked decrease in plasma cholesterol levels counterbalanced by the accumulation of triglycerides in lipid droplets in hepatocytes. To evaluate the role of cholesterol and bile acid synthesis in this hepatic lipidosis, as well as the possible role of lipid transport from peripheral tissues, we developed a stable, small interfering RNA (siRNA)-mediated cell culture model for the suppression of POR. POR mRNA and protein expression were decreased by greater than 50% in McArdle-RH7777 rat hepatoma cells 10 days after transfection with a POR-siRNA expression plasmid, and POR expression was nearly completely extinguished by day 20. Immunofluorescent analysis revealed a marked accumulation of lipid droplets in cells by day 15, accompanied by a nearly 2-fold increase in cellular triglyceride content, replicating the lipidosis seen in hepatic POR-null mouse liver. In contrast, suppression of CYP51A1 (lanosterol demethylase) did not result in lipid accumulation, indicating that loss of cholesterol synthesis is not the basis for this lipidosis. Indeed, addition of cholesterol to the medium appeared to augment the lipidosis in POR-suppressed cells, whereas removal of lipids from the medium reversed the lipidosis. Oxysterols did not accumulate in POR-suppressed cells, discounting a role for liver X receptor in stimulating triglyceride synthesis, but addition of chenodeoxycholate significantly repressed lipid accumulation, suggesting that the absence of bile acids and loss of farnesoid X receptor stimulation lead to excessive triglyceride synthesis.

Multi-Layer Soft Frequency Reuse Scheme for 5G Heterogeneous Cellular Networks

DEFF Research Database (Denmark)

Shakir, Md. Hossain; Tariq, Faisal; Safdar, Ghazanfar

2017-01-01

Heterogeneous network (HetNet) is a promising cell deployment technique where low power access points are deployed overlaid on a macrocell system. It attains high throughput by intelligently reusing spectrum, and brings a trade-off between energy- and spectral-efficiency. An efficient resource...... allocation strategy is required to significantly improve its throughput in a bid to meet the fifth-generation (5G) high data rate requirements. In this correspondence, a new resource allocation scheme for HetNet, called multi-level soft frequency reuse for HetNet (ML-SFR HetNet), is proposed which increases...... the throughput several fold. We derived spectrum and power allocation expression for a generalized HetNet scenario. In addition, analytical expressions for the throughput and area spectral efficiency (ASE) are also developed. The simulations results demonstrates the efficiency of the proposed scheme which...

Isolation and characterization of DNA-dependent ATPases from the Novikoff Hepatoma

International Nuclear Information System (INIS)

Thomas, D.C.

1984-01-01

Four DNA-dependent ATPases have been purified to apparent homogeneity from extracts of the Novikoff Hepatoma, and named ATPases II, III, IV, and V. The physical and enzymological properties of ATPases II, III, and V are nearly identical, and from tryptic peptide mapping these proteins were determined to be related, though they are still chromatographically distinct; all appear to be dimers. ATPaseIV is unique among the ATPases, and is probably a monomer. ATPase V appears much more stable to thermal inactivation than the similar curves generated by ATPases II, and III. ATPase IV, however, projects of a heat-inactivation curve intermediate to these two types. ATPase II is labelled to a much higher degree than the others when treated with a heterologous protein kinase using gamma-[ 32 P]-ATP. When ATPase II was treated with this kinase, and subsequently run over a DNA-cellulose column, the profile of ATPase II was found to contain small peaks of activity in the positions where ATPases III and V normally elute, suggesting that ATPase II may be a dephosphorylated form of the other two. The ATPases have been extensively characterized with respect to reaction products and requirements, substrate utilization, DNA effector requirements, and effects of ATP analogs

Cellular promoters incorporated into the adenovirus genome: effects of viral regulatory elements on transcription rates and cell specificity of albumin and beta-globin promoters.

OpenAIRE

Babiss, L E; Friedman, J M; Darnell, J E

1986-01-01

In the accompanying paper (Friedman et al., Mol. Cell. Biol. 6:3791-3797, 1986), hepatoma-specific expression of the rat albumin promoter within the adenovirus genome was demonstrated. However, the rate of transcription was very low compared with that of the endogenous chromosomal albumin gene. Here we show that in hepatoma cells the adenovirus E1A enhancer, especially in the presence of E1A protein, greatly stimulates transcription from the albumin promoter but not the mouse beta-globin prom...

Comparison of the effects of Mylabris and Acanthopanax senticosus on promising cancer marker polyamines in plasma of a Hepatoma-22 mouse model using HPLC-ESI-MS.

Science.gov (United States)

Wang, Qian; Wang, Yixiang; Liu, Ran; Yan, Xu; Li, Yujiao; Fu, Hui; Bi, Kaishun; Li, Qing

2013-02-01

A simple and sensitive method for the simultaneous determination of plasma concentrations of five polyamines in normal and Hepatoma-22 mice, and mice treated with Mylabris and Acanthopanax senticosus was developed by HPLC-ESI-MS. Male Kunming mice were divided into nine groups, a control group (inoculation without treatment), a positive group (Cyclophosphamide), treatment groups [Mylabris (4, 8, 16 mg/kg), Acanthopanax senticosus (6, 12, 24 g/kg)] and a normal group (without inoculation). Twenty-four hours after the last administration, plasma samples were collected. The derived polyamines were separated on a C(18) column by a gradient elution using methanol-water with excellent linearity within the range from 2.5 to 1000 ng/mL. Polyamines were confirmed as useful biochemical markers of hepatoma. The differences in anti-cancer therapeutic efficacy between Mylabris and Acanthopanax senticosus might contribute to the variability of polyamine levels in vivo. This HPLC-ESI-MS method was successfully applied to investigate the relationship between polyamines and cancer in mice and might be a useful method to test the activity of potential anti-tumor drugs. Copyright © 2012 John Wiley & Sons, Ltd.

Excision of foreign gene product with cathepsin D in chicken hepatoma cell line

International Nuclear Information System (INIS)

Sato, Masaharu; Kawashima, Tsuyoshi; Aosasa, Masayoshi; Horiuchi, Hiroyuki; Furusawa, Shuichi; Matsuda, Haruo

2005-01-01

To easily and rapidly recover exogenous gene products from chicken egg yolk, we constructed pVTG-catD (VTG, vitellogenin; catD, cathepsin D), a vector cassette carrying two catD-recognition signal peptides (catD-RSPs) in addition to the cloning site. An enhanced green fluorescence protein (EGFP)-encoding DNA fragment was ligated into the pVTG-catD. When the resultant construct pVTG-EGFP-catD containing histidine- and myc-tags was transfected into the chicken hepatoma cell line LMH, EGFP-expression at 24 h post-cultivation was confirmed by fluorescence microscopy. Because a signal peptide (NTVLAEF) encoded in pVTG-EGFP-catD is recognized by catD, the VTG-EGFP fusion protein digested with catD was detectable by Western blotting. Digested exogenous gene product was recovered with nickel resin. These results indicate that catD-recognition sites bearing pVTG-catD and His-tags are functional in chicken LMH cells. Therefore, the system described here may be of use in making excision exogenous gene products in the chicken and in creating homozygous knock-in chickens

Fluoro-sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence and recovery

Science.gov (United States)

Carr, Brian I.; Cavallini, Aldo; Lippolis, Catia; D’Alessandro, Rosalba; Messa, Caterina; Refolo, Maria Grazia; Tafaro, Angela

2015-01-01

To evaluate the growth-inhibitory properties of the potent multi-kinase antagonist Regorafenib (Fluoro-Sorafenib), which was synthesized as a more potent Sorafenib, a Raf inhibitor and to determine whether similar mechanisms were involved, human hepatoma cell lines were grown in the presence or absence of Regorafanib and examined for growth inhibition. Western blots were performed for Raf targets, for apoptosis and autophagy. Regorafenib inhibited growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner. Multiple signaling pathways were altered, including MAP kinases phospho-ERK and phospho-JNK and its target phospho-c-Jun. There was evidence for apoptosis by FACS, cleavage of caspases and increased Bax levels; as well as induction of autophagy, as judged by increased Beclin-1 and LC3 (II) levels. Prolonged drug exposure resulted in cell quiescence. Full growth recovery occurred after drug removal, unlike with doxorubicin chemotherapy. Regorafenib is a potent inhibitor of cell growth. Cells surviving Regorafenib treatment remain viable, but quiescent and capable of regrowth following drug removal. The reversibility of tumor cell growth suppression after drug removal may have clinical implications. PMID:22777740

Isolation and establishment of radiotolerant hepatoma cell subline

International Nuclear Information System (INIS)

Jin Wensen; Kong Zhaolu; Zhang Jianghong; Shen Zhifen; Tong Shungao; Ji Huajun; Jin Yizun

2009-01-01

Objective: To induce and isolate the monoclonal cell subline, in order to establish the experimental model for further investigating biologic characteristics in radiotolerant hepatoma cells. Methods: HepG2 cells were irradiated by γ-rays at the dose of 2 Gy each time with the total absorbed dose of 60 Gy. After monoclonal cell being selected and extensively cultured, the cell subline was named as HepG2/R60. Furthermore, HepG2/R60 cells were identified by observing the changes of morphology, ultrastructure, growth characteristics and radiosensitivity. The levels of radioresistant correlative gene mRNA in HepG2/R60 cells after exposure to 2 Gy irradiation, were also detected by RT-PCR, and then compared with parental HepG2 cells. Results: HepG2/R60 cell subline was successfully established by fractionated irradiation at 2 Gy. HepG2/R60 cells displayed higher irregularity, the clearer appearance and dissociation of cell junctions compared with parental HepG2 cells. Ultrastnictural investigations through transmission electron microscopy (TEM) showed that there was an increase of microvillus on the surfaces of HepG2/R60 cells with plenty of rough endo-plasmic reticulum, abundance of mitochondria and viable Golgi complex. Further observation found that the growth of HepG2/R60 cells was slower and its population doubling time (PDT) prolonged arrived at 34.9 h. Moreover, the radiosensitivity of HepG2/R60 cells was lower than that of parental HepG2 cells. Additionally, the levels of radioresistance correlative genes were increased in HepG2/R60 cells by 2 Gy irradiaiton Conclusions: Radiotolerant cell subline - HepG2/R60 was successfully isolated and established by fractionated irradiation. (authors)

qpure: A tool to estimate tumor cellularity from genome-wide single-nucleotide polymorphism profiles.

Directory of Open Access Journals (Sweden)

Sarah Song

Full Text Available Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to error due to heterogeneity within lesions and cellularity differences between the sample viewed during pathological review and tissue used for research purposes. In this paper we describe a statistical model to estimate tumour cellularity from SNP array profiles of paired tumour and normal samples using shifts in SNP allele frequency at regions of loss of heterozygosity (LOH in the tumour. We also provide qpure, a software implementation of the method. Our experiments showed that there is a medium correlation 0.42 ([Formula: see text]-value=0.0001 between tumor cellularity estimated by qpure and pathology review. Interestingly there is a high correlation 0.87 ([Formula: see text]-value [Formula: see text] 2.2e-16 between cellularity estimates by qpure and deep Ion Torrent sequencing of known somatic KRAS mutations; and a weaker correlation 0.32 ([Formula: see text]-value=0.004 between IonTorrent sequencing and pathology review. This suggests that qpure may be a more accurate predictor of tumour cellularity than pathology review. qpure can be downloaded from https://sourceforge.net/projects/qpure/.

Melanoma cells revive an embryonic transcriptional network to dictate phenotypic heterogeneity.

Science.gov (United States)

Vandamme, Niels; Berx, Geert

2014-01-01

Compared to the overwhelming amount of literature describing how epithelial-to-mesenchymal transition (EMT)-inducing transcription factors orchestrate cellular plasticity in embryogenesis and epithelial cells, the functions of these factors in non-epithelial contexts, such as melanoma, are less clear. Melanoma is an aggressive tumor arising from melanocytes, endowed with unique features of cellular plasticity. The reversible phenotype-switching between differentiated and invasive phenotypes is increasingly appreciated as a mechanism accounting for heterogeneity in melanoma and is driven by oncogenic signaling and environmental cues. This phenotypic switch is coupled with an intriguing and somewhat counterintuitive signaling switch of EMT-inducing transcription factors. In contrast to carcinomas, different EMT-inducing transcription factors have antagonizing effects in melanoma. Balancing between these different EMT transcription factors is likely the key to successful metastatic spread of melanoma.

Cellular network entropy as the energy potential in Waddington's differentiation landscape

Science.gov (United States)

Banerji, Christopher R. S.; Miranda-Saavedra, Diego; Severini, Simone; Widschwendter, Martin; Enver, Tariq; Zhou, Joseph X.; Teschendorff, Andrew E.

2013-01-01

Differentiation is a key cellular process in normal tissue development that is significantly altered in cancer. Although molecular signatures characterising pluripotency and multipotency exist, there is, as yet, no single quantitative mark of a cellular sample's position in the global differentiation hierarchy. Here we adopt a systems view and consider the sample's network entropy, a measure of signaling pathway promiscuity, computable from a sample's genome-wide expression profile. We demonstrate that network entropy provides a quantitative, in-silico, readout of the average undifferentiated state of the profiled cells, recapitulating the known hierarchy of pluripotent, multipotent and differentiated cell types. Network entropy further exhibits dynamic changes in time course differentiation data, and in line with a sample's differentiation stage. In disease, network entropy predicts a higher level of cellular plasticity in cancer stem cell populations compared to ordinary cancer cells. Importantly, network entropy also allows identification of key differentiation pathways. Our results are consistent with the view that pluripotency is a statistical property defined at the cellular population level, correlating with intra-sample heterogeneity, and driven by the degree of signaling promiscuity in cells. In summary, network entropy provides a quantitative measure of a cell's undifferentiated state, defining its elevation in Waddington's landscape. PMID:24154593

Small regulatory RNA-induced growth rate heterogeneity of Bacillus subtilis.

Science.gov (United States)

Mars, Ruben A T; Nicolas, Pierre; Ciccolini, Mariano; Reilman, Ewoud; Reder, Alexander; Schaffer, Marc; Mäder, Ulrike; Völker, Uwe; van Dijl, Jan Maarten; Denham, Emma L

2015-03-01

Isogenic bacterial populations can consist of cells displaying heterogeneous physiological traits. Small regulatory RNAs (sRNAs) could affect this heterogeneity since they act by fine-tuning mRNA or protein levels to coordinate the appropriate cellular behavior. Here we show that the sRNA RnaC/S1022 from the Gram-positive bacterium Bacillus subtilis can suppress exponential growth by modulation of the transcriptional regulator AbrB. Specifically, the post-transcriptional abrB-RnaC/S1022 interaction allows B. subtilis to increase the cell-to-cell variation in AbrB protein levels, despite strong negative autoregulation of the abrB promoter. This behavior is consistent with existing mathematical models of sRNA action, thus suggesting that induction of protein expression noise could be a new general aspect of sRNA regulation. Importantly, we show that the sRNA-induced diversity in AbrB levels generates heterogeneity in growth rates during the exponential growth phase. Based on these findings, we hypothesize that the resulting subpopulations of fast- and slow-growing B. subtilis cells reflect a bet-hedging strategy for enhanced survival of unfavorable conditions.

From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity

Directory of Open Access Journals (Sweden)

Guido Gambara

2018-02-01

Full Text Available Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (microenvironment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D cell cultures and patient-derived tumor xenografts (PDX as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue.

Degradation of surface-labeled hepatoma membrane polypeptides: effect of inhibitors

International Nuclear Information System (INIS)

Hare, J.F.; Huston, M.

1984-01-01

When their membrane proteins were labeled with 125I by lactoperoxidase, dividing hepatoma cells lost radioactivity to the medium in a biphasic manner (T1/2 . 16-26 h, greater than 40 h). Lysosomotropic weak bases, chloroquine, and NH4Cl inhibited the rapid phase by 59%. More than 50% of the radioactivity which accumulates in the media from dividing cells during the first 4 h after labeling was trichloroacetic acid-soluble, and was identified as iodotyrosine. Iodotyrosine release from labeled membrane proteins was 60-71% inhibited by lysosomotropic agents chloroquine and NH4Cl as well as the sodium-proton ionophore, monensin. The inhibitory effect of NH4Cl and monensin was reversible. Inhibitors of microtubule and microfilament function and transglutamination had no effect on release of iodotyrosine to the medium, but trypsin-like protease inhibitors, p-aminobenzamidine, tosyl-L-lysine/chloromethylketone, and phenylmethylsulfonyl fluoride, as well as the cathepsin B inhibitor, leupeptin, inhibited by 21-24%. Iodotyrosine release showed a biphasic Arrhenius plot with an activation energy of 17 kcal/mol above but 27 kcal/mol below 20 degrees C. These results indicate that cell membrane polypeptides require a temperature-limiting event as well as passage through an ion-sensitive compartment prior to their complete degradation to constituent amino acids. In contrast to other lysosomal-mediated events, however, iodinated membrane proteins of dividing cells are degraded in a manner insensitive to agents which disrupt the cytoskeleton

Effects of the peroxisome proliferator clofibric acid on superoxide dismutase expression in the human HepG2 hepatoma cell line.

Science.gov (United States)

Bécuwe, P; Bianchi, A; Keller, J M; Dauça, M

1999-09-15

We examined the effects of clofibric acid, a peroxisome proliferator, on the production of superoxide radicals, on the levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and on the expression of superoxide dismutases (SODs) in the human HepG2 hepatoma cell line. To this end, HepG2 cells were treated for 1 or 5 days with 0.25, 0.50, or 0.75 mM clofibric acid. The production of superoxide radicals was only enhanced in HepG2 cells exposed for 5 days to the different clofibric acid concentrations. However, this overproduction of superoxide radicals was not accompanied by increased rates of lipid peroxidation, as the MDA and 4-HNE levels did not change significantly. Manganese (Mn) SOD activity was increased when HepG2 cells were treated for 1 day with 0.50 or 0.75 mM clofibric acid. For this duration of treatment, no change was observed in total SOD and copper/zinc (Cu/Zn) SOD activities. For a 5-day treatment, total SOD and MnSOD activities as well as the enzyme apoprotein and MnSOD mRNA levels increased whatever the clofibric acid concentration used. This transcriptional induction of the MnSOD gene was correlated with an activation of the activator protein-1 transcription factor for 1 and 5 days of treatment, but was independent of nuclear factor-kappa B and of peroxisome proliferator-activated receptor. On the other hand, the PP exerted very little effect if any on Cu,ZnSOD expression. In contrast to rodent data, PP treatment of human hepatoma cells induces MnSOD expression.

Non-invasive quality evaluation of confluent cells by image-based orientation heterogeneity analysis.

Science.gov (United States)

Sasaki, Kei; Sasaki, Hiroto; Takahashi, Atsuki; Kang, Siu; Yuasa, Tetsuya; Kato, Ryuji

2016-02-01

In recent years, cell and tissue therapy in regenerative medicine have advanced rapidly towards commercialization. However, conventional invasive cell quality assessment is incompatible with direct evaluation of the cells produced for such therapies, especially in the case of regenerative medicine products. Our group has demonstrated the potential of quantitative assessment of cell quality, using information obtained from cell images, for non-invasive real-time evaluation of regenerative medicine products. However, image of cells in the confluent state are often difficult to evaluate, because accurate recognition of cells is technically difficult and the morphological features of confluent cells are non-characteristic. To overcome these challenges, we developed a new image-processing algorithm, heterogeneity of orientation (H-Orient) processing, to describe the heterogeneous density of cells in the confluent state. In this algorithm, we introduced a Hessian calculation that converts pixel intensity data to orientation data and a statistical profiling calculation that evaluates the heterogeneity of orientations within an image, generating novel parameters that yield a quantitative profile of an image. Using such parameters, we tested the algorithm's performance in discriminating different qualities of cellular images with three types of clinically important cell quality check (QC) models: remaining lifespan check (QC1), manipulation error check (QC2), and differentiation potential check (QC3). Our results show that our orientation analysis algorithm could predict with high accuracy the outcomes of all types of cellular quality checks (>84% average accuracy with cross-validation). Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

CdTe quantum dots with daunorubicin induce apoptosis of multidrug-resistant human hepatoma HepG2/ADM cells: in vitro and in vivo evaluation

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Shi Lixin

2011-01-01

Full Text Available Abstract Cadmium telluride quantum dots (Cdte QDs have received significant attention in biomedical research because of their potential in disease diagnosis and drug delivery. In this study, we have investigated the interaction mechanism and synergistic effect of 3-mercaptopropionic acid-capped Cdte QDs with the anti-cancer drug daunorubicin (DNR on the induction of apoptosis using drug-resistant human hepatoma HepG2/ADM cells. Electrochemical assay revealed that Cdte QDs readily facilitated the uptake of the DNR into HepG2/ADM cells. Apoptotic staining, DNA fragmentation, and flow cytometry analysis further demonstrated that compared with Cdte QDs or DNR treatment alone, the apoptosis rate increased after the treatment of Cdte QDs together with DNR in HepG2/ADM cells. We observed that Cdte QDs treatment could reduce the effect of P-glycoprotein while the treatment of Cdte QDs together with DNR can clearly activate apoptosis-related caspases protein expression in HepG2/ADM cells. Moreover, our in vivo study indicated that the treatment of Cdte QDs together with DNR effectively inhibited the human hepatoma HepG2/ADM nude mice tumor growth. The increased cell apoptosis rate was closely correlated with the enhanced inhibition of tumor growth in the studied animals. Thus, Cdte QDs combined with DNR may serve as a possible alternative for targeted therapeutic approaches for some cancer treatments.

Connexin-based intercellular communication and astrocyte heterogeneity.

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Theis, Martin; Giaume, Christian

2012-12-03

This review gives an overview of the current knowledge on connexin-mediated communication in astrocytes, covering gap junction and hemichannel functions mediated by connexins. Astroglia is the main brain cell type that expresses the largest amount of connexin and exhibits high level of gap junctional communication compared to neurons and oligodendrocytes. However, in certain developmental and regional situations, astrocytes are also coupled with oligodendrocytes and neurons. This heterotypic coupling is infrequent and minor in terms of extent of the coupling area, which does not mean that it is not important in terms of cell interaction. Here, we present an update on heterogeneity of connexin expression and function at the molecular, subcellular, cellular and networking levels. Interestingly, while astrocytes were initially considered as a homogenous population, there is now increasing evidence for morphological, developmental, molecular and physiological heterogeneity of astrocytes. Consequently, the specificity of gap junction channel- and hemichannel-mediated communication, which tends to synchronize cell populations, is also a parameter to take into account when neuroglial interactions are investigated. This article is part of a Special Issue entitled Electrical Synapses. Copyright © 2012 Elsevier B.V. All rights reserved.

Genotoxicity and induction of DNA damage responsive genes by food-borne heterocyclic aromatic amines in human hepatoma HepG2 cells.

Science.gov (United States)

Pezdirc, Marko; Žegura, Bojana; Filipič, Metka

2013-09-01

Heterocyclic aromatic amines (HAAs) are potential human carcinogens formed in well-done meats and fish. The most abundant are 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-Amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (4,8-DiMeIQx) and 2-Amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ). HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes, that is well characterized, however the genomic and intervening responses are not well explored. We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs. Comet assay revealed increase in formation of DNA strand breaks by PhIP, MeIQx and IQ but not 4,8-DiMeIQx, whereas increased formation of micronuclei was not observed. The four HAAs up-regulated expression of genes encoding metabolic enzymes CYP1A1, CYP1A2 and UGT1A1 and expression of TP53 and its downstream regulated genes CDKN1A, GADD45α and BAX. Consistent with the up-regulation of CDKN1A and GADD45α the cell-cycle analysis showed arrest in S-phase by PhIP and IQ, and in G1-phase by 4,8-DiMeIQx and MeIQx. The results indicate that upon exposure to HAAs the cells respond with the cell-cycle arrest, which enables cells to repair the damage or eliminate them by apoptosis. However, elevated expression of BCL2 and down-regulation of BAX may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate. Copyright © 2013 Elsevier Ltd. All rights reserved.

Basil extract inhibits the sulfotransferase mediated formation of DNA adducts of the procarcinogen 1'-hydroxyestragole by rat and human liver S9 homogenates and in HepG2 human hepatoma cells

NARCIS (Netherlands)

Jeurissen, S.M.F.; Punt, A.; Delatour, T.; Rietjens, I.M.C.M.

2008-01-01

The effects of a basil extract on the sulfation and concomitant DNA adduct formation of the proximate carcinogen 1¿-hydroxyestragole were studied using rat and human liver S9 homogenates and the human hepatoma cell line HepG2. Basil was chosen since it contains the procarcinogen estragole that can

Organizing the Cellular and Molecular Heterogeneity in High Grade Serous Ovarian Cancer by Mass Cytometry

Science.gov (United States)

2015-10-01

about more informed changes to treatment modalities. To accomplish this vision with HG-SOC, we are using a single cell technology , mass cytometry... extracted from the composite MST. Clusters are represented as bubbles, the size of which corresponds to the number of cells in the cluster. The level of...Fantl WJ, Nolan GP. Transient partial permeabilization with saponin enables cellular barcoding prior to surface marker staining. Cytometry A. 2014 Dec;85

Radiation-induced cell disintegrations in cultured rat hepatoma cells JTC 2

International Nuclear Information System (INIS)

Sakka, Masatoshi

1979-01-01

Disintegration of hepatoma cells of rat were recorded by time lapse cinemicrography for more than 5 days and about 1000 pedigrees were analyzed. Five generations were followed up in control and 2 or 3 generations in irradiated cells. Cells were attached on vessel wall spreading themselves in intermitotic phase while they stood up from the wall in mitotic phase taking a roun form. When a cell disintegrates in interphase the disintegration is called D sub( s) and one in mitotic period D sub( r). The frequency of D sub( s)S' is about 3 times as much as D sub( r)S'. An age of a disintegrated cell in generation 1 and 2 was measured as the previous mitosis was age 0. Generation times of the comparable generations of surviving sister branches of the same pedigrees were used as controls. Most disintegration took place at the same age with surviving sisters indicating a determined, not at random, age of cell death. A cell in an initial state flowed to any one of the following states with or without irradiation; surviving, disintegrated, end cell or escaping out of observation field. A single exposure of 400 to 900 R induced a typical reproductive death but effective extinction of clones was observed only in small pedigrees. Temporary hypothermia and hyperthermia immediately after exposure had no remarkable lethal effects on several early generations. (author)

Tyramine-O-sulfate is produced and secreted by human hepatoma cells, line HepG2

International Nuclear Information System (INIS)

Liu, M.C.; Yu, S.; Suiko, M.

1987-01-01

Human hepatoma cells, line HepG2, were metabolically labeled with [ 35 S]sulfate. The spent medium separated following 24 hr labeling was subjected to ultrafiltration using an Amicon Centricon unit. The filtrate obtained was analyzed by a two-dimensional separation procedure combining high-voltage electrophoresis and thin-layer chromatography. The autoradiograph taken from the cellulose thin-layer plate following the analysis revealed the presence of tyramine-O-[ 35 ]sulfate in addition to tyrosine-O-[ 35 ]sulfate. Using adenosine, 3'-phosphate, 5'-phospho[ 35 S]sulfate as the sulfate donor, it was shown that tyramine was actively sulfated to form tyramine-O-[ 35 S]sulfate as catalyzed by the sulfotransferase(s) present in dog liver homogenate. Attempts to decarboxylate tyrosine-O-sulfate to tyramine-O-sulfate using intrinsic p-tyrosine decarboxylase present in dog liver homogenate, however, were unsuccessful. Employing purified Streptococcus faecalis tyrosine decarboxylase, it was shown that L-tyrosine was actively decarboxylated to tyramine, whereas tyrosine-O-sulfate could not serve as a substrate

Over-expression and siRNA of a novel environmental lipopolysaccharide-responding gene on the cell cycle of the human hepatoma-derived cell line HepG2

International Nuclear Information System (INIS)

Du Kejun; Chai Yubo; Hou Lichao; Chang Wenhui; Chen Suming; Luo Wenjing; Cai Tongjian; Zhang Xiaonan; Chen Nanchun; Chen Yaoming; Chen Jingyuan

2008-01-01

Lipopolysaccharide (LPS) is the toxic determinant for Gram-negative bacterium infection. The individual response to LPS was related to its gene background. It is necessary to identify new molecules and signaling transduction pathways about LPS. The present study was undertaken to evaluate the effects of a novel environmental lipopolysaccharide-responding (Elrg) gene on the regulation of proliferation and cell cycle of the hepatoma-derived cell line, HepG2. By means of RT-PCR, the new molecule of Elrg was generated from a human dental pulp cell cDNA library. Expression level of Elrg in HepG2 cells was remarkably upgraded by the irritation of LPS. Localization of Elrg in HepG2 cells was positioned mainly in cytoplasm. HepG2 cells were markedly arrested in the G1 phase by over-expressing Elrg. The percentage of HepG2 cells in G1 phase partly decreased after Elrg-siRNA. In conclusion, Elrg is probably correlative with LPS responding. Elrg is probably a new protein in cytoplasm which plays an important role in regulating cell cycle. The results will deepen our understanding about the potential effects of Elrg on the human hepatoma-derived cell line HepG2

Immunological response induced by cryoablation against murine H22 hepatoma cell line in vivo.

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Yang, Xueling; Li, Xiaoli; Guo, Zhi; Si, Tongguo; Yu, Haipeng; Xing, Wenge

2018-02-01

To describe immunological consequences induced by cryoablation against H22 cells in vivo. Adult BALB/c mice underwent subcutaneous implantation of H22 cells. All of them were assigned into three groups randomly: group A (false surgery), group B (cryoablation) and group C (cryoablation plus Freund's adjuvant). Animals were sacrificed 1, 2 and 3 weeks after treatment. Serum IFN-γ and IL-4, Th1/Th2 in spleens and cytotoxicity were detected. Compared with that of group A, (1) INF-γ of group B was higher, but IL-4 was lower; cryoablation plus Freund's adjuvant enhanced these effects. (2) Th1/Th2 rose significantly in both group B and group C. (3) Strong cytolytic activity against H22 cells of group B and group C was found on day 7, 14 and 21. Our study showed a marked shift toward Th1 and IFN-γ expression after cryoablation, with an immuno-stimulatory effect against murine H22 hepatoma Cell. Copyright © 2017. Published by Elsevier Inc.

Organizing the Cellular and Molecular Heterogeneity in High-Grade Serous Ovarian Cancer by Mass Cytometry

Science.gov (United States)

2013-10-01

Acknowledgements The authors wish to thank Drs Scott Tanner, Olga Ornatsky, Dmitry Bandura , Mitch Winnik and Mark Nitz for their critical reading of this...Quality assurance for polychromatic flow cytometry using a suite of calibration beads. Nat Protoc 2012, 7:2067-2079. 23. Baranov VI, Quinn Z, Bandura ... Bandura DR, Tanner SD, Dick J: Multiple cellular antigen detection by ICP-MS. J Immunol Methods 2006, 308:68-76. 25. Ornatsky OI, Kinach R, Bandura DR

Can complex cellular processes be governed by simple linear rules?

Science.gov (United States)

Selvarajoo, Kumar; Tomita, Masaru; Tsuchiya, Masa

2009-02-01

Complex living systems have shown remarkably well-orchestrated, self-organized, robust, and stable behavior under a wide range of perturbations. However, despite the recent generation of high-throughput experimental datasets, basic cellular processes such as division, differentiation, and apoptosis still remain elusive. One of the key reasons is the lack of understanding of the governing principles of complex living systems. Here, we have reviewed the success of perturbation-response approaches, where without the requirement of detailed in vivo physiological parameters, the analysis of temporal concentration or activation response unravels biological network features such as causal relationships of reactant species, regulatory motifs, etc. Our review shows that simple linear rules govern the response behavior of biological networks in an ensemble of cells. It is daunting to know why such simplicity could hold in a complex heterogeneous environment. Provided physical reasons can be explained for these phenomena, major advancement in the understanding of basic cellular processes could be achieved.

Metabolic Flux Distribution during Defatting of Steatotic Human Hepatoma (HepG2 Cells

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Gabriel Yarmush

2016-01-01

Full Text Available Methods that rapidly decrease fat in steatotic hepatocytes may be helpful to recover severely fatty livers for transplantation. Defatting kinetics are highly dependent upon the extracellular medium composition; however, the pathways involved are poorly understood. Steatosis was induced in human hepatoma cells (HepG2 by exposure to high levels of free fatty acids, followed by defatting using plain medium containing no fatty acids, or medium supplemented with a cocktail of defatting agents previously described before. We measured the levels of 28 extracellular metabolites and intracellular triglyceride, and fed the data into a steady-state mass balance model to estimate strictly intracellular fluxes. We found that during defatting, triglyceride content decreased, while beta-oxidation, the tricarboxylic acid cycle, and the urea cycle increased. These fluxes were augmented by defatting agents, and even more so by hyperoxic conditions. In all defatting conditions, the rate of extracellular glucose uptake/release was very small compared to the internal supply from glycogenolysis, and glycolysis remained highly active. Thus, in steatotic HepG2 cells, glycolysis and fatty acid oxidation may co-exist. Together, these pathways generate reducing equivalents that are supplied to mitochondrial oxidative phosphorylation.

3D hierarchical computational model of wood as a cellular material with fibril reinforced, heterogeneous multiple layers

DEFF Research Database (Denmark)

Qing, Hai; Mishnaevsky, Leon

2009-01-01

A 3D hierarchical computational model of deformation and stiffness of wood, which takes into account the structures of wood at several scale levels (cellularity, multilayered nature of cell walls, composite-like structures of the wall layers) is developed. At the mesoscale, the softwood cell...... cellular model. With the use of the developed hierarchical model, the influence of the microstructure, including microfibril angles (MFAs, which characterizes the orientation of the cellulose fibrils with respect to the cell axis), the thickness of the cell wall, the shape of the cell cross...... is presented as a 3D hexagon-shape-tube with multilayered walls. The layers in the softwood cell are considered as considered as composite reinforced by microfibrils (celluloses). The elastic properties of the layers are determined with Halpin–Tsai equations, and introduced into mesoscale finite element...

Effect of heterogeneous microvasculature distribution on drug delivery to solid tumour

International Nuclear Information System (INIS)

Zhan, Wenbo; Xu, Xiao Yun; Gedroyc, Wladyslaw

2014-01-01

Most of the computational models of drug transport in vascular tumours assume a uniform distribution of blood vessels through which anti-cancer drugs are delivered. However, it is well known that solid tumours are characterized by dilated microvasculature with non-uniform diameters and irregular branching patterns. In this study, the effect of heterogeneous vasculature on drug transport and uptake is investigated by means of mathematical modelling of the key physical and biochemical processes in drug delivery. An anatomically realistic tumour model accounting for heterogeneous distribution of blood vessels is reconstructed based on magnetic resonance images of a liver tumour. Numerical simulations are performed for different drug delivery modes, including direct continuous infusion and thermosensitive liposome-mediated delivery, and the anti-cancer effectiveness is evaluated through changes in tumour cell density based on predicted intracellular concentrations. Comparisons are made between regions of different vascular density, and between the two drug delivery modes. Our numerical results show that both extra- and intra-cellular concentrations in the liver tumour are non-uniform owing to the heterogeneous distribution of tumour vasculature. Drugs accumulate faster in well-vascularized regions, where they are also cleared out more quickly, resulting in less effective tumour cell killing in these regions. Compared with direct continuous infusion, the influence of heterogeneous vasculature on anti-cancer effectiveness is more pronounced for thermosensitive liposome-mediated delivery. (paper)

Fluorescent BODIPY Rotor: Viscometer for Cellular Organelles and Membrane-Mimicking Vesicles

Science.gov (United States)

Kimball, J.; Raut, S.; Fudala, R.; Doan, H.; Maliwal, B.; Sabnis, N.; Lacko, A.; Gryczynski, I.; Dzyuba, S.; Gryczynski, Z.

2015-03-01

Many cellular processes, such as mass and signal transport, metabolism and protein-protein interactions are governed in part by diffusion, and thus affected by their local microviscosity. Changes in this microviscosity has also been linked to various diseases, including atherosclerosis, Alzheimer's disease and diabetes. Therefore, directly measuring the heterogeneous viscosity of cellular constitutes can lead to greater understanding of these processes. To this effect, a novel homodiemeric BODIPY dye was evaluated as a fluorescent rotor probe for this application. A linear dependence on viscosity in the range of typical cellular microviscosity was established for steady-state and time-resolved properties of the dye. It was then embedded in vitro to membrane-mimicking lipid vesicles (DPPC, POPC, and POPC plus cholesterol) and results indicated it to be a viable sensor for lifetime-based determination of microviscosity. The BODIPY dye was lastly endocytosed by SKOV3 cells and Fluorescence Lifetime Imaging Microscopy (FLIM) was performed, successfully mapping the viscosity of internal cell components. This work was supported by the NIH Grant R01EB12003, the NSF Grant CBET-1264608, and the INFOR Grant from TCU.

Basil extract inhibits the sulfotransferase mediated formation of DNA adducts of the procarcinogen 1′-hydroxyestragole by rat and human liver S9 homogenates and in HepG2 human hepatoma cells

NARCIS (Netherlands)

Jeurissen, S.M.F.; Punt, A.; Delatour, T.; Rietjens, I.M.C.M.

2008-01-01

The effects of a basil extract on the sulfation and concomitant DNA adduct formation of the proximate carcinogen 1′-hydroxyestragole were studied using rat and human liver S9 homogenates and the human hepatoma cell line HepG2. Basil was chosen since it contains the procarcinogen estragole that can

Single-cell RNA sequencing reveals metallothionein heterogeneity during hESC differentiation to definitive endoderm

Directory of Open Access Journals (Sweden)

Junjie Lu

2018-04-01

Full Text Available Differentiation of human pluripotent stem cells towards definitive endoderm (DE is the critical first step for generating cells comprising organs such as the gut, liver, pancreas and lung. This in-vitro differentiation process generates a heterogeneous population with a proportion of cells failing to differentiate properly and maintaining expression of pluripotency factors such as Oct4. RNA sequencing of single cells collected at four time points during a 4-day DE differentiation identified high expression of metallothionein genes in the residual Oct4-positive cells that failed to differentiate to DE. Using X-ray fluorescence microscopy and multi-isotope mass spectrometry, we discovered that high intracellular zinc level corresponds with persistent Oct4 expression and failure to differentiate. This study improves our understanding of the cellular heterogeneity during in-vitro directed differentiation and provides a valuable resource to improve DE differentiation efficiency. Keywords: hPSC, Differentiation, Definitive endoderm, Heterogeneity, Single cell, RNA sequencing

Health and Cellular Impacts of Air Pollutants: From Cytoprotection to Cytotoxicity

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Karine Andreau

2012-01-01

Full Text Available Air pollution as one of the ravages of our modern societies is primarily linked to urban centers, industrial activities, or road traffic. These atmospheric pollutants have been incriminated in deleterious health effects by numerous epidemiological and in vitro studies. Environmental air pollutants are a heterogeneous mixture of particles suspended into a liquid and gaseous phase which trigger the disruption of redox homeostasis—known under the term of cellular oxidative stress—in relation with the establishment of inflammation and cell death via necrosis, apoptosis, or autophagy. Activation or repression of the apoptotic process as an adaptative response to xenobiotics might lead to either acute or chronic toxicity. The purpose of this paper is to highlight the central role of oxidative stress induced by air pollutants and to focus on the subsequent cellular impacts ranging from cytoprotection to cytotoxicity by decreasing or stimulating apoptosis, respectively.

Large epidemic thresholds emerge in heterogeneous networks of heterogeneous nodes

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Yang, Hui; Tang, Ming; Gross, Thilo

2015-08-01

One of the famous results of network science states that networks with heterogeneous connectivity are more susceptible to epidemic spreading than their more homogeneous counterparts. In particular, in networks of identical nodes it has been shown that network heterogeneity, i.e. a broad degree distribution, can lower the epidemic threshold at which epidemics can invade the system. Network heterogeneity can thus allow diseases with lower transmission probabilities to persist and spread. However, it has been pointed out that networks in which the properties of nodes are intrinsically heterogeneous can be very resilient to disease spreading. Heterogeneity in structure can enhance or diminish the resilience of networks with heterogeneous nodes, depending on the correlations between the topological and intrinsic properties. Here, we consider a plausible scenario where people have intrinsic differences in susceptibility and adapt their social network structure to the presence of the disease. We show that the resilience of networks with heterogeneous connectivity can surpass those of networks with homogeneous connectivity. For epidemiology, this implies that network heterogeneity should not be studied in isolation, it is instead the heterogeneity of infection risk that determines the likelihood of outbreaks.

Large epidemic thresholds emerge in heterogeneous networks of heterogeneous nodes.

Science.gov (United States)

Yang, Hui; Tang, Ming; Gross, Thilo

2015-08-21

One of the famous results of network science states that networks with heterogeneous connectivity are more susceptible to epidemic spreading than their more homogeneous counterparts. In particular, in networks of identical nodes it has been shown that network heterogeneity, i.e. a broad degree distribution, can lower the epidemic threshold at which epidemics can invade the system. Network heterogeneity can thus allow diseases with lower transmission probabilities to persist and spread. However, it has been pointed out that networks in which the properties of nodes are intrinsically heterogeneous can be very resilient to disease spreading. Heterogeneity in structure can enhance or diminish the resilience of networks with heterogeneous nodes, depending on the correlations between the topological and intrinsic properties. Here, we consider a plausible scenario where people have intrinsic differences in susceptibility and adapt their social network structure to the presence of the disease. We show that the resilience of networks with heterogeneous connectivity can surpass those of networks with homogeneous connectivity. For epidemiology, this implies that network heterogeneity should not be studied in isolation, it is instead the heterogeneity of infection risk that determines the likelihood of outbreaks.

Urokinase-type plasminogen activator (uPA) stimulates triglyceride synthesis in Huh7 hepatoma cells via p38-dependent upregulation of DGAT2.

Science.gov (United States)

Paland, Nicole; Gamliel-Lazarovich, Aviva; Coleman, Raymond; Fuhrman, Bianca

2014-11-01

The liver is the central organ of fatty acid and triglyceride metabolism. Oxidation and synthesis of fatty acids and triglycerides is under the control of peroxisome-proliferator-activated receptors (PPAR) α. Impairment of these receptors' function contributes to the accumulation of triglycerides in the liver resulting in non-alcoholic fatty liver disease. Urokinase-type plasminogen activator (uPA) was shown to regulate gene expression in the liver involving PPARγ transcriptional activity. In this study we questioned whether uPA modulates triglyceride metabolism in the liver, and investigated the mechanisms involved in the observed processes. Huh7 hepatoma cells were incubated with increasing concentrations of uPA for 24 h uPA dose-dependently increased the cellular triglyceride mass, and this effect resulted from increased de novo triglyceride synthesis mediated by the enzyme diglyceride acyltransferase 2 (DGAT2). Also, the amount of free fatty acids was highly up regulated by uPA through activation of the transcription factor SREBP-1. Chemical activation of PPARα further increased uPA-stimulated triglyceride synthesis, whereas inhibition of p38, an upstream activator of PPARα, completely abolished the stimulatory effect of uPA on both triglyceride synthesis and DGAT2 upregulation. The effect of uPA on triglyceride synthesis in Huh7 cells was mediated via binding to its receptor, the uPAR. In vivo studies in uPAR(-/-) mice demonstrated that no lipid droplets were observed in their livers compared to C57BL/6 mice and the triglyceride levels were significantly lower. This study presents a new biological function of the uPA/uPAR system in the metabolism of triglycerides and might present a new target for an early therapeutic intervention for NAFLD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A novel staining protocol for multiparameter assessment of cell heterogeneity in Phormidium populations (cyanobacteria employing fluorescent dyes.

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Daria Tashyreva

Full Text Available Bacterial populations display high heterogeneity in viability and physiological activity at the single-cell level, especially under stressful conditions. We demonstrate a novel staining protocol for multiparameter assessment of individual cells in physiologically heterogeneous populations of cyanobacteria. The protocol employs fluorescent probes, i.e., redox dye 5-cyano-2,3-ditolyl tetrazolium chloride, 'dead cell' nucleic acid stain SYTOX Green, and DNA-specific fluorochrome 4',6-diamidino-2-phenylindole, combined with microscopy image analysis. Our method allows simultaneous estimates of cellular respiration activity, membrane and nucleoid integrity, and allows the detection of photosynthetic pigments fluorescence along with morphological observations. The staining protocol has been adjusted for, both, laboratory and natural populations of the genus Phormidium (Oscillatoriales, and tested on 4 field-collected samples and 12 laboratory strains of cyanobacteria. Based on the mentioned cellular functions we suggest classification of cells in cyanobacterial populations into four categories: (i active and intact; (ii injured but active; (iii metabolically inactive but intact; (iv inactive and injured, or dead.

Concentration of sup(99m)Tc-Sn-N-pyridoxyl-5-methyltryptophan, a biliary agent, in distant metastases of hepatomas

Energy Technology Data Exchange (ETDEWEB)

Hasegawa, Y; Nakano, S; Ibuka, K; Hashizume, T; Sasaki, Y; Imaoka, S; Ishiguro, S; Tanaka, S; Kasugai, H; Okano, Y

1985-03-01

During the last 2 years, eight patients with hepatocellular carcinoma who were suspected of having distant metastases have been studied to determine whether a new biliary agent, sup(99m)Tc-Sn-N-pyridoxyl-5-methyl-tryptophan (sup(99m)Tc-PMT), is taken up by extrahepatic tumors. In all eight patients, scintigrams showed a clearly increased uptake of sup(99m)Tc-PMT radioactivity by the extrahepatic tumors. In contrast, an increased uptake by the tumors of gallium citrate Ga 67 was only detected in four of the seven patients examined. The results obtained in this study suggest that sup(99m)Tc-PMT is useful both for characterizing the nature of extrahepatic tumors in patients with hepatoma and for detecting the metastases.

A heterogeneous lattice gas model for simulating pedestrian evacuation

Science.gov (United States)

Guo, Xiwei; Chen, Jianqiao; Zheng, Yaochen; Wei, Junhong

2012-02-01

Based on the cellular automata method (CA model) and the mobile lattice gas model (MLG model), we have developed a heterogeneous lattice gas model for simulating pedestrian evacuation processes in an emergency. A local population density concept is introduced first. The update rule in the new model depends on the local population density and the exit crowded degree factor. The drift D, which is one of the key parameters influencing the evacuation process, is allowed to change according to the local population density of the pedestrians. Interactions including attraction, repulsion, and friction between every two pedestrians and those between a pedestrian and the building wall are described by a nonlinear function of the corresponding distance, and the repulsion forces increase sharply as the distances get small. A critical force of injury is introduced into the model, and its effects on the evacuation process are investigated. The model proposed has heterogeneous features as compared to the MLG model or the basic CA model. Numerical examples show that the model proposed can capture the basic features of pedestrian evacuation, such as clogging and arching phenomena.

Dioxin-like activity of brominated dioxins as individual compounds or mixtures in in vitro reporter gene assays with rat and mouse hepatoma cell lines.

Science.gov (United States)

Suzuki, G; Nakamura, M; Michinaka, C; Tue, N M; Handa, H; Takigami, H

2017-10-01

In vitro reporter gene assays detecting dioxin-like compounds have been developed and validated since the middle 1990's, and applied to the determination of dioxin-like activities in various samples for their risk management. Data on characterizing the potency of individual brominated dioxins and their activity in mixture with chlorinated dioxins are still limited on the cell-based assay. This study characterized the dioxin-like activities of the 32 brominated dioxins, such as polybrominated dibenzo-p-dioxins, polybrominated dibenzofurans (PBDFs), coplanar polybrominated biphenyls, mixed halogenated dibenzo-p-dioxins and dibenzofurans (PXDFs), as a sole component or in a mixture by DR-CALUX (dioxin-responsive chemically activated luciferase expression) using the rat hepatoma H4IIE cell line and XDS-CALUX (xenobiotic detection systems-chemically activated luciferase expression) assays using the mouse hepatoma H1L6.1 cell line. The 2,3,7,8-TCDD-relative potencies (REPs) of most of the brominated dioxins were within a factor of 10 of the WHO toxicity equivalency factor (WHO-TEF) for the chlorinated analogues. The REPs of a few PXDFs were an order of magnitude higher than the corresponding WHO-TEFs, indicating their toxicological importance. Results with reconstituted mixtures suggest that the activity of brominated and chlorinated dioxins in both CALUX assays was dose-additive. Thus, obtained results indicated the applicability of the CALUX assays as screening tools of brominated dioxins together with their chlorinated analogues. Copyright © 2017 Elsevier Ltd. All rights reserved.

Point process models for localization and interdependence of punctate cellular structures.

Science.gov (United States)

Li, Ying; Majarian, Timothy D; Naik, Armaghan W; Johnson, Gregory R; Murphy, Robert F

2016-07-01

Accurate representations of cellular organization for multiple eukaryotic cell types are required for creating predictive models of dynamic cellular function. To this end, we have previously developed the CellOrganizer platform, an open source system for generative modeling of cellular components from microscopy images. CellOrganizer models capture the inherent heterogeneity in the spatial distribution, size, and quantity of different components among a cell population. Furthermore, CellOrganizer can generate quantitatively realistic synthetic images that reflect the underlying cell population. A current focus of the project is to model the complex, interdependent nature of organelle localization. We built upon previous work on developing multiple non-parametric models of organelles or structures that show punctate patterns. The previous models described the relationships between the subcellular localization of puncta and the positions of cell and nuclear membranes and microtubules. We extend these models to consider the relationship to the endoplasmic reticulum (ER), and to consider the relationship between the positions of different puncta of the same type. Our results do not suggest that the punctate patterns we examined are dependent on ER position or inter- and intra-class proximity. With these results, we built classifiers to update previous assignments of proteins to one of 11 patterns in three distinct cell lines. Our generative models demonstrate the ability to construct statistically accurate representations of puncta localization from simple cellular markers in distinct cell types, capturing the complex phenomena of cellular structure interaction with little human input. This protocol represents a novel approach to vesicular protein annotation, a field that is often neglected in high-throughput microscopy. These results suggest that spatial point process models provide useful insight with respect to the spatial dependence between cellular structures. �

Insulin regulation of Na/K pump activity in rat hepatoma cells

International Nuclear Information System (INIS)

Gelehrter, T.D.; Shreve, P.D.; Dilworth, V.M.

1984-01-01

Insulin rapidly increases Na/K pump activity in HTC rat hepatoma cells in tissue culture, as measured by the ouabain-sensitive influx of the potassium analogue 86Rb+. Increased influx is observed within minutes and is maximal (70% above control) within 1-2 h. The effect appears to be mediated by the insulin receptors, as: the concentration dependence on insulin is identical to that for insulin induction of tyrosine aminotransferase and stimulation of 2-aminoisobutyric acid transport, proinsulin is 6% as potent as insulin, and the effect is blocked by anti-receptor antibodies. The early stimulation of potassium influx is not blocked by cycloheximide and is not associated with an increased number of pump sites as measured by 3 H-ouabain binding. The insulin effect is blocked by amiloride, which blocks sodium influx, and is mimicked by the sodium ionophore monensin, which increases sodium influx and intracellular accumulation. Insulin also rapidly increases the initial rate of 22 Na+ influx, suggesting that insulin may enhance Na/K pump activity, in part, by increasing intracellular sodium concentration. Incubation of HTC cells with insulin for 24 h causes complete unresponsiveness to the insulin induction of transaminase and stimulation of amino acid transport, a phenomenon mediated by postbinding mechanisms. In contrast, similar incubation with insulin does not cause unresponsiveness to the insulin stimulation of Na/K pump activity. Therefore, the site of regulation of responsiveness to insulin must be distal to, or separate from, those events causing stimulation of ion fluxes

An agent-based model of cellular dynamics and circadian variability in human endotoxemia.

Directory of Open Access Journals (Sweden)

Tung T Nguyen

Full Text Available As cellular variability and circadian rhythmicity play critical roles in immune and inflammatory responses, we present in this study an agent-based model of human endotoxemia to examine the interplay between circadian controls, cellular variability and stochastic dynamics of inflammatory cytokines. The model is qualitatively validated by its ability to reproduce circadian dynamics of inflammatory mediators and critical inflammatory responses after endotoxin administration in vivo. Novel computational concepts are proposed to characterize the cellular variability and synchronization of inflammatory cytokines in a population of heterogeneous leukocytes. Our results suggest that there is a decrease in cell-to-cell variability of inflammatory cytokines while their synchronization is increased after endotoxin challenge. Model parameters that are responsible for IκB production stimulated by NFκB activation and for the production of anti-inflammatory cytokines have large impacts on system behaviors. Additionally, examining time-dependent systemic responses revealed that the system is least vulnerable to endotoxin in the early morning and most vulnerable around midnight. Although much remains to be explored, proposed computational concepts and the model we have pioneered will provide important insights for future investigations and extensions, especially for single-cell studies to discover how cellular variability contributes to clinical implications.

Clonal Heterogeneity in the Neuronal and Glial Differentiation of Dental Pulp Stem/Progenitor Cells

Directory of Open Access Journals (Sweden)

Fraser I. Young

2016-01-01

Full Text Available Cellular heterogeneity presents an important challenge to the development of cell-based therapies where there is a fundamental requirement for predictable and reproducible outcomes. Transplanted Dental Pulp Stem/Progenitor Cells (DPSCs have demonstrated early promise in experimental models of spinal cord injury and stroke, despite limited evidence of neuronal and glial-like differentiation after transplantation. Here, we report, for the first time, on the ability of single cell-derived clonal cultures of murine DPSCs to differentiate in vitro into immature neuronal-like and oligodendrocyte-like cells. Importantly, only DPSC clones with high nestin mRNA expression levels were found to successfully differentiate into Map2 and NF-positive neuronal-like cells. Neuronally differentiated DPSCs possessed a membrane capacitance comparable with primary cultured striatal neurons and small inward voltage-activated K+ but not outward Na+ currents were recorded suggesting a functionally immature phenotype. Similarly, only high nestin-expressing clones demonstrated the ability to adopt Olig1, Olig2, and MBP-positive immature oligodendrocyte-like phenotype. Together, these results demonstrate that appropriate markers may be used to provide an early indication of the suitability of a cell population for purposes where differentiation into a specific lineage may be beneficial and highlight that further understanding of heterogeneity within mixed cellular populations is required.

Cockayne's syndrome: correlation of clinical features with cellular sensitivity of RNA synthesis to UV irradiation

International Nuclear Information System (INIS)

Lehmann, A.R.; Thompson, A.F.; Harcourt, S.A.

1993-01-01

Cockayne's syndrome (CS) is a rare autosomal recessive disorder with dwarfism, mental retardation, and otherwise clinically heterogeneous features. In cultured CS fibroblasts, the failure of RNA synthesis to recover to normal rates after UV-C irradiation provides a useful and relatively simple diagnostic test. We have measured post-UV-C RNA synthesis in 52 patients for whom a clinical diagnosis of CS was considered a possibility. Twenty-nine patients showed the defect characteristic of CS cells, and 23 had a normal response. We have attempted to correlate the cellular diagnosis with the different clinical features of the disorder. Clinical details of the patients were obtained from referring clinicians in the form of a questionnaire. Our results show that, apart from the cardinal features of dwarfism and mental retardation, sun sensitivity correlated best with a positive cellular diagnosis. Pigmentary retinopathy, gait defects, and dental caries were also good positive indicators, although several patients with a positive cellular diagnosis did not have these features. (Author)

On the area spectral efficiency improvement of heterogeneous network by exploiting the integration of macro-femto cellular networks

KAUST Repository

Shakir, Muhammad; Alouini, Mohamed-Slim

2012-01-01

. In this paper, we consider a Heterogeneous network where we complement the macrocell network with low-power low-cost user deployed nodes, such as femtocell base stations to increase the mean achievable capacity of the system. In this context, we integrate macro

Homogenizing bacterial cell factories: Analysis and engineering of phenotypic heterogeneity.

Science.gov (United States)

Binder, Dennis; Drepper, Thomas; Jaeger, Karl-Erich; Delvigne, Frank; Wiechert, Wolfgang; Kohlheyer, Dietrich; Grünberger, Alexander

2017-07-01

In natural habitats, microbes form multispecies communities that commonly face rapidly changing and highly competitive environments. Thus, phenotypic heterogeneity has evolved as an innate and important survival strategy to gain an overall fitness advantage over cohabiting competitors. However, in defined artificial environments such as monocultures in small- to large-scale bioreactors, cell-to-cell variations are presumed to cause reduced production yields as well as process instability. Hence, engineering microbial production toward phenotypic homogeneity is a highly promising approach for synthetic biology and bioprocess optimization. In this review, we discuss recent studies that have unraveled the cell-to-cell heterogeneity observed during bacterial gene expression and metabolite production as well as the molecular mechanisms involved. In addition, current single-cell technologies are briefly reviewed with respect to their applicability in exploring cell-to-cell variations. We highlight emerging strategies and tools to reduce phenotypic heterogeneity in biotechnological expression setups. Here, strain or inducer modifications are combined with cell physiology manipulations to achieve the ultimate goal of equalizing bacterial populations. In this way, the majority of cells can be forced into high productivity, thus reducing less productive subpopulations that tend to consume valuable resources during production. Modifications in uptake systems, inducer molecules or nutrients represent valuable tools for diminishing heterogeneity. Finally, we address the challenge of transferring homogeneously responding cells into large-scale bioprocesses. Environmental heterogeneity originating from extrinsic factors such as stirring speed and pH, oxygen, temperature or nutrient distribution can significantly influence cellular physiology. We conclude that engineering microbial populations toward phenotypic homogeneity is an increasingly important task to take biotechnological

Hepatoma-derived growth factor-related protein-3 is a novel angiogenic factor.

Directory of Open Access Journals (Sweden)

Michelle E LeBlanc

Full Text Available Hepatoma-derived growth factor-related protein-3 (Hdgfrp3 or HRP-3 was recently reported as a neurotrophic factor and is upregulated in hepatocellular carcinoma to promote cancer cell survival. Here we identified HRP-3 as a new endothelial ligand and characterized its in vitro and in vivo functional roles and molecular signaling. We combined open reading frame phage display with multi-round in vivo binding selection to enrich retinal endothelial ligands, which were systematically identified by next generation DNA sequencing. One of the identified endothelial ligands was HRP-3. HRP-3 expression in the retina and brain was characterized by Western blot and immunohistochemistry. Cell proliferation assay showed that HRP-3 stimulated the growth of human umbilical vein endothelial cells (HUVECs. HRP-3 induced tube formation of HUVECs in culture. Wound healing assay indicated that HRP-3 promoted endothelial cell migration. HRP-3 was further confirmed for its in vitro angiogenic activity by spheroid sprouting assay. HRP-3 extrinsically activated the extracellular-signal-regulated kinase ½ (ERK1/2 pathway in endothelial cells. The angiogenic activity of HRP-3 was independently verified by mouse cornea pocket assay. Furthermore, in vivo Matrigel plug assay corroborated HRP-3 activity to promote new blood vessel formation. These results demonstrated that HRP-3 is a novel angiogenic factor.

Rapid internalization of the insulin receptor in rat hepatoma cells

International Nuclear Information System (INIS)

Backer, J.M.; White, M.F.; Kahn, C.R.

1987-01-01

The authors have studied the internalization of the insulin receptor (IR) in rat hepatoma cells (Fao). The cells were surface-iodinated at 4 0 C, stimulated with insulin at 37 0 C, and then cooled rapidly, trypsinized at 4 0 C and solubilized. The IR was immunoprecipitated with a specific antibody, and internalization of the IR was assessed by the appearance of trypsin-resistant bands on SDS-PAGE. Insulin induced the internalization of surface receptors with a t 1/2 of 9-10 mins; cells not exposed to insulin internalized less than 20% of the IR during 1 h at 37 0 C. Further experiments demonstrated that the accumulation of trypsin-resistant IR paralleled a loss of receptor from the cell surface. Insulin-stimulated cells were chilled and iodinated at 4 0 C, followed by solubilization, immunoprecipitation and SDS-PAGE; alternatively, insulin-stimulated cells were chilled, surface-bound ligand removed by washing the cells at pH 4.2, and specific [ 125 I]insulin binding measured at 4 0 C. Both techniques confirmed the disappearance of IR from the cell surface at rates comparable to the insulin-stimulated internalization described above. The total amount of phosphotyrosine-containing IR, as assessed by immunoprecipitation with an anti-phosphotyrosine antibody, remained constant during this time interval, suggesting that active kinase is translocated into the cell. In summary, the authors data indicate that insulin binding increases the rate of IR internalization of Fao cells. This relocation may facilitate the interaction of the activated tyrosine kinase in the IR with intracellular substrates, thus transmitting the insulin signal to metabolic pathways

HBx induced AFP receptor expressed to activate PI3K/AKT signal to promote expression of Src in liver cells and hepatoma cells

International Nuclear Information System (INIS)

Zhu, Mingyue; Guo, Junli; Li, Wei; Xia, Hua; Lu, Yan; Dong, Xu; Chen, Yi; Xie, Xieju; Fu, Shigan; Li, Mengsen

2015-01-01

Hepatitis B virus (HBV)-X protein(HBx) is a transactivator of host several cellular genes including alpha-fetoprotein(AFP) and AFP receptor(AFPR) which contributes to HBV-associated tumor development. The expression of AFP/AFPR are correlated with hepatocellular carcinoma(HCC)-initial cells. But the role of AFP and AFPR in promoting occurrence of HBV-related HCC were still unclear. A total of 71 clinical patients’ liver specimens, normal human liver cells L-02 and HCC cell lines, PLC/PRF/5 were selected for analyzing the effects of HBx on expression of AFP, AFPR and Src. The expression of goal proteins were detected by Immunohistochemical stained and Western blotting; HBx-expressed vectors were constructed and transfected into L-02 cells, laser confocal microscopy was applied to observe expression and location of AFP, AFPR and Src in the normal liver cells and HCC cells, soft agar colony formation assay was used to observe colonies formed of the cells. We confirmed HBx gives preference to promote the expression of AFP and AFPR; HBx priors to up-regulate the expression of AFPR and AFP in L-02 cells and in normal liver specimens; AFPR signal been able to stimulate Src expression. The results also indicated that phosphatidylinositol 3-kinase(PI3K) inhibitors Ly294002 and GDC0941 effectively suppress AFPR mediated up-regulation expression of Src in AFPR positive HCC lines. HBx priors to drive the expression of AFP and AFPR to promote expression of Src in normal liver cells and hepatoma cells; AFP and AFPR maybe play pivotal role in HBV-related hepatocarcinogenesis; Targeting AFPR is an available therapeutic strategy of HCC. The online version of this article (doi:10.1186/s12885-015-1384-9) contains supplementary material, which is available to authorized users

QoE-Driven D2D Media Services Distribution Scheme in Cellular Networks

Directory of Open Access Journals (Sweden)

Mingkai Chen

2017-01-01

Full Text Available Device-to-device (D2D communication has been widely studied to improve network performance and considered as a potential technological component for the next generation communication. Considering the diverse users’ demand, Quality of Experience (QoE is recognized as a new degree of user’s satisfaction for media service transmissions in the wireless communication. Furthermore, we aim at promoting user’s Mean of Score (MOS value to quantify and analyze user’s QoE in the dynamic cellular networks. In this paper, we explore the heterogeneous media service distribution in D2D communications underlaying cellular networks to improve the total users’ QoE. We propose a novel media service scheme based on different QoE models that jointly solve the massive media content dissemination issue for cellular networks. Moreover, we also investigate the so-called Media Service Adaptive Update Scheme (MSAUS framework to maximize users’ QoE satisfaction and we derive the popularity and priority function of different media service QoE expression. Then, we further design Media Service Resource Allocation (MSRA algorithm to schedule limited cellular networks resource, which is based on the popularity function to optimize the total users’ QoE satisfaction and avoid D2D interference. In addition, numerical simulation results indicate that the proposed scheme is more effective in cellular network content delivery, which makes it suitable for various media service propagation.

MiR-520b suppresses proliferation of hepatoma cells through targeting ten-eleven translocation 1 (TET1) mRNA

Energy Technology Data Exchange (ETDEWEB)

Zhang, Weiying; Lu, Zhanping; Gao, Yuen [State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin (China); Ye, Lihong [State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin (China); Song, Tianqiang, E-mail: tjchi@hotmai.com [Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin (China); Zhang, Xiaodong, E-mail: zhangxd@nankai.edu.cn [State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin (China)

2015-05-08

Accumulating evidence indicates that microRNAs are able to act as oncogenes or tumor suppressor genes in human cancer. We previously reported that miR-520b was down-regulated in hepatocellular carcinoma (HCC) and its deregulation was involved in hepatocarcinogenesis. In the present study, we report that miR-520b suppresses cell proliferation in HCC through targeting the ten-eleven translocation 1 (TET1) mRNA. Notably, we identified that miR-520b was able to target 3′-untranslated region (3′UTR) of TET1 mRNA by luciferase reporter gene assays. Then, we revealed that miR-520b was able to reduce the expression of TET1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blotting analysis. In terms of function, 5-ethynyl-2-deoxyuridine (EdU) incorporation and colony formation assays demonstrated that the forced miR-520b expression remarkably inhibited proliferation of hepatoma cells, but TET1 overexpression could rescue the inhibition of cell proliferation mediated by miR-520b. Furthermore, anti-miR-520b enhanced proliferation of hepatoma cells, whereas silencing of TET1 abolished anti-miR-520b-induced acceleration of cell proliferation. Then, we validated that the expression levels of miR-520b were negatively related to those of TET1 mRNA in clinical HCC tissues. Thus, we conclude that miR-520b depresses proliferation of liver cancer cells through targeting 3′UTR of TET1 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. - Highlights: • TET1 is a novel target gene of miR-520b. • TET1 is upregulated in clinical HCC tissues. • MiR-520b is negatively correlated with TET1 in clinical HCC tissues. • MiR-520b depresses the proliferation of HCC cells through targeting TET1 mRNA.

Pointwise mutual information quantifies intratumor heterogeneity in tissue sections labeled with multiple fluorescent biomarkers

Directory of Open Access Journals (Sweden)

Daniel M Spagnolo

2016-01-01

Full Text Available Background: Measures of spatial intratumor heterogeneity are potentially important diagnostic biomarkers for cancer progression, proliferation, and response to therapy. Spatial relationships among cells including cancer and stromal cells in the tumor microenvironment (TME are key contributors to heterogeneity. Methods: We demonstrate how to quantify spatial heterogeneity from immunofluorescence pathology samples, using a set of 3 basic breast cancer biomarkers as a test case. We learn a set of dominant biomarker intensity patterns and map the spatial distribution of the biomarker patterns with a network. We then describe the pairwise association statistics for each pattern within the network using pointwise mutual information (PMI and visually represent heterogeneity with a two-dimensional map. Results: We found a salient set of 8 biomarker patterns to describe cellular phenotypes from a tissue microarray cohort containing 4 different breast cancer subtypes. After computing PMI for each pair of biomarker patterns in each patient and tumor replicate, we visualize the interactions that contribute to the resulting association statistics. Then, we demonstrate the potential for using PMI as a diagnostic biomarker, by comparing PMI maps and heterogeneity scores from patients across the 4 different cancer subtypes. Estrogen receptor positive invasive lobular carcinoma patient, AL13-6, exhibited the highest heterogeneity score among those tested, while estrogen receptor negative invasive ductal carcinoma patient, AL13-14, exhibited the lowest heterogeneity score. Conclusions: This paper presents an approach for describing intratumor heterogeneity, in a quantitative fashion (via PMI, which departs from the purely qualitative approaches currently used in the clinic. PMI is generalizable to highly multiplexed/hyperplexed immunofluorescence images, as well as spatial data from complementary in situ methods including FISSEQ and CyTOF, sampling many different

Heterogeneity within populations of recombinant Chinese hamster ovary cells expressing human interferon-gamma.

Science.gov (United States)

Coppen, S R; Newsam, R; Bull, A T; Baines, A J

1995-04-20

The Chinese hamster ovary (CHO) cell line has great commercial importance in the production of recombinant human proteins, especially those for therapeutic use. Much attention has been paid to CHO cell population physiology in order to define factors affecting product fidelity and yield. Such studies have revealed that recombinant proteins, including human interferon-gamma (IFN-gamma), can be heterogeneous both in glycosylation and in proteolytic processing. The type of heterogeneity observed depends on the growth physiology of the cell population, although the relationship between them is complex. In this article we report results of a cytological study of the CHO320 line which expresses recombinant human IFN-gamma. When grown in suspension culture, this cell line exhibited three types of heterogeneity: (1) heterogeneity of the production of IFN-gamma within the cell population, (2) heterogeneity of the number of nuclei and mitotic spindles in dividing cells, and (3) heterogeneity of cellular environment. The last of these arises from cell aggregates which form in suspension culture: Some cells are exposed to the culture medium; others are fully enclosed within the mass with little or no direct access to the medium. Thus, live cells producing IFN-gamma are heterogeneous in their environment, with variable access to O(2) and nutrients. Within the aggregates, it appears that live cells proliferate on a dead cell mass. The layer of live cells can be several cells deep. Specific cell-cell attachments are observed between the living cells in these aggregates. Two proteins, known to be required for the formation of certain types of intercellular junctions, spectrin and vinculin, have been localized to the regions of cell-cell contact. The aggregation of the cells appears to be an active process requiring protein synthesis. (c) 1995 John Wiley & Sons, Inc.

Energy-Efficient Resource Allocation for Phantom Cellular Networks with Imperfect CSI

KAUST Repository

Abdelhady, Amr Mohamed Abdelaziz

2017-03-28

Multi-tier heterogeneous networks have become an essential constituent for next generation cellular networks. Meanwhile, energy efficiency (EE) has been considered a critical design criterion along with the traditional spectral efficiency (SE) metric. In this context, we study power and spectrum allocation for a two-tier phantom cellular network, The optimization framework includes both EE and SE. We consider densely deployed phantom cellular networks and model the EE optimization problem taking into consideration the inevitable interference in this setup and imperfect channel estimation impairments. To this end, we propose three resource allocation strategies aiming at optimizing this network EE performance metric. Furthermore, we investigate the effect of changing some system parameters on the performance of these strategies, such as phantom cells resource units share, number of deployed phantom cells within a macro cell , number of pilots, and the phantom cells transmission power budget. It is found that increasing the number of pilots will deteriorate the EE performance of the whole setup, while increasing phantom cells transmission power budget will not affect the EE of the whole setup significantly. In addition, we observed that it is always useful to allocate most of the network resource units to the phantom cells tier.

Energy-Efficient Resource Allocation for Phantom Cellular Networks with Imperfect CSI

KAUST Repository

Abdelhady, Amr Mohamed Abdelaziz; Amin, Osama; Alouini, Mohamed-Slim

2017-01-01

Multi-tier heterogeneous networks have become an essential constituent for next generation cellular networks. Meanwhile, energy efficiency (EE) has been considered a critical design criterion along with the traditional spectral efficiency (SE) metric. In this context, we study power and spectrum allocation for a two-tier phantom cellular network, The optimization framework includes both EE and SE. We consider densely deployed phantom cellular networks and model the EE optimization problem taking into consideration the inevitable interference in this setup and imperfect channel estimation impairments. To this end, we propose three resource allocation strategies aiming at optimizing this network EE performance metric. Furthermore, we investigate the effect of changing some system parameters on the performance of these strategies, such as phantom cells resource units share, number of deployed phantom cells within a macro cell , number of pilots, and the phantom cells transmission power budget. It is found that increasing the number of pilots will deteriorate the EE performance of the whole setup, while increasing phantom cells transmission power budget will not affect the EE of the whole setup significantly. In addition, we observed that it is always useful to allocate most of the network resource units to the phantom cells tier.

The finite state projection approach to analyze dynamics of heterogeneous populations

Science.gov (United States)

Johnson, Rob; Munsky, Brian

2017-06-01

Population modeling aims to capture and predict the dynamics of cell populations in constant or fluctuating environments. At the elementary level, population growth proceeds through sequential divisions of individual cells. Due to stochastic effects, populations of cells are inherently heterogeneous in phenotype, and some phenotypic variables have an effect on division or survival rates, as can be seen in partial drug resistance. Therefore, when modeling population dynamics where the control of growth and division is phenotype dependent, the corresponding model must take account of the underlying cellular heterogeneity. The finite state projection (FSP) approach has often been used to analyze the statistics of independent cells. Here, we extend the FSP analysis to explore the coupling of cell dynamics and biomolecule dynamics within a population. This extension allows a general framework with which to model the state occupations of a heterogeneous, isogenic population of dividing and expiring cells. The method is demonstrated with a simple model of cell-cycle progression, which we use to explore possible dynamics of drug resistance phenotypes in dividing cells. We use this method to show how stochastic single-cell behaviors affect population level efficacy of drug treatments, and we illustrate how slight modifications to treatment regimens may have dramatic effects on drug efficacy.

Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light

International Nuclear Information System (INIS)

Lehmann, A.R.; Arlett, C.F.; Broughton, B.C.

1988-01-01

Trichothiodystrophy (TTD) is an autosomal recessive disorder characterized by brittle hair with reduced sulfur content, ichthyosis, peculiar face, and mental and physical retardation. Some patients are photosensitive. A previous study by Stefanini et al. showed that cells from four photosensitive patients with TTD had a molecular defect in DNA repair, which was not complemented by cells from xeroderma pigmentosum, complementation group D. In a detailed molecular and cellular study of the effects of UV light on cells cultured from three further TTD patients who did not exhibit photosensitivity we have found an array of different responses. In cells from the first patient, survival, excision repair, and DNA and RNA synthesis following UV irradiation were all normal, whereas in cells from the second patient all these responses were similar to those of excision-defective xeroderma pigmentosum (group D) cells. With the third patient, cell survival measured by colony-forming ability was normal following UV irradiation, even though repair synthesis was only 50% of normal and RNA synthesis was severely reduced. The excision-repair defect in these cells was not complemented by other TTD cell strains. These cellular characteristics of patient 3 have not been described previously for any other cell line. The normal survival may be attributed to the finding that the deficiency in excision-repair is confined to early times after irradiation. Our results pose a number of questions about the relationship between the molecular defect in DNA repair and the clinical symptoms of xeroderma pigmentosum and TTD

Uplink Interference Analysis for Two-tier Cellular Networks with Diverse Users under Random Spatial Patterns

OpenAIRE

Bao, Wei; Liang, Ben

2013-01-01

Multi-tier architecture improves the spatial reuse of radio spectrum in cellular networks, but it introduces complicated heterogeneity in the spatial distribution of transmitters, which brings new challenges in interference analysis. In this work, we present a stochastic geometric model to evaluate the uplink interference in a two-tier network considering multi-type users and base stations. Each type of tier-1 users and tier-2 base stations are modeled as independent homogeneous Poisson point...

Wireless traffic steering for green cellular networks

CERN Document Server

Zhang, Shan; Zhou, Sheng; Niu, Zhisheng; Shen, Xuemin (Sherman)

2016-01-01

This book introduces wireless traffic steering as a paradigm to realize green communication in multi-tier heterogeneous cellular networks. By matching network resources and dynamic mobile traffic demand, traffic steering helps to reduce on-grid power consumption with on-demand services provided. This book reviews existing solutions from the perspectives of energy consumption reduction and renewable energy harvesting. Specifically, it explains how traffic steering can improve energy efficiency through intelligent traffic-resource matching. Several promising traffic steering approaches for dynamic network planning and renewable energy demand-supply balancing are discussed. This book presents an energy-aware traffic steering method for networks with energy harvesting, which optimizes the traffic allocated to each cell based on the renewable energy status. Renewable energy demand-supply balancing is a key factor in energy dynamics, aimed at enhancing renewable energy sustainability to reduce on-grid energy consum...

Alterations in microRNA expression profile in HCV-infected hepatoma cells: Involvement of miR-491 in regulation of HCV replication via the PI3 kinase/Akt pathway

Energy Technology Data Exchange (ETDEWEB)

Ishida, Hisashi; Tatsumi, Tomohide; Hosui, Atsushi; Nawa, Takatoshi; Kodama, Takahiro; Shimizu, Satoshi; Hikita, Hayato; Hiramatsu, Naoki; Kanto, Tatsuya [Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita 565-0871 (Japan); Hayashi, Norio [Kansai Rosai Hospital, 3-1-69, Inabaso, Amagasaki 660-8511 (Japan); Takehara, Tetsuo, E-mail: takehara@gh.med.osaka-u.ac.jp [Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita 565-0871 (Japan)

2011-08-19

Highlights: {yields} HCV infection upregulated miR-192, -194, -215, downregulated miR-320, -491. {yields} Transfection of miR-192, -215, and -491 enhanced HCV replication. {yields} Transfection of miR-491 inhibited Akt phosphorylation. {yields} Akt inhibition could be responsible for augmentation of HCV replication by miR-491. -- Abstract: The aim of this study was to investigate the role of microRNA (miRNA) on hepatitis C virus (HCV) replication in hepatoma cells. Using miRNA array analysis, miR-192/miR-215, miR-194, miR-320, and miR-491 were identified as miRNAs whose expression levels were altered by HCV infection. Among them, miR-192/miR-215 and miR-491 were capable of enhancing replication of the HCV replicon as well as HCV itself. HCV IRES activity or cell proliferation was not increased by forced expression of miR-192/miR-215 or miR-491. Investigation of signaling pathways revealed that miR-491 specifically suppressed the phosphoinositol-3 (PI3) kinase/Akt pathway. Under inhibition of PI3 kinase by LY294002, the suppressive effect of miR-491 on HCV replication was abolished, indicating that suppression of HCV replication by miR-491 was dependent on the PI3 kinase/Akt pathway. miRNAs altered by HCV infection would then affect HCV replication, which implies a complicated mechanism for regulating HCV replication. HCV-induced miRNA may be involved in changes in cellular properties including hepatocarcinogenesis.

Reversible adaptive plasticity: A mechanism for neuroblastoma cell heterogeneity and chemo-resistance

Directory of Open Access Journals (Sweden)

Lina eChakrabarti

2012-08-01

Full Text Available We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD or sphere forming, anchorage independent (AI growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, β-catenin and PDGFRβ enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

Reversible Adaptive Plasticity: A Mechanism for Neuroblastoma Cell Heterogeneity and Chemo-Resistance

Energy Technology Data Exchange (ETDEWEB)

Chakrabarti, Lina; Abou-Antoun, Thamara; Vukmanovic, Stanislav; Sandler, Anthony D., E-mail: asandler@childrensnational.org [The Joseph E. Robert Center for Surgical Care, Children’s National Medical Center, Washington, DC (United States); The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Medical Center, Washington, DC (United States)

2012-08-02

We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD) or sphere forming, anchorage independent (AI) growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity, and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, β-catenin, and PDGFRβ enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic, and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

Stable Regulation of Cell Cycle Events in Mycobacteria: Insights From Inherently Heterogeneous Bacterial Populations.

Science.gov (United States)

Logsdon, Michelle M; Aldridge, Bree B

2018-01-01

Model bacteria, such as E. coli and B. subtilis , tightly regulate cell cycle progression to achieve consistent cell size distributions and replication dynamics. Many of the hallmark features of these model bacteria, including lateral cell wall elongation and symmetric growth and division, do not occur in mycobacteria. Instead, mycobacterial growth is characterized by asymmetric polar growth and division. This innate asymmetry creates unequal birth sizes and growth rates for daughter cells with each division, generating a phenotypically heterogeneous population. Although the asymmetric growth patterns of mycobacteria lead to a larger variation in birth size than typically seen in model bacterial populations, the cell size distribution is stable over time. Here, we review the cellular mechanisms of growth, division, and cell cycle progression in mycobacteria in the face of asymmetry and inherent heterogeneity. These processes coalesce to control cell size. Although Mycobacterium smegmatis and Mycobacterium bovis Bacillus Calmette-Guérin (BCG) utilize a novel model of cell size control, they are similar to previously studied bacteria in that initiation of DNA replication is a key checkpoint for cell division. We compare the regulation of DNA replication initiation and strategies used for cell size homeostasis in mycobacteria and model bacteria. Finally, we review the importance of cellular organization and chromosome segregation relating to the physiology of mycobacteria and consider how new frameworks could be applied across the wide spectrum of bacterial diversity.

Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies.

Science.gov (United States)

Turtoi, Andrei; Blomme, Arnaud; Debois, Delphine; Somja, Joan; Delvaux, David; Patsos, Georgios; Di Valentin, Emmanuel; Peulen, Olivier; Mutijima, Eugène Nzaramba; De Pauw, Edwin; Delvenne, Philippe; Detry, Olivier; Castronovo, Vincent

2014-03-01

Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demonstrate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of targetable antigens. © 2014 by the American Association for the Study of Liver Diseases.

Protection of betulin against cadmium-induced apoptosis in hepatoma cells

International Nuclear Information System (INIS)

Oh, Seon-Hee; Choi, Jeong-Eun; Lim, Sung-Chul

2006-01-01

The protective effects of betulin (BT) against cadmium (Cd)-induced cytotoxicity have been previously reported. However, the mechanisms responsible for these protective effects are unclear. Therefore, this study investigated the mechanisms responsible for the protection of BT against Cd-induced cytotoxicity in human hepatoma cell lines. The protection of BT against Cd cytotoxicity was more effective in the HepG2 than in the Hep3B cells. The protection of BT on Cd-induced cytotoxicity in the HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by PI staining and DNA fragmentation analysis. The anti-apoptosis exerted by BT involved the blocking of Cd-induced reactive oxygen species (ROS) generation, the abrogation of the Cd-induced Fas upregulation, the blocking of caspase-8-dependent Bid activation, and subsequent inhibition of mitochondrial pathway. The BT pretreatment did not affect the p21 and p53 expression levels, when compared with those of the treated cells with Cd alone. BT induced the transient S phase arrest at an early stage and the G /G 1 arrest at a relatively late stage, but it did not observe the sub-G1 apoptotic peak. In the Hep3B cells, Cd did not induce ROS generation. The BT pretreatment partially inhibited the Cd-induced apoptosis, which was related with the incomplete blockage in caspase-9 or -3 activation, as well as in Bax activation. Taken together, it was found that Cd can induce apoptosis via the Fas-dependent and -independent apoptosis pathways. However, the observed protective effects of BT were clearly more sensitive to Fas-expressing HepG2 cells than to Fas-deficient Hep3B cells

The synergistic radiosensitizing effect of tirapazamine-conjugated gold nanoparticles on human hepatoma HepG2 cells under X-ray irradiation

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Liu X

2016-07-01

Full Text Available Xi Liu,1–4 Yan Liu,1–4 Pengcheng Zhang,1–4 Xiaodong Jin,1–3 Xiaogang Zheng,1–4 Fei Ye,1–4 Weiqiang Chen,1–3 Qiang Li1–3 1Institute of Modern Physics, 2Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, 3Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou, 4School of Life Science, University of Chinese Academy of Sciences, Beijing, People’s Republic of China Abstract: Reductive drug-functionalized gold nanoparticles (AuNPs have been proposed to enhance the damage of X-rays to cells through improving hydroxyl radical production by secondary electrons. In this work, polyethylene glycol-capped AuNPs were conjugated with tirapazamine (TPZ moiety, and then thioctyl TPZ (TPZs-modified AuNPs (TPZs-AuNPs were synthesized. The TPZs-AuNPs were characterized by transmission electron microscopy, ultraviolet-visible spectra, dynamic light scattering, and inductively coupled plasma mass spectrometry to have a size of 16.6±2.1 nm in diameter and a TPZs/AuNPs ratio of ~700:1. In contrast with PEGylated AuNPs, the as-synthesized TPZs-AuNPs exhibited 20% increment in hydroxyl radical production in water at 2.0 Gy, and 19% increase in sensitizer enhancement ratio at 10% survival fraction for human hepatoma HepG2 cells under X-ray irradiation. The production of reactive oxygen species in HepG2 cells exposed to X-rays in vitro demonstrated a synergistic radiosensitizing effect of AuNPs and TPZ moiety. Thus, the reductive drug-conjugated TPZs-AuNPs as a kind of AuNP radiosensitizer with low gold loading provide a new strategy for enhancing the efficacy of radiation therapy. Keywords: AuNPs, radiation enhancement, synergistic effect, human hepatoma cells, hydroxyl radical production

RhoC is essential for TGF-β1-induced invasive capacity of rat ascites hepatoma cells

International Nuclear Information System (INIS)

Mukai, M.; Endo, H.; Iwasaki, T.; Tatsuta, M.; Togawa, A.; Nakamura, H.; Inoue, M.

2006-01-01

Transforming growth factor-β1 (TGF-β1) is a multifunctional growth factor that plays a role in cell proliferation, differentiation, extracellular matrix production, apoptosis, and cell motility. We show here that TGF-β1 increased the invasiveness of MM1 cells, which are a highly invasive clone of rat ascites hepatoma cells. Both mRNA and protein levels of RhoC but not RhoA in TGF-β1-treated MM1 cells increased. In parallel with this increase in expression, RhoC activity was induced by TGF-β1 treatment. When RhoC was overexpressed in MM1 cells, the invasive capacity increased. The RhoC-overexpressing cells formed more nodules than did mock cells when injected into rat peritoneum. Furthermore, when RhoC expression was reduced by transfection with shRNA/RhoC, the invasiveness of MM1 cells decreased with concomitant suppression of RhoC expression. Thus, the induced expression of RhoC by TGF-β1 in MM1 cells plays a critical role in TGF-β1-induced cell migration

Self-Consistent Scheme for Spike-Train Power Spectra in Heterogeneous Sparse Networks.

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Pena, Rodrigo F O; Vellmer, Sebastian; Bernardi, Davide; Roque, Antonio C; Lindner, Benjamin

2018-01-01

Recurrent networks of spiking neurons can be in an asynchronous state characterized by low or absent cross-correlations and spike statistics which resemble those of cortical neurons. Although spatial correlations are negligible in this state, neurons can show pronounced temporal correlations in their spike trains that can be quantified by the autocorrelation function or the spike-train power spectrum. Depending on cellular and network parameters, correlations display diverse patterns (ranging from simple refractory-period effects and stochastic oscillations to slow fluctuations) and it is generally not well-understood how these dependencies come about. Previous work has explored how the single-cell correlations in a homogeneous network (excitatory and inhibitory integrate-and-fire neurons with nearly balanced mean recurrent input) can be determined numerically from an iterative single-neuron simulation. Such a scheme is based on the fact that every neuron is driven by the network noise (i.e., the input currents from all its presynaptic partners) but also contributes to the network noise, leading to a self-consistency condition for the input and output spectra. Here we first extend this scheme to homogeneous networks with strong recurrent inhibition and a synaptic filter, in which instabilities of the previous scheme are avoided by an averaging procedure. We then extend the scheme to heterogeneous networks in which (i) different neural subpopulations (e.g., excitatory and inhibitory neurons) have different cellular or connectivity parameters; (ii) the number and strength of the input connections are random (Erdős-Rényi topology) and thus different among neurons. In all heterogeneous cases, neurons are lumped in different classes each of which is represented by a single neuron in the iterative scheme; in addition, we make a Gaussian approximation of the input current to the neuron. These approximations seem to be justified over a broad range of parameters as

Self-Consistent Scheme for Spike-Train Power Spectra in Heterogeneous Sparse Networks

Directory of Open Access Journals (Sweden)

Rodrigo F. O. Pena

2018-03-01

Full Text Available Recurrent networks of spiking neurons can be in an asynchronous state characterized by low or absent cross-correlations and spike statistics which resemble those of cortical neurons. Although spatial correlations are negligible in this state, neurons can show pronounced temporal correlations in their spike trains that can be quantified by the autocorrelation function or the spike-train power spectrum. Depending on cellular and network parameters, correlations display diverse patterns (ranging from simple refractory-period effects and stochastic oscillations to slow fluctuations and it is generally not well-understood how these dependencies come about. Previous work has explored how the single-cell correlations in a homogeneous network (excitatory and inhibitory integrate-and-fire neurons with nearly balanced mean recurrent input can be determined numerically from an iterative single-neuron simulation. Such a scheme is based on the fact that every neuron is driven by the network noise (i.e., the input currents from all its presynaptic partners but also contributes to the network noise, leading to a self-consistency condition for the input and output spectra. Here we first extend this scheme to homogeneous networks with strong recurrent inhibition and a synaptic filter, in which instabilities of the previous scheme are avoided by an averaging procedure. We then extend the scheme to heterogeneous networks in which (i different neural subpopulations (e.g., excitatory and inhibitory neurons have different cellular or connectivity parameters; (ii the number and strength of the input connections are random (Erdős-Rényi topology and thus different among neurons. In all heterogeneous cases, neurons are lumped in different classes each of which is represented by a single neuron in the iterative scheme; in addition, we make a Gaussian approximation of the input current to the neuron. These approximations seem to be justified over a broad range of

Three-dimensional microscopic deformation measurements on cellular solids.

Science.gov (United States)

Genovese, K

2016-07-01

The increasing interest in small-scale problems demands novel experimental protocols providing dense sets of 3D deformation data of complex shaped microstructures. Obtaining such information is particularly significant for the study of natural and engineered cellular solids for which experimental data collected at macro scale and describing the global mechanical response provide only limited information on their function/structure relationship. Cellular solids, in fact, due their superior mechanical performances to a unique arrangement of the bulk material properties (i.e. anisotropy and heterogeneity) and cell structural features (i.e. pores shape, size and distribution) at the micro- and nano-scales. To address the need for full-field experimental data down to the cell level, this paper proposes a single-camera stereo-Digital Image Correlation (DIC) system that makes use of a wedge prism in series to a telecentric lens for performing surface shape and deformation measurements on microstructures in three dimensions. Although the system possesses a limited measurement volume (FOV~2.8×4.3mm(2), error-free DOF ~1mm), large surface areas of cellular samples can be accurately covered by employing a sequential image capturing scheme followed by an optimization-based mosaicing procedure. The basic principles of the proposed method together with the results of the benchmarking of its metrological performances and error analysis are here reported and discussed in detail. Finally, the potential utility of this method is illustrated with micro-resolution three-dimensional measurements on a 3D printed honeycomb and on a block sample of a Luffa sponge under compression. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cockayne's syndrome: correlation of clinical features with cellular sensitivity of RNA synthesis to UV irradiation

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Lehmann, A.R.; Thompson, A.F.; Harcourt, S.A. (Medical Research Council, Brighton (United Kingdom). Cell Mutation Unit); Stefanini, Miria (Consiglio Nazionale delle Ricerche, Pavia (Italy). Ist. di Genetica Biochimica ed Evoluzionistica); Norris, P.G. (Addenbrooke' s Hospital, Cambridge (United Kingdom))

1993-08-01

Cockayne's syndrome (CS) is a rare autosomal recessive disorder with dwarfism, mental retardation, and otherwise clinically heterogeneous features. In cultured CS fibroblasts, the failure of RNA synthesis to recover to normal rates after UV-C irradiation provides a useful and relatively simple diagnostic test. We have measured post-UV-C RNA synthesis in 52 patients for whom a clinical diagnosis of CS was considered a possibility. Twenty-nine patients showed the defect characteristic of CS cells, and 23 had a normal response. We have attempted to correlate the cellular diagnosis with the different clinical features of the disorder. Clinical details of the patients were obtained from referring clinicians in the form of a questionnaire. Our results show that, apart from the cardinal features of dwarfism and mental retardation, sun sensitivity correlated best with a positive cellular diagnosis. Pigmentary retinopathy, gait defects, and dental caries were also good positive indicators, although several patients with a positive cellular diagnosis did not have these features. (Author).

Cytotoxicity of the dicarboximide fungicides, vinclozolin and iprodione, in rat hepatoma-derived Fa32 cells.

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Dierickx, Paul J

2004-10-01

Dicarboximide fungicides are widely used to control various fungal species. Their primary action is not known, due to a lack of knowledge concerning the mechanism of action of the dicarboximide group. The cytotoxicities of vinclozolin and iprodione in rat hepatoma-derived Fa32 cells were investigated. Cytotoxicity was measured by neutral red uptake inhibition after treatment for 24 hours. Iprodione was more toxic than vinclozolin. Vinclozolin was less toxic in glutathione-depleted cells than in control cells. This was also true for iprodione at lower concentrations, but iprodione became more toxic at higher concentrations. Both the fungicides increased the endogenous glutathione content by 20% after 1 hour. After 24 hours, the glutathione content was doubled by vinclozolin, but was not affected by iprodione. No effect on glutathione S-transferase activity or reactive oxygen species formation could be observed. Cytochrome P450-dependent ethoxyresorufin-O-deethylase and pentoxyresorufin-O-depentylase activities were moderately activated by iprodione and strongly activated by vinclozolin. A glutathione-related cytochrome P450-dependent metabolic attack of vinclozolin and iprodione could be responsible for their cytotoxicity in Fa32 cells. Further research is needed to fully elucidate these (or other) mechanisms.

Characterization of Morphological and Cellular Events Underlying Oral Regeneration in the Sea Anemone, Nematostella vectensis

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Aldine R. Amiel

2015-12-01

Full Text Available Cnidarians, the extant sister group to bilateria, are well known for their impressive regenerative capacity. The sea anemone Nematostella vectensis is a well-established system for the study of development and evolution that is receiving increased attention for its regenerative capacity. Nematostella is able to regrow missing body parts within five to six days after its bisection, yet studies describing the morphological, cellular, and molecular events underlying this process are sparse and very heterogeneous in their experimental approaches. In this study, we lay down the basic framework to study oral regeneration in Nematostella vectensis. Using various imaging and staining techniques we characterize in detail the morphological, cellular, and global molecular events that define specific landmarks of this process. Furthermore, we describe in vivo assays to evaluate wound healing success and the initiation of pharynx reformation. Using our described landmarks for regeneration and in vivo assays, we analyze the effects of perturbing either transcription or cellular proliferation on the regenerative process. Interestingly, neither one of these experimental perturbations has major effects on wound closure, although they slightly delay or partially block it. We further show that while the inhibition of transcription blocks regeneration in a very early step, inhibiting cellular proliferation only affects later events such as pharynx reformation and tentacle elongation.

Stochastic fluctuations and distributed control of gene expression impact cellular memory.

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Guillaume Corre

Full Text Available Despite the stochastic noise that characterizes all cellular processes the cells are able to maintain and transmit to their daughter cells the stable level of gene expression. In order to better understand this phenomenon, we investigated the temporal dynamics of gene expression variation using a double reporter gene model. We compared cell clones with transgenes coding for highly stable mRNA and fluorescent proteins with clones expressing destabilized mRNA-s and proteins. Both types of clones displayed strong heterogeneity of reporter gene expression levels. However, cells expressing stable gene products produced daughter cells with similar level of reporter proteins, while in cell clones with short mRNA and protein half-lives the epigenetic memory of the gene expression level was completely suppressed. Computer simulations also confirmed the role of mRNA and protein stability in the conservation of constant gene expression levels over several cell generations. These data indicate that the conservation of a stable phenotype in a cellular lineage may largely depend on the slow turnover of mRNA-s and proteins.

Extracellular concentration of homocysteine in human cell lines is influenced by specific inhibitors of cyst(e)ine transport.

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Hultberg, Björn

2004-04-01

Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Studies of the cellular uptake systems for homocysteine are scarce, but membrane transporters of cyst(e)ine seem to be involved. In the present study the cellular uptake of extracellular homocysteine in HeLa and hepatoma cell lines is investigated by using several different transport inhibitors for cellular uptake of cyst(e)ine. It is shown that systems A and Xc- are the main transport systems for homocysteine uptake in HeLa cells. It is also confirmed that the magnitude of homocysteine uptake in hepatoma cells is lower than in HeLa cells. However, in the presence of high amounts of extracellular homocysteine both cell types exhibited a high elimination of homocysteine, which was inhibited by the presence of inhibitors of systems A or Xc-. It is possible that there is normally a high turnover of homocysteine in cell cultures, which is not detected by occasional determinations of homocysteine concentrations. The complex pattern of homocysteine production, release, uptake and distribution between different cells in the body is important to examine further in order to possibly be able to modulate the elimination of homocysteine from circulation and thereby lower the risk of cardiovascular disease.

Chemopreventive Activities of Sulforaphane and Its Metabolites in Human Hepatoma HepG2 Cells

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Peng Liu

2018-05-01

Full Text Available Sulforaphane (SFN exhibits chemopreventive effects through various mechanisms. However, few studies have focused on the bioactivities of its metabolites. Here, three metabolites derived from SFN were studied, known as sulforaphane glutathione, sulforaphane cysteine and sulforaphane-N-acetylcysteine. Their effects on cell viability, DNA damage, tumorigenicity, cell migration and adhesion were measured in human hepatoma HepG2 cells, and their anti-angiogenetic effects were determined in a 3D co-culture model of human umbilical vein endothelial cells (HUVECs and pericytes. Results indicated that these metabolites at high doses decreased cancer cell viability, induced DNA damage and inhibited motility, and impaired endothelial cell migration and tube formation. Additionally, pre-treatment with low doses of SFN metabolites protected against H2O2 challenge. The activation of the nuclear factor E2-related factor 2 (Nrf2-antioxidant response element (ARE pathway and the induction of intracellular glutathione (GSH played an important role in the cytoprotective effects of SFN metabolites. In conclusion, SFN metabolites exhibited similar cytotoxic and cytoprotective effects to SFN, which proves the necessity to study the mechanisms of action of not only SFN but also of its metabolites. Based on the different tissue distribution profiles of these metabolites, the most relevant chemical forms can be selected for targeted chemoprevention.

Secretion of One Adipokine Nampt/Visfatin Suppresses the Inflammatory Stress-Induced NF-κB Activity and Affects Nampt-Dependent Cell Viability in Huh-7 Cells

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Yi-Ching Lin

2015-01-01

Full Text Available Nampt/visfatin acts in both intracellular and extracellular compartments to regulate multiple biological roles, including NAD metabolism, cancer, inflammation, and senescence. However, its function in chronic inflammation and carcinogenesis in hepatocellular carcinoma (HCC has not been well-defined. Here we use Huh-7 hepatoma cells as a model to determine how Nampt/visfatin affects cellular survival under oxidative stress. We found that the transition of Nampt/visfatin from intracellular into extracellular form was induced by H2O2 treatment in 293T cells and confirmed that this phenomenon was not due to cell death but through the secretion of Nampt/visfatin. In addition, Nampt/visfatin suppressed cell viability in oxidative treatment in Huh-7 cells and acted on the inhibition of hepatoma cell growth. Oxidative stress also reduced the Nampt-mediated activation of NF-κB gene expression. In this study, we identify a novel feature of Nampt/visfatin which functions as an adipokine that can be secreted upon cellular stress. Our results provide an example to understand how adipokine interacts with chemotherapeutic treatment by oxidative stress in HCC.

Potentiating effect of graphene nanomaterials on aromatic environmental pollutant-induced cytochrome P450 1A expression in the topminnow fish hepatoma cell line PLHC-1.

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Lammel, Tobias; Boisseaux, Paul; Navas, José M

2015-09-01

Graphene and its derivatives are an emerging class of carbon nanomaterial with great potential for a broad range of industrial and consumer applications. However, their increasing production and use is expected to result in release of nano-sized graphene platelets into the environment, where they may interact with chemical pollutants modifying their fate and toxic potential. The objective of this study was to assess whether graphene nanoplatelets can act as vector for aromatic environmental pollutants increasing their cellular uptake and associated hazardous effects in vitro. For this purpose, cell cultures of the topminnow fish (Poeciliopsis lucida) hepatoma cell line PLHC-1 were simultaneously (and successively) exposed to graphene nanoplatelets (graphene oxide (GO) or carboxyl graphene (CXYG)) and an aryl hydrocarbon receptor (AhR) agonist (β-naphthoflavone (β-NF), benzo(k)fluoranthene (BkF) or 3,3',4,4',5,5'-hexachlorobiphenyl (PCB169)). Following exposure cytochrome P450 1A (Cyp1A) induction was assessed by measuring cyp1A mRNA expression levels using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and Cyp1A-dependent ethoxyresorufin-O-deethylase (EROD) activity. It was observed that pre- and co-exposure of cells to GO and CXYG nanoplatelets had a potentiating effect on β-NF, BkF, and PCB169-dependent Cyp1A induction suggesting that graphene nanoplatelets increase the effective concentration of AhR agonists by facilitating their passive diffusion into the cells by damaging the cells' plasma membrane and/or by transporting them over the plasma membrane via a Trojan horse-like mechanism. The results demonstrate the existence of combination effects between nanomaterials and environmental pollutants and stress the importance of considering these effects when evaluating their respective hazard. © 2014 Wiley Periodicals, Inc.

Inhibition effects of 125I-triplex forming oligonucleotide to hepatoma cells

International Nuclear Information System (INIS)

Lv Zhongwei; Hou Min; Cai Haidong; Yuan Xueyu; Yang Yuehua; Yuan Shidong; He Junmin

2007-01-01

Objective: Triplex forming oligonucleotide (TFO) has been reported as a new antigene strategy. The purpose of this study was to observe the inhibition effects of 125 I-TFO on hepatoma cells and to investigate the possibility of using 125 I-TFO as an antigene radiotherapy technique for hepatocellular carcinoma (HCC) related to HBV. Methods: TFO complementary to the initiator of S gene of HBV was synthesized and labeled with 125 I. HepG2.2.15 cells, in which HBV genome was integrated, were incubated with 125 I-TFO, TFO and 125 I respectively. After incubation, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) of each group were assayed with ELISA and the survival rate of cells in each group was determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide (MTT) reduction assay. Results: 125 I-TFO showed a high stability with a radiolabeling rate of >93%. The radiochemical purity of labeled compound was 90.8%, 81.1% and 73.2% respectively after 12, 48 and 72 h at 37 degree C. The peak inhibition effect of 125 I-TFO on synthesizing HBsAg and HBeAg by HepG2.2.15 cells were found at 48 h after transfection, with significantly the highest inhibition rate of 45.2% for HBsAg and 74.5% for HBeAg expression among the three groups(P 125 I-TFO may inhibit the antigen expression of HBV and the growth of hepatocarcinoma cells, thus it may provide a new approach to develop gene-based radiotherapeutic pharmaceuticals for anti-HBV and HCC. (authors)

Heterogeneity mapping of protein expression in tumors using quantitative immunofluorescence.

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Faratian, Dana; Christiansen, Jason; Gustavson, Mark; Jones, Christine; Scott, Christopher; Um, InHwa; Harrison, David J

2011-10-25

Morphologic heterogeneity within an individual tumor is well-recognized by histopathologists in surgical practice. While this often takes the form of areas of distinct differentiation into recognized histological subtypes, or different pathological grade, often there are more subtle differences in phenotype which defy accurate classification (Figure 1). Ultimately, since morphology is dictated by the underlying molecular phenotype, areas with visible differences are likely to be accompanied by differences in the expression of proteins which orchestrate cellular function and behavior, and therefore, appearance. The significance of visible and invisible (molecular) heterogeneity for prognosis is unknown, but recent evidence suggests that, at least at the genetic level, heterogeneity exists in the primary tumor(1,2), and some of these sub-clones give rise to metastatic (and therefore lethal) disease. Moreover, some proteins are measured as biomarkers because they are the targets of therapy (for instance ER and HER2 for tamoxifen and trastuzumab (Herceptin), respectively). If these proteins show variable expression within a tumor then therapeutic responses may also be variable. The widely used histopathologic scoring schemes for immunohistochemistry either ignore, or numerically homogenize the quantification of protein expression. Similarly, in destructive techniques, where the tumor samples are homogenized (such as gene expression profiling), quantitative information can be elucidated, but spatial information is lost. Genetic heterogeneity mapping approaches in pancreatic cancer have relied either on generation of a single cell suspension(3), or on macrodissection(4). A recent study has used quantum dots in order to map morphologic and molecular heterogeneity in prostate cancer tissue(5), providing proof of principle that morphology and molecular mapping is feasible, but falling short of quantifying the heterogeneity. Since immunohistochemistry is, at best, only semi

Overexpression of thyroid hormone beta1 nuclear receptor is associated with an increased proliferation of human hepatoma cells

International Nuclear Information System (INIS)

Lin, K.; Lin, Y.; McPhie, P.; Cheng S.

1994-01-01

It is evaluated the expression of thyroid hormone nuclear receptors (TRs) and their possible roles in the carcinogenesis of human hepatocarcinoma. The expression of TRβ and TRα genes was evaluated at both the mRNA and protein levels. The expression of TRβ1 and TRα1 mRNAs is similar to those found in normal liver. However, the expression of TR isoform proteins depends on the cell-type. The expression of TRα1 protein is low in all cell lines examined. However, TRβ1 protein is overexpressed in Mahlavu, SK-Hep-1, and HA22T, moderately expressed in J5, J7, and J328 and is very low in HepG2, Hep3B, and PLC/PRF/5 cells. The proliferation of cells in which TRβ1 is overexpressed is stimulated by the thyroid hormone, 3,3',5-triiodo-L-thyronine. These results suggest that TRβ1 not TRα1, is probably involved in the proliferation of hepatoma cells

Heterogeneous network architectures

DEFF Research Database (Denmark)

Christiansen, Henrik Lehrmann

2006-01-01

is flexibility. This thesis investigates such heterogeneous network architectures and how to make them flexible. A survey of algorithms for network design is presented, and it is described how using heuristics can increase the speed. A hierarchical, MPLS based network architecture is described......Future networks will be heterogeneous! Due to the sheer size of networks (e.g., the Internet) upgrades cannot be instantaneous and thus heterogeneity appears. This means that instead of trying to find the olution, networks hould be designed as being heterogeneous. One of the key equirements here...... and it is discussed that it is advantageous to heterogeneous networks and illustrated by a number of examples. Modeling and simulation is a well-known way of doing performance evaluation. An approach to event-driven simulation of communication networks is presented and mixed complexity modeling, which can simplify...

Caspase-8 acts as a key upstream executor of mitochondria during justicidin A-induced apoptosis in human hepatoma cells.

Science.gov (United States)

Su, Chun-Li; Huang, Lynn L H; Huang, Li-Min; Lee, Jenq-Chang; Lin, Chun-Nan; Won, Shen-Jeu

2006-05-29

Justicia procumbens is a traditional Taiwanese herbal remedy used to treat fever, pain, and cancer. Justicidin A, isolated from Justicia procumbens, has been reported to suppress in vitro growth of several tumor cell lines as well as hepatoma cells. In this study, justicidin A activated caspase-8 to increase tBid, disrupted mitochondrial membrane potential (Delta psi(m)), and caused the release of cytochrome c and Smac/DIABLO in Hep 3B and Hep G2 cells. Justicidin A also reduced Bcl-x(L) and increased Bax and Bak in mitochondria. Caspase-8 inhibitor (Z-IETD) attenuated the justicidin A-induced disruption of Delta psi(m). Growth of Hep 3B implanted in NOD-SCID mice was suppressed significantly by oral justicidin A (20 mg/kg/day). These results indicate that justicidin A-induced apoptosis in these cells proceeds via caspase-8 and is followed by mitochondrial disruption.

Transformation of Epithelial Ovarian Cancer Stemlike Cells into Mesenchymal Lineage via EMT Results in Cellular Heterogeneity and Supports Tumor Engraftment

Science.gov (United States)

Jiang, Hua; Lin, Xiaolong; Liu, Yingtao; Gong, Wenjia; Ma, Xiaoling; Yu, Yinhua; Xie, Yi; Sun, Xiaoxi; Feng, Youji; Janzen, Viktor; Chen, Tong

2012-01-01

Ovarian cancers are heterogeneous and contain stemlike cells that are able to self-renew and are responsible for sustained tumor growth. Metastasis in the peritoneal cavity occurs more frequently in ovarian cancer than in other malignancies, but the underlying mechanism remains largely unknown. We have identified that ovarian cancer stemlike cells (CSCs), which were defined as side population (SP) cells, were present in patients’ ascitic fluid and mesenchymally transformed cell lines, ES-2 and HO-8910PM. SP cells, which were sorted from both cell lines and implanted into immunocompromised mice, were localized to the xenografted tumor boundary. In addition, SP cells exhibited an epithelial phenotype and showed a distinct gene expression profile with reduced expression of cell adhesion molecules (CAMs), indicating that SP cells exert an important role in ovarian cancer progression on the basis of their delicate interaction with the surrounding microenvironment and anatomical localization in tumors. In contrast, non-SP cells exhibited a more mesenchymal phenotype and showed more increased invasive potential than SP cells. This heterogeneity was observed as an endogenous transformation via the epithelial–mesenchymal transition (EMT) process. Inhibition of the EMT process by Snail1 silencing reduced the SP cell frequency, and affected their invasive capacity and engraftment. These findings illustrate the interplay between epithelial ovarian CSCs and the EMT, and exert a link to explain tumor heterogeneity and its necessity for ovarian cancer maintenance, metastasis and progression. PMID:22801793

Correlation Between Minimum Apparent Diffusion Coefficient (ADCmin) and Tumor Cellularity: A Meta-analysis.

Science.gov (United States)

Surov, Alexey; Meyer, Hans Jonas; Wienke, Andreas

2017-07-01

Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique based on measure of water diffusion that can provide information about tissue microstructure, especially about cell count. Increase of cell density induces restriction of water diffusion and decreases apparent diffusion coefficient (ADC). ADC can be divided into three sub-parameters: ADC minimum or ADC min , mean ADC or ADC mean and ADC maximum or ADC max Some studies have suggested that ADC min shows stronger correlations with cell count in comparison to other ADC fractions and may be used as a parameter for estimation of tumor cellularity. The aim of the present meta-analysis was to summarize correlation coefficients between ADC min and cellularity in different tumors based on large patient data. For this analysis, MEDLINE database was screened for associations between ADC and cell count in different tumors up to September 2016. For this work, only data regarding ADC min were included. Overall, 12 publications with 317 patients were identified. Spearman's correlation coefficient was used to analyze associations between ADC min and cellularity. The reported Pearson correlation coefficients in some publications were converted into Spearman correlation coefficients. The pooled correlation coefficient for all included studies was ρ=-0.59 (95% confidence interval (CI)=-0.72 to -0.45), heterogeneity Tau 2 =0.04 (pcorrelated moderately with tumor cellularity. The calculated correlation coefficient is not stronger in comparison to the reported coefficient for ADC mean and, therefore, ADC min does not represent a better means to reflect cellularity. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Assessing heterogeneity in oligomeric AAA+ machines.

Science.gov (United States)

Sysoeva, Tatyana A

2017-03-01

ATPases Associated with various cellular Activities (AAA+ ATPases) are molecular motors that use the energy of ATP binding and hydrolysis to remodel their target macromolecules. The majority of these ATPases form ring-shaped hexamers in which the active sites are located at the interfaces between neighboring subunits. Structural changes initiate in an active site and propagate to distant motor parts that interface and reshape the target macromolecules, thereby performing mechanical work. During the functioning cycle, the AAA+ motor transits through multiple distinct states. Ring architecture and placement of the catalytic sites at the intersubunit interfaces allow for a unique level of coordination among subunits of the motor. This in turn results in conformational differences among subunits and overall asymmetry of the motor ring as it functions. To date, a large amount of structural information has been gathered for different AAA+ motors, but even for the most characterized of them only a few structural states are known and the full mechanistic cycle cannot be yet reconstructed. Therefore, the first part of this work will provide a broad overview of what arrangements of AAA+ subunits have been structurally observed focusing on diversity of ATPase oligomeric ensembles and heterogeneity within the ensembles. The second part of this review will concentrate on methods that assess structural and functional heterogeneity among subunits of AAA+ motors, thus bringing us closer to understanding the mechanism of these fascinating molecular motors.

Stable Regulation of Cell Cycle Events in Mycobacteria: Insights From Inherently Heterogeneous Bacterial Populations

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Michelle M. Logsdon

2018-03-01

Full Text Available Model bacteria, such as E. coli and B. subtilis, tightly regulate cell cycle progression to achieve consistent cell size distributions and replication dynamics. Many of the hallmark features of these model bacteria, including lateral cell wall elongation and symmetric growth and division, do not occur in mycobacteria. Instead, mycobacterial growth is characterized by asymmetric polar growth and division. This innate asymmetry creates unequal birth sizes and growth rates for daughter cells with each division, generating a phenotypically heterogeneous population. Although the asymmetric growth patterns of mycobacteria lead to a larger variation in birth size than typically seen in model bacterial populations, the cell size distribution is stable over time. Here, we review the cellular mechanisms of growth, division, and cell cycle progression in mycobacteria in the face of asymmetry and inherent heterogeneity. These processes coalesce to control cell size. Although Mycobacterium smegmatis and Mycobacterium bovis Bacillus Calmette-Guérin (BCG utilize a novel model of cell size control, they are similar to previously studied bacteria in that initiation of DNA replication is a key checkpoint for cell division. We compare the regulation of DNA replication initiation and strategies used for cell size homeostasis in mycobacteria and model bacteria. Finally, we review the importance of cellular organization and chromosome segregation relating to the physiology of mycobacteria and consider how new frameworks could be applied across the wide spectrum of bacterial diversity.

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line.

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Yang, Darong; Zuo, Chaohui; Wang, Xiaohong; Meng, Xianghe; Xue, Binbin; Liu, Nianli; Yu, Rong; Qin, Yuwen; Gao, Yimin; Wang, Qiuping; Hu, Jun; Wang, Ling; Zhou, Zebin; Liu, Bing; Tan, Deming; Guan, Yang; Zhu, Haizhen

2014-04-01

The absence of a robust cell culture system for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has limited the analysis of the virus lifecycle and drug discovery. We have established a hepatoma cell line, HLCZ01, the first cell line, to the authors' knowledge, supporting the entire lifecycle of both HBV and HCV. HBV surface antigen (HBsAg)-positive particles can be observed in the supernatant and the lumen of the endoplasmic reticulum of the cells via electron microscopy. Interestingly, HBV and HCV clinical isolates propagate in HLCZ01 cells. Both viruses replicate in the cells without evidence of overt interference. HBV and HCV entry are blocked by antibodies against HBsAg and human CD81, respectively, and the replication of HBV and HCV is inhibited by antivirals. HLCZ01 cells mount an innate immune response to virus infection. The cell line provides a powerful tool for exploring the mechanisms of virus entry and replication and the interaction between host and virus, facilitating the development of novel antiviral agents and vaccines.

Magnetic resonance imaging findings of cellular angiofibroma of the tunica vaginalis of the testis: a case report.

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Ntorkou, Alexandra A; Tsili, Athina C; Giannakis, Dimitrios; Batistatou, Anna; Stavrou, Sotirios; Sofikitis, Nikolaos; Argyropoulou, Maria I

2016-03-31

Cellular angiofibroma represents a rare mesenchymal tumor typically involving the inguinoscrotal area in middle-aged men. Although the origin of this benign tumor is unknown, it is histologically classified as an angiomyxoid tumor. Cellular angiofibroma is characterized by a diversity of pathological and imaging features. An accurate preoperative diagnosis is challenging. Magnetic resonance imaging examination of the scrotum has been reported as a valuable adjunct modality in the investigation of scrotal pathology. The technique by providing both structural and functional information is useful in the differentiation between extratesticular and intratesticular diseases and in the preoperative characterization of the histologic nature of various scrotal lesions. There are few reports in the English literature addressing the magnetic resonance imaging findings of cellular angiofibroma of the scrotum and no reports on functional magnetic resonance imaging data. Here we present the first case of a cellular angiofibroma arising from the tunica vaginalis of the testis and we discuss the value of a multiparametric magnetic resonance protocol, including diffusion-weighted imaging, magnetization transfer imaging and dynamic contrast-enhanced magnetic resonance imaging in the preoperative diagnosis of this rare neoplasm. A 47-year Greek man presented with a painless left scrotal swelling, which had gradually enlarged during the last 6 months. Magnetic resonance imaging of his scrotum displayed a left paratesticular mass, in close proximity to the tunica vaginalis, with heterogeneous high signal intensity on T2-weighted images and no areas of restricted diffusion. The tumor was hypointense on magnetization transfer images, suggestive for the presence of macromolecules. On dynamic contrast-enhanced magnetic resonance imaging the mass showed intense heterogeneous enhancement with a type II curve. Magnetic resonance imaging findings were strongly suggestive of a benign

Cellular gravity

NARCIS (Netherlands)

F.C. Gruau; J.T. Tromp (John)

1999-01-01

textabstractWe consider the problem of establishing gravity in cellular automata. In particular, when cellular automata states can be partitioned into empty, particle, and wall types, with the latter enclosing rectangular areas, we desire rules that will make the particles fall down and pile up on

Dynamic heterogeneity in life histories

DEFF Research Database (Denmark)

Tuljapurkar, Shripad; Steiner, Uli; Orzack, Steven Hecht

2009-01-01

or no fixed heterogeneity influences this trait. We propose that dynamic heterogeneity provides a 'neutral' model for assessing the possible role of unobserved 'quality' differences between individuals. We discuss fitness for dynamic life histories, and the implications of dynamic heterogeneity...... generate dynamic heterogeneity: life-history differences produced by stochastic stratum dynamics. We characterize dynamic heterogeneity in a range of species across taxa by properties of the Markov chain: the entropy, which describes the extent of heterogeneity, and the subdominant eigenvalue, which...... distributions of lifetime reproductive success. Dynamic heterogeneity contrasts with fixed heterogeneity: unobserved differences that generate variation between life histories. We show by an example that observed distributions of lifetime reproductive success are often consistent with the claim that little...

Analytical study of cell liver proliferation and serum AFP in various liver diseases other than hepatomas

Energy Technology Data Exchange (ETDEWEB)

Takino, T; Okuda, K; Kitamura, O; Takahashi, T; Ashihara, T [Kyoto Prefectural Univ. of Medicine (Japan)

1974-12-01

Cell proliferative activity in the liver tissue obtained in 50 cases by liver biopsy, was analyzed using in vitro labeling of /sup 3/H-thymidine autoradiography. The proliferating cells were found to be located mainly in the periportal areas of the lobules. The mean labeling indices of the liver cells were 0.06 % in chronic hepatitis in its active form, 0.05 % in pre-cirrhosis of the liver, 0.03 % in liver cirrhosis, 0.02 % in chronic hepatitis in an inactive form and 0.018 % in acute hepatitis at the restoractive stage. The labeling indices of the liver parenchymal cells of each specimen studied were very low being at most 0.2 %. On the other hand, when the serum AFP was analyzed by radioimmunoassay technique in 185 patients with various liver diseases, level of the mean serum AFP in each group of the liver diseases was found to correspond to that of the proliferative activity of the liver cells in its respective group. From these data it was suggested that the proliferative activity of the liver cells in various liver diseases, with the exception of hepatomas, was closely related to release of AFP into the serum.

Apoptosis and changes in glucose transport early after treatment of Morris hepatoma with gemcitabine

International Nuclear Information System (INIS)

Haberkorn, U.; Bellemann, M.E.; Brix, G.; Kamencic, H.; Traut, U.; Kinscherf, R.; Doll, J.; Blatter, J.

2001-01-01

Apoptosis has been described as an energy-consuming process. This combined in vivo/in vitro study investigated the effects of the antineoplastic agent gemcitabine on tumour metabolism and on the induction of apoptosis. Dynamic positron emission tomography (PET) measurements of fluorine-18 fluorodeoxyglucose (FDG) uptake were done in rats bearing Morris hepatoma prior to and after therapy with 90 mg gemcitabine/kg b.w. Furthermore, thymidine (TdR) incorporation into the DNA of these tumours was determined. In vitro measurements of FDG and TdR uptake were performed immediately and 24 h after the end of gemcitabine treatment, and the amount of apoptotic cells was determined using the TUNEL reaction. In vivo an increase in FDG transport and phosphorylation occurred early after gemcitabine treatment, although TdR incorporation into the DNA of the tumours declined. In vitro, an enhanced glucose transport, an increase in TdR uptake in the cytoplasm and a decrease in TdR incorporation in the nucleic acid fraction early after treatment occurred. Inhibition of glucose transport caused an increase in the amount of apoptotic cells. The increase in glucose uptake and TdR metabolism early after therapy is interpreted as a stress reaction of the tumour cells, protecting the cells from apoptosis during this early period after exposure to cytotoxic drugs like gemcitabine. (orig.)

Apoptosis and changes in glucose transport early after treatment of Morris hepatoma with gemcitabine

Energy Technology Data Exchange (ETDEWEB)

Haberkorn, U. [Heidelberg Univ. (Germany). Abt. fuer Klinische Nuklearmedizin; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg (Germany); Bellemann, M.E. [Department of Biomedical Engineering, University of Applied Sciences, Jena (Germany); Brix, G. [Department of Medical Radiation Hygiene, Federal Office for Radiation Protection, Neuherberg (Germany); Kamencic, H.; Traut, U.; Kinscherf, R. [Heidelberg Univ. (Germany). Inst. fuer Anatomie und Zellbiologie; Morr, I.; Altmann, A. [Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg (Germany); Doll, J. [Dept. of Medical Physics, German Cancer Research Center, Heidelberg (Germany); Blatter, J. [Lilly GmbH Germany, Bad Homburg (Germany)

2001-04-01

Apoptosis has been described as an energy-consuming process. This combined in vivo/in vitro study investigated the effects of the antineoplastic agent gemcitabine on tumour metabolism and on the induction of apoptosis. Dynamic positron emission tomography (PET) measurements of fluorine-18 fluorodeoxyglucose (FDG) uptake were done in rats bearing Morris hepatoma prior to and after therapy with 90 mg gemcitabine/kg b.w. Furthermore, thymidine (TdR) incorporation into the DNA of these tumours was determined. In vitro measurements of FDG and TdR uptake were performed immediately and 24 h after the end of gemcitabine treatment, and the amount of apoptotic cells was determined using the TUNEL reaction. In vivo an increase in FDG transport and phosphorylation occurred early after gemcitabine treatment, although TdR incorporation into the DNA of the tumours declined. In vitro, an enhanced glucose transport, an increase in TdR uptake in the cytoplasm and a decrease in TdR incorporation in the nucleic acid fraction early after treatment occurred. Inhibition of glucose transport caused an increase in the amount of apoptotic cells. The increase in glucose uptake and TdR metabolism early after therapy is interpreted as a stress reaction of the tumour cells, protecting the cells from apoptosis during this early period after exposure to cytotoxic drugs like gemcitabine. (orig.)

DNA binding properties of dioxin receptors in wild-type and mutant mouse hepatoma cells

International Nuclear Information System (INIS)

Cuthill, S.; Poellinger, L.

1988-01-01

The current model of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) entails stimulation of target gene transcription via the formation of dioxin-receptor complexes and subsequent accumulation of the complexes within the cell nucleus. Here, the authors have analyzed the DNA binding properties of the dioxin receptor in wild-type mouse hepatoma (Hepa 1c1c7) cells and a class of nonresponsive mutant cells which fail to accumulate dioxin-receptor complexes within the nucleus in vivo. In vitro, both the wild-type and mutant [ 3 H]dioxin-receptor complexes exhibited low affinity for DNA-cellulose (5-8% and around 4% retention, respectively) in the absence of prior biochemical manipulations. However, following chromatography on heparin-Sepharose, the wild-type but not the mutant dioxin receptor was transformed to a species with an increased affinity for DNA (40-50% retention on DNA-cellulose). The gross molecular structure of the mutant, non DNA binding dioxin receptor did not appear to be altered as compared to that of the wild-type receptor. These results imply that the primary deficiency in the mutant dioxin receptor form may reside at the DNA binding level and that, in analogy to steroid hormone receptors, DNA binding of the receptor may be an essential step in the regulation of target gene transcription by dioxin

The inhibition effect of 2,3,7,8-tetrachlorinated dibenzo-p-dioxin-induced aryl hydrocarbon receptor activation in human hepatoma cells with the treatment of cadmium chloride

International Nuclear Information System (INIS)

Chao, How-Ran; Tsou, Tsui-Chun; Chen, Hung-Ta; Chang, Eddy Essen; Tsai, Feng-Yuan; Lin, Ding-Yan; Chen, Fu-An; Wang, Ya-Fen

2009-01-01

Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), considered as endocrine disruptors, tend to accumulate in fatty tissues. Dioxin-responsive element chemical activated luciferase gene expression assay (DRE-luciferase assay) has been recognized as a semi-quantitative method for screening dioxins for its fast and low-cost as compared with HRGC/HRMS. However, some problems with the bioassay, including specificity, detection variation resulted from different cleanup strategies, and uncertainty of false-negative or false-positive results, remain to be overcome. Cadmium is a prevalent environmental contaminant around the world. This study was aimed to examine the effects of cadmium on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of aryl hydrocarbon receptor (AhR)-mediated gene expression in human hepatoma cells (Huh7-DRE-Luc cells and Huh7 cells). Ethoxyresorufin-O-deethylase (EROD) and DRE-luciferase assay were employed to determine the enzyme activity of cytochrome P450 1A1 (CYP1A1) and activation of AhR, respectively. The results showed that Cd 2+ levels significantly inhibited the induction of TCDD-induced CYP1A1 and DRE luciferase activation in hepatoma cells. The 50% inhibited concentrations (IC 50 ) of CdCl 2 were 0.414 μM (95% confidence interval (C.I.): 0.230-0.602 μM) in Huh7-DRE-Luc cells and 23.2 μM (95% C.I.: 21.7-25.4 μM) in Huh7 cells. Accordingly, prevention of interference with non-dioxin-like compounds in a DRE-luciferase assay is of great importance in an extensive cleanup procedure.

Iso-suillin isolated from Suillus luteus, induces G1 phase arrest and apoptosis in human hepatoma SMMC-7721 cells.

Science.gov (United States)

Jia, Zhi-Qiang; Chen, Ying; Yan, Yong-Xin; Zhao, Jun-Xia

2014-01-01

Iso-suillin, a natural product isolated from Suillus luteus, has been shown to inhibit the growth of some cancer cell lines. However, the molecular mechanisms of action of this compound are poorly understood. The purpose of this study was to investigate how iso-suillin inhibits proliferation and induces apoptosis in a human hepatoma cell line (SMMC-7721). We demonstrated the effects of iso-suillin on cell proliferation and apoptosis in SMMC-7721 cells, with no apparent toxicity in normal human lymphocytes, using colony formation assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis. Western blotting was used to examine the expression of G1 phase-regulated and apoptosis-associated protein levels in iso-suillin treated SMMC-7721 cells. The results indicated that iso-suillin significantly decreased viability, induced G1 phase arrest and triggered apoptosis in SMMC-7721cells. Taken together, these results suggest the potential of iso-suillin as a candidate for liver cancer treatment.

Modelling the collective response of heterogeneous cell populations to stationary gradients and chemical signal relay

Science.gov (United States)

Pineda, M.; Eftimie, R.

2017-12-01

The directed motion of cell aggregates toward a chemical source occurs in many relevant biological processes. Understanding the mechanisms that control this complex behavior is of great relevance for our understanding of developmental biological processes and many diseases. In this paper, we consider a self-propelled particle model for the movement of heterogeneous subpopulations of chemically interacting cells towards an imposed stable chemical gradient. Our simulations show explicitly how self-organisation of cell populations (which could lead to engulfment or complete cell segregation) can arise from the heterogeneity of chemotactic responses alone. This new result complements current theoretical and experimental studies that emphasise the role of differential cell-cell adhesion on self-organisation and spatial structure of cellular aggregates. We also investigate how the speed of individual cell aggregations increases with the chemotactic sensitivity of the cells, and decreases with the number of cells inside the aggregates

Effects of PARP-1 inhibitors AG-014699 and AZD2281 on proliferation and apoptosis of human hepatoma cell line HepG2

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DU Senrong

2015-06-01

Full Text Available ObjectiveTo observe the inhibitory and pro-apoptotic effects of two poly(ADP-ribose polymerase (PARP-1 inhibitors, AG-014699 and AZD2281, on human hepatoma HepG2 cells and preliminarily explore the mechanism by which AG-014699 induces HepG2 cell apoptosis, and to provide a new therapeutic target for hepatoma. MethodsThe effects of different concentrations of AG-014699 and AZD2281 on HepG2 cell proliferation were determined by MTT assay. The cell apoptosis rate was measured by flow cytometry. The expression levels of caspase-3 and caspase-8 were measured by Western Blot. Inter-group comparison was made by t test. ResultsBoth AG-014699 and AZD2281 suppressed HepG2 cell proliferation in a time- and dose-dependent manner. However, the sensitivity of HepG2 cells to the two PARP-1 inhibitors was different. The half-maximal inhibitory concentrations of AG-014699 and AZD2281 at 48 h determined by MTT assay were about 20 μmol/L and 400 μmol/L, respectively. Flow cytometry and Western blot were not used to evaluate the apoptosis of HepG2 cells exposed to AZD2281 to which these cells were not sensitive. HepG2 cell apoptosis could be induced by 10, 30, and 50 μmol/L AG-014699, and the highest apoptosis rate at 48 h was significantly higher than that of the control group (3100%±2.13% vs 09%±0013%, P＜0.01. Compared with those in the control group, the protein levels of caspase-3 and caspase-8 in HepG2 cells after 48-h exposure to 30, and 50 μmol/L AG-014699 increased. ConclusionThe two PARP-1 inhibitors AG-014699 and AZD2281 can inhibit the proliferation of HepG2 cells, which showed different sensitivities to the two inhibitors. AG-014699 can induce HepG2 cell apoptosis by up-regulating the protein expression of caspase-3 and caspase-8.

Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression

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Eduard Willms

2018-04-01

Full Text Available Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs that function as mediators of intercellular communication by transferring biological information between cells. Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and

Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression.

Science.gov (United States)

Willms, Eduard; Cabañas, Carlos; Mäger, Imre; Wood, Matthew J A; Vader, Pieter

2018-01-01

Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs) that function as mediators of intercellular communication by transferring biological information between cells. Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and disease.

Cellular MR Imaging

Directory of Open Access Journals (Sweden)

Michel Modo

2005-07-01

Full Text Available Cellular MR imaging is a young field that aims to visualize targeted cells in living organisms. In order to provide a different signal intensity of the targeted cell, they are either labeled with MR contrast agents in vivo or prelabeled in vitro. Either (ultrasmall superparamagnetic iron oxide [(USPIO] particles or (polymeric paramagnetic chelates can be used for this purpose. For in vivo cellular labeling, Gd3+- and Mn2+- chelates have mainly been used for targeted hepatobiliary imaging, and (USPIO-based cellular imaging has been focused on imaging of macrophage activity. Several of these magneto-pharmaceuticals have been FDA-approved or are in late-phase clinical trials. As for prelabeling of cells in vitro, a challenge has been to induce a sufficient uptake of contrast agents into nonphagocytic cells, without affecting normal cellular function. It appears that this issue has now largely been resolved, leading to an active research on monitoring the cellular biodistribution in vivo following transplantation or transfusion of these cells, including cell migration and trafficking. New applications of cellular MR imaging will be directed, for instance, towards our understanding of hematopoietic (immune cell trafficking and of novel guided (stem cell-based therapies aimed to be translated to the clinic in the future.

Programmable cellular arrays. Faults testing and correcting in cellular arrays

International Nuclear Information System (INIS)

Cercel, L.

1978-03-01

A review of some recent researches about programmable cellular arrays in computing and digital processing of information systems is presented, and includes both combinational and sequential arrays, with full arbitrary behaviour, or which can realize better implementations of specialized blocks as: arithmetic units, counters, comparators, control systems, memory blocks, etc. Also, the paper presents applications of cellular arrays in microprogramming, in implementing of a specialized computer for matrix operations, in modeling of universal computing systems. The last section deals with problems of fault testing and correcting in cellular arrays. (author)

Quantification of the heterogeneity of prognostic cellular biomarkers in ewing sarcoma using automated image and random survival forest analysis.

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Claudia Bühnemann

Full Text Available Driven by genomic somatic variation, tumour tissues are typically heterogeneous, yet unbiased quantitative methods are rarely used to analyse heterogeneity at the protein level. Motivated by this problem, we developed automated image segmentation of images of multiple biomarkers in Ewing sarcoma to generate distributions of biomarkers between and within tumour cells. We further integrate high dimensional data with patient clinical outcomes utilising random survival forest (RSF machine learning. Using material from cohorts of genetically diagnosed Ewing sarcoma with EWSR1 chromosomal translocations, confocal images of tissue microarrays were segmented with level sets and watershed algorithms. Each cell nucleus and cytoplasm were identified in relation to DAPI and CD99, respectively, and protein biomarkers (e.g. Ki67, pS6, Foxo3a, EGR1, MAPK localised relative to nuclear and cytoplasmic regions of each cell in order to generate image feature distributions. The image distribution features were analysed with RSF in relation to known overall patient survival from three separate cohorts (185 informative cases. Variation in pre-analytical processing resulted in elimination of a high number of non-informative images that had poor DAPI localisation or biomarker preservation (67 cases, 36%. The distribution of image features for biomarkers in the remaining high quality material (118 cases, 104 features per case were analysed by RSF with feature selection, and performance assessed using internal cross-validation, rather than a separate validation cohort. A prognostic classifier for Ewing sarcoma with low cross-validation error rates (0.36 was comprised of multiple features, including the Ki67 proliferative marker and a sub-population of cells with low cytoplasmic/nuclear ratio of CD99. Through elimination of bias, the evaluation of high-dimensionality biomarker distribution within cell populations of a tumour using random forest analysis in quality

Quantification of the heterogeneity of prognostic cellular biomarkers in ewing sarcoma using automated image and random survival forest analysis.

Science.gov (United States)

Bühnemann, Claudia; Li, Simon; Yu, Haiyue; Branford White, Harriet; Schäfer, Karl L; Llombart-Bosch, Antonio; Machado, Isidro; Picci, Piero; Hogendoorn, Pancras C W; Athanasou, Nicholas A; Noble, J Alison; Hassan, A Bassim

2014-01-01

Driven by genomic somatic variation, tumour tissues are typically heterogeneous, yet unbiased quantitative methods are rarely used to analyse heterogeneity at the protein level. Motivated by this problem, we developed automated image segmentation of images of multiple biomarkers in Ewing sarcoma to generate distributions of biomarkers between and within tumour cells. We further integrate high dimensional data with patient clinical outcomes utilising random survival forest (RSF) machine learning. Using material from cohorts of genetically diagnosed Ewing sarcoma with EWSR1 chromosomal translocations, confocal images of tissue microarrays were segmented with level sets and watershed algorithms. Each cell nucleus and cytoplasm were identified in relation to DAPI and CD99, respectively, and protein biomarkers (e.g. Ki67, pS6, Foxo3a, EGR1, MAPK) localised relative to nuclear and cytoplasmic regions of each cell in order to generate image feature distributions. The image distribution features were analysed with RSF in relation to known overall patient survival from three separate cohorts (185 informative cases). Variation in pre-analytical processing resulted in elimination of a high number of non-informative images that had poor DAPI localisation or biomarker preservation (67 cases, 36%). The distribution of image features for biomarkers in the remaining high quality material (118 cases, 104 features per case) were analysed by RSF with feature selection, and performance assessed using internal cross-validation, rather than a separate validation cohort. A prognostic classifier for Ewing sarcoma with low cross-validation error rates (0.36) was comprised of multiple features, including the Ki67 proliferative marker and a sub-population of cells with low cytoplasmic/nuclear ratio of CD99. Through elimination of bias, the evaluation of high-dimensionality biomarker distribution within cell populations of a tumour using random forest analysis in quality controlled tumour

Cellular radiosensitivity of small-cell lung cancer cell lines

International Nuclear Information System (INIS)

Krarup, Marianne; Poulsen, Hans Skovgaard; Spang-Thomsen, Mogens

1997-01-01

Purpose: The objective of this study was to determine the radiobiological characteristics of a panel of small-cell lung cancer (SCLC) cell lines by use of a clonogenic assay. In addition, we tested whether comparable results could be obtained by employing a growth extrapolation method based on the construction of continuous exponential growth curves. Methods and Materials: Fifteen SCLC cell lines were studied, applying a slightly modified clonogenic assay and a growth extrapolation method. A dose-survival curve was obtained for each experiment and used for calculating several survival parameters. The multitarget single hit model was applied to calculate the cellular radiosensitivity (D 0 ), the capacity for sublethal damage repair (D q ), and the extrapolation number (n). Values for α and β were determined from best-fit curves according to the linear-quadratic model and these values were applied to calculate the surviving fraction after 2-Gy irradiation (SF 2 ). Results: In our investigation, the extrapolation method proved to be inappropriate for the study of in vitro cellular radiosensitivity due to lack of reproducibility. The results obtained by the clonogenic assay showed that the cell lines studied were radiobiologically heterogeneous with no discrete features of the examined parameters including the repair capacity. Conclusion: The results indicate that SCLC tumors per se are not generally candidates for hyperfractionated radiotherapy

Overexpression of thyroid hormone beta1 nuclear receptor is associated with an increased proliferation of human hepatoma cells

Energy Technology Data Exchange (ETDEWEB)

Lin, K; Lin, Y; McPhie, P [Chang-Gung College of Medicine and Technology, Graduate Institute of Clinical Medicine, Taoyuan (Taiwan, Province of China); Cheng, S [National Cancer Inst., Bethesda, MD (United States)

1994-12-31

It is evaluated the expression of thyroid hormone nuclear receptors (TRs) and their possible roles in the carcinogenesis of human hepatocarcinoma. The expression of TR{beta}1 and TR{alpha} genes was evaluated at both the mRNA and protein levels. The expression of TR{beta}1 and TR{alpha}1 mRNAs is similar to those found in normal liver. However, the expression of TR isoform proteins depends on the cell-type. The expression of TRaplha1 protein is low in all cell lines examined. However, TR{Beta}1 protein is overexpressed in Mahlavu, SK-Hep-1, and HA22T, moderately expressed in J5, J7, and J328 and is very low HepG2, Hep3B, and PLC/PRF/5 cells. The proliferation of cells in which TR{beta}1 is overexpressed is stimulated by the thyroid hormone, 3,3`,5- triiodo-L-thyronine. These results suggest that TR{beta}1, not TR{alpha}1, is probably involved in the prolifaration of hepatoma cells.

Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy

International Nuclear Information System (INIS)

Bayindir, Petek; Guillerman, Robert Paul; Hicks, M.J.; Chintagumpala, M.M.

2009-01-01

Cellular mesoblastic nephroma has been associated with a more aggressive course than classic mesoblastic nephroma, including local recurrences and metastases. To define the clinicopathologic and imaging features distinguishing cellular from classic mesoblastic nephroma. Retrospective review of clinical charts and imaging studies of ten children with mesoblastic nephroma from 1996 to 2007 at a large children's hospital. In six children the mesoblastic nephroma was pure cellular, in two mixed, and in two classic. The mean ages at diagnosis were 107 days for those with the cellular form, and 32 days for those with the classic form. Hypoechoic or low-attenuation regions representing necrosis or hemorrhage were found in all children with the cellular form and in none of those with the classic form. Hypertension was present in 70% and hypercalcemia in 20% of the children and resolved following nephrectomy. Two cellular tumors encased major abdominal vessels. Local recurrence and metastases occurred within 6 months of tumor resection in two children with the cellular form. Intraspinal extension and intratumoral pseudoaneurysm were seen in one child with the cellular form. The cellular tumors shared histopathologic features with infantile fibrosarcoma (IFS), and RT-PCR testing in two children with the cellular form revealed the t(12;15) ETV6-NTRK3 gene fusion common to IFS. Distinct from the classic form, cellular mesoblastic nephroma is more heterogeneous in appearance on imaging, tends to be larger and present later in infancy, and can exhibit aggressive behavior including vascular encasement and metastasis. Intraspinal extension and intratumoral pseudoaneurysm are previously unreported findings encountered in our cellular mesoblastic nephroma series. The shared histopathology and translocation gene fusion support the concept of cellular mesoblastic nephroma as the renal form of IFS. (orig.)

Wi-Fi Hotspot Auto-Discovery: A Practical & Energy-Aware System for Smart Objects using Cellular Signals

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Nithyananthan Poosamani

2015-08-01

Full Text Available The Internet of Things (IoT paradigm aims to interconnect a variety of heterogeneous Smart Objects (SO using energy-efficient methodologies and standard communication protocols. A majority of consumer devices sold today come equipped with wireless LAN and cellular technology to connect with the world-wide network. To discover Wi-Fi hot spots, there is a need for constant scanning of Wi-Fi radio in these devices and results in significant battery drain. We present PRiSM, a practical system to automatically locate Wi-Fi hotspots while Wi-Fi radio is turned off, by using the statistical characteristics of cellular signals. Cellular signals are received at zero extra cost in mobile devices and hence PRiSM is highly energy-efficient. It is a lightweight client-side only implementation and needs no prior knowledge on floor plans or wireless infrastructure. We implement PRiSM on Android-based devices and show up to 96% of energy savings in Wi-Fi sensing operations which is equivalent to saving up to 16% of total battery capacity, together with an average prediction accuracy of up to 98%.

47 CFR 22.970 - Unacceptable interference to part 90 non-cellular 800 MHz licensees from cellular radiotelephone...

Science.gov (United States)

2010-10-01

...-cellular 800 MHz licensees from cellular radiotelephone or part 90-800 MHz cellular systems. 22.970 Section... MOBILE SERVICES Cellular Radiotelephone Service § 22.970 Unacceptable interference to part 90 non-cellular 800 MHz licensees from cellular radiotelephone or part 90-800 MHz cellular systems. (a) Definition...

[Diagnostic imaging of high-grade astrocytoma: heterogeneity of clinical manifestation, image characteristics, and histopathological findings].

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Okajima, Kaoru; Ohta, Yoshio

2012-10-01

Recent developments in diagnostic radiology, which have enabled accurate differential diagnoses of brain tumors, have been well described in the last three decades. MR and PET imaging can also provide information to predict histological grades and prognoses that might influence treatment strategies. However, high-grade astrocytomas consist of many different subtypes that are associated with different imaging and histological characteristics. Hemorrhage and necrosis results in a variety of imaging features, and infiltrative tumor growth entrapping normal neurons may cause different clinical manifestations. We reviewed patients with high-grade astrocytomas that showed various imaging characteristics, with special emphasis on initial symptoms and histological features. Clinicopathological characteristics of astrocytomas were also compared with other malignant tumors. Neurological deficits were not notable in patients with grade 3-4 astrocytomas when they showed infiltrative tumor growth, while brain metastases with compact cellular proliferation caused more neurological symptoms. Infiltrative tumors did not show any enhancing masses on MR imaging, but these tumors may show intratumor heterogeneity. Seizures were reported to be more frequent in low-grade glioma and in secondary glioblastoma. Tumor heterogeneity was also reported in molecular genetic profile, and investigators identified some subsets of astrocytomas. They investigated IHD1/2 mutation, EGFR amplification, TP53 mutation, Ki-67 index, etc. In summary, high-grade astrocytomas are not homogenous groups of tumors, and this is associated with the heterogeneity of clinical manifestation, image characteristics, and histopathological findings. Molecular studies may explain the tumor heterogeneity in the near future.

NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels.

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Roman H Haefeli

Full Text Available Short-chain quinones are described as potent antioxidants and in the case of idebenone have already been under clinical investigation for the treatment of neuromuscular disorders. Due to their analogy to coenzyme Q10 (CoQ10, a long-chain quinone, they are widely regarded as a substitute for CoQ10. However, apart from their antioxidant function, this provides no clear rationale for their use in disorders with normal CoQ10 levels. Using recombinant NAD(PH:quinone oxidoreductase (NQO enzymes, we observed that contrary to CoQ10 short-chain quinones such as idebenone are good substrates for both NQO1 and NQO2. Furthermore, the reduction of short-chain quinones by NQOs enabled an antimycin A-sensitive transfer of electrons from cytosolic NAD(PH to the mitochondrial respiratory chain in both human hepatoma cells (HepG2 and freshly isolated mouse hepatocytes. Consistent with the substrate selectivity of NQOs, both idebenone and CoQ1, but not CoQ10, partially restored cellular ATP levels under conditions of impaired complex I function. The observed cytosolic-mitochondrial shuttling of idebenone and CoQ1 was also associated with reduced lactate production by cybrid cells from mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS patients. Thus, the observed activities separate the effectiveness of short-chain quinones from the related long-chain CoQ10 and provide the rationale for the use of short-chain quinones such as idebenone for the treatment of mitochondrial disorders.

Developmental heterogeneity in DNA packaging patterns influences T-cell activation and transmigration.

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Soumya Gupta

Full Text Available Cellular differentiation programs are accompanied by large-scale changes in nuclear organization and gene expression. In this context, accompanying transitions in chromatin assembly that facilitates changes in gene expression and cell behavior in a developmental system are poorly understood. Here, we address this gap and map structural changes in chromatin organization during murine T-cell development, to describe an unusual heterogeneity in chromatin organization and associated functional correlates in T-cell lineage. Confocal imaging of DNA assembly in cells isolated from bone marrow, thymus and spleen reveal the emergence of heterogeneous patterns in DNA organization in mature T-cells following their exit from the thymus. The central DNA pattern dominated in immature precursor cells in the thymus whereas both central and peripheral DNA patterns were observed in naïve and memory cells in circulation. Naïve T-cells with central DNA patterns exhibited higher mechanical pliability in response to compressive loads in vitro and transmigration assays in vivo, and demonstrated accelerated expression of activation-induced marker CD69. T-cell activation was characterized by marked redistribution of DNA assembly to a central DNA pattern and increased nuclear size. Notably, heterogeneity in DNA patterns recovered in cells induced into quiescence in culture, suggesting an internal regulatory mechanism for chromatin reorganization. Taken together, our results uncover an important component of plasticity in nuclear organization, reflected in chromatin assembly, during T-cell development, differentiation and transmigration.

47 CFR 22.909 - Cellular markets.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 2 2010-10-01 2010-10-01 false Cellular markets. 22.909 Section 22.909... Cellular Radiotelephone Service § 22.909 Cellular markets. Cellular markets are standard geographic areas used by the FCC for administrative convenience in the licensing of cellular systems. Cellular markets...

Multiscale image analysis reveals structural heterogeneity of the cell microenvironment in homotypic spheroids.

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Schmitz, Alexander; Fischer, Sabine C; Mattheyer, Christian; Pampaloni, Francesco; Stelzer, Ernst H K

2017-03-03

Three-dimensional multicellular aggregates such as spheroids provide reliable in vitro substitutes for tissues. Quantitative characterization of spheroids at the cellular level is fundamental. We present the first pipeline that provides three-dimensional, high-quality images of intact spheroids at cellular resolution and a comprehensive image analysis that completes traditional image segmentation by algorithms from other fields. The pipeline combines light sheet-based fluorescence microscopy of optically cleared spheroids with automated nuclei segmentation (F score: 0.88) and concepts from graph analysis and computational topology. Incorporating cell graphs and alpha shapes provided more than 30 features of individual nuclei, the cellular neighborhood and the spheroid morphology. The application of our pipeline to a set of breast carcinoma spheroids revealed two concentric layers of different cell density for more than 30,000 cells. The thickness of the outer cell layer depends on a spheroid's size and varies between 50% and 75% of its radius. In differently-sized spheroids, we detected patches of different cell densities ranging from 5 × 10 5 to 1 × 10 6  cells/mm 3 . Since cell density affects cell behavior in tissues, structural heterogeneities need to be incorporated into existing models. Our image analysis pipeline provides a multiscale approach to obtain the relevant data for a system-level understanding of tissue architecture.

Heterogeneity in white blood cells has potential to confound DNA methylation measurements.

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Bjorn T Adalsteinsson

Full Text Available Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50-179 and in two white blood cell fractions (n = 20, isolated using density gradient centrifugation, in four CGIs (CpG Islands located in genes HHEX (10 CpG sites assayed, KCNJ11 (8 CpGs, KCNQ1 (4 CpGs and PM20D1 (7 CpGs. Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter explained up to 40% (p<0.0001 of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4-15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.

Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity.

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Albini, Adriana; Bruno, Antonino; Gallo, Cristina; Pajardi, Giorgio; Noonan, Douglas M; Dallaglio, Katiuscia

2015-01-01

Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.

Ginsenoside Rh2 Induces Human Hepatoma Cell Apoptosisvia Bax/Bak Triggered Cytochrome C Release and Caspase-9/Caspase-8 Activation

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Xiao-Xi Guo

2012-11-01

Full Text Available Ginsenoside Rh2 (G-Rh2 has been shown to induce apoptotic cell death in a variety of cancer cells. However, the details of the signal transduction cascade involved in G-Rh2-induced cell death is unclear. In this manuscript we elucidate the molecular mechanism of G-Rh2-induced apoptosis in human hepatoma SK-HEP-1 cells by demonstrating that G-Rh2 causes rapid and dramatic translocation of both Bak and Bax, which subsequently triggers mitochondrial cytochrome c release and consequent caspase activation. Interestingly, siRNA-based gene inactivation of caspase-8 effectively delays caspase-9 activation and apoptosis induced by G-Rh2, indicating that caspase-8 also plays an important role in the G-Rh2-induced apoptosis program. Taken together, our results indicate that G-Rh2 employs a multi pro-apoptotic pathway to execute cancer cell death, suggesting a potential role for G-Rh2 as a powerful chemotherapeutic agent.

Enhancement of esculetin on Taxol-induced apoptosis in human hepatoma HepG2 cells

International Nuclear Information System (INIS)

Kuo, H.-C.; Lee, H.-J.; Hu, C.-C.; Shun, H.-I; Tseng, T.-H.

2006-01-01

The potential use of low dose chemotherapy has been appealing since lower dosages are more attainable during cancer therapy and cause less toxicity in patients. Combination therapy of Taxol, a promising frontline chemotherapy agent, with natural anti-tumor agents that are considerably less toxic with a capability of activating additional apoptotic signals or inhibiting survival signals may provide a rational molecular basis for novel chemotherapeutic strategies. Esculetin, a well-known lipoxygenase inhibitor, showed an inhibitory effect on the cell cycle progression of HL-60 cells in our previous study. In this report, the effects of a concomitant administration of esculetin and Taxol were investigated in human hepatoma HepG2 cells. Firstly, esculetin alone could exert an antiproliferation effect together with an inhibitory effect on the activation of ERKs and p38 MAPK. As compared to the treatment with Taxol only, a co-administration with esculetin and Taxol could result in a further enhancement of apoptosis as revealed by DNA fragmentation assay and Annexin-V-based assay. Meanwhile, immunoblotting analysis also showed that the co-administration of esculetin and Taxol could increase the expression of Bax and the cytosolic release of cytochrome C and enhance the expression of Fas and Fas ligand while the activation of caspase-8 and caspase-3 was also increased. Finally, the ERK cascade was proven to be involved in the enhancement of esculetin on the Taxol-induced apoptosis

Composition of Lycium barbarum polysaccharides and their apoptosis-inducing effect on human hepatoma SMMC-7721 cells

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Qian Zhang

2015-11-01

Full Text Available Background: Lycium barbarum polysaccharide (LBP is a natural functional component that has a variety of biological activities. The molecular structures and apoptosis-inducing activities on human hepatoma SMMC-7721 cells of two LBP fractions, LBP-d and LBP-e, were investigated. Results: The results showed that LBP-d and LBP-e both consist of protein, uronic acid, and neutral sugars in different proportions. The structure of LBP was characterized by gas chromatography, periodate oxidation, and Smith degradation. LBP-d was composed of eight kinds of monosaccharides (fucose, ribose, rhamnose, arabinose, xylose, mannose, galactose, and glucose, while LBP-e was composed of six kinds of monosaccharides (fucose, rhamnose, arabinose, mannose, galactose, and glucose. LBP-d and LBP-e blocked SMMC-7721 cells at the G0/G1 and S phases with an inhibition ratio of 26.70 and 45.13%, respectively, and enhanced the concentration of Ca2 + in the cytoplasm of SMMC-7721. Conclusion: The contents of protein, uronic acid, and galactose in LBP-e were much higher than those in LBP-d, which might responsible for their different bioactivities. The results showed that LBP can be provided as a potential chemotherapeutic agent drug to treat cancer.

A Bio-Inspired QoS-Oriented Handover Model in Heterogeneous Wireless Networks

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Daxin Tian

2014-01-01

Full Text Available We propose a bio-inspired model for making handover decision in heterogeneous wireless networks. It is based on an extended attractor selection model, which is biologically inspired by the self-adaptability and robustness of cellular response to the changes in dynamic environments. The goal of the proposed model is to guarantee multiple terminals’ satisfaction by meeting the QoS requirements of those terminals’ applications, and this model also attempts to ensure the fairness of network resources allocation, in the meanwhile, to enable the QoS-oriented handover decision adaptive to dynamic wireless environments. Some numerical simulations are preformed to validate our proposed bio-inspired model in terms of adaptive attractor selection in different noisy environments. And the results of some other simulations prove that the proposed handover scheme can adapt terminals’ network selection to the varying wireless environment and benefits the QoS of multiple terminal applications simultaneously and automatically. Furthermore, the comparative analysis also shows that the bio-inspired model outperforms the utility function based handover decision scheme in terms of ensuring a better QoS satisfaction and a better fairness of network resources allocation in dynamic heterogeneous wireless networks.

Co-operation of the transcription factor hepatocyte nuclear factor-4 with Sp1 or Sp3 leads to transcriptional activation of the human haem oxygenase-1 gene promoter in a hepatoma cell line.

Science.gov (United States)

Takahashi, Shigeru; Matsuura, Naomi; Kurokawa, Takako; Takahashi, Yuji; Miura, Takashi

2002-11-01

We reported previously that the 5'-flanking region (nucleotides -1976 to -1655) of the human haem oxygenase-1 ( hHO-1 ) gene enhances hHO-1 promoter activity in human hepatoma HepG2 cells, but not in HeLa cells [Takahashi, Takahashi, Ito, Nagano, Shibahara and Miura (1999) Biochim. Biophys. Acta 1447, 231-235]. To define more precisely the regulatory elements involved, in the present study we have functionally dissected this region and localized the enhancer to a 50 bp fragment (-1793 to -1744). Site-direct mutagenesis analysis revealed that two regions were responsible for this enhancer activity, i.e. a hepatocyte nuclear factor-4 (HNF-4) homologous region and a GC box motif homologous region. Mutation in either region alone moderately decreased enhancer activity. However, mutations in both regions reduced promoter activity to the basal level. Electrophoretic mobility-shift assays demonstrated that the P5-2 fragment (-1793 to -1744) interacted with at least two nuclear factors, i.e. HNF-4 and Sp1/Sp3. Co-transfection experiments using Drosophila SL2 cells revealed that HNF-4 and Sp1/Sp3 synergistically stimulated the enhancer activity of the P5-2 fragment. These results indicate that co-operation of HNF-4 with Sp1 or Sp3 leads to the activation of hHO-1 gene expression in hepatoma cells.

Inhibition effects of {sup 125}I-triplex forming oligonucleotide to hepatoma cells

Energy Technology Data Exchange (ETDEWEB)

Zhongwei, Lv; Min, Hou; Haidong, Cai; Xueyu, Yuan; Yuehua, Yang; Shidong, Yuan [Department of Nuclear Medicine, 10th People' s Hospital, Tongji Univ., Shanghai (China); Junmin, He

2007-08-15

Objective: Triplex forming oligonucleotide (TFO) has been reported as a new antigene strategy. The purpose of this study was to observe the inhibition effects of {sup 125}I-TFO on hepatoma cells and to investigate the possibility of using {sup 125}I-TFO as an antigene radiotherapy technique for hepatocellular carcinoma (HCC) related to HBV. Methods: TFO complementary to the initiator of S gene of HBV was synthesized and labeled with {sup 125}I. HepG2.2.15 cells, in which HBV genome was integrated, were incubated with {sup 125}I-TFO, TFO and {sup 125}I respectively. After incubation, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) of each group were assayed with ELISA and the survival rate of cells in each group was determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide (MTT) reduction assay. Results: {sup 125}I-TFO showed a high stability with a radiolabeling rate of >93%. The radiochemical purity of labeled compound was 90.8%, 81.1% and 73.2% respectively after 12, 48 and 72 h at 37 degree C. The peak inhibition effect of {sup 125}I-TFO on synthesizing HBsAg and HBeAg by HepG2.2.15 cells were found at 48 h after transfection, with significantly the highest inhibition rate of 45.2% for HBsAg and 74.5% for HBeAg expression among the three groups(P<0.01 ). As the transfection time prolonged its inhibition effects were stronger. Conclusion: {sup 125}I-TFO may inhibit the antigen expression of HBV and the growth of hepatocarcinoma cells, thus it may provide a new approach to develop gene-based radiotherapeutic pharmaceuticals for anti-HBV and HCC. (authors)

Cellular Interrogation: Exploiting Cell-to-Cell Variability to Discriminate Regulatory Mechanisms in Oscillatory Signalling.

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Estrada, Javier; Andrew, Natalie; Gibson, Daniel; Chang, Frederick; Gnad, Florian; Gunawardena, Jeremy

2016-07-01

The molecular complexity within a cell may be seen as an evolutionary response to the external complexity of the cell's environment. This suggests that the external environment may be harnessed to interrogate the cell's internal molecular architecture. Cells, however, are not only nonlinear and non-stationary, but also exhibit heterogeneous responses within a clonal, isogenic population. In effect, each cell undertakes its own experiment. Here, we develop a method of cellular interrogation using programmable microfluidic devices which exploits the additional information present in cell-to-cell variation, without requiring model parameters to be fitted to data. We focussed on Ca2+ signalling in response to hormone stimulation, which exhibits oscillatory spiking in many cell types and chose eight models of Ca2+ signalling networks which exhibit similar behaviour in simulation. We developed a nonlinear frequency analysis for non-stationary responses, which could classify models into groups under parameter variation, but found that this question alone was unable to distinguish critical feedback loops. We further developed a nonlinear amplitude analysis and found that the combination of both questions ruled out six of the models as inconsistent with the experimentally-observed dynamics and heterogeneity. The two models that survived the double interrogation were mathematically different but schematically identical and yielded the same unexpected predictions that we confirmed experimentally. Further analysis showed that subtle mathematical details can markedly influence non-stationary responses under parameter variation, emphasising the difficulty of finding a "correct" model. By developing questions for the pathway being studied, and designing more versatile microfluidics, cellular interrogation holds promise as a systematic strategy that can complement direct intervention by genetics or pharmacology.

Biomechanics of cellular solids.

Science.gov (United States)

Gibson, Lorna J

2005-03-01

Materials with a cellular structure are widespread in nature and include wood, cork, plant parenchyma and trabecular bone. Natural cellular materials are often mechanically efficient: the honeycomb-like microstructure of wood, for instance, gives it an exceptionally high performance index for resisting bending and buckling. Here we review the mechanics of a wide range of natural cellular materials and examine their role in lightweight natural sandwich structures (e.g. iris leaves) and natural tubular structures (e.g. plant stems or animal quills). We also describe two examples of engineered biomaterials with a cellular structure, designed to replace or regenerate tissue in the body.

Cellular Reflectarray Antenna

Science.gov (United States)

Romanofsky, Robert R.

2010-01-01

The cellular reflectarray antenna is intended to replace conventional parabolic reflectors that must be physically aligned with a particular satellite in geostationary orbit. These arrays are designed for specified geographical locations, defined by latitude and longitude, each called a "cell." A particular cell occupies nominally 1,500 square miles (3,885 sq. km), but this varies according to latitude and longitude. The cellular reflectarray antenna designed for a particular cell is simply positioned to align with magnetic North, and the antenna surface is level (parallel to the ground). A given cellular reflectarray antenna will not operate in any other cell.

Concomitant radiation therapy and doxorubicin by continuous Infusion in advanced malignancies - A phase I-II study - evidence of synergistic effect in Soft tissue sarcomas and hepatomas

International Nuclear Information System (INIS)

Rosenthal, C.J.; Bhutiani, I.; Rotman, M.

1986-01-01

This paper attempts to establish the dose and the duration of administration of doxorubicin infusion having the best therapeutic index and to determine the dose of radiation which in combination with the optimal dose of doxorubicin administered by continuous infusion would have the best therapeutic index. The authors attempt to find the nature and the incidence of side effects of these combined modalities of therapy. The therapeutic effect of the optimal doxorubicin infusion dose in combination with concomitant radiotherapy is assessed in a preliminary study and it was found to have a significant enhancing effect in a few cases of hepatomas and in most of the cases of recurrent and metastatic soft tissue sarcomas

Sub-cellular mRNA localization modulates the regulation of gene expression by small RNAs in bacteria

Science.gov (United States)

Teimouri, Hamid; Korkmazhan, Elgin; Stavans, Joel; Levine, Erel

2017-10-01

Small non-coding RNAs can exert significant regulatory activity on gene expression in bacteria. In recent years, substantial progress has been made in understanding bacterial gene expression by sRNAs. However, recent findings that demonstrate that families of mRNAs show non-trivial sub-cellular distributions raise the question of how localization may affect the regulatory activity of sRNAs. Here we address this question within a simple mathematical model. We show that the non-uniform spatial distributions of mRNA can alter the threshold-linear response that characterizes sRNAs that act stoichiometrically, and modulate the hierarchy among targets co-regulated by the same sRNA. We also identify conditions where the sub-cellular organization of cofactors in the sRNA pathway can induce spatial heterogeneity on sRNA targets. Our results suggest that under certain conditions, interpretation and modeling of natural and synthetic gene regulatory circuits need to take into account the spatial organization of the transcripts of participating genes.

Linearizable cellular automata

International Nuclear Information System (INIS)

Nobe, Atsushi; Yura, Fumitaka

2007-01-01

The initial value problem for a class of reversible elementary cellular automata with periodic boundaries is reduced to an initial-boundary value problem for a class of linear systems on a finite commutative ring Z 2 . Moreover, a family of such linearizable cellular automata is given

Heterogeneous Wireless Networks for Smart Grid Distribution Systems: Advantages and Limitations.

Science.gov (United States)

Khalifa, Tarek; Abdrabou, Atef; Shaban, Khaled; Gaouda, A M

2018-05-11

Supporting a conventional power grid with advanced communication capabilities is a cornerstone to transferring it to a smart grid. A reliable communication infrastructure with a high throughput can lay the foundation towards the ultimate objective of a fully automated power grid with self-healing capabilities. In order to realize this objective, the communication infrastructure of a power distribution network needs to be extended to cover all substations including medium/low voltage ones. This shall enable information exchange among substations for a variety of system automation purposes with a low latency that suits time critical applications. This paper proposes the integration of two heterogeneous wireless technologies (such as WiFi and cellular 3G/4G) to provide reliable and fast communication among primary and secondary distribution substations. This integration allows the transmission of different data packets (not packet replicas) over two radio interfaces, making these interfaces act like a one data pipe. Thus, the paper investigates the applicability and effectiveness of employing heterogeneous wireless networks (HWNs) in achieving the desired reliability and timeliness requirements of future smart grids. We study the performance of HWNs in a realistic scenario under different data transfer loads and packet loss ratios. Our findings reveal that HWNs can be a viable data transfer option for smart grids.

Heterogeneous Wireless Networks for Smart Grid Distribution Systems: Advantages and Limitations

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Tarek Khalifa

2018-05-01

Full Text Available Supporting a conventional power grid with advanced communication capabilities is a cornerstone to transferring it to a smart grid. A reliable communication infrastructure with a high throughput can lay the foundation towards the ultimate objective of a fully automated power grid with self-healing capabilities. In order to realize this objective, the communication infrastructure of a power distribution network needs to be extended to cover all substations including medium/low voltage ones. This shall enable information exchange among substations for a variety of system automation purposes with a low latency that suits time critical applications. This paper proposes the integration of two heterogeneous wireless technologies (such as WiFi and cellular 3G/4G to provide reliable and fast communication among primary and secondary distribution substations. This integration allows the transmission of different data packets (not packet replicas over two radio interfaces, making these interfaces act like a one data pipe. Thus, the paper investigates the applicability and effectiveness of employing heterogeneous wireless networks (HWNs in achieving the desired reliability and timeliness requirements of future smart grids. We study the performance of HWNs in a realistic scenario under different data transfer loads and packet loss ratios. Our findings reveal that HWNs can be a viable data transfer option for smart grids.

Electromagnetic cellular interactions.

Science.gov (United States)

Cifra, Michal; Fields, Jeremy Z; Farhadi, Ashkan

2011-05-01

Chemical and electrical interaction within and between cells is well established. Just the opposite is true about cellular interactions via other physical fields. The most probable candidate for an other form of cellular interaction is the electromagnetic field. We review theories and experiments on how cells can generate and detect electromagnetic fields generally, and if the cell-generated electromagnetic field can mediate cellular interactions. We do not limit here ourselves to specialized electro-excitable cells. Rather we describe physical processes that are of a more general nature and probably present in almost every type of living cell. The spectral range included is broad; from kHz to the visible part of the electromagnetic spectrum. We show that there is a rather large number of theories on how cells can generate and detect electromagnetic fields and discuss experimental evidence on electromagnetic cellular interactions in the modern scientific literature. Although small, it is continuously accumulating. Copyright © 2010 Elsevier Ltd. All rights reserved.

Genetic heterogeneity of retinitis pigmentosa

OpenAIRE

Hartono, Hartono

2015-01-01

Genetic heterogeneity is a phenomenon in which a genetic disease can be transmitted by several modes of inheritance. The understanding of genetic heterogeneity is important in giving genetic counselling.The presence of genetic heterogeneity can be explained by the existence of:1.different mutant alleles at a single locus, and2.mutant alleles at different loci affecting the same enzyme or protein, or affecting different enzymes or proteins.To have an overall understanding of genetic heterogene...

Cellular aging of mitochondrial DNA-depleted cells

International Nuclear Information System (INIS)

Park, Sun Young; Choi, Bongkun; Cheon, Hwanju; Pak, Youngmi Kim; Kulawiec, Mariola; Singh, Keshav K.; Lee, Myung-Shik

2004-01-01

We have reported that mitochondrial DNA-depleted ρ 0 cells are resistant to cell death. Because aged cells have frequent mitochondrial DNA mutations, the resistance of ρ 0 cells against cell death might be related to the apoptosis resistance of aged cells and frequent development of cancers in aged individuals. We studied if ρ 0 cells have features simulating aged cells. SK-Hep1 hepatoma ρ 0 cells showed typical morphology associated with aging such as increased size and elongated appearance. They had increased senescence-associated β-Gal activity, lipofuscin pigment, and plasminogen activator inhibitor-1 expression. Consistent with their decreased proliferation, the expression of mitotic cyclins was decreased and that of cdk inhibitors was increased. Rb hypophosphorylation and decreased telomerase activity were also noted. Features simulating aged cells were also observed in MDA-MB-435 ρ 0 cells. These results support the mitochondrial theory of aging, and suggest that ρ 0 cells could serve as an in vitro model for aged cells

Deciphering dendritic cell heterogenity in immunity

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Michaël eChopin

2012-02-01

Full Text Available Dendritic cells (DCs are specialized antigen presenting cells that are exquisitely adapted to sense pathogens and induce the development of adaptive immune responses. They form a complex network of phenotypically and functionally distinct subsets. Within this network, individual DC subsets display highly specific roles in local immunosurveillance, migration and antigen presentation. This division of labor amongst DCs offers great potential to tune the immune response by harnessing subset-specific attributes of DCs in the clinical setting. Until recently, our understanding of DC subsets has been limited and paralleled by poor clinical translation and efficacy. We have now begun to unravel how different DC subsets develop within a complex multilayered system. These finding open up exciting possibilities for targeted manipulation of DC subsets. Furthermore, ground-breaking developments overcoming a major translational obstacle – identification of similar DC populations in mouse and man – now set the stage for significant advances in the field. Here we explore the determinants that underpin cellular and transcriptional heterogeneity within the DC network, how these influence DC distribution and localization at steady-state, and the capacity of DCs to present antigens via direct or cross-presentation during pathogen infection.

PhysioSpace: relating gene expression experiments from heterogeneous sources using shared physiological processes.

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Michael Lenz

Full Text Available Relating expression signatures from different sources such as cell lines, in vitro cultures from primary cells and biopsy material is an important task in drug development and translational medicine as well as for tracking of cell fate and disease progression. Especially the comparison of large scale gene expression changes to tissue or cell type specific signatures is of high interest for the tracking of cell fate in (trans- differentiation experiments and for cancer research, which increasingly focuses on shared processes and the involvement of the microenvironment. These signature relation approaches require robust statistical methods to account for the high biological heterogeneity in clinical data and must cope with small sample sizes in lab experiments and common patterns of co-expression in ubiquitous cellular processes. We describe a novel method, called PhysioSpace, to position dynamics of time series data derived from cellular differentiation and disease progression in a genome-wide expression space. The PhysioSpace is defined by a compendium of publicly available gene expression signatures representing a large set of biological phenotypes. The mapping of gene expression changes onto the PhysioSpace leads to a robust ranking of physiologically relevant signatures, as rigorously evaluated via sample-label permutations. A spherical transformation of the data improves the performance, leading to stable results even in case of small sample sizes. Using PhysioSpace with clinical cancer datasets reveals that such data exhibits large heterogeneity in the number of significant signature associations. This behavior was closely associated with the classification endpoint and cancer type under consideration, indicating shared biological functionalities in disease associated processes. Even though the time series data of cell line differentiation exhibited responses in larger clusters covering several biologically related patterns, top scoring

Heterogeneous reactors

International Nuclear Information System (INIS)

Moura Neto, C. de; Nair, R.P.K.

1979-08-01

The microscopic study of a cell is meant for the determination of the infinite multiplication factor of the cell, which is given by the four factor formula: K(infinite) = n(epsilon)pf. The analysis of an homogeneous reactor is similar to that of an heterogeneous reactor, but each factor of the four factor formula can not be calculated by the formulas developed in the case of an homogeneous reactor. A great number of methods was developed for the calculation of heterogeneous reactors and some of them are discussed. (Author) [pt

Heterogeneous gas core reactor

International Nuclear Information System (INIS)

Han, K.I.

1977-01-01

Preliminary investigations of a heterogeneous gas core reactor (HGCR) concept suggest that this potential power reactor offers distinct advantages over other existing or conceptual reactor power plants. One of the most favorable features of the HGCR is the flexibility of the power producing system which allows it to be efficiently designed to conform to a desired optimum condition without major conceptual changes. The arrangement of bundles of moderator/coolant channels in a fissionable gas or mixture of gases makes a truly heterogeneous nuclear reactor core. It is this full heterogeneity for a gas-fueled reactor core which accounts for the novelty of the heterogeneous gas core reactor concept and leads to noted significant advantages over previous gas core systems with respect to neutron and fuel economy, power density, and heat transfer characteristics. The purpose of this work is to provide an insight into the design, operating characteristics, and safety of a heterogeneous gas core reactor system. The studies consist mainly of neutronic, energetic and kinetic analyses of the power producing and conversion systems as a preliminary assessment of the heterogeneous gas core reactor concept and basic design. The results of the conducted research indicate a high potential for the heterogeneous gas core reactor system as an electrical power generating unit (either large or small), with an overall efficiency as high as 40 to 45%. The HGCR system is found to be stable and safe, under the conditions imposed upon the analyses conducted in this work, due to the inherent safety of ann expanding gaseous fuel and the intrinsic feedback effects of the gas and water coolant

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

OpenAIRE

Wang, Yi-Cheng; Chen, Yi-Ming; Lin, Yan-Jun; Liu, Shih-Ping; Chiang, En-Pei Isabel

2011-01-01

Glycine N-methyltransferase (GNMT) is a major hepatic enzyme that converts S-adenosylmethionine to S-adenosylhomocysteine while generating sarcosine from glycine, hence it can regulate mediating methyl group availability in mammalian cells. GNMT is also a major hepatic folate binding protein that binds to, and, subsequently, may be inhibited by 5-methyltetrafolate. GNMT is commonly diminished in human hepatoma; yet its role in cellular folate metabolism, in tumorigenesis and antifolate therap...

Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress

OpenAIRE

Mohammad, Mohammad K; Avila, Diana; Zhang, Jingwen; Barve, Shirish; Arteel, Gavin; McClain, Craig; Joshi-Barve, Swati

2012-01-01

Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentration...

Heterogeneity in pineapple fruit quality results from plant heterogeneity at flower induction.

Science.gov (United States)

Fassinou Hotegni, V Nicodème; Lommen, Willemien J M; Agbossou, Euloge K; Struik, Paul C

2014-01-01

Heterogeneity in fruit quality constitutes a major constraint in agri-food chains. In this paper the sources of the heterogeneity in pineapple in the field were studied in four experiments in commercial pineapple fields. The aims were to determine (a) whether differences in pineapple fruit quality among individual fruits are associated with differences in vigor of the individual plants within the crop at the time of artificial flower induction; and (b) whether the side shoots produced by the plant during the generative phase account for the fruit quality heterogeneity. Two pineapple cultivars were considered: cv. Sugarloaf and cv. Smooth Cayenne. Plant vigor at the time of artificial flower induction was measured by three variates: the number of functional leaves, the D-leaf length and their cross product. Fruit quality attributes measured at harvest time included external attributes (weight and height of fruit, infructescence and crown) and internal quality attributes [total soluble solids (TSS), pH, translucent flesh]. Results showed that the heterogeneity in fruit weight was a consequence of the heterogeneity in vigor of the plants at the moment of flower induction; that effect was mainly on the infructescence weight and less or not on the crown weight. The associations between plant vigor variates at flower induction and the internal quality attributes of the fruit were poor and/or not consistent across experiments. The weight of the slips (side shoots) explained part of the heterogeneity in fruit weight, infructescence weight and fruit height in cv. Sugarloaf. Possibilities for reducing the variation in fruit quality by precise cultural practices are discussed.

Heterogeneity in pineapple fruit quality results from plant heterogeneity at flower induction

Directory of Open Access Journals (Sweden)

V. Nicodeme eFassinou Hotegni

2014-12-01

Full Text Available Heterogeneity in fruit quality constitutes a major constraint in agri-food chains. In this paper the sources of the heterogeneity in pineapple in the field were studied in four experiments in commercial pineapple fields. The aims were to determine (a whether differences in pineapple fruit quality among individual fruits are associated with differences in vigor of the individual plants within the crop at the time of artificial flower induction; and (b whether the side shoots produced by the plant during the generative phase account for the fruit quality heterogeneity. Two pineapple cultivars were considered: cv. Sugarloaf and cv. Smooth Cayenne. Plant vigor at the time of artificial flower induction was measured by three variates: the number of functional leaves, the D-leaf length and their cross product. Fruit quality attributes measured at harvest time included external attributes (weight and height of fruit, infructescence and crown and internal quality attributes (total soluble solids, pH, translucent flesh. Results showed that the heterogeneity in fruit weight was a consequence of the heterogeneity in vigor of the plants at the moment of flower induction; that effect was mainly on the infructescence weight and less or not on the crown weight. The association between plant vigor variates at flower induction and the internal quality attributes of the fruit were poor and/or not consistent across experiments. The weight of the slips (side shoots, explained part of the heterogeneity in fruit weight, infructescence weight and fruit height in cv. Sugarloaf. Possibilities for reducing the variation in fruit quality by precise cultural practices are discussed.

Molecular basis of the functional heterogeneity of the muscarinic acetylcholine receptor

International Nuclear Information System (INIS)

Numa, S.; Fukuda, K.; Kubo, T.; Maeda, A.; Akiba, I.; Bujo, H.; Nakai, J.; Mishina, M.; Higashida, H.

1988-01-01

The muscarinic acetylcholine receptor (mAChR) mediates a variety of cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides, and modulation of potassium channels, through the action of guanine-nucleotide-binding regulatory proteins (G proteins). The question then arises as to whether multiple mAChR species exist that are responsible for the various biochemical and physiological effects. In fact, pharmacologically distinguishable forms of the mAChR occur in different tissues and have been provisionally classified into M 1 (I), M 2 cardiac (II), and M 2 glandular (III) subtypes on the basis of their difference in apparent affinity for antagonists. Here, the authors have made attempts to understand the molecular basis of the functional heterogeneity of the mAChR, using recombinant DNA technology

Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation

International Nuclear Information System (INIS)

Honma, Yuichi; Harada, Masaru

2013-01-01

Hepatocellular carcinoma (HCC) is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Recent studies of the molecular mechanisms responsible for tumor initiation and progression have identified several potential molecular targets in HCC. Sorafenib is a multi-kinase inhibitor shown to have survival benefits in advanced HCC. It acts by inhibiting the serine/threonine kinases and the receptor type tyrosine kinases. In preclinical experiments sorafenib had anti-proliferative activity in hepatoma cells and it reduced tumor angiogenesis and increased apoptosis. Here, we demonstrate for the first time that the cytotoxic mechanisms of sorafenib include its inhibitory effects on protein ubiquitination, unfolded protein response (UPR) and keratin phosphorylation in response to endoplasmic reticulum (ER) stress. Moreover, we show that combined treatment with sorafenib and proteasome inhibitors (PIs) synergistically induced a marked increase in cell death in hepatoma- and hepatocyte-derived cells. These observations may open the way to potentially interesting treatment combinations that may augment the effect of sorafenib, possibly including drugs that promote ER stress. Because sorafenib blocked the cellular defense mechanisms against hepatotoxic injury not only in hepatoma cells but also in hepatocyte-derived cells, we must be careful to avoid severe liver injury. -- Graphical abstract: Display Omitted -- Highlights: •We examined the cytotoxic mechanisms of sorafenib in hepatoma cells. •Sorafenib induces cell death via apoptotic and necrotic fashion. •Sorafenib inhibits protein ubiquitination and unfolded protein response. •Autophagy induced by sorafenib may affect its cytotoxicity. •Sorafenib inhibits keratin phosphorylation and cytoplasmic inclusion formation

Regulatory RNPs: a novel class of ribonucleoproteins that potentially contribute to ribosome heterogeneity

Directory of Open Access Journals (Sweden)

Aaron R. Poole

2017-09-01

Full Text Available Many ribonucleoproteins (RNPs, which are comprised of noncoding RNA and associated proteins, are involved in essential cellular processes such as translation and pre-mRNA splicing. One class of RNP is the small Cajal body-specific RNP (scaRNP, which contributes to the biogenesis of small nuclear RNPs (snRNPs that are central components of the spliceosome. Three scaRNAs are internally processed, generating stable nucleolus-enriched RNAs of unknown function. Here, we provide data that show that these RNAs become part of RNPs we term regulatory RNPs (regRNPs. Most modifications within rRNA (predominantly pseudouridylation and ribose 2′-O-methylation are conducted by small nucleolar RNPs (snoRNPs, and we provide evidence that the activity of at least some of these snoRNPs is under the control of regRNPs. Because modifications within rRNA can vary in different physiological or pathological situations, rRNA modifications are thought to be the major source of ribosome heterogeneity. Our identification of regRNPs thus provides a potential mechanism for how ribosome heterogeneity may be accomplished. This work also provides additional functional connections between the Cajal body and the nucleolus.

Cellular Particle Dynamics simulation of biomechanical relaxation processes of multi-cellular systems

Science.gov (United States)

McCune, Matthew; Kosztin, Ioan

2013-03-01

Cellular Particle Dynamics (CPD) is a theoretical-computational-experimental framework for describing and predicting the time evolution of biomechanical relaxation processes of multi-cellular systems, such as fusion, sorting and compression. In CPD, cells are modeled as an ensemble of cellular particles (CPs) that interact via short range contact interactions, characterized by an attractive (adhesive interaction) and a repulsive (excluded volume interaction) component. The time evolution of the spatial conformation of the multicellular system is determined by following the trajectories of all CPs through numerical integration of their equations of motion. Here we present CPD simulation results for the fusion of both spherical and cylindrical multi-cellular aggregates. First, we calibrate the relevant CPD model parameters for a given cell type by comparing the CPD simulation results for the fusion of two spherical aggregates to the corresponding experimental results. Next, CPD simulations are used to predict the time evolution of the fusion of cylindrical aggregates. The latter is relevant for the formation of tubular multi-cellular structures (i.e., primitive blood vessels) created by the novel bioprinting technology. Work supported by NSF [PHY-0957914]. Computer time provided by the University of Missouri Bioinformatics Consortium.

Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity

KAUST Repository

Othman, Basmah A.; Greenwood, Christina; AbuElela, Ayman; Bharath, Anil A.; Chen, Shu; Theodorou, Ioannis; Douglas, Trevor; Uchida, Maskai; Ryan, Mary; Merzaban, Jasmeen; Porter, Alexandra E.

2016-01-01

ZnO nanoparticles (NPs) are reported to show a high degree of cancer cell selectivity with potential use in cancer imaging and therapy. Questions remain about the mode by which the ZnO NPs cause cell death, whether they exert an intra- or extracellular effect, and the resistance among different cancer cell types to ZnO NP exposure. The present study quantifies the variability between the cellular toxicity, dynamics of cellular uptake, and dissolution of bare and RGD (Arg-Gly-Asp)-targeted ZnO NPs by MDA-MB-231 cells. Compared to bare ZnO NPs, RGD-targeting of the ZnO NPs to integrin αvβ3 receptors expressed on MDA-MB-231 cells appears to increase the toxicity of the ZnO NPs to breast cancer cells at lower doses. Confocal microscopy of live MDA-MB-231 cells confirms uptake of both classes of ZnO NPs with a commensurate rise in intracellular Zn2+ concentration prior to cell death. The response of the cells within the population to intracellular Zn2+ is highly heterogeneous. In addition, the results emphasize the utility of dynamic and quantitative imaging in understanding cell uptake and processing of targeted therapeutic ZnO NPs at the cellular level by heterogeneous cancer cell populations, which can be crucial for the development of optimized treatment strategies.

Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity

KAUST Repository

Othman, Basmah A.

2016-04-01

ZnO nanoparticles (NPs) are reported to show a high degree of cancer cell selectivity with potential use in cancer imaging and therapy. Questions remain about the mode by which the ZnO NPs cause cell death, whether they exert an intra- or extracellular effect, and the resistance among different cancer cell types to ZnO NP exposure. The present study quantifies the variability between the cellular toxicity, dynamics of cellular uptake, and dissolution of bare and RGD (Arg-Gly-Asp)-targeted ZnO NPs by MDA-MB-231 cells. Compared to bare ZnO NPs, RGD-targeting of the ZnO NPs to integrin αvβ3 receptors expressed on MDA-MB-231 cells appears to increase the toxicity of the ZnO NPs to breast cancer cells at lower doses. Confocal microscopy of live MDA-MB-231 cells confirms uptake of both classes of ZnO NPs with a commensurate rise in intracellular Zn2+ concentration prior to cell death. The response of the cells within the population to intracellular Zn2+ is highly heterogeneous. In addition, the results emphasize the utility of dynamic and quantitative imaging in understanding cell uptake and processing of targeted therapeutic ZnO NPs at the cellular level by heterogeneous cancer cell populations, which can be crucial for the development of optimized treatment strategies.

Size-mediated cytotoxicity of nanocrystalline titanium dioxide, pure and zinc-doped hydroxyapatite nanoparticles in human hepatoma cells

International Nuclear Information System (INIS)

Devanand Venkatasubbu, G.; Ramasamy, S.; Avadhani, G. S.; Palanikumar, L.; Kumar, J.

2012-01-01

Nanoparticles are highly used in biological applications including nanomedicine. In this present study, the interaction of HepG2 hepatocellular carcinoma cells (HCC) with hydroxyapatite (HAp), zinc-doped hydroxyapatite, and titanium dioxide (TiO 2 ) nanoparticles were investigated. Hydroxyapatite, zinc-doped hydroxyapatite and titanium dioxide nanoparticles were prepared by wet precipitation method. They were subjected to isochronal annealing at different temperatures. Particle morphology and size distribution were characterized by X-ray diffraction and transmission electron microscope. The nanoparticles were co-cultured with HepG2 cells. MTT assay was employed to evaluate the proliferation of tumor cells. The DNA damaging effect of HAp, Zn-doped HAp, and TiO 2 nanoparticles in human hepatoma cells (HepG2) were evaluated using DNA fragmentation studies. The results showed that in HepG2 cells, the anti-tumor activity strongly depend on the size of nanoparticles in HCC cells. Cell cycle arrest analysis for HAp, zinc-doped HAp, and TiO 2 nanoparticles revealed the influence of HAp, zinc-doped HAp, and titanium dioxide nanoparticles on the apoptosis of HepG2 cells. The results imply that the novel nano nature effect plays an important role in the biomedicinal application of nanoparticles.

CD147 stimulates hepatoma cells escaping from immune surveillance of T cells by interaction with Cyclophilin A.

Science.gov (United States)

Ren, Yi-Xin; Wang, Shu-Jing; Fan, Jian-Hui; Sun, Shi-Jie; Li, Xia; Padhiar, Arshad Ahmed; Zhang, Jia-Ning

2016-05-01

T cells play an important role in tumor immune surveillance. CD147 is a member of immunoglobulin superfamily present on the surface of many tumor cells and mediates malignant cell behaviors. Cyclophilin A (CypA) is an intracellular protein promoting inflammation when released from cells. CypA is a natural ligand for CD147. In this study, CD147 specific short hairpin RNAs (shRNA) were transfected into murine hepatocellular carcinoma Hepa1-6 cells to assess the effects of CD147 on hepatoma cells escaping from immune surveillance of T cells. We found extracellular CypA stimulated cell proliferation through CD147 by activating ERK1/2 signaling pathway. Downregulation of CD147 expression on Hepa1-6 cells significantly suppressed tumor progression in vivo, and decreased cell viability when co-cultured with T cells in vitro. Importantly, knockdown of CD147 on Hepa1-6 cells resulted in significantly increased T cells chemotaxis induced by CypA both in vivo and in vitro. These findings provide novel mechanisms how tumor cells escaping from immune surveillance of T cells. We provide a potential therapy for hepatocellular carcinoma by targeting CD147 or CD147-CypA interactions. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Heterogeneity in pineapple fruit quality results from plant heterogeneity at flower induction

NARCIS (Netherlands)

Fassinou Hotegni, V.N.; Lommen, W.J.M.; Agbossou, E.K.; Struik, P.C.

2014-01-01

Heterogeneity in fruit quality constitutes a major constraint in agri-food chains. In this paper the sources of the heterogeneity in pineapple in the field were studied in four experiments in commercial pineapple fields. The aims were to determine (a) whether differences in pineapple fruit quality

T2-weighted images are superior to other MR image types for the determination of diffuse intrinsic pontine glioma intratumoral heterogeneity.

Science.gov (United States)

Harward, Stephen; Harrison Farber, S; Malinzak, Michael; Becher, Oren; Thompson, Eric M

2018-03-01

Diffuse intrinsic pontine glioma (DIPG) remains the main cause of death in children with brain tumors. Given the inefficacy of numerous peripherally delivered agents to treat DIPG, convection enhanced delivery (CED) of therapeutic agents is a promising treatment modality. The purpose of this study was to determine which MR imaging type provides the best discrimination of intratumoral heterogeneity to guide future stereotactic implantation of CED catheters into the most cellular tumor regions. Patients ages 18 years or younger with a diagnosis of DIPG from 2000 to 2015 were included. Radiographic heterogeneity index (HI) of the tumor was calculated by measuring the standard deviation of signal intensity of the tumor (SD Tumor ) normalized to the genu of the corpus callosum (SD Corpus Callosum ). Four MR image types (T2-weighted, contrast-enhanced T1-weighted, FLAIR, and ADC) were analyzed at several time points both before and after radiotherapy and chemotherapy. HI values across these MR image types were compared and correlated with patient survival. MR images from 18 patients with DIPG were evaluated. The mean survival ± standard deviation was 13.8 ± 13.7 months. T2-weighted images had the highest HI (mean ± SD, 5.1 ± 2.5) followed by contrast-enhanced T1-weighted images (3.7 ± 1.5), FLAIR images (3.0 ± 1.1), and ADC maps (1.6 ± 0.4). ANOVA demonstrated that HI values were significantly higher for T2-weighted images than FLAIR (p image HI values increased, while FLAIR and ADC HI values decreased. Univariate and multivariate analyses did not reveal a relationship between HI values and patient survival (p > 0.05). For children with DIPG, T2-weighted MRI demonstrates the greatest signal intensity variance suggesting tumor heterogeneity. Within this heterogeneity, T2-weighted signal hypointensity is known to correlate with increased cellularity and thus may represent a putative target for CED catheter placement in future clinical

Monte-Carlo model development for evaluation of current clinical target volume definition for heterogeneous and hypoxic glioblastoma.

Science.gov (United States)

Moghaddasi, L; Bezak, E; Harriss-Phillips, W

2016-05-07

Clinical target volume (CTV) determination may be complex and subjective. In this work a microscopic-scale tumour model was developed to evaluate current CTV practices in glioblastoma multiforme (GBM) external radiotherapy. Previously, a Geant4 cell-based dosimetry model was developed to calculate the dose deposited in individual GBM cells. Microscopic extension probability (MEP) models were then developed using Matlab-2012a. The results of the cell-based dosimetry model and MEP models were combined to calculate survival fractions (SF) for CTV margins of 2.0 and 2.5 cm. In the current work, oxygenation and heterogeneous radiosensitivity profiles were incorporated into the GBM model. The genetic heterogeneity was modelled using a range of α/β values (linear-quadratic model parameters) associated with different GBM cell lines. These values were distributed among the cells randomly, taken from a Gaussian-weighted sample of α/β values. Cellular oxygen pressure was distributed randomly taken from a sample weighted to profiles obtained from literature. Three types of GBM models were analysed: homogeneous-normoxic, heterogeneous-normoxic, and heterogeneous-hypoxic. The SF in different regions of the tumour model and the effect of the CTV margin extension from 2.0-2.5 cm on SFs were investigated for three MEP models. The SF within the beam was increased by up to three and two orders of magnitude following incorporation of heterogeneous radiosensitivities and hypoxia, respectively, in the GBM model. However, the total SF was shown to be overdominated by the presence of tumour cells in the penumbra region and to a lesser extent by genetic heterogeneity and hypoxia. CTV extension by 0.5 cm reduced the SF by a maximum of 78.6  ±  3.3%, 78.5  ±  3.3%, and 77.7  ±  3.1% for homogeneous and heterogeneous-normoxic, and heterogeneous hypoxic GBMs, respectively. Monte-Carlo model was developed to quantitatively evaluate SF for genetically

Resource Management for Device-to-Device Communications in Heterogeneous Networks Using Stackelberg Game

Directory of Open Access Journals (Sweden)

Yinuo He

2014-01-01

Full Text Available Device-to-device (D2D communications and femtocell systems can bring significant benefits to users’ throughput. However, the complicated three-tier interference among macrocell, femtocell, and D2D systems is a challenging issue in heterogeneous networks. As D2D user equipment (UE can cause interference to cellular UE, scheduling and allocation of channel resources and power of D2D communication need elaborate coordination. In this paper, we propose a joint scheduling and resource allocation scheme to improve the performance of D2D communication. We take UE rate and UE fairness into account by performing interference management. First, we construct a Stackelberg game framework in which we group a macrocellular UE, a femtocellular UE, and a D2D UE to form a two-leader one-follower pair. The cellular UE are leaders, and D2D UE is the follower who buys channel resources from the leaders. We analyze the equilibrium of the game and obtain solutions to the equilibrium. Second, we propose an algorithm for joint scheduling of D2D pairs based on their utility. Finally, we perform computer simulations to study the performance of the proposed scheme.

Dynamic behavior of cellular materials and cellular structures: Experiments and modeling

Science.gov (United States)

Gao, Ziyang

Cellular solids, including cellular materials and cellular structures (CMS), have attracted people's great interests because of their low densities and novel physical, mechanical, thermal, electrical and acoustic properties. They offer potential for lightweight structures, energy absorption, thermal management, etc. Therefore, the studies of cellular solids have become one of the hottest research fields nowadays. From energy absorption point of view, any plastically deformed structures can be divided into two types (called type I and type II), and the basic cells of the CMS may take the configurations of these two types of structures. Accordingly, separated discussions are presented in this thesis. First, a modified 1-D model is proposed and numerically solved for a typical type II structure. Good agreement is achieved with the previous experimental data, hence is used to simulate the dynamic behavior of a type II chain. Resulted from different load speeds, interesting collapse modes are observed, and the parameters which govern the cell's post-collapse behavior are identified through a comprehensive non-dimensional analysis on general cellular chains. Secondly, the MHS specimens are chosen as an example of type I foam materials because of their good uniformity of the cell geometry. An extensive experimental study was carried out, where more attention was paid to their responses to dynamic loadings. Great enhancement of the stress-strain curve was observed in dynamic cases, and the energy absorption capacity is found to be several times higher than that of the commercial metal foams. Based on the experimental study, finite elemental simulations and theoretical modeling are also conducted, achieving good agreements and demonstrating the validities of those models. It is believed that the experimental, numerical and analytical results obtained in the present study will certainly deepen the understanding of the unsolved fundamental issues on the mechanical behavior of

Heterogeneity effects in neutron transport computations

International Nuclear Information System (INIS)

Gelbard, E.M.

1975-01-01

A nuclear reactor is, generally, an intricate heterogeneous structure whose adjacent components may differ radically in their neutronic properties. The heterogeneities in the structure of the reactor complicate the work of the reactor analyst and tend to degrade the efficiency of the numerical methods used in reactor computations. Two types of heterogeneity effects are considered. First, certain singularities in the solution of the neutron transport equation, induced by heterogeneities, are briefly described. Second, the effect of heterogeneities on neutron leakage rates, and consequently on effective diffusion coefficients, are discussed. (5 figures) (U.S.)

Statistical mechanics of cellular automata

International Nuclear Information System (INIS)

Wolfram, S.

1983-01-01

Cellular automata are used as simple mathematical models to investigate self-organization in statistical mechanics. A detailed analysis is given of ''elementary'' cellular automata consisting of a sequence of sites with values 0 or 1 on a line, with each site evolving deterministically in discrete time steps according to p definite rules involving the values of its nearest neighbors. With simple initial configurations, the cellular automata either tend to homogeneous states, or generate self-similar patterns with fractal dimensions approx. =1.59 or approx. =1.69. With ''random'' initial configurations, the irreversible character of the cellular automaton evolution leads to several self-organization phenomena. Statistical properties of the structures generated are found to lie in two universality classes, independent of the details of the initial state or the cellular automaton rules. More complicated cellular automata are briefly considered, and connections with dynamical systems theory and the formal theory of computation are discussed

Wireless Cellular Mobile Communications

OpenAIRE

Zalud, V.

2002-01-01

In this article is briefly reviewed the history of wireless cellular mobile communications, examined the progress in current second generation (2G) cellular standards and discussed their migration to the third generation (3G). The European 2G cellular standard GSM and its evolution phases GPRS and EDGE are described somewhat in detail. The third generation standard UMTS taking up on GSM/GPRS core network and equipped with a new advanced access network on the basis of code division multiple ac...

Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma.

Science.gov (United States)

Inda, Maria-del-Mar; Bonavia, Rudy; Mukasa, Akitake; Narita, Yoshitaka; Sah, Dinah W Y; Vandenberg, Scott; Brennan, Cameron; Johns, Terrance G; Bachoo, Robert; Hadwiger, Philipp; Tan, Pamela; Depinho, Ronald A; Cavenee, Webster; Furnari, Frank

2010-08-15

Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically

The hyper-radiosensitivity effect of human hepatoma SMMC-7721 cells exposed to low dose γ-rays and 12C ions

International Nuclear Information System (INIS)

Jin Xiaodong; Li Qiang; Li Wenjian; Wang Jufang; Guo Chuanling; Hao Jifang

2006-01-01

Hypersensitive response of mammalian cells in cell killing to X- and γ-rays has been reported at doses below 1 Gy. The purpose of this study was to examine the low dose sensitivity of human hepatoma SMMC-7721 cells irradiated with 6 Co γ-rays and 50 MeV/u 12 C ions. Experiments using γ-rays and charged particle irradiation were performed, particularly in the low dose range from 0 to 2 Gy. The survival effect of SMMC-7721 cells was measured by means of standard clonogenic assay in conjunction with a cell sorter. The result indicates SMMC-7721 cells showed hyper-radiosensitive response at low doses and increased radio-resistance at larger single doses for the carbon ions (LET = 45.2 keV/μm) and the γ-rays. However, the HRS/IRR effect caused by high-LET irradiation is different from that by low-LET radiation. This might possibly be due to the difference in the mode of energy deposition by particle beam and low-LET irradiation

MSAT and cellular hybrid networking

Science.gov (United States)

Baranowsky, Patrick W., II

Westinghouse Electric Corporation is developing both the Communications Ground Segment and the Series 1000 Mobile Phone for American Mobile Satellite Corporation's (AMSC's) Mobile Satellite (MSAT) system. The success of the voice services portion of this system depends, to some extent, upon the interoperability of the cellular network and the satellite communication circuit switched communication channels. This paper will describe the set of user-selectable cellular interoperable modes (cellular first/satellite second, etc.) provided by the Mobile Phone and described how they are implemented with the ground segment. Topics including roaming registration and cellular-to-satellite 'seamless' call handoff will be discussed, along with the relevant Interim Standard IS-41 Revision B Cellular Radiotelecommunications Intersystem Operations and IOS-553 Mobile Station - Land Station Compatibility Specification.

Cell surface profiling using high-throughput flow cytometry: a platform for biomarker discovery and analysis of cellular heterogeneity.

Directory of Open Access Journals (Sweden)

Craig A Gedye

Full Text Available Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell

Cell surface profiling using high-throughput flow cytometry: a platform for biomarker discovery and analysis of cellular heterogeneity.

Science.gov (United States)

Gedye, Craig A; Hussain, Ali; Paterson, Joshua; Smrke, Alannah; Saini, Harleen; Sirskyj, Danylo; Pereira, Keira; Lobo, Nazleen; Stewart, Jocelyn; Go, Christopher; Ho, Jenny; Medrano, Mauricio; Hyatt, Elzbieta; Yuan, Julie; Lauriault, Stevan; Meyer, Mona; Kondratyev, Maria; van den Beucken, Twan; Jewett, Michael; Dirks, Peter; Guidos, Cynthia J; Danska, Jayne; Wang, Jean; Wouters, Bradly; Neel, Benjamin; Rottapel, Robert; Ailles, Laurie E

2014-01-01

Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC) platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell markers.

Patterned biofilm formation reveals a mechanism for structural heterogeneity in bacterial biofilms.

Science.gov (United States)

Gu, Huan; Hou, Shuyu; Yongyat, Chanokpon; De Tore, Suzanne; Ren, Dacheng

2013-09-03

Bacterial biofilms are ubiquitous and are the major cause of chronic infections in humans and persistent biofouling in industry. Despite the significance of bacterial biofilms, the mechanism of biofilm formation and associated drug tolerance is still not fully understood. A major challenge in biofilm research is the intrinsic heterogeneity in the biofilm structure, which leads to temporal and spatial variation in cell density and gene expression. To understand and control such structural heterogeneity, surfaces with patterned functional alkanthiols were used in this study to obtain Escherichia coli cell clusters with systematically varied cluster size and distance between clusters. The results from quantitative imaging analysis revealed an interesting phenomenon in which multicellular connections can be formed between cell clusters depending on the size of interacting clusters and the distance between them. In addition, significant differences in patterned biofilm formation were observed between wild-type E. coli RP437 and some of its isogenic mutants, indicating that certain cellular and genetic factors are involved in interactions among cell clusters. In particular, autoinducer-2-mediated quorum sensing was found to be important. Collectively, these results provide missing information that links cell-to-cell signaling and interaction among cell clusters to the structural organization of bacterial biofilms.

Applications of Gene Editing Technologies to Cellular Therapies.

Science.gov (United States)

Rein, Lindsay A M; Yang, Haeyoon; Chao, Nelson J

2018-03-27

Hematologic malignancies are characterized by genetic heterogeneity, making classic gene therapy with a goal of correcting 1 genetic defect ineffective in many of these diseases. Despite initial tribulations, gene therapy, as a field, has grown by leaps and bounds with the recent development of gene editing techniques including zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeat (CRISPR) sequences and CRISPR-associated protein-9 (Cas9) nuclease or CRISPR/Cas9. These novel technologies have been applied to efficiently and specifically modify genetic information in target and effector cells. In particular, CRISPR/Cas9 technology has been applied to various hematologic malignancies and has also been used to modify and improve chimeric antigen receptor-modified T cells for the purpose of providing effective cellular therapies. Although gene editing is in its infancy in malignant hematologic diseases, there is much room for growth and application in the future. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Mechanical characterization of disordered and anisotropic cellular monolayers

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Nestor-Bergmann, Alexander; Johns, Emma; Woolner, Sarah; Jensen, Oliver E.

2018-05-01

We consider a cellular monolayer, described using a vertex-based model, for which cells form a spatially disordered array of convex polygons that tile the plane. Equilibrium cell configurations are assumed to minimize a global energy defined in terms of cell areas and perimeters; energy is dissipated via dynamic area and length changes, as well as cell neighbor exchanges. The model captures our observations of an epithelium from a Xenopus embryo showing that uniaxial stretching induces spatial ordering, with cells under net tension (compression) tending to align with (against) the direction of stretch, but with the stress remaining heterogeneous at the single-cell level. We use the vertex model to derive the linearized relation between tissue-level stress, strain, and strain rate about a deformed base state, which can be used to characterize the tissue's anisotropic mechanical properties; expressions for viscoelastic tissue moduli are given as direct sums over cells. When the base state is isotropic, the model predicts that tissue properties can be tuned to a regime with high elastic shear resistance but low resistance to area changes, or vice versa.

HETEROGENEOUS INTEGRATION TECHNOLOGY

Science.gov (United States)

2017-08-24

AFRL-RY-WP-TR-2017-0168 HETEROGENEOUS INTEGRATION TECHNOLOGY Dr. Burhan Bayraktaroglu Devices for Sensing Branch Aerospace Components & Subsystems...Final September 1, 2016 – May 1, 2017 4. TITLE AND SUBTITLE HETEROGENEOUS INTEGRATION TECHNOLOGY 5a. CONTRACT NUMBER In-house 5b. GRANT NUMBER N/A...provide a structure for this review. The history and the current status of integration technologies in each category are examined and product examples are

Search efficiency of biased migration towards stationary or moving targets in heterogeneously structured environments

Science.gov (United States)

Azimzade, Youness; Mashaghi, Alireza

2017-12-01

Efficient search acts as a strong selective force in biological systems ranging from cellular populations to predator-prey systems. The search processes commonly involve finding a stationary or mobile target within a heterogeneously structured environment where obstacles limit migration. An open generic question is whether random or directionally biased motions or a combination of both provide an optimal search efficiency and how that depends on the motility and density of targets and obstacles. To address this question, we develop a simple model that involves a random walker searching for its targets in a heterogeneous medium of bond percolation square lattice and used mean first passage time (〈T 〉 ) as an indication of average search time. Our analysis reveals a dual effect of directional bias on the minimum value of 〈T 〉 . For a homogeneous medium, directionality always decreases 〈T 〉 and a pure directional migration (a ballistic motion) serves as the optimized strategy, while for a heterogeneous environment, we find that the optimized strategy involves a combination of directed and random migrations. The relative contribution of these modes is determined by the density of obstacles and motility of targets. Existence of randomness and motility of targets add to the efficiency of search. Our study reveals generic and simple rules that govern search efficiency. Our findings might find application in a number of areas including immunology, cell biology, ecology, and robotics.

Partial differential equations for self-organization in cellular and developmental biology

International Nuclear Information System (INIS)

Baker, R E; Gaffney, E A; Maini, P K

2008-01-01

Understanding the mechanisms governing and regulating the emergence of structure and heterogeneity within cellular systems, such as the developing embryo, represents a multiscale challenge typifying current integrative biology research, namely, explaining the macroscale behaviour of a system from microscale dynamics. This review will focus upon modelling how cell-based dynamics orchestrate the emergence of higher level structure. After surveying representative biological examples and the models used to describe them, we will assess how developments at the scale of molecular biology have impacted on current theoretical frameworks, and the new modelling opportunities that are emerging as a result. We shall restrict our survey of mathematical approaches to partial differential equations and the tools required for their analysis. We will discuss the gap between the modelling abstraction and biological reality, the challenges this presents and highlight some open problems in the field. (invited article)

Stochastic cellular automata model of cell migration, proliferation and differentiation: validation with in vitro cultures of muscle satellite cells.

Science.gov (United States)

Garijo, N; Manzano, R; Osta, R; Perez, M A

2012-12-07

Cell migration and proliferation has been modelled in the literature as a process similar to diffusion. However, using diffusion models to simulate the proliferation and migration of cells tends to create a homogeneous distribution in the cell density that does not correlate to empirical observations. In fact, the mechanism of cell dispersal is not diffusion. Cells disperse by crawling or proliferation, or are transported in a moving fluid. The use of cellular automata, particle models or cell-based models can overcome this limitation. This paper presents a stochastic cellular automata model to simulate the proliferation, migration and differentiation of cells. These processes are considered as completely stochastic as well as discrete. The model developed was applied to predict the behaviour of in vitro cell cultures performed with adult muscle satellite cells. Moreover, non homogeneous distribution of cells has been observed inside the culture well and, using the above mentioned stochastic cellular automata model, we have been able to predict this heterogeneous cell distribution and compute accurate quantitative results. Differentiation was also incorporated into the computational simulation. The results predicted the myotube formation that typically occurs with adult muscle satellite cells. In conclusion, we have shown how a stochastic cellular automata model can be implemented and is capable of reproducing the in vitro behaviour of adult muscle satellite cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

Top-down cellular pyramids

Energy Technology Data Exchange (ETDEWEB)

Wu, A Y; Rosenfeld, A

1983-10-01

A cellular pyramid is an exponentially tapering stack of arrays of processors (cells), where each cell is connected to its neighbors (siblings) on its own level, to a parent on the level above, and to its children on the level below. It is shown that in some situations, if information flows top-down only, from fathers to sons, then a cellular pyramid may be no faster than a one-level cellular array; but it may be possible to use simpler cells in the pyramid case. 23 references.

Cellular decomposition in vikalloys

International Nuclear Information System (INIS)

Belyatskaya, I.S.; Vintajkin, E.Z.; Georgieva, I.Ya.; Golikov, V.A.; Udovenko, V.A.

1981-01-01

Austenite decomposition in Fe-Co-V and Fe-Co-V-Ni alloys at 475-600 deg C is investigated. The cellular decomposition in ternary alloys results in the formation of bcc (ordered) and fcc structures, and in quaternary alloys - bcc (ordered) and 12R structures. The cellular 12R structure results from the emergence of stacking faults in the fcc lattice with irregular spacing in four layers. The cellular decomposition results in a high-dispersion structure and magnetic properties approaching the level of well-known vikalloys [ru

Global Detection of Live Virtual Machine Migration Based on Cellular Neural Networks

Directory of Open Access Journals (Sweden)

Kang Xie

2014-01-01

Full Text Available In order to meet the demands of operation monitoring of large scale, autoscaling, and heterogeneous virtual resources in the existing cloud computing, a new method of live virtual machine (VM migration detection algorithm based on the cellular neural networks (CNNs, is presented. Through analyzing the detection process, the parameter relationship of CNN is mapped as an optimization problem, in which improved particle swarm optimization algorithm based on bubble sort is used to solve the problem. Experimental results demonstrate that the proposed method can display the VM migration processing intuitively. Compared with the best fit heuristic algorithm, this approach reduces the processing time, and emerging evidence has indicated that this new approach is affordable to parallelism and analog very large scale integration (VLSI implementation allowing the VM migration detection to be performed better.

Global detection of live virtual machine migration based on cellular neural networks.

Science.gov (United States)

Xie, Kang; Yang, Yixian; Zhang, Ling; Jing, Maohua; Xin, Yang; Li, Zhongxian

2014-01-01

In order to meet the demands of operation monitoring of large scale, autoscaling, and heterogeneous virtual resources in the existing cloud computing, a new method of live virtual machine (VM) migration detection algorithm based on the cellular neural networks (CNNs), is presented. Through analyzing the detection process, the parameter relationship of CNN is mapped as an optimization problem, in which improved particle swarm optimization algorithm based on bubble sort is used to solve the problem. Experimental results demonstrate that the proposed method can display the VM migration processing intuitively. Compared with the best fit heuristic algorithm, this approach reduces the processing time, and emerging evidence has indicated that this new approach is affordable to parallelism and analog very large scale integration (VLSI) implementation allowing the VM migration detection to be performed better.

A Reinforcement Sensor Embedded Vertical Handoff Controller for Vehicular Heterogeneous Wireless Networks

Directory of Open Access Journals (Sweden)

Lin Ma

2013-11-01

Full Text Available Vehicular communication platforms that provide real-time access to wireless networks have drawn more and more attention in recent years. IEEE 802.11p is the main radio access technology that supports communication for high mobility terminals, however, due to its limited coverage, IEEE 802.11p is usually deployed by coupling with cellular networks to achieve seamless mobility. In a heterogeneous cellular/802.11p network, vehicular communication is characterized by its short time span in association with a wireless local area network (WLAN. Moreover, for the media access control (MAC scheme used for WLAN, the network throughput dramatically decreases with increasing user quantity. In response to these compelling problems, we propose a reinforcement sensor (RFS embedded vertical handoff control strategy to support mobility management. The RFS has online learning capability and can provide optimal handoff decisions in an adaptive fashion without prior knowledge. The algorithm integrates considerations including vehicular mobility, traffic load, handoff latency, and network status. Simulation results verify that the proposed algorithm can adaptively adjust the handoff strategy, allowing users to stay connected to the best network. Furthermore, the algorithm can ensure that RSUs are adequate, thereby guaranteeing a high quality user experience.

in Heterogeneous Media

Directory of Open Access Journals (Sweden)

Saeed Balouchi

2013-01-01

Full Text Available Fractured reservoirs contain about 85 and 90 percent of oil and gas resources respectively in Iran. A comprehensive study and investigation of fractures as the main factor affecting fluid flow or perhaps barrier seems necessary for reservoir development studies. High degrees of heterogeneity and sparseness of data have incapacitated conventional deterministic methods in fracture network modeling. Recently, simulated annealing (SA has been applied to generate stochastic realizations of spatially correlated fracture networks by assuming that the elastic energy of fractures follows Boltzmann distribution. Although SA honors local variability, the objective function of geometrical fracture modeling is defined for homogeneous conditions. In this study, after the introduction of SA and the derivation of the energy function, a novel technique is presented to adjust the model with highly heterogeneous data for a fractured field from the southwest of Iran. To this end, the regular object-based model is combined with a grid-based technique to cover the heterogeneity of reservoir properties. The original SA algorithm is also modified by being constrained in different directions and weighting the energy function to make it appropriate for heterogeneous conditions. The simulation results of the presented approach are in good agreement with the observed field data.

Optimal Control of Heterogeneous Systems with Endogenous Domain of Heterogeneity

International Nuclear Information System (INIS)

Belyakov, Anton O.; Tsachev, Tsvetomir; Veliov, Vladimir M.

2011-01-01

The paper deals with optimal control of heterogeneous systems, that is, families of controlled ODEs parameterized by a parameter running over a domain called domain of heterogeneity. The main novelty in the paper is that the domain of heterogeneity is endogenous: it may depend on the control and on the state of the system. This extension is crucial for several economic applications and turns out to rise interesting mathematical problems. A necessary optimality condition is derived, where one of the adjoint variables satisfies a differential inclusion (instead of equation) and the maximization of the Hamiltonian takes the form of “min-max”. As a consequence, a Pontryagin-type maximum principle is obtained under certain regularity conditions for the optimal control. A formula for the derivative of the objective function with respect to the control from L ∞ is presented together with a sufficient condition for its existence. A stylized economic example is investigated analytically and numerically.

Bird diversity and environmental heterogeneity in North America: A test of the area-heterogeneity trade-off

Science.gov (United States)

Rachel Chocron; Curtis H. Flather; Ronen Kadmon

2015-01-01

Aim: Deterministic niche theory predicts that increasing environmental heterogeneity increases species richness. In contrast, a recent stochastic model suggests that heterogeneity has a unimodal effect on species richness since high levels of heterogeneity reduce the effective area available per species, thereby increasing the likelihood of stochastic...

The circadian rhythm induced by the heterogeneous network structure of the suprachiasmatic nucleus

Science.gov (United States)

Gu, Changgui; Yang, Huijie

2016-05-01

In mammals, the master clock is located in the suprachiasmatic nucleus (SCN), which is composed of about 20 000 nonidentical neuronal oscillators expressing different intrinsic periods. These neurons are coupled through neurotransmitters to form a network consisting of two subgroups, i.e., a ventrolateral (VL) subgroup and a dorsomedial (DM) subgroup. The VL contains about 25% SCN neurons that receive photic input from the retina, and the DM comprises the remaining 75% SCN neurons which are coupled to the VL. The synapses from the VL to the DM are evidently denser than that from the DM to the VL, in which the VL dominates the DM. Therefore, the SCN is a heterogeneous network where the neurons of the VL are linked with a large number of SCN neurons. In the present study, we mimicked the SCN network based on Goodwin model considering four types of networks including an all-to-all network, a Newman-Watts (NW) small world network, an Erdös-Rényi (ER) random network, and a Barabási-Albert (BA) scale free network. We found that the circadian rhythm was induced in the BA, ER, and NW networks, while the circadian rhythm was absent in the all-to-all network with weak cellular coupling, where the amplitude of the circadian rhythm is largest in the BA network which is most heterogeneous in the network structure. Our finding provides an alternative explanation for the induction or enhancement of circadian rhythm by the heterogeneity of the network structure.

Stochastic multi-scale analysis of homogenised properties considering uncertainties in cellular solid microstructures using a first-order perturbation

Directory of Open Access Journals (Sweden)

Khairul Salleh Basaruddin

Full Text Available Randomness in the microstructure due to variations in microscopic properties and geometrical information is used to predict the stochastically homogenised properties of cellular media. Two stochastic problems at the micro-scale level that commonly occur due to fabrication inaccuracies, degradation mechanisms or natural heterogeneity were analysed using a stochastic homogenisation method based on a first-order perturbation. First, the influence of Young's modulus variation in an adhesive on the macroscopic properties of an aluminium-adhesive honeycomb structure was investigated. The fluctuations in the microscopic properties were then combined by varying the microstructure periodicity in a corrugated-core sandwich plate to obtain the variation of the homogenised property. The numerical results show that the uncertainties in the microstructure affect the dispersion of the homogenised property. These results indicate the importance of the presented stochastic multi-scale analysis for the design and fabrication of cellular solids when considering microscopic random variation.

Quantifying spatial heterogeneity from images

International Nuclear Information System (INIS)

Pomerantz, Andrew E; Song Yiqiao

2008-01-01

Visualization techniques are extremely useful for characterizing natural materials with complex spatial structure. Although many powerful imaging modalities exist, simple display of the images often does not convey the underlying spatial structure. Instead, quantitative image analysis can extract the most important features of the imaged object in a manner that is easier to comprehend and to compare from sample to sample. This paper describes the formulation of the heterogeneity spectrum to show the extent of spatial heterogeneity as a function of length scale for all length scales to which a particular measurement is sensitive. This technique is especially relevant for describing materials that simultaneously present spatial heterogeneity at multiple length scales. In this paper, the heterogeneity spectrum is applied for the first time to images from optical microscopy. The spectrum is measured for thin section images of complex carbonate rock cores showing heterogeneity at several length scales in the range 10-10 000 μm.

Energy Efficient Resource Allocation for Phantom Cellular Networks

KAUST Repository

Abdelhady, Amr

2016-04-01

Multi-tier heterogeneous networks have become an essential constituent for next generation cellular networks. Meanwhile, energy efficiency (EE) has been considered a critical design criterion along with the traditional spectral efficiency (SE) metric. In this context, we study power and spectrum allocation for the recently proposed two-tier network architecture known as phantom cellular networks. The optimization framework includes both EE and SE. First, we consider sparsely deployed cells experiencing negligible interference and assume perfect channel state information (CSI). For this setting, we propose an algorithm that finds the SE and EE resource allocation strategies. Then, we compare the performance of both design strategies versus number of users, and phantom cells share of the total available resource units (RUs). We aim to investigate the effect of some system parameters to achieve improved SE performance at a non-significant loss in EE performance, or vice versa. It is found that increasing phantom cells share of RUs decreases the SE performance loss due to EE optimization when compared with the optimized SE performance. Second, we consider the densely deployed phantom cellular networks and model the EE optimization problem having into consideration the inevitable interference and imperfect channel estimation. To this end, we propose three resource allocation strategies aiming at optimizing the EE performance metric of this network. Furthermore, we investigate the effect of changing some of the system parameters on the performance of the proposed strategies, such as phantom cells share of RUs, number of deployed phantom cells within a macro cell coverage, number of pilots and the maximum power available for transmission by the phantom cells BSs. It is found that increasing the number of pilots deteriorates the EE performance of the whole setup, while increasing maximum power available for phantom cells transmissions reduces the EE of the whole setup in a

Cellular automata analysis and applications

CERN Document Server

Hadeler, Karl-Peter

2017-01-01

This book focuses on a coherent representation of the main approaches to analyze the dynamics of cellular automata. Cellular automata are an inevitable tool in mathematical modeling. In contrast to classical modeling approaches as partial differential equations, cellular automata are straightforward to simulate but hard to analyze. In this book we present a review of approaches and theories that allow the reader to understand the behavior of cellular automata beyond simulations. The first part consists of an introduction of cellular automata on Cayley graphs, and their characterization via the fundamental Cutis-Hedlund-Lyndon theorems in the context of different topological concepts (Cantor, Besicovitch and Weyl topology). The second part focuses on classification results: What classification follows from topological concepts (Hurley classification), Lyapunov stability (Gilman classification), and the theory of formal languages and grammars (Kůrka classification). These classifications suggest to cluster cel...

Interconnecting heterogeneous database management systems

Science.gov (United States)

Gligor, V. D.; Luckenbaugh, G. L.

1984-01-01

It is pointed out that there is still a great need for the development of improved communication between remote, heterogeneous database management systems (DBMS). Problems regarding the effective communication between distributed DBMSs are primarily related to significant differences between local data managers, local data models and representations, and local transaction managers. A system of interconnected DBMSs which exhibit such differences is called a network of distributed, heterogeneous DBMSs. In order to achieve effective interconnection of remote, heterogeneous DBMSs, the users must have uniform, integrated access to the different DBMs. The present investigation is mainly concerned with an analysis of the existing approaches to interconnecting heterogeneous DBMSs, taking into account four experimental DBMS projects.

Heterogeneous continuous-time random walks

Science.gov (United States)

Grebenkov, Denis S.; Tupikina, Liubov

2018-01-01

We introduce a heterogeneous continuous-time random walk (HCTRW) model as a versatile analytical formalism for studying and modeling diffusion processes in heterogeneous structures, such as porous or disordered media, multiscale or crowded environments, weighted graphs or networks. We derive the exact form of the propagator and investigate the effects of spatiotemporal heterogeneities onto the diffusive dynamics via the spectral properties of the generalized transition matrix. In particular, we show how the distribution of first-passage times changes due to local and global heterogeneities of the medium. The HCTRW formalism offers a unified mathematical language to address various diffusion-reaction problems, with numerous applications in material sciences, physics, chemistry, biology, and social sciences.

CYP1A1 and CYP1A2 expression: Comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines

International Nuclear Information System (INIS)

Uno, Shigeyuki; Endo, Kaori; Ishida, Yuji; Tateno, Chise; Makishima, Makoto; Yoshizato, Katsutoshi; Nebert, Daniel W.

2009-01-01

Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how 'human-like' can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1 C YP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+) s evere-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs.

Heterogeneous production of proteases from Brazilian clinical isolates of Pseudomonas aeruginosa.

Science.gov (United States)

Galdino, Anna Clara M; Viganor, Lívia; Ziccardi, Mariangela; Nunes, Ana Paula F; Dos Santos, Kátia R N; Branquinha, Marta H; Santos, André L S

2017-12-01

Pseudomonas aeruginosa is an important human pathogen that causes severe infections in a wide range of immunosuppressed patients. Herein, we evaluated the proteolytic profiles of 96 Brazilian clinical isolates of P. aeruginosa recovered from diverse anatomical sites. Cell-associated and extracellular proteases were evidenced by gelatin-SDS-PAGE and by the cleavage of soluble gelatin. Elastase was measured by using the peptide substrate N-succinyl-Ala-Ala-Ala-p-nitroanilide. The prevalence of elastase genes (lasA and lasB) was evaluated by PCR. Bacterial extracts were initially applied on gelatin-SDS-PAGE and the results revealed four distinct zymographic profiles as follows: profile I (composed by bands of 145, 118 and 50kDa), profile II (118 and 50kDa), profile III (145kDa) and profile IV (118kDa). All the proteolytic enzymes were inhibited by EDTA, identifying them as metalloproteases. The profile I was the most detected in both cellular (79.2%) and extracellular (84.4%) extracts. Overall, gelatinase and elastase activities measured in the spent culture media were significantly higher (around 2-fold) compared to the cellular extracts and the production level varied according to the site of bacterial isolation. For instance, tracheal secretion isolates produced elevated amount of gelatinase and elastase measured in both cellular and extracellular extracts. The prevalence of elastase genes revealed that 100% isolates were lasB-positive and 85.42% lasA-positive. Some positive/negative correlations were showed concerning the production of gelatinase, elastase, isolation site and antimicrobial susceptibility. The protease production was highly heterogeneous in Brazilian clinical isolates of P. aeruginosa, which corroborates the genomic/metabolic versatility of this pathogen. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

MIMO Communication for Cellular Networks

CERN Document Server

Huang, Howard; Venkatesan, Sivarama

2012-01-01

As the theoretical foundations of multiple-antenna techniques evolve and as these multiple-input multiple-output (MIMO) techniques become essential for providing high data rates in wireless systems, there is a growing need to understand the performance limits of MIMO in practical networks. To address this need, MIMO Communication for Cellular Networks presents a systematic description of MIMO technology classes and a framework for MIMO system design that takes into account the essential physical-layer features of practical cellular networks. In contrast to works that focus on the theoretical performance of abstract MIMO channels, MIMO Communication for Cellular Networks emphasizes the practical performance of realistic MIMO systems. A unified set of system simulation results highlights relative performance gains of different MIMO techniques and provides insights into how best to use multiple antennas in cellular networks under various conditions. MIMO Communication for Cellular Networks describes single-user,...

Primary observation on the effect of APBMV on tumor weight and general physical condition of hepatoma 22-bearing mice after radiotherapy

International Nuclear Information System (INIS)

Kong Tianhan; Wei Ling; Han Xuefei; Dong Weihua

2000-01-01

Objective: To observe the effect of antineoplastic polypeptide from buthus martensii venom (APBMV) combined with radiotherapy on hepatoma-bearing mouse. Methods: Hundreds H22-bearing mice were used in this experiment. The tumor growth inhibiting rate (IR%), WBC count, hemoglobin content, activity of superoxide dismutase (SOD), level of lipid peroxide (LPO) and spleens index (SI) were used as the parameters. After radiotherapy (RT) or after administration of different dosage of APBMV combined with RT, the changes of these parameters were observed. Results: On the 6th and 9th day after radiotherapy, the tumor weights decreased after administrating APBMV combined with RT, in which IR were 78.29% and 70.45%, respectively (comparing with RT and APBMV group, P 0.05) among all groups. SOD activity was the lowest and LPO level was the highest in RT group (comparing with the control group, P 22 -bearing mice, SOD activity increased and LPO level decreased evidently (comparing with RT group, P 22 was stronger than radiation or APBMV alone. APBMV can also antagonize radiation injury on H 22 -bearing mice

Effects of exogenous cyclic AMP on growth characteristics and radiation response of Reuber H35 hepatoma cells

International Nuclear Information System (INIS)

van Rijn, J.; van Den Berg, J.; van Meeteren, A.; van Wijk, R.

1983-01-01

Reuber H35 rat hepatoma cells, clone KRC, were used to study the effect of cyclic AMP on radiation-induced cell death. Treatment of logarithmically growing cultures with 0.5 mM cAMP for 17 hr prior to irradiation resulted in a decreased cell survival. Similar results were obtained with cultures irradiated after treatment with Bt 2 cAMP. Treatment of H35 cells with cAMP or Bt 2 cAMP caused inhibition of their proliferation and resulted in an accumulation of cells in early S phase and depletion of G2-phase cells. In synchronized cultures cells were relatively radioresistant during their S phase. In addition to single-dose treatment with X rays, the effect of Bt 2 cAMP on radiation-induced cell death was studied during fractionated irradiation wtih 2.5 Gy per day. This fractionated irradiation resulted in a dose-reduction factor of 1.6 at the 10% survival level and a 10-fold decrease in the surviving cell population due to the cooperative effects of Bt 2 cAMP on growth rate and radiation survival. The effect of cAMP on radiation-induced mitotic delay was also studied. It appeared that where cAMP had on effect on the progression of G2 cells into mitosis, it prevented cells from recovery from the X-ray mitotic delay in G2

Study on radiation regulation of hypoxia inducible factor-1α expression and its correlation with hepatoma radiosensitivity

International Nuclear Information System (INIS)

Jin Wensen; Kong Zhaolu; Shen Zhifen; Tong Shungao; Ji Huajun; Jin Yizun

2008-01-01

Objective: To study the regulation of hypoxia inducible factor-1α (HIF-1α) expression in hepatoma cells after irradiation and the expression of HIF-1α effect on the radiosensitivity of heptoma cells. Methods: HepG2 cells were pretreated by Cobalt chloride (COCl 2 ), a chemical hypoxia agent, to induce and stabilize the expression of HIF-1α, and then exposed to different γ-irradiation doses. Clonogenic assay was used to evaluate HepG2 cell survival fraction (SF) after irradiation under normoxia and chemical hypoxia. Reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblot assay (Western blot) were utilized to detect the changes of intracellular HIF-1α on the level of transcripation and translation. Results: Cell survival level was elevated by chemical hypoxia and there was a statistical difference between chemical hypoxic group and normoxic group. The ratios of SF(SF co /SF o 2 )on two different conditions were increased with irradiation doses. Meanwhile, the irradiation induced up-regulation of HIF-1α in dose-dependent manner. The expression of HIF-1α was correlated with HepG2 cell survival level to some extent. Conclusions: Irradiation could up-regulate the level of HIF-1α expression in HepG2 cells under chemical hypoxic condition. The cells survival level might be influenced by the changes in HIF-1α expression. (authors)

Cellular communications a comprehensive and practical guide

CERN Document Server

Tripathi, Nishith

2014-01-01

Even as newer cellular technologies and standards emerge, many of the fundamental principles and the components of the cellular network remain the same. Presenting a simple yet comprehensive view of cellular communications technologies, Cellular Communications provides an end-to-end perspective of cellular operations, ranging from physical layer details to call set-up and from the radio network to the core network. This self-contained source forpractitioners and students represents a comprehensive survey of the fundamentals of cellular communications and the landscape of commercially deployed

Asociación de las incidencias de hepatoma, las cirrosis y la hepatitis B en Cali

Directory of Open Access Journals (Sweden)

Jorge H. Rojas

2000-12-01

Full Text Available El propósito de la investigación fue medir y comparar las incidencias del hepatoma (carcinoma hepatocelular, CHC, la cirrosis hepatocelular y la hepatitis B en la ciudad de Cali y clasificar las comunas de la ciudad según el riesgo de infección y sus complicaciones crónicas, para así establecer prioridades para las comunas más vulnerables y orientar eficientemente las acciones de promoción y prevención. No había estudios similares que expresaran la correlación y dinámica entre estos tres eventos en la región de las Américas. Se revisaron !as bases de datos del registro de población de cáncer y de mortalidad de la Secretaría de Salud Pública de Cali correspondientes a 1994; además, la de Vigilancia Epidemiológíca del Programa Ampliado de lnmunizaciones de Cali y del Laboratorio de Salud Pública de Cali de 1996. Se calcularon las incidencias de las enfermedades objeto de estudio según edad, sexo, comuna y Sistema Local de Salud (SILOS y el coeficiente de correlación de Pearson (r entre ellas, según comunas y silos. Los r fueron altos y significativos estadísticamente según silos, asi: CHC-CIRROSIS, r=0.82; IC: 0.03-0.98 y P

Magnetohydrodynamics cellular automata

International Nuclear Information System (INIS)

Hatori, Tadatsugu.

1990-02-01

There has been a renewal of interest in cellular automata, partly because they give an architecture for a special purpose computer with parallel processing optimized to solve a particular problem. The lattice gas cellular automata are briefly surveyed, which are recently developed to solve partial differential equations such as hydrodynamics or magnetohydrodynamics. A new model is given in the present paper to implement the magnetic Lorentz force in a more deterministic and local procedure than the previous one. (author)

Magnetohydrodynamic cellular automata

Energy Technology Data Exchange (ETDEWEB)

Hatori, Tadatsugu [National Inst. for Fusion Science, Nagoya (Japan)

1990-03-01

There has been a renewal of interest in cellular automata, partly because they give an architecture for a special purpose computer with parallel processing optimized to solve a particular problem. The lattice gas cellular automata are briefly surveyed, which are recently developed to solve partial differential equations such as hydrodynamics or magnetohydrodynamics. A new model is given in the present paper to implement the magnetic Lorentz force in a more deterministic and local procedure than the previous one. (author).

Magnetohydrodynamic cellular automata

International Nuclear Information System (INIS)

Hatori, Tadatsugu

1990-01-01

There has been a renewal of interest in cellular automata, partly because they give an architecture for a special purpose computer with parallel processing optimized to solve a particular problem. The lattice gas cellular automata are briefly surveyed, which are recently developed to solve partial differential equations such as hydrodynamics or magnetohydrodynamics. A new model is given in the present paper to implement the magnetic Lorentz force in a more deterministic and local procedure than the previous one. (author)

Modeling cellular systems

CERN Document Server

Matthäus, Franziska; Pahle, Jürgen

2017-01-01

This contributed volume comprises research articles and reviews on topics connected to the mathematical modeling of cellular systems. These contributions cover signaling pathways, stochastic effects, cell motility and mechanics, pattern formation processes, as well as multi-scale approaches. All authors attended the workshop on "Modeling Cellular Systems" which took place in Heidelberg in October 2014. The target audience primarily comprises researchers and experts in the field, but the book may also be beneficial for graduate students.

Cellular Angiofibroma of the Nasopharynx.

Science.gov (United States)

Erdur, Zülküf Burak; Yener, Haydar Murat; Yilmaz, Mehmet; Karaaltin, Ayşegül Batioğlu; Inan, Hakki Caner; Alaskarov, Elvin; Gozen, Emine Deniz

2017-11-01

Angiofibroma is a common tumor of the nasopharynx region but cellular type is extremely rare in head and neck. A 13-year-old boy presented with frequent epistaxis and nasal obstruction persisting for 6 months. According to the clinical symptoms and imaging studies juvenile angiofibroma was suspected. Following angiographic embolization total excision of the lesion by midfacial degloving approach was performed. Histological examination revealed that the tumor consisted of staghorn blood vessels and irregular fibrous stroma. Stellate fibroblasts with small pyknotic to large vesicular nuclei were seen in a highly cellular stroma. These findings identified cellular angiofibroma mimicking juvenile angiofibroma. This article is about a very rare patient of cellular angiofibroma of nasopharynx.

Analysis of changes in energy and redox states in HepG2 hepatoma and C6 glioma cells upon exposure to cadmium

International Nuclear Information System (INIS)

Yang, M.S.; Yu, L.C.; Gupta, R.C.

2004-01-01

The energy and redox states of the HepG2 hepatoma and the C6 glioma cells were studied by quantifying the levels of ATP, ADP, AMP, GSH, and GSSG. These values were used to calculate the energy charge potential (ECP = [ATP + 0.5ADP]/TAN), total adenosine nucleotides (TAN = ATP + ADP + AMP), total glutathione (TG = [GSH + GSSG]/TAN), and the redox state (GSH/GSSG ratio). For comparison between cell types, the level of each energy metabolite (ATP, ADP, and AMP) was normalized against TAN of the respective cell. The results showed that ATP:ADP:AMP ratio was 0.76:0.11:0.13 for the HepG2 cells and 0.80:0.11:0.09 for the C6 glioma cells. ECP was 0.81 ± 0.01 and 0.85 ± 0.01 for the HepG2 and the C6 glioma cells, respectively. GSH/GSSG ratio was 2.66 ± 0.16 and 3.63 ± 0.48 for HepG2 and C6 glioma cells, respectively. TG was 3.2 ± 0.54 for the HepG2 cells and 2.43 ± 0.18 for the C6 glioma cells, indicating that the level of total glutathione is more than two to three times higher than the total energy metabolites in these cell lines. Following a 3-h incubation in medium containing different concentrations of Cd, there was a dose-dependent decrease in cell viability. The 3-h LC 50 for the HepG2 cells was 0.5 mM and that for the C6 glioma cells was 0.4 mM. Cellular TAN decreased with a decrease in cell viability. Upon careful analysis of the energy state, there was a significant increase in relative amount of ATP and decrease in ADP and AMP in both cells as Cd concentration increased from 0 to 0.1, 0.2, and 0.6 mM. However, ECP in both cell lines increased, which indicated that the level of high energy phosphate was adequate. There was also a significant increase in TG and a significant decrease in GSH/GSSG in the C6 glioma cells when cells were exposed to as low as 0.1 mM Cd, which suggested that the cellular redox state was compromised. The HepG2 cells, on the other hand, showed no significant change in both TG and GSH/GSSG level until Cd concentration reached 0.6 m

47 CFR 22.923 - Cellular system configuration.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 2 2010-10-01 2010-10-01 false Cellular system configuration. 22.923 Section... MOBILE SERVICES Cellular Radiotelephone Service § 22.923 Cellular system configuration. Mobile stations... directly or through cellular repeaters. Auxiliary test stations may communicate with base or mobile...

Update schemes of multi-velocity floor field cellular automaton for pedestrian dynamics

Science.gov (United States)

Luo, Lin; Fu, Zhijian; Cheng, Han; Yang, Lizhong

2018-02-01

Modeling pedestrian movement is an interesting problem both in statistical physics and in computational physics. Update schemes of cellular automaton (CA) models for pedestrian dynamics govern the schedule of pedestrian movement. Usually, different update schemes make the models behave in different ways, which should be carefully recalibrated. Thus, in this paper, we investigated the influence of four different update schemes, namely parallel/synchronous scheme, random scheme, order-sequential scheme and shuffled scheme, on pedestrian dynamics. The multi-velocity floor field cellular automaton (FFCA) considering the changes of pedestrians' moving properties along walking paths and heterogeneity of pedestrians' walking abilities was used. As for parallel scheme only, the collisions detection and resolution should be considered, resulting in a great difference from any other update schemes. For pedestrian evacuation, the evacuation time is enlarged, and the difference in pedestrians' walking abilities is better reflected, under parallel scheme. In face of a bottleneck, for example a exit, using a parallel scheme leads to a longer congestion period and a more dispersive density distribution. The exit flow and the space-time distribution of density and velocity have significant discrepancies under four different update schemes when we simulate pedestrian flow with high desired velocity. Update schemes may have no influence on pedestrians in simulation to create tendency to follow others, but sequential and shuffled update scheme may enhance the effect of pedestrians' familiarity with environments.

Cellular modelling of secondary radial growth in conifer trees: application to Pinus radiata (D. Don).

Science.gov (United States)

Forest, Loïc; Demongeot, Jacques; Demongeota, Jacques

2006-05-01

The radial growth of conifer trees proceeds from the dynamics of a merismatic tissue called vascular cambium or cambium. Cambium is a thin layer of active proliferating cells. The purpose of this paper was to model the main characteristics of cambial activity and its consecutive radial growth. Cell growth is under the control of the auxin hormone indole-3-acetic. The model is composed of a discrete part, which accounts for cellular proliferation, and a continuous part involving the transport of auxin. Cambium is modeled in a two-dimensional cross-section by a cellular automaton that describes the set of all its constitutive cells. Proliferation is defined as growth and division of cambial cells under neighbouring constraints, which can eliminate some cells from the cambium. The cell-growth rate is determined from auxin concentration, calculated with the continuous model. We studied the integration of each elementary cambial cell activity into the global coherent movement of macroscopic morphogenesis. Cases of normal and abnormal growth of Pinus radiata (D. Don) are modelled. Abnormal growth includes deformed trees where gravity influences auxin transport, producing heterogeneous radial growth. Cross-sectional microscopic views are also provided to validate the model's hypothesis and results.

Recursive definition of global cellular-automata mappings

International Nuclear Information System (INIS)

Feldberg, R.; Knudsen, C.; Rasmussen, S.

1994-01-01

A method for a recursive definition of global cellular-automata mappings is presented. The method is based on a graphical representation of global cellular-automata mappings. For a given cellular-automaton rule the recursive algorithm defines the change of the global cellular-automaton mapping as the number of lattice sites is incremented. A proof of lattice size invariance of global cellular-automata mappings is derived from an approximation to the exact recursive definition. The recursive definitions are applied to calculate the fractal dimension of the set of reachable states and of the set of fixed points of cellular automata on an infinite lattice

Intratumor and Intertumor Heterogeneity in Melanoma

Directory of Open Access Journals (Sweden)

Tomasz M. Grzywa

2017-12-01

Full Text Available Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed.

Cellular and molecular screening of connective tissue dysplasia in adolescent athletes (pilot study

Directory of Open Access Journals (Sweden)

M. V. Dvornichenko

2017-01-01

Full Text Available The purpose of the study is to evaluate the cellular and molecular parameters of bone remodeling in the blood as potential markers of undifferentiated forms of connective tissue dysplasiaMaterials and methods. The structural and functional status of cellular elements of in vitro culturing of mononuclear leukocytes of peripheral blood in adolescent athletes connected with phenotypic manifestations of undifferentiated connective tissue dysplasia (UCTD were investigated. 25 pupils of sport schools from 10–14 years old (main disciplines: figure skating, gymnastics, athletics were examined with the help of express analysis. The average age of the examined adolescents was (12,0 ± 1,7 years. Clinical examination of adolescents allowed ranking the UCTD signs on a scale of 4–11,5 points.Results. A comparison of questionnaire survey results and an evaluation of bone remodeling distant markers allowed the revelation of 2 groups in the distribution of adolescent athletes: those with minimal signs of UCTD (scores lesser than 7 points – 10 pupils, and those with expressed UCTD phenotype (scores are equal or more than 7 points –15 pupils. Significant statistical decrease in the content of collagen type I degradation products (CrossLaps (by 80% and ionized calcium (by 5% has been determined in the peripheral blood of adolescent athletes with expressed UCTD phenotype. In conditions of short-term 72-h cultivation of mononuclear leukocytes in the presence of a 3D matrix imitating the properties of the mineral substance of the regenerating bone tissue, morphofunctional features of cellular reaction in adolescent athletes with clinical manifestations of UCTD, as well the heterogeneity of the cell population associated with the appearance of cells with an osteoblast-like phenotype in the blood have been revealed. The results of investigation propose the use of distant cellular and molecular parameters of bone remodeling to screen the mechanisms and dynamics

BIOZON: a system for unification, management and analysis of heterogeneous biological data

Directory of Open Access Journals (Sweden)

Yona Golan

2006-02-01

Full Text Available Abstract Background Integration of heterogeneous data types is a challenging problem, especially in biology, where the number of databases and data types increase rapidly. Amongst the problems that one has to face are integrity, consistency, redundancy, connectivity, expressiveness and updatability. Description Here we present a system (Biozon that addresses these problems, and offers biologists a new knowledge resource to navigate through and explore. Biozon unifies multiple biological databases consisting of a variety of data types (such as DNA sequences, proteins, interactions and cellular pathways. It is fundamentally different from previous efforts as it uses a single extensive and tightly connected graph schema wrapped with hierarchical ontology of documents and relations. Beyond warehousing existing data, Biozon computes and stores novel derived data, such as similarity relationships and functional predictions. The integration of similarity data allows propagation of knowledge through inference and fuzzy searches. Sophisticated methods of query that span multiple data types were implemented and first-of-a-kind biological ranking systems were explored and integrated. Conclusion The Biozon system is an extensive knowledge resource of heterogeneous biological data. Currently, it holds more than 100 million biological documents and 6.5 billion relations between them. The database is accessible through an advanced web interface that supports complex queries, "fuzzy" searches, data materialization and more, online at http://biozon.org.

3D Bioprinting of Heterogeneous Aortic Valve Conduits with Alginate/Gelatin Hydrogels

Science.gov (United States)

Duan, Bin; Hockaday, Laura A.; Kang, Kevin H.; Butcher, Jonathan T.

2013-01-01

Heart valve disease is a serious and growing public health problem for which prosthetic replacement is most commonly indicated. Current prosthetic devices are inadequate for younger adults and growing children. Tissue engineered living aortic valve conduits have potential for remodeling, regeneration, and growth, but fabricating natural anatomical complexity with cellular heterogeneity remain challenging. In the current study, we implement 3D bioprinting to fabricate living alginate/gelatin hydrogel valve conduits with anatomical architecture and direct incorporation of dual cell types in a regionally constrained manner. Encapsulated aortic root sinus smooth muscle cells (SMC) and aortic valve leaflet interstitial cells (VIC) were viable within alginate/gelatin hydrogel discs over 7 days in culture. Acellular 3D printed hydrogels exhibited reduced modulus, ultimate strength, and peak strain reducing slightly over 7-day culture, while the tensile biomechanics of cell-laden hydrogels were maintained. Aortic valve conduits were successfully bioprinted with direct encapsulation of SMC in the valve root and VIC in the leaflets. Both cell types were viable (81.4±3.4% for SMC and 83.2±4.0% for VIC) within 3D printed tissues. Encapsulated SMC expressed elevated alpha-smooth muscle actin when printed in stiff matrix, while VIC expressed elevated vimentin in soft matrix. These results demonstrate that anatomically complex, heterogeneously encapsulated aortic valve hydrogel conduits can be fabricated with 3D bioprinting. PMID:23015540

Cellular senescence and organismal aging.

Science.gov (United States)

Jeyapalan, Jessie C; Sedivy, John M

2008-01-01

Cellular senescence, first observed and defined using in vitro cell culture studies, is an irreversible cell cycle arrest which can be triggered by a variety of factors. Emerging evidence suggests that cellular senescence acts as an in vivo tumor suppression mechanism by limiting aberrant proliferation. It has also been postulated that cellular senescence can occur independently of cancer and contribute to the physiological processes of normal organismal aging. Recent data have demonstrated the in vivo accumulation of senescent cells with advancing age. Some characteristics of senescent cells, such as the ability to modify their extracellular environment, could play a role in aging and age-related pathology. In this review, we examine current evidence that links cellular senescence and organismal aging.

Zeno's paradox in quantum cellular automata

Energy Technology Data Exchange (ETDEWEB)

Groessing, G [Atominst. der Oesterreichischen Universitaeten, Vienna (Austria); Zeilinger, A [Inst. fuer Experimentalphysik, Univ. Innsbruck (Austria)

1991-07-01

The effect of Zeno's paradox in quantum theory is demonstrated with the aid of quantum mechanical cellular automata. It is shown that the degree of non-unitarity of the cellular automaton evolution and the frequency of consecutive measurements of cellular automaton states are operationally indistinguishable. (orig.).

Zeno's paradox in quantum cellular automata

International Nuclear Information System (INIS)

Groessing, G.; Zeilinger, A.

1991-01-01

The effect of Zeno's paradox in quantum theory is demonstrated with the aid of quantum mechanical cellular automata. It is shown that the degree of non-unitarity of the cellular automaton evolution and the frequency of consecutive measurements of cellular automaton states are operationally indistinguishable. (orig.)

Viscous fingering with permeability heterogeneity

International Nuclear Information System (INIS)

Tan, C.; Homsy, G.M.

1992-01-01

Viscous fingering in miscible displacements in the presence of permeability heterogeneities is studied using two-dimensional simulations. The heterogeneities are modeled as stationary random functions of space with finite correlation scale. Both the variance and scale of the heterogeneities are varied over modest ranges. It is found that the fingered zone grows linearly in time in a fashion analogous to that found in homogeneous media by Tan and Homsy [Phys. Fluids 31, 1330 (1988)], indicating a close coupling between viscous fingering on the one hand and flow through preferentially more permeable paths on the other. The growth rate of the mixing zone increases monotonically with the variance of the heterogeneity, as expected, but shows a maximum as the correlation scale is varied. The latter is explained as a ''resonance'' between the natural scale of fingers in homogeneous media and the correlation scale

Validation of self-reported cellular phone use

DEFF Research Database (Denmark)

Samkange-Zeeb, Florence; Berg, Gabriele; Blettner, Maria

2004-01-01

BACKGROUND: In recent years, concern has been raised over possible adverse health effects of cellular telephone use. In epidemiological studies of cancer risk associated with the use of cellular telephones, the validity of self-reported cellular phone use has been problematic. Up to now there is ......BACKGROUND: In recent years, concern has been raised over possible adverse health effects of cellular telephone use. In epidemiological studies of cancer risk associated with the use of cellular telephones, the validity of self-reported cellular phone use has been problematic. Up to now...... there is very little information published on this subject. METHODS: We conducted a study to validate the questionnaire used in an ongoing international case-control study on cellular phone use, the "Interphone study". Self-reported cellular phone use from 68 of 104 participants who took part in our study...... was compared with information derived from the network providers over a period of 3 months (taken as the gold standard). RESULTS: Using Spearman's rank correlation, the correlation between self-reported phone use and information from the network providers for cellular phone use in terms of the number of calls...

Quantification of heterogeneity observed in medical images

International Nuclear Information System (INIS)

Brooks, Frank J; Grigsby, Perry W

2013-01-01

There has been much recent interest in the quantification of visually evident heterogeneity within functional grayscale medical images, such as those obtained via magnetic resonance or positron emission tomography. In the case of images of cancerous tumors, variations in grayscale intensity imply variations in crucial tumor biology. Despite these considerable clinical implications, there is as yet no standardized method for measuring the heterogeneity observed via these imaging modalities. In this work, we motivate and derive a statistical measure of image heterogeneity. This statistic measures the distance-dependent average deviation from the smoothest intensity gradation feasible. We show how this statistic may be used to automatically rank images of in vivo human tumors in order of increasing heterogeneity. We test this method against the current practice of ranking images via expert visual inspection. We find that this statistic provides a means of heterogeneity quantification beyond that given by other statistics traditionally used for the same purpose. We demonstrate the effect of tumor shape upon our ranking method and find the method applicable to a wide variety of clinically relevant tumor images. We find that the automated heterogeneity rankings agree very closely with those performed visually by experts. These results indicate that our automated method may be used reliably to rank, in order of increasing heterogeneity, tumor images whether or not object shape is considered to contribute to that heterogeneity. Automated heterogeneity ranking yields objective results which are more consistent than visual rankings. Reducing variability in image interpretation will enable more researchers to better study potential clinical implications of observed tumor heterogeneity

Quantification of heterogeneity observed in medical images.

Science.gov (United States)

Brooks, Frank J; Grigsby, Perry W

2013-03-02

There has been much recent interest in the quantification of visually evident heterogeneity within functional grayscale medical images, such as those obtained via magnetic resonance or positron emission tomography. In the case of images of cancerous tumors, variations in grayscale intensity imply variations in crucial tumor biology. Despite these considerable clinical implications, there is as yet no standardized method for measuring the heterogeneity observed via these imaging modalities. In this work, we motivate and derive a statistical measure of image heterogeneity. This statistic measures the distance-dependent average deviation from the smoothest intensity gradation feasible. We show how this statistic may be used to automatically rank images of in vivo human tumors in order of increasing heterogeneity. We test this method against the current practice of ranking images via expert visual inspection. We find that this statistic provides a means of heterogeneity quantification beyond that given by other statistics traditionally used for the same purpose. We demonstrate the effect of tumor shape upon our ranking method and find the method applicable to a wide variety of clinically relevant tumor images. We find that the automated heterogeneity rankings agree very closely with those performed visually by experts. These results indicate that our automated method may be used reliably to rank, in order of increasing heterogeneity, tumor images whether or not object shape is considered to contribute to that heterogeneity. Automated heterogeneity ranking yields objective results which are more consistent than visual rankings. Reducing variability in image interpretation will enable more researchers to better study potential clinical implications of observed tumor heterogeneity.

47 CFR 90.672 - Unacceptable interference to non-cellular 800 MHz licensees from 800 MHz cellular systems or part...

Science.gov (United States)

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Unacceptable interference to non-cellular 800 MHz licensees from 800 MHz cellular systems or part 22 Cellular Radiotelephone systems, and within the... Procedures and Process-Unacceptable Interference § 90.672 Unacceptable interference to non-cellular 800 MHz...

Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine

International Nuclear Information System (INIS)

Velsor, Leonard W.; Kovacevic, Miro; Goldstein, Mark; Leitner, Heather M.; Lewis, William; Day, Brian J.

2004-01-01

The toxicity of nucleoside reverse transcriptase inhibitors (NRTIs) is linked to altered mitochondrial DNA (mtDNA) replication and subsequent disruption of cellular energetics. This manifests clinically as elevated concentrations of lactate in plasma. The mechanism(s) underlying how the changes in mtDNA replication lead to lactic acidosis remains unclear. It is hypothesized that mitochondrial oxidative stress links the changes in mtDNA replication to mitochondrial dysfunction and ensuing NRTIs toxicity. To test this hypothesis, changes in mitochondrial function, mtDNA amplification efficiency, and oxidative stress were assessed in HepG2-cultured human hepatoblasts treated with the NRTI stavudine (2',3'-didehydro-2',3'-deoxythymidine or d4T) for 48 h. d4T produced significant mitochondrial dysfunction with a 1.5-fold increase in cellular lactate to pyruvate ratios. In addition, d4T caused a dose-dependent decrease in mtDNA amplification and a correlative increase in abundance of markers of mitochondrial oxidative stress. Manganese (III) meso-tetrakis (4-benzoic acid) porphyrin, MnTBAP, a catalytic antioxidant, ameliorated or reversed d4T-induced changes in cell injury, energetics, mtDNA amplification, and mitochondrial oxidative stress. In conclusion, d4T treatment elevates mitochondrial reactive oxygen species (ROS), enhances mitochondrial oxidative stress, and contributes mechanistically to NRTI-induced toxicity. These deleterious events may be potentiated in acquired immunodeficiency syndrome (AIDS) by human immunodeficiency virus (HIV) infection itself, coinfection (e.g., viral hepatitis), aging, substance, and alcohol use

Origami interleaved tube cellular materials

International Nuclear Information System (INIS)

Cheung, Kenneth C; Tachi, Tomohiro; Calisch, Sam; Miura, Koryo

2014-01-01

A novel origami cellular material based on a deployable cellular origami structure is described. The structure is bi-directionally flat-foldable in two orthogonal (x and y) directions and is relatively stiff in the third orthogonal (z) direction. While such mechanical orthotropicity is well known in cellular materials with extruded two dimensional geometry, the interleaved tube geometry presented here consists of two orthogonal axes of interleaved tubes with high interfacial surface area and relative volume that changes with fold-state. In addition, the foldability still allows for fabrication by a flat lamination process, similar to methods used for conventional expanded two dimensional cellular materials. This article presents the geometric characteristics of the structure together with corresponding kinematic and mechanical modeling, explaining the orthotropic elastic behavior of the structure with classical dimensional scaling analysis. (paper)

Origami interleaved tube cellular materials

Science.gov (United States)

Cheung, Kenneth C.; Tachi, Tomohiro; Calisch, Sam; Miura, Koryo

2014-09-01

A novel origami cellular material based on a deployable cellular origami structure is described. The structure is bi-directionally flat-foldable in two orthogonal (x and y) directions and is relatively stiff in the third orthogonal (z) direction. While such mechanical orthotropicity is well known in cellular materials with extruded two dimensional geometry, the interleaved tube geometry presented here consists of two orthogonal axes of interleaved tubes with high interfacial surface area and relative volume that changes with fold-state. In addition, the foldability still allows for fabrication by a flat lamination process, similar to methods used for conventional expanded two dimensional cellular materials. This article presents the geometric characteristics of the structure together with corresponding kinematic and mechanical modeling, explaining the orthotropic elastic behavior of the structure with classical dimensional scaling analysis.

The implications of heterogeneity for repository performance assessments

International Nuclear Information System (INIS)

Jackson, C.P.; Porter, J.D.; Morris, S.T.; Herbert, A.W.

1991-01-01

We outline the current views of the Nirex Disposal Safety Assessment Team on heterogeneity, we describe the pragmatic approach to modelling the consequences of heterogeneity that is being currently used, we present work that is being undertaken in the Nirex Safety Assessment Research Programme to develop improved models and we discuss the implications of heterogeneity for site investigation. We point out the need to develop simple models for use in probabilistic analyses. Heterogeneity leads to dispersion, which is currently modelled using a simple diffusion-like model. We discuss the differences between structured heterogeneity, such as fracture zones, and random heterogeneity. We consider that the geostatistical approach to modelling random heterogeneity is probably that most suitable for the needs of Nirex. More measurements are needed in order to characterize heterogeneous media than to characterize homogeneous media. 18 refs., 4 figs

Engineering Microbial Metabolite Dynamics and Heterogeneity.

Science.gov (United States)

Schmitz, Alexander C; Hartline, Christopher J; Zhang, Fuzhong

2017-10-01

As yields for biological chemical production in microorganisms approach their theoretical maximum, metabolic engineering requires new tools, and approaches for improvements beyond what traditional strategies can achieve. Engineering metabolite dynamics and metabolite heterogeneity is necessary to achieve further improvements in product titers, productivities, and yields. Metabolite dynamics, the ensemble change in metabolite concentration over time, arise from the need for microbes to adapt their metabolism in response to the extracellular environment and are important for controlling growth and productivity in industrial fermentations. Metabolite heterogeneity, the cell-to-cell variation in a metabolite concentration in an isoclonal population, has a significant impact on ensemble productivity. Recent advances in single cell analysis enable a more complete understanding of the processes driving metabolite heterogeneity and reveal metabolic engineering targets. The authors present an overview of the mechanistic origins of metabolite dynamics and heterogeneity, why they are important, their potential effects in chemical production processes, and tools and strategies for engineering metabolite dynamics and heterogeneity. The authors emphasize that the ability to control metabolite dynamics and heterogeneity will bring new avenues of engineering to increase productivity of microbial strains. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intratumor and Intertumor Heterogeneity in Melanoma.

Science.gov (United States)

Grzywa, Tomasz M; Paskal, Wiktor; Włodarski, Paweł K

2017-12-01

Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Estimating cellular network performance during hurricanes

International Nuclear Information System (INIS)

Booker, Graham; Torres, Jacob; Guikema, Seth; Sprintson, Alex; Brumbelow, Kelly

2010-01-01

Cellular networks serve a critical role during and immediately after a hurricane, allowing citizens to contact emergency services when land-line communication is lost and serving as a backup communication channel for emergency responders. However, due to their ubiquitous deployment and limited design for extreme loading events, basic network elements, such as cellular towers and antennas are prone to failures during adverse weather conditions such as hurricanes. Accordingly, a systematic and computationally feasible approach is required for assessing and improving the reliability of cellular networks during hurricanes. In this paper we develop a new multi-disciplinary approach to efficiently and accurately assess cellular network reliability during hurricanes. We show how the performance of a cellular network during and immediately after future hurricanes can be estimated based on a combination of hurricane wind field models, structural reliability analysis, Monte Carlo simulation, and cellular network models and simulation tools. We then demonstrate the use of this approach for assessing the improvement in system reliability that can be achieved with discrete topological changes in the system. Our results suggest that adding redundancy, particularly through a mesh topology or through the addition of an optical fiber ring around the perimeter of the system can be an effective way to significantly increase the reliability of some cellular systems during hurricanes.

MiR-30e suppresses proliferation of hepatoma cells via targeting prolyl 4-hydroxylase subunit alpha-1 (P4HA1) mRNA

Energy Technology Data Exchange (ETDEWEB)

Feng, Guoxing [State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin (China); Shi, Hui [State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin (China); Li, Jiong; Yang, Zhe [State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin (China); Fang, Runping; Ye, Lihong [State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin (China); Zhang, Weiying, E-mail: zhwybao@nankai.edu.cn [State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin (China); Zhang, Xiaodong, E-mail: zhangxd@nankai.edu.cn [State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin (China)

2016-04-08

Aberrant microRNA expression has been shown to be characteristic of many cancers. It has been reported that the expression levels of miR-30e are decreased in liver cancer tissues. However, the role of miR-30e in hepatocellular carcinoma remains poorly understood. In the present study, we investigated the significance of miR-30e in hepatocarcinogenesis. Bioinformatics analysis reveals a putative target site of miR-30e in the 3′-untranslated region (3′UTR) of prolyl 4-hydroxylase subunit alpha-1 (P4HA1) mRNA. Moreover, luciferase reporter gene assays verified that miR-30e directly targeted 3′UTR of P4HA1 mRNA. Then, we demonstrated that miR-30e was able to reduce the expression of P4HA1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blot analysis. Enforced expression of miR-30e suppressed proliferation of HepG2 cells by 5-ethynyl-2-deoxyuridine (EdU) assay and reduced colony formation of these cells by colony formation analysis. Conversely, anti-miR-30e enhanced the proliferation of hepatoma cells in vitro. Interestingly, the ectopic expression of P4HA1 could efficiently rescue the inhibition of cell proliferation mediated by miR-30e in HepG2 cells. Meanwhile, silencing of P4HA1 abolished the anti-miR-30e-induced proliferation of cells. Clinically, quantitative real-time PCR showed that miR-30e was down-regulated in liver tumor tissues relative to their peritumor tissues. The expression levels of miR-30e were negatively correlated to those of P4HA1 mRNA in clinical liver tumor tissues. Thus, we conclude that miR-30e suppresses proliferation of hepatoma cells through targeting P4HA1 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. - Highlights: • P4HA1 is a novel target gene of miR-30e. • P4HA1 is increased in clinical HCC tissues. • MiR-30e is negatively correlated with P4HA1 in clinical HCC tissues. • MiR-30e suppresses the proliferation of HCC cells through

Assaying Cellular Viability Using the Neutral Red Uptake Assay.

Science.gov (United States)

Ates, Gamze; Vanhaecke, Tamara; Rogiers, Vera; Rodrigues, Robim M

2017-01-01

The neutral red uptake assay is a cell viability assay that allows in vitro quantification of xenobiotic-induced cytotoxicity. The assay relies on the ability of living cells to incorporate and bind neutral red, a weak cationic dye, in lysosomes. As such, cytotoxicity is expressed as a concentration-dependent reduction of the uptake of neutral red after exposure to the xenobiotic under investigation. The neutral red uptake assay is mainly used for hazard assessment in in vitro toxicology applications. This method has also been introduced in regulatory recommendations as part of 3T3-NRU-phototoxicity-assay, which was regulatory accepted in all EU member states in 2000 and in the OECD member states in 2004 as a test guideline (TG 432). The present protocol describes the neutral red uptake assay using the human hepatoma cell line HepG2, which is often employed as an alternative in vitro model for human hepatocytes. As an example, the cytotoxicity of acetaminophen and acetyl salicylic acid is assessed.

Design Technology for Heterogeneous Embedded Systems

CERN Document Server

O'Connor, Ian; Piguet, Christian

2012-01-01

Designing technology to address the problem of heterogeneous embedded systems, while remaining compatible with standard “More Moore” flows, i.e. capable of handling simultaneously both silicon complexity and system complexity, represents one of the most important challenges facing the semiconductor industry today. While the micro-electronics industry has built its own specific design methods to focus mainly on the management of complexity through the establishment of abstraction levels, the emergence of device heterogeneity requires new approaches enabling the satisfactory design of physically heterogeneous embedded systems for the widespread deployment of such systems. This book, compiled largely from a set of contributions from participants of past editions of the Winter School on Heterogeneous Embedded Systems Design Technology (FETCH), proposes a broad and holistic overview of design techniques used to tackle the various facets of heterogeneity in terms of technology and opportunities at the physical ...

The cellular memory disc of reprogrammed cells.

Science.gov (United States)

Anjamrooz, Seyed Hadi

2013-04-01

The crucial facts underlying the low efficiency of cellular reprogramming are poorly understood. Cellular reprogramming occurs in nuclear transfer, induced pluripotent stem cell (iPSC) formation, cell fusion, and lineage-switching experiments. Despite these advances, there are three fundamental problems to be addressed: (1) the majority of cells cannot be reprogrammed, (2) the efficiency of reprogramming cells is usually low, and (3) the reprogrammed cells developed from a patient's own cells activate immune responses. These shortcomings present major obstacles for using reprogramming approaches in customised cell therapy. In this Perspective, the author synthesises past and present observations in the field of cellular reprogramming to propose a theoretical picture of the cellular memory disc. The current hypothesis is that all cells undergo an endogenous and exogenous holographic memorisation such that parts of the cellular memory dramatically decrease the efficiency of reprogramming cells, act like a barrier against reprogramming in the majority of cells, and activate immune responses. Accordingly, the focus of this review is mainly to describe the cellular memory disc (CMD). Based on the present theory, cellular memory includes three parts: a reprogramming-resistance memory (RRM), a switch-promoting memory (SPM) and a culture-induced memory (CIM). The cellular memory arises genetically, epigenetically and non-genetically and affects cellular behaviours. [corrected].

Cosserat modeling of cellular solids

NARCIS (Netherlands)

Onck, P.R.

Cellular solids inherit their macroscopic mechanical properties directly from the cellular microstructure. However, the characteristic material length scale is often not small compared to macroscopic dimensions, which limits the applicability of classical continuum-type constitutive models. Cosserat

Synergistic cytotoxicity and mechanism of caffeine and lysozyme on hepatoma cell line HepG2

Science.gov (United States)

Yang, Hongchao; Li, Jingjuan; Cui, Lin; Ren, Yanqing; Niu, Liying; Wang, Xinguo; Huang, Yun; Cui, Lijian

2018-03-01

The influences of caffeine, lysozyme and the joint application of them on the hepatoma cell line HepG2 proliferation inhibition and cell apoptosis were observed by 3-(4, 5-dimethyl-2-thiazyl)-2, 5-diphenyl-2H-tetrazolium bromide assay and Hoechst 33342, which showed the proliferation inhibition rate of the joint application on HepG2 cells was 47.21%, significantly higher than caffeine or lysozyme, and the joint application promoted the apoptosis of HepG2 cells obviously. Van't Hoff classical thermodynamics formula, the Föster theory of non-radiation energy transfer and fluorescence phase diagram were used to manifest that the process of lysozyme binding to caffeine followed a two-state model, which was spontaneous at low temperature driven by enthalpy change, and the predominant intermolecular force was hydrogen bonding or Van der Waals force to stabilize caffeine-lysozyme complex with the distance 5.86 nm. The attenuated total reflection-Fourier transform infrared spectra indicated that caffeine decreased the relative contents of α-helix and β-turn, which inferred the structure of lysozyme tended to be "loose". Synchronous fluorescence spectra and ultraviolet spectra supported the above conclusion. The amino acid residues in the cleft of lysozyme were exposed and electropositivity was increased attributing to the loose structure, which were conducive to increasing caffeine concentration on the HepG2 cell surface by electrostatic interaction to show synergistic effect. The great quantities of microvilli on the liver cancer cell membrane surface, is beneficial for the lysozyme-caffeine compound to aggregate on cell surface to increase the concentration of caffeine to play stronger physiological role by electrostatic effect.

Recursive definition of global cellular-automata mappings

DEFF Research Database (Denmark)

Feldberg, Rasmus; Knudsen, Carsten; Rasmussen, Steen

1994-01-01

A method for a recursive definition of global cellular-automata mappings is presented. The method is based on a graphical representation of global cellular-automata mappings. For a given cellular-automaton rule the recursive algorithm defines the change of the global cellular-automaton mapping...... as the number of lattice sites is incremented. A proof of lattice size invariance of global cellular-automata mappings is derived from an approximation to the exact recursive definition. The recursive definitions are applied to calculate the fractal dimension of the set of reachable states and of the set...

The experimental study on the radioimmunotherapy of the hepatoma in nude mice model with intratumoral injection of 131I-human anti-HBsAg Fab

International Nuclear Information System (INIS)

Luo Rongcheng; Wu Guichen; Han Huanxing; You Changxuan; Ding Xuemei; Li Aimin; Wang Chuanbin; Zhang Mingjiang

2001-01-01

Objective: To study the therapeutic efficacy of radioimmunotherapy of 131 I-human anti-HBsAg Fab via different routes of administration. Methods: The human hepatoma bearing nude mice we reinjected with 131 I-human anti-HBsAg Fab intra-tumor (IT) and intra-peritoneum (IP). Biodistribution was measured on the 5th day. The tumor growth inhibition rate was determined by measurement of tumor volume. Results: In the IT-treated mice, tumor uptake of 131 I-human anti-HBsAg Fab was four-fold greater than in the IP-treated mice, and normal organ uptake was half of that in the IP-treated mice. At the 3rd week after the infusion, the tumor growth inhibition rate in IT-treated mice was higher than that in the IP-treated mice. Conclusions: Intratumoral administration of 131 I-human anti-HBsAg Fab makes high level of radioactivity retained in tumor with significantly lower radioactivity retained in normal tissues, and provides a more effective regional therapy

Quantum dot multiplexing for the profiling of cellular receptors

Science.gov (United States)

Lee-Montiel, Felipe T.; Li, Peter; Imoukhuede, P. I.

2015-11-01

The profiling of cellular heterogeneity has wide-reaching importance for our understanding of how cells function and react to their environments in healthy and diseased states. Our ability to interpret and model cell behavior has been limited by the difficulties of measuring cell differences, for example, comparing tumor and non-tumor cells, particularly at the individual cell level. This demonstrates a clear need for a generalizable approach to profile fluorophore sites on cells or molecular assemblies on beads. Here, a multiplex immunoassay for simultaneous detection of five different angiogenic markers was developed. We targeted angiogenic receptors in the vascular endothelial growth factor family (VEGFR1, VEGFR2 and VEGFR3) and Neuropilin (NRP) family (NRP1 and NRP2), using multicolor quantum dots (Qdots). Copper-free click based chemistry was used to conjugate the monoclonal antibodies with 525, 565, 605, 655 and 705 nm CdSe/ZnS Qdots. We tested and performed colocalization analysis of our nanoprobes using the Pearson correlation coefficient statistical analysis. Human umbilical vein endothelial cells (HUVEC) were tested. The ability to easily monitor the molecular indicators of angiogenesis that are a precursor to cancer in a fast and cost effective system is an important step towards personalized nanomedicine.The profiling of cellular heterogeneity has wide-reaching importance for our understanding of how cells function and react to their environments in healthy and diseased states. Our ability to interpret and model cell behavior has been limited by the difficulties of measuring cell differences, for example, comparing tumor and non-tumor cells, particularly at the individual cell level. This demonstrates a clear need for a generalizable approach to profile fluorophore sites on cells or molecular assemblies on beads. Here, a multiplex immunoassay for simultaneous detection of five different angiogenic markers was developed. We targeted angiogenic receptors

Organizational heterogeneity of vertebrate genomes.

Science.gov (United States)

Frenkel, Svetlana; Kirzhner, Valery; Korol, Abraham

2012-01-01

Genomes of higher eukaryotes are mosaics of segments with various structural, functional, and evolutionary properties. The availability of whole-genome sequences allows the investigation of their structure as "texts" using different statistical and computational methods. One such method, referred to as Compositional Spectra (CS) analysis, is based on scoring the occurrences of fixed-length oligonucleotides (k-mers) in the target DNA sequence. CS analysis allows generating species- or region-specific characteristics of the genome, regardless of their length and the presence of coding DNA. In this study, we consider the heterogeneity of vertebrate genomes as a joint effect of regional variation in sequence organization superimposed on the differences in nucleotide composition. We estimated compositional and organizational heterogeneity of genome and chromosome sequences separately and found that both heterogeneity types vary widely among genomes as well as among chromosomes in all investigated taxonomic groups. The high correspondence of heterogeneity scores obtained on three genome fractions, coding, repetitive, and the remaining part of the noncoding DNA (the genome dark matter--GDM) allows the assumption that CS-heterogeneity may have functional relevance to genome regulation. Of special interest for such interpretation is the fact that natural GDM sequences display the highest deviation from the corresponding reshuffled sequences.

Organizational heterogeneity of vertebrate genomes.

Directory of Open Access Journals (Sweden)

Svetlana Frenkel

Full Text Available Genomes of higher eukaryotes are mosaics of segments with various structural, functional, and evolutionary properties. The availability of whole-genome sequences allows the investigation of their structure as "texts" using different statistical and computational methods. One such method, referred to as Compositional Spectra (CS analysis, is based on scoring the occurrences of fixed-length oligonucleotides (k-mers in the target DNA sequence. CS analysis allows generating species- or region-specific characteristics of the genome, regardless of their length and the presence of coding DNA. In this study, we consider the heterogeneity of vertebrate genomes as a joint effect of regional variation in sequence organization superimposed on the differences in nucleotide composition. We estimated compositional and organizational heterogeneity of genome and chromosome sequences separately and found that both heterogeneity types vary widely among genomes as well as among chromosomes in all investigated taxonomic groups. The high correspondence of heterogeneity scores obtained on three genome fractions, coding, repetitive, and the remaining part of the noncoding DNA (the genome dark matter--GDM allows the assumption that CS-heterogeneity may have functional relevance to genome regulation. Of special interest for such interpretation is the fact that natural GDM sequences display the highest deviation from the corresponding reshuffled sequences.

Fiber Bundle Model Under Heterogeneous Loading

Science.gov (United States)

Roy, Subhadeep; Goswami, Sanchari

2018-03-01

The present work deals with the behavior of fiber bundle model under heterogeneous loading condition. The model is explored both in the mean-field limit as well as with local stress concentration. In the mean field limit, the failure abruptness decreases with increasing order k of heterogeneous loading. In this limit, a brittle to quasi-brittle transition is observed at a particular strength of disorder which changes with k. On the other hand, the model is hardly affected by such heterogeneity in the limit where local stress concentration plays a crucial role. The continuous limit of the heterogeneous loading is also studied and discussed in this paper. Some of the important results related to fiber bundle model are reviewed and their responses to our new scheme of heterogeneous loading are studied in details. Our findings are universal with respect to the nature of the threshold distribution adopted to assign strength to an individual fiber.

Evaluation of Structural Cellular Glass

Science.gov (United States)

Adams, M. A.; Zwissler, J. G.

1984-01-01

Preliminary design information presented. First report discusses state of structural-cellular-glass programs as of June 1979. Second report gives further details of program to develop improved cellular glasses and to characterize properties of glasses and commercially available materials.

Tumor Heterogeneity and Drug Resistance

International Nuclear Information System (INIS)

Kucerova, L.; Skolekova, S.; Kozovska, Z.

2015-01-01

New generation of sequencing methodologies revealed unexpected complexity and genomic alterations linked with the tumor subtypes. This diversity exists across the tumor types, histologic tumor subtypes and subsets of the tumor cells within the same tumor. This phenomenon is termed tumor heterogeneity. Regardless of its origin and mechanisms of development it has a major impact in the clinical setting. Genetic, phenotypic and expression pattern diversity of tumors plays critical role in the selection of suitable treatment and also in the prognosis prediction. Intratumoral heterogeneity plays a key role in the intrinsic and acquired chemoresistance to cytotoxic and targeted therapies. In this review we focus on the mechanisms of intratumoral and inter tumoral heterogeneity and their relationship to the drug resistance. Understanding of the mechanisms and spatiotemporal dynamics of tumor heterogeneity development before and during the therapy is important for the ability to design individual treatment protocols suitable in the given molecular context. (author)

Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth

Energy Technology Data Exchange (ETDEWEB)

Yang, Hao [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Institute of Pharmacology and Toxicology, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222000, Jiangsu (China); Wang, Juan [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Fan, Jin-hong; Zhang, Ya-qi; Zhao, Jun-xian [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Dai, Xiao-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Liu, Qi; Shen, Yan-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Liu, Chang [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Sun, Wei-dong, E-mail: zyykjc@sina.com [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Sun, Yun, E-mail: ysun@yzu.edu.cn [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China)

2017-01-15

Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth. - Highlights: • Ilexgenin A exerts anti-inflammatory and anti-angiogenesis effects in hepatoma. • Ilexgenin A may exert these effects through inhibition of STAT3 and PI3K pathways. • Ilexgenin A exhibits synergistic effects with Sorafenib on hepatoma growth

Experimental study on 131I-labelled anti-alpha-fetoprotein antibodies in the diagnosis of rat hepatoma

International Nuclear Information System (INIS)

Terashima, Hiromi

1980-01-01

The tumor-specificity of 131 I-labelled anti-α-fetoprotein antibodies was evaluated in rats using α-fetoprotein-producing AH66C4 rat hepatoma as a model. 1) Following the 12 hour incubation of 125 I-labelled anti-α-fetoprotein antibodies and tumor cells, microautoradiography revealed marked radioactivity in and around the tumor cells. This suggested that the labelled antibodies accumulated around the cells and were combined with the α-fetoprotein secreted from the cells. 2) The tumor was transplanted subcutaneously into the thighs of rats. There was marked accumulation of 131 I-antibodies in the tumor with cyst formation, but there was none in the tumor without cyst formation. The accumulation was enhanced by the administration of non-labelled antibodies to the rats before the administration of 131 I-antibodies. The α-fetoprotein level was higher in the cyst than in any other organ. 131 I-labelled horse-γ-globulins administered as a control, also accumulated in the tumor with cyst but the degree of accumulation did not exceed that of the 131 I-antibodies. The amount of 131 I-antibodies accumulated increased, while that of 131 I-horse-γ-globulins decreased with time. This indicated that the accumulation of the γ-globulins in the tumor was nonspecific and that it was related to the blood pool. These results strongly suggest that the accumulation of 131 I-antibodies in the tumor with cyst formation was a specific antigen-antibody reaction, and the present procedure reported is applicable in the specific diagnosis of such kinds of α-fetoprotein secreting tumor. (author)

Epigenetics and Cellular Metabolism

OpenAIRE

Wenyi Xu; Fengzhong Wang; Zhongsheng Yu; Fengjiao Xin

2016-01-01

Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the proce...

Simulating tumor growth in confined heterogeneous environments

International Nuclear Information System (INIS)

Gevertz, Jana L; Torquato, Salvatore; Gillies, George T

2008-01-01

The holy grail of computational tumor modeling is to develop a simulation tool that can be utilized in the clinic to predict neoplastic progression and propose individualized optimal treatment strategies. In order to develop such a predictive model, one must account for many of the complex processes involved in tumor growth. One interaction that has not been incorporated into computational models of neoplastic progression is the impact that organ-imposed physical confinement and heterogeneity have on tumor growth. For this reason, we have taken a cellular automaton algorithm that was originally designed to simulate spherically symmetric tumor growth and generalized the algorithm to incorporate the effects of tissue shape and structure. We show that models that do not account for organ/tissue geometry and topology lead to false conclusions about tumor spread, shape and size. The impact that confinement has on tumor growth is more pronounced when a neoplasm is growing close to, versus far from, the confining boundary. Thus, any clinical simulation tool of cancer progression must not only consider the shape and structure of the organ in which a tumor is growing, but must also consider the location of the tumor within the organ if it is to accurately predict neoplastic growth dynamics

Energy-Efficient User Association Strategy for Hyperdense Heterogeneous Networking in the Fifth Generation Systems

Directory of Open Access Journals (Sweden)

Lei Li

2015-01-01

Full Text Available Redesigning user association strategies to improve energy efficiency (EE has been viewed as one of the promising shifting paradigms for the fifth generation (5G cellular networks. In this paper, we investigate how to optimize users’ association to enhance EE for hyper dense heterogeneous networking in the 5G cellular networks, where the low-power node (LPN much outnumbers the high-power node (HPN. To characterize that densely deployed LPNs would undertake a majority of high-rate services, while HPNs mainly support coverage; the EE metric is defined as average weighted EE of access nodes with the unit of bit per joule. Then, the EE optimization objective function is formulated and proved to be nonconvex. Two mathematical transformation techniques are presented to solve the nonconvex problem. In the first case, the original problem is reformulated as an equivalent problem involving the maximization of a biconcave function. In the second case, it is equivalent to a concave minimization problem. We focus on the solution of the biconcave framework, and, by exploiting the biconcave structure, a novel iterative algorithm based on dual theory is proposed, where a partially optimal solution can be achieved. Simulation results have verified the effectiveness of the proposed algorithm.

CD81 Receptor Regions outside the Large Extracellular Loop Determine Hepatitis C Virus Entry into Hepatoma Cells

Directory of Open Access Journals (Sweden)

Pia Banse

2018-04-01

Full Text Available Hepatitis C virus (HCV enters human hepatocytes using four essential entry factors, one of which is human CD81 (hCD81. The tetraspanin hCD81 contains a large extracellular loop (LEL, which interacts with the E2 glycoprotein of HCV. The role of the non-LEL regions of hCD81 (intracellular tails, four transmembrane domains, small extracellular loop and intracellular loop is poorly understood. Here, we studied the contribution of these domains to HCV susceptibility of hepatoma cells by generating chimeras of related tetraspanins with the hCD81 LEL. Our results show that non-LEL regions in addition to the LEL determine susceptibility of cells to HCV. While closely related tetraspanins (X. tropicalis CD81 and D. rerio CD81 functionally complement hCD81 non-LEL regions, distantly related tetraspanins (C. elegans TSP9 amd D. melanogaster TSP96F do not and tetraspanins with intermediate homology (hCD9 show an intermediate phenotype. Tetraspanin homology and susceptibility to HCV correlate positively. For some chimeras, infectivity correlates with surface expression. In contrast, the hCD9 chimera is fully surface expressed, binds HCV E2 glycoprotein but is impaired in HCV receptor function. We demonstrate that a cholesterol-coordinating glutamate residue in CD81, which hCD9 lacks, promotes HCV infection. This work highlights the hCD81 non-LEL regions as additional HCV susceptibility-determining factors.

Cell signaling heterogeneity is modulated by both cell-intrinsic and -extrinsic mechanisms: An integrated approach to understanding targeted therapy.

Science.gov (United States)

Kim, Eunjung; Kim, Jae-Young; Smith, Matthew A; Haura, Eric B; Anderson, Alexander R A

2018-03-01

During the last decade, our understanding of cancer cell signaling networks has significantly improved, leading to the development of various targeted therapies that have elicited profound but, unfortunately, short-lived responses. This is, in part, due to the fact that these targeted therapies ignore context and average out heterogeneity. Here, we present a mathematical framework that addresses the impact of signaling heterogeneity on targeted therapy outcomes. We employ a simplified oncogenic rat sarcoma (RAS)-driven mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signaling pathway in lung cancer as an experimental model system and develop a network model of the pathway. We measure how inhibition of the pathway modulates protein phosphorylation as well as cell viability under different microenvironmental conditions. Training the model on this data using Monte Carlo simulation results in a suite of in silico cells whose relative protein activities and cell viability match experimental observation. The calibrated model predicts distributional responses to kinase inhibitors and suggests drug resistance mechanisms that can be exploited in drug combination strategies. The suggested combination strategies are validated using in vitro experimental data. The validated in silico cells are further interrogated through an unsupervised clustering analysis and then integrated into a mathematical model of tumor growth in a homogeneous and resource-limited microenvironment. We assess posttreatment heterogeneity and predict vast differences across treatments with similar efficacy, further emphasizing that heterogeneity should modulate treatment strategies. The signaling model is also integrated into a hybrid cellular automata (HCA) model of tumor growth in a spatially heterogeneous microenvironment. As a proof of concept, we simulate tumor responses to targeted therapies in a spatially segregated tissue structure containing tumor

Modeling the mechanics of cancer: effect of changes in cellular and extra-cellular mechanical properties.

Science.gov (United States)

Katira, Parag; Bonnecaze, Roger T; Zaman, Muhammad H

2013-01-01

Malignant transformation, though primarily driven by genetic mutations in cells, is also accompanied by specific changes in cellular and extra-cellular mechanical properties such as stiffness and adhesivity. As the transformed cells grow into tumors, they interact with their surroundings via physical contacts and the application of forces. These forces can lead to changes in the mechanical regulation of cell fate based on the mechanical properties of the cells and their surrounding environment. A comprehensive understanding of cancer progression requires the study of how specific changes in mechanical properties influences collective cell behavior during tumor growth and metastasis. Here we review some key results from computational models describing the effect of changes in cellular and extra-cellular mechanical properties and identify mechanistic pathways for cancer progression that can be targeted for the prediction, treatment, and prevention of cancer.

Manipulating the Cellular Circadian Period of Arginine Vasopressin Neurons Alters the Behavioral Circadian Period.

Science.gov (United States)

Mieda, Michihiro; Okamoto, Hitoshi; Sakurai, Takeshi

2016-09-26

As the central pacemaker in mammals, the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is a heterogeneous structure consisting of multiple types of GABAergic neurons with distinct chemical identities [1, 2]. Although individual cells have a cellular clock driven by autoregulatory transcriptional/translational feedback loops of clock genes, interneuronal communication among SCN clock neurons is likely essential for the SCN to generate a highly robust, coherent circadian rhythm [1]. However, neuronal mechanisms that determine circadian period length remain unclear. The SCN is composed of two subdivisions: a ventral core region containing vasoactive intestinal peptide (VIP)-producing neurons and a dorsal shell region characterized by arginine vasopressin (AVP)-producing neurons. Here we examined whether AVP neurons act as pacemaker cells that regulate the circadian period of behavior rhythm in mice. The deletion of casein kinase 1 delta (CK1δ) specific to AVP neurons, which was expected to lengthen the period of cellular clocks [3-6], lengthened the free-running period of circadian behavior as well. Conversely, the overexpression of CK1δ specific to SCN AVP neurons shortened the free-running period. PER2::LUC imaging in slices confirmed that cellular circadian periods of the SCN shell were lengthened in mice without CK1δ in AVP neurons. Thus, AVP neurons may be an essential component of circadian pacemaker cells in the SCN. Remarkably, the alteration of the shell-core phase relationship in the SCN of these mice did not impair the generation per se of circadian behavior rhythm, thereby underscoring the robustness of the SCN network. Copyright © 2016 Elsevier Ltd. All rights reserved.

Imaging metabolic heterogeneity in cancer.

Science.gov (United States)

Sengupta, Debanti; Pratx, Guillem

2016-01-06

As our knowledge of cancer metabolism has increased, it has become apparent that cancer metabolic processes are extremely heterogeneous. The reasons behind this heterogeneity include genetic diversity, the existence of multiple and redundant metabolic pathways, altered microenvironmental conditions, and so on. As a result, methods in the clinic and beyond have been developed in order to image and study tumor metabolism in the in vivo and in vitro regimes. Both regimes provide unique advantages and challenges, and may be used to provide a picture of tumor metabolic heterogeneity that is spatially and temporally comprehensive. Taken together, these methods may hold the key to appropriate cancer diagnoses and treatments in the future.

Cellular Stress Response to Engineered Nanoparticles: Effect of Size, Surface Coating, and Cellular Uptake

Science.gov (United States)

CELLULAR STRESS RESPONSE TO ENGINEERED NANOPARTICLES: EFFECT OF SIZE, SURFACE COATING, AND CELLULAR UPTAKE RY Prasad 1, JK McGee2, MG Killius1 D Ackerman2, CF Blackman2 DM DeMarini2 , SO Simmons2 1 Student Services Contractor, US EPA, RTP, NC 2 US EPA, RTP, NC The num...

TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions.

Science.gov (United States)

Das, Anshuman; Hirai-Yuki, Asuka; González-López, Olga; Rhein, Bethany; Moller-Tank, Sven; Brouillette, Rachel; Hensley, Lucinda; Misumi, Ichiro; Lovell, William; Cullen, John M; Whitmire, Jason K; Maury, Wendy; Lemon, Stanley M

2017-09-05

Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4°C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both Tim1 -/- Ifnar1 -/- and Tim4 -/- Ifnar1 -/- double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in Ifnar1 -/- mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in Tim1 -/- Ifnar1 -/- mice compared to Ifnar1 -/- mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice. IMPORTANCE T cell immunoglobulin and mucin-containing domain protein 1 (TIM1) was reported more than

Mechanism(s of Toxic Action of Zn2+ and Selenite: A Study on AS-30D Hepatoma Cells and Isolated Mitochondria

Directory of Open Access Journals (Sweden)

Elena A. Belyaeva

2011-01-01

Full Text Available Mitochondria of AS-30D rat ascites hepatoma cells are found to be the main target for Zn2+ and sodium selenite (Na2SeO3. High [mu]M concentrations of Zn2+ or selenite were strongly cytotoxic, killing the AS-30D cells by both apoptotic and necrotic ways. Both Zn2+ and selenite produced strong changes in intracellular generation of reactive oxygen species (ROS and the mitochondrial dysfunction via the mitochondrial electron transport chain (mtETC disturbance, the membrane potential dissipation, and the mitochondrial permeability transition pore opening. The significant distinctions in toxic action of Zn2+ and selenite on AS-30D cells were found. Selenite induced a much higher intracellular ROS level (the early event compared to Zn2+ but a lower membrane potential loss and a lower decrease of the uncoupled respiration rate of the cells, whereas the mtETC disturbance was the early and critical event in the mechanism of Zn2+ cytotoxicity. Sequences of events manifested in the mitochondrial dysfunction produced by the metal/metalloid under test are compared with those obtained earlier for Cd2+, Hg2+, and Cu2+ on the same model system.

Hepatitis B virus DNA integration and transactivation of cellular genes

Directory of Open Access Journals (Sweden)

Vijay Kumar

2007-02-01

Full Text Available

Chronic hepatitis B virus (HBV infection is etiologically related to human hepatocellular carcinoma (HCC. Most HCCs contain integrated HBV DNA in hepatocyte, suggesting that the integration may be involved in carcinogenesis. Available data on the integrants from human hepatocellular carcinomas seem to represent primary integrants as well as the products of secondary rearrangements. By means of structural analyses of the possible primary integrants, it has been observed that the replication intermediates of the viral genome are the preferred substrates for integration. The integrated HBV DNA and the target cellular DNA are invariably associated with deletions, possibly reflecting the substrate for, and the mechanism of, the integration reaction. The host DNA sequences as well as the target site of integration in chromosomes are selected randomly suggesting that HBV DNA integration should bring about random mutagenic effects. Analysis of the samples recovered from hepatocellular carcinomas show that the integrated HBV DNA can mediate secondary rearrangements of chromosomes, such as translocations, inversions, deletions and (possibly amplifications. The integration of HBV DNA into the host genome occurs at early steps of clonal tumor expansion. The integration has been shown in a number of cases to affect a variety of cancer-related genes and to exert insertional mutagenesis. However, in contrast to the woodchuck model, in which specific HBV-DNA integration is detectable in most cases, insertional activation or inactivation of cellular genes appears to be a rare event in man. The discovery of transactivating functions exerted by HBx and truncated HBs(urface proteins supports the notion that these could be relevant to hepatocarcinogenesis as these transactivator sequences have been found in a large number of HCC tumors or hepatoma-derived cell lines. The HBx

Green heterogeneous wireless networks

CERN Document Server

Ismail, Muhammad; Nee, Hans-Peter; Qaraqe, Khalid A; Serpedin, Erchin

2016-01-01

This book focuses on the emerging research topic "green (energy efficient) wireless networks" which has drawn huge attention recently from both academia and industry. This topic is highly motivated due to important environmental, financial, and quality-of-experience (QoE) considerations. Specifically, the high energy consumption of the wireless networks manifests in approximately 2% of all CO2 emissions worldwide. This book presents the authors’ visions and solutions for deployment of energy efficient (green) heterogeneous wireless communication networks. The book consists of three major parts. The first part provides an introduction to the "green networks" concept, the second part targets the green multi-homing resource allocation problem, and the third chapter presents a novel deployment of device-to-device (D2D) communications and its successful integration in Heterogeneous Networks (HetNets). The book is novel in that it specifically targets green networking in a heterogeneous wireless medium, which re...

Synthesis and preliminary evaluation of 9-(4-[{sup 18}F]fluoro-3-hydroxymethylbutyl) guanine ([{sup 18}F]FHBG) in HSV1-tk gene transduced hepatoma cell

Energy Technology Data Exchange (ETDEWEB)

Moon, Byung Seok; Lee, Tae Sup [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Myoung Keun [Yonsei University, Wonju (Korea, Republic of)] (and others)

2006-08-15

The HSV1-tk reporter gene system is the most widely used system because of its advantage that direct monitoring is possible without the introduction of a separate reporter gene in case of HSV1-tk suicide gene therapy. In this study, we investigate the usefulness of the reporter probe (substrate), 9-(4-[{sup 18}F]fluoro-3-hydroxymethylbutyl) guanine ([{sup 18}F]FHBG) for non-invasive reporter gene imaging using PET in HSV1-tk expressing hepatoma model. Radiolabeled FHBG was prepared in 8 steps from a commercially available triester. The labeling reaction was carried out by NCA nucleophilic substitution with K[{sup 18}F]/K2.2.2. in acetonitrile using N2-monomethoxytrityl-9-[4-(tosly)-3-monomethoxytritylmethylbutl] guanine as a precursor, followed by deprotection with 1 N HCI. Preliminary biological properties of the probe were evaluated with MCA cells and MCA-tk cells transduced with HSV1-tk reporter gene. In vitro uptake and release-out studies of [{sup 18}F]FHBG were performed, and was analyzed correlation between [{sup 18}F]FHBG uptake ratio according to increasing numeric count of MCA-tk cells and degree of gene expression. MicroPET scan image was obtained with MCA and MCA-tk tumor beating Balb/c-nude mouse model. [{sup 18}F]FHBG was purified by reverse phase semi-HPLC system and collected at around 16-18 min. Radiochemical yield was about 20-25% (corrected for decay), radiochemical purity was > 95% and specific activity was around > 55.5 GBq/ {mu} mol. Specific accumulation of [{sup 18}F]FHBG was observed in HSV1-tk gene transduced MCA-tk cells but not MCA cells, and consecutive 1 hour release-out results showed more than 86% of uptaked [{sup 18}F]FHBG was retained inside of cells. The uptake of [{sup 18}F]FHBG was showed a highly significant linear correlation (R{sup 2} = 0.995) with increasing percentage of MCA-tk numeric cell count. In microPET scan images, remarkable difference of accumulation was observed for the two type of tumors. [{sup 18}F]FHBG appears

Imaging Cellular Proliferation in Prostate Cancer with Positron Emission Tomography

Directory of Open Access Journals (Sweden)

Hossein Jadvar

2015-07-01

Full Text Available Prostate cancer remains a major public health problem worldwide. Imaging plays an important role in the assessment of disease at all its clinical phases, including staging, restaging after definitive therapy, evaluation of therapy response, and prognostication. Positron emission tomography with a number of biologically targeted radiotracers has been demonstrated to have potential diagnostic and prognostic utility in the various clinical phases of this prevalent disease. Given the remarkable biological heterogeneity of prostate cancer, one major unmet clinical need that remains is the non-invasive imaging-based characterization of prostate tumors. Accurate tumor characterization allows for image-targeted biopsy and focal therapy as well as facilitates objective assessment of therapy effect. PET in conjunction with radiotracers that track the thymidine salvage pathway of DNA synthesis may be helpful to fulfill this necessity. We review briefly the preclinical and pilot clinical experience with the two major cellular proliferation radiotracers, [18F]-3’-deoxy-3’-fluorothymidine and [18F]-2’-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil in prostate cancer.

Microbial population heterogeneity versus bioreactor heterogeneity: evaluation of Redox Sensor Green as an exogenous metabolic biosensor

DEFF Research Database (Denmark)

Baert, Jonathan; Delepierre, Anissa; Telek, Samuel

2016-01-01

Microbial heterogeneity in metabolic performances has attracted a lot of attention, considering its potential impact on industrial bioprocesses. However, little is known about the impact of extracellular perturbations (i.e. bioreactor heterogeneity) on cell-to-cell variability in metabolic...

Epigenetics and Cellular Metabolism

Directory of Open Access Journals (Sweden)

Wenyi Xu

2016-01-01

Full Text Available Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc. is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.

Cellular-based preemption system

Science.gov (United States)

Bachelder, Aaron D. (Inventor)

2011-01-01

A cellular-based preemption system that uses existing cellular infrastructure to transmit preemption related data to allow safe passage of emergency vehicles through one or more intersections. A cellular unit in an emergency vehicle is used to generate position reports that are transmitted to the one or more intersections during an emergency response. Based on this position data, the one or more intersections calculate an estimated time of arrival (ETA) of the emergency vehicle, and transmit preemption commands to traffic signals at the intersections based on the calculated ETA. Additional techniques may be used for refining the position reports, ETA calculations, and the like. Such techniques include, without limitation, statistical preemption, map-matching, dead-reckoning, augmented navigation, and/or preemption optimization techniques, all of which are described in further detail in the above-referenced patent applications.