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Sample records for fhc exhibits tumorigenic

  1. Rat embryo fibroblast cells expressing human papillomavirus 1a genes exhibit altered growth properties and tumorigenicity.

    PubMed Central

    Green, M; Brackmann, K H; Loewenstein, P M

    1986-01-01

    Human papillomavirus 1a (HPV1a) induces benign tumors (papillomas or warts) in humans under natural conditions of infection but has not been found to replicate significantly in cell culture or in experimental animals. To establish model systems to study the oncogenic properties and expression of HPV genes, we established cell lines by cotransfecting the 3Y1 rat fibroblast cell line with HPV1a DNA constructs containing an intact early gene region and the Tn5 neomycin resistance gene. Most cell lines selected for expression of the neomycin resistance gene by treatment with the antibiotic G-418 contained viral DNA in a high-molecular-weight form. The growth characteristics of several cell lines containing high copy numbers of HPV1a DNA were studied further. They were shown to differ from the parental cell line and from G-418-resistant cell lines that did not incorporate viral DNA in the following properties: morphological alteration, increased cell density at confluence, growth in 0.5% serum, efficient anchorage-independent growth in soft agar, and rapid formation of tumors in nude mice. Those cell lines that possessed altered growth properties and tumorigenicity were found to express abundant quantities of polyadenylated virus-specific RNA species in the cytoplasm. Images PMID:3023676

  2. Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer

    PubMed Central

    Guo, Hui; Zhong, Yan; Jackson, Amanda L.; Clark, Leslie H.; Kilgore, Josh; Zhang, Lu; Han, Jianjun; Sheng, Xiugui; Gilliam, Timothy P.; Gehrig, Paola A.; Zhou, Chunxiao; Bae, Victoria L.

    2016-01-01

    Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers. PMID:26959121

  3. A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity.

    PubMed

    Li, Peng; Du, Fang; Yuelling, Larra W; Lin, Tiffany; Muradimova, Renata E; Tricarico, Rossella; Wang, Jun; Enikolopov, Grigori; Bellacosa, Alfonso; Wechsler-Reya, Robert J; Yang, Zeng-jie

    2013-12-01

    It is generally believed that cerebellar granule neurons originate exclusively from granule neuron precursors (GNPs) in the external germinal layer (EGL). Here we identified a rare population of neuronal progenitors in mouse developing cerebellum that expresses Nestin. Although Nestin is widely considered a marker for multipotent stem cells, these Nestin-expressing progenitors (NEPs) are committed to the granule neuron lineage. Unlike conventional GNPs, which reside in the outer EGL and proliferate extensively, NEPs reside in the deep part of the EGL and are quiescent. Expression profiling revealed that NEPs are distinct from GNPs and, in particular, express markedly reduced levels of genes associated with DNA repair. Consistent with this, upon aberrant activation of Sonic hedgehog (Shh) signaling, NEPs exhibited more severe genomic instability and gave rise to tumors more efficiently than GNPs. These studies revealed a previously unidentified progenitor for cerebellar granule neurons and a cell of origin for medulloblastoma.

  4. Family health climate scale (FHC-scale): development and validation

    PubMed Central

    2014-01-01

    Background The family environment is important for explaining individual health behaviour. While previous research mostly focused on influences among family members and dyadic interactions (parent-child), the purpose of this study was to develop a new measure, the Family Health Climate Scale (FHC-Scale), using a family-based approach. The FHC is an attribute of the whole family and describes an aspect of the family environment that is related to health and health behaviour. Specifically, a questionnaire measuring the FHC (a) for nutrition (FHC-NU) and (b) for activity behaviour (FHC-PA) was developed and validated. Methods In Study 1 (N = 787) the FHC scales were refined and validated. The sample was randomly divided into two subsamples. With random sample I exploratory factor analyses were conducted and items were selected according to their psychometric quality. In a second step, confirmatory factor analyses were conducted using the random sample II. In Study 2 (N = 210 parental couples) the construct validity was tested by correlating the FHC to self-determined motivation of healthy eating and physical activity as well as the families’ food environment and joint physical activities. Results Exploratory factor analyses with random sample I (Study 1) revealed a four (FHC-NU) and a three (FHC-PA) factor model. These models were cross-validated with random sample II and demonstrated an acceptable fit [FHC-PA: χ2 = 222.69, df = 74, p < .01; χ2/df = 3.01; CFI = .96; SRMR = .04; RMSEA = .07, CI .06/.08; FHC-NU: χ2 = 278.30, df = 113, p < .01, χ2/df = 2.46, CFI = .96; SRMR = .04; RMSEA = .06, CI .05/.07]. The perception of FHC correlated (p < .01) with the intrinsic motivation of healthy eating (r = .42) and physical activity (r = .56). Moreover, parental perceptions of FHC-NU correlated with household soft drink availability (r = -.31) and perceptions of FHC-PA with the frequency of

  5. Analysis of fae and fhcD genes in Mono Lake, California.

    PubMed

    Nercessian, Olivier; Kalyuzhnaya, Marina G; Joye, Samantha B; Lidstrom, Mary E; Chistoserdova, Ludmila

    2005-12-01

    Genes for two enzymes of the tetrahydromethanopterin-linked C(1) transfer pathway (fae and fhcD) were detected in hypersaline, hyperalkaline Mono Lake (California), via PCR amplification and analysis. Low diversity for fae and fhcD was noted, in contrast to the diversity previously detected in a freshwater lake, Lake Washington (Washington).

  6. Protein from intestinal Eimeria protozoan stimulates IL-12 release from dendritic cells, exhibits antitumor properties in vivo and is correlated with low intestinal tumorigenicity.

    PubMed

    Rosenberg, Barnett; Juckett, David A; Aylsworth, Charles F; Dimitrov, Nikolay V; Ho, Siu-Cheong; Judge, John W; Kessel, Sarah; Quensen, Janet; Wong, Kwai-Pheng Ho; Zlatkin, Igor; Zlatkin, Tanya

    2005-05-01

    The small intestine (SI) of vertebrates exhibits low tumorigenesis and rarely supports metastatic growth from distant tumors. Many theories have been proposed to address this phenomenon, but none has been consistently supported. One candidate mechanism is that the vast immunologic compartment of the SI provides a heightened level of tumor immunosurveillance. Consistent with this, we have identified a molecule of low abundance from bovine SI that has the hallmarks of a potent immunostimulant and may be associated with the natural suppression of cancer in the intestinal tract. The protein originates from an endemic gut protozoan, Eimeria spp., and is homologous to the antigen 3-1E previously isolated from the avian apicomplexan E. acervulina. We show here that it is a very potent stimulator of IL-12 release from dendritic cells, upregulates inflammatory modulators in vivo (IL-12, MCP-1, IL-6, TNF-alpha and INF-gamma) and has antitumor properties in mice. In addition, it is synergistic in vitro with anti-CD40 antibody, IFN-gamma, IL-4 and GM-CSF; is active across species barriers in vivo; and has no observable toxicity. Based on these activities, we speculate that it is an inducer of protozoan-targeted innate immunity, which may explain its potential benefit to the intestinal tract and potency as an agent in cancer immunotherapy.

  7. Fluorescence Lifetime of Actin in the FHC Transgenic Heart1

    PubMed Central

    Mettikolla, P.; Luchowski, R.; Gryczynski, I.; Gryczynski, Z.; Szczesna-Cordary, D.; Borejdo, J.

    2009-01-01

    Clinical studies have revealed that the D166V mutation in the ventricular myosin regulatory light chain (RLC) can cause a malignant phenotype of familial hypertrophic cardiomyopathy (FHC). It has been proposed that RLC induced FHC in the heart originates at the level of the myosin cross-bridge due to alterations in the rates of cross-bridge cycling. In this report we examine whether the environment of an active cross-bridge in cardiac myofibrils from transgenic (Tg) mice is altered by the D166V mutation in RLC. The cross-bridge environment was monitored by tracking the fluorescence lifetime (τ) of Alexa488-phalloidin labeled actin. The fluorescence lifetime is the averaged rate of decay of a fluorescent species from the excited state, which strongly depends on various environmental factors. We observed that the lifetime was high when cross-bridges were bound to actin and low when they were dissociated from it. The lifetime was measured every 50 msec from the center half of the I-band during 60 sec of rigor, relaxation and contraction of muscle. We found no differences between lifetimes of Tg-WT and Tg-D166V muscle during rigor, relaxation and contraction. The duty ratio expressed as a fraction of time that cross-bridges spend attached to the thin filaments during isometric contraction was similar in Tg-WT and Tg-D166V muscles. Since independent measurements showed a large decrease in the cross-bridge turnover rate in Tg-D166V muscle compared to Tg-WT, the fact that the duty cycle remains constant suggests that the D166V mutation of RLC causes a decrease in the rate of cross-bridge attachment to actin. PMID:19159226

  8. Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer1

    PubMed Central

    Schointuch, Monica N.; Gilliam, Timothy P.; Stine, Jessica E.; Han, Xiaoyun; Zhou, Chunxiao; Gehrig, Paola A.; Kim, Kenneth; Bae-Jump, Victoria L.

    2014-01-01

    OBJECTIVE Our goal was to evaluate the effects of simvastatin on endometrial cancer cell lines and primary cultures of endometrial cancer cells. METHODS Cell proliferation in the ECC-1 and Ishikawa endometrial cancer cell lines and primary cultures of endometrial cancer cells was assessed by MTT assay. Apoptosis and cell cycle were detected by Annexin V assay and propidium iodide staining, respectively. Reactive oxygen species and cell adhesion were assessed using ELISA assays. Invasion was analyzed using a transwell invasion assay. Mitochondrial DNA damage was confirmed using qPCR. The effects of simvastatin on the AKT/mTOR and MAPK pathways were determined by Western blotting. RESULTS Simvastatin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines and 5/8 primary cultures of endometrial cancer cells. Simvastatin treatment resulted in G1 cell cycle arrest, a reduction in the enzymatic activity of HMG-CoA, induction of apoptosis as well as DNA damage and cellular stress. Treatment with simvastatin resulted in inhibition of the MAPK pathway and exhibited differential effects on the AKT/mTOR pathway in the ECC-1 and Ishikawa cells. Minimal change in AKT phosphorylation was seen in both cell lines. An increase in phosphorylated S6 was seen in ECC-1 and a decrease was seen in Ishikawa. Treatment with simvastatin reduced cell adhesion and invasion (p<0.01) in both cell lines. CONCLUSION Simvastatin had significant anti-proliferative and anti-metastatic effects in endometrial cancer cells, possibly through modulation of the MAPK and AKT/mTOR pathways, suggesting that statins may be a promising treatment strategy for endometrial cancer. PMID:24880141

  9. Familial hypertrophic cardiomyopathy: functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development

    PubMed Central

    Brenner, Bernhard; Seebohm, Benjamin; Tripathi, Snigdha; Montag, Judith; Kraft, Theresia

    2014-01-01

    Familial hypertrophic cardiomyopathy (FHC) is the most frequent inherited cardiac disease. It has been related to numerous mutations in many sarcomeric and even some non-sarcomeric proteins. So far, however, no common mechanism has been identified by which the many different mutations in different sarcomeric and non-sarcomeric proteins trigger development of the FHC phenotype. Here we show for different MYH7 mutations variance in force pCa-relations from normal to highly abnormal as a feature common to all mutations we studied, while direct functional effects of the different FHC-mutations, e.g., on force generation, ATPase or calcium sensitivity of the contractile system, can be quite different. The functional variation among individual M. soleus fibers of FHC-patients is accompanied by large variation in mutant vs. wildtype β-MyHC-mRNA. Preliminary results show a similar variation in mutant vs. wildtype β-MyHC-mRNA among individual cardiomyocytes. We discuss our previously proposed concept as to how different mutations in the β-MyHC and possibly other sarcomeric and non-sarcomeric proteins may initiate an FHC-phenotype by functional variation among individual cardiomyocytes that results in structural distortions within the myocardium, leading to cellular and myofibrillar disarray. In addition, distortions can activate stretch-sensitive signaling in cardiomyocytes and non-myocyte cells which is known to induce cardiac remodeling with interstitial fibrosis and hypertrophy. Such a mechanism will have major implications for therapeutic strategies to prevent FHC-development, e.g., by reducing functional imbalances among individual cardiomyocytes or by inhibition of their triggering of signaling paths initiating remodeling. Targeting increased or decreased contractile function would require selective targeting of mutant or wildtype protein to reduce functional imbalances. PMID:25346696

  10. Tumorigenic DNA viruses

    SciTech Connect

    Klein, G.

    1989-01-01

    The eighth volume of Advances in Viral Oncology focuses on the three major DNA virus groups with a postulated or proven tumorigenic potential: papillomaviruses, animal hepatitis viruses, and the Epstein-Bar virus. In the opening chapters, the contributors analyze the evidence that papillomaviruses and animal hepatitis viruses are involved in tumorigenesis and describe the mechanisms that trigger virus-host cell interactions. A detailed section on the Epstein-Barr virus (EBV) - comprising more than half the book - examines the transcription and mRNA processing patterns of the virus genome; the mechanisms by which EBV infects lymphoid and epithelial cells; the immunological aspects of the virus; the actions of EBV in hosts with Acquired Immune Deficiency Syndrome; and the involvement of EBV in the etiology of Burkitt's lymphoma.

  11. Enhanced tumorigenicity by mitochondrial DNA mild mutations.

    PubMed

    Cruz-Bermúdez, Alberto; Vallejo, Carmen G; Vicente-Blanco, Ramiro J; Gallardo, María Esther; Fernández-Moreno, Miguel Ángel; Quintanilla, Miguel; Garesse, Rafael

    2015-05-30

    To understand how mitochondria are involved in malignant transformation we have generated a collection of transmitochondrial cybrid cell lines on the same nuclear background (143B) but with mutant mitochondrial DNA (mtDNA) variants with different degrees of pathogenicity. These include the severe mutation in the tRNALys gene, m.8363G>A, and the three milder yet prevalent Leber's hereditary optic neuropathy (LHON) mutations in the MT-ND1 (m.3460G>A), MT-ND4 (m.11778G>A) and MT-ND6 (m.14484T>C) mitochondrial genes. We found that 143B ρ0 cells devoid of mtDNA and cybrids harboring wild type mtDNA or that causing severe mitochondrial dysfunction do not produce tumors when injected in nude mice. By contrast cybrids containing mild mutant mtDNAs exhibit different tumorigenic capacities, depending on OXPHOS dysfunction.The differences in tumorigenicity correlate with an enhanced resistance to apoptosis and high levels of NOX expression. However, the final capacity of the different cybrid cell lines to generate tumors is most likely a consequence of a complex array of pro-oncogenic and anti-oncogenic factors associated with mitochondrial dysfunction.Our results demonstrate the essential role of mtDNA in tumorigenesis and explain the numerous and varied mtDNA mutations found in human tumors, most of which give rise to mild mitochondrial dysfunction.

  12. MicroRNAs as potential biomarkers for VERO cell tumorigenicity.

    PubMed

    Teferedegne, Belete; Macauley, Juliete; Foseh, Gideon; Dragunsky, Eugenia; Chumakov, Konstantin; Murata, Haruhiko; Peden, Keith; Lewis, Andrew M

    2014-08-20

    MicroRNA expression appears to capture the process of neoplastic development in vitro in the VERO line of African green monkey kidney (AGMK) cells (Teferedegne et al. PLoS One 2010;5(12):e14416). In that study, specific miRNA signatures were correlated with the transition, during serial tissue-culture passage, of low-density passaged 10-87 VERO cells from a non-tumorigenic phenotype at passage (p) 148 to a tumorigenic phenotype at p256. In the present study, six miRNAs (miR-376a, miR-654-3p, miR-543, miR-299-3p, miR-134 and miR-369-3p) were chosen from the identified signature miRNAs for evaluation of their use as potential biomarkers to track the progression of neoplastic development in VERO cells. Cells from the 10-87 VERO cell line at passage levels from p148 to p256 were inoculated into newborn and adult athymic nude mice. No tumors were observed in animals inoculated with cells from p148 to p186. In contrast, tumor incidences of 20% developed only in newborn mice that received 10-87 VERO cells at p194, p234 and p256. By qPCR profiling of the signature miRNAs of 10-87 VERO cells from these cell banks, we identified p194 as the level at which signature miRNAs elevated concurrently with the acquisition of tumorigenic phenotype with similar levels expressed beyond this passage. In wound-healing assays at 10-passage intervals between p150 to p250, the cells displayed a progressive increase in migration from p165 to p186; beginning at p194 and higher passages thereafter, the cells exhibited the highest rates of migration. By qPCR analysis, the same signature miRNAs were overexpressed with concomitant acquisition of the tumorigenic phenotype in another lineage of 10-87 VERO cells passaged independently at high density. Correlation between the passages at which the cells expressed a tumorigenic phenotype and the passages representing peaks in expression levels of signature miRNAs indicates that these miRNAs are potential biomarkers for the expression of the VERO cell

  13. Hypoxia-Regulated Delta-like 1 Homologue Enhances Cancer Cell Stemness and Tumorigenicity

    PubMed Central

    Kim, Yuri; Lin, Qun; Zelterman, Daniel; Yun, Zhong

    2010-01-01

    Reduced oxygenation, or hypoxia, inhibits differentiation and facilitates stem cell maintenance. Hypoxia commonly occurs in solid tumors and promotes malignant progression. Hypoxic tumors are aggressive and exhibit stem cell–like characteristics. It remains unclear, however, whether and how hypoxia regulates cancer cell differentiation and maintains cancer cell stemness. Here, we show that hypoxia increases the expression of the stem cell gene DLK1, or delta-like 1 homologue (Drosophila), in neuronal tumor cells. Inhibition of DLK1 enhances spontaneous differentiation, decreases clonogenicity, and reduces in vivo tumor growth. Overexpression of DLK1 inhibits differentiation and enhances tumorigenic potentials. We further show that the DLK1 cytoplasmic domain, especially Tyrosine339 and Serine355, is required for maintaining both clonogenicity and tumorigenicity. Because elevated DLK1 expression is found in many tumor types, our observations suggest that hypoxia and DLK1 may constitute an important stem cell pathway for the regulation of cancer stem cell–like functionality and tumorigenicity. PMID:19934310

  14. An in vivo screening system to identify tumorigenic genes.

    PubMed

    Ihara, T; Hosokawa, Y; Kumazawa, K; Ishikawa, K; Fujimoto, J; Yamamoto, M; Muramkami, T; Goshima, N; Ito, E; Watanabe, S; Semba, K

    2017-04-06

    Screening for oncogenes has mostly been performed by in vitro transformation assays. However, some oncogenes might not exhibit their transforming activities in vitro unless putative essential factors from in vivo microenvironments are adequately supplied. Here, we have developed an in vivo screening system that evaluates the tumorigenicity of target genes. This system uses a retroviral high-efficiency gene transfer technique, a large collection of human cDNA clones corresponding to ~70% of human genes and a luciferase-expressing immortalized mouse mammary epithelial cell line (NMuMG-luc). From 845 genes that were highly expressed in human breast cancer cell lines, we focused on 205 genes encoding membrane proteins and/or kinases as that had the greater possibility of being oncogenes or drug targets. The 205 genes were divided into five subgroups, each containing 34-43 genes, and then introduced them into NMuMG-luc cells. These cells were subcutaneously injected into nude mice and monitored for tumor development by in vivo imaging. Tumors were observed in three subgroups. Using DNA microarray analyses and individual tumorigenic assays, we found that three genes, ADORA2B, PRKACB and LPAR3, were tumorigenic. ADORA2B and LPAR3 encode G-protein-coupled receptors and PRKACB encodes a protein kinase A catalytic subunit. Cells overexpressing ADORA2B, LPAR3 or PRKACB did not show transforming phenotypes in vitro, suggesting that transformation by these genes requires in vivo microenvironments. In addition, several clinical data sets, including one for breast cancer, showed that the expression of these genes correlated with lower overall survival rate.

  15. Test Series 2: seismic-fragility tests of naturally-aged Class 1E Exide FHC-19 battery cells

    SciTech Connect

    Bonzon, L. L.; Hente, D. B.; Kukreti, B. M.; Schendel, J.; Tulk, J. D.; Janis, W. J.; Black, D. A.; Paulsen, G. D.; Aucoin, B. D.

    1985-03-01

    The seismic-fragility of naturally-aged nuclear station safety-related batteries is of interest for two reasons: (1) to determine actual failure modes and their thresholds and (2) to determine the validity of using the electrical capacity of individual cells as an indicator of the ''end-of-life'' of a battery if subjected to a seismic event. This report, the second in a test series of an extensive seismic research program, covers the testing of 10-year old lead-calcium Exide FHC-19 cells from the Calvert Cliffs Nuclear Power Station operated by the Baltimore Gas and Electric Company. The Exide cells were tested in two configurations using a triaxial shake table: single-cell tests, both rigidly and loosely mounted; and multicell (three-cell) tests, mounted in a typical battery rack. A total of six electrically active cells was used in the two different cell configurations.

  16. SV40-IMMORTALIZED NON-TUMORIGENIC AND TUMORIGENIC CELL LINES DIFFER IN EXPRESSION OF HALLMARK VIRAL RESPONSE MRNAS

    EPA Science Inventory

    SV40-Immortalized Non-Tumorigenic and Tumorigenic Cell Lines Differ in Expression of Hallmark Viral Response mRNAs.

    Prior to the use of an in vitra/in viva transformation system to examine the tumorigenic activity of environmental contaminants, in vitra gene expression pa...

  17. Folate levels modulate oncogene-induced replication stress and tumorigenicity

    PubMed Central

    Lamm, Noa; Maoz, Karin; Bester, Assaf C; Im, Michael M; Shewach, Donna S; Karni, Rotem; Kerem, Batsheva

    2015-01-01

    Chromosomal instability in early cancer stages is caused by replication stress. One mechanism by which oncogene expression induces replication stress is to drive cell proliferation with insufficient nucleotide levels. Cancer development is driven by alterations in both genetic and environmental factors. Here, we investigated whether replication stress can be modulated by both genetic and non-genetic factors and whether the extent of replication stress affects the probability of neoplastic transformation. To do so, we studied the effect of folate, a micronutrient that is essential for nucleotide biosynthesis, on oncogene-induced tumorigenicity. We show that folate deficiency by itself leads to replication stress in a concentration-dependent manner. Folate deficiency significantly enhances oncogene-induced replication stress, leading to increased DNA damage and tumorigenicity in vitro. Importantly, oncogene-expressing cells, when grown under folate deficiency, exhibit a significantly increased frequency of tumor development in mice. These findings suggest that replication stress is a quantitative trait affected by both genetic and non-genetic factors and that the extent of replication stress plays an important role in cancer development. PMID:26197802

  18. Skin tumorigenic potential of benzanthrone: prevention by ascorbic acid.

    PubMed

    Dwivedi, Neelam; Kumar, Sandeep; Ansari, Kausar M; Khanna, S K; Das, Mukul

    2013-09-01

    Benzanthrone (BA) exposed occupational workers have been found to exhibit toxicological manifestations in the skin, thus it is quite likely that long term exposure may lead to skin tumorigenicity. Thus, attempts were made to elucidate the tumor initiating and promoting potentials of pure (PBA) and commercial benzanthrone (CBA). Additionally, the preventive role of ascorbic acid (AsA) was also assessed. PBA showed tumor initiating activity while CBA demonstrated tumor initiating as well as promoting activities in two-stage mouse skin tumor protocol. Further, prior treatment of AsA to PBA and CBA followed by twice weekly application of 12-o-tetradecanoyl phorbal myristate acetate (TPA) resulted into delayed onset of tumor formation and similarly single application of 7,12-dimethylbenz [α] anthracene (DMBA) followed by twice weekly application of AsA and CBA showed an increase in the latency period. Thus, AsA showed a protective effect against CBA promoted skin tumor. Furthermore, the topical application of CBA significantly increased the levels of xenobiotic enzymes. The animals topically treated with AsA along with topical application of CBA, restored all the impairment observed in enzyme activities. Thus, this study suggested that AsA can be useful in preventing PBA and CBA induced skin tumorigenicity.

  19. Interfacial geometry dictates cancer cell tumorigenicity

    NASA Astrophysics Data System (ADS)

    Lee, Junmin; Abdeen, Amr A.; Wycislo, Kathryn L.; Fan, Timothy M.; Kilian, Kristopher A.

    2016-08-01

    Within the heterogeneous architecture of tumour tissue there exists an elusive population of stem-like cells that are implicated in both recurrence and metastasis. Here, by using engineered extracellular matrices, we show that geometric features at the perimeter of tumour tissue will prime a population of cells with a stem-cell-like phenotype. These cells show characteristics of cancer stem cells in vitro, as well as enhanced tumorigenicity in murine models of primary tumour growth and pulmonary metastases. We also show that interfacial geometry modulates cell shape, adhesion through integrin α5β1, MAPK and STAT activity, and initiation of pluripotency signalling. Our results for several human cancer cell lines suggest that interfacial geometry triggers a general mechanism for the regulation of cancer-cell state. Similar to how a growing tumour can co-opt normal soluble signalling pathways, our findings demonstrate how cancer can also exploit geometry to orchestrate oncogenesis.

  20. [The Fernando Henrique Cardoso (FHC) and Luiz Inácio Lula da Silva (Lula) governments and the policy for the civil servant workforce of the Brazilian government].

    PubMed

    Costa, Nilson do Rosario; Lamarca, Isabel

    2013-06-01

    This article analyzes the configuration of the active civil servant workforce of the Brazilian government during Fernando Henrique Cardoso - FHC - (1995-2002) and Luiz Inácio Lula da Silva - Lula - (2003-2010) mandates. The article associates the condition of the workforce of the Brazilian government with the changes in the government coalition. The residual participation of the Ministry of Health (MOH) in the direct provision of public services influenced the downward trend of the federal workforce.The implementation of the Unified Health System (SUS) was strongly affected by the structural adjustment of the workforce at the federal level during the decades of 1990 and 2000.

  1. In vivo mutagenicity of conazole fungicides correlates with tumorigenicity

    EPA Science Inventory

    Triadimefon, propiconazole, and myclobutanil are conazoles, an important class of agricultural and therapeutic fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. All three conazoles are generally inactive in short-term genotoxicity te...

  2. Coordination of signalling networks and tumorigenic properties by ABL in glioblastoma cells

    PubMed Central

    Arechederra, Maria; Baeza, Nathalie; Figarella-Branger, Dominique; Helmbacher, Françoise; Maina, Flavio

    2016-01-01

    The cytoplasmic tyrosine kinase ABL exerts positive or negative effects in solid tumours according to the cellular context, thus functioning as a “switch modulator”. The therapeutic effects of drugs targeting a set of signals encompassing ABL have been explored in several solid tumours. However, the net contribution of ABL inhibition by these agents remains elusive as these drugs also act on other signalling components. Here, using glioblastoma (GBM) as a cellular paradigm, we report that ABL inhibition exacerbates mesenchymal features as highlighted by down-regulation of epithelial markers and up-regulation of mesenchymal markers. Cells with permanent ABL inhibition exhibit enhanced motility and invasive capabilities, while proliferation and tumorigenic properties are reduced. Intriguingly, permanent ABL inhibition also interferes with GBM neurosphere formation and with expression of stemness markers in sphere-cultured GBM cells. Furthermore, we show that the molecular and biological characteristics of GBM cells with impaired ABL are reversible by restoring ABL levels, thus uncovering a remarkable plasticity of GBM cells to ABL threshold. A phospho-signalling screen revealed that loss of tumorigenic and self-renewal properties in GBM cells under permanent ABL inhibition coincide with drastic changes in the expression and/or phosphorylation levels of multiple signalling components. Our findings identify ABL as a crucial player for migration, invasion, proliferation, tumorigenic, and stem-cell like properties of GBM cells. Taken together, this work supports the notion that the oncogenic role of ABL in GBM cells is associated with its capability to coordinate a signalling setting that determines tumorigenic and stem-cell like properties. PMID:27732969

  3. Identification of Coordinately Regulated Functional Modules in Thyroid Tissues from Rats Exposed to a Tumorigenic and a Non-Tumorigenic Conazole Fungicide Using Oncomine®

    EPA Science Inventory

    Conazoles are triazole- or imidazole-containing fungicides used in agriculture and medicine. Using transcriptomic analysis of rat thyroid tissues exposed to either tumorigenic or non-tumorigenic structurally related conazoles, we identified new findings on thyroid gene expressio...

  4. Neonatal mouse assay for tumorigenicity: alternative to the chronic rodent bioassay.

    PubMed

    Flammang, T J; Tungeln, L S; Kadlubar, F F; Fu, P P

    1997-10-01

    The chronic rodent bioassay for tumors has been utilized systematically for 25 years to identify chemicals with carcinogenic potential in man. In general, those chemicals exhibiting tumorigenicity at multiple sites in both mice and rats have been regarded as possessing strong carcinogenic potential in humans. In comparison, the value of data collected for those test chemicals exhibiting more sporadic tumorigenicity results (e.g., single species/single sex or dose-independent) has been questioned. As knowledge of the carcinogenic process has increased, several alternative test systems, usually faster and less expensive than the 2-year bioassay, have been suggested for identification of the strongly acting, transspecies carcinogens. The International Conference on Harmonization for Technical Requirements for the Registration of Pharmaceuticals for Human Use has proposed an international standard that allows for the use of one long-term rodent carcinogenicity study, plus one supplementary study to identify potential human pharmaceutical carcinogens. The neonatal mouse assay for tumorigenicity has been used since 1959; however, relative to other alternate tests, little has been written about this system. It is clear that this assay system successfully identifies transspecies carcinogens from numerous chemical classes, thus recommending itself as a strong candidate for a supplementary study to identify potential human carcinogens. In contrast, there are decidedly less data available from this assay in response to pharmaceuticals shown to exhibit weak and/or conflicting results in the 2-year bioassay, knowledge invaluable to the regulatory process. This paper reviews the historical development and our experience with the neonatal mouse assay and includes suggestions for a standardized protocol and strategies to document its response to "weak" and/or "nongenotoxic" carcinogens.

  5. Quantitative changes in endogenous DNA damage correlate with conazole mutagenicity and tumorigenicity.

    EPA Science Inventory

    The mouse liver tumorigenic conazolefungicides triadimefon and propiconazole have previously been shown to be in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses, whereas the nontumorigenic conazole myclobutanil w...

  6. Transcriptional responses in thyroid tissues from rats treated with a tumorigenic and a non-tumorigenic triazole conazole fungicide

    SciTech Connect

    Hester, Susan D. Nesnow, Stephen

    2008-03-15

    Conazoles are azole-containing fungicides that are used in agriculture and medicine. Conazoles can induce follicular cell adenomas of the thyroid in rats after chronic bioassay. The goal of this study was to identify pathways and networks of genes that were associated with thyroid tumorigenesis through transcriptional analyses. To this end, we compared transcriptional profiles from tissues of rats treated with a tumorigenic and a non-tumorigenic conazole. Triadimefon, a rat thyroid tumorigen, and myclobutanil, which was not tumorigenic in rats after a 2-year bioassay, were administered in the feed to male Wistar/Han rats for 30 or 90 days similar to the treatment conditions previously used in their chronic bioassays. Thyroid gene expression was determined using high density Affymetrix GeneChips (Rat 230{sub 2}). Gene expression was analyzed by the Gene Set Expression Analyses method which clearly separated the tumorigenic treatments (tumorigenic response group (TRG)) from the non-tumorigenic treatments (non-tumorigenic response group (NRG)). Core genes from these gene sets were mapped to canonical, metabolic, and GeneGo processes and these processes compared across group and treatment time. Extensive analyses were performed on the 30-day gene sets as they represented the major perturbations. Gene sets in the 30-day TRG group had over representation of fatty acid metabolism, oxidation, and degradation processes (including PPAR{gamma} and CYP involvement), and of cell proliferation responses. Core genes from these gene sets were combined into networks and found to possess signaling interactions. In addition, the core genes in each gene set were compared with genes known to be associated with human thyroid cancer. Among the genes that appeared in both rat and human data sets were: Acaca, Asns, Cebpg, Crem, Ddit3, Gja1, Grn, Jun, Junb, and Vegf. These genes were major contributors in the previously developed network from triadimefon-treated rat thyroids. It is

  7. Exhibiting Lives

    ERIC Educational Resources Information Center

    Golden, Deborah; Elbaz-Luwisch, Freema

    2007-01-01

    This paper examines some of the dilemmas that accompany the emergence of the personal voice in scholarly work, by taking a close, grounded look at the way in which these unfolded in a specific academic course. As part of the course, entitled "A cultural approach to the life cycle", students were asked to participate in a group exhibition in which…

  8. Tumorigenic effects of dichloroacetic acid in female F344 rats

    EPA Science Inventory

    Introduction: Dichloroacetic acid (DCA) is a halogenated organic acid produced during oxidant disinfection of drinking water. Prior studies indicate that DCA may increase liver tumors in mice. Here we evaluated the hepatic tumorigenicity of DCA in female rats when given alone ...

  9. Museum Exhibit

    NASA Technical Reports Server (NTRS)

    1991-01-01

    A TSP from NASA Tech Briefs provided the solution to an electrical problem at a Florida museum. When a model train would not start without a jerk, a Marshall Space Flight Center development called pulse width control was adapted. The new circuit enables the train to start smoothly and reduces construction and maintenance costs. The same technology is also used in another hands-on exhibit. Applications of other TSPs are anticipated.

  10. Outdoor Exhibits

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The National Data Buoy Center (NDBC) at the John C. Stennis Space Center has exhibits located in front of the Visitors Center. These boat-shaped buoys are moored in areas of the ocean that experience hostile environmental conditions. The instruments installed gather information and relay it to the National Weather Service by satellite. Nomad buoys are 20 feet long and weigh 13,900 pounds. They provide information on wind speed and direction, humidity levels, air and sea surface temperature and air pressure. U.S. Coast Guard ships transport buoys to their mooring sites.

  11. Tumorigenic properties of alternative osteopontin isoforms in mesothelioma

    SciTech Connect

    Ivanov, Sergey V.; Ivanova, Alla V.; Goparaju, Chandra M.V.; Chen, Yuanbin; Beck, Amanda; Pass, Harvey I.

    2009-05-08

    Osteopontin (SPP1) is an inflammatory cytokine that we previously characterized as a diagnostic marker in patients with asbestos-induced malignant mesothelioma (MM). While SPP1 shows both pro- and anti-tumorigenic biological effects, little is known about the molecular basis of these activities. In this study, we demonstrate that while healthy pleura possesses all three differentially spliced SPP1 isoforms (A-C), in clinical MM specimens isoform A is markedly up-regulated and predominant. To provide a clue to possible functions of the SPP1 isoforms we next performed their functional evaluation via transient expression in MM cell lines. As a result, we report that isoforms A-C demonstrate different activities in cell proliferation, wound closure, and invasion assays. These findings suggest different functions for SPP1 isoforms and underline pro-tumorigenic properties of isoforms A and B.

  12. ATM kinase sustains HER2 tumorigenicity in breast cancer.

    PubMed

    Stagni, Venturina; Manni, Isabella; Oropallo, Veronica; Mottolese, Marcella; Di Benedetto, Anna; Piaggio, Giulia; Falcioni, Rita; Giaccari, Danilo; Di Carlo, Selene; Sperati, Francesca; Cencioni, Maria Teresa; Barilà, Daniela

    2015-04-16

    ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.

  13. Pouterin, a novel potential cytotoxic lectin-like protein with apoptosis-inducing activity in tumorigenic mammalian cells.

    PubMed

    Boleti, Ana Paula de A; Ventura, Cláudio A; Justo, Giselle Z; Silva, Rodrigo A; de Sousa, Ana Carolina T; Ferreira, Carmen V; Yano, Tomomasa; Macedo, Maria Lígia R

    2008-06-15

    In this study, the cytotoxicity of pouterin in tumorigenic and non-tumorigenic mammalian cell lines was investigated. We found that HeLa, Hep-2 and HT-29 tumor cells were highly sensitive to pouterin cytotoxicity in a dose-dependent manner, whereas non-tumorigenic Vero cells and human lymphocytes were relatively resistant to the protein. Among the tumor cell lines, HeLa cells showed the highest susceptibility to pouterin cytotoxicity, exhibiting a time-dependent increase in LDH leakage and an IC(50) value of 5mug/mL. Morphological alterations such as rounding, cell shrinkage and chromatin condensation, consistent with apoptotic cell death were observed. Apoptosis induction was demonstrated by DNA fragmentation as detected by terminal dUTP nick-end labeling (TUNEL). Furthermore, HeLa cells incubated with pouterin showed disruption of the actin cytoskeleton. Western blot analysis revealed that pouterin caused increased expression of p21, thus indicating cell cycle arrest. Subsequent studies provided evidence that apoptosis may be partially explained in the activation of the tumor necrosis factor receptor 1 (TNFR1) signaling. Interestingly, a time-dependent decrease of the expression of p65 nuclear factor kappa B (NFkappaB) subunit, concomitant with a downregulation of the inhibitor of apoptosis protein 1 (IAP1) was observed, suggesting that TNFR-mediated apoptosis is the predominant pathway induced by pouterin in HeLa cells.

  14. Altered tumor cell growth and tumorigenicity in models of microgravity

    NASA Astrophysics Data System (ADS)

    Yamauchi, K.; Taga, M.; Furian, L.; Odle, J.; Sundaresan, A.; Pellis, N.; Andrassy, R.; Kulkarni, A.

    Spaceflight environment and microgravity (MG) causes immune dysfunction and is a major health risk to humans, especially during long-term space missions. The effects of microgravity environment on tumor growth and carcinogenesis are yet unknown. Hence, we investigated the effects of simulated MG (SMG) on tumor growth and tumorigenicity using in vivo and in vitro models. B16 melanoma cells were cultured in static flask (FL) and rotating wall vessel bioreactors (BIO) to measure growth and properties, melanin production and apoptosis. BIO cultures had 50% decreased growth (p<0.01), increased doubling time and a 150% increase in melanin production (p<0.05). Flow cytometric analysis showed increased apoptosis in BIO. When BIO cultured melanoma cells were inoculated sc in mice there was a significant increase in tumorigenicity as compared to FL cells. Thus SMG may have supported &selected highly tumorigenic cells and it is pos sible that in addition to decreased immune function MG may alter tumor cell characteristics and invasiveness. Thus it is important to study effects of microgravity environment and its stressors using experimental tumors and SMG to understand and evaluate carcinogenic responses to true microgravity. Further studies on carcinogenic events and their mechanisms will allow us develop and formulate countermeasures and protect space travelers. Additional results will be presented. (Supported by NASA NCC8-168 grant, ADK)

  15. Triple negative breast cancers comprise a highly tumorigenic cell subpopulation detectable by its high responsiveness to a Sox2 regulatory region 2 (SRR2) reporter

    PubMed Central

    Jung, Karen; Gupta, Nidhi; Wang, Peng; Lewis, Jamie T.; Gopal, Keshav; Wu, Fang; Ye, Xiaoxia; Alshareef, Abdulraheem; Abdulkarim, Bassam S.; Douglas, Donna N.; Kneteman, Norman M.; Lai, Raymond

    2015-01-01

    We have recently described a novel phenotypic dichotomy within estrogen receptor-positive breast cancer cells; the cell subset responsive to a Sox2 regulatory region (SRR2) reporter (RR cells) are significantly more tumorigenic than the reporter unresponsive (RU) cells. Here, we report that a similar phenomenon also exists in triple negative breast cancer (TNBC), with RR cells more tumorigenic than RU cells. First, examination of all 3 TNBC cell lines stably infected with the SRR2 reporter revealed the presence of a cell subset exhibiting reporter activity. Second, RU and RR cells purified by flow cytometry showed that RR cells expressed higher levels of CD44, generated more spheres in a limiting dilution mammosphere formation assay, and formed larger and more complex structures in Matrigel. Third, within the CD44High/CD24− tumor-initiating cell population derived from MDA-MB-231, RR cells were significantly more tumorigenic than RU cells in an in vivo SCID/Beige xenograft mouse model. Examination of 4 TNBC tumors from patients also revealed the presence of a RR cell subset, ranging from 1.1-3.8%. To conclude, we described a novel phenotypic heterogeneity within TNBC, and the SRR2 reporter responsiveness is a useful marker for identifying a highly tumorigenic cell subset within the CD44High/CD24−tumor-initiating cell population. PMID:25868977

  16. Effect of MUC1/β-catenin interaction on the tumorigenic capacity of pancreatic CD133(+) cells.

    PubMed

    Sousa, Andreia Mota; Rei, Margarida; Freitas, Rita; Ricardo, Sara; Caffrey, Thomas; David, Leonor; Almeida, Raquel; Hollingsworth, Michael Anthony; Santos-Silva, Filipe

    2016-09-01

    Despite the fact that the biological function of cluster of differentiation (CD)133 remains unclear, this glycoprotein is currently used in the identification and isolation of tumor-initiating cells from certain malignant tumors, including pancreatic cancer. In the present study, the involvement of mucin 1 (MUC1) in the signaling pathways of a highly tumorigenic CD133+ cellular subpopulation sorted from the pancreatic cancer cell line HPAF-II was evaluated. The expression of MUC1-cytoplasmic domain (MUC1-CD) and oncogenic signaling transducers (epidermal growth factor receptor, protein kinase C delta, glycogen synthase kinase 3 beta and growth factor receptor-bound protein 2), as well as the association between MUC1 and β-catenin, were characterized in HPAF-II CD133+ and CD133low cell subpopulations and in tumor xenografts generated from these cells. Compared with HPAF CD133(low) cells, HPAF-II CD133+ cancer cells exhibited increased tumorigenic potential in immunocompromised mice, which was associated with overexpression of MUC1 and with the accordingly altered expression profile of MUC1-associated signaling partners. Additionally, MUC1-CD/β-catenin interactions were increased both in the HPAF-II CD133+ cell subpopulation and derived tumor xenografts compared with HPAF CD133(low) cells. These results suggest that, in comparison with HPAF CD133(low) cells, CD133+ cells exhibit higher expression of MUC1, which contributes to their tumorigenic phenotype through increased interaction between MUC1-CD and β-catenin, which in turn modulates oncogenic signaling cascades.

  17. Shed syndecan-2 enhances tumorigenic activities of colon cancer cells

    PubMed Central

    Choi, Sojoong; Choi, Youngsil; Jun, Eunsung; Kim, In-San; Kim, Seong-Eun; Jung, Sung-Ae; Oh, Eok-Soo

    2015-01-01

    Because earlier studies showed the cell surface heparan sulfate proteoglycan, syndecan-2, sheds from colon cancer cells in culture, the functional roles of shed syndecan-2 were assessed. A non-cleavable mutant of syndecan-2 in which the Asn148-Leu149 residues were replaced with Asn148-Ile149, had decreased shedding, less cancer-associated activities of syndecan-2 in vitro, and less syndecan-2-mediated metastasis of mouse melanoma cells in vivo, suggesting the importance of shedding on syndecan-2-mediated pro-tumorigenic functions. Indeed, shed syndecan-2 from cancer-conditioned media and recombinant shed syndecan-2 enhanced cancer-associated activities, and depletion of shed syndecan-2 abolished these effects. Similarly, shed syndecan-2 was detected from sera of patients from advanced carcinoma (625.9 ng/ml) and promoted cancer-associated activities. Furthermore, a series of syndecan-2 deletion mutants showed that the tumorigenic activity of shed syndecan-2 resided in the C-terminus of the extracellular domain and a shed syndecan-2 synthetic peptide (16 residues) was sufficient to establish subcutaneous primary growth of HT29 colon cancer cells, pulmonary metastases (B16F10 cells), and primary intrasplenic tumor growth and liver metastases (4T1 cells). Taken together, these results demonstrate that shed syndecan-2 directly enhances colon cancer progression and may be a promising therapeutic target for controlling colon cancer development. PMID:25686828

  18. PCDH10 is required for the tumorigenicity of glioblastoma cells

    SciTech Connect

    Echizen, Kanae; Nakada, Mitsutoshi; Hayashi, Tomoatsu; Sabit, Hemragul; Furuta, Takuya; Nakai, Miyuki; Koyama-Nasu, Ryo; Nishimura, Yukiko; Taniue, Kenzui; Morishita, Yasuyuki; Hirano, Shinji; Terai, Kenta; Todo, Tomoki; Ino, Yasushi; Mukasa, Akitake; Takayanagi, Shunsaku; Ohtani, Ryohei; Saito, Nobuhito; Akiyama, Tetsu

    2014-01-31

    Highlights: • PCDH10 is required for the proliferation, survival and self-renewal of glioblastoma cells. • PCDH10 is required for glioblastoma cell migration and invasion. • PCDH10 is required for the tumorigenicity of glioblastoma cells. • PCDH10 may be a promising target for the therapy of glioblastoma. - Abstract: Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell–cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma.

  19. Quantitative changes in endogenous DNA adducts correlate with conazole mutagenicity and tumorigenicity in mouse liver.

    EPA Science Inventory

    We have previously shown that the conazole fungicides triadimefon and propiconazole, which are tumorigenic in mouse liver, are in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses. The nontumorigenic conazole myclo...

  20. Quantitative changes in endogenous DNA adducts correlate with conazole mutagenicity and tumorigenicity in mouse liver.**

    EPA Science Inventory

    We have previously shown that the conazole fungicides triadimefon and propiconazole, which are tumorigenic in mouse liver, are in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses. The nontumorigenic conazole myclo...

  1. Differential In Vivo Tumorigenicity of Distinct Subpopulations from a Luminal-Like Breast Cancer Xenograft

    PubMed Central

    Skrbo, Nirma; Hjortland, Geir-Olav; Kristian, Alexandr; Holm, Ruth; Nord, Silje; Prasmickaite, Lina; Engebraaten, Olav; Mælandsmo, Gunhild M.; Sørlie, Therese; Andersen, Kristin

    2014-01-01

    Intratumor heterogeneity caused by genetic, phenotypic or functional differences between cancer cell subpopulations is a considerable clinical challenge. Understanding subpopulation dynamics is therefore central for both optimization of existing therapy and for development of new treatment. The aim of this study was to isolate subpopulations from a primary tumor and by comparing molecular characteristics of these subpopulations, find explanations to their differing tumorigenicity. Cell subpopulations from two patient derived in vivo models of primary breast cancer, ER+ and ER-, were identified. EpCAM+ cells from the ER+ model gave rise to tumors independently of stroma cell support. The tumorigenic fraction was further divided based on SSEA-4 and CD24 expression. Both markers were expressed in ER+ breast cancer biopsies. FAC-sorted cells based on EpCAM, SSEA-4 and CD24 expression were subsequently tested for differences in functionality by in vivo tumorigenicity assay. Three out of four subpopulations of cells were tumorigenic and showed variable ability to recapitulate the marker expression of the original tumor. Whole genome expression analysis of the sorted populations disclosed high similarity in the transcriptional profiles between the tumorigenic populations. Comparing the non-tumorigenic vs the tumorigenic populations, 44 transcripts were, however, significantly differentially expressed. A subset of these, 26 identified and named genes, highly expressed in the non-tumorigenic population, predicted longer overall survival (N = 737, p<0.0001) and distant metastasis free survival (DMFS) (N = 1379, p<0.0001) when performing Kaplan-Meier survival analysis using the GOBO online database. The 26 gene set correlated with longer DMFS in multiple breast cancer subgroups. Copy number profiling revealed no aberrations that could explain the observed differences in tumorigenicity. This study emphasizes the functional variability among cell populations that are

  2. Nonylphenol effects on human prostate non tumorigenic cells.

    PubMed

    Forte, Maurizio; Di Lorenzo, Mariana; Carrizzo, Albino; Valiante, Salvatore; Vecchione, Carmine; Laforgia, Vincenza; De Falco, Maria

    2016-05-16

    Nonylphenol (NP) is an industrial chemical with estrogenic activity both in vivo and in vitro; estrogens play a critical role in the development of prostate and may be the cause of some pathological states, including cancer. In this study we examined the effects of NP on human prostate non tumorigenic epithelial cells (PNT1A) investigating on cell proliferation, interaction with estrogen receptors (ERs) and gene expression of genes involved in prostate diseases. We found that NP affects cell proliferation at 10(-6)M, promoting a cytoplasm-nucleus translocation of ERα and not ERβ, like the natural estrogen 17β-estradiol (E2). Moreover, we showed that NP enhances gene expression of key regulators of cell cycle. Estrogen selective antagonist ICI182780 in part reverted the observed effects of NP. These results confirm the estrogenic activity of NP and suggest that other transduction pathways may be involved in NP action on prostate.

  3. Arginyltransferase ATE1 suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers

    PubMed Central

    Rai, Reena; Zhang, Fangliang; Colavita, Kristen; Leu, Nicolae Adrian; Kurosaka, Satoshi; Kumar, Akhilesh; Birnbaum, Michael D.; Győrffy, Balázs; Dong, Dawei W.; Shtutman, Michael; Kashina, Anna

    2015-01-01

    Arginylation is an emerging posttranslational modification mediated by arginyltransferase (ATE1) that is essential for mammalian embryogenesis and regulation of the cytoskeleton. Here, we discovered that Ate1 knockout embryonic fibroblasts exhibit tumorigenic properties, including abnormally rapid contact-independent growth, reduced ability to form cell-cell contacts, and chromosomal aberrations. Ate1 knockout fibroblasts can form large colonies in Matrigel and exhibit invasive behavior, unlike wild type fibroblasts. Furthermore, Ate1 knockout cells form tumors in subcutaneous xenograft assays in immunocompromised mice. Abnormal growth in these cells can be partially rescued by reintroduction of stably expressed specific Ate1 isoforms, which also reduce the ability of these cells to form tumors. Tumor array studies and bioinformatics analysis show that Ate1 is down-regulated in several types of human cancer samples at the protein level, and that its transcription level inversely correlates with metastatic progression and patient survival. We conclude that Ate1 knockout results in carcinogenic transformation of cultured fibroblasts, suggesting that in addition to its previously known activities Ate1 gene is essential for tumor suppression and also likely participates in suppression of metastatic growth. PMID:26686093

  4. Loss of giant obscurins from breast epithelium promotes epithelial-to-mesenchymal transition, tumorigenicity and metastasis

    PubMed Central

    Shriver, M; Stroka, KM; Vitolo, MI; Martin, S; Huso, DL; Konstantopoulos, K; Kontrogianni-Konstantopoulos, A

    2015-01-01

    Obscurins, encoded by the single OBSCN gene, are giant cytoskeletal proteins with structural and regulatory roles. The OBSCN gene is highly mutated in different types of cancers. Loss of giant obscurins from breast epithelial cells confers them with a survival and growth advantage, following exposure to DNA-damaging agents. Here we demonstrate that the expression levels and subcellular distribution of giant obscurins are altered in human breast cancer biopsies compared with matched normal samples. Stable clones of non-tumorigenic MCF10A cells lacking giant obscurins fail to form adhesion junctions, undergo epithelial-to-mesenchymal transition and generate >100-μm mammospheres bearing markers of cancer-initiating cells. Obscurin-knockdown MCF10A cells display markedly increased motility as a sheet in 2-dimensional (2D) substrata and individually in confined spaces and invasion in 3D matrices. In line with these observations, actin filaments redistribute to extending filopodia where they exhibit increased dynamics. MCF10A cells that stably express the K-Ras oncogene and obscurin short hairpin RNA (shRNA), but not scramble control shRNA, exhibit increased primary tumor formation and lung colonization after subcutaneous and tail vein injections, respectively. Collectively, our findings reveal that loss of giant obscurins from breast epithelium results in disruption of the cell–cell contacts and acquisition of a mesenchymal phenotype that leads to enhanced tumorigenesis, migration and invasiveness in vitro and in vivo. PMID:25381817

  5. A microRNA signature for tumorigenic conazoles in mouse liver.

    EPA Science Inventory

    Triadimefon, propiconazole and myclobutanil are conazoles, an important class of agricultural and therapeutic fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants o...

  6. Altered microRNA expression induced by tumorigenic conazoles in mouse liver.

    EPA Science Inventory

    Triadimefon, propiconazole, and myclobutanil are conazoles, an important class of agricultural and therapeutic fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants ...

  7. A potential microRNA signature for tumorigenic conazoles in mouse liver

    EPA Science Inventory

    Triadimefon, propiconazole and myclobutanil are conazoles, an important class of agricultural fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants of conazole tumor...

  8. IN VIVO MUTAGENICITY OF CONAZOLE FUNGICIDES CORRELATES WITH TUMORIGENICITY-JOURNAL

    EPA Science Inventory

    Triadimefon, propiconazole, and myclobutanil are conazoles, an important class of agricultural and therapeutic fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. All three conazoles are generally inactive in short-term genotoxicity t...

  9. Syndecan-1 alterations during the tumorigenic progression of human colonic Caco-2 cells induced by human Ha-ras or polyoma middle T oncogenes.

    PubMed Central

    Levy, P.; Munier, A.; Baron-Delage, S.; Di Gioia, Y.; Gespach, C.; Capeau, J.; Cherqui, G.

    1996-01-01

    The products of ras and src proto-oncogenes are frequently activated in a constitutive state in human colorectal cancer. In this study we attempted to establish whether the tumorigenic progression induced by oncogenic activation of p21ras and pp60c-src in human colonic Caco-2 cells is associated with specific alterations of syndecan-1, a membrane-anchored proteoglycan playing a role in cell-matrix interaction and neoplastic growth control. To this end, we used Caco-2 cells made highly tumorigenic by transfection with an activated (Val 12) human Ha-ras gene or with the polyoma middle T (Py-MT) oncogene, a constitutive activator of pp60c-src tyrosine kinase activity. Compared with control vector-transfected Caco-2 cells, both oncogene-transfected cell lines (1) contained smaller amounts of membrane-anchored PGs; (2) exhibited decreased syndecan-1 expression at the protein but not the mRNA level; (3) synthesized 35S-labelled syndecan-1 with decreased specific activity; (4) produced a syndecan-1 ectodomain with a lower molecular mass and reduced GAG chain size and sulphation; and (5) expressed heparanase degradative activity. These results show that the dramatic activation of the tumorigenic potential induced by oncogenic p21ras or Py-MT/pp60c-src in Caco-2 cells is associated with marked alterations of syndecan-1 expression at the translational and post-translational levels. Images Figure 2 PMID:8695359

  10. LKB1 expression reverses the tumorigenicity of L02 cells.

    PubMed

    Liang, Xiaoyan; Xu, Ge; Gao, Qing; Tao, Xiaohong

    2016-08-01

    The tumor-suppressor liver kinase B1 (LKB1), a highly conserved and ubiquitously expressed protein kinase, plays a critical role in tumorigenesis. In the present study, we revealed that human hepatic L02 cells had severely impaired endogenous LKB1 expression as gauged by western blot, northern blot and RT-PCR analyses. Stable ectopic expression of LKB1 in L02 cells resulted in decreased cell growth, hypophosphorylation of Rb, and marked attenuation of colony formation on soft agar. Inoculation of L02 cells into immunocompromised mice resulted in the development of subcutaneous tumors, which could be completely abrogated by ectopic LKB1 expression. The tumors that formed in the mouse model recapitulated the histopathological features of hepatocellular carcinoma under the microscope. Our results jointly suggest that severely compromised endogenous LKB1 expression in the L02 cell line may confer to L02 cells tumor-initiating capacities in vivo and in vitro, and ectopic LKB1 expression antagonizes the tumorigenic properties of L02 cells. Our findings imply that caution may be needed to interpret the results obtained on the widely used human hepatic L02 cell line. The L02 cell line may be a new model to define the cellular mechanisms of liver transformation, and to unravel the molecular mechanisms underlying the growth suppressive effect of LKB1.

  11. Psoralen-containing sunscreen is tumorigenic in hairless mice

    SciTech Connect

    Cartwright, L.E.; Walter, J.F.

    1983-06-01

    Sunscreens containing 5-methoxypsoralen (5-MOP) are currently being marketed to promote tanning by inducing psoralen-mediated ultraviolet (UV) A (320-400 nm) melanogenesis. The rationale is that this may prevent UVB (290-320 nm) radiation-induced skin damage. However, mouse studies have shown that 5-MOP has the same cutaneous photocarcinogenic potential as 8-methoxypsoralen. In addition, the 5-MOP--containing sunscreen Sun System III (SS III), when combined with UVA, induces epidermal ornithine decarboxylase activity, an enzyme associated with tumor promotion. Therefore, we investigated whether SS III had sufficient psoralen concentration to be tumorigenic in hairless mice exposed to chronic, intermittent UVA radiation. SS III was applied to hairless mice 5 days per week for 20 weeks. After each application the mice were exposed to 2.5 to 10 joules/cm2 UVA radiation. All test groups developed atypical squamous papillomas in direct proportion to the dosage of UVA radiation received. A shorter latency period for tumor development was seen with larger UVA doses. Test animals followed up to 1 year developed invasive squamous cell tumors. Control groups (SS III without UVA and UVA without SS III) remained free of tumors. Animals receiving SS III plus UVA developed persistent skin thickening and increased dermal cyst formation similar to that reported with chronic exposure to UVB, a known carcinogenic wavelength.

  12. Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice

    PubMed Central

    Yue, Feng; Karki, Anju; Castro, Beatriz; Wirbisky, Sara E.; Bidwell, Christopher A.; Freeman, Jennifer L.

    2016-01-01

    Liposarcomas (LPSs) are the most common soft-tissue cancer. Because of the lack of animal models, the cellular origin and molecular regulation of LPS remain unclear. Here, we report that mice with adipocyte-specific activation of Notch signaling (Ad/N1ICD) develop LPS with complete penetrance. Lineage tracing confirms the adipocyte origin of Ad/N1ICD LPS. The Ad/N1ICD LPS resembles human dedifferentiated LPS in histological appearance, anatomical localization, and gene expression signature. Before transformation, Ad/N1ICD adipocytes undergo dedifferentiation that leads to lipodystrophy and metabolic dysfunction. Although concomitant Pten deletion normalizes the glucose metabolism of Ad/N1ICD mice, it dramatically accelerates the LPS prognosis and malignancy. Transcriptomes and lipidomics analyses indicate that Notch activation suppresses lipid metabolism pathways that supply ligands to Pparγ, the master regulator of adipocyte homeostasis. Accordingly, synthetic Pparγ ligand supplementation induces redifferentiation of Ad/N1ICD adipocytes and tumor cells, and prevents LPS development in Ad/N1ICD mice. Importantly, the Notch target HES1 is abundantly expressed in human LPS, and Notch inhibition suppresses the growth of human dedifferentiated LPS xenografts. Collectively, ectopic Notch activation is sufficient to induce dedifferentiation and tumorigenic transformation of mature adipocytes in mouse. PMID:27573812

  13. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

    PubMed Central

    Fessart, Delphine; Domblides, Charlotte; Avril, Tony; Eriksson, Leif A; Begueret, Hugues; Pineau, Raphael; Malrieux, Camille; Dugot-Senant, Nathalie; Lucchesi, Carlo; Chevet, Eric; Delom, Frederic

    2016-01-01

    The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis. DOI: http://dx.doi.org/10.7554/eLife.13887.001 PMID:27240165

  14. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties.

    PubMed

    Fessart, Delphine; Domblides, Charlotte; Avril, Tony; Eriksson, Leif A; Begueret, Hugues; Pineau, Raphael; Malrieux, Camille; Dugot-Senant, Nathalie; Lucchesi, Carlo; Chevet, Eric; Delom, Frederic

    2016-05-30

    The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.

  15. Soft fibrin gels promote selection and growth of tumorigenic cells

    NASA Astrophysics Data System (ADS)

    Liu, Jing; Tan, Youhua; Zhang, Huafeng; Zhang, Yi; Xu, Pingwei; Chen, Junwei; Poh, Yeh-Chuin; Tang, Ke; Wang, Ning; Huang, Bo

    2012-08-01

    The identification of stem-cell-like cancer cells through conventional methods that depend on stem cell markers is often unreliable. We developed a mechanical method for selecting tumorigenic cells by culturing single cancer cells in fibrin matrices of ~100 Pa in stiffness. When cultured within these gels, primary human cancer cells or single cancer cells from mouse or human cancer cell lines grew within a few days into individual round colonies that resembled embryonic stem cell colonies. Subcutaneous or intravenous injection of 10 or 100 fibrin-cultured cells in syngeneic or severe combined immunodeficiency mice led to the formation of solid tumours at the site of injection or at the distant lung organ much more efficiently than control cancer cells selected using conventional surface marker methods or cultured on conventional rigid dishes or on soft gels. Remarkably, as few as ten such cells were able to survive and form tumours in the lungs of wild-type non-syngeneic mice.

  16. Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia.

    PubMed

    Vaughen, John; Igaki, Tatsushi

    2016-12-19

    Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.

  17. Soluble Suppression of Tumorigenicity 2 and Echocardiography in Sepsis

    PubMed Central

    Yang, Hyun Suk; Kim, Hanah; Magrini, Laura; Marino, Rossella

    2016-01-01

    Soluble suppression of tumorigenicity 2 (sST2) has emerged as a biomarker of cardiac stretch or remodeling, and has demonstrated a role in acutely decompensated heart failure. However, its role in sepsis-induced cardiac dysfunction is still unknown. We explored whether sST2 serum concentration reflects either systolic or diastolic dysfunction as measured by Doppler echocardiography. In a total of 127 patients with sepsis, correlations between sST2 and blood pressure, left ventricular (LV) ejection fraction, LV diastolic filling (ratio of early transmitral flow velocity to early diastolic mitral annulus velocity), and resting pulmonary arterial pressure were evaluated. Correlations between sST2 and other sepsis biomarkers (high-sensitivity C-reactive protein [hs-CRP] and procalcitonin) were also examined. sST2 showed a moderate correlation with mean arterial pressure (r=-0.3499) but no correlation with LV ejection fraction, diastolic filling, or resting pulmonary hypertension. It showed moderate correlations with hs-CRP and procalcitonin (r=0.2608 and r=0.3829, respectively). sST2 might have a role as a biomarker of shock or inflammation, but it cannot reflect echocardiographic findings of LV ejection fraction or diastolic filling in sepsis. PMID:27578513

  18. Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial-to-mesenchymal transition (EMT) in bladder cancer.

    PubMed

    Islam, S S; Mokhtari, R B; Noman, A S; Uddin, M; Rahman, M Z; Azadi, M A; Zlotta, A; van der Kwast, T; Yeger, H; Farhat, W A

    2016-05-01

    Activation of the sonic hedgehog (Shh) signaling pathway controls tumorigenesis in a variety of cancers. Here, we show a role for Shh signaling in the promotion of epithelial-to-mesenchymal transition (EMT), tumorigenicity, and stemness in the bladder cancer. EMT induction was assessed by the decreased expression of E-cadherin and ZO-1 and increased expression of N-cadherin. The induced EMT was associated with increased cell motility, invasiveness, and clonogenicity. These progression relevant behaviors were attenuated by treatment with Hh inhibitors cyclopamine and GDC-0449, and after knockdown by Shh-siRNA, and led to reversal of the EMT phenotype. The results with HTB-9 were confirmed using a second bladder cancer cell line, BFTC905 (DM). In a xenograft mouse model TGF-β1 treated HTB-9 cells exhibited enhanced tumor growth. Although normal bladder epithelial cells could also undergo EMT and upregulate Shh with TGF-β1 they did not exhibit tumorigenicity. The TGF-β1 treated HTB-9 xenografts showed strong evidence for a switch to a more stem cell like phenotype, with functional activation of CD133, Sox2, Nanog, and Oct4. The bladder cancer specific stem cell markers CK5 and CK14 were upregulated in the TGF-β1 treated xenograft tumor samples, while CD44 remained unchanged in both treated and untreated tumors. Immunohistochemical analysis of 22 primary human bladder tumors indicated that Shh expression was positively correlated with tumor grade and stage. Elevated expression of Ki-67, Shh, Gli2, and N-cadherin were observed in the high grade and stage human bladder tumor samples, and conversely, the downregulation of these genes were observed in the low grade and stage tumor samples. Collectively, this study indicates that TGF-β1-induced Shh may regulate EMT and tumorigenicity in bladder cancer. Our studies reveal that the TGF-β1 induction of EMT and Shh is cell type context dependent. Thus, targeting the Shh pathway could be clinically beneficial in the

  19. CdSe magic-sized quantum dots incorporated in biomembrane models at the air-water interface composed of components of tumorigenic and non-tumorigenic cells.

    PubMed

    Goto, Thiago E; Lopes, Carla C; Nader, Helena B; Silva, Anielle C A; Dantas, Noelio O; Siqueira, José R; Caseli, Luciano

    2016-07-01

    Cadmium selenide (CdSe) magic-sized quantum dots (MSQDs) are semiconductor nanocrystals with stable luminescence that are feasible for biomedical applications, especially for in vivo and in vitro imaging of tumor cells. In this work, we investigated the specific interaction of CdSe MSQDs with tumorigenic and non-tumorigenic cells using Langmuir monolayers and Langmuir-Blodgett (LB) films of lipids as membrane models for diagnosis of cancerous cells. Surface pressure-area isotherms and polarization modulation reflection-absorption spectroscopy (PM-IRRAS) showed an intrinsic interaction between the quantum dots, inserted in the aqueous subphase, and Langmuir monolayers constituted either of selected lipids or of tumorigenic and non-tumorigenic cell extracts. The films were transferred to solid supports to obtain microscopic images, providing information on their morphology. Similarity between films with different compositions representing cell membranes, with or without the quantum dots, was evaluated by atomic force microscopy (AFM) and confocal microscopy. This study demonstrates that the affinity of quantum dots for models representing cancer cells permits the use of these systems as devices for cancer diagnosis.

  20. SOX9-mediated upregulation of LGR5 is important for glioblastoma tumorigenicity

    SciTech Connect

    Hiraoka, Koji; Hayashi, Tomoatsu; Kaneko, Ryusuke; Nasu-Nishimura, Yukiko; Koyama-Nasu, Ryo; Kawasaki, Yoshihiro; Akiyama, Tetsu

    2015-05-01

    LGR5 plays an important role in the self-renewal of stem cells and is used as a marker identifying self-renewing stem cells in small intestine and hair follicles. Moreover, LGR5 has been reported to be overexpressed in several cancers. SOX9 is a transcription factor that plays a key role in development, differentiation and lineage commitment in various tissues. It has also been reported that SOX9 is overexpressed in a variety of cancers and contributes to their malignant phenotype. Here we show that LGR5 is required for the tumorigenicity of glioblastoma cells. We further show that SOX9 is upregulated in glioblastoma cells and directly enhances the expression of LGR5. We also demonstrate that knockdown of SOX9 suppresses the proliferation and tumorigenicity of glioblastoma cells. These results suggest that SOX9-mediated transcriptional regulation of LGR5 is critical for the tumorigenicity of glioblastoma cells. We speculate that the SOX9-LGR5 pathway could be a potentially promising target for the therapy of glioblastoma. - Highlights: • LGR5 is required for the tumorigenicity of glioblastoma cells. • SOX9 directly enhances the expression of LGR5. • SOX9 is required for the tumorigenicity of glioblastoma cells.

  1. Tumorigenic Polyploid Cells Contain Elevated ROS and are Selectively Targeted by Antioxidant Treatment

    PubMed Central

    Roh, Meejeon; van der Meer, Riet; Abdulkadir, Sarki A.

    2011-01-01

    Polyploidy has been linked to tumorigenicity mainly due to the chromosomal aberrations. Elevated reactive oxygen species (ROS) generation, on the other hand, has also been associated with oncogenic transformation in most cancer cells. However, a possible link between ploidy and ROS is largely unexplored. Here we have exemined the role of ROS in the tumorigenicity of polyploid cells. We show that polyploid prostate and mammary epithelial cells contain higher levels of ROS due to their higher mitochondrial contents. ROS levels and mitochondrial mass are also higher in dihydrocytochalasin B (DCB)-induced polyploid cells, suggesting that higher levels of ROS observed in polyploid cell can occur due to cytokinesis failure. Interestingly, polyploid cells were more sensitive to the inhibitory effect of the antioxidant, N-Acetyl-L-cysteine (NAC), than control diploid cells. Treatment of polyploid/diploid cells with NAC led to the selective elimination of polyploid cells over time and abrogated the tumorigenicity of polyploid cells. This effect was partially mediated via the Akt signaling pathway. We next explored a possible role for ROS in promoting chromosomal instability by analyzing the effects of ROS on the mitotic stage of the cell cycle. Enhancing ROS levels by treating cells with hydrogen peroxide delayed not only entry into and but also exit from mitosis. Furthermore, increasing ROS levels significantly increased taxol resistance. Our results indicated that increased ROS in polyploid cells can contribute to tumorigenicity and highlight the therapeutic potential of antioxidants by selectively targeting the tumorigenic polyploid cells and by reversing taxol resistance. PMID:21503880

  2. Molecular alterations in tumorigenic human bronchial and breast epithelial cells induced by high let radiation

    NASA Astrophysics Data System (ADS)

    Hei, T. K.; Zhao, Y. L.; Roy, D.; Piao, C. Q.; Calaf, G.; Hall, E. J.

    Carcinogenesis is a multi-stage process with sequence of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer. In the present study, immortalized human bronchial (BEP2D) and breast (MCF-10F) cells were irradiated with graded doses of either 150 keV/μm alpha particles or 1 GeV/nucleon 56Fe ions. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Cell fusion studies indicated that radiation-induced tumorigenic phenotype in BEP2D cells could be completely suppressed by fusion with non-tumorigenic BEP2D cells. The differential expressions of known genes between tumorigenic bronchial and breast cells induced by alpha particles and their respective control cultures were compared using cDNA expression array. Among the 11 genes identified to be differentially expressed in BEP2D cells, three ( DCC, DNA-PK and p21 CIPI) were shown to be consistently down-regulated by 2 to 4 fold in all the 5 tumor cell lines examined. In contrast, their expressions in the fusion cell lines were comparable to control BEP2D cells. Similarly, expression levels of a series of genes were found to be altered in a step-wise manner among tumorigenic MCF-10F cells. The results are highly suggestive that functional alterations of these genes may be causally related to the carcinogenic process.

  3. Nitric oxide-releasing nanoparticles: synthesis, characterization, and cytotoxicity to tumorigenic cells

    NASA Astrophysics Data System (ADS)

    Pelegrino, Milena T.; Silva, Letícia C.; Watashi, Carolina M.; Haddad, Paula S.; Rodrigues, Tiago; Seabra, Amedea B.

    2017-02-01

    Nitric oxide (NO) is involved in several biological processes, including toxicity against tumor cells. The aim of this study was to synthesize, characterize, and evaluate the cytotoxicity of NO-releasing chitosan nanoparticles. A thiol-containing molecule, mercaptosuccinic acid (MSA), was encapsulated (encapsulation efficiency of 99%) in chitosan/sodium tripolyphosphate nanoparticles (CS NPs). The obtained nanoparticles showed an average hydrodynamic size of 108.40 ± 0.96 nm and polydispersity index of 0.26 ± 0.01. MSA-CS NPs were nitrosated leading to S-nitroso-MSA-CS NPs, which act as NO donor. The cytotoxicity of CS NPs, MSA-CS NPs, and S-nitroso-MSA-CS NPs were evaluated in several tumor cells, including human hepatocellular carcinoma (HepG2), mouse melanoma (B16F10), and human chronic myeloid leukemia (K562) cell lines and Lucena-1, a vincristine-resistant K562 cell line. Both CS NPs and MSA-CS NPs did not cause toxic effects in these cells, whereas S-nitroso-MSA-CS NPs caused potent cytotoxic effects in all the tested tumor cell lines. The half-maximal inhibitory concentration values of S-nitroso-MSA-CS NPs were 19.7, 10.5, 22.8, and 27.8 μg·mL-1 for HepG2, B16F10, K562, and Lucena-1 cells, respectively. In contrast, S-nitroso-MSA-CS NPs exhibited lower cytotoxic to non-tumorigenic melanocytes (Melan-A) when compared with melanoma B16F10. Therefore, the results highlight the potential use of NO-releasing CS NPs in antitumor chemotherapy.

  4. Transformation and Tumorigenicity Testing of Simian Cell Lines and Evaluation of Poliovirus Replication

    PubMed Central

    Dotti, Silvia; Lombardo, Tina; Villa, Riccardo; Cacciamali, Andrea; Zanotti, Cinzia; Andreani, Nadia Andrea; Cinotti, Stefano; Ferrari, Maura

    2017-01-01

    The key role of cell cultures in different scientific fields is worldwide recognized, both as in vitro research models alternative to laboratory animals and substrates for biological production. However, many safety concerns rise from the use of animal/human cell lines that may be tumorigenic, leading to potential adverse contaminations in cell-derived biologicals. In order to evaluate the suitability of 13 different cell lines for Poliovirus vaccine production, safety and quality, in vitro/in vivo tumorigenicity and Poliovirus propagation properties were evaluated. Our results revealed that non-human primate cell lines CYNOM-K1, FRhK-4, 4MBr-5 and 4647 are free of tumorigenic features and represent highly susceptible substrates for attenuated Sabin Poliovirus strains. In particular, FRhK-4 and 4647 cell lines are characterized by a higher in vitro replication, resulting indicated for the use in large-scale production field. PMID:28046048

  5. Ethics on Exhibit

    ERIC Educational Resources Information Center

    Vick, Randy M.

    2011-01-01

    This article discusses ethical questions raised by an exhibition of work by an artist with a history of mental illness and the exhibition's relevance to art therapy and “outsider art” discourse on the subject. Considerations for how such an exhibit could be handled had the circumstances included an art therapist and art therapy client are…

  6. Decreased tumorigenicity correlates with expression of altered cell surface carbohydrates in Lec9 CHO cells.

    PubMed Central

    Ripka, J; Shin, S; Stanley, P

    1986-01-01

    To investigate a role for surface carbohydrates in cellular malignancy, 15 different glycosylation-defective CHO cell mutants were examined for their tumorigenic and metastatic capacities after subcutaneous injection into nude mice. Most of the glycosylation mutants displayed similar or slightly decreased tumorigenicity compared with parental CHO cells. Neither parental CHO cells nor any of the mutants were observed to metastasize. However, independent isolates of one mutant type, Lec9, showed a dramatic reduction in tumor formation. The altered carbohydrates expressed at the surface of Lec9 cells appeared to be responsible for their loss of tumorigenicity, because revertants for lectin resistance were able to form tumors, and a double mutant (Lec9.Lec1) that expressed a Lec1 glycosylation phenotype also formed tumors. Finally, Lec9 cells were able to form tumors in gamma-irradiated nude mice, suggesting that recognition by an irradiation-sensitive host cell(s) was responsible for their reduced tumorigenicity in untreated nude mice. PMID:3785164

  7. Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity

    PubMed Central

    2010-01-01

    Background The serine/threonine kinase PIM1 has been implicated as an oncogene in various human cancers including lymphomas, gastric, colorectal and prostate carcinomas. In mouse models, Pim1 is known to cooperate with c-Myc to promote tumorigenicity. However, there has been limited analysis of the tumorigenic potential of Pim1 overexpression in benign and malignant human prostate cancer cells in vivo. Methods We overexpressed Pim1 in three human prostate cell lines representing different disease stages including benign (RWPE1), androgen-dependent cancer (LNCaP) and androgen-independent cancer (DU145). We then analyzed in vitro and in vivo tumorigenicity as well as the effect of Pim1 overexpression on c-MYC transcriptional activity by reporter assays and gene expression profiling using an inducible MYC-ER system. To validate that Pim1 induces tumorigenicity and target gene expression by modulating c-MYC transcriptional activity, we inhibited c-MYC using a small molecule inhibitor (10058-F4) or RNA interference. Results Overexpression of Pim1 alone was not sufficient to convert the benign RWPE1 cell to malignancy although it enhanced their proliferation rates when grown as xenografts in vivo. However, Pim1 expression enhanced the in vitro and in vivo tumorigenic potentials of the human prostate cancer cell lines LNCaP and DU145. Reporter assays revealed increased c-MYC transcriptional activity in Pim1-expressing cells and mRNA expression profiling demonstrated that a large fraction of c-MYC target genes were also regulated by Pim1 expression. The c-MYC inhibitor 10058-F4 suppressed the tumorigenicity of Pim1-expressing prostate cancer cells. Interestingly, 10058-F4 treatment also led to a reduction of Pim1 protein but not mRNA. Knocking-down c-MYC using short hairpin RNA reversed the effects of Pim1 on Pim1/MYC target genes. Conclusion Our results suggest an in vivo role of Pim1 in promoting prostate tumorigenesis although it displayed distinct oncogenic activities

  8. An Exhibit for Touching.

    ERIC Educational Resources Information Center

    Hunt, Susan

    1979-01-01

    An exhibit designed for visually handicapped persons presented by the Kalamazoo (Michigan) Institute of Art included bronze sculptures and oil paintings from the institute's permanent collection. (CL)

  9. A Teaching Aids Exhibition.

    ERIC Educational Resources Information Center

    Mahanja, Salah

    1985-01-01

    Describes an exhibition for the benefit of teachers of English in Arab Primary Schools, which was prepared by third-year students at the Teachers College for Arab Teachers. The exhibition included games, songs, audiovisual aids, crossword puzzles, vocabulary, spelling booklets, preposition aids, and worksheet and lesson planning aids. (SED)

  10. Communicating Science through Exhibitions

    NASA Astrophysics Data System (ADS)

    Dusenbery, P.; Harold, J.; Morrow, C.

    It is critically important for the public to better understand the scientific process. Museum exhibitions are an important part of informal science education that can effectively reach public audiences as well as school groups. They provide an important gateway for the public to learn about compelling scientific endeavors. There are many ways for scientists to help develop science exhibitions. The Space Science Institute (SSI) is a national leader in producing traveling science exhibitions and their associated educational programming (i.e. interactive websites, educator workshops, public talks, instructional materials). Two of its exhibitions, Space Weather Center and MarsQuest, are currently on tour. Another exhibition, Alien Earths, is in development. The Space Weather Center was developed in partnership with various research missions at NASA's Goddard Space Flight Center. MarsQuest is a 5000 square-foot traveling exhibition. The exhibit's second 3-year tour began this January at the Detroit Science Center. It is enabling millions of Americans to share in the excitement of the scientific exploration of Mars and to learn more about their own planet in the process. The 3,000 square-foot traveling exhibition, called Alien Earths, will bring origins-related research and discoveries to students and the American public. Alien Earths has four interrelated exhibit areas: Our Place in Space, Star Birth, PlanetQuest, and Search for Life. Exhibit visitors will explore the awesome events surrounding the birth of stars and planets; they will join scientists in the hunt for planets outside our solar system including those that may be in ``habitable zones'' around other stars; and finally they will be able to learn about how scientists are looking for signs of life beyond Earth. Besides the exhibits, SSI is also developing interactive web sites based on exhibit themes. New technologies are transforming the Web from a static medium to an interactive environment with tremendous

  11. New Hurricane Exhibit

    NASA Technical Reports Server (NTRS)

    2007-01-01

    A new exhibit in StenniSphere depicting NASA's role in hurricane prediction and research and SSC's role in helping the region recover from Hurricane Katrina. The cyclone-shaped exhibit focuses on the effects of the Aug. 29, 2005 storm and outlines how NASA is working to improve weather forecasting. Through photos, 3-D models and digital animations, the exhibit tells the story of what happened inside the storm and how NASA's scientific research can increase the accuracy of hurricane tracking and modeling.

  12. Expression of the alpha subunit of human chorionic gonadotropin is specifically correlated with tumorigenic expression in human cell hybrids.

    PubMed Central

    Stanbridge, E J; Rosen, S W; Sussman, H H

    1982-01-01

    The expression of HeLa parent phenotype protein markers, the alpha subunit of human chorionic gonadotropin and placental alkaline phosphatase isoenzymes, has been evaluated in paired tumorigenic and nontumorigenic HeLa-fibroblast human cell hybrids. Both of these proteins have been used clinically as markers of malignancy. The results showed that both are expressed in the hybrids. Expression of the gonadotropin subunit in the hybrids is specifically correlated with tumorigenicity; the placental alkaline phosphatase isoenzyme showed no such correlation and was expressed in both tumorigenic and nontumorigenic hybrids. PMID:6959112

  13. Test Control Center exhibit

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Have you ever wondered how the engineers at John C. Stennis Space Center in Hancock County, Miss., test fire a Space Shuttle Main Engine? The Test Control Center exhibit at StenniSphere can answer your questions by simulating the test firing of a Space Shuttle Main Engine. A recreation of one of NASA's test control centers, the exhibit explains and portrays the 'shake, rattle and roar' that happens during a real test firing.

  14. Communicating Science through Exhibitions

    NASA Astrophysics Data System (ADS)

    Dusenbery, Paul

    2005-04-01

    It is critically important for the public to better understand the scientific process. Museum exhibitions are an important part of informal science education that can effectively reach public audiences as well as school groups. They provide an important gateway for the public to learn about compelling scientific endeavors. Science exhibitions also provide a marvelous opportunity for scientists to become engaged in the exhibit development process. The Space Science Institute (SSI) is a national leader in producing traveling science exhibitions and their associated educational programming (i.e. interactive websites, educator workshops, public talks, instructional materials). The focus of this presentation will be on two of its exhibit projects: MarsQuest (on tour for four years) and Alien Earths (its tour began early in 2005). MarsQuest is enabling millions of Americans to share in the excitement of the scientific exploration of Mars and to learn more about their own planet in the process. Alien Earths will bring origins-related research and discoveries to students and the American public. It has four interrelated exhibit areas: Our Place in Space, Star Birth, Planet Quest, and Search for Life. Exhibit visitors will explore the awesome events surrounding the birth of stars and planets; they will join scientists in the hunt for planets outside our solar system including those that may be in ``habitable zones'' around other stars; and finally they will be able to learn about how scientists are looking for signs of life beyond Earth. SSI is also developing interactive web sites based on exhibit themes. New technologies are transforming the Web from a static medium to an interactive environment with tremendous potential for informal education and inquiry-based investigations. This talk will focus on the role informal science projects play in effectively communicating science to a broad, public audience.

  15. Effects of maple (Acer) plant part extracts on proliferation, apoptosis and cell cycle arrest of human tumorigenic and non-tumorigenic colon cells.

    PubMed

    González-Sarrías, Antonio; Li, Liya; Seeram, Navindra P

    2012-07-01

    Phenolic-enriched extracts of maple sap and syrup, obtained from the sugar and red maple species (Acer saccharum Marsh, A. rubrum L., respectively), are reported to show anticancer effects. Despite traditional medicinal uses of various other parts of these plants by Native Americans, they have not been investigated for anticancer activity. Here leaves, stems/twigs, barks and sapwoods of both maple species were evaluated for antiproliferative effects against human colon tumorigenic (HCT-116, HT-29, Caco-2) and non-tumorigenic (CCD-18Co) cells. Extracts were standardized to total phenolic and ginnalin-A (isolated in our laboratory) levels. Overall, the extracts inhibited the growth of the colon cancer more than normal cells (over two-fold), their activities increased with their ginnalin-A levels, with red > sugar maple extracts. The red maple leaf extract, which contained the highest ginnalin-A content, was the most active extract (IC₅₀  = 35 and 16 µg/mL for extract and ginnalin-A, respectively). The extracts were not cytotoxic nor did they induce apoptosis of the colon cancer cells. However, cell cycle analyses revealed that the antiproliferative effects of the extracts were mediated through cell cycle arrest in the S-phase. The results from the current study suggest that these maple plant part extracts may have potential anticolon cancer effects.

  16. Goodness-of-fit methods for additive-risk models in tumorigenicity experiments.

    PubMed

    Ghosh, Debashis

    2003-09-01

    In tumorigenicity experiments, a complication is that the time to event is generally not observed, so that the time to tumor is subject to interval censoring. One of the goals in these studies is to properly model the effect of dose on risk. Thus, it is important to have goodness of fit procedures available for assessing the model fit. While several estimation procedures have been developed for current-status data, relatively little work has been done on model-checking techniques. In this article, we propose numerical and graphical methods for the analysis of current-status data using the additive-risk model, primarily focusing on the situation where the monitoring times are dependent. The finite-sample properties of the proposed methodology are examined through numerical studies. The methods are then illustrated with data from a tumorigenicity experiment.

  17. Tumorigenic Xenopus cells express several maternal and early embryonic mRNAs

    SciTech Connect

    Picard, J.J.; Pelle, R.; Schonne, E.; Dworkin-Rastl, E.; Dworkin, M.B.

    1986-11-01

    Recombinant cDNA libraries were constructed from poly (A)/sup +/ RNA isolated from different stages of oogenesis and embryogenesis from the clawed toad Xenopus laevis. Hybridization analyses were used to describe the accumulation of specific RNAs represented by these cDNA clones in oocytes, embryos, adult liver, a cell line derived from Xenopus borealis embryos (Xb693), and a tumorigenic substrain of that cell line (Xb693T). It was found that from 550 cDNA clones analyses, six sequences accumulate to higher titers in poly(A)/sup +/ RNA isolated from the tumorigenic cell line compared with the nontumorigenic cell line. All six sequences were expressed at high levels during oogenesis. DNA sequencing of these three sequences followed by a computer search of protein data banks has identified them as coding for the glycolytic enzyme enolase, the ATP-ADP carrier protein, and a-tubulin.

  18. Silencing of carboxypeptidase E inhibits cell proliferation, tumorigenicity, and metastasis of osteosarcoma cells

    PubMed Central

    Fan, Shuli; Li, Xu; Li, Leiming; Wang, Liguo; Du, Zhangzhen; Yang, Yan; Zhao, Jiansong; Li, Yan

    2016-01-01

    Carboxypeptidase E (CPE), a prohormone processing enzyme, has been implicated in the progression of multiple malignancies. However, the biological role and molecular mechanisms of CPE in osteosarcoma remain elusive. In this study, we assessed the effects of CPE on cell proliferation, tumorigenicity, migration, and invasion in osteosarcoma. Our results showed that silencing of CPE significantly inhibited cell proliferation, caused cell cycle arrest at G0/G1 phase, decreased the expression levels of cell cycle protein, cyclin D1, and inhibited tumorigenicity in vivo. Additionally, CPE downregulation repressed the migratory and invasive capacities of osteosarcoma cells in vitro. Furthermore, overexpression of CPE-ΔN (a splice variant of CPE) enhanced the cell growth, migration, and invasion of osteosarcoma cells. It is possible that both CPE forms are involved in the tumorigenesis and development of osteosarcoma, and therefore CPE may provide a promising biological target for osteosarcoma therapy. PMID:27274275

  19. Inhibition of heregulin expression blocks tumorigenicity and metastasis of breast cancer

    SciTech Connect

    Tsai, Miaw-Sheue; Shamon-Taylor, Lisa A.; Mehmi, Inderjit; Tang, Careen K.; Cardillo, Marina; Lupu, Ruth

    2001-12-20

    The growth factor Heregulin (HRG) is expressed in 30% of breast cancer tumors. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether blockage of HRG reduces the aggressiveness of breast cancer cells demonstrated that transfection of MDA-MB-231 with an HRG antisense cDNA suppressed proliferation, tumorigenicity, and metastasis. Blockage of the aggressive phenotype is mediated possibly through inactivation of the erbB signaling pathways and a decrease in MMP-9 activity. Our study is the first to report that HRG is a key promoter of breast cancer progression and should be deemed as a potential target in developing therapies for the treatment of breast carcinomas.

  20. Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.

    PubMed

    Kurek, Kyle C; Del Mare, Sara; Salah, Zaidoun; Abdeen, Suhaib; Sadiq, Hussain; Lee, Suk-Hee; Gaudio, Eugenio; Zanesi, Nicola; Jones, Kevin B; DeYoung, Barry; Amir, Gail; Gebhardt, Mark; Warman, Matthew; Stein, Gary S; Stein, Janet L; Lian, Jane B; Aqeilan, Rami I

    2010-07-01

    The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease.

  1. The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenes

    DTIC Science & Technology

    2015-12-01

    Tumorigenes PRINCIPAL INVESTIGATOR: Xiaoming Ju, MD CONTRACTING ORGANIZATION: Thomas Jefferson University Philadelphia, PA 19107 REPORT DATE: December 2015...COVERED (From - To) 30Sep2011 - 29Sep2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER The Role of Retinal Determination Gene Network (RDGN) in...by DACH1 in vitro and in vivo and showed using ChIP analysis the binding of DACH1 to key target genes. We used genetic deletion studies to identify

  2. Isolation of stem-like cells from spontaneous feline mammary carcinomas: Phenotypic characterization and tumorigenic potential

    SciTech Connect

    Barbieri, Federica; Wurth, Roberto; Ratto, Alessandra; Campanella, Chiara; Vito, Guendalina; Thellung, Stefano; Daga, Antonio; Cilli, Michele; Ferrari, Angelo; Florio, Tullio

    2012-04-15

    Current carcinogenesis theory states that only a small subset of tumor cells, the cancer stem cells or tumor initiating cells (TICs), are responsible for tumor formation and progression. Human breast cancer-initiating cells have been identified as CD44-expressing cells, which retain tumorigenic activity and display stem cell-like properties. Spontaneous feline mammary carcinoma (FMC) is an aggressive cancer, which shows biological similarities to the human tumor counterpart. We report the isolation and phenotypic characterization of FMC-derived stem/progenitor cells, showing in vitro self-renewal, long-lasting proliferation and in vivo tumorigenicity. Twenty-one FMC samples were collected, histologically classified and characterized for the expression of Ki67, EGFR, ER-{alpha} and CD44, by immunohistochemistry. By culture in stem cell permissive conditions, we isolated, from 13 FMCs, a CD44-positive subpopulation able to survive and proliferate in vitro as mammospheres of different sizes and morphologies. When injected in NOD/SCID mice, FMC stem-like cells initiate tumors, generating cell heterogeneity and recapitulating the original histotype. In serum-containing medium, spheroid cells showed differentiation properties as shown by morphological changes, the loss of CD44 expression and tumorigenic potential. These data show that stem-defined culture of FMC enriches for TICs and validate the use of these cells as a suitable model for comparative oncology studies of mammary biology and testing therapeutic strategies aimed at eradicating TICs. -- Highlights: Black-Right-Pointing-Pointer Feline mammary carcinoma contain a sub-population of stem-like cells expressing CD44 Black-Right-Pointing-Pointer These grow as spheres in serum-free medium and self-renew Black-Right-Pointing-Pointer Isolated stem-like cancer cells initiate tumor in immunodeficient mice Black-Right-Pointing-Pointer Xenografted tumors are phenotypically similar to the original tumor Black

  3. Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL1 and menin

    PubMed Central

    Svoboda, Laurie K.; Bailey, Natashay; Van Noord, Raelene A.; Krook, Melanie A.; Harris, Ashley; Cramer, Cassondra; Jasman, Brooke; Patel, Rajiv M.; Thomas, Dafydd; Borkin, Dmitry; Cierpicki, Tomasz; Grembecka, Jolanta; Lawlor, Elizabeth R.

    2017-01-01

    Developmental transcription programs are epigenetically regulated by the competing actions of polycomb and trithorax (TrxG) protein complexes, which repress and activate genes, respectively. Ewing sarcoma is a developmental tumor that is associated with widespread de-regulation of developmental transcription programs, including HOX programs. Posterior HOXD genes are abnormally over-expressed by Ewing sarcoma and HOXD13, in particular, contributes to the tumorigenic phenotype. In MLL1 fusion-driven leukemia, aberrant activation of HOXA genes is epigenetically mediated by the TrxG complex and HOXA gene expression and leukemogenesis are critically dependent on the protein-protein interaction between the TrxG proteins MLL1 and menin. Based on these data, we investigated whether posterior HOXD gene activation and Ewing sarcoma tumorigenicity are similarly mediated by and dependent on MLL1 and/or menin. Our findings demonstrate that Ewing sarcomas express high levels of both MLL1 and menin and that continued expression of both proteins is required for maintenance of tumorigenicity. In addition, exposure of Ewing sarcoma cells to MI-503, an inhibitor of the MLL1-menin protein-protein interaction developed for MLL1-fusion driven leukemia, leads to loss of tumorigenicity and down-regulated expression of the posterior HOXD gene cluster. Together these data demonstrate an essential role for MLL1 and menin in mediating tumor maintenance and posterior HOXD gene activation in Ewing sarcoma. A critical dependency of these tumors on the MLL1-menin interaction presents a potentially novel therapeutic target. PMID:27888797

  4. Swamp to Space exhibit

    NASA Technical Reports Server (NTRS)

    2000-01-01

    The menacing-looking alligator is really harmless. It is one of the realistic props to help convince visitors that the feel of the swamp is real in StenniSphere's Swamp to Space exhibit at John C. Stennis Space Center in Hancock County, Miss. The historical section of the Swamp to Space exhibit tells the story of why and how Stennis Space Center came to be. It also pays tribute to the families who moved their homes to make way for the space age in Mississippi.

  5. REST controls self-renewal and tumorigenic competence of human glioblastoma cells.

    PubMed

    Conti, Luciano; Crisafulli, Laura; Caldera, Valentina; Tortoreto, Monica; Brilli, Elisa; Conforti, Paola; Zunino, Franco; Magrassi, Lorenzo; Schiffer, Davide; Cattaneo, Elena

    2012-01-01

    The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.

  6. MIF Maintains the Tumorigenic Capacity of Brain Tumor-Initiating Cells by Directly Inhibiting p53.

    PubMed

    Fukaya, Raita; Ohta, Shigeki; Yaguchi, Tomonori; Matsuzaki, Yumi; Sugihara, Eiji; Okano, Hideyuki; Saya, Hideyuki; Kawakami, Yutaka; Kawase, Takeshi; Yoshida, Kazunari; Toda, Masahiro

    2016-05-01

    Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphere-forming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro However, testing for tumorigenicity revealed two distinct cell types, brain tumor-initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells. Cancer Res; 76(9); 2813-23. ©2016 AACR.

  7. Genomic instability and tumorigenic induction in immortalized human bronchial epithelial cells by heavy ions

    NASA Astrophysics Data System (ADS)

    Hei, T. K.; Piao, C. Q.; Wu, L. J.; Willey, J. C.; Hall, E. J.

    1998-11-01

    Carcinogenesis is postulated to be a progressive multistage process characterized by an increase in genomic instability and clonal selection with each mutational event endowing a selective growth advantage. Genomic instability as manifested by the amplification of specific gene fragments is common among tumor and transformed cells. In the present study, immortalized human bronchial (BEP2D) cells were irradiated with graded doses of either 1GeV/nucleon 56Fe ions or 150 keV/μm alpha particles. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Tumorigenic cells showed neither ras mutations nor deletion in the p16 tumor suppressor gene. In contrast, they harbored mutations in the p53 gene and over-expressed cyclin D1. Genomic instability among transformed cells at various stage of the carcinogenic process was examined based on frequencies of PALA resistance. Incidence of genomic instability was highest among established tumor cell lines relative to transformed, non-tumorigenic and control cell lines. Treatment of BEP2D cells with a 4 mM dose of the aminothiol WR-1065 significantly reduced their neoplastic transforming response to 56Fe particles. This model provides an opportunity to study the cellular and molecular mechanisms involved in malignant transformation of human epithelial cells by heavy ions.

  8. Pictures at an Exhibition.

    ERIC Educational Resources Information Center

    Kunz, Walter S., Jr.

    1997-01-01

    Describes the Youth Art Month exhibit in Howard County (Maryland) where students submitted their art focusing on school buildings and their interiors. Their art reveals concerns and desires about overcrowding, space utilization, school building height, outside lighting, solitude needs, and visual stimulation. The artwork is discussed in terms of…

  9. Exhibitions in Sight.

    ERIC Educational Resources Information Center

    Wasserman, Burton

    1978-01-01

    Early in the eighteenth century, Pompeii was discovered, a city that had been hidden for sixteen centuries by volcanic lava. There is a traveling exhibition of the sculptures, friezes, mosaics, and paintings being shown around the United States. Described is the history and contents of "Pompeii--A.D. 79." (RK)

  10. 1989 Architectural Exhibition Winners.

    ERIC Educational Resources Information Center

    School Business Affairs, 1990

    1990-01-01

    Winners of the 1989 Architectural Exhibition sponsored annually by the ASBO International's School Facilities Research Committee include the Brevard Performing Arts Center (Melbourne, Florida), the Capital High School (Santa Fe, New Mexico), Gage Elementary School (Rochester, Minnesota), the Lakewood (Ohio) High School Natatorium, and three other…

  11. Exhibition in Sight

    ERIC Educational Resources Information Center

    Wasserman, Burton

    1978-01-01

    Ludwig Mies van der Rohe is known primarily as an architect. However, he also designed chairs and tables. Discusses an exhibit held in New York City a few months ago which showed how well the famous architect achieved his goals in the area of furniture design. (Author/RK)

  12. Starship 2040 Exhibit

    NASA Technical Reports Server (NTRS)

    2001-01-01

    This photograph shows the Starship 2040 leaving the Marshall Space Flight Center (MSFC) for the exhibit site. Developed by the Space Transportation Directorate at MSFC, the Starship 2040 exhibit is housed in a 48-ft (14.6-m) tractor and trailer rig, permitting it to travel around the Nation, demonstrating NASA's vision of what commercial spaceflight might be like 40 years from now. All the irnovations suggested aboard the exhibit, automated vehicle health monitoring systems, high-energy propulsion drive, navigational aids and emergency and safety systems, are based on concepts and technologies now being studied at NASA Centers and partner institutions around the Nation. NASA is the nation's premier agency for development of the space transportation system, including future-generation reusable launch vehicles. Such systems, the keys to a 'real' Starship 2040, require revolutionary advances in critical aerospace technologies, from thermal, magnetic, chemical, and propellantless propulsion systems to new energy sources such as space solar power or antimatter propulsion. These and other advances are now being studied, developed, and tested at NASA field centers and partner institutions all over the Nation.

  13. Starship 2040 Exhibit

    NASA Technical Reports Server (NTRS)

    2002-01-01

    This photograph shows onlookers viewing displays within the Starship 2040 exhibit on display at Joe Davis Stadium in Huntsville, Alabama. Developed by the Space Transportation Directorate at Marshall Space Flight Center (MSFC), the Starship 2040 exhibit is housed in a 48-ft (14.6-m) tractor and trailer rig, permitting it to travel around the Nation, demonstrating NASA's vision of what commercial spaceflight might be like 40 years from now. All the irnovations suggested aboard the exhibit (automated vehicle health monitoring systems, high-energy propulsion drive, navigational aids, and emergency and safety systems) are based on concepts and technologies now being studied at NASA Centers and partner institutions around the Nation. NASA is the Nation's premier agency for development of the space transportation system, including future-generation reusable launch vehicles. Such systems, the keys to a 'real' Starship 2040, require revolutionary advances in critical aerospace technologies, from thermal, magnetic, chemical, and propellantless propulsion systems to new energy sources such as space solar power or antimatter propulsion. These and other advances are now being studied, developed, and tested at NASA field centers and partner institutions all over the Nation.

  14. Starship 2040 Exhibit

    NASA Technical Reports Server (NTRS)

    2002-01-01

    This photograph shows Justin Varnadore, son of a Marshall TV employee, at the controls of one of the many displays within the Starship 2040 exhibit on display at Joe Davis Stadium in Huntsville, Alabama. Developed by the Space Transportation Directorate at Marshall Space Flight Center (MSFC), the Starship 2040 exhibit is housed in a 48-ft (14.6-m) tractor and trailer rig, permitting it to travel around the Nation, demonstrating NASA's vision of what commercial spaceflight might be like 40 years from now. All the irnovations suggested aboard the exhibit (automated vehicle health monitoring systems, high-energy propulsion drive, navigational aids, and emergency and safety systems) are based on concepts and technologies now being studied at NASA Centers and partner institutions around the Nation. NASA is the Nation's premier agency for development of the space transportation system, including future-generation reusable launch vehicles. Such systems, the keys to a 'real' Starship 2040, require revolutionary advances in critical aerospace technologies, from thermal, magnetic, chemical, and propellantless propulsion systems to new energy sources such as space solar power or antimatter propulsion. These and other advances are now being studied, developed, and tested at NASA field centers and partner institutions all over the Nation.

  15. Online Exhibits & Concept Maps

    NASA Astrophysics Data System (ADS)

    Douma, M.

    2009-12-01

    Presenting the complexity of geosciences to the public via the Internet poses a number of challenges. For example, utilizing various - and sometimes redundant - Web 2.0 tools can quickly devour limited time. Do you tweet? Do you write press releases? Do you create an exhibit or concept map? The presentation will provide participants with a context for utilizing Web 2.0 tools by briefly highlighting methods of online scientific communication across several dimensions. It will address issues of: * breadth and depth (e.g. from narrow topics to well-rounded views), * presentation methods (e.g. from text to multimedia, from momentary to enduring), * sources and audiences (e.g. for experts or for the public, content developed by producers to that developed by users), * content display (e.g. from linear to non-linear, from instructive to entertaining), * barriers to entry (e.g. from an incumbent advantage to neophyte accessible, from amateur to professional), * cost and reach (e.g. from cheap to expensive), and * impact (e.g. the amount learned, from anonymity to brand awareness). Against this backdrop, the presentation will provide an overview of two methods of online information dissemination, exhibits and concept maps, using the WebExhibits online museum (www.webexhibits.org) and SpicyNodes information visualization tool (www.spicynodes.org) as examples, with tips on how geoscientists can use either to communicate their science. Richly interactive online exhibits can serve to engage a large audience, appeal to visitors with multiple learning styles, prompt exploration and discovery, and present a topic’s breadth and depth. WebExhibits, which was among the first online museums, delivers interactive information, virtual experiments, and hands-on activities to the public. While large, multidisciplinary exhibits on topics like “Color Vision and Art” or “Calendars Through the Ages” require teams of scholars, user interface experts, professional writers and editors

  16. Space Shuttle Cockpit exhibit

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Want to sit in the cockpit of the Space Shuttle and watch astronauts work in outer space? At StenniSphere, you can do that and much more. StenniSphere, the visitor center at John C. Stennis Space Center in Hancock County, Miss., presents 14,000-square-feet of interactive exhibits that depict America's race for space as well as a glimpse of the future. StenniSphere is open free of charge from 9 a.m. to 5 p.m. daily.

  17. Starship 2040 Exhibit

    NASA Technical Reports Server (NTRS)

    2002-01-01

    This photograph shows the Starship 2040 on display at Joe Davis Stadium in Huntsville, Alabama. Developed by the Space Transportation Directorate at Marshall Space Flight Center (MSFC), the Starship 2040 exhibit is housed in a 48-ft (14.6-m) tractor and trailer rig, permitting it to travel around the Nation, demonstrating NASA's vision of what commercial spaceflight might be like 40 years from now. All the irnovations suggested aboard the exhibit (automated vehicle health monitoring systems, high-energy propulsion drive, navigational aids, and emergency and safety systems) are based on concepts and technologies now being studied at NASA Centers and partner institutions around the Nation. NASA is the Nation's premier agency for development of the space transportation system, including future-generation reusable launch vehicles. Such systems, the keys to a 'real' Starship 2040, require revolutionary advances in critical aerospace technologies, from thermal, magnetic, chemical, and propellantless propulsion systems to new energy sources such as space solar power or antimatter propulsion. These and other advances are now being studied, developed, and tested at NASA field centers and partner institutions all over the Nation.

  18. Baculovirus-Mediated miRNA Regulation to Suppress Hepatocellular Carcinoma Tumorigenicity and Metastasis

    PubMed Central

    Chen, Chiu-Ling; Wu, Jaw-Ching; Chen, Guan-Yu; Yuan, Pei-Hsiang; Tseng, Yen-Wen; Li, Kuei-Chang; Hwang, Shiaw-Min; Hu, Yu-Chen

    2015-01-01

    MicroRNA 122 (miR-122) is a tumor suppressor for hepatocellular carcinoma (HCC) but is lowly expressed in HCC cells. MiR-151 is aberrantly overexpressed in HCC cells and promotes HCC metastasis yet its roles on HCC tumorigenicity are unknown. To combat HCC tumorigenicity/metastasis, we developed Sleeping Beauty (SB)-based hybrid baculovirus (BV) vectors that expressed (i) miR-122 precursors (pre-miR-122), (ii) miR-151 sponges, or (iii) pre-miR-122 and miR-151 sponges. Transduction of aggressive HCC cells (Mahlavu) with the pre-miR-122-expressing BV tremendously enhanced miR-122 levels for >6 weeks, suppressed the levels of downstream effectors (e.g., ADAM10 and Bcl-w), proliferation, anchorage-independent growth, motility and migration/invasion in vitro. Intratumoral injection of the pre-miR-122-expressing BV attenuated the HCC growth/metastasis. The miR-151 sponges-expressing BV diminished the miR-151 levels for 6 weeks, enhanced RhoGDIA expression, suppressed RhoGTPases, as well as motility and migration/invasion of Mahlavu cells. Intratumoral injection of the miR-151 sponge-expressing BV impeded not only HCC metastasis but also cell proliferation, MMP expression and tumor growth in vivo. The BV co-expressing pre-miR-122 and miR-151 sponges also simultaneously enhanced miR-122 expression and inhibited miR-151, and conferred antitumor/anti-metastasis effects albeit lack of synergism. These data implicate the potentials of the SB-based hybrid BV for persistently modulating miRNA and suppressing HCC tumorigenicity/metastasis. PMID:25023326

  19. miR-150 Suppresses the Proliferation and Tumorigenicity of Leukemia Stem Cells by Targeting the Nanog Signaling Pathway

    PubMed Central

    Xu, Dan-dan; Zhou, Peng-jun; Wang, Ying; Zhang, Yi; Zhang, Rong; Zhang, Li; Chen, Su-hong; Fu, Wu-yu; Ruan, Bi-bo; Xu, Hai-peng; Hu, Chao-zhi; Tian, Lu; Qin, Jin-hong; Wang, Sheng; Wang, Xiao; Liu, Qiu-ying; Ren, Zhe; Gu, Xue-kui; Li, Yao-he; Liu, Zhong; Wang, Yi-fei

    2016-01-01

    Proliferation, a key feature of cancer cells, accounts for the majority of cancer-related diseases resulting in mortality. MicroRNAs (miRNAs) plays important post-transcriptional modulation roles by acting on multiple signaling pathways, but the underlying mechanism in proliferation and tumorigenicity is unclear. Here, we identified the role of miR-150 in proliferation and tumorigenicity in leukemia stem cells (LSCs; CD34+CD38- cells). miR-150 expression was significantly down-regulated in LSCs from leukemia cell lines and clinical samples. Functional assays demonstrated that increased miR-150 expression inhibited proliferation and clonal and clonogenic growth, enhanced chemosensitivity, and attenuated tumorigenic activity of LSCs in vitro. Transplantation animal studies revealed that miR-150 overexpression progressively abrogates tumor growth. Immunohistochemistry assays demonstrated that miR-150 overexpression enhanced caspase-3 level and reduced Ki-67 level. Moreover, luciferase reporter assays indicated Nanog is a direct and functional target of miR-150. Nanog silencing using small interfering RNA recapitulated anti-proliferation and tumorigenicity inhibition effects. Furthermore, miR-150 directly down-regulated the expression of other cancer stem cell factors including Notch2 and CTNNB1. These results provide insights into the specific biological behavior of miR-150 in regulating LSC proliferation and tumorigenicity. Targeting this miR-150/Nanog axis would be a helpful therapeutic strategy to treat acute myeloid leukemia. PMID:27917123

  20. The pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells.

    PubMed

    Koyama-Nasu, R; Haruta, R; Nasu-Nishimura, Y; Taniue, K; Katou, Y; Shirahige, K; Todo, T; Ino, Y; Mukasa, A; Saito, N; Matsui, M; Takahashi, R; Hoshino-Okubo, A; Sugano, H; Manabe, E; Funato, K; Akiyama, T

    2014-04-24

    Increasing evidence suggests that brain tumors arise from the transformation of neural stem/precursor/progenitor cells. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma. Here we show that anaplastic lymphoma kinase (ALK) and its ligand pleiotrophin are required for the self-renewal and tumorigenicity of glioblastoma stem cells (GSCs). Furthermore, we demonstrate that pleiotrophin is transactivated directly by SOX2, a transcription factor essential for the maintenance of both neural stem cells and GSCs. We speculate that the pleiotrophin-ALK axis may be a promising target for the therapy of glioblastoma.

  1. miR-199a-3p targets stemness-related and mitogenic signaling pathways to suppress the expansion and tumorigenic capabilities of prostate cancer stem cells

    PubMed Central

    Liu, Ruifang; Liu, Can; Liu, Bigang; Jeter, Collene; Calhoun-Davis, Tammy; Li, Yandong; Yang, Tao; Wang, Junchen; Tang, Dean G.

    2016-01-01

    Human cancers exhibit significant cellular heterogeneity featuring tumorigenic cancer stem cells (CSCs) in addition to more differentiated progeny with limited tumor-initiating capabilities. Recent studies suggest that microRNAs (miRNAs) regulate CSCs and tumor development. A previous library screening for differential miRNA expression in CD44+ (and other) prostate CSC vs. non-CSC populations identified miR-199a-3p to be among the most highly under-expressed miRNAs in CSCs. In this study, we characterized the biological functions of miR-199a-3p in CD44+ prostate cancer (PCa) cells and in tumor regeneration. Overexpression of miR-199a-3p in purified CD44+ or bulk PCa cells, including primary PCa, inhibited proliferation and clonal expansion without inducing apoptosis. miR-199a-3p overexpression also diminished tumor-initiating capacities of CD44+ PCa cells as well as tumor regeneration from bulk PCa cells. Importantly, inducible miR-199a-3p expression in pre-established prostate tumors in NOD/SCID mice inhibited tumor growth. Using target prediction program and luciferase assays, we show mechanistically that CD44 is a direct functional target of miR-199a-3p in PCa cells. Moreover, miR-199a-3p also directly or indirectly targeted several additional mitogenic molecules, including c-MYC, cyclin D1 (CCND1) and EGFR. Taken together, our results demonstrate how the aberrant loss of a miRNA-mediated mechanism can lead to the expansion and tumorigenic activity of prostate CSCs, further supporting the development and implementation of miRNA mimics for cancer treatment. PMID:27447749

  2. Tumorigenic transformation of murine keratinocytes by the E5 genes of bovine papillomavirus type 1 and human papillomavirus type 16.

    PubMed Central

    Leptak, C; Ramon y Cajal, S; Kulke, R; Horwitz, B H; Riese, D J; Dotto, G P; DiMaio, D

    1991-01-01

    To examine the biological properties of the bovine papillomavirus type 1 (BPV) and human papillomavirus type 16 (HPV16) E5 genes, each was cloned separately into a retroviral expression vector and helper-free recombinant viruses were generated in packaging cell lines. The BPV E5 retroviruses efficiently caused morphologic and tumorigenic transformation of cultured lines of murine fibroblasts, whereas the HPV16 E5 viruses were inactive in these assays. In contrast, infection of the p117 established line of murine epidermal keratinocytes with either the BPV or the HPV16 E5 retrovirus resulted in the generation of tumorigenic cells. Pam212 murine keratinocytes were also transformed to tumorigenicity by the HPV16 E5 gene but not by the gene carrying a frameshift mutation. These results establish that the HPV16 E5 gene is a transforming gene in cells related to its normal host epithelial cells. Images PMID:1658398

  3. Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity

    PubMed Central

    Luanpitpong, Sudjit; Wang, Liying; Castranova, Vincent; Dinu, Cerasela Zoica; Issaragrisil, Surapol; Chen, Yi Charlie; Rojanasakul, Yon

    2016-01-01

    Tumor microenvironment has been recognized as a key determinant of tumor formation and metastasis, but how tumor microenvironment is affected by nanomaterials is essentially unknown. Here, we investigated whether carbon nanotubes (CNTs), a widely used nanomaterial with known carcinogenic potential, can affect cancer-associated fibroblasts (CAFs), which are a key component of tumor microenvironment that provides necessary support for tumor growth. We show for the first time that single-walled CNT and to a lesser extent multi-walled and its COOH-functionalized form induced CAF-like cells, which are non-tumorigenic in animals, but promote tumor growth of human lung carcinoma and CNT-transformed lung epithelial cells. The mechanism by which CNT-induced CAF-like cells promote tumor growth involved the acquisition of cancer stem cells (CSCs) in cancer population. Gene knockdown experiments showed that an expression of podoplanin on CAF-like cells is essential for their effects, indicating the functional role of CAF-like cells and podoplanin in CNT tumorigenic process. Our findings unveil a novel mechanism of CNT-induced carcinogenesis through the induction of CAF-like cells that support CSCs and drive tumor formation. Our results also suggest the potential utility of podoplanin as a mechanism-based biomarker for rapid screening of carcinogenicity of CNTs and related nanomaterials for their safer design. PMID:27996035

  4. Tumorigenic potential of mononucleated small cells of Hodgkin lymphoma cell lines.

    PubMed

    Ikeda, Jun-ichiro; Mamat, Suhana; Tian, Tian; Wang, Yi; Rahadiani, Nur; Aozasa, Katsuyuki; Morii, Eiichi

    2010-12-01

    Tumor cells with tumorigenic potential are limited to a small cell population known as cancer stem cells (CSCs). CSCs yield both CSCs and non-CSCs, whereas non-CSCs do not yield CSCs. CSCs have not been identified in any malignant lymphomas. Hodgkin lymphoma (HL) is a mostly B-cell neoplasm that can be diagnosed by the presence of multinucleated (Reed-Sternberg; RS) cells admixed with Hodgkin cells with distinct nucleoli and various inflammatory cells. Here, the tumorigenic potential of cells with a single nucleus (S) and cells with multiple nuclei (M), which may be equivalent to Hodgkin and RS cells, respectively, was examined in HL cell lines L1236 and L428. Cultures of single S cells yielded both S and M cells, whereas M cell cultures yielded only M cells. When either cultured in methylcellulose or inoculated into NOD/SCID mice, the colony number and tumor size were both larger in S than in M cells. Concentrations of intracellular reactive oxygen species (ROS) were at low levels in a portion of S cells that abundantly expressed FoxO3a, a transcription factor that regulates ROS-degrading enzymes. In clinical samples of HL, FoxO3a was expressed in mononuclear Hodgkin cells but not in multinucleated RS cells. These findings suggest that smaller cells or Hodgkin cells that show low-ROS concentrations and high FoxO3a expression levels might be candidates for HL CSCs.

  5. BMI-1 promotes Ewing sarcoma tumorigenicity independent of CDKN2A-repression

    PubMed Central

    Douglas, Dorothea; Hsu, Jessie Hao-Ru; Hung, Long; Cooper, Aaron; Abdueva, Diana; van Doorninck, John; Peng, Grace; Shimada, Hiro; Triche, Timothy J.; Lawlor, Elizabeth R.

    2008-01-01

    Deregulation of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we have investigated if the Ewing's Sarcoma Family of Tumors (ESFT) express BMI-1 and whether it functions as an oncogene in this highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by ESFT cells and that, although it does not significantly affect proliferation or survival, BMI-1 actively promotes anchorage independent growth in vitro and tumorigenicity in vivo. Moreover, we find that BMI-1 promotes the tumorigenicity of both p16-wild type and p16-null cell lines demonstrating that the mechanism of BMI-1 oncogenic function in ESFT is, at least in part, independent of CDKN2A repression. Expression profiling studies of ESFT cells following BMI-1 knockdown reveal that BMI-1 regulates the expression of hundreds of downstream target genes including, in particular, genes involved in both differentiation and development as well as cell:cell and cell:matrix adhesion. Gain and loss of function assays confirm that BMI-1 represses expression of the adhesion-associated basement membrane protein nidogen 1. In addition, while BMI-1 promotes ESFT adhesion, nidogen 1 inhibits cellular adhesion in vitro. Together these data support a pivotal role for BMI-1 ESFT pathogenesis and suggest that its oncogenic function in these tumors is in part mediated through modulation of adhesion pathways. PMID:18701473

  6. BRIP1 inhibits the tumorigenic properties of cervical cancer by regulating RhoA GTPase activity

    PubMed Central

    ZOU, WEI; MA, XIANGDONG; HUA, WEI; CHEN, BILIANG; HUANG, YANHONG; WANG, DETANG; CAI, GUOQING

    2016-01-01

    Breast cancer 1, early onset (BRCA1)-interacting protein 1 (BRIP1), a DNA-dependent adenosine triphosphatase and DNA helicase, is required for BRCA-associated DNA damage repair functions, and may be associated with the tumorigenesis and aggressiveness of various cancers. The present study investigated the expression of BRIP1 in normal cervix tissues and cervical carcinoma via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry assays. BRIP1 expression was observed to be reduced in squamous cancer tissue and adenocarcinoma compared with normal cervix tissue, and there were significant correlations between the reduction in BRIP1 expression and unfavorable variables, including the International Federation of Gynecologists and Obstetricians stage and presence of lymph node metastases. In order to elucidate the role of BRIP1 in cervical cancer, a BRIP1 recombinant plasmid was constructed and overexpressed in a cervical cancer cell line (HeLa). The ectopic expression of BRIP1 markedly inhibited the tumorigenic properties of HeLa cells in vitro, as demonstrated by decreased cell growth, invasion and adhesion, and increased cell apoptosis. In addition, it was identified that the inhibitory tumorigenic properties of BRIP1 may be partly attributed to the attenuation of RhoA GTPase activity. The present study provides a novel insight into the essential role of BRIP1 in cervical cancer, and suggests that BRIP1 may be a useful therapeutic target for the treatment of this common malignancy. PMID:26870246

  7. Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy*

    PubMed Central

    Puto, Lorena A.; Brognard, John; Hunter, Tony

    2015-01-01

    The DAXX transcriptional repressor was originally associated with apoptotic cell death. However, recent evidence that DAXX represses several tumor suppressor genes, including the DAPK1 and DAPK3 protein kinases, and is up-regulated in many cancers argues that a pro-survival role may predominate in a cancer context. Here, we report that DAXX has potent growth-enhancing effects on primary prostatic malignancy through inhibition of autophagy. Through stable gene knockdown and mouse subcutaneous xenograft studies, we demonstrate that DAXX promotes tumorigenicity of human ALVA-31 and PC3 prostate cancer (PCa) cells in vivo. Importantly, DAXX represses expression of essential autophagy modulators DAPK3 and ULK1 in vivo, revealing autophagy suppression as a mechanism through which DAXX promotes PCa tumorigenicity. Furthermore, DAXX knockdown increases autophagic flux in cultured PCa cells. Finally, interrogation of the OncomineTM database suggests that DAXX overexpression is associated with malignant transformation in several human cancers, including prostate and pancreatic cancers. Thus, DAXX may represent a new cancer biomarker for the detection of aggressive disease, whose tissue-specific down-regulation can serve as an improved therapeutic modality. Our results establish DAXX as a pro-survival protein in PCa and reveal that, in the early stages of tumorigenesis, autophagy suppresses prostate tumor formation. PMID:25903140

  8. Highly tumorigenic hepatocellular carcinoma cell line with cancer stem cell-like properties

    PubMed Central

    Cassim, Shamir; Lapierre, Pascal; Bilodeau, Marc

    2017-01-01

    There are limited numbers of models to study hepatocellular carcinoma (HCC) in vivo in immunocompetent hosts. In an effort to develop a cell line with improved tumorigenicity, we derived a new cell line from Hepa1-6 cells through an in vivo passage in C57BL/6 mice. The resulting Dt81Hepa1-6 cell line showed enhanced tumorigenicity compared to Hepa1-6 with more frequent (28±12 vs. 0±0 lesions at 21 days) and more rapid tumor development (21 (100%) vs. 70 days (10%)) in C57BL/6 mice. The minimal Dt81Hepa1-6 cell number required to obtain visible tumors was 100,000 cells. The Dt81Hepa1-6 cell line showed high hepatotropism with subcutaneous injection leading to liver tumors without development of tumors in lungs or spleen. In vitro, Dt81Hepa1-6 cells showed increased anchorage-independent growth (34.7±6.8 vs. 12.3±3.3 colonies; P<0.05) and increased EpCAM (8.7±1.1 folds; P<0.01) and β-catenin (5.4±1.0 folds; P<0.01) expression. A significant proportion of Dt81Hepa1-6 cells expressed EpCAM compared to Hepa1-6 (34.8±1.1% vs 0.9±0.13%; P<0.001). Enriched EpCAM+ Dt81Hepa1-6 cells led to higher tumor load than EpCAM- Dt81Hepa1-6 cells (1093±74 vs 473±100 tumors; P<0.01). The in vivo selected Dt81Hepa1-6 cell line shows high liver specificity and increased tumorigenicity compared to Hepa1-6 cells. These properties are associated with increased expression of EpCAM and β-catenin confirming that EpCAM+ HCC cells comprise a subset with characteristics of tumor-initiating cells with stem/progenitor cell features. The Dt81Hepa1-6 cell line with its cancer stem cell-like properties will be a useful tool for the study of hepatocellular carcinoma in vivo. PMID:28152020

  9. Silencing of Kv4.1 potassium channels inhibits cell proliferation of tumorigenic human mammary epithelial cells

    SciTech Connect

    Jang, Soo Hwa; Choi, Changsun; Hong, Seong-Geun; Yarishkin, Oleg V.; Bae, Young Min; Kim, Jae Gon; O'Grady, Scott M.; Kang, Kyung-Sun; Ryu, Pan Dong; Lee, So Yeong

    2009-06-26

    Potassium channel activity has been shown to facilitate cell proliferation in cancer cells. In the present study, the role of Kv4.1 channels in immortal and tumorigenic human mammary epithelial cells was investigated. Kv4.1 protein expression was positively correlated with tumorigenicity. Moreover, transfection with siRNAs targeting Kv4.1 mRNA suppressed proliferation of tumorigenic mammary epithelial cells. Experiments using mRNA isolated from human breast cancer tissues revealed that the level of Kv4.1 mRNA expression varied depending on the stage of the tumor. Kv4.1 protein expression increased during stages T2 and T3 compared to normal tissue. These results demonstrated that Kv4.1 plays a role in proliferation of tumorigenic human mammary epithelial cells. In addition, elevated Kv4.1 expression may be useful as a diagnostic marker for staging mammary tumors and selective blockers of Kv4.1 may serve to suppress tumor cell proliferation.

  10. Scaffold-Free Coculture Spheroids of Human Colonic Adenocarcinoma Cells and Normal Colonic Fibroblasts Promote Tumorigenicity in Nude Mice123

    PubMed Central

    Park, Jong-il; Lee, Jisu; Kwon, Ju-Lee; Park, Hong-Bum; Lee, Su-Yel; Kim, Ji-Yeon; Sung, Jaekye; Kim, Jin Man; Song, Kyu Sang; Kim, Kyung-Hee

    2016-01-01

    The aim of this study was to form a scaffold-free coculture spheroid model of colonic adenocarcinoma cells (CACs) and normal colonic fibroblasts (NCFs) and to use the spheroids to investigate the role of NCFs in the tumorigenicity of CACs in nude mice. We analysed three-dimensional (3D) scaffold-free coculture spheroids of CACs and NCFs. CAC Matrigel invasion assays and tumorigenicity assays in nude mice were performed to examine the effect of NCFs on CAC invasive behaviour and tumorigenicity in 3D spheroids. We investigated the expression pattern of fibroblast activation protein-α (FAP-α) by immunohistochemical staining. CAC monocultures did not form densely-packed 3D spheroids, whereas cocultured CACs and NCFs formed 3D spheroids. The 3D coculture spheroids seeded on a Matrigel extracellular matrix showed higher CAC invasiveness compared to CACs alone or CACs and NCFs in suspension. 3D spheroids injected into nude mice generated more and faster-growing tumors compared to CACs alone or mixed suspensions consisting of CACs and NCFs. FAP-α was expressed in NCFs-CACs cocultures and xenograft tumors, whereas monocultures of NCFs or CACs were negative for FAP-α expression. Our findings provide evidence that the interaction between CACs and NCFs is essential for the tumorigenicity of cancer cells as well as for tumor propagation. PMID:26947885

  11. Suppression of tumorigenicity in transformed cells after transfection with vinculin cDNA

    PubMed Central

    1992-01-01

    Transfection of chicken vinculin cDNA into two tumor cell lines expressing diminished levels of the endogenous protein, brought about a drastic suppression of their tumorigenic ability. The SV-40-transformed Balb/c 3T3 line (SVT2) contains four times less vinculin than the parental 3T3 cells, and the rat adenocarcinoma BSp73ASML has no detectable vinculin. Restoration of vinculin in these cells, up to the levels found in 3T3 cells, resulted in an apparent increase in substrate adhesiveness, a decrease in the ability to grow in soft agar, and suppression of their capacity to develop tumors after injection into syngeneic hosts or nude mice. These results suggest that vinculin, a cytoplasmic component of cell-matrix and cell-cell adhesions, may have a major suppressive effect on the transformed phenotype. PMID:1400584

  12. CDO, an Hh-coreceptor, mediates lung cancer cell proliferation and tumorigenicity through Hedgehog signaling.

    PubMed

    Leem, Young-Eun; Ha, Hye-Lim; Bae, Ju-Hyeon; Baek, Kwan-Hyuck; Kang, Jong-Sun

    2014-01-01

    Hedgehog (Hh) signaling plays essential roles in various developmental processes, and its aberrant regulation results in genetic disorders or malignancies in various tissues. Hyperactivation of Hh signaling is associated with lung cancer development, and there have been extensive efforts to investigate how to control Hh signaling pathway and regulate cancer cell proliferation. In this study we investigated a role of CDO, an Hh co-receptor, in non-small cell lung cancer (NSCLC). Inhibition of Hh signaling by SANT-1 or siCDO in lung cancer cells reduced proliferation and tumorigenicity, along with the decrease in the expression of the Hh components. Histological analysis with NSCLC mouse tissue demonstrated that CDO was expressed in advanced grade of the cancer, and precisely co-localized with GLI1. These data suggest that CDO is required for proliferation and survival of lung cancer cells via Hh signaling.

  13. Effects of space flight exposure on cell growth, tumorigenicity and gene expression in cancer cells

    NASA Astrophysics Data System (ADS)

    Yang, Cheng; Li, Yuehui; Zhang, Zhijie; Luo, Chen; Tong, Yongqing; Zhou, Guohua; Xie, Pingli; Hu, Jinyue; Li, Guancheng

    2008-12-01

    It is well recognized that harsh outer space environment, consisting of microgravity and radiation, poses significant health risks for human cells. To investigate potential effects of the space environment exposure on cancer cells we examined the biological changes in Caski cells carried by the "Shen Zhou IV" spaceship. After exposure for 7 days in spaceflight, 1440 survival subclonal cell lines were established and 4 cell lines were screened. 44F10 and 17E3 were selected because of their increased cell proliferation and tumorigenesis, while 48A9 and 31F2 had slower cytological events. Experiments with cell proliferation assay, flow cytometry, soft agar assay, tumorigenesis assay and DNA microarray analysis have shown that selected cell lines presented multiple biological changes in cell morphology, cell growth, tumorigenicity and gene expression. These results suggest that space environment exposure can make significant biological impact on cancer cells and provide an entry point to find the immunological target of tumorigenesis.

  14. CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

    PubMed Central

    Leem, Young-Eun; Ha, Hye-Lim; Bae, Ju-Hyeon; Baek, Kwan-Hyuck; Kang, Jong-Sun

    2014-01-01

    Hedgehog (Hh) signaling plays essential roles in various developmental processes, and its aberrant regulation results in genetic disorders or malignancies in various tissues. Hyperactivation of Hh signaling is associated with lung cancer development, and there have been extensive efforts to investigate how to control Hh signaling pathway and regulate cancer cell proliferation. In this study we investigated a role of CDO, an Hh co-receptor, in non-small cell lung cancer (NSCLC). Inhibition of Hh signaling by SANT-1 or siCDO in lung cancer cells reduced proliferation and tumorigenicity, along with the decrease in the expression of the Hh components. Histological analysis with NSCLC mouse tissue demonstrated that CDO was expressed in advanced grade of the cancer, and precisely co-localized with GLI1. These data suggest that CDO is required for proliferation and survival of lung cancer cells via Hh signaling. PMID:25369201

  15. Carcinogens show comedogenic activity: a potential animal screen for tumorigenic substances.

    PubMed

    Kligman, A M; Kligman, L H

    1994-12-09

    Formation of a comedo, an impaction of horny cells in sebaceous follicles, entails a metaplastic change in the differentiation patterns of the follicular epithelium. Since metaplasia is a requisite early stage in carcinogenesis, we postulated that carcinogens might be comedogenic. The rabbit ear was used to assay the comedogenic potentialities of an array of known tumorigens. Complete carcinogens and some tumor promotors were invariably strongly comedogenic at concentrations of 1.0% and below. Comedogenic chemicals commonly found in skin care products usually required concentrations of 40% and greater to induce comedones which were small in comparison to carcinogen induced comedones. We suggest that the rabbit ear model might be an easy and reliable way to screen for carcinogenicity.

  16. Tumorigenic agents in unburned processed tobacco: N-nitrosodiethanolamine and 1,1-dimethylhydrazine.

    PubMed

    Schmeltz, I; Abidi, S; Hoffmann, D

    1977-01-01

    Two tumorigenic agents, N-nitrosodiethanolamine and 1,1-dimethylhydrazine, have been isolated from tobacco for the first time. The former, a reportedly weak hepatic carcinogen in rats, varied in amounts from a low of 0.1 ppb in flue-cured tobacco not treated with the herbicide MH-30, to a high of 173 ppb in Burley tobacco to which the herbicide had been applied prior to harvesting. MH-30 (maleic hydrazide) used by farmers to remove 'suckers' from tobacco plants, is commonly formulated as the diethanolamine salt. 1,1-Dimethylhydrazine, reported to induce tumors in mice, ranged in amounts from 60 to 147 ppb, except in the case of Burley tobacco where none was detected (detection limit: 0.1 ng). The source of the nitrosamine in the tobacco appears to be the MH-30, whereas that of dimethylhydrazine has not been determined.

  17. AS30D Model of Hepatocellular Carcinoma: Tumorigenicity and Preliminary Characterization by Imaging, Histopathology, and Immunohistochemistry

    SciTech Connect

    Thompson, Scott M.; Callstrom, Matthew R.; Knudsen, Bruce; Anderson, Jill L.; Butters, Kim A.; Grande, Joseph P.; Roberts, Lewis R.; Woodrum, David A.

    2013-02-15

    This study was designed to determine the tumorigenicity of the AS30D HCC cell line following orthotopic injection into rat liver and preliminarily characterize the tumor model by both magnetic resonance imaging (MRI) and ultrasound (US) as well as histopathology and immunohistochemistry.MaterialsAS30D cell line in vitro proliferation was assessed by using MTT assay. Female rats (N = 5) underwent injection of the AS30D cell line into one site in the liver. Rats subsequently underwent MR imaging at days 7 and 14 to assess tumor establishment and volume. One rat underwent US of the liver at day 7. Rats were euthanized at day 7 or 14 and livers were subjected to gross, histopathologic (H and E), and immunohistochemical (CD31) analysis to assess for tumor growth and neovascularization. AS30D cell line demonstrated an in vitro doubling time of 33.2 {+-} 5.3 h. MR imaging demonstrated hyperintense T2-weighted and hypointense T1-weighted lesions with tumor induction in five of five and three of three sites at days 7 and 14, respectively. The mean (SD) tumor volume was 126.1 {+-} 36.2 mm{sup 3} at day 7 (N = 5). US of the liver demonstrated a well-circumscribed, hypoechoic mass and comparison of tumor dimensions agreed well with MRI. Analysis of H and E- and CD31-stained sections demonstrated moderate-high grade epithelial tumors with minimal tumor necrosis and evidence of diffuse intratumoral and peritumoral neovascularization by day 7. AS30D HCC cell line is tumorigenic following orthotopic injection into rat liver and can be used to generate an early vascularizing, slower-growing rat HCC tumor model.

  18. Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells.

    PubMed

    Barszczyk, Mark; Buczkowicz, Pawel; Castelo-Branco, Pedro; Mack, Stephen C; Ramaswamy, Vijay; Mangerel, Joshua; Agnihotri, Sameer; Remke, Marc; Golbourn, Brian; Pajovic, Sanja; Elizabeth, Cynthia; Yu, Man; Luu, Betty; Morrison, Andrew; Adamski, Jennifer; Nethery-Brokx, Kathleen; Li, Xiao-Nan; Van Meter, Timothy; Dirks, Peter B; Rutka, James T; Taylor, Michael D; Tabori, Uri; Hawkins, Cynthia

    2014-12-01

    Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

  19. Tumorigenicity of acrylamide and its metabolite glycidamide in the neonatal mouse bioassay

    PubMed Central

    Von Tungeln, Linda S.; Doerge, Daniel R.; da Costa, Gonçalo Gamboa; Marques, M. Matilde; Witt, William M.; Koturbash, Igor; Pogribny, Igor P.; Beland, Frederick A.

    2012-01-01

    Acrylamide is a high-volume industrial chemical, a component of cigarette smoke, and a product formed in certain foods prepared at high temperatures. Previously, we compared the extent of DNA adduct formation and mutations in B6C3F1/Tk mice treated neonatally with acrylamide or glycidamide to obtain information concerning the mechanism of acrylamide genotoxicity. We have now examined the tumorigenicity of acrylamide and glycidamide in mice treated neonatally. Male B6C3F1 mice were injected intraperitoneally on postnatal days 1, 8, and 15 with 0.0, 0.14, or 0.70 mmol acrylamide or glycidamide per kg body weight per day and the tumorigenicity was assessed after one year. Survival in each of the groups was >87%, there were no differences in body weights among the groups, and the only treatment-related neoplasms involved the liver. The incidence of combined hepatocellular adenoma or carcinoma was 3.8% in the control group, 8.3% in the 0.14 mmol acrylamide and glycidamide per kg body weight groups, 4.2% in the 0.70 mmol acrylamide per kg body weight group, and 71.4% in the 0.70 mmol glycidamide per kg body weight group. Analysis of the hepatocellular tumors indicated that the increased incidence observed in mice administered 0.70 mmol glycidamide per kg body weight was associated with A→ G and A → T mutations at codon 61 of H-ras. These results, combined with our previous data on DNA adduct formation and mutation induction, suggest that the carcinogenicity of acrylamide is dependent upon its metabolism to glycidamide, a pathway that is deficient in neonatal mice. PMID:22336951

  20. Persistent ERK/MAPK Activation Promotes Lactotrope Differentiation and Diminishes Tumorigenic Phenotype

    PubMed Central

    Booth, Allyson; Trudeau, Tammy; Gomez, Crystal; Lucia, M. Scott

    2014-01-01

    The signaling pathways that govern the lactotrope-specific differentiated phenotype, and those that control lactotrope proliferation in both physiological and pathological lactotrope expansion, are poorly understood. Moreover, the specific role of MAPK signaling in lactotrope proliferation vs differentiation, whether activated phosphorylated MAPK is sufficient for prolactinoma tumor formation remain unknown. Given that oncogenic Ras mutations and persistently activated phosphorylated MAPK are found in human tumors, including prolactinomas and other pituitary tumors, a better understanding of the role of MAPK in lactotrope biology is required. Here we directly examined the role of persistent Ras/MAPK signaling in differentiation, proliferation, and tumorigenesis of rat pituitary somatolactotrope GH4 cells. We stimulated Ras/MAPK signaling in a persistent, long-term manner (over 6 d) in GH4 cells using two distinct approaches: 1) a doxycycline-inducible, oncogenic V12Ras expression system; and 2) continuous addition of exogenous epidermal growth factor. We find that long-term activation of the Ras/MAPK pathway over 6 days promotes differentiation of the bihormonal somatolactotrope GH4 precursor cell into a prolactin-secreting, lactotrope cell phenotype in vitro and in vivo with GH4 cell xenograft tumors. Furthermore, we show that persistent activation of the Ras/MAPK pathway not only fails to promote cell proliferation, but also diminishes tumorigenic characteristics in GH4 cells in vitro and in vivo. These data demonstrate that activated MAPK promotes differentiation and is not sufficient to drive tumorigenesis, suggesting that pituitary lactotrope tumor cells have the ability to evade the tumorigenic fate that is often associated with Ras/MAPK activation. PMID:25361391

  1. Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties

    PubMed Central

    Novitskiy, Sergey V.; Pickup, Michael W.; Chytil, Anna; Polosukhina, Dina; Owens, Philip; Moses, Harold L.

    2012-01-01

    By crossing LysM-Cre and TGF-β type II receptor (Tgfbr2) floxed mice we achieved specific deletion of Tgfbr2 in myeloid cells (Tgfbr2MyeKO mice). S.c.-injected (LLC, EL4-OVA) and implanted (MMTV-PyMT) carcinoma cells grow slower in Tgfbr2MyeKO mice. The number of CD45+ cells in the tumor tissue was the same in both genotypes of mice, but upon analysis, the percentage of T cells (CD45+CD3+) in the KO mice was increased. By flow cytometry analysis, we did not detect any differences in the number and phenotype of TAMs, CD11b+Gr1+, and DCs in Tgfbr2MyeKO compared with Tgfbr2MyeWT mice. ELISA and qRT-PCR data showed differences in myeloid cell functions. In Tgfbr2MyeKO TAMs, TNF-α secretion was increased, basal IL-6 secretion was down-regulated, TGF-β did not induce any VEGF response, and there was decreased MMP9 and increased MMP2 and iNOS expression. TGF-β did not have any effect on CD11b+Gr1+ cells isolated from Tgfbr2MyeKO mice in the regulation of Arg, iNOS, VEGF, and CXCR4, and moreover, these cells have decreased suppressive activity relative to T cell proliferation. Also, we found that DCs from tumor tissue of Tgfbr2MyeKO mice have increased antigen-presented properties and an enhanced ability to stimulate antigen-specific T cell proliferation. We conclude that Tgfbr2 in myeloid cells has a negative role in the regulation of anti-tumorigenic functions of these cells, and deletion of this receptor decreases the suppressive function of CD11b+Gr1+ cells and increases antigen-presenting properties of DCs and anti-tumorigenic properties of TAMs. PMID:22685318

  2. Multiple Breast Cancer Cell-Lines Derived from a Single Tumor Differ in Their Molecular Characteristics and Tumorigenic Potential

    PubMed Central

    Mosoyan, Goar; Nagi, Chandandeep; Marukian, Svetlana; Teixeira, Avelino; Simonian, Anait; Resnick-Silverman, Lois; DiFeo, Analisa; Johnston, Dean; Reynolds, Sandra R.; Roses, Daniel F.; Mosoian, Arevik

    2013-01-01

    Background Breast cancer cell lines are widely used tools to investigate breast cancer biology and to develop new therapies. Breast cancer tissue contains molecularly heterogeneous cell populations. Thus, it is important to understand which cell lines best represent the primary tumor and have similarly diverse phenotype. Here, we describe the development of five breast cancer cell lines from a single patient’s breast cancer tissue. We characterize the molecular profiles, tumorigenicity and metastatic ability in vivo of all five cell lines and compare their responsiveness to 4-hydroxytamoxifen (4-OHT) treatment. Methods Five breast cancer cell lines were derived from a single patient’s primary breast cancer tissue. Expression of different antigens including HER2, estrogen receptor (ER), CK8/18, CD44 and CD24 was determined by flow cytometry, western blotting and immunohistochemistry (IHC). In addition, a Fuorescent In Situ Hybridization (FISH) assay for HER2 gene amplification and p53 genotyping was performed on all cell lines. A xenograft model in nude mice was utilized to assess the tumorigenic and metastatic abilities of the breast cancer cells. Results We have isolated, cloned and established five new breast cancer cell lines with different tumorigenicity and metastatic abilities from a single primary breast cancer. Although all the cell lines expressed low levels of ER, their growth was estrogen-independent and all had high-levels of expression of mutated non-functional p53. The HER2 gene was rearranged in all cell lines. Low doses of 4-OHT induced proliferation of these breast cancer cell lines. Conclusions All five breast cancer cell lines have different antigenic expression profiles, tumorigenicity and organ specific metastatic abilities although they derive from a single tumor. None of the studied markers correlated with tumorigenic potential. These new cell lines could serve as a model for detailed genomic and proteomic analyses to identify mechanisms

  3. Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors

    PubMed Central

    Guo, Wei; Zheng, Yabing; Xu, Bing; Ma, Fang; Li, Chang; Zhang, Xiaoqian; Wang, Yao; Chang, Xiaotian

    2017-01-01

    Background Peptidylarginine deiminase (PAD) catalyzes the conversion of arginine residues to citrulline residues, termed citrullination. Recent studies have suggested that PAD isoform 2 (PADI2) plays an important role in tumors, although its tumorigenic effect and mechanism are largely unknown. Materials and methods Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to investigate the expression level of PADI2 in various tumor tissues and patient blood samples, respectively. MNK-45 and Bel-7402 tumor cell lines originating from gastric and liver tumors, respectively, were treated with anti-PADI2 siRNA, and the subsequent cell proliferation, apoptosis and migration were observed. Polymerase chain reaction (PCR) arrays, including Cancer PathwayFinder, Oncogenes and Tumor Suppressor Genes, p53 Signaling Pathway, Signal Transduction Pathway and Tumor Metastasis PCR arrays, were used to investigate the tumorigenic pathway of PADI2 in the siRNA-treated tumor cells. This analysis was verified by real-time PCR. Results Immunohistochemistry detected significantly increased expression of PADI2 in invasive breast ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung cancer, ovarian serous papillary adenocarcinoma and papillary thyroid carcinoma samples. ELISA detected a twofold increase in PADI2 expression in the blood of 48.3% of patients with liver cancer, 38% of patients with cervical carcinoma and 32% of patients with gastric carcinoma. Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression. PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments

  4. Traveling Exhibitions: translating current science into effective science exhibitions

    NASA Astrophysics Data System (ADS)

    Dusenbery, P.; Morrow, C.; Harold, J.

    The Space Science Institute (SSI) of Boulder, Colorado has recently developed two museum exhibits called the Space Weather Center and MarsQuest. It is currently planning to develop two other exhibitions called Cosmic Origins and InterActive Earth. Museum exhibitions provide research scientists the opportunity to engage in a number of activities that are vital to the success of earth and space outreach programs. The Space Weather Center was developed in partnership with various research missions at NASA's Goddard Space Flight Center. The focus of the presentation will be on the Institute's MarsQuest exhibition. This project is a 5000 square-foot, 2.5M, traveling exhibition that is now touring the country. The exhibit's 3-year tour is enabling millions of Americans to share in the excitement of the scientific exploration of Mars and learn more about their own planet in the process. The associated planetarium show and education program will also be described, with particular emphasis on workshops to orient host museum staff (e.g. museum educators and docents). The workshops make innovative connections between the exhibitions interactive experiences and lesson plans aligned with the National Science Education Standards. SSI is also developing an interactive web site called MarsQuest On-line. The linkage between the web site, education program and exhibit will be discussed. MarsQuest and SSI's other exhibitions are good models for actively involving scientists and their discoveries to help improve informal science education in the museum community and for forging a stronger connection between formal and informal education.

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

    PubMed Central

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

    2015-01-01

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

  6. Ewing's sarcoma cells with CD57-associated increase of tumorigenicity and with neural crest-like differentiation capacity.

    PubMed

    Wahl, Joachim; Bogatyreva, Liubov; Boukamp, Petra; Rojewski, Markus; van Valen, Frans; Fiedler, Jörg; Hipp, Nora; Debatin, Klaus-Michael; Beltinger, Christian

    2010-09-01

    The Ewing family of tumors (EFT) is an important group of pediatric malignancies with a guarded prognosis. Little is known about the heterogeneity of EFT cells, and the cellular origin of EFT is disputed. We now add evidence that EFT are heterogeneous by showing that EFT cells from spheres growing in serum-free medium are markedly more tumorigenic than adherently growing EFT cells. Furthermore, EFT cells strongly expressing CD57 (HNK-1), a surface marker for migrating and proliferating neural crest cells, are more tumorigenic than cells with low expression of CD57, possibly mediated in part by enhanced adhesion and invasion. We contribute to the controversy about the cellular origin of EFT by clonal analysis, showing that EFT cells can differentiate similar to neural crest cells. These data increase our knowledge about the pathogenesis and heterogeneity of EFT.

  7. A highly invasive subpopulation of MDA-MB-231 breast cancer cells shows accelerated growth, differential chemoresistance, features of apocrine tumors and reduced tumorigenicity in vivo

    PubMed Central

    Mirisola, Valentina; Esposito, Alessia Isabella; Reverberi, Daniele; Matis, Serena; Maffei, Massimo; Giaretti, Walter; Viale, Maurizio; Gangemi, Rosaria; Emionite, Laura; Astigiano, Simonetta; Cilli, Michele; Bachmeier, Beatrice E.; Killian, Peter H.; Albini, Adriana; Pfeffer, Ulrich

    2016-01-01

    The acquisition of an invasive phenotype is a prerequisite for metastasization, yet it is not clear whether or to which extent the invasive phenotype is linked to other features characteristic of metastatic cells. We selected an invasive subpopulation from the triple negative breast cancer cell line MDA-MB-231, performing repeated cycles of preparative assays of invasion through Matrigel covered membranes. The invasive sub-population of MDA-MB-231 cells exhibits stronger migratory capacity as compared to parental cells confirming the highly invasive potential of the selected cell line. Prolonged cultivation of these cells did not abolish the invasive phenotype. ArrayCGH, DNA index quantification and karyotype analyses confirmed a common genetic origin of the parental and invasive subpopulations and revealed discrete structural differences of the invasive subpopulation including increased ploidy and the absence of a characteristic amplification of chromosome 5p14.1-15.33. Gene expression analyses showed a drastically altered expression profile including features of apocrine breast cancers and of invasion related matrix-metalloproteases and cytokines. The invasive cells showed accelerated proliferation, increased apoptosis, and an altered pattern of chemo-sensitivity with lower IC50 values for drugs affecting the mitotic apparatus. However, the invasive cell population is significantly less tumorigenic in orthotopic mouse xenografts suggesting that the acquisition of the invasive capacity and the achievement of metastatic growth potential are distinct events. PMID:27626697

  8. Evaluation of tumorigenic potential of CeO2 and Fe2O3 engineered nanoparticles by a human cell in vitro screening model.

    PubMed

    Stueckle, Todd A; Davidson, Donna C; Derk, Raymond; Kornberg, Tiffany G; Schwegler-Berry, Diane; Pirela, Sandra V; Deloid, Glen; Demokritou, Philip; Luanpitpong, Sudjit; Rojanasakul, Yon; Wang, Liying

    2017-04-01

    With rapid development of novel nanotechnologies that incorporate engineered nanomaterials (ENMs) into manufactured products, long-term, low dose ENM exposures in occupational settings is forecasted to occur with potential adverse outcomes to human health. Few ENM human health risk assessment efforts have evaluated tumorigenic potential of ENMs. Two widely used nano-scaled metal oxides (NMOs), cerium oxide (nCeO2) and ferric oxide (nFe2O3) were screened in the current study using a sub-chronic exposure to human primary small airway epithelial cells (pSAECs). Multi-walled carbon nanotubes (MWCNT), a known ENM tumor promoter, was used as a positive control. Advanced dosimetry modeling was employed to ascertain delivered vs. administered dose in all experimental conditions. Cells were continuously exposed in vitro to deposited doses of 0.18 μg/cm(2) or 0.06 μg/cm(2) of each NMO or MWCNT, respectively, over 6 and 10 weeks, while saline- and dispersant-only exposed cells served as passage controls. Cells were evaluated for changes in several cancer hallmarks, as evidence for neoplastic transformation. At 10 weeks, nFe2O3- and MWCNT-exposed cells displayed a neoplastic-like transformation phenotype with significant increased proliferation, invasion and soft agar colony formation ability compared to controls. nCeO2-exposed cells showed increased proliferative capacity only. Isolated nFe2O3 and MWCNT clones from soft agar colonies retained their respective neoplastic-like phenotypes. Interestingly, nFe2O3-exposed cells, but not MWCNT cells, exhibited immortalization and retention of the neoplastic phenotype after repeated passaging (12 - 30 passages) and after cryofreeze and thawing. High content screening and protein expression analyses in acute exposure ENM studies vs. immortalized nFe2O3 cells, and isolated ENM clones, suggested that long-term exposure to the tested ENMs resulted in iron homeostasis disruption, an increased labile ferrous iron pool, and subsequent

  9. Effect of Doxorubicin/Pluronic SP1049C on Tumorigenicity, Aggressiveness, DNA Methylation and Stem Cell Markers in Murine Leukemia

    PubMed Central

    Li, Shu; Kabanov, Alexander V.

    2013-01-01

    Purpose Pluronic block copolymers are potent sensitizers of multidrug resistant cancers. SP1049C, a Pluronic-based micellar formulation of doxorubicin (Dox) has completed Phase II clinical trial and demonstrated safety and efficacy in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction. This study elucidates the ability of SP1049C to deplete cancer stem cells (CSC) and decrease tumorigenicity of cancer cells in vivo. Experimental Design P388 murine leukemia ascitic tumor was grown in BDF1 mice. The animals were treated with: (a) saline, (b) Pluronics alone, (c) Dox or (d) SP1049C. The ascitic cancer cells were isolated at different passages and examined for 1) in vitro colony formation potential, 2) in vivo tumorigenicity and aggressiveness, 3) development of drug resistance and Wnt signaling activation 4) global DNA methylation profiles, and 5) expression of CSC markers. Results SP1049C treatment reduced tumor aggressiveness, in vivo tumor formation frequency and in vitro clonogenic potential of the ascitic cells compared to drug, saline and polymer controls. SP1049C also prevented overexpression of BCRP and activation of Wnt-β-catenin signaling observed with Dox alone. Moreover, SP1049C significantly altered the DNA methylation profiles of the cells. Finally, SP1049C decreased CD133+ P388 cells populations, which displayed CSC-like properties and were more tumorigenic compared to CD133− cells. Conclusions SP1049C therapy effectively suppresses the tumorigenicity and aggressiveness of P388 cells in a mouse model. This may be due to enhanced activity of SP1049C against CSC and/or altered epigenetic regulation restricting appearance of malignant cancer cell phenotype. PMID:23977261

  10. BC047440 antisense eukaryotic expression vectors inhibited HepG2 cell proliferation and suppressed xenograft tumorigenicity.

    PubMed

    Zheng, Lu; Liang, Ping; Zhou, JianBo; Huang, XiaoBing; Wen, Yu; Wang, Zheng; Li, Jing

    2012-02-01

    The biological functions of the BC047440 gene highly expressed by hepatocellular carcinoma (HCC) are unknown. The objective of this study was to reconstruct antisense eukaryotic expression vectors of the gene for inhibiting HepG(2) cell proliferation and suppressing their xenograft tumorigenicity. The full-length BC047440 cDNA was cloned from human primary HCC by RT-PCR. BC047440 gene fragments were ligated with pMD18-T simple vectors and subsequent pcDNA3.1(+) plasmids to construct the recombinant antisense eukaryotic vector pcDNA3.1(+)BC047440AS. The endogenous BC047440 mRNA abundance in target gene-transfected, vector-transfected and naive HepG(2) cells was semiquantitatively analyzed by RT-PCR and cell proliferation was measured by the MTT assay. Cell cycle distribution and apoptosis were profiled by flow cytometry. The in vivo xenograft experiment was performed on nude mice to examine the effects of antisense vector on tumorigenicity. BC047440 cDNA fragments were reversely inserted into pcDNA3.1(+) plasmids. The antisense vector significantly reduced the endogenous BC047440 mRNA abundance by 41% in HepG(2) cells and inhibited their proliferation in vitro (P < 0.01). More cells were arrested by the antisense vector at the G(1) phase in an apoptosis-independent manner (P = 0.014). Additionally, transfection with pcDNA3.1(+)BC047440AS significantly reduced the xenograft tumorigenicity in nude mice. As a novel cell cycle regulator associated with HCC, the BC047440 gene was involved in cell proliferation in vitro and xenograft tumorigenicity in vivo through apoptosis-independent mechanisms.

  11. Spontaneously formed tumorigenic hybrids of Meth A sarcoma cells and macrophages in vivo.

    PubMed

    Busund, Lill-Tove R; Killie, Mette K; Bartnes, Kristian; Seljelid, Rolf

    2003-08-20

    We have recently demonstrated that malignant cells can hybridize with tissue macrophages in vitro, giving rise to tumorigenic hybrids. We now demonstrate that this can occur spontaneously in vivo as a result of fusion between inoculated Meth A sarcoma cells and host cells, presumably macrophages. Thus, from tumor cell suspensions prepared by collagenase perfusion and density centrifugation, hybrid cells could be isolated that were neoplastic but in contrast to Meth A expressed macrophage markers and had phagocytic capacity. Their morphologic features were intermediate between Meth A and macrophages. By taking advantage of a semiallogeneic experimental system by inoculation of Meth A cells from BALB/c (H-2 K(d)) into (BALB.K x BALB/c) F(1) (H-2(k/d)), hybrid cells from these tumors could be shown to express MHC antigens of both the Meth A and the host haplotypes. Hybrid cells grew faster than Meth A cells in vivo, indicating acquisition of growth-promoting properties through heterotypic cell fusion.

  12. Static and animated molecular views of a tumorigenic chemical bound to DNA

    SciTech Connect

    Broyde, S.; Xu, Rong ); Hingerty, B.E. ); O'Handley, S.F.; Krugh, T.R. . Dept. of Chemistry)

    1991-01-01

    Static and dynamic molecular views of a short segment of DNA modified by the tumorigenic aromatic amine 2-acetylaminofluorene (AAF) have been realized by a combination of high resolution nuclear magnetic resonance (NMR) studies in solution and molecular mechanics and molecular dynamics simulations carried out on supercomputers. Thus, the effect of AAF on the structure of the Watson-Crick B-DNA double helix has been elucidated, after two decades of intense interest, via a powerful synergy between state-of-the-art supercomputing NMR investigations. The AAF is situated in the minor groove of a B-DNA double helix which flexes and bends, and the carcinogen moves between positions where it is stacked with adjacent DNA base and positions where it protrudes further into the groove. The AAF modified DNA base, guanine, is displaced from its normal situation paired with partner cytosine. Also, a base pair adjacent to the modification becomes more mobile. These molecular views offer some possible insight on the early molecular events that may implicate AAF in tumor initiation. 16 refs., 3 figs.

  13. Elasticity and tumorigenic characteristics of cells in a monolayer after nanosecond pulsed electric field exposure.

    PubMed

    Steuer, A; Wende, K; Babica, P; Kolb, J F

    2017-04-01

    Nanosecond pulsed electric fields (nsPEFs) applied to cells can induce different biological effects depending on pulse duration and field strength. One known process is the induction of apoptosis whereby nsPEFs are currently investigated as a novel cancer therapy. Another and probably related change is the breakdown of the cytoskeleton. We investigated the elasticity of rat liver epithelial cells WB-F344 in a monolayer using atomic force microscopy (AFM) with respect to the potential of cells to undergo malignant transformation or to develop a potential to metastasize. We found that the elastic modulus of the cells decreased significantly within the first 8 min after treatment with 20 pulses of 100 ns and with a field strength of 20 kV/cm but was still higher than the elasticity of their tumorigenic counterpart WB-ras. AFM measurements and immunofluorescent staining showed that the cellular actin cytoskeleton became reorganized within 5 min. However, both a colony formation assay and a cell migration assay revealed no significant changes after nsPEF treatment, implying that cells seem not to adopt malignant characteristics associated with metastasis formation despite the induced transient changes to elasticity and cytoskeleton that can be observed for up to 1 h.

  14. Tumorigenic activity of Merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice

    PubMed Central

    Spurgeon, Megan E.; Cheng, Jingwei; Bronson, Roderick T.; Lambert, Paul F.; DeCaprio, James A.

    2015-01-01

    Merkel cell polyomavirus (MCPyV) is frequently associated with Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine skin cancer. Most MCC tumors contain integrated copies of the viral genome with persistent expression of the MCPyV large T (LT) and small T (ST) antigen. MCPyV isolated from MCC typically contain wild type ST but truncated forms of LT that retain the N-terminus but delete the C-terminus and render LT incapable of supporting virus replication. To determine the oncogenic activity of MCC tumor-derived T antigens in vivo, a conditional, tissue-specific mouse model was developed. Keratin 14-mediated Cre recombinase expression induced expression of MCPyV T antigens in stratified squamous epithelial cells and Merkel cells of the skin epidermis. Mice expressing MCPyV T antigens developed hyperplasia, hyperkeratosis, and acanthosis of the skin with additional abnormalities in whisker pads, footpads and eyes. Nearly half of the mice also developed cutaneous papillomas. Evidence for neoplastic progression within stratified epithelia included increased cellular proliferation, unscheduled DNA synthesis, increased E2F-responsive genes levels, disrupted differentiation, and presence of a DNA damage response. These results indicate that MCPyV T antigens are tumorigenic in vivo, consistent with their suspected etiological role in human cancer. PMID:25596282

  15. hsa-miR-4485 regulates mitochondrial functions and inhibits the tumorigenicity of breast cancer cells.

    PubMed

    Sripada, Lakshmi; Singh, Kritarth; Lipatova, Anastasiya V; Singh, Aru; Prajapati, Paresh; Tomar, Dhanendra; Bhatelia, Khyati; Roy, Milton; Singh, Rochika; Godbole, Madan M; Chumakov, Peter M; Singh, Rajesh

    2017-02-20

    The modulation of mitochondrial functions is important for maintaining cellular homeostasis. Mitochondria essentially depend on the import of RNAs and proteins encoded by the nuclear genome. MicroRNAs encoded in the nucleus can translocate to mitochondria and target the genome, affecting mitochondrial function. Here, we analyzed the role of miR-4485 in the regulation of mitochondrial functions. We showed that miR-4485 translocated to mitochondria where its levels varied in response to different stress conditions. A direct binding of miR-4485 to mitochondrial 16S rRNA was demonstrated. MiR-4485 regulated the processing of pre-rRNA at the 16S rRNA-ND1 junction and the translation of downstream transcripts. MiR-4485 modulated mitochondrial complex I activity, the production of ATP, ROS levels, caspase-3/7 activation, and apoptosis. Transfection of a miR-4485 mimic downregulated the expression of regulatory glycolytic pathway genes and reduced the clonogenic ability of breast cancer cells. Ectopic expression of miR-4485 in MDA-MB-231 breast carcinoma cells decreased the tumorigenicity in a nude mouse xenograft model. Furthermore, levels of both precursor and mature miR-4485 are decreased in tumor tissue of breast cancer patients. We conclude that the mitochondria-targeted miR-4485 may act as a tumor suppressor in breast carcinoma cells by negatively regulating mitochondrial RNA processing and mitochondrial functions.

  16. Phenotypic differentiation does not affect tumorigenicity of primary human colon cancer initiating cells.

    PubMed

    Dubash, Taronish D; Hoffmann, Christopher M; Oppel, Felix; Giessler, Klara M; Weber, Sarah; Dieter, Sebastian M; Hüllein, Jennifer; Zenz, Thorsten; Herbst, Friederike; Scholl, Claudia; Weichert, Wilko; Werft, Wiebke; Benner, Axel; Schmidt, Manfred; Schneider, Martin; Glimm, Hanno; Ball, Claudia R

    2016-02-28

    Within primary colorectal cancer (CRC) a subfraction of all tumor-initiating cells (TIC) drives long-term progression in serial xenotransplantation. It has been postulated that efficient maintenance of TIC activity in vitro requires serum-free spheroid culture conditions that support a stem-like state of CRC cells. To address whether tumorigenicity is indeed tightly linked to such a stem-like state in spheroids, we transferred TIC-enriched spheroid cultures to serum-containing adherent conditions that should favor their differentiation. Under these conditions, primary CRC cells did no longer grow as spheroids but formed an adherent cell layer, up-regulated colon epithelial differentiation markers, and down-regulated TIC-associated markers. Strikingly, upon xenotransplantation cells cultured under either condition equally efficient formed serially transplantable tumors. Clonal analyses of individual lentivirally marked TIC clones cultured under either culture condition revealed no systematic differences in contributing clone numbers, indicating that phenotypic differentiation does not select for few individual clones adapted to unfavorable culture conditions. Our results reveal that CRC TIC can be propagated under conditions previously thought to induce their elimination. This phenotypic plasticity allows addressing primary human CRC TIC properties in experimental settings based on adherent cell growth.

  17. Chemical and toxicological characterization of residential oil burner emissions: II. Mutagenic, tumorigenic, and potential teratogenic activity.

    PubMed Central

    Braun, A G; Busby, W F; Liber, H L; Thilly, W G

    1987-01-01

    Extracts of effluents from a modern residential oil burner have been evaluated in several toxicological assay systems. Bacterial mutagens were detected in extracts from both the particulate and vapor phase emissions. Effluents from continuous operation were an order of magnitude less mutagenic than those from cyclic (5 min on, 10 min off) operations. No difference in the yield of bacterial mutagens per gram of fuel burned was found between cyclic operation under low and moderate sooting conditions. On the basis of elution behavior from alumina it appeared that the bacterial mutagens collected from high sooting effluents were more polar than those from low sooting effluent. An extract that was mutagenic in bacteria did not induce a significant increase in mutation frequency to human lymphoblasts. No evidence of tumorigenicity was observed in a limited number of newborn mice after IP injection of effluent extract when compared to historical control data. Putative nonmutagenic teratogens were detected in effluent using an attachment inhibition assay. The level of these agents was reduced in effluents from continuous oil burner operation. PMID:3665866

  18. ASBEL, an ANA/BTG3 antisense transcript required for tumorigenicity of ovarian carcinoma.

    PubMed

    Yanagida, Satoshi; Taniue, Kenzui; Sugimasa, Hironobu; Nasu, Emiko; Takeda, Yasuko; Kobayashi, Mana; Yamamoto, Tadashi; Okamoto, Aikou; Akiyama, Tetsu

    2013-01-01

    Mammalian genomes encode numerous antisense non-coding RNAs, which are assumed to be involved in the regulation of the sense gene expression. However, the mechanisms of their action and involvement in the development of diseases have not been well elucidated. The ANA/BTG3 protein is an antiproliferative protein whose expression is downregulated in prostate and lung cancers. Here we show that an antisense transcript of the ANA/BTG3 gene, termed ASBEL, negatively regulates the levels of ANA/BTG3 protein, but not of ANA/BTG3 mRNA and is required for proliferation and tumorigenicity of ovarian clear cell carcinoma. We further show that knockdown of ANA/BTG3 rescues growth inhibition caused by ASBEL knockdown. Moreover, we demonstrate that ASBEL forms duplexes with ANA/BTG3 mRNA in the nucleus and suppresses its cytoplasmic transportation. Our findings illustrate a novel function for an antisense transcript that critically promotes tumorigenesis by suppressing translation of the sense gene by inhibiting its cytoplasmic transportation.

  19. A tumorigenic murine Sertoli cell line that is temperature-sensitive for differentiation.

    PubMed Central

    Boekelheide, K.; Lee, J. W.; Hall, S. J.; Rhind, N. R.; Zaret, K. S.

    1993-01-01

    The Sertoli cell is the epithelial cell within the seminiferous tubule responsible for supporting germ cells. Most current in vitro studies of Sertoli cell function use primary cultures because of the limited number of available Sertoli cell lines. In addition, few in vivo models of Sertoli cell malignancy have been described. In this study, a tumorigenic Sertoli cell line was developed by infection of isolated murine Sertoli cells by simian virus 40 tsA255; the ts mutation causes the inactivation of the large T antigen at elevated temperatures. A cloned Sertoli cell line, called S14-1, demonstrated temperature-dependent growth in soft agar and formed tumors in nude mice. Electron microscopy of the S14-1-derived tumor revealed extensive basal intercellular junctions and tubulobulbarlike processes supporting its Sertoli cell origin. Cytogenetic analysis showed that S14-1 cells were aneuploid with an average of 70 chromosomes per cell. At the nonpermissive (40 C) temperature, S14-1 cells in vitro demonstrated a reduced growth rate, enhanced secretion of transferrin, and increased expression of sulfated glycoprotein-2 messenger RNA, indicating the cells manifested increased differentiation following large T antigen inactivation. The murine S14-1 Sertoli cell line should be useful for both in vitro studies of Sertoli cell function and in vivo studies of Sertoli cell malignancy. Images Figure 1 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8214009

  20. Alterations of p53 in tumorigenic human bronchial epithelial cells correlate with metastatic potential

    NASA Technical Reports Server (NTRS)

    Piao, C. Q.; Willey, J. C.; Hei, T. K.; Hall, E. J. (Principal Investigator)

    1999-01-01

    The cellular and molecular mechanisms of radiation-induced lung cancer are not known. In the present study, alterations of p53 in tumorigenic human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells induced by a single low dose of either alpha-particles or 1 GeV/nucleon (56)Fe were analyzed by PCR-single-stranded conformation polymorphism (SSCP) coupled with sequencing analysis and immunoprecipitation assay. A total of nine primary and four secondary tumor cell lines, three of which were metastatic, together with the parental BEP2D and primary human bronchial epithelial (NHBE) cells were studied. The immunoprecipitation assay showed overexpression of mutant p53 proteins in all the tumor lines but not in NHBE and BEP2D cells. PCR-SSCP and sequencing analysis found band shifts and gene mutations in all four of the secondary tumors. A G-->T transversion in codon 139 in exon 5 that replaced Lys with Asn was detected in two tumor lines. One mutation each, involving a G-->T transversion in codon 215 in exon 6 (Ser-->lle) and a G-->A transition in codon 373 in exon 8 (Arg-->His), was identified in the remaining two secondary tumors. These results suggest that p53 alterations correlate with tumorigenesis in the BEP2D cell model and that mutations in the p53 gene may be indicative of metastatic potential.

  1. Suppression of laminin-5 expression leads to increased motility, tumorigenicity, and invasion

    SciTech Connect

    Yuen Hengwai; Ziober, Amy F.; Gopal, Pallavi; Nasrallah, Ilya; Falls, Erica M.; Meneguzzi, Guerrino; Ang, Hwee-Quan; Ziober, Barry L. . E-mail: bziober@mail.med.upenn.edu

    2005-09-10

    Laminin-5 (Ln-5) is expressed in several human carcinomas and hypothesized to contribute to tumor invasion. To understand the role of Ln-5 in human cancers, we stably delivered small interfering RNAs (siRNAs) directed against the Ln-5 {gamma}2 chain into JHU-022-SCC cells (022), a non-invasive oral squamous cell carcinoma (OSCC) cell line which secretes Ln-5. Lysates from {gamma}2 siRNA cells (022-si{gamma}2) had nearly undetectable levels of the {gamma}2 chain while the {alpha}3 and {beta}3 subunits of Ln-5 remained unchanged compared to parental and control. In conditioned medium from 022-si{gamma}2 cells, the {gamma}2 chain and the Ln-5 heterotrimer were barely detectable, similar to an invasive OSCC cell line. Conditioned medium from 022-si{gamma}2 cells contained less {alpha}3 and {beta}3 subunits than both parental and control. Although the proliferation and adhesive properties of the 022-si{gamma}2 cells remained similar to parental and control cells, 022-si{gamma}2 cells showed increased detachment and a fibroblastic morphology similar to invasive cells. Moreover, migration, in vitro invasion, and in vivo tumorigenicity were enhanced in 022-si{gamma}2 cells. Our results suggest that the Ln-5 {gamma}2 chain regulates the secretion of the {alpha}3 and {beta}3 subunits. More importantly, suppression of Ln-5 results in a phenotype that is representative of invasive tumor cells.

  2. β-Catenin Does Not Confer Tumorigenicity When Introduced into Partially Transformed Human Mesenchymal Stem Cells.

    PubMed

    Piperdi, Sajida; Austin-Page, Lukas; Geller, David; Ahluwalia, Manpreet; Gorlick, Sarah; Gill, Jonathan; Park, Amy; Zhang, Wendong; Li, Nan; Chung, So Hak; Gorlick, Richard

    2012-01-01

    Although osteosarcoma is the most common primary malignant bone tumor in children and adolescents, its cell of origin and the genetic alterations are unclear. Previous studies have shown that serially introducing hTERT, SV40 large TAg, and H-Ras transforms human mesenchymal stem cells into two distinct sarcomas cell populations, but they do not form osteoid. In this study, β-catenin was introduced into mesenchymal stem cells already containing hTERT and SV40 large TAg to analyze if this resulted in a model which more closely recapitulated osteosarcoma. Results. Regardless of the level of induced β-catenin expression in the stable transfectants, there were no marked differences induced in their phenotype or invasion and migration capacity. Perhaps more importantly, none of them formed tumors when injected into immunocompromised mice. Moreover, the resulting transformed cells could be induced to osteogenic and chondrogenic differentiation but not to adipogenic differentiation. Conclusions. β-catenin, although fostering osteogenic differentiation, does not induce the malignant features and tumorigenicity conveyed by oncogenic H-RAS when introduced into partly transformed mesenchymal stem cells. This may have implications for the role of β-catenin in osteosarcoma pathogenesis. It also may suggest that adipogenesis is an earlier branch point than osteogenesis and chondrogenesis in normal mesenchymal differentiation.

  3. Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma.

    PubMed

    Potu, Harish; Peterson, Luke F; Kandarpa, Malathi; Pal, Anupama; Sun, Hanshi; Durham, Alison; Harms, Paul W; Hollenhorst, Peter C; Eskiocak, Ugur; Talpaz, Moshe; Donato, Nicholas J

    2017-02-15

    ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition. Usp9x and Ets-1 levels are coincidently elevated in melanoma with highest levels detected in metastatic tumours versus normal skin or benign skin lesions. Notably, Ets-1 is induced by BRAF or MEK kinase inhibition, resulting in increased NRAS expression, which could be blocked by inactivation of Usp9x and therapeutic combination of Usp9x and MEK inhibitor fully suppressed melanoma growth. Thus, Usp9x modulates the Ets-1/NRAS regulatory network and may have biologic and therapeutic implications.

  4. Low-Dose Pesticide Mixture Induces Senescence in Normal Mesenchymal Stem Cells (MSC) and Promotes Tumorigenic Phenotype in Premalignant MSC.

    PubMed

    Hochane, Mazene; Trichet, Valerie; Pecqueur, Claire; Avril, Pierre; Oliver, Lisa; Denis, Jerome; Brion, Regis; Amiaud, Jerome; Pineau, Alain; Naveilhan, Philippe; Heymann, Dominique; Vallette, François M; Olivier, Christophe

    2017-03-01

    Humans are chronically exposed to multiple environmental pollutants such as pesticides with no significant evidence about the safety of such poly-exposures. We exposed mesenchymal stem cells (MSC) to very low doses of mixture of seven pesticides frequently detected in food samples for 21 days in vitro. We observed a permanent phenotype modification with a specific induction of an oxidative stress-related senescence. Pesticide mixture also induced a shift in MSC differentiation towards adipogenesis but did not initiate a tumorigenic transformation. In modified MSC in which a premalignant phenotype was induced, the exposure to pesticide mixture promoted tumorigenic phenotype both in vitro and in vivo after cell implantation, in all nude mice. Our results suggest that a common combination of pesticides can induce a premature ageing of adult MSC, and as such could accelerate age-related diseases. Exposure to pesticide mixture may also promote the tumorigenic transformation in a predisposed stromal environment. Abstract Video Link: https://youtu.be/mfSVPTol-Gk Stem Cells 2017;35:800-811.

  5. Antagonistic Cross-Regulation between Sox9 and Sox10 Controls an Anti-tumorigenic Program in Melanoma

    PubMed Central

    Shakhova, Olga; Cheng, Phil; Mishra, Pravin J.; Zingg, Daniel; Schaefer, Simon M.; Debbache, Julien; Häusel, Jessica; Matter, Claudia; Guo, Theresa; Davis, Sean; Meltzer, Paul; Mihic-Probst, Daniela; Moch, Holger; Wegner, Michael; Merlino, Glenn; Levesque, Mitchell P.; Dummer, Reinhard; Santoro, Raffaella; Cinelli, Paolo; Sommer, Lukas

    2015-01-01

    Melanoma is the most fatal skin cancer, but the etiology of this devastating disease is still poorly understood. Recently, the transcription factor Sox10 has been shown to promote both melanoma initiation and progression. Reducing SOX10 expression levels in human melanoma cells and in a genetic melanoma mouse model, efficiently abolishes tumorigenesis by inducing cell cycle exit and apoptosis. Here, we show that this anti-tumorigenic effect functionally involves SOX9, a factor related to SOX10 and upregulated in melanoma cells upon loss of SOX10. Unlike SOX10, SOX9 is not required for normal melanocyte stem cell function, the formation of hyperplastic lesions, and melanoma initiation. To the contrary, SOX9 overexpression results in cell cycle arrest, apoptosis, and a gene expression profile shared by melanoma cells with reduced SOX10 expression. Moreover, SOX9 binds to the SOX10 promoter and induces downregulation of SOX10 expression, revealing a feedback loop reinforcing the SOX10 low/SOX9 high ant,m/ii-tumorigenic program. Finally, SOX9 is required in vitro and in vivo for the anti-tumorigenic effect achieved by reducing SOX10 expression. Thus, SOX10 and SOX9 are functionally antagonistic regulators of melanoma development. PMID:25629959

  6. Cancer stem-like cells derived from chemoresistant tumors have a unique capacity to prime tumorigenic myeloid cells.

    PubMed

    Yamashina, Tsunaki; Baghdadi, Muhammad; Yoneda, Akihiro; Kinoshita, Ichiro; Suzu, Shinya; Dosaka-Akita, Hirotoshi; Jinushi, Masahisa

    2014-05-15

    Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells from CD14(+) monocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-R-specific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5(+) CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors. Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumor-associated CSF1 receptor(+) M2 macrophages in patients with non-small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments.

  7. Neural Stem Cell Tumorigenicity and Biodistribution Assessment for Phase I Clinical Trial in Parkinson’s Disease

    PubMed Central

    Garitaonandia, Ibon; Gonzalez, Rodolfo; Christiansen-Weber, Trudy; Abramihina, Tatiana; Poustovoitov, Maxim; Noskov, Alexander; Sherman, Glenn; Semechkin, Andrey; Snyder, Evan; Kern, Russell

    2016-01-01

    Human pluripotent stem cells (PSC) have the potential to revolutionize regenerative medicine. However undifferentiated PSC can form tumors and strict quality control measures and safety studies must be conducted before clinical translation. Here we describe preclinical tumorigenicity and biodistribution safety studies that were required by the US Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) prior to conducting a Phase I clinical trial evaluating the safety and tolerability of human parthenogenetic stem cell derived neural stem cells ISC-hpNSC for treating Parkinson’s disease (ClinicalTrials.gov Identifier NCT02452723). To mitigate the risk of having residual PSC in the final ISC-hpNSC population, we conducted sensitive in vitro assays using flow cytometry and qRT-PCR analyses and in vivo assays to determine acute toxicity, tumorigenicity and biodistribution. The results from these safety studies show the lack of residual undifferentiated PSC, negligible tumorigenic potential by ISC-hpNSC and provide additional assurance to their clinical application. PMID:27686862

  8. Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma

    PubMed Central

    Potu, Harish; Peterson, Luke F.; Kandarpa, Malathi; Pal, Anupama; Sun, Hanshi; Durham, Alison; Harms, Paul W.; Hollenhorst, Peter C.; Eskiocak, Ugur; Talpaz, Moshe; Donato, Nicholas J.

    2017-01-01

    ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition. Usp9x and Ets-1 levels are coincidently elevated in melanoma with highest levels detected in metastatic tumours versus normal skin or benign skin lesions. Notably, Ets-1 is induced by BRAF or MEK kinase inhibition, resulting in increased NRAS expression, which could be blocked by inactivation of Usp9x and therapeutic combination of Usp9x and MEK inhibitor fully suppressed melanoma growth. Thus, Usp9x modulates the Ets-1/NRAS regulatory network and may have biologic and therapeutic implications. PMID:28198367

  9. Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway.

    PubMed

    Li, Bin; Tsao, Sai Wah; Li, Yuk Yin; Wang, Xianghong; Ling, Ming Tat; Wong, Yong Chuan; He, Qing Yu; Cheung, Annie L M

    2009-12-01

    Id-1 (inhibitor of differentiation or DNA binding) is a helix-loop-helix protein that is overexpressed in many types of cancer including esophageal squamous cell carcinoma (ESCC). We previously reported that ectopic Id-1 expression activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in human esophageal cancer cells. In this study, we confirmed a positive correlation between Id-1 and phospho-AKT (Ser473) expressions in ESCC cell lines, as well as in ESCC on a tissue microarray. To investigate the significance of Id-1 in esophageal cancer progression, ESCC cells with stable ectopic Id-1 expression were inoculated subcutaneously into the flank of nude mice and were found to form larger tumors that showed elevated Ki-67 proliferation index and increased angiogenesis, as well as reduced apoptosis, compared with control cells expressing the empty vector.The Id-1-overexpressing cells also exhibited enhanced metastatic potential in the experimental metastasis assay. Treatment with the PI3K inhibitor LY294002 attenuated the tumor promotion effects of Id-1, indicating that the effects were mediated by the PI3K/AKT signaling pathway. In addition, our in vitro experiments showed that ectopic Id-1 expression altered the expression levels of markers associated with epithelial-mesenchymal transition and enhanced the migration ability of esophageal cancer cells. The Id-1-overexpressing ESCC cells also exhibited increased invasive potential, which was in part due to PI3K/AKT-dependent modulation of matrix metalloproteinase-9 expression. In conclusion, our results provide the first evidence that Id-1 promotes tumorigenicity and metastasis of human esophageal cancer in vivo and that the PI3K inhibitor LY294002 can attenuate these effects.

  10. Role of mitogen activated protein kinases in skin tumorigenicity of Patulin

    SciTech Connect

    Saxena, Neha; Ansari, Kausar M.; Kumar, Rahul; Chaudhari, Bhushan P.; Dwivedi, Premendra D.; Das, Mukul

    2011-12-15

    WHO has highlighted the need to evaluate dermal toxicity of mycotoxins including Patulin (PAT), detected in several fruits. In this study the skin carcinogenic potential of topically applied PAT was investigated. Single topical application of PAT (400 nmol) showed enhanced cell proliferation ({approx} 2 fold), along with increased generation of ROS and activation of ERK, p38 and JNK MAPKs, in mouse skin. PAT exposure also showed activation of downstream target proteins, c-fos, c-Jun and NF-{kappa}B transcription factors. Further, single topical application of PAT (400 nmol) followed by twice weekly application of TPA resulted in tumor formation after 14 weeks, indicating the tumor initiating activity of PAT. However no tumors were observed when PAT was used either as a complete carcinogen (80 nmol) or as a tumor promoter (20 nmol and 40 nmol) for 25 weeks. Histopathological findings of tumors found in PAT/TPA treated mice showed that these tumors were of squamous cell carcinoma type and similar to those found in the positive control group (DMBA/TPA) along with significant increase of lipid peroxidation and decrease in free sulfydryls, catalase, superoxide dismutase and glutathione reductase activities. The results suggest the possible role of free radicals in PAT mediated dermal tumorigenicity involving MAPKs. -- Highlights: Black-Right-Pointing-Pointer Single topical application of Patulin showed enhanced cell proliferation. Black-Right-Pointing-Pointer Patulin activate MAPKs, c-fos, c-Jun and NF-{kappa}B transcription factors. Black-Right-Pointing-Pointer Patulin showed skin tumor initiating potential. Black-Right-Pointing-Pointer We could not detect skin tumor promoting potential of Patulin at the tested dose. Black-Right-Pointing-Pointer However prolonged exposure of Patulin at a higher dose may promote tumor.

  11. Overexpression of 14-3-3σ counteracts tumorigenicity by positively regulating p73 in vivo

    PubMed Central

    GENG, CUIZHI; SANG, MEIXIANG; YANG, RUILING; GAO, WEI; ZHOU, TAO; WANG, SHIJIE

    2011-01-01

    14-3-3σ, one of the 14-3-3 family members, was initially identified as a human mammary epithelium-specific marker 1. The expression of 14-3-3σ is directly regulated by p53. It has been demonstrated that 14-3-3σ stabilizes p53 and enhances its transcriptional activity through the interaction with p53, suggesting that 14-3-3σ has a positive feedback effect on p53. Our previous study showed that 14-3-3σ is a direct transcriptional target of p73 and enhances the p73-mediated transcriptional as well as pro-apoptotic activity in vitro. In the present study, we explored the tumor-suppressive effect of 14-3-3σ by establishing a breast cancer xenograft nude mouse model with an inducible expression of 14-3-3σ or with an inducible expression of p53/p73 plus 14-3-3σ with ADR treatment. Tumor formation was then assayed. Moreover, 66 primary breast cancer specimens and paired tumor-free breast specimens obtained from the female patients were examined. Results showed that the expression of p73 and 14-3-3σ in breast cancer specimens was significantly lower than the tumor-free breast specimens and that 14-3-3σ expression was positively correlated with the expression of p73. Furthermore, overexpression of 14-3-3σ counteracts tumorigenicity by positively regulating p73 in p53-mutated or -deficient cancers in vivo. Therefore, our results may lead to the use of 14-3-3σ in the therapeutic application for the p53-mutated and p73-expressed breast cancer patients. PMID:22848285

  12. Tumorigenic transformation of human breast epithelial cells induced by mitochondrial DNA depletion.

    PubMed

    Kulawiec, Mariola; Safina, Alfiya; Desouki, Mohamed Mokhtar; Still, Ivan; Matsui, Sei-Ichi; Bakin, Andrei; Singh, Keshav K

    2008-11-01

    Human mitochondrial DNA (mtDNA) encodes 13 proteins involved in oxidative phosphorylation (OXPHOS). In order to investigate the role of mitochondrial OXPHOS genes in breast tumorigenesis, we have developed a breast epithelial cell line devoid of mtDNA (rho(0) cells). Our analysis revealed that depletion of mtDNA in breast epithelial cells results in in vitro tumorigenic phenotype as well as breast tumorigenesis in a xenograft model. We identified two major gene networks which were differentially regulated between parental and rho(0) epithelial cells. The focal proteins in these networks include (i) FN1 (fibronectin) and (ii) p53. Bioinformatic analyses of FN1 network identified laminin, integrin and 3 of 6 members of peroxiredoxin whose expression were altered in rho(0) epithelial cells. In the p53 network, we identified SMC4 and WRN whose changes in expression suggest that this network may affect chromosomal stability. Consistent with above finding our study revealed an increase in DNA double strand breaks and unique chromosomal rearrangements in rho(0) breast epithelial cells. Additionally, we identified tight junction proteins claudin-1 and claudin-7 in p53 network. To determine the functional relevance of altered gene expression, we focused on detailed analyses of claudin-1 and -7 proteins in breast tumorigenesis. Our study determined that (i) claudin-1 and 7 were indeed downregulated in rho(0) breast epithelial cells, (ii) downregulation of claudin-1 or -7 led to neoplastic transformation of breast epithelial cells, and (iii) claudin-1 and -7 were also downregulated in primary breast tumors. Together, our study suggest that mtDNA encoded OXPHOS genes play a key role in transformation of breast epithelial cells and that multiple pathway involved in mitochondria-to-nucleus retrograde regulation contribute to transformation of breast epithelial cells.

  13. Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.

    PubMed

    Singh, Bhupendra; Owens, Kjerstin M; Bajpai, Prachi; Desouki, Mohamed Mokhtar; Srinivasasainagendra, Vinodh; Tiwari, Hemant K; Singh, Keshav K

    2015-01-01

    Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic

  14. β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells.

    PubMed

    Xu, Jinhua; Prosperi, Jenifer R; Choudhury, Noura; Olopade, Olufunmilayo I; Goss, Kathleen H

    2015-01-01

    Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether β-catenin was necessary for tumorigenic behaviors in vivo and in vitro. β-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of β-catenin-specific small hairpin RNAs (shRNAs). Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that β-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, β-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. β-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and form anchorage-independent colonies in soft agar. β-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that β-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity.

  15. Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer.

    PubMed

    He, Xiaoping; Khurana, Ashwani; Roy, Debarshi; Kaufmann, Scott; Shridhar, Viji

    2014-10-15

    The expression of human Sulfatase1 (HSulf-1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf-1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf-1-deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA-transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf-1-deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf-1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf-1-deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf-1 expression in OV202 Sh1 cells. Enhanced expression of HSulf-1 in HSulf-1-deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf-1 were due to increased p-ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf-1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf-1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression.

  16. Transformation of human osteoblast cells to the tumorigenic phenotype by depleted uranium-uranyl chloride.

    PubMed Central

    Miller, A C; Blakely, W F; Livengood, D; Whittaker, T; Xu, J; Ejnik, J W; Hamilton, M M; Parlette, E; John, T S; Gerstenberg, H M; Hsu, H

    1998-01-01

    Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Although the health effects of occupational uranium exposure are well known, limited data exist regarding the long-term health effects of internalized DU in humans. We established an in vitro cellular model to study DU exposure. Microdosimetric assessment, determined using a Monte Carlo computer simulation based on measured intracellular and extracellular uranium levels, showed that few (0.0014%) cell nuclei were hit by alpha particles. We report the ability of DU-uranyl chloride to transform immortalized human osteoblastic cells (HOS) to the tumorigenic phenotype. DU-uranyl chloride-transformants are characterized by anchorage-independent growth, tumor formation in nude mice, expression of high levels of the k-ras oncogene, reduced production of the Rb tumor-suppressor protein, and elevated levels of sister chromatid exchanges per cell. DU-uranyl chloride treatment resulted in a 9.6 (+/- 2.8)-fold increase in transformation frequency compared to untreated cells. In comparison, nickel sulfate resulted in a 7.1 (+/- 2.1)-fold increase in transformation frequency. This is the first report showing that a DU compound caused human cell transformation to the neoplastic phenotype. Although additional studies are needed to determine if protracted DU exposure produces tumors in vivo, the implication from these in vitro results is that the risk of cancer induction from internalized DU exposure may be comparable to other biologically reactive and carcinogenic heavy-metal compounds (e.g., nickel). Images Figure 1 Figure 2 Figure 3 PMID:9681973

  17. Neogenin expression may be inversely correlated to the tumorigenicity of human breast cancer

    PubMed Central

    Lee, Jeong Eon; Kim, Hee Joung; Bae, Ji Yeon; Kim, Seok Won; Park, Joon-Suk; Shin, Hyuk Jai; Han, Wonshik; Kim, Sung-Won; Kang, Kyung-Sun; Noh, Dong-Young

    2005-01-01

    Background Neogenin is expressed in cap cells that have been suggested to be mammary stem or precursor cells. Neogenin is known to play an important role in mammary morphogenesis; however its relationship to tumorigenesis remains to be elucidated. Methods To compare the expression levels of neogenin in cells with different tumorigenicity, the expression levels in M13SV1, M13SV1R2 and M13SV1R2N1 cells, which are immortalized derivatives of type I human breast epithelial cells, were evaluated. Then we measured the expression level of neogenin in paired normal and cancer tissues from eight breast cancer patients. Tissue array analysis was performed for 54 human breast tissue samples with different histology, and the results were divided into four categories (none, weak, moderate, strong) by a single well-trained blinded pathologist and statistically analyzed. Results The nontumorigenic M13SV1 cells and normal tissues showed stronger expression of neogenin than the M13SV1R2N1 cells and the paired cancer tissues. In the tissue array, all (8/8) of the normal breast tissues showed strong neogenin expression, while 93.5% (43/46) of breast cancer tissues had either no expression or only moderate levels of neogenin expression. There was a significant difference, in the expression level of neogenin, in comparisons between normal and infiltrating ductal carcinoma (p < 0.001). Conclusion Neogenin may play a role in mammary carcinogenesis as well as morphogenesis, and the expression may be inversely correlated with mammary carcinogenicity. The value of neogenin as a potential prognostic factor needs further evaluation. PMID:16324219

  18. The role of transforming growth factor alpha production and ErbB-2 overexpression in induction of tumorigenicity of lung epithelial cells.

    PubMed Central

    Hamburger, A. W.; Fernandes, A.; Murakami, M.; Gerwin, B. I.

    1998-01-01

    Over-expression of erbB-2 is associated with shortened survival of patients with lung adenocarcinomas. We demonstrated that human lung epithelial cells, overexpressing erbB-2, formed tumours in nude mice only when high levels of transforming growth factor (TGF)-alpha were produced (E6T cells). To define the role that TGF-alpha production played in induction of tumorigenicity, a non-tumorigenic TGF-alpha-negative clone of ErbB-2 overexpressing cells (E2 cells) was transfected with an expression vector for TGF-alpha (E2alpha cells). Transfected clones produced TGF-alpha at 11-25% of the level produced by the E6T cell line. Tumorigenic E6T cells transfected with a TGF-alpha antisense vector (E6TA cells) expressed only 6% of the TGF-alpha level of the parental cells. Clones of E6T, E6TA, E2 and E2alpha were inoculated into athymic nude mice to measure tumorigenic potential. E6T cells formed tumours with a 70% efficiency. E2, E6TA and E2alpha cells failed to form tumours. The levels of EGFR were similar in non-tumorigenic E2 and tumorigenic E6T cells but higher in E2alpha and E6TA cells, and ErbB-2 were greatly overexpressed in an E2alpha clone. In vitro, ErbB-2 co-immunoprecipitated with EGFR in lysates of unstimulated E6T and E2alpha TGF-alpha-producing cells, indicating that the lower TGF-alpha levels were sufficient to induce in vitro heterodimerization. These studies suggest that induction of the tumorigenic phenotype depends on achieving a threshold level of TGF-alpha sufficient to activate downstream signalling by ErbB-2 containing active heterodimers. Images Figure 1 Figure 2 Figure 3 PMID:9569041

  19. 12-O-Tetradecanoylphorbol-13-acetate (TPA) is anti-tumorigenic in liver cancer cells via inhibiting YAP through AMOT

    PubMed Central

    Zhu, Guoqing; Chen, Yan; Zhang, Xiao; Wu, Qi; Zhao, Yinghui; Chen, Yuxin; Sun, Fenyong; Qiao, Yongxia; Wang, Jiayi

    2017-01-01

    TPA stimulates carcinogenesis in various types of cancers. However, we found that TPA inhibits transformative phenotypes in liver cancer cells via the translocation of YAP from the nucleus, where it functions as a transcriptional co-factor, to the cytoplasm. Such effects led to a separation of YAP from its dependent transcription factors. The inhibitory effects of TPA on YAP were AMOT dependent. Without AMOT, TPA was unable to alter YAP activity. Importantly, the depletion of YAP and AMOT blocked the TPA-reduced transformative phenotypes. In sum, TPA has been established as an anti-tumorigenic drug in liver cancer cells via YAP and AMOT. PMID:28322318

  20. Nontumorigenic squamous cell carcinoma line converted to tumorigenicity with methyl methanesulfonate without activation of HRAS or MYC.

    PubMed

    Milo, G E; Shuler, C; Kurian, P; French, B T; Mannix, D G; Noyes, I; Hollering, J; Sital, N; Schuller, D; Trewyn, R W

    1990-02-01

    Plasticity of human tumor populations could account for the reason why many tumorigenic human cell lines lose this feature when grown in culture. Methyl methanesulfonate (MMS) was used to convert premalignant squamous cell carcinoma (SCC) cell line SCC-83-01-82 to a malignant phenotype. The MMS-treated SCC-83-01-82 cells (MMS-SCC-83-01-82) produced progressively growing tumors in 5 of 11 splenectomized BALB/c nude mice within 3-5 months. A cell line, designated SCC-83-01-82 CA, was established in vitro from one of the mouse tumors and was repassaged successively. This SCC-83-01-82 CA cell line was aggressively tumorigenic. A tumor greater than or equal to 2.0 cm in size was present within a month, as opposed to the 3-5 months required for the tumors produced by the MMS-SCC-83-01-82 cells. Examination of frozen cross sections by in situ hybridization revealed that focal areas of the tumor produced by the MMS-SCC-83-01-82 cells expressed MYC and HRAS mRNA. However, by the third passage in vivo, the levels of expression of the corresponding genes in the mouse tumors were undetectable. Blot-hybridization analysis of the RNA from the MMS-SCC-83-01-82 cells and the subsequently derived tumors and cells did not indicate any consistent overexpression of MYC, HRAS, or KRAS. Restriction fragment length polymorphism analysis of both MYC and HRAS genes revealed neither rearrangement nor amplification of MYC nor point mutation in the 11th or 12th codon of HRAS. The data suggest that alterations in MYC and HRAS were not directly involved in either the initial transformation or MMS-induced tumorigenic conversion of the SCC-83-01-82 cell line. Persistence of tumorigenicity after reisolation of the MMS-converted premalignant SCC-83-01-82 cells did not disappear immediately following the treatment with MMS.

  1. Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity.

    PubMed

    Xia, Qingsu; Zhao, Yuewei; Von Tungeln, Linda S; Doerge, Daniel R; Lin, Ge; Cai, Lining; Fu, Peter P

    2013-09-16

    Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N(2)-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6)-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic pyrrolizidine alkaloid, platyphylliine, a pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of

  2. Toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil.

    PubMed

    Wolf, Douglas C; Allen, James W; George, Michael H; Hester, Susan D; Sun, Guobin; Moore, Tanya; Thai, Sheau-Fung; Delker, Don; Winkfield, Ernest; Leavitt, Sharon; Nelson, Gail; Roop, Barbara C; Jones, Carlton; Thibodeaux, Julie; Nesnow, Stephen

    2006-01-01

    Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for triadimefon. Male Wistar/Han rats were treated with triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were

  3. Lung tumorigenic interactions in strain A/J mice of five environmental polycyclic aromatic hydrocarbons.

    PubMed Central

    Nesnow, S; Mass, M J; Ross, J A; Galati, A J; Lambert, G R; Gennings, C; Carter, W H; Stoner, G D

    1998-01-01

    The binary, ternary, quaternary, and quintary interactions of a five-component mixture of carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs) using response surface analyses are described. Initially, lung tumor dose-response curves in strain A/J mice for each of the individual PAHs benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), dibenz[a,h]anthracene (DBA), 5-methylchrysene (5MC), and cyclopenta[cd]pyrene (CPP) were obtained. From these data, doses were selected for the quintary mixture study based on toxicity, survival, range of response, and predicted tumor yields. The ratios of doses among PAHs were designed to simulate PAH ratios found in environmental air and combustion samples. Quintary mixtures of B[a]P, B[b]F, DBA, 5MC, and CPP were administered to male strain A/J mice in a 2(5) factorial 32-dose group dosing scheme (combinations of five PAHs each at either high or low doses) and lung adenomas were scored. Comparison of observed lung adenoma formation with that expected from additivity identified both greater than additive and less than additive interactions that were dose related i.e., greater than additive at lower doses and less than additive at higher doses. To identify specific interactions, a response surface analysis using response addition was applied to the tumor data. This response surface model contained five dose, ten binary, ten ternary, five quaternary, and one quintary parameter. This analysis produced statistically significant values of 16 parameters. The model and model parameters were evaluated by estimating the dose-response relationships for each of the five PAHs. The predicted dose-response curves for all five PAHs indicated a good estimation. The binary interaction functions were dominated for the most part by DBA and were inhibitory. The response surface model predicted, to a significant degree, the observed lung tumorigenic responses of the quintary mixtures. These data suggest that although interactions between

  4. Failure of catalase to protect against aflatoxin B{sub 1}-induced mouse lung tumorigenicity

    SciTech Connect

    Guindon, Katherine A.; Foley, Julie F.; Maronpot, Robert R.; Massey, Thomas E.

    2008-03-01

    The carcinogenic mycotoxin aflatoxin B{sub 1} (AFB{sub 1}) induces 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung, an effect that can be prevented by treatment with polyethylene glycol-conjugated catalase (PEG-CAT). G {yields} T transversion mutation in K-ras, an early event in AFB{sub 1}-induced mouse lung carcinogenesis, is thought to result from AFB{sub 1}-8,9-exo-epoxide binding to DNA to form AFB{sub 1}-N{sup 7}-guanine, but may also result from formation of 8-OHdG. Therefore, oxidative DNA damage may be important in AFB{sub 1} carcinogenicity. The objective of this study was to determine whether PEG-CAT would prevent AFB{sub 1} tumorigenicity. Mouse lung tumorigenesis was assessed following treatment of female A/J mice with 300 kU/kg PEG-CAT ip and/or 50 mg/kg AFB{sub 1}. Mice were killed 7 months post-treatment and tumors greater than 1 mm in diameter were excised. Unexpectedly, the mean number of tumors per mouse in the PEG-CAT + AFB{sub 1} group (8.81 {+-} 3.64, n = 47) was greater than that of the group treated with AFB{sub 1} alone (7.05 {+-} 3.45, n = 42) (P < 0.05). The tumors obtained from mice treated with PEG-CAT + AFB{sub 1} were larger than those from mice treated with AFB{sub 1} alone (P < 0.05). There was no difference in K-ras exon 1 mutation spectrum or in the histological diagnosis of tumors between AFB{sub 1} and PEG-CAT + AFB{sub 1} groups (P > 0.05). In vitro incubation with mouse liver catalase (CAT) resulted in conversion of [{sup 3}H]AFB{sub 1} into a DNA-binding species, a possible explanation for the results observed in vivo. These results demonstrate that PEG-CAT is not protective against AFB{sub 1} carcinogenicity in mouse lung despite preventing DNA oxidation.

  5. Thermoelectric device exhibiting decreased stress

    SciTech Connect

    Heath, D.L.; Chou, D.J.

    1985-02-05

    A thermoelectric device exhibiting both structural integrity and decreased stress across the device notwithstanding the application of thermally cycled temperature differentials thereacross includes, electrically interconnected thermoelectric elements and a rigidly affixed substrate. Thermal stress is relieved by using flexible conductors to interconnect the thermoelectric elements, and by the use of a flexile joint to attach a second substrate to the remainder of the device. Complete elimination of the second substrate may also be used to eliminate stress. Presence of the rigidly affixed substrate gives the device sufficient structural integrity to enable it to withstand rugged conditions.

  6. Large holograms in traveling exhibitions

    NASA Astrophysics Data System (ADS)

    Christakis, Anne-Marie

    1994-01-01

    The presentation of large holograms in travelling exhibitions has always posed problems, mainly due to lack of space. The Museum of Holography was consequently required to develop, with Jean-Francois Moreau, display consoles which are light, affordable and completely detachable. In a permanent exposition at the Forum des Halles in Paris, the Museum displays a room with 22 holograms, each measuring 1 m X 1 m, in a structure designed by the architect Fabien Vienne. The different systems used by the Museum are presented here.

  7. Complementation of non-tumorigenicity of HPV18-positive cervical carcinoma cells involves differential mRNA expression of cellular genes including potential tumor suppressor genes on chromosome 11q13.

    PubMed

    Kehrmann, Angela; Truong, Ha; Repenning, Antje; Boger, Regina; Klein-Hitpass, Ludger; Pascheberg, Ulrich; Beckmann, Alf; Opalka, Bertram; Kleine-Lowinski, Kerstin

    2013-01-01

    The fusion between human tumorigenic cells and normal human diploid fibroblasts results in non-tumorigenic hybrid cells, suggesting a dominant role for tumor suppressor genes in the generated hybrid cells. After long-term cultivation in vitro, tumorigenic segregants may arise. The loss of tumor suppressor genes on chromosome 11q13 has been postulated to be involved in the induction of the tumorigenic phenotype of human papillomavirus (HPV)18-positive cervical carcinoma cells and their derived tumorigenic hybrid cells after subcutaneous injection in immunocompromised mice. The aim of this study was the identification of novel cellular genes that may contribute to the suppression of the tumorigenic phenotype of non-tumorigenic hybrid cells in vivo. We used cDNA microarray technology to identify differentially expressed cellular genes in tumorigenic HPV18-positive hybrid and parental HeLa cells compared to non-tumorigenic HPV18-positive hybrid cells. We detected several as yet unknown cellular genes that play a role in cell differentiation, cell cycle progression, cell-cell communication, metastasis formation, angiogenesis, antigen presentation, and immune response. Apart from the known differentially expressed genes on 11q13 (e.g., phosphofurin acidic cluster sorting protein 1 (PACS1) and FOS ligand 1 (FOSL1 or Fra-1)), we detected novel differentially expressed cellular genes located within the tumor suppressor gene region (e.g., EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) and leucine rich repeat containing 32 (LRRC32) (also known as glycoprotein-A repetitions predominant (GARP)) that may have potential tumor suppressor functions in this model system of non-tumorigenic and tumorigenic HeLa x fibroblast hybrid cells.

  8. Collaborative virtual environments art exhibition

    NASA Astrophysics Data System (ADS)

    Dolinsky, Margaret; Anstey, Josephine; Pape, Dave E.; Aguilera, Julieta C.; Kostis, Helen-Nicole; Tsoupikova, Daria

    2005-03-01

    This panel presentation will exhibit artwork developed in CAVEs and discuss how art methodologies enhance the science of VR through collaboration, interaction and aesthetics. Artists and scientists work alongside one another to expand scientific research and artistic expression and are motivated by exhibiting collaborative virtual environments. Looking towards the arts, such as painting and sculpture, computer graphics captures a visual tradition. Virtual reality expands this tradition to not only what we face, but to what surrounds us and even what responds to our body and its gestures. Art making that once was isolated to the static frame and an optimal point of view is now out and about, in fully immersive mode within CAVEs. Art knowledge is a guide to how the aesthetics of 2D and 3D worlds affect, transform, and influence the social, intellectual and physical condition of the human body through attention to psychology, spiritual thinking, education, and cognition. The psychological interacts with the physical in the virtual in such a way that each facilitates, enhances and extends the other, culminating in a "go together" world. Attention to sharing art experience across high-speed networks introduces a dimension of liveliness and aliveness when we "become virtual" in real time with others.

  9. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer.

    PubMed

    Wilson, Andrew J; Fadare, Oluwole; Beeghly-Fadiel, Alicia; Son, Deok-Soo; Liu, Qi; Zhao, Shilin; Saskowski, Jeanette; Uddin, Md Jashim; Daniel, Cristina; Crews, Brenda; Lehmann, Brian D; Pietenpol, Jennifer A; Crispens, Marta A; Marnett, Lawrence J; Khabele, Dineo

    2015-08-28

    Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors.

  10. Long non-coding RNA MALAT1 promotes gastric cancer tumorigenicity and metastasis by regulating vasculogenic mimicry and angiogenesis.

    PubMed

    Li, Yue; Wu, Zhenzhen; Yuan, Jia; Sun, Li; Lin, Li; Huang, Na; Bin, Jianping; Liao, Yulin; Liao, Wangjun

    2017-06-01

    MALAT1 is an oncogenic long non-coding RNA that has been found to promote the proliferation of many malignant cell types and non-malignant human umbilical vein endothelial cells (HUVECs). However, the functions of MALAT1 in vasculogenic mimicry (VM) and angiogenesis and the potential mechanisms responsible have not yet been investigated in any malignancy. Here, in situ hybridization and CD31/periodic acid-Schiff double staining of 150 gastric cancer (GC) clinical specimens revealed that MALAT1 expression was tightly associated with densities of VM and endothelial vessels. MALAT1 knockdown markedly reduced GC cell migration, invasion, tumorigenicity, metastasis, and VM, while restricting HUVEC angiogenesis and increasing vascular permeability. Moreover, MALAT1 was found to regulate expression of VE-cadherin, β-catenin, MMPs 2 and 9, MT1-MMP, p-ERK, p-FAK, and p-paxillin, which have been established as classical markers of VM and angiogenesis and components of associated signaling pathways. Consistent with this, the p-ERK inhibitors U0126 and PD98059 both effectively blocked GC cell VM. In conclusion, MALAT1 can promote tumorigenicity and metastasis in GC by facilitating VM and angiogenesis via the VE-cadherin/β-catenin complex and ERK/MMP and FAK/paxillin signaling pathways.

  11. Preliminary whole-exome sequencing reveals mutations that imply common tumorigenicity pathways in multiple endocrine neoplasia type 1 patients

    PubMed Central

    Arenas, Minerva Angélica Romero; Fowler, Richard G.; Lucas, F. Anthony San; Shen, Jie; Rich, Thereasa A.; Grubbs, Elizabeth G.; Lee, Jeffrey E.; Scheet, Paul; Perrier, Nancy D.; Zhao, Hua

    2016-01-01

    Background Whole-exome sequencing studies have not established definitive somatic mutation patterns among patients with sporadic hyperparathyroidism (HPT). No sequencing has evaluated multiple endocrine neoplasia type 1 (MEN1)-related HPT. We sought to perform whole-exome sequencing in HPT patients to identify somatic mutations and associated biological pathways and tumorigenic networks. Methods Whole-exome sequencing was performed on blood and tissue from HPT patients (MEN1 and sporadic) and somatic single nucleotide variants (SNVs) were identified. Stop-gain and stop-loss SNVs were analyzed with Ingenuity Pathways Analysis (IPA). Loss of heterozygosity (LOH) was also assessed. Results Sequencing was performed on 4 MEN1 and 10 sporadic cases. Eighteen stop-gain/stop-loss SNV mutations were identified in 3 MEN1 patients. One complex network was identified on IPA: Cellular function and maintenance, tumor morphology, and cardiovascular disease (IPA score = 49). A nonsynonymous SNV of TP53 (lysine-to-glutamic acid change at codon 81) identified in a MEN1 patient was suggested to be a driver mutation (Cancer-specific High-throughput Annotation of Somatic Mutations; P = .002). All MEN1 and 3/10 sporadic specimens demonstrated LOH of chromosome 11. Conclusion Whole-exome sequencing revealed somatic mutations in MEN1 associated with a single tumorigenic network, whereas sporadic pathogenesis seemed to be more diverse. A somatic TP53 mutation was also identified. LOH of chromosome 11 was seen in all MEN1 and 3 of 10 sporadic patients. PMID:25456907

  12. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

    PubMed Central

    Wilson, Andrew J.; Fadare, Oluwole; Beeghly-Fadiel, Alicia; Son, Deok-Soo; Liu, Qi; Zhao, Shilin; Saskowski, Jeanette; Uddin, Md. Jashim; Daniel, Cristina; Crews, Brenda; Lehmann, Brian D.; Pietenpol, Jennifer A.; Crispens, Marta A.; Marnett, Lawrence J.; Khabele, Dineo

    2015-01-01

    Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors. PMID:25972361

  13. Nucleolin-binding by ErbB2 enhances tumorigenicity of ErbB2-positive breast cancer

    PubMed Central

    Wolfson, Eya; Goldenberg, Maria; Solomon, Shira; Frishberg, Amit; Pinkas-Kramarski, Ronit

    2016-01-01

    ErbB2 is an important member of the ErbB family, which activates growth and proliferation signaling pathways. ErbB2 is often overexpressed in various malignancies, especially in breast cancer, and is a common target for anti-cancer drugs. Breast cancer is currently one of the leading mortality causes in women, and acquired resistance to ErbB2-targeted therapies is a major obstacle in its treatment. Thus, understanding ErbB2-mediated signaling is crucial for further development of anti-cancer therapeutics and disease treatment. Previously, we have reported that the ErbB receptors interact with the major nucleolar protein nucleolin. In addition to its function in the nucleoli of cells, nucleolin participates in various cellular processes at the cytoplasm and cell-surface. Deregulated nucleolin is frequently overexpressed on the membrane of cancer cells. Here, we show that nucleolin increases colony formation and anchorage-independent growth of ErbB2-overexpressing cells. Importantly, this enhanced tumorigenicity also occurs in human ErbB2-positive breast cancer patients; namely, nucleolin overexpression in these patients is associated with reduced patient survival rates and increased disease-risk. ErbB2-nucleolin complexes are formed endogenously in both normal and cancer cells, and their effect on tumorigenicity is mediated through activation of ErbB2 signaling. Accordingly, nucleolin inhibition reduces cell viability and ErbB2 activation in ErbB2-positive cancer cells. PMID:27542246

  14. Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia-derived cells via aberrant AKT activation.

    PubMed

    Yamaguchi, Kazunori; Takanashi, Tomoka; Nasu, Kentaro; Tamai, Keiichi; Mochizuki, Mai; Satoh, Ikuro; Ine, Shoji; Sasaki, Osamu; Satoh, Kennichi; Tanaka, Nobuyuki; Harigae, Hideo; Sugamura, Kazuo

    2016-05-01

    The transplantation of human cancer cells into immunodeficient NOD/SCID/IL-2Rγc(null) (NOG) mice often causes highly malignant cell populations like cancer stem cells to emerge. Here, by serial transplantation in NOG mice, we established two highly tumorigenic adult T-cell leukemia-derived cell lines, ST1-N6 and TL-Om1-N8. When transplanted s.c., these cells formed tumors significantly earlier and from fewer initial cells than their parental lines ST1 and TL-Om1. We found that protein kinase B (AKT) signaling was upregulated in ST1-N6 and TL-Om1-N8 cells, and that this upregulation was due to the decreased expression of a negative regulator, INPP5D. Furthermore, the introduction of a constitutively active AKT mutant expression vector into ST1 cells augmented the tumorigenicity of the cells, whereas treatment with the AKT inhibitor MK-2206 attenuated the progression of tumors induced by ST1-N6 cells. Collectively, our results reveal that the AKT signaling pathway plays a critical role in the malignancy of adult T-cell leukemia-derived cells.

  15. Expression of murine interleukin 7 in a murine glioma cell line results in reduced tumorigenicity in vivo.

    PubMed Central

    Aoki, T; Tashiro, K; Miyatake, S; Kinashi, T; Nakano, T; Oda, Y; Kikuchi, H; Honjo, T

    1992-01-01

    We have examined the immunoregulatory effect of local and continuous secretion of interleukin 7 (IL-7) from murine glioma cells (203-glioma) engineered by murine IL-7 gene transfection. Secretion of IL-7 from glioma cells did not result in morphology or growth rate changes but did reduce tumorigenicity in vivo in proportion to the amount of IL-7 produced. This reduction in tumorigenicity could be reversed in a dose-dependent fashion by injection of anti-IL-7 neutralizing monoclonal antibody at the tumor site. Mice immunized with IL-7-producing glioma cells showed a specific immune response to 203-glioma but not to two other syngeneic cell lines (B-16, a melanoma, and YM-12, a fibrosarcoma). IL-7-producing glioma cells were not rejected in mice depleted of CD8+ cells but were rejected in mice depleted of CD4+ or NK1.1+ cells. These results suggest that CD8+ T cells may play an important role in tumor rejection. Images PMID:1570303

  16. The effects and mechanisms of SLC34A2 on tumorigenicity in human non-small cell lung cancer stem cells.

    PubMed

    Jiang, Zhanxin; Hao, Yanhong; Ding, Xiaoquan; Zhang, Zhibin; Liu, Peng; Wei, Xueqiang; Xi, Junfeng

    2016-08-01

    A novel paradigm in tumor biology suggests that non-small cell lung cancer (NSCLC) growth is driven by lung cancer stem cell-like cells (LCSCs), but molecular mechanisms regulating tumorigenic and self-renewal potential of LCSCs are still unclear. Here, we aim to investigate biological function of SLC34A2 in regulating tumorigenicity of LCSCs and its underlying mechanisms. Our findings testified that CD166(+) cells which were derived from fresh primary NSCLC samples displayed stem cell-like features. Fluorescence-activated cell sorting (FACS) analysis showed the presence of a variable fraction of CD166 cells in 15 out of 15 NSCLC samples. Significantly, CD166(+) LCSCs from primary NSCLC tumors expressed high level of SLC34A2 which was required for CD166(+) LCSCs tumorigenic and self-renewal potential. In NSCLC patient cohort, increased SLC34A2 expression correlated with histology, which suggests a potential role of SLC34A2 in CD166(+) LCSCs. Furthermore, Wnt/β-catenin pathway and Bmi1 were found necessary for tumorigenicity and self-renewal capacity of CD166(+) LCSCs by a series in vitro and in vivo experiments. Then, our study indicated that SLC34A2 regulated Bmi1 to promote tumorigenic and self-renewal potential of CD166(+) LCSCs through Wnt/β-catenin pathway. In this study, the characterization of molecular basis of SLC34A2 in CD166(+) LCSCs not only allows for better understanding of the mechanisms regulating tumorigenicity of this specific population of NSCLC cells but also provides insight into the gradual improvement of more effective cancer therapies against this disease.

  17. Benzo[b]fluoranthene: tumorigenicity in strain A/J mouse lungs, DNA adducts and mutations in the Ki-ras oncogene.

    PubMed

    Mass, M J; Abu-Shakra, A; Roop, B C; Nelson, G; Galati, A J; Stoner, G D; Nesnow, S; Ross, J A

    1996-08-01

    The polycyclic aromatic hydrocarbon benzo[b]fluoranthene (B[b]F) is a pervasive constituent of environmental combustion products. We sought to examine the lung tumorigenic activity of B[b]F in strain A/J mice, to study the relationship between formation and decay of B[b]F-DNA adducts and to examine mutations in the Ki-ras proto-oncogene in DNA from B[b]F-induced tumors. Mice were given i.p. injections of 0, 10, 50, 100 or 200 mg/kg body wt and lung adenomas were scored after 8 months. B[b]F induced significant numbers of mouse lung adenomas in a dose-related fashion, with the highest dose (200 mg/kg) yielding 6.95 adenomas/ mouse, with 100% of the mice exhibiting an adenoma. In mice given tricaprylin, the vehicle control, there were 0.60 adenomas/mouse, with 55% of the mice exhibiting an adenoma. Based on dose, B[b]F was less active than benzo[a]pyrene. DNA adducts were analyzed qualitatively and quantitatively by 32P-post-labeling in lungs of strain A/J mice 1, 3, 5, 7, 14 and 21 days after i.p. injection. Maximal levels of adduction occurred 5 days after treatment with the 200 mg/kg dose group, producing 1230 amol B[b]F-DNA adducts/microgram DNA. The major B[b]F-DNA adduct was identified by co-chromatography as trans-9, 10-dihydroxy-anti-11, 12-epoxy-5-hydroxy-9, 10, 11, 12-tetra-hydro-B[b]F-deoxyguanosine. Approximately 86% of the tumors had a mutation in codon 12 of the Ki-ras oncogene, as determined by direct DNA sequencing of PCR-amplified exon 1 and single-stranded conformation polymorphism analysis. Analysis of the Ki-ras mutation spectrum in 25 of 29 B[b]F-induced tumors revealed the predominant mutation to be a G-->T transversion in the first or second base of codon 12, congruous with the DNA adduct data. Our data are consistent with previous reports in mouse skin implicating a phenolic diol epoxide as the proximate carcinogenic form of B[b]F that binds to guanine.

  18. A Tetrameric Peptide Derived from Bovine Lactoferricin Exhibits Specific Cytotoxic Effects against Oral Squamous-Cell Carcinoma Cell Lines.

    PubMed

    Solarte, Víctor A; Rosas, Jaiver E; Rivera, Zuly J; Arango-Rodríguez, Martha L; García, Javier E; Vernot, Jean-Paul

    2015-01-01

    Several short linear peptides derived from cyclic bovine lactoferricin were synthesized and tested for their cytotoxic effect against the oral cavity squamous-cell carcinoma (OSCC) cell lines CAL27 and SCC15. As a control, an immortalized and nontumorigenic cell line, Het-1A, was used. Linear peptides based on the RRWQWR core sequence showed a moderate cytotoxic effect and specificity towards tumorigenic cells. A tetrameric peptide, LfcinB(20-25)4, containing the RRWQWR motif, exhibited greater cytotoxic activity (>90%) in both OSCC cell lines compared to the linear lactoferricin peptide or the lactoferrin protein. Additionally, this tetrameric peptide showed the highest specificity towards tumorigenic cells among the tested peptides. Interestingly, this effect was very fast, with cell shrinkage, severe damage to cell membrane permeability, and lysis within one hour of treatment. Our results are consistent with a necrotic effect rather than an apoptotic one and suggest that this tetrameric peptide could be considered as a new candidate for the therapeutic treatment of OSCC.

  19. A Tetrameric Peptide Derived from Bovine Lactoferricin Exhibits Specific Cytotoxic Effects against Oral Squamous-Cell Carcinoma Cell Lines

    PubMed Central

    Solarte, Víctor A.; Rosas, Jaiver E.; Rivera, Zuly J.; Arango-Rodríguez, Martha L.; García, Javier E.; Vernot, Jean-Paul

    2015-01-01

    Several short linear peptides derived from cyclic bovine lactoferricin were synthesized and tested for their cytotoxic effect against the oral cavity squamous-cell carcinoma (OSCC) cell lines CAL27 and SCC15. As a control, an immortalized and nontumorigenic cell line, Het-1A, was used. Linear peptides based on the RRWQWR core sequence showed a moderate cytotoxic effect and specificity towards tumorigenic cells. A tetrameric peptide, LfcinB(20–25)4, containing the RRWQWR motif, exhibited greater cytotoxic activity (>90%) in both OSCC cell lines compared to the linear lactoferricin peptide or the lactoferrin protein. Additionally, this tetrameric peptide showed the highest specificity towards tumorigenic cells among the tested peptides. Interestingly, this effect was very fast, with cell shrinkage, severe damage to cell membrane permeability, and lysis within one hour of treatment. Our results are consistent with a necrotic effect rather than an apoptotic one and suggest that this tetrameric peptide could be considered as a new candidate for the therapeutic treatment of OSCC. PMID:26609531

  20. Expression of the MyoD1 muscle determination gene defines differentiation capability but not tumorigenicity of human rhabdomyosarcomas.

    PubMed Central

    Hiti, A L; Bogenmann, E; Gonzales, F; Jones, P A

    1989-01-01

    Several human rhabdomyosarcoma cell lines, cultured primary tumor explants, and biopsies of tumor and normal skeletal muscle tissue expressed a 2.0-kilobase transcript that hybridized to the mouse muscle determination gene MyoD1. This transcript was found in tumor cell lines and primary explants that developed multinucleated myotubes but was absent in Wilms' tumors or cell lines and primary explants that developed multinucleated myotubes but was absent in Wilms' tumors or cell lines derived from other mesenchymal tumor cell types. Expression of the human homolog of MyoD1 therefore can define a tumor as a rhabdomyosarcoma. Transfection of the mouse MyoD1 gene into the human rhabdomyosarcoma cell line RD increased the ability of the tumor cells to differentiate into multinucleated myotubes and enhanced myosin heavy-chain gene expression but did not decrease tumorigenicity in nude mice. Images PMID:2601695

  1. Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation

    PubMed Central

    Šolman, Maja; Ligabue, Alessio; Blaževitš, Olga; Jaiswal, Alok; Zhou, Yong; Liang, Hong; Lectez, Benoit; Kopra, Kari; Guzmán, Camilo; Härmä, Harri; Hancock, John F; Aittokallio, Tero; Abankwa, Daniel

    2015-01-01

    Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer. DOI: http://dx.doi.org/10.7554/eLife.08905.001 PMID:26274561

  2. Introduction of a normal human chromosome 11 into a Wilm's tumor cell line controls its tumorigenic expression

    SciTech Connect

    Weissman, B.E.; Saxon, P.J.; Pasquale, S.R.; Jones, G.R.; Geiser, A.G.; Stanbridge, E.J.

    1987-04-10

    The development of Wilm's tumor, a pediatric nephroblastoma, has been associated with a deletion in the p13 region of chromosome 11. The structure and function or functions of this deleted genetic material are unknown. The role of this deletion in the process of malignant transformation was investigated by introducing a normal human chromosome 11 into a Wilms' tumor cell line by means of the microcell transfer technique. These variant cells, derived by microcell hybridization, expressed similar transformed traits in culture as the parental cell line. Furthermore, expression of several proto-oncogenes by the parental cells was unaffected by the introduction of this chromosome. However, the ability of these cells to form tumors in nude mice was completely suppressed. Transfer of other chromosomes, namely X and 13, had no effect on the tumorigenicity of the Wilms' tumor cells. These studies provide support for the existence of genetic information on chromosome 11 which can control the malignant expression of Wilm's tumor cells.

  3. The Transmembrane Domain of CEACAM1-4S Is a Determinant of Anchorage Independent Growth and Tumorigenicity

    PubMed Central

    Lawson, Erica L.; Mills, David R.; Brilliant, Kate E.; Hixson, Douglas C.

    2012-01-01

    CEACAM1 is a multifunctional Ig-like cell adhesion molecule expressed by epithelial cells in many organs. CEACAM1-4L and CEACAM1-4S, two isoforms produced by differential splicing, are predominant in rat liver. Previous work has shown that downregulation of both isoforms occurs in rat hepatocellular carcinomas. Here, we have isolated an anchorage dependent clone, designated 253T-NT that does not express detectable levels of CEACAM1. Stable transfection of 253-NT cells with a wild type CEACAM1-4S expression vector induced an anchorage independent growth in vitro and a tumorigenic phenotype in vivo. These phenotypes were used as quantifiable end points to examine the functionality of the CEACAM1-4S transmembrane domain. Examination of the CEACAM1 transmembrane domain showed N-terminal GXXXG dimerization sequences and C-terminal tyrosine residues shown in related studies to stabilize transmembrane domain helix-helix interactions. To examine the effects of transmembrane domain mutations, 253-NT cells were transfected with transmembrane domain mutants carrying glycine to leucine or tyrosine to valine substitutions. Results showed that mutation of transmembrane tyrosine residues greatly enhanced growth in vitro and in vivo. Mutation of transmembrane dimerization motifs, in contrast, significantly reduced anchorage independent growth and tumorigenicity. 253-NT cells expressing CEACAM1-4S with both glycine to leucine and tyrosine to valine mutations displayed the growth-enhanced phenotype of tyrosine mutants. The dramatic effect of transmembrane domain mutations constitutes strong evidence that the transmembrane domain is an important determinant of CEACAM1-4S functionality and most likely by other proteins with transmembrane domains containing dimerization sequences and/or C-terminal tyrosine residues. PMID:22235309

  4. Fatty acid synthase inhibitors induce apoptosis in non-tumorigenic melan-a cells associated with inhibition of mitochondrial respiration.

    PubMed

    Rossato, Franco A; Zecchin, Karina G; La Guardia, Paolo G; Ortega, Rose M; Alberici, Luciane C; Costa, Rute A P; Catharino, Rodrigo R; Graner, Edgard; Castilho, Roger F; Vercesi, Aníbal E

    2014-01-01

    The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat induce

  5. Fatty Acid Synthase Inhibitors Induce Apoptosis in Non-Tumorigenic Melan-A Cells Associated with Inhibition of Mitochondrial Respiration

    PubMed Central

    Rossato, Franco A.; Zecchin, Karina G.; La Guardia, Paolo G.; Ortega, Rose M.; Alberici, Luciane C.; Costa, Rute A. P.; Catharino, Rodrigo R.; Graner, Edgard; Castilho, Roger F.; Vercesi, Aníbal E.

    2014-01-01

    The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat

  6. Role of diaxial versus diequatorial hydroxyl groups in the tumorigenic activity of a benzo[a]pyrene bay-region diol epoxide.

    PubMed Central

    Chang, R L; Wood, A W; Conney, A H; Yagi, H; Sayer, J M; Thakker, D R; Jerina, D M; Levin, W

    1987-01-01

    Tumorigenic activities of the (7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro derivatives of benzo[a]pyrene [(+)-B[a]P diol epoxide-2] and 6-fluorobenzo[a]pyrene (6-FB[a]P diol epoxide-2) were evaluated in newborn CD-1 mice. A total dose of 14 nmol of either diol epoxide was administered to preweanling mice, and tumorigenic activity was determined when the mice were 32 to 36 weeks old. At the termination of the study, 13% of solvent-treated control mice had developed lung tumors with an average of 0.19 tumor per mouse. No other tumors were observed in control animals. (+)-B[a]P diol epoxide-2 induced pulmonary tumors in 60% of the mice with an average of 1.9 tumors per mouse, and 14% of the male mice developed hepatic tumors with an average of 0.18 tumor per mouse. In contrast, 6-FB[a]P diol epoxide-2 had no significant tumorigenic activity at the 14-nmol dose. Although both bay-region diol epoxides have the same absolute configuration, (7R,8S,9S,10R), the hydroxyl groups of (+)-B[a]P diol epoxide-2 prefer the pseudoequatorial conformation whereas the hydroxyl groups of 6-FB[a]P diol epoxide-2 prefer the pseudoaxial conformation. The tumorigenicity results reported here are the first direct demonstration that conformation of the hydroxyl groups in a bay-region diol epoxide, in addition to the documented effect of absolute configuration, is an important determinant in the tumorigenic activity of these ultimate carcinogens. PMID:3479808

  7. Exhibits Enhanced by Stand-Alone Computers.

    ERIC Educational Resources Information Center

    Van Rennes, Eve C.

    Both the development and evaluation of one of a set of computer programs designed for use by visitors as adjuncts to museum exhibits are described. Museum displays used were (1) a static, behind-glass exhibit on evolution; (2) a hands-on primitive stone age tools exhibit; and (3) a Foucault pendulum. A computer placed next to each exhibit served…

  8. Tumorigenic effects of endocrine-disrupting chemicals are alleviated by licorice (Glycyrrhiza glabra) root extract through suppression of AhR expression in mammalian cells.

    PubMed

    Chu, Xiao Ting; de la Cruz, Joseph; Hwang, Seong Gu; Hong, Heeok

    2014-01-01

    Endocrine-disrupting chemicals (EDCs) have been reported to interfere with estrogen signaling. Exposure to these chemicals decreases the immune response and causes a wide range of diseases in animals and humans. Recently, many studies showed that licorice (Glycyrrhiza glabra) root extract (LRE) commonly called "gamcho" in Korea exhibits antioxidative, chemoprotective, and detoxifying properties. This study aimed to investigate the mechanism of action of LRE and to determine if and how LRE can alleviate the toxicity of EDCs. LRE was prepared by vacuum evaporation and freeze-drying after homogenization of licorice root powder that was soaked in 80% ethanol for 72 h. We used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a representative EDC, which is known to induce tumors or cancers; MCF-7 breast cancer cells, used as a tumor model, were treated with TCDD and various concentrations of LRE (0, 50, 100, 200, 400 μg/mL) for 24, 48, and 72 h. As a result, TCDD stimulated MCF-7 cell proliferation, but LRE significantly inhibited TCDD-induced MCF-7 cell proliferation in a dose- and time-dependent manner. The expression of TCDD toxicity-related genes, i.e., aryl hydrocarbon receptor (AhR), AhR nuclear translocator, and cytochrome P450 1A1, was also down-regulated by LRE in a dose-dependent manner. Analysis of cell cycle distribution after treatment of MCF-7 cells with TCDD showed that LRE inhibited the proliferation of MCF-7 cells via G2/M phase arrest. Reverse transcription-polymerase chain reaction and Western blot analysis also revealed that LRE dose-dependently increased the expression of the tumor suppressor genes p53 and p27 and down-regulated the expression of cell cycle-related genes. These data suggest that LRE can mitigate the tumorigenic effects of TCDD in breast cancer cells by suppression of AhR expression and cell cycle arrest. Thus, LRE can be used as a potential toxicity-alleviating agent against EDC-mediated diseases.

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

    PubMed Central

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

    2017-01-01

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

  10. Learning by Doing, Creating a Museum Exhibit.

    ERIC Educational Resources Information Center

    Main, Sarah; Kallquist, Dierdre

    2000-01-01

    Describes an exhibit called Kid's Kitchen, built within a major exhibit called Biodiversity: Life Supporting Life, in order to discuss environmental prompts hidden within the kitchen designed to surprise students and get them thinking. (ASK)

  11. Science Education Through a Museum Exhibit

    ERIC Educational Resources Information Center

    Chaparian, Azad; And Others

    1973-01-01

    Describes the polywater exhibit at the Worcester Science Center in Massachusetts. Curiosity and interest are stimulated in young people by allowing them to handle the materials in the exhibit and by providing them with instructions for making polywater. (JR)

  12. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA.

    PubMed

    Tan, An S; Baty, James W; Dong, Lan-Feng; Bezawork-Geleta, Ayenachew; Endaya, Berwini; Goodwin, Jacob; Bajzikova, Martina; Kovarova, Jaromira; Peterka, Martin; Yan, Bing; Pesdar, Elham Alizadeh; Sobol, Margarita; Filimonenko, Anatolyj; Stuart, Shani; Vondrusova, Magdalena; Kluckova, Katarina; Sachaphibulkij, Karishma; Rohlena, Jakub; Hozak, Pavel; Truksa, Jaroslav; Eccles, David; Haupt, Larisa M; Griffiths, Lyn R; Neuzil, Jiri; Berridge, Michael V

    2015-01-06

    We report that tumor cells without mitochondrial DNA (mtDNA) show delayed tumor growth, and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory (super)complexes was correlated with acquisition of respiratory function. Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest pathophysiological processes for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.

  13. 29 CFR 2200.70 - Exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... prohibits its convenient transportation and storage. A party may offer into evidence photographs, models or... separate file designated for rejected exhibits. (e) Return of physical exhibits. A party may on motion request the return of a physical exhibit within 30 days after expiration of the time for filing a...

  14. Reduced tumorigenicity of rodent tumour cells and tumour explants following infection with wild type and mutant herpes simplex virus, bovine mammillitis virus and encephalomyocarditis virus.

    PubMed Central

    Skinner, G. R.; Cowan, M.; Davies, J.; Brookes, K.; Billstrom, M.; Buchan, A.

    1988-01-01

    The tumorigenicity of neoplastic hamster and mouse cell lines and tumour explants was reduced by infection with herpes simplex virus (HSV-1), a thymidine-kinaseless mutant of herpes simplex virus, namely 'MDK', encephalomyocarditis virus (EMC) and bovine mammillitis virus (BMV). There was an approximate relationship between duration of virus infection in vitro and reduction in incidence and/or rate of tumour development. The rate of tumour development was also reduced by 'site inoculation' of virus (HSV-1) at various time intervals following inoculation of tumorigenic BHK 21 cells indicating that virus was capable of reducing the rate of tumour development in a situation where the neoplastic cells were already transplanted into the susceptible host species. It is suggested that the therapeutic role of wild type, mutant or recombinant viruses merits further exploration towards prevention and treatment of human cancer. PMID:2846027

  15. Reduced tumorigenicity of rodent tumour cells and tumour explants following infection with wild type and mutant herpes simplex virus, bovine mammillitis virus and encephalomyocarditis virus.

    PubMed

    Skinner, G R; Cowan, M; Davies, J; Brookes, K; Billstrom, M; Buchan, A

    1988-08-01

    The tumorigenicity of neoplastic hamster and mouse cell lines and tumour explants was reduced by infection with herpes simplex virus (HSV-1), a thymidine-kinaseless mutant of herpes simplex virus, namely 'MDK', encephalomyocarditis virus (EMC) and bovine mammillitis virus (BMV). There was an approximate relationship between duration of virus infection in vitro and reduction in incidence and/or rate of tumour development. The rate of tumour development was also reduced by 'site inoculation' of virus (HSV-1) at various time intervals following inoculation of tumorigenic BHK 21 cells indicating that virus was capable of reducing the rate of tumour development in a situation where the neoplastic cells were already transplanted into the susceptible host species. It is suggested that the therapeutic role of wild type, mutant or recombinant viruses merits further exploration towards prevention and treatment of human cancer.

  16. The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas.

    PubMed

    Komohara, Yoshihiro; Morita, Tomoko; Annan, Dorcas A; Horlad, Hasita; Ohnishi, Koji; Yamada, Sohsuke; Nakayama, Toshiyuki; Kitada, Shohei; Suzu, Shinya; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Akashi, Koichi; Takeya, Motohiro; Jinushi, Masahisa

    2015-09-01

    Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC.

  17. Cellular tumorigenicity in nude mice. Test of associations among loss of cell-surface fibronectin, anchorage independence, and tumor-forming ability

    PubMed Central

    1979-01-01

    Fibronectin (FN; also called large external transformation-sensitive [LETS] protein or cell-surface protein [CSP]) is a large cell-surface glycoprotein that is frequently observed to be either absent or greatly reduced on the surfaces of malignant cells grown in vitro. Because FN may be a useful molecular marker of cellular malignancy, we have carried out an extensive screening to test the specific association among the degree of expression of FN, anchorage-independent growth, and tumorigenicity in the athymic nude mouse. A variety of diploid cell strains and established cell lines were tested for the expression of surface FN by indirect immunofluorescence using rabbit antisera against human cold insoluble globulin, rodent plasma FN, or chicken cell- surface FN. Concomitantly, the cells were assayed for tumor formation in nude mice and for the ability to form colonies in methylcellulose. Tumorigenic cells often showed very low surface fluorescence, confirming earlier reports. However, many highly tumorigenic fibroblast lines from several species stained strongly with all three antisera. In contrast, the anchorage-independent phenotype was nearly always associated with tumorigenicity in approximately 35 cell lines examined in this study. In another series of experiments, FN-positive but anchorage-independent cells were grown as tumors in nude mice and then reintroduced into culture. In five of the six tumor-derived cell lines, cell-surface FN was not significantly reduced; one such cell line showed very little surface FN. Our data thus indicate that the loss of cell-surface FN is not a necessary step in the process of malignant transformation and that the growth of FN-positive cells as tumors does not require a prior selection in vivo for FN-negative subpopulations. PMID:383723

  18. Changes in the expression of proteins associated with aerobic glycolysis and cell migration are involved in tumorigenic ability of two glioma cell lines

    PubMed Central

    2012-01-01

    Background The most frequent and malignant brain cancer is glioblastoma multiforme (GBM). In gliomas, tumor progression and poor prognosis are associated with the tumorigenic ability of the cells. U87MG cells (wild-type p53) are known to be tumorigenic in nude mice, but T98G cells (mutant p53) are not tumorigenic. We investigated the proteomic profiling of these two cell lines in order to gain new insights into the mechanisms that may be involved in tumorigenesis. Results We found 24 differentially expressed proteins between T98G and U87MG cells. Gene Ontology supports the notion that over-representation of differentially expressed proteins is involved in glycolysis, cell migration and stress oxidative response. Among those associated with the glycolysis pathway, TPIS and LDHB are up-regulated in U87MG cells. Measurement of glucose consumption and lactate production suggests that glycolysis is more effective in U87MG cells. On the other hand, G6PD expression was 3-fold higher in T98G cells and this may indicate a shift to the pentose-phosphate pathway. Moreover, GRP78 expression was also three-fold higher in T98G than in U87MG cells. Under thapsigargin treatment both cell lines showed increased GRP78 expression and the effect of this agent was inversely correlated to cell migration. Quantitative RT-PCR and immunohistochemistry of GRP78 in patient samples indicated a higher level of expression of GRP78 in grade IV tumors compared to grade I and non-neoplastic tissues, respectively. Conclusions Taken together, these results suggest an important role of proteins involved in key functions such as glycolysis and cell migration that may explain the difference in tumorigenic ability between these two glioma cell lines and that may be extrapolated to the differential aggressiveness of glioma tumors. PMID:22943417

  19. Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity.

    PubMed

    Salah, Zaidoun; Melino, Gerry; Aqeilan, Rami I

    2011-03-01

    The Hippo tumor suppressor pathway, originally defined in fruit flies, regulates cellular proliferation and survival and exerts profound effects on normal mammalian cell fate and tumorigenesis. The present understanding of Hippo pathway components and mechanisms remains incomplete in cancer. WW domain-containing proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY)-containing targets. In this study, we report that the E3 ubiquitin ligase ITCH regulates stability of LATS1, a serine/threonine kinase in the Hippo pathway, through protein-protein interaction of the PPxY motifs of LATS1 with the WW domains of ITCH. Ubiquitination of LATS1 catalyzed by ITCH stimulated the proteasomal degradation of LATS1. Furthermore, ITCH-mediated degradation of LATS1 was associated with enhanced cell growth, induction of epithelial-mesenchymal transition, and increased tumorigenicity. Conversely, ITCH depletion increased LATS1 levels, enhancing FAS-induced apoptosis and reducing proliferation, survival, and migration. These phenotypes were rescued when both ITCH and LATS1 were depleted. Together, our results reveal a novel functional link between ITCH and the Hippo pathway, deepening their critical roles in tumorigenesis.

  20. Epigenetic silencing of miR-181b contributes to tumorigenicity in colorectal cancer by targeting RASSF1A.

    PubMed

    Zhao, Lun-De; Zheng, Wei-Wei; Wang, Gao-Xiang; Kang, Xiao-Chun; Qin, Lei; Ji, Juan-Juan; Hao, Sha

    2016-05-01

    Aberrant microRNA expression is common in colorectal cancer and DNA methylation is believed to be responsible for this alteration. In this study, we performed evaluation in vivo and in vitro to determine the role of miR-181b as a potential diagnostic and prognostic biomarker in colorectal cancer. Ninety-seven pairs of colorectal cancer tissues and adjacent normal tissues were collected. The expression level and methylation status of miR-181b was determined in tissue samples and multiple colorectal cancer cell lines. RASSF1A, a predicted target gene of miR-181b, was investigated in vitro. Further mechanistic explorations were conducted. It was found that miR-181b expression was frequently downregulated in cancer samples. This lower expression level resulted from higher hypermethylation in cancer tissue and was closely related to TNM stage. Following artificial synthesis of miR-181b stimulation, colorectal cancer cell proliferation was greatly inhibited in CRC cells while apoptosis percentage markedly increased. miR-181b achieved the tumor suppressive effects via direct targeting of the RASSF1A gene. This study indicated the clinical significance of miR-181b and the influence of miR-181b promoter region in epigenetic silencing of tumorigenicity in colorectal cancer, and implied the possible usage of miR-181b as a diagnostic and prognostic biomarker in colorectal cancer.

  1. Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β.

    PubMed

    Wang, Mei; Liu, Yang; Zou, Jiahua; Yang, Rui; Xuan, Fan; Wang, Yi; Gao, Ning; Cui, Hongjuan

    2015-04-20

    Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial event in the pathogenesis of neuroblastoma is to promote proliferation of neuroblasts, which is closely related to poor survival. However, mechanisms for regulation of cell proliferation and tumorigenicity in neuroblastoma are not well understood. Here, we report that overexpression of TAZ in neuroblastoma BE(2)-C cells causes increases in cell proliferation, self renewal and colony formation, which was restored back to its original levels by knockdown of TAZ in TAZ-overexpression cells. Inhibition of endogenous TAZ attenuated cell proliferation, colony formation and tumor development in neuroblastoma SK-N-AS cell, which could be rescued by re-introduction of TAZ into TAZ-knockdown cells. In addition, we found that overexpressing TAZ-mediated induction of CTGF and PDGF-β expression, cell proliferation and colony formation were inhibited by knocking down CTGF and PDGF-β with siRNA in TAZ-overexpressing cell. Overall, our findings suggested that TAZ plays an essential role in regulating cell proliferation and tumorigenesis in neuroblastoma cells. Thus, TAZ seems to be a novel and promising target for the treatment of neuroblastoma.

  2. Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth

    PubMed Central

    Mahlknecht, Georg; Maron, Ruth; Mancini, Maicol; Schechter, Bilha; Sela, Michael; Yarden, Yosef

    2013-01-01

    Aptamers, oligonucleotides able to avidly bind cellular targets, are emerging as promising therapeutic agents, analogous to monoclonal antibodies. We selected from a DNA library an aptamer specifically recognizing human epidermal growth factor receptor 2 (ErbB-2/HER2), a receptor tyrosine kinase, which is overexpressed in a variety of human cancers, including breast and gastric tumors. Treatment of human gastric cancer cells with a trimeric version (42 nucleotides) of the selected aptamer (14 nucleotides) resulted in reduced cell growth in vitro, but a monomeric version was ineffective. Likewise, when treated with the trimeric aptamer, animals bearing tumor xenografts of human gastric origin reflected reduced rates of tumor growth. The antitumor effect of the aptamer was nearly twofold stronger than that of a monoclonal anti–ErbB-2/HER2 antibody. Consistent with aptamer-induced intracellular degradation of ErbB-2/HER2, incubation of gastric cancer cells with the trimeric aptamer promoted translocation of ErbB-2/HER2 from the cell surface to cytoplasmic puncta. This translocation was associated with a lysosomal hydrolase-dependent clearance of the ErbB-2/HER2 protein from cell extracts. We conclude that targeting ErbB-2/HER2 with DNA aptamers might retard the tumorigenic growth of gastric cancer by means of accelerating lysosomal degradation of the oncoprotein. This work exemplifies the potential pharmacological utility of aptamers directed at cell surface proteins, and it highlights an endocytosis-mediated mechanism of tumor inhibition. PMID:23630281

  3. Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity.

    PubMed

    Rappa, Germana; Mercapide, Javier; Lorico, Aurelio

    2012-06-01

    Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in immunodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer-mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm.

  4. Overexpression of PHRF1 attenuates the proliferation and tumorigenicity of non-small cell lung cancer cells

    PubMed Central

    Wang, Yadong; Wang, Haiyu; Pan, Teng; Li, Li; Li, Jiangmin; Yang, Haiyan

    2016-01-01

    The aim of this study was to investigate the potential role of PHRF1 in lung tumorigenesis. Western blot analysis was used to detect the expression of proteins. Quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, soft agar assay and tumor formation assay in nude mice were applied. Cell cycle distribution was analyzed by flow cytometry. The lower level of PHRF1 mRNA was observed in human lung cancer tissues than that in paracancerous tissues. The decreased expression of PHRF1 protein was observed in H1299 and H1650 cell lines than that in 16HBE and BEAS-2B cell lines. The decreased expression of PHRF1 protein was observed in malignant 16HBE cells compared to control cells. The reduced expression of PHRF1 protein was observed in mice lung tissues treated with BaP than that in control group. Overexpression of PHRF1 inhibited H1299 cell proliferation, colony formation in vitro and growth of tumor xenograft in vivo, and arrested cell cycle in G1 phase. The decreased expression of TGIF and c-Myc proteins and the increased expression of p21 protein were observed in H1299-PHRF1 cells compared with H1299-pvoid cells. In conclusion, our findings suggest that overexpression of PHRF1 attenuated the proliferation and tumorigenicity of non-small cell lung cancer cell line of H1299. PMID:27608840

  5. Deubiquitinating enzyme USP22 positively regulates c-Myc stability and tumorigenic activity in mammalian and breast cancer cells.

    PubMed

    Kim, Dongyeon; Hong, Ahyoung; Park, Hye In; Shin, Woo Hyun; Yoo, Lang; Jeon, Seo Jeong; Chung, Kwang Chul

    2017-02-04

    The proto-oncogene c-Myc has a pivotal function in growth control, differentiation and apoptosis and is frequently affected in human cancer, including breast cancer. Ubiquitin-specific protease 22 (USP22), a member of the USP family of deubiquitinating enzymes (DUBs), mediates deubiquitination of target proteins, including histone H2B and H2A, telomeric repeat binding factor 1, and cyclin B1. USP22 is also a component of the mammalian SAGA transcriptional co-activating complex. In this study, we explored the functional role of USP22 in modulating c-Myc stability and its physiological relevance in breast cancer progression. We found that USP22 promotes deubiquitination of c-Myc in several breast cancer cell lines, resulting in increased levels of c-Myc. Consistent with this, USP22 knockdown reduces c-Myc levels. Furthermore, overexpression of USP22 stimulates breast cancer cell growth and colony formation, and increases c-Myc tumorigenic activity. In conclusion, the present study reveals that USP22 in breast cancer cell lines increases c-Myc stability through c-Myc deubiquitination, which is closely correlated with breast cancer progression. This article is protected by copyright. All rights reserved.

  6. Gene amplification and microsatellite instability induced in tumorigenic human bronchial epithelial cells by alpha particles and heavy ions

    NASA Technical Reports Server (NTRS)

    Piao, C. Q.; Hei, T. K.; Hall, E. J. (Principal Investigator)

    2001-01-01

    Gene amplification and microsatellite alteration are useful markers of genomic instability in tumor and transformed cell lines. It has been suggested that genomic instability contributes to the progression of tumorigenesis by accumulating genetic changes. In this study, amplification of the carbamyl-P-synthetase, aspartate transcarbamylase, dihydro-orotase (CAD) gene in transformed and tumorigenic human bronchial epithelial (BEP2D) cells induced by either alpha particles or (56)Fe ions was assessed by measuring resistance to N-(phosphonacetyl)-l-aspartate (PALA). In addition, alterations of microsatellite loci located on chromosomes 3p and 18q were analyzed in a series of primary and secondary tumor cell lines generated in nude mice. The frequency of PALA-resistant colonies was 1-3 x 10(-3) in tumor cell lines, 5-8 x 10(-5) in transformed cells prior to inoculation into nude mice, and less than 10(-7) in control BEP2D cells. Microsatellite alterations were detected in all 11 tumor cell lines examined at the following loci: D18S34, D18S363, D18S877, D3S1038 and D3S1607. No significant difference in either PALA resistance or microsatellite instability was found in tumor cell lines that were induced by alpha particles compared to those induced by (56)Fe ions.

  7. miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway

    PubMed Central

    Isobe, Taichi; Hisamori, Shigeo; Hogan, Daniel J; Zabala, Maider; Hendrickson, David G; Dalerba, Piero; Cai, Shang; Scheeren, Ferenc; Kuo, Angera H; Sikandar, Shaheen S; Lam, Jessica S; Qian, Dalong; Dirbas, Frederick M; Somlo, George; Lao, Kaiqin; Brown, Patrick O; Clarke, Michael F; Shimono, Yohei

    2014-01-01

    MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression. DOI: http://dx.doi.org/10.7554/eLife.01977.001 PMID:25406066

  8. Forced Trefoil Factor Family Peptide 3 (TFF3) Expression Reduces Growth, Viability, and Tumorigenicity of Human Retinoblastoma Cell Lines

    PubMed Central

    Winter, Claudia; Pikos, Stefanie; Stephan, Harald; Dünker, Nicole

    2016-01-01

    Trefoil factor family (TFF) peptides have been shown to effect cell proliferation, apoptosis, migration and invasion of normal cells and various cancer cell lines. In the literature TFF peptides are controversially discussed as tumor suppressors and potential tumor progression factors. In the study presented, we investigated the effect of TFF3 overexpression on growth, viability, migration and tumorigenicity of the human retinoblastoma cell lines Y-79, WERI-Rb1, RBL-13 and RBL-15. As revealed by WST-1 and TUNEL assays as well as DAPI and BrdU cell counts, recombinant human TFF3 significantly lowers retinoblastoma cell viability and increases apoptosis levels. Transient TFF3 overexpression likewise significantly increases RB cell apoptosis. Stable, lentiviral TFF3 overexpression lowers retinoblastoma cell viability, proliferation and growth and significantly increases cell death in retinoblastoma cells. Blockage experiments using a broad-spectrum caspase inhibitor and capase-3 immunocytochemistry revealed the involvement of caspases in general and of caspase-3 in particular in TFF3 induced apoptosis in retinoblastoma cell lines. Soft agarose and in ovo chicken chorioallantoic membrane (CAM) assays revealed that TFF3 overexpression influences anchorage independent growth and significantly decreases the size of tumors forming from retinoblastoma cells. Our study demonstrates that forced TFF3 expression exerts a significant pro-apoptotic, anti-proliferative, and tumor suppressive effect in retinoblastoma cells, setting a starting point for new additive chemotherapeutic approaches in the treatment of retinoblastoma. PMID:27626280

  9. STK31 Is a Cell-Cycle Regulated Protein That Contributes to the Tumorigenicity of Epithelial Cancer Cells

    PubMed Central

    Kuo, Pao-Lin; Huang, Yung-Ling; Hsieh, Christine Chin-Jung; Lee, Jenq-Chang; Lin, Bo-Wen; Hung, Liang-Yi

    2014-01-01

    Serine/threonine kinase 31 (STK31) is one of the novel cancer/testis antigens for which its biological functions remain largely unclear. Here, we demonstrate that STK31 is overexpressed in many human colorectal cancer cell lines and tissues. STK31 co-localizes with pericentrin in the centrosomal region throughout all phases of the cell cycle. Interestingly, when cells undergo mitosis, STK31 also localizes to the centromeres, central spindle, and midbody. This localization behavior is similar to that of chromosomal passenger proteins, which are known to be the important players of the spindle assembly checkpoint. The expression of STK31 is cell cycle-dependent through the regulation of a putative D-box near its C-terminal region. Ectopically-expressed STK31-GFP increases cell migration and invasive ability without altering the proliferation rate of cancer cells, whereas the knockdown expression of endogenous STK31 by lentivirus-derived shRNA results in microtubule assembly defects that prolong the duration of mitosis and lead to apoptosis. Taken together, our results suggest that the aberrant expression of STK31 contributes to tumorigenicity in somatic cancer cells. STK31 might therefore act as a potential therapeutic target in human somatic cancers. PMID:24667656

  10. Cloning and characterization of a cDNA encoding transformation-sensitive tropomyosin isoform 3 from tumorigenic human fibroblasts

    SciTech Connect

    Lin, C.S.; Leavitt, J.

    1988-01-01

    The authors isolated a cDNA clone from the tumorigenic human fibroblast cell line HuT-14 that contains the entire protein coding region of tropomyosin isoform 3 (Tm3) and 781 base pairs of 5'- and 3'-untranslated sequences. Tm3, despite its apparent smaller molecular weight than Tm1 in two-dimensional gels, has the same peptide length as Tm1 (284 amino acids) and shares 83% homology with Tm1. Tm3 cDNA hybridized to an abundant mRNA of 1.3 kilobases in fetal muscle and cardiac muscle, suggesting that Tm3 is related to an ..cap alpha../sub fast/-tropomyosin. The first 188 amino acids of Tm3 are identical to those of rat or rabbit skeletal muscle ..cap alpha..-tropomyosin, and the last 71 amino acids differ from those of rat smooth muscle ..cap alpha..-tropomyosin by only 1 residue. Tm3 therefore appears to be encoded by the same gene that encodes the fast skeletal muscle ..cap alpha..-tropomyosin and the smooth muscle ..cap alpha..-tropomyosin via an alternative RNA-splicing mechanism. In contrast to Tm4 and Tm5, Tm3 has a small gene family, with, at best, only one pseudogene.

  11. Suppression of growth in vitro and tumorigenicity in vivo of human carcinoma cell lines by transfected p16INK4.

    PubMed

    Spillare, E A; Okamoto, A; Hagiwara, K; Demetrick, D J; Serrano, M; Beach, D; Harris, C C

    1996-05-01

    The function of p16INK4 as a putative tumor suppressor gene was examined by investigating its ability to inhibit the growth of cancer cell lines in vitro and tumor formation in vivo. A p16INK4 cDNA expression vector was transfected into five human cancer cell lines that varied in their p16INK4 and retinoblastoma (Rb) status. Suppression of colony-forming efficiency was seen in four cell lines. Of two cell lines wild type for p16INK4 but null for Rb protein expression, one (Hep 3B) showed inhibition of colony formation, whereas the other (Saos-2) did not. This observation may demonstrate involvement of p16INK4 independent of Rb. The transfected p16INK4 gene was frequently selected against and lost during continued growth in vitro. When compared to the colon carcinoma cell line (DLD-1),p16INK4-transfected DLD-1 clone 1 cells were less tumorigenic in athymic nude mice. Tumors arising from p16INK4-transfected DLD-1 clones, which were growth suppressed in vitro, either lost the integrated exogenous p16INK4 or expressed reduced amounts of p16INK4 protein. Therefore, p16INK4 was also selected against during tumor formation in vivo. These data are consistent with the hypothesis that p16INK4 is a tumor suppressor gene.

  12. Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo.

    PubMed

    Urakawa, Hiroshi; Nishida, Yoshihiro; Wasa, Junji; Arai, Eisuke; Zhuo, Lisheng; Kimata, Koji; Kozawa, Eiji; Futamura, Naohisa; Ishiguro, Naoki

    2012-01-15

    Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Previous studies demonstrated that inhibition of HA suppressed the tumorigenicity of various malignant tumors including breast cancer. 4-methylumbelliferone (MU) has been reported to inhibit HA synthesis in several cell types. However, few studies have focused on the effects of HA inhibition in breast cancer cells by MU, nor the effects on bone metastasis. We hypothesized that MU would suppress the progression of bone metastasis via inhibition of HA synthesis. Here, we investigated the effects of MU on HA expression in MDA-MB-231 breast cancer cell line in addition to their tumorigenicity in vitro and in vivo. HAS2 mRNA expression was downregulated after 6 and 24 hr treatment with MU. Quantitative analysis of HA revealed that MU significantly inhibited the intracellular and cell surface HA. MU significantly inhibited cell growth and induced apoptosis as determined by cell proliferation and TUNEL assays, respectively. Phosphorylation of Akt was suppressed after 12 and 24 hr treatment with MU. MU treatment also inhibited cell motility as well as cell invasiveness. MU also inhibited cell growth and motility in murine fibroblast cell line NIH3T3. In vivo, administration of MU inhibited the expansion of osteolytic lesions on soft X-rays in mouse breast cancer xenograft models. HA accumulation in bone metastatic lesions was perturbed peripherally. These data suggest that MU might be a therapeutic candidate for bone metastasis of breast cancer via suppression of HA synthesis and accumulation.

  13. Graviola: A Novel Promising Natural-Derived Drug That Inhibits Tumorigenicity and Metastasis of Pancreatic Cancer Cells In Vitro and In Vivo Through Altering Cell Metabolism

    PubMed Central

    Torres, María P.; Rachagani, Satyanarayana; Purohit, Vinee; Pandey, Poomy; Joshi, Suhasini; Moore, Erik D.; Johansson, Sonny L.; Singh, Pankaj K.; Ganti, Apar K.; Batra, Surinder K.

    2012-01-01

    Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease. PMID:22475682

  14. Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism.

    PubMed

    Torres, María P; Rachagani, Satyanarayana; Purohit, Vinee; Pandey, Poomy; Joshi, Suhasini; Moore, Erik D; Johansson, Sonny L; Singh, Pankaj K; Ganti, Apar K; Batra, Surinder K

    2012-10-01

    Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease.

  15. Hop bitter acids inhibit tumorigenicity of hepatocellular carcinoma cells in vitro.

    PubMed

    Saugspier, Michael; Dorn, Christoph; Czech, Barbara; Gehrig, Manfred; Heilmann, Jörg; Hellerbrand, Claus

    2012-10-01

    Bitter acids (BAs) from the hop plant Humulus lupulus L. exhibit multiple beneficial biological properties with promising effects in cancer therapy and prevention, but information regarding the effects on hepatocellular carcinoma (HCC) is missing. Here, we used two different hop bitter acid extracts enriched for either α-acids or β-acids to obtain insight into whether biological activity varies between these two groups of BAs. At a concentration of 25 µg/ml, only the β-acid rich started to induce aspartate transaminase (AST) release, and a significant increase was detected with 50 µg/ml of both extracts. Already at lower concentrations both extracts led to a dose-dependent inhibition of proliferation, and migration was suppressed at a concentration as low as 5 µg/ml in HCC cells. The focus on different signaling pathways revealed an inhibition of ERK1/2 phosphorylation, downregulation of AP-1 activity and an alleviation of nuclear factor κB (NFκB) activity in HepG2 cells incubated with 5 µg/ml of both extracts, whereby the β-acid rich extract showed more pronounced effects. In conclusion, we identified ERK1/2, AP-1 and NFκB, which are important factors in tumor development and progression, as targets of hop BAs. Thus, these data suggest the potential use of BAs as functional nutrients for both prevention and treatment of HCC.

  16. Space exhibitions: the science encounters the public

    NASA Astrophysics Data System (ADS)

    Coliolo, F.; Menendez, M.

    The widespread dissemination of science has always been one pillar of the development of human knowledge. There are several methods to structure interaction with the public: media, conferences, various written genres, and exhibitions. But: how to attract the public? How to arouse interest among future generation, insatiable for knowledge? In this paper we focus on space exhibitions, whose content combines mystery, discovery and science. The preparation of an exhibition is based on guidelines discussed between an interdisciplinary team and the exhibition project manager, the purpose of which is to find a coherent "strategy" to select information and to choose a concise, efficient, smart and original way to "visualize" the messages. Exhibition visitors are "privileged" because the interactivity is first emotive, then mental and cultural; the audience is universal. The goal of an exhibition is not to explain the content, but to stimulate the audience's curiosity in an attractive environment. We show some photos of ESA exhibitions, and try to understand if the visual impact is the first step towards a "multi-sensory" approach to communication. "A good exhibition can never be replaced by a book, a film or a lecture. A good exhibition creates a thirst for books, film, lectures. A good exhibition changes the visitors"(J. Wagensberg, Modern scientific museology")

  17. Superconductive microstrip exhibiting negative differential resistivity

    DOEpatents

    Huebener, R.P.; Gallus, D.E.

    1975-10-28

    A device capable of exhibiting negative differential electrical resistivity over a range of values of current and voltage is formed by vapor- depositing a thin layer of a material capable of exhibiting superconductivity on an insulating substrate, establishing electrical connections at opposite ends of the deposited strip, and cooling the alloy into its superconducting range. The device will exhibit negative differential resistivity when biased in the current- induced resistive state.

  18. Hepatitis B virus X protein mutants exhibit distinct biological activities in hepatoma Huh7 cells

    SciTech Connect

    Liu Xiaohong; Zhang Shuhui; Lin Jing; Zhang Shunmin; Feitelson, Mark A.; Gao Hengjun; Zhu Minghua

    2008-09-05

    The role of the hepatitis B virus X protein (HBx) in hepatocarcinogenesis remains controversial. To investigate the biological impact of hepatitis B virus x gene (HBx) mutation on hepatoma cells, plasmids expressing the full-length HBx or HBx deletion mutants were constructed. The biological activities in these transfectants were analyzed by a series of assays. Results showed that HBx3'-20 and HBx3'-40 amino acid deletion mutants exhibited an increase in cellular proliferation, focus formation, tumorigenicity, and invasive growth and metastasis through promotion of the cell cycle from G0/G1 to the S phase, when compared with the full-length HBx. In contrast, HBx3'-30 amino acid deletion mutant repressed cell proliferation by blocking in G1 phase. The expression of P53, p21{sup WAF1}, p14{sup ARF}, and MDM2 proteins was regulated by expression of HBx mutants. In conclusions, HBx variants showed different effects and functions on cell proliferation and invasion by regulation of the cell cycle progression and its associated proteins expression.

  19. The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics.

    PubMed

    Boesch, Maximilian; Zeimet, Alain G; Reimer, Daniel; Schmidt, Stefan; Gastl, Guenther; Parson, Walther; Spoeck, Franziska; Hatina, Jiri; Wolf, Dominik; Sopper, Sieghart

    2014-08-30

    Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype. In different cell lines, either ABCG2 or ABCB1 was found to be responsible for this effect. Purified SP cells featured virtually all characteristics of bona fide CSC, including clonogenicity, asymmetric division and high tumorigenicity in vivo. Using in-depth phenotyping by multicolor flow cytometry, we found that among the investigated ovarian cancer cell lines the SP compartment exhibits tremendous heterogeneity and is composed of multiple phenotypically distinct subpopulations. Thus, our study confirms previous results showing that CSC are contained within the SP. However, the exact identity of the CSC is still disguised by the high complexity of the CSC-containing compartment. Further functional studies are needed to determine whether a single cellular subset can unambiguously be defined as CSC or whether multiple stem cell-like cells with different properties coexist. Moreover, the observed heterogeneity may reflect a high level of plasticity and likely influences tumor progression, escape from immune-surveillance and development of resistance to anticancer therapies and should therefore be considered in the development of new treatment strategies.

  20. The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics

    PubMed Central

    Boesch, Maximilian; Zeimet, Alain G.; Reimer, Daniel; Schmidt, Stefan; Gastl, Guenther; Parson, Walther; Spoeck, Franziska; Hatina, Jiri

    2014-01-01

    Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype. In different cell lines, either ABCG2 or ABCB1 was found to be responsible for this effect. Purified SP cells featured virtually all characteristics of bona fide CSC, including clonogenicity, asymmetric division and high tumorigenicity in vivo. Using in-depth phenotyping by multicolor flow cytometry, we found that among the investigated ovarian cancer cell lines the SP compartment exhibits tremendous heterogeneity and is composed of multiple phenotypically distinct subpopulations. Thus, our study confirms previous results showing that CSC are contained within the SP. However, the exact identity of the CSC is still disguised by the high complexity of the CSC-containing compartment. Further functional studies are needed to determine whether a single cellular subset can unambiguously be defined as CSC or whether multiple stem cell-like cells with different properties coexist. Moreover, the observed heterogeneity may reflect a high level of plasticity and likely influences tumor progression, escape from immune-surveillance and development of resistance to anticancer therapies and should therefore be considered in the development of new treatment strategies. PMID:25216521

  1. Encountering Nanotechnology in an Interactive Exhibition

    ERIC Educational Resources Information Center

    Murriello, Sandra E.; Knobel, Marcelo

    2008-01-01

    This article offers findings from a learning sciences-informed evaluation of a nanoscience and nanotechnology exhibition called Nano-Aventura (NanoAdventure), based on four interactive-collaborative games and two narrated videos. This traveling exhibition was developed in Brazil by the Museu Exploratorio de Ciencias for children and teenagers…

  2. Learning4Life on the Exhibit Floor

    ERIC Educational Resources Information Center

    Sullivan, Margaret

    2009-01-01

    The exhibit floor is a wealth of knowledge. One can read, view, and listen to information presented in many formats. Somewhere on the exhibit floor there are experts on every topic, ready and waiting for one's questions. But like any research topic, frequently a structured search is required to find the best answers. This article discusses how to…

  3. Evaluation of Clientele Impact of Science Exhibits.

    ERIC Educational Resources Information Center

    Talisayon, Vivien M.

    1998-01-01

    Explores the use of an impact evaluation model across time and clientele groups that is used to evaluate exhibits from two science centers in Manila. Questionnaire and interview data indicate that students prefer exhibits that produce sound, light, and motion. (DDR)

  4. 49 CFR 250.2 - Required exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... statement, together with supporting evidence, that the probable value of the assets of the railroad in the... carrier's existing railroad. (5) As Exhibit 5, statement showing miles of line owned; miles operated... carried; and identification of the ten most important industries served. (6) As Exhibit 6, statement as...

  5. Science Fiction Exhibits as STEM Gateways

    NASA Astrophysics Data System (ADS)

    Robie, Samantha

    Women continue to hold less than a quarter of all STEM jobs in the United States, prompting many museums to develop programs and exhibits with the express goal of interesting young girls in scientific fields. At the same time, a number of recent museum exhibits have harnessed the popularity of pop culture and science fiction in order to interest general audiences in STEM subject matter, as well as using the exhibits as springboards to expand or shift mission goals and focus. Because science fiction appears to be successful at raising interest in STEM fields, it may be an effective way to garner the interest of young girls in STEM in particular. This research seeks to describe the ways in which museums are currently using science fiction exhibits to interest young girls in STEM fields and careers. Research focused on four institutions across the country hosting three separate exhibits, and included staff interviews and content analysis of exhibit descriptions, promotional materials, a summative evaluation and supplementary exhibit productions. In some ways, science fiction exhibits do serve young girls, primarily through the inclusion of female role models, staff awareness, and prototype testing to ensure interactives are attractive to girls as well as to boys. However, STEM appears to be underutilized, which may be partly due to a concern within the field that the outcome of targeting a specific gender could be construed as "stereotyping".

  6. Strategies for Determining Exhibit Effectiveness. Final Report.

    ERIC Educational Resources Information Center

    Shettel, Harris H.; And Others

    This project was designed to develop research strategies and hypotheses for evaluating the effectiveness of exhibits. An exhibit on the role of the Federal Government in science and technology was used as the subject matter. Two basic groups of viewers were used, casual viewers and paid experimental viewers. Both were tested on knowledge gained…

  7. Tumorigenic risk of human induced pluripotent stem cell explants cultured on mouse SNL76/7 feeder cells

    SciTech Connect

    Kamada, Mizuna; Mitsui, Youji Kumazaki, Tsutomu; Kawahara, Yuta; Matsuo, Taira; Takahashi, Tomoko

    2014-10-24

    Highlights: • hiPS cell explants formed malignant tumors when SNL76/7 feeder cells were used. • Multi type tumors developed by interaction of SNL76/7 feeder cells with hiPS cells. • Tumorigenic risk occurs by co-culture of hiPS cells with SNL76/7 feeder cells. - Abstract: The potential for tumor formation from transplanted human induced pluripotent stem cell (hiPSC) derivatives represents a high risk in their application to regenerative medicine. We examined the genetic origin and characteristics of tumors, that were formed when 13 hiPSC lines, established by ourselves, and 201B7 hiPSC from Kyoto University were transplanted into severe combined immune-deficient (SCID) mice. Though teratomas formed in 58% of mice, five angiosarcomas, one malignant solitary fibrous tumor and one undifferentiated pleomorphic sarcoma formed in the remaining mice. Three malignant cell lines were established from the tumors, which were derived from mitomycin C (MMC)-treated SNL76/7 (MMC-SNL) feeder cells, as tumor development from fusion cells between MMC-SNL and hiPSCs was negative by genetic analysis. While parent SNL76/7 cells produced malignant tumors, neither MMC-SNL nor MMC-treated mouse embryo fibroblast (MEF) produced malignant tumors. When MMC-SNL feeder cells were co-cultured with hiPSCs, growing cell lines were generated, that expressed genes similar to the parent SNL76/7 cells. Thus, hiPSCs grown on MMC-SNL feeder cells have a high risk of generating feeder-derived malignant tumors. The possible mechanism(s) of growth restoration and the formation of multiple tumor types are discussed with respect of the interactions between MMC-SNL and hiPSC.

  8. Persistent Exposure to Porphyromonas gingivalis Promotes Proliferative and Invasion Capabilities, and Tumorigenic Properties of Human Immortalized Oral Epithelial Cells

    PubMed Central

    Geng, Fengxue; Liu, Junchao; Guo, Yan; Li, Chen; Wang, Hongyang; Wang, Hongyan; Zhao, Haijiao; Pan, Yaping

    2017-01-01

    Recent epidemiological studies revealed a significant association between oral squamous cell carcinoma (OSCC) and Porphyromonas gingivalis, a major pathogen of periodontal disease. As a keystone pathogen of periodontitis, P. gingivalis is known not only to damage local periodontal tissues, but also to evade the host immune system and eventually affect systemic health. However, its role in OSCC has yet to be defined. To explore the underlying effect of chronic P. gingivalis infection on OSCC and to identify relevant biomarkers as promising targets for therapy and prevention, we established a novel model by exposing human immortalized oral epithelial cells (HIOECs) to P. gingivalis at a low multiplicity of infection (MOI) for 5–23 weeks. The P. gingivalis infected HIOECs were monitored for tumor biological alteration by proliferation, wound healing, transwell invasion, and gelatin zymography assays. Microarray and proteomic analyses were performed on HIOECs infected with P. gingivalis for 15 weeks, and some selected data were validated by quantitative real-time PCR and (or) western blot on cells infected for 15 and 23 weeks. Persistent exposure to P. gingivalis caused cell morphological changes, increased proliferation ability with higher S phase fraction in the cell cycle, and promoted cell migratory and invasive properties. In combining results of bioinformatics analyses and validation assays, tumor-related genes such as NNMT, FLI1, GAS6, lncRNA CCAT1, PDCD1LG2, and CD274 may be considered as the key regulators in tumor-like transformation in response to long-time exposure of P. gingivalis. In addition, some useful clinical biomarkers and novel proteins were also presented. In conclusion, P. gingivalis could promote tumorigenic properties of HIOECs, indicating that chronic P. gingivalis infection may be considered as a potential risk factor for oral cancer. The key regulators detected from the present model might be used in monitoring the development of OSCC with

  9. Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity.

    PubMed

    Odate, Seiichi; Veschi, Veronica; Yan, Shuang; Lam, Norris; Woessner, Richard; Thiele, Carol J

    2017-04-01

    Purpose: Neuroblastoma is a pediatric tumor of peripheral sympathoadrenal neuroblasts. The long-term event-free survival of children with high-risk neuroblastoma is still poor despite the improvements with current multimodality treatment protocols. Activated JAK/STAT3 pathway plays an important role in many human cancers, suggesting that targeting STAT3 is a promising strategy for treating high-risk neuroblastoma.Experimental Design: To evaluate the biologic consequences of specific targeting of STAT3 in neuroblastoma, we assessed the effect of tetracycline (Tet)-inducible STAT3 shRNA and the generation 2.5 antisense oligonucleotide AZD9150 which targets STAT3 in three representative neuroblastoma cell line models (AS, NGP, and IMR32).Results: Our data indicated that Tet-inducible STAT3 shRNA and AZD9150 inhibited endogenous STAT3 and STAT3 target genes. Tet-inducible STAT3 shRNA and AZD9150 decreased cell growth and tumorigenicity. In vivo, STAT3 inhibition by Tet-inducible STAT3 shRNA or AZD9150 alone had little effect on growth of established tumors. However, when treated xenograft tumor cells were reimplanted into mice, there was a significant decrease in secondary tumors in the mice receiving AZD9150-treated tumor cells compared with the mice receiving ntASO-treated tumor cells. This indicates that inhibition of STAT3 decreases the tumor-initiating potential of neuroblastoma cells. Furthermore, inhibition of STAT3 significantly increased neuroblastoma cell sensitivity to cisplatin and decreased tumor growth and increased the survival of tumor-bearing mice in vivoConclusions: Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional chemotherapy for patients with high-risk neuroblastoma. Clin Cancer Res; 23(7); 1771-84. ©2016 AACR.

  10. Differential expression of centrosome regulators in Her2+ breast cancer cells versus non-tumorigenic MCF10A cells

    PubMed Central

    2014-01-01

    Centrosome amplification (CA) amongst particular breast cancer subtypes (Her2+ subtype) is associated with genomic instability and aggressive tumor phenotypes. However, changes in signaling pathways associated with centrosome biology have not been fully explored in subtype specific models. Novel centrosome regulatory genes that are selectively altered in Her2+ breast cancer cells are of interest in discerning why CA is more prevalent in this subtype. To determine centrosome/cell cycle genes that are altered in Her2+ cells that display CA (HCC1954) versus non-tumorigenic cells (MCF10A), we carried out a gene microarray. Expression differences were validated by real-time PCR and Western blotting. After the microarray validation, we pursued a panel of upregulated and downregulated genes based on novelty/relevance to centrosome duplication. Functional experiments measuring CA and BrdU incorporation were completed after genetic manipulation of targets (TTK, SGOL1, MDM2 and SFRP1). Amongst genes that were downregulated in HCC1954 cells, knockdown of MDM2 and SFRP1 in MCF10A cells did not consistently induce CA or impaired BrdU incorporation. Conversely, amongst upregulated genes in HCC1954 cells, knockdown of SGOL1 and TTK decreased CA in breast cancer cells, while BrdU incorporation was only altered by SGOL1 knockdown. We also explored the Kaplan Meier Plot resource and noted that MDM2 and SFRP1 are positively associated with relapse free survival in all breast cancer subtypes, while TTK is negatively correlated with overall survival of Luminal A patients. Based on this functional screen, we conclude that SGOL1 and TTK are important modulators of centrosome function in a breast cancer specific model. PMID:25278993

  11. Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells.

    PubMed

    Liu, Jing; Xiao, Zhijie; Wong, Sunny Kit-Man; Tin, Vicky Pui-Chi; Ho, Ka-Yan; Wang, Junwen; Sham, Mai-Har; Wong, Maria Pik

    2013-10-01

    Limited improvement in long term survival of lung cancer patients has been achieved by conventional chemotherapy or targeted therapy. To explore the potentials of tumor initiating cells (TIC)-directed therapy, it is essential to identify the cell targets and understand their maintenance mechanisms. We have analyzed the performance of ALDH/CD44 co-expression as TIC markers and treatment targets of lung cancer using well-validated in vitro and in vivo analyses in multiple established and patient-derived lung cancer cells. The ALDH(hi)CD44(hi) subset showed the highest enhancement of stem cell phenotypic properties compared to ALDH(hi)CD44(lo), ALDH(lo)CD44(hi), ALDH(lo)CD44(lo) cells and unsorted controls. They showed higher invasion capacities, pluripotency genes and epithelial-mesenchymal transition transcription factors expression, lower intercellular adhesion protein expression and higher G2/M phase cell cycle fraction. In immunosuppressed mice, the ALDH(hi)CD44(hi)xenografts showed the highest tumor induction frequency, serial transplantability, shortest latency, largest volume and highest growth rates. Inhibition of sonic Hedgehog and Notch developmental pathways reduced ALDH+CD44+ compartment. Chemotherapy and targeted therapy resulted in higher AALDH(hi)CD44(hi) subset viability and ALDH(lo)CD44(lo) subset apoptosis fraction. ALDH inhibition and CD44 knockdown led to reduced stemness gene expression and sensitization to drug treatment. In accordance, clinical lung cancers containing a higher abundance of ALDH and CD44-coexpressing cells was associated with lower recurrence-free survival. Together, results suggested theALDH(hi)CD44(hi)compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDH(hi)CD44(hi)TIC maintenance would be beneficial for the development of long term lung cancer control.

  12. Heterogeneous nuclear ribonucleoprotein K upregulates the kinetochore complex component NUF2 and promotes the tumorigenicity of colon cancer cells

    SciTech Connect

    Sugimasa, Hironobu; Taniue, Kenzui; Kurimoto, Akiko; Takeda, Yasuko; Kawasaki, Yoshihiro; Akiyama, Tetsu

    2015-03-27

    Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a multi-functional protein involved in transcription, mRNA splicing, mRNA stabilization and translation. Although hnRNP K has been suggested to play a role in the development of many cancers, its molecular function in colorectal cancer has remained elusive. Here we show that hnRNP K plays an important role in the mitotic process in HCT116 colon cancer cells. Furthermore, we demonstrate that hnRNP K directly transactivates the NUF2 gene, the product of which is a component of the NDC80 kinetochore complex and which is known to be critical for a stable spindle microtubule-kinetochore attachment. In addition, knockdown of both hnRNP K and NUF2 caused failure in metaphase chromosome alignment and drastic decrease in the growth of colon cancer cells. These results suggest that the hnRNP K-NUF2 axis is important for the mitotic process and proliferation of colon cancer cells and that this axis could be a target for the therapy of colon cancer. - Highlights: • hnRNP K is required for the tumorigenicity of colon cancer cells. • hnRNP K binds to the promoter region of NUF2 and activates its transcription. • NUF2 expression is correlated with hnRNP K expression in colorectal cancer tissue. • hnRNP K and NUF2 are required for metaphase chromosome alignment. • The hnRNP K-NUF2 axis is important for the proliferation of colon cancer cells.

  13. Tumorigenic Potential of Olfactory Bulb-Derived Human Adult Neural Stem Cells Associates with Activation of TERT and NOTCH1

    PubMed Central

    Ricci-Vitiani, Lucia; Cenciarelli, Carlo; Petrucci, Giovanna; Milazzo, Luisa; Montano, Nicola; Tabolacci, Elisabetta; Maira, Giulio; Larocca, Luigi M.; Pallini, Roberto

    2009-01-01

    Background Multipotent neural stem cells (NSCs) have been isolated from neurogenic regions of the adult brain. Reportedly, these cells can be expanded in vitro under prolonged mitogen stimulation without propensity to transform. However, the constitutive activation of the cellular machinery required to bypass apoptosis and senescence places these cells at risk for malignant transformation. Methodology/Principal Findings Using serum-free medium supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), we established clonally derived NS/progenitor cell (NS/PC) cultures from the olfactory bulb (OB) of five adult patients. The NS/PC cultures obtained from one OB specimen lost growth factor dependence and neuronal differentiation at early passage. These cells developed glioblastoma tumors upon xenografting in immunosuppressed mice. The remaining NS/PC cultures were propagated either as floating neurospheres or as adherent monolayers with mainteinance of growth factor dependence and multipotentiality at late passage. These cells were engrafted onto the CNS of immunosuppressed rodents. Overall, the grafted NS/PCs homed in the host parenchyma showing ramified morphology and neuronal marker expression. However, a group of animals transplanted with NS/PCs obtained from an adherent culture developed fast growing tumors histologically resembling neuroesthesioblastoma. Cytogenetic and molecular analyses showed that the NS/PC undergo chromosomal changes with repeated in vitro passages under mitogen stimulation, and that up-regulation of hTERT and NOTCH1 associates with in vivo tumorigenicity. Conclusions/Significance Using culturing techniques described in current literature, NS/PCs arise from the OB of adult patients which in vivo either integrate in the CNS parenchyma showing neuron-like features or initiate tumor formation. Extensive xenografting studies on each human derived NS cell line appear mandatory before any use of these cells in the

  14. Alterations in tumorigenicity of embryonal carcinoma cells by IGF-I triple-helix induced changes in immunogenicity and apoptosis.

    PubMed

    Ly, A; Francois, J C; Upegui-Gonzalez, L C; Swiercz, B; Bedel, C; Duc, H T; Bout, D; Trojan, J

    2000-12-08

    IGF-I antisense gene therapy has been applied successfully to animal models of glioma, hepatoma and teratocarcinoma. The antisense strategy has shown that tumor cells transfected with vectors encoding IGF-I antisense RNA lose tumorigenicity, become immunogenic and are associated with tumor specific immune response involving CD8+ lymphocytes. An IGF-I triple helix approach to gene therapy for glioma was recently described. The approach we have taken is to establish parameters of change using the IGF-I triple helix strategy. PCC-3 embryonal carcinoma cells derived from murine teratocarcinoma which express IGF-I were used as a model. The cells were transfected with vector which encodes an oligoribonucleotide that forms RNA-IGF-I DNA triple-helix structure. The triple-helix stops the production of IGF-I. Cells transfected in this manner underwent changes in phenotype and an increase in MHC-I and B-7 cell surface molecules. They also showed enhancement in the production of apoptotic cells (60-70%). The "triple helix" transfected cells lost the ability to induce tumor when injected subcutaneously in syngeneic 129 Sv mice. When co-transfected in vitro with expression vectors encoding both MHC-I and B-7 cDNA in antisense orientation, the "triple-helix" transfected cells were down-regulated in expression of MHC-I and B-7 and the number of apoptotic cells was significantly decreased. Injection of the doubly co-transfected cells into 129 Sv mice was associated with induction of teratocarcinoma. Comparison between antisense and triple-helix transfected cells strategies showed similar immunogenic and apoptotic changes. The findings suggest that triple-helix technology may offer a new clinical approach to treatement of tumors expressing IGF-I.

  15. Anti-inflammatory and Anti-tumorigenic Effects of Açai Berry in Helicobacter felis-infected mice

    PubMed Central

    Lee, Ju Yup; Kim, Nayoung; Choi, Yoon Jeong; Nam, Ryoung Hee; Lee, Seonmin; Ham, Min Hee; Suh, Ji Hyung; Choi, Yoon Jin; Lee, Hye Seung; Lee, Dong Ho

    2016-01-01

    Background: The aim of this study was to evaluate the anti-inflammatory and anti-tumorigenic effect of açai berry after chronic Helicobacter felis colonization in the stomachs of C57BL/6 mice. Methods: A total of 57 four-week-old female C57BL/6 mice (18 control mice and 39 experimental mice) were used. The mice were administered orogastrically with vehicle only or vehicle containing H. felis, 5 times every other day. After inoculation of H. felis, mice were fed either a standard or an açai-containing diet and then sacrificed at 4, 24, and 52 weeks. The infection status and degree of inflammation were determined by culture and histopathology. The level of gastric mucosal myeloperoxidase (MPO), TNF-α, and interleukin-1β (IL-1β) were measured by ELISA. Results: At 24 weeks after inoculation, mucosal atrophy and mucous metaplasia appeared in all infected mice. At 52 weeks after inoculation, dysplastic change was noted in 10%, 25%, and 50% of mice in the H. felis-control, H. felis-açai 5%, and H. felis-açai 10% groups, respectively. The neutrophil, monocyte, atrophy, and metaplasia grades of infected mice showed no significant difference among the H. felis-infected groups. H. felis-infected mice fed with açai berry showed no significant difference compared with H. felis-infected control mice in gastric mucosal MPO, TNF-α, and IL-1β levels. Conclusions: H. felis that colonized the stomachs of C57BL/6 mice provoked inflammation, and induced mucosal atrophy, metaplasia, and dysplasia. However, açai berry did not effectively prohibit the gastric carcinogenesis which was induced by chronic H. felis infection. PMID:27051649

  16. Therapeutic dosages of aspirin counteract the IL-6 induced pro-tumorigenic effects by slowing down the ribosome biogenesis rate

    PubMed Central

    Brighenti, Elisa; Giannone, Ferdinando Antonino; Fornari, Francesca; Onofrillo, Carmine; Govoni, Marzia; Montanaro, Lorenzo; Treré, Davide; Derenzini, Massimo

    2016-01-01

    Chronic inflammation is a risk factor for the onset of cancer and the regular use of aspirin reduces the risk of cancer development. Here we showed that therapeutic dosages of aspirin counteract the pro-tumorigenic effects of the inflammatory cytokine interleukin(IL)-6 in cancer and non-cancer cell lines, and in mouse liver in vivo. We found that therapeutic dosages of aspirin prevented IL-6 from inducing the down-regulation of p53 expression and the acquisition of the epithelial mesenchymal transition (EMT) phenotypic changes in the cell lines. This was the result of a reduction in c-Myc mRNA transcription which was responsible for a down-regulation of the ribosomal protein S6 expression which, in turn, slowed down the rRNA maturation process, thus reducing the ribosome biogenesis rate. The perturbation of ribosome biogenesis hindered the Mdm2-mediated proteasomal degradation of p53, throughout the ribosomal protein-Mdm2-p53 pathway. P53 stabilization hindered the IL-6 induction of the EMT changes. The same effects were observed in livers from mice stimulated with IL-6 and treated with aspirin. It is worth noting that aspirin down-regulated ribosome biogenesis, stabilized p53 and up-regulated E-cadherin expression in unstimulated control cells also. In conclusion, these data showed that therapeutic dosages of aspirin increase the p53-mediated tumor-suppressor activity of the cells thus being in this way able to reduce the risk of cancer onset, either or not linked to chronic inflammatory processes. PMID:27557515

  17. 7 CFR Exhibit G to Subpart E of... - Exhibit G to Subpart E of Part 1980

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 14 2010-01-01 2009-01-01 true Exhibit G to Subpart E of Part 1980 G Exhibit G to Subpart E of Part 1980 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING... Program Pt. 1980, Subpt. E, Exh. G Exhibit G to Subpart E of Part 1980 Note: The Exhibit is not...

  18. 43 CFR 4.824 - Exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Procedural Rules Applicable to Practice and Procedure for Hearings, Decisions, and Administrative Review... Interior-Effectuation of Title VI of the Civil Rights Act of 1964 Procedures § 4.824 Exhibits....

  19. 18 CFR 32.2 - Required exhibits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... of operating such facilities. Exhibit B. A general or key map on a scale not greater than 20 miles to... facilities used for the generation and transmission of electric energy, indicating on said map the...

  20. The Making of a Museum Exhibition.

    ERIC Educational Resources Information Center

    Bleecker, Samuel E.

    1979-01-01

    Discusses the preparation of the Reptile and Amphibian exhibition at the American Museum of Natural History. Various steps involved in developing the ten showcases in a six-year period are presented. (SA)

  1. 18 CFR 153.8 - Required exhibits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) Exhibit D. If the proposal is for a pipeline interconnection to import or export natural gas, a copy of... authority, that will issue each required authorization; the date each request for authorization...

  2. Communicating Complex Sciences by Means of Exhibitions

    NASA Astrophysics Data System (ADS)

    Schneider, S.

    2011-12-01

    Earth Sciences will have to take over the leading role in global sustainable policy and in discussions about climate change. Efforts to raise attention within the politically responsible communities as well as in the public are getting more and more support by executive and advisory boards all over the world. But how can you successfully communicate complex sciences? For example, to start communication about climate change, the first step is to encourage people to be concerned about climate change. After that, one has to start thinking about how to present data and how to include the presented data into an unprejudiced context. Therefore, the communication toolbox offers various methods to reach diverse audiences. The R&D programme GEOTECHNOLOGIEN conducts roving exhibitions as one of its most successful communication tools. With roving exhibitions GEOTECHNOLOGIEN is able to get in touch with different audiences at once. The main purpose and theme of these exhibitions is to convey the everyday means of climate change to the visitors. It is within the responsibility of science to communicate the effects of a phenomenon like climate change as well as the impact of research results to the everyday life of people. Currently, a GEOTECHNOLOGIEN roving exhibition on remote sensing with satellites deals with various issues of environmental research, including a chapter on climate change. By following the 3M-concept (Meaning - Memorable - Moving), exhibitions allow to connect the visitors daily environment and personal experiences with the presented issues and objects. Therefore, hands-on exhibits, exciting multimedia effects and high-tech artefacts have to be combined with interpretive text elements to highlight the daily significance of the scientific topics and the exhibition theme respectively. To create such an exhibition, strong conceptual planning has to be conducted. This includes the specification of stern financial as well as time wise milestones. In addition

  3. When Do Children Exhibit a "Yes" Bias?

    ERIC Educational Resources Information Center

    Okanda, Mako; Itakura, Shoji

    2010-01-01

    This study investigated whether one hundred and thirty-five 3- to 6-year-old children exhibit a yes bias to various yes-no questions and whether their knowledge status affects the production of a yes bias. Three-year-olds exhibited a yes bias to all yes-no questions such as "preference-object" and "knowledge-object" questions pertaining to…

  4. Reaching the Public through Traveling Exhibitions

    NASA Astrophysics Data System (ADS)

    Dusenbery, P. B.; Harold, J. B.; Morrow, C. A.

    2004-11-01

    The Space Science Institute (SSI) of Boulder, Colorado has recently developed two museum exhibits called Alien Earths and MarsQuest. It has just started to develop another exhibit called Giant Planets. These exhibitions provide research scientists the opportunity to engage in a number of activities that are vital to the success of these major outreach programs. Alien Earths was developed in partnership with various research missions. The focus of the presentation will be on MarsQuest and Giant Planets. MarsQuest is a 5000 square-foot, \\$3M, traveling exhibition that is now touring the country. The exhibit's second 3-year tour will enable millions of Americans to share in the excitement of the scientific exploration of Mars and learn more about their own planet in the process. The associated planetarium show and education program will also be described, with particular emphasis on workshops to orient museum staff (e.g. museum educators and docents) and workshops for master educators near host museums and science centers. The workshops make innovative connections between the exhibition's interactive experiences and lesson plans aligned with the National Science Education Standards. These exhibit programs are good models for actively involving scientists and their discoveries to help improve informal science education in the museum community and for forging a stronger connection between formal and informal education. The presentation will also discuss how Giant Planets, a proposed 3500 square-foot traveling exhibition on the mysteries and discoveries of the outer planets, will be able to take advantage of the connections and resources that have been developed by the MarsQuest project.

  5. An Astrobiology Microbes Exhibit and Education Module

    NASA Technical Reports Server (NTRS)

    Lindstrom, Marilyn M.; Allen, Jaclyn S.; Stocco, Karen; Tobola, Kay; Olendzenski, Lorraine

    2001-01-01

    Telling the story of NASA-sponsored scientific research to the public in exhibits is best done by partnerships of scientists and museum professionals. Likewise, preparing classroom activities and training teachers to use them should be done by teams of teachers and scientists. Here we describe how we used such partnerships to develop a new astrobiology augmentation to the Microbes! traveling exhibit and a companion education module. "Additional information is contained in the original extended abstract."

  6. Sex differences in science museum exhibit attraction

    NASA Astrophysics Data System (ADS)

    Arámbula Greenfield, Teresa

    This study examines the relative attraction of hands-on, interactive science museum exhibits for females and males. Studies have demonstrated that such exhibits can be effective learning experiences for children, with both academic and affective benefits. Other studies have shown that girls and boys do not always experience the same science-related educational opportunities and that, even when they do, they do not necessarily receive the same benefits from them. These early differences can lead to more serious educational and professional disparities later in life. As interactive museum exhibits represent a science experience that is-readily available to both girls and boys, the question arose as to whether they were being used similarly by the two groups as well as by adult women and men. It was found that both girls and boys used all types of exhibits, but that girls were more likely than boys to use puzzles and exhibits focusing on the human body; boys were more likely than girls to use computers and exhibits illustrating physical science principles. However, this was less true of children accompanied by adults (parents) than it was of unaccompanied children on school field trips who roamed the museum more freely.Received: 16 February 1994; Revised: 3 February 1995;

  7. A Computer-Assisted 3D Model for Analyzing the Aggregation of Tumorigenic Cells Reveals Specialized Behaviors and Unique Cell Types that Facilitate Aggregate Coalescence

    PubMed Central

    Scherer, Amanda; Kuhl, Spencer; Wessels, Deborah; Lusche, Daniel F.; Hanson, Brett; Ambrose, Joseph; Voss, Edward; Fletcher, Emily; Goldman, Charles; Soll, David R.

    2015-01-01

    We have developed a 4D computer-assisted reconstruction and motion analysis system, J3D-DIAS 4.1, and applied it to the reconstruction and motion analysis of tumorigenic cells in a 3D matrix. The system is unique in that it is fast, high-resolution, acquires optical sections using DIC microscopy (hence there is no associated photoxicity), and is capable of long-term 4D reconstruction. Specifically, a z-series at 5 μm increments can be acquired in less than a minute on tissue samples embedded in a 1.5 mm thick 3D Matrigel matrix. Reconstruction can be repeated at intervals as short as every minute and continued for 30 days or longer. Images are converted to mathematical representations from which quantitative parameters can be derived. Application of this system to cancer cells from established lines and fresh tumor tissue has revealed unique behaviors and cell types not present in non-tumorigenic lines. We report here that cells from tumorigenic lines and tumors undergo rapid coalescence in 3D, mediated by specific cell types that we have named “facilitators” and “probes.” A third cell type, the “dervish”, is capable of rapid movement through the gel and does not adhere to it. These cell types have never before been described. Our data suggest that tumorigenesis in vitro is a developmental process involving coalescence facilitated by specialized cells that culminates in large hollow spheres with complex architecture. The unique effects of select monoclonal antibodies on these processes demonstrate the usefulness of the model for analyzing the mechanisms of anti-cancer drugs. PMID:25790299

  8. Chondroitin Sulfate-E Is a Negative Regulator of a Pro-Tumorigenic Wnt/Beta-Catenin-Collagen 1 Axis in Breast Cancer Cells

    PubMed Central

    Willis, Catherine M.; Klüppel, Michael

    2014-01-01

    Expression of the glycosaminoglycan chondroitin sulfate-E (CS-E) is misregulated in many human cancers, including breast cancer. Cell-surface associated CS-E has been shown to have pro-tumorigenic functions, and pharmacological treatment with exogenous CS-E has been proposed to interfere with tumor progression mediated by endogenous CS-E. However, the effects of exogenous CS-E on breast cancer cell behavior, and the molecular mechanisms deployed by CS-E are not well understood. We show here that treatment with CS-E, but not other chondroitin forms, could interfere with the invasive protrusion formation and migration of breast cancer cells in three-dimensional organotypic cultures. Microarray analysis identified transcriptional programs controlled by CS-E in these cells. Importantly, negative regulation of the pro-metastatic extracellular matrix gene Col1a1 was required for the anti-migratory effects of exogenous CS-E. Knock-down of Col1a1 gene expression mimics the effects of CS-E treatment, while exposing cells to a preformed collagen I matrix interfered with the anti-migratory effects of CS-E. In addition, CS-E specifically interfered with Wnt/beta-catenin signaling, a known pro-tumorigenic pathway. Lastly, we demonstrate that Col1a1 is a positively regulated target gene of the Wnt/beta-catenin pathway in breast cancer cells. Together, our data identify treatment with exogenous CS-E as negative regulatory mechanism of breast cancer cell motility through interference with a pro-tumorigenic Wnt/beta-catenin - Collagen I axis. PMID:25090092

  9. FAAH inhibition enhances anandamide mediated anti-tumorigenic effects in non-small cell lung cancer by downregulating the EGF/EGFR pathway.

    PubMed

    Ravi, Janani; Sneh, Amita; Shilo, Konstantin; Nasser, Mohd W; Ganju, Ramesh K

    2014-05-15

    The endocannabinoid anandamide (AEA), a neurotransmitter was shown to have anti-cancer effects. Fatty acid amide hydrolase (FAAH) metabolizes AEA and decreases its anti-tumorigenic activity. In this study, we have analyzed the role of FAAH inhibition in non-small cell lung cancer (NSCLC). We have shown that FAAH and CB1 receptor which is activated by AEA are expressed in lung adenocarcinoma patient samples and NSCLC cell lines A549 and H460. Since the synthetic analogue of anandamide (Met-F-AEA) did not possess significant anti-tumorigenic effects, we used Met-F-AEA in combination with FAAH inhibitor URB597 which significantly reduced EGF (epidermal growth factor)-induced proliferative and chemotactic activities in vitro when compared to anti-tumorigenic activity of Met-F-AEA alone. Further analysis of signaling mechanisms revealed that Met-F-AEA in combination with URB597 inhibits activation of EGFR and its downstream signaling ERK, AKT and NF-kB. In addition, it inhibited MMP2 secretion and stress fiber formation. We have also shown that the Met-F-AEA in combination with URB597 induces G0/G1 cell cycle arrest by downregulating cyclin D1 and CDK4 expressions, ultimately leading to apoptosis via activation of caspase-9 and PARP. Furthermore, the combination treatment inhibited tumor growth in a xenograft nude mouse model system. Tumors derived from Met-F-AEA and URB597 combination treated mice showed reduced EGFR, AKT and ERK activation and MMP2/MMP9 expressions when compared to Met-F-AEA or URB597 alone. Taken together, these data suggest in EGFR overexpressing NSCLC that the combination of Met-F-AEA with FAAH inhibitor resulted in superior therapeutic response compared to individual compound activity alone.

  10. Tumorigenicity of simian virus 40-hepatocyte cell lines: effect of in vitro and in vivo passage on expression of liver-specific genes and oncogenes.

    PubMed Central

    Woodworth, C D; Kreider, J W; Mengel, L; Miller, T; Meng, Y L; Isom, H C

    1988-01-01

    Five simian virus 40 (SV40)-hepatocyte cell lines were examined for tumorigenicity and the effect of in vitro passage on the expression of four liver-specific genes (albumin, transferrin, alpha 1-antitrypsin, and phosphoenolpyruvate carboxykinase), two oncogenes (c-Ha-ras and c-raf), and two genes associated with hepatocarcinogenesis (alpha-fetoprotein and placental-type glutathione-S-transferase). At low passage (12 to 22), all five cell lines expressed the four liver-specific genes at levels similar to those in the liver and were not tumorigenic or were weakly tumorigenic. At high passage (33 to 61), the cell lines formed carcinomas, and four out of five cell lines produced primary tumors that metastasized. At least two cell lines produced well-differentiated hepatocellular carcinomas that expressed liver-specific RNAs. Levels of expression of liver-specific genes changed with time in culture. Some of the changes in liver-specific gene expression in the tumor tissue (such as for the phosphoenolpyruvate carboxykinase gene) paralleled those that occurred with in vitro passage, while other changes (such as for the albumin gene) did not parallel those that occurred with in vitro passage. Correlations between enhanced expression of c-Ha-ras and tumorigenic potential and between the process of SV40 immortalization and induced expression of c-raf and glutathione-S-transferase-P were observed. Induction of alpha-fetoprotein was detected with in vitro and in vivo passage only in the CWSV14 cell line and was paralleled by diminished albumin expression. In conclusion, we developed a model system with five SV40-hepatocyte cell lines, tumors induced by them, and tumor cell lines to examine changes in gene expression that accompany the progression from a normal cell to a hepatocellular carcinoma. Because the SV40-hepatocyte cell lines and tumor cell lines remain highly differentiated and vary in the magnitude of expression of specific genes, they can be used to study the

  11. Macrophages Facilitate Coal Tar Pitch Extract-Induced Tumorigenic Transformation of Human Bronchial Epithelial Cells Mediated by NF-κB

    PubMed Central

    Feng, Feifei; Wu, Yiming; Zhang, Shaofeng; Liu, Yu; Qin, Lijuan; Wu, Yongjun; Yan, Zhen; Wu, Weidong

    2012-01-01

    Objective Chronic respiratory inflammation has been associated with lung cancer. Tumor-associated macrophages (TAMs) play a critical role in the formation of inflammation microenvironment. We sought to characterize the role of TAMs in coal tar pitch extract (CTPE)-induced tumorigenic transformation of human bronchial epithelial cells and the underlying mechanisms. Methods The expression of TAMs-specific CD68 in lung cancer tissues and paired adjacent tissues from cancer patients was determined using immunostaining. Co-culture of human bronchial epithelial cells (BEAS-2B) and macrophage-like THP-1 cells were conducted to evaluate the promotive effect of macrophages on CTPE-induced tumorigenic transformation of BEAS-2B cells. BEAS-2B cells were first treated with 2.4 µg/mL CTPE for 72 hours. After removal of CTPE, the cells were continuously cultured either with or without THP-1 cells and passaged using trypsin-EDTA. Alterations of cell cycle, karyotype, colony formation in soft agar and tumor xenograft growth in nude mice of BEAS-2B cells at passages 10, 20 and 30, indicative of tumorigenecity, were determined, respectively. In addition, mRNA and protein levels of NF-κB in BEAS-2B cells were measured with RT-PCR and western blot, respectively. B(a)P was used as the positive control. Results The over-expression of TAMs-specific CD68 around lung tumor tissues was detected and associated with lung cancer progression. The tumorigenic alterations of BEAS-2B cells including increase in cell growth rate, number of cells with aneuploidy, clonogenicity in soft agar, and tumor size in nude mice in vivo occurred at passage 10, becoming significant at passages 20 and 30 of the co-culture following CTPE removal in compared to BEAS-2B cells alone. In addition, the expression levels of NF-κB in BEAS-2B cells were positively correlated to the malignancy of BEAS-2B cells under different conditions of treatment. Conclusion The presence of macrophages facilitated CTPE

  12. Using Comparative Planetology in Exhibit Development

    NASA Astrophysics Data System (ADS)

    Dusenbery, P. B.; Harold, J. B.; Morrow, C. A.

    2004-12-01

    It is critically important for the public to better understand the scientific process. Museum exhibitions are an important part of informal science education that can effectively reach public audiences as well as school groups. They provide an important gateway for the public to learn about compelling scientific endeavors. The Space Science Institute (SSI) is a national leader in producing traveling science exhibitions and their associated educational programming (i.e. interactive websites, educator workshops, public talks, instructional materials). The focus of this presentation will be on three of its exhibit projects: MarsQuest (currently on tour), Alien Earths (in fabrication), and Giant Planets (in development). MarsQuest is enabling millions of Americans to share in the excitement of the scientific exploration of Mars and to learn more about their own planet in the process. Alien Earths will bring origins-related research and discoveries to students and the American public. It has four interrelated exhibit areas: Our Place in Space, Star Birth, PlanetQuest, and Search for Life. Exhibit visitors will explore the awesome events surrounding the birth of stars and planets; they will join scientists in the hunt for planets outside our solar system including those that may be in "habitable zones" around other stars; and finally they will be able to learn about how scientists are looking for signs of life beyond Earth. Giant Planets: Exploring the Outer Solar System will take advantage of the excitement generated by the Cassini mission and bring planetary and origins research and discoveries to students and the public. It will be organized around four thematic areas: Our Solar System; Colossal Worlds; Moons, Rings, and Fields; and Make Space for Kids. Giant Planets will open in 2007. This talk will focus on the importance of making Earth comparisons in the conceptual design of each exhibit and will show several examples of how these comparisons were manifested in

  13. Tumorigenic poxviruses: genomic organization and DNA sequence of the telomeric region of the Shope fibroma virus genome.

    PubMed

    Upton, C; DeLange, A M; McFadden, G

    1987-09-01

    Shope fibroma virus (SFV), a tumorigenic poxvirus, has a 160-kb linear double-stranded DNA genome and possesses terminal inverted repeats (TIRs) of 12.4 kb. The DNA sequence of the terminal 5.5 kb of the viral genome is presented and together with previously published sequences completes the entire sequence of the SFV TIR. The terminal 400-bp region contains no major open reading frames (ORFs) but does possess five related imperfect palindromes. The remaining 5.1 kb of the sequence contains seven tightly clustered and tandemly oriented ORFs, four larger than 100 amino acids in length (T1, T2, T4, and T5) and three smaller ORFs (T3A, T3B, and T3C). All are transcribed toward the viral hairpin and almost all possess the consensus sequence TTTTTNT near their 3' ends which has been implicated for the transcription termination of vaccinia virus early genes. Searches of the published DNA database revealed no sequences with significant homology with this region of the SFV genome but when the protein database was searched with the translation products of ORFs T1-T5 it was found that the N-terminus of the putative T4 polypeptide is closely related to the signal sequence of the hemagglutinin precursor from influenza A virus, suggesting that the T4 polypeptide may be secreted from SFV-infected cells. Examination of other SFV ORFs shows that T1 and T2 also possess signal-like hydrophobic amino acid stretches close to their N-termini. The protein database search also revealed that the putative T2 protein has significant homology to the insulin family of polypeptides. In terms of sequence repetitions, seven tandemly repeated copies of the hexanucleotide ATTGTT and three flanking regions of dyad symmetry were detected, all in ORF T3C. A search for palindromic sequences also revealed two clusters, one in ORF T3A/B and a second in ORF T2. ORF T2 harbors five short sequence domains, each of which consists of a 6-bp short palindrome and a 10- to 18-bp larger palindrome. The

  14. Localized pulses exhibiting a missilelike slow decay.

    PubMed

    Shaarawi, Amr M; Maged, Maha A; Besieris, Ioannis M; Hashish, Essam

    2006-08-01

    We investigate the quasi-missile behavior of known localized wave solutions, such as the modified power spectrum and splash pulses. We demonstrate that source-free localized waves can exhibit slow decay rates analogous to Wu's missile solutions, which are characterized by an amplitude decay rate slower than 1/R over an unlimited range. When excited from a finite aperture, the missilelike decay is not exhibited by all localized waves showing such behavior in the source-free situation. On the other hand, localized wave missiles generated from a finite aperture have peaks that exhibit quasi-missile decay. In an extended intermediate range between the near- and the far-field regions, these pulses decay at a rate slower than 1/R before switching to the usual 1/R decay.

  15. Localized pulses exhibiting a missilelike slow decay

    NASA Astrophysics Data System (ADS)

    Shaarawi, Amr M.; Maged, Maha A.; Besieris, Ioannis M.; Hashish, Essam

    2006-08-01

    We investigate the quasi-missile behavior of known localized wave solutions, such as the modified power spectrum and splash pulses. We demonstrate that source-free localized waves can exhibit slow decay rates analogous to Wu's missile solutions, which are characterized by an amplitude decay rate slower than 1/R over an unlimited range. When excited from a finite aperture, the missilelike decay is not exhibited by all localized waves showing such behavior in the source-free situation. On the other hand, localized wave missiles generated from a finite aperture have peaks that exhibit quasi-missile decay. In an extended intermediate range between the near- and the far-field regions, these pulses decay at a rate slower than 1/R before switching to the usual 1/R decay.

  16. The Gravity- Powered Calculator, a Galilean Exhibit

    NASA Astrophysics Data System (ADS)

    Cerreta, Pietro

    2014-04-01

    The Gravity-Powered Calculator is an exhibit of the Exploratorium in San Francisco. It is presented by its American creators as an amazing device that extracts the square roots of numbers, using only the force of gravity. But if you analyze his concept construction one can not help but recall the research of Galileo on falling bodies, the inclined plane and the projectile motion; exactly what the American creators did not put into prominence with their exhibit. Considering the equipment only for what it does, in my opinion, is very reductive compared to the historical roots of the Galilean mathematical physics contained therein. Moreover, if accurate deductions are contained in the famous study of S. Drake on the Galilean drawings and, in particular on Folio 167 v, the parabolic paths of the ball leaping from its launch pad after descending a slope really actualize Galileo's experiments. The exhibit therefore may be best known as a `Galilean calculator'.

  17. Human Muse cells, non-tumorigenic pluripotent-like stem cells, have the capacity for liver regeneration by specific homing and replenishment of new hepatocytes in liver fibrosis mouse model.

    PubMed

    Iseki, Masahiro; Kushida, Yoshihiro; Wakao, Shohei; Akimoto, Takahiro; Mizuma, Masamichi; Motoi, Fuyuhiko; Asada, Ryuta; Shimizu, Shinobu; Unno, Michiaki; Chazenbalk, Gregorio; Dezawa, Mari

    2016-11-02

    Muse cells, a novel type of non-tumorigenic pluripotent-like stem cells reside in the bone marrow, skin and adipose tissue, are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-Muse cells to repair the liver fibrosis model of immunodeficient mice was evaluated in this study. They exhibited the ability for differentiation spontaneously into hepatoblast/hepatocyte-lineage cells and high migration toward the serum and liver tissue of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated into the liver, but not into other organs except the lower rate in the lung at 2 weeks after intravenous injection into the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1±15.2%), human albumin (54.3±8.2%) and anti-trypsin (47.9±4.6%)-positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human-CYP1A2, and human-Glc-6-Pase, at 8 weeks. Recovery in serum total bilirubin and albumin, and significant attenuation of fibrosis were recognized with statistical differences between the Muse group and control groups which received the vehicle or the same number of non-Muse cells, namely cells other than Muse cells in bone marrow mesenchymal stem cells. Thus, unlike ES and iPS cells, Muse cells are unique in their efficient migration and integration into damaged liver only by intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They are suggested to repair liver fibrosis in two simple steps; expansion after collection from the bone marrow and intravenous injection. Such feasible strategy might provide impressive regenerative performance to liver disease patients.

  18. 18 CFR 32.2 - Required exhibits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... facilities used for the generation and transmission of electric energy, indicating on said map the points... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Required exhibits. 32.2 Section 32.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT...

  19. 18 CFR 32.2 - Required exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... facilities used for the generation and transmission of electric energy, indicating on said map the points... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Required exhibits. 32.2 Section 32.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT...

  20. 18 CFR 34.4 - Required exhibits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Required exhibits. 34.4 Section 34.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT APPLICATION FOR AUTHORIZATION OF THE ISSUANCE...

  1. FluxBase: An Interactive Art Exhibition.

    ERIC Educational Resources Information Center

    Huntley, Joan S.; Partridge, Michael

    1992-01-01

    Describes a computer program that gives Fluxus exhibition attendees an opportunity to experience the Flux objects in the spirit in which they were originally created. Suggests that the computer program provides a virtual approximation to the original art works without damaging them. (RS)

  2. 32 CFR 705.24 - Exhibits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... be displayed in any appropriate location or event (including commercially owned spaces such as... for Navy exhibits in events of international or national scope, or those requiring major coordination... will be used. See Armed Forces Request Form, § 705.36. (4) Requests for exceptions to policy...

  3. 32 CFR 705.24 - Exhibits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... be displayed in any appropriate location or event (including commercially owned spaces such as... for Navy exhibits in events of international or national scope, or those requiring major coordination... will be used. See Armed Forces Request Form, § 705.36. (4) Requests for exceptions to policy...

  4. 32 CFR 705.24 - Exhibits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... be displayed in any appropriate location or event (including commercially owned spaces such as... for Navy exhibits in events of international or national scope, or those requiring major coordination... will be used. See Armed Forces Request Form, § 705.36. (4) Requests for exceptions to policy...

  5. 32 CFR 705.24 - Exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... be displayed in any appropriate location or event (including commercially owned spaces such as... for Navy exhibits in events of international or national scope, or those requiring major coordination... will be used. See Armed Forces Request Form, § 705.36. (4) Requests for exceptions to policy...

  6. Do Online Students Exhibit Different Learning Styles

    ERIC Educational Resources Information Center

    Hausler, Joel; Sanders, John W.; Young, Barbara

    2007-01-01

    We examined the relationship between learning styles and student type. This research seeks to examine if online students exhibit different learning styles from onsite students; and, if so, what accommodations relating to learning style differences may be made for online students? Students (N = 80) were asked to complete an online survey in order…

  7. The medial prefrontal cortex exhibits money illusion

    PubMed Central

    Weber, Bernd; Rangel, Antonio; Wibral, Matthias; Falk, Armin

    2009-01-01

    Behavioral economists have proposed that money illusion, which is a deviation from rationality in which individuals engage in nominal evaluation, can explain a wide range of important economic and social phenomena. This proposition stands in sharp contrast to the standard economic assumption of rationality that requires individuals to judge the value of money only on the basis of the bundle of goods that it can buy—its real value—and not on the basis of the actual amount of currency—its nominal value. We used fMRI to investigate whether the brain's reward circuitry exhibits money illusion. Subjects received prizes in 2 different experimental conditions that were identical in real economic terms, but differed in nominal terms. Thus, in the absence of money illusion there should be no differences in activation in reward-related brain areas. In contrast, we found that areas of the ventromedial prefrontal cortex (vmPFC), which have been previously associated with the processing of anticipatory and experienced rewards, and the valuation of goods, exhibited money illusion. We also found that the amount of money illusion exhibited by the vmPFC was correlated with the amount of money illusion exhibited in the evaluation of economic transactions. PMID:19307555

  8. Comic Strips to Accompany Science Museum Exhibits

    ERIC Educational Resources Information Center

    Chung, Beom Sun; Park, Eun-mi; Kim, Sang-Hee; Cho, Sook-kyoung; Chung, Min Suk

    2016-01-01

    Science museums make the effort to create exhibits with amusing explanations. However, existing explanation signs with lengthy text are not appealing, and as such, visitors do not pay attention to them. In contrast, conspicuous comic strips composed of simple drawings and humors can attract science museum visitors. This study attempted to reveal…

  9. After Terror Charges, Artist Exhibits Academic Freedom

    ERIC Educational Resources Information Center

    Wilson, Robin

    2008-01-01

    Steven Kurtz, a professor of visual studies at the State University of New York, has been working with various bacteria as part of his counterculture exhibit artworks for nearly 20 years. Four years ago, federal agents raided his home in a bioterrorism investigation. The federal agents had been called to the house by local police officers…

  10. 18 CFR 156.5 - Exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... such enterprises or operations, a detailed explanation of each such relationship, including the... relationship. (5) Exhibit F—Location of facilities. A geographical map of suitable scale and detail showing all... proposed customers; derivation of numbers of customers proposed to be served; individual consumer peak...

  11. 18 CFR 157.14 - Exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... explanation of each such relationship, including the percentage of voting strength represented by such... detailed explanation of each such relationship. (5) Exhibit E—Other pending applications and filings. A... abandoned. This map, or an additional map, shall clearly show the relationship of the new facilities to...

  12. 18 CFR 153.8 - Required exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... LNG, evidence that an appropriate and qualified concern will properly and safely receive or deliver such LNG, including a report containing detailed engineering and design information. The Commission... Office of Energy Projects, 888 First Street, NE., Washington, DC 20426; (6) Exhibit E-1. If the...

  13. 18 CFR 50.7 - Applications: exhibits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Applications: exhibits. 50.7 Section 50.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT APPLICATIONS FOR PERMITS TO SITE...

  14. 18 CFR 50.7 - Applications: exhibits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Applications: exhibits. 50.7 Section 50.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE FEDERAL POWER ACT APPLICATIONS FOR PERMITS TO SITE...

  15. 18 CFR 153.8 - Required exhibits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... LNG, evidence that an appropriate and qualified concern will properly and safely receive or deliver such LNG, including a report containing detailed engineering and design information. The Commission... Office of Energy Projects, 888 First Street, NE., Washington, DC 20426; (6) Exhibit E-1. If the...

  16. 18 CFR 156.5 - Exhibits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... separate volume or volumes shall indicate on the cover thereof applicant's name and bear Docket No. CP... an equivalent Btu basis. (12) Exhibit K—Cost of facilities. A detailed estimate of total capital cost.... (vii) A balance sheet and income statement (12 months) of most recent date available....

  17. 18 CFR 156.5 - Exhibits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... separate volume or volumes shall indicate on the cover thereof applicant's name and bear Docket No. CP... an equivalent Btu basis. (12) Exhibit K—Cost of facilities. A detailed estimate of total capital cost.... (vii) A balance sheet and income statement (12 months) of most recent date available....

  18. The palaeontological exhibition: a venue for dialogue.

    PubMed

    Murriello, Sandra

    2015-01-01

    Understanding the dialogue between museums and their visitors enables museums to subsist, undergo transformations and become consolidated as socially valued cultural venues. The Museo de La Plata (Argentina) was created in the late nineteenth century as a natural history museum, and this study shows that currently the museum is valued socially as a venue for family leisure and education, at which people make sense to the objects exhibited through characteristics conferred upon them by both the institution and the visitor. Nevertheless, such dialogue is somehow affected by the museographic proposal and the public interpretation of the institutional narrative, which could be analysed within the frame of contextual learning. As a consequence, the evolutionary idea that the museum aims to communicate is distorted by the public. This article highlights the importance of considering the visitors' interpretations when planning museum exhibitions, a perspective that has been rather absent in the Argentinian museums.

  19. Barium hexaferrite (M-phase) exhibiting superstructure

    SciTech Connect

    Ganapathi, L.; Gopalakrishnan, J.; Rao, C.N.R.

    1984-05-01

    Barium hexaferrite (M-phase) prepared by the flux method is found to exhibit a ..sqrt..3a x ..sqrt..3a superstructure similar to barium hexaaluminate. Morgan and Shaw as well as Iyi et al have recently reported the formation of a barium-rich phase of barium hexaaluminate possessing a ..sqrt..3a x ..sqrt..3a superstructure of the magnetoplumbite structure. In view of the similarities between the layer structures of ..beta..-aluminas and the corresponding ferrites the authors have been carrying out electron microscopic investigations of potassium ..beta..-alumina and BaA1/sub 12/O/sub 19/ along with ferrites of similar compositions. They have obtained electron diffraction patterns of barium hexaaluminate identical to those obtained by Morgan and Shaw and Iyi et al, but more interestingly, they have found a phase of barium hexaferrite (M-phase) exhibiting the ..sqrt..3a x ..sqrt..3a superstructure.

  20. Naval Meteorology and Oceanography Command exhibit

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Designed to entertain while educating, StenniSphere at the John C. Stennis Space Center in Hancock County, Miss., includes informative displays and exhibits from NASA and other agencies located at Stennis, such as this one from the Naval Meteorology and Oceanography Command. Visitors can 'travel' three-dimensionally under the sea and check on the weather back home in the Weather Center. StenniSphere is open free of charge from 9 a.m. to 5 p.m. daily.

  1. Naval Meteorology and Oceanography Command exhibit entrance

    NASA Technical Reports Server (NTRS)

    2000-01-01

    StenniSphere at NASA's John C. Stennis Space Center in Hancock County, Miss., invites visitors to discover why America comes to Stennis Space Center before going into space. Designed to entertain while educating, StenniSphere includes informative displays and exhibits from NASA and other agencies located at Stennis, such as this one from the Naval Meteorology and Oceanography Command. Visitors can 'travel' three-dimensionally under the sea and check on the weather back home in the Weather Center.

  2. Art exhibit focuses on African astronomy

    NASA Astrophysics Data System (ADS)

    Showstack, Randy

    2012-07-01

    Connections between Africans and astronomy are the focus of a new exhibition in the National Museum of African Art in Washington, D. C. "African Cosmos: Stellar Arts," which includes artwork, cultural items, and scientific displays from ancient to contemporary times, is the first major exhibit "that brings together arts and science focused on Africa's contribution to keen observations of the heavens over time," curator Christine Mullen Kreamer said at a 20 June news briefing. Among the exhibit's nearly 100 objects are an ancient Egyptian mummy board that includes a representation of the sky goddess Nut, sculptures by the Dogon people of Mali depicting figures in relation to the cosmos, a video that uses data from two square degrees of the Hubble Space Telescope Cosmic Evolution Survey, and a nearly floor-to-ceiling "Rainbow Serpent" constructed of plastic containers by Benin artist Hazoume. An untitled acrylic painting (Figure 1) by South African Gavin Jantjes evokes a myth of the Khoi San people of southern Africa, as it portrays a girl throwing evening fire embers into the night sky, where they remained as the Milky Way.

  3. When do children exhibit a "yes" bias?

    PubMed

    Okanda, Mako; Itakura, Shoji

    2010-01-01

    This study investigated whether one hundred and thirty-five 3- to 6-year-old children exhibit a yes bias to various yes-no questions and whether their knowledge status affects the production of a yes bias. Three-year-olds exhibited a yes bias to all yes-no questions such as preference-object and knowledge-object questions pertaining to objects, and knowledge-face questions pertaining to facial expressions. Four-year-olds tended to say "yes" only to knowledge-object questions. Five-year-olds did not show any strong response tendency. Six-year-olds exhibited a nay-saying bias to knowledge-face questions. Also, 3-year-olds could indicate the correct option when asked questions with 2 response options. It suggested that 3-year-olds tended to inappropriately say "yes" to yes-no questions, although they knew the answers to the questions. The mechanism of a yes bias was discussed.

  4. The E = mc{sup 2} exhibition

    SciTech Connect

    Henderson, D.; Peshkin, M.

    1995-08-01

    The goal of this DOE-supported exhibition is to demystify Einstein`s formula E = mc{sup 2} by illustrating the interchangeability of matter (m) and energy (E), c{sup 2} being the exchange rate. The exhibition has two major parts, {open_quotes}matter into energy{close_quotes} and {open_quotes}energy into matter{close_quotes}, plus a video to connect them. {open_quotes}Matter into energy{close_quotes} has now been completed and has been placed on the museum floor. Positrons from a {sup 22}Na source are annihilated to produce gamma rays that are caught in NaI detectors. The viewer can alter the alignment of the detectors and observe the consequences for the rates of single and coincident counts. The viewer can also observe the effects of placing absorbers in front of the counters. Prototype explanatory graphics were placed around the exhibit and those will probably be changed after we have some experience with their effectiveness. The connecting video is in the process of being produced in collaboration with Fermilab. A cloud chamber for {open_quotes}energy into matter{close_quotes}, where gamma rays from a small Th source will produce observable pairs, was purchased and work to make the pairs visible has commenced.

  5. 7 CFR Exhibit G to Subpart E of... - Exhibit G to Subpart E of Part 1980

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 14 2011-01-01 2011-01-01 false Exhibit G to Subpart E of Part 1980 G Exhibit G to Subpart E of Part 1980 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE SERVICE, RURAL UTILITIES SERVICE, AND FARM SERVICE AGENCY,...

  6. In-depth N-glycome profiling of paired colorectal cancer and non-tumorigenic tissues reveals cancer-, stage- and EGFR-specific protein N-glycosylation.

    PubMed

    Sethi, Manveen K; Kim, Hoguen; Park, Cheol Keun; Baker, Mark S; Paik, Young-Ki; Packer, Nicolle H; Hancock, William S; Fanayan, Susan; Thaysen-Andersen, Morten

    2015-10-01

    Glycomics may assist in uncovering the structure-function relationships of protein glycosylation and identify glycoprotein markers in colorectal cancer (CRC) research. Herein, we performed label-free quantitative glycomics on a carbon-liquid chromatography-tandem mass spectrometry-based analytical platform to accurately profile the N-glycosylation changes associated with CRC malignancy. N-Glycome profiling was performed on isolated membrane proteomes of paired tumorigenic and adjacent non-tumorigenic colon tissues from a cohort of five males (62.6 ± 13.1 y.o.) suffering from colorectal adenocarcinoma. The CRC tissues were typed according to their epidermal growth factor receptor (EGFR) status by western blotting and immunohistochemistry. Detailed N-glycan characterization and relative quantitation identified an extensive structural heterogeneity with a total of 91 N-glycans. CRC-specific N-glycosylation phenotypes were observed including an overrepresentation of high mannose, hybrid and paucimannosidic type N-glycans and an under-representation of complex N-glycans (P < 0.05). Sialylation, in particular α2,6-sialylation, was significantly higher in CRC tumors relative to non-tumorigenic tissues, whereas α2,3-sialylation was down-regulated (P < 0.05). CRC stage-specific N-glycosylation was detected by high α2,3-sialylation and low bisecting β1,4-GlcNAcylation and Lewis-type fucosylation in mid-late relative to early stage CRC. Interestingly, a novel link between the EGFR status and the N-glycosylation was identified using hierarchical clustering of the N-glycome profiles. EGFR-specific N-glycan signatures included high bisecting β1,4-GlcNAcylation and low α2,3-sialylation (both P < 0.05) relative to EGFR-negative CRC tissues. This is the first study to correlate CRC stage and EGFR status with specific N-glycan features, thus advancing our understanding of the mechanisms causing the biomolecular deregulation associated with CRC.

  7. Mars in their eyes - a cartoon exhibition

    NASA Astrophysics Data System (ADS)

    Pillinger, Pi.

    Recently a collection of 120 cartoons which tell the story of Mars exploration and scientific discovery, past, present and future, was held in London. We discuss the aims of the exhibition, to what extent we believe the original aims were met and report on additional outreach opportunities resulting from the project. The overriding aim was to capitalise on the popular appeal of accessible art - most people admit to enjoying cartoons. This was strengthened by hanging the originals of cartoons which had, mostly, been published in newspapers and magazines in a wide selection of countries. The provenances served to indicate the attraction of Mars to a wide public. We were fortunate to work with the Cartoon Art Trust of the UK who was in the process of relocating to new premises and opening as The Cartoon Museum, in the tourist area of Bloomsbury, central London, very close to the British Museum. "Mars in their Eyes" ran for 10 weeks during April to July 2006; immediately following which a selection of the cartoons was displayed at the week-long Royal Society Summer Exhibition. We explore the differences between the two exhibitions and comment on the various audience responses. We use this comparison to discuss whether a project which is primarily art can be extended to explain science. Does the coupling merely result in dumbing-down of both cultures or is there a true synergy? The experience has led us to coin the phrase "extreme outreach". Projects which are as ambitious as "Mars in their Eyes", without the security of a safe, captive audience, for example at a Science Centre, must be judged by different criteria. Indeed if the project does not meet comparable targets like large visitor numbers, then the honest evaluation of such details can only inform future activities and must not be reflected in the future funding of only "safe" outreach activities.

  8. Art Therapy Exhibitions: Exploitation or Advocacy?

    PubMed

    Davis, Terri

    2017-01-01

    Promoting awareness of human trafficking by sharing trauma survivors' art and summaries of their life stories suggests ethical complexities that have been typically neglected by bioethicists. Although these survivors voluntarily share the objects they created during art therapy sessions, they are still at risk of harm, including further exploitation, due to their vulnerability, high rates of victim sensitivity, and the mental health consequences of their traumatic experiences. While some argue that the benefits of sublimation and art therapy for human trafficking survivors make sharing their art worth the risk, anti-trafficking organizations and supporters of such art exhibitions have responsibilities to be trauma informed.

  9. A metafluid exhibiting strong optical magnetism.

    PubMed

    Sheikholeslami, Sassan N; Alaeian, Hadiseh; Koh, Ai Leen; Dionne, Jennifer A

    2013-09-11

    Advances in the field of metamaterials have enabled unprecedented control of light-matter interactions. Metamaterial constituents support high-frequency electric and magnetic dipoles, which can be used as building blocks for new materials capable of negative refraction, electromagnetic cloaking, strong visible-frequency circular dichroism, and enhancing magnetic or chiral transitions in ions and molecules. While all metamaterials to date have existed in the solid-state, considerable interest has emerged in designing a colloidal metamaterial or "metafluid". Such metafluids would combine the advantages of solution-based processing with facile integration into conventional optical components. Here we demonstrate the colloidal synthesis of an isotropic metafluid that exhibits a strong magnetic response at visible frequencies. Protein-antibody interactions are used to direct the solution-phase self-assembly of discrete metamolecules comprised of silver nanoparticles tightly packed around a single dielectric core. The electric and magnetic response of individual metamolecules and the bulk metamaterial solution are directly probed with optical scattering and spectroscopy. Effective medium calculations indicate that the bulk metamaterial exhibits a negative effective permeability and a negative refractive index at modest fill factors. This metafluid can be synthesized in large-quantity and high-quality and may accelerate development of advanced nanophotonic and metamaterial devices.

  10. Molecular dynamics simulation of a tumorigenic benzo[a]pyrene metabolite bound to DNA at a single strand-double strand junction

    SciTech Connect

    Singh, S.B.; Li, B.; Shapiro, R.

    1994-12-31

    It is widely believed that cancer can be initiated when certain biochemically activated chemical substances bind to DNA to produce a covalently linked adduct. Attachment of the substance to DNA can affect the DNA shape, leading to unfortunate biological consequences. These may include replication errors, which could be among the events that start the cellular processes ultimately yielding malignant tumors. Consequently, an understanding at the molecular level of how the DNA shape is affected by such chemicals is critical to understanding the primary event in chemical carcinogenesis. If one could establish structural hallmarks that distinguish DNA bound by a malignant chemical from DNA bound by a benign one, it might ultimately be possible to employ computational tools, instead of bacterial or animal testing, to screen chemical substances for mutagenic and tumorigenic potential.

  11. Disorder in Milk Proteins: α-Lactalbumin. Part B. A Multifunctional Whey Protein Acting as an Oligomeric Molten Globular "Oil Container" in the Anti-Tumorigenic Drugs, Liprotides.

    PubMed

    Uversky, Vladimir N; Permyakov, Serge E; Breydo, Leonid; Redwan, Elrashdy M; Almehdar, Hussein A; Permyakov, Eugene A

    2016-07-15

    This is a second part of the three-part article from a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. We continue to describe α-lactalbumin, a small globular Ca2+-binding protein, which besides being one of the two components of lactose synthase that catalyzes the final step of the lactose biosynthesis in the lactating mammary gland, possesses a multitude of other functions. In fact, recent studies indicated that some partially folded forms of this protein possess noticeable bactericidal activity and other forms might be related to induction of the apoptosis of tumor cells. In its anti-tumorigenic function, oligomeric α-lactalbumin serves as a founding member of a new family of anticancer drugs termed liprotides (for lipids and partially denatured proteins), where an oligomeric molten globular protein acts as an "oil container" or cargo for the delivery of oleic acid to the cell membranes.

  12. 17 CFR 229.601 - (Item 601) Exhibits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... by reference, the exhibits required in the exhibit table shall be filed as indicated, as part of the... exhibit table. The exhibit index shall indicate, by handwritten, typed, printed, or other legible form of... index is located. For a description of each of the exhibits included in the exhibit table, see...

  13. Doxycycline-Regulated p16(MTS1) Expression Suppresses the Anchorage-Independence and Tumorigenicity of Breast Cancer Cell Lines that Lack Endogenous p16.

    PubMed

    Todd, Maria C; Langan, Thomas A; Sclafani, Robert A

    2017-01-01

    The RB pathway controls the critical transition from G1 into S phase of the mammalian cell cycle. Deregulation of the RB pathway by means of RB or p16 inactivation has been implicated in the development of virtually all human cancers. Such findings have led to the view that the loss of RB-mediated regulation at the G1/S checkpoint is a precondition for human malignancy. Our analysis of the RB-positive MCF-7 and ZR75.1 breast cancer cell lines revealed a lack of endogenous p16 protein expression as a result of the homozygous deletion and methylation of the p16 gene at the CDKN2A locus, respectively. We employed the TET-OFF inducible expression system to investigate the effects of non-growth inhibitory levels of functional p16 protein upon the in vitro and in vivo transformed properties of the MCF-7 and ZR75.1 cell lines. Stable transfectants of MCF-7 and ZR75.1 cells were isolated that expressed different levels of p16 protein in the absence of doxycycline (DOX) but continued to proliferate in culture. Transfectants that expressed modest levels of p16 (relative to SV40 T antigen-transformed HBL-100 breast epithelial cells) demonstrated a marked suppression of anchorage-independent growth in soft agar. Further, the induction of moderate and high levels of p16 (relative to HBL-100) resulted in the suppression of tumorigenicity of both MCF-7 and ZR75.1 cells as assayed by injection into nude mice. From these data, we concluded that RB pathway restoration by non-growth inhibitory levels of p16 protein was sufficient to revert breast cancer cells to a non-transformed and non-tumorigenic state.

  14. Doxycycline-Regulated p16MTS1 Expression Suppresses the Anchorage-Independence and Tumorigenicity of Breast Cancer Cell Lines that Lack Endogenous p16

    PubMed Central

    Todd, Maria C; Langan, Thomas A; Sclafani, Robert A

    2017-01-01

    The RB pathway controls the critical transition from G1 into S phase of the mammalian cell cycle. Deregulation of the RB pathway by means of RB or p16 inactivation has been implicated in the development of virtually all human cancers. Such findings have led to the view that the loss of RB-mediated regulation at the G1/S checkpoint is a precondition for human malignancy. Our analysis of the RB-positive MCF-7 and ZR75.1 breast cancer cell lines revealed a lack of endogenous p16 protein expression as a result of the homozygous deletion and methylation of the p16 gene at the CDKN2A locus, respectively. We employed the TET-OFF inducible expression system to investigate the effects of non-growth inhibitory levels of functional p16 protein upon the in vitro and in vivo transformed properties of the MCF-7 and ZR75.1 cell lines. Stable transfectants of MCF-7 and ZR75.1 cells were isolated that expressed different levels of p16 protein in the absence of doxycycline (DOX) but continued to proliferate in culture. Transfectants that expressed modest levels of p16 (relative to SV40 T antigen-transformed HBL-100 breast epithelial cells) demonstrated a marked suppression of anchorage-independent growth in soft agar. Further, the induction of moderate and high levels of p16 (relative to HBL-100) resulted in the suppression of tumorigenicity of both MCF-7 and ZR75.1 cells as assayed by injection into nude mice. From these data, we concluded that RB pathway restoration by non-growth inhibitory levels of p16 protein was sufficient to revert breast cancer cells to a non-transformed and non-tumorigenic state. PMID:28243323

  15. Long-term exposures to low doses of silver nanoparticles enhanced in vitro malignant cell transformation in non-tumorigenic BEAS-2B cells.

    PubMed

    Choo, Wun Hak; Park, Cho Hee; Jung, Shi Eun; Moon, Byeonghak; Ahn, Huiyeon; Ryu, Jung Seok; Kim, Keun-Soo; Lee, Yong Hwa; Yu, Il Je; Oh, Seung Min

    2016-12-01

    To predict carcinogenic potential of AgNPs on the respiratory system, BEAS-2B cells (human bronchial epithelial cells) were chronically exposed to low- and non-cytotoxic dose (0.13 and 1.33μg/ml) of AgNPs for 4months (#40 passages). To assess malignant cell transformation of chronic exposure to AgNPs, several bioassays including anchorage independent agar colony formation, cell migration/invasion assay, and epithelial-mesenchymal transition (EMT) were performed in BEAS-2B cells. Chronic exposure to AgNPs showed a significant increase of anchorage independent agar colony formation and cell migration/invasion. EMT, which is the loss of epithelial markers (E-Cadherin and Keratin) and the gain of mesenchymal marker (N-cadherin and Vimentin), was induced by chronic exposure to AgNPs. These responses indicated that chronic exposure to AgNPs could acquire characteristics of tumorigenic cells from normal BEAS-2B cells. In addition, caspase-3, p-p53, p-p38, and p-JNK were significantly decreased, while p-ERK1/2 was significantly increased. MMP-9 related to cell migration/invasion was upregulated, while a MMP-9 inhibitor, TIMP-1 was down-regulated. These results indicated that BEAS-2B cells exposed to AgNPs could induce anti-apoptotic response/anoikis resistance, and cell migration/invasion by complex regulation of MAPK kinase (p38, JNK, and ERK) and p53 signaling pathways. Therefore, we suggested that long-term exposure to low-dose of AgNPs could enhance malignant cell transformation in non-tumorigenic BEAS-2B cells. Our findings provide useful information needed to assess the carcinogenic potential of AgNPs.

  16. Supercomputing meets seismology in earthquake exhibit

    ScienceCinema

    Blackwell, Matt; Rodger, Arthur; Kennedy, Tom

    2016-07-12

    When the California Academy of Sciences created the "Earthquake: Evidence of a Restless Planet" exhibit, they called on Lawrence Livermore to help combine seismic research with the latest data-driven visualization techniques. The outcome is a series of striking visualizations of earthquakes, tsunamis and tectonic plate evolution. Seismic-wave research is a core competency at Livermore. While most often associated with earthquakes, the research has many other applications of national interest, such as nuclear explosion monitoring, explosion forensics, energy exploration, and seismic acoustics. For the Academy effort, Livermore researchers simulated the San Andreas and Hayward fault events at high resolutions. Such calculations require significant computational resources. To simulate the 1906 earthquake, for instance, visualizing 125 seconds of ground motion required over 1 billion grid points, 10,000 time steps, and 7.5 hours of processor time on 2,048 cores of Livermore's Sierra machine.

  17. Supercomputing meets seismology in earthquake exhibit

    SciTech Connect

    Blackwell, Matt; Rodger, Arthur; Kennedy, Tom

    2013-10-03

    When the California Academy of Sciences created the "Earthquake: Evidence of a Restless Planet" exhibit, they called on Lawrence Livermore to help combine seismic research with the latest data-driven visualization techniques. The outcome is a series of striking visualizations of earthquakes, tsunamis and tectonic plate evolution. Seismic-wave research is a core competency at Livermore. While most often associated with earthquakes, the research has many other applications of national interest, such as nuclear explosion monitoring, explosion forensics, energy exploration, and seismic acoustics. For the Academy effort, Livermore researchers simulated the San Andreas and Hayward fault events at high resolutions. Such calculations require significant computational resources. To simulate the 1906 earthquake, for instance, visualizing 125 seconds of ground motion required over 1 billion grid points, 10,000 time steps, and 7.5 hours of processor time on 2,048 cores of Livermore's Sierra machine.

  18. Virtual auditorium concepts for exhibition halls

    NASA Astrophysics Data System (ADS)

    Evans, Jack; Himmel, Chad; Knight, Sarah

    2002-11-01

    Many communities lack good performance facilities for symphonic music, opera, dramatic and musical arts, but have basic convention, exhibition or assembly spaces. It should be possible to develop performance space environments within large multipurpose facilities that will accommodate production and presentation of dramatic arts. Concepts for moderate-cost, temporary enhancements that transform boxy spaces into more intimate, acoustically articulated venues will be presented. Acoustical criteria and design parameters will be discussed in the context of creating a virtual auditorium within the building envelope. Physical, economic, and logistical limitations affect implementation. Sound reinforcement system augmentation can supplement the room conversion. Acceptable control of reflection patterns, reverberation, and to some extent, ambient noise, may be achieved with an array of nonpermanent reflector and absorber elements. These elements can sculpture an enclosure to approach the shape and acoustic characteristics of an auditorium. Plan and section illustrations will be included.

  19. A Traveling Exhibit of Cassini Image Science

    NASA Astrophysics Data System (ADS)

    Burns, Joseph A.; Hedman, M. M.; Tiscareno, M. S.; Ebel, D.; Mac Low, M.; Lovett, L. E.; Burns, J. K.; Schaff, N.; Bilson, E. M.

    2007-10-01

    An exhibit of Cassini's images will open at NYC's American Museum of Natural History in March 2008 and then visit the Johnson Art Museum (Cornell) throughout fall 2008, including during next year's DPS. It is under consideration by several other venues in the States and overseas. The exhibit will feature 40-50 images, ranging from letter size to large posters, taken by remote-sensing instruments aboard Cassini and Huygens. Photos will be organized into a half-dozen thematic clusters (e.g., organized by celestial target or by physical process); a panel will introduce each grouping with individual images identified briefly. The Saturn system is a perfect vehicle to educate citizens about planetary science and origins. The images’ beauty should capture the public's attention, allowing us to then engage their curiosity about the relevant science. Among the Saturn system's broad suite of objects are Enceladus and Titan, two satellites of astrobiological interest; moreover, the rings display many processes active in other astrophysical disks. Several auxiliary ideas will be implemented. In Ithaca, we will project images at night against the museum's sand-colored exterior walls. A 10-12 minute musical composition has been commissioned from Roberto Sierra to open the show. We will encourage school children to participate in a human orrery circling the museum and will seek volunteers to participate in several Saturnalia. At Cornell we will involve the university and local communities, by taping their reactions to the images’ exquisite beauty as well as to their scientific content. Cassini will be the E/PO focus of next year's DPS meeting; those materials will be employed throughout the fall at New York schools and be available to travel with the show. We intend to work with NYC partners to offer teacher credits for associated weekend courses. We will produce classroom materials, including a DVD, for teacher use.

  20. Application of an imaging system to a museum exhibition for developing interactive exhibitions

    NASA Astrophysics Data System (ADS)

    Miyata, Kimiyoshi; Inoue, Yuka; Takiguchi, Takahiro; Tsumura, Norimichi; Nakaguchi, Toshiya; Miyake, Yoichi

    2009-10-01

    In the National Museum of Japanese History, 215,759 artifacts are stored and used for research and exhibitions. In museums, due to the limitation of space in the galleries, a guidance system is required to satisfy visitors' needs and to enhance their understanding of the artifacts. We introduce one exhibition using imaging technology to improve visitors' understanding of a kimono (traditional Japanese clothing) exhibition. In the imaging technology introduced, one data projector, one display with touch panel interface, and magnifiers were used as exhibition tools together with a real kimono. The validity of this exhibition method was confirmed by results from a visitors' interview survey. Second, to further develop the interactive guidance system, an augmented reality system that consisted of cooperation between the projector and a digital video camera was also examined. A white paper board in the observer's hand was used as a projection screen and also as an interface to control the images projected on the board. The basic performance of the proposed system was confirmed; however continuous development was necessary for applying the system to actual exhibitions.

  1. Exhibition of Stochastic Resonance in Vestibular Perception

    NASA Technical Reports Server (NTRS)

    Galvan-Garza, R. C.; Clark, T. K.; Merfeld, D. M.; Bloomberg, J. J.; Oman, C. M.; Mulavara, A. P.

    2016-01-01

    Astronauts experience sensorimotor changes during spaceflight, particularly during G-transitions. Post flight sensorimotor changes include spatial disorientation, along with postural and gait instability that may degrade operational capabilities of the astronauts and endanger the crew. A sensorimotor countermeasure that mitigates these effects would improve crewmember safety and decrease risk. The goal of this research is to investigate the potential use of stochastic vestibular stimulation (SVS) as a technology to improve sensorimotor function. We hypothesize that low levels of SVS will improve sensorimotor perception through the phenomenon of stochastic resonance (SR), when the response of a nonlinear system to a weak input signal is enhanced by the application of a particular nonzero level of noise. This study aims to advance the development of SVS as a potential countermeasure by 1) demonstrating the exhibition of stochastic resonance in vestibular perception, a vital component of sensorimotor function, 2) investigating the repeatability of SR exhibition, and 3) determining the relative contribution of the semicircular canals (SCC) and otolith (OTO) organs to vestibular perceptual SR. A constant current stimulator was used to deliver bilateral bipolar SVS via electrodes placed on each of the mastoid processes, as previously done. Vestibular perceptual motion recognition thresholds were measured using a 6-degree of freedom MOOG platform and a 150 trial 3-down/1-up staircase procedure. In the first test session, we measured vestibular perceptual thresholds in upright roll-tilt at 0.2 Hz (SCC+OTO) with SVS ranging from 0-700 µA. In a second test session a week later, we re-measured roll-tilt thresholds with 0, optimal (from test session 1), and 1500 µA SVS levels. A subset of these subjects, plus naive subjects, participated in two additional test sessions in which we measured thresholds in supine roll-rotation at 0.2 Hz (SCC) and upright y-translation at 1 Hz

  2. Plant shoots exhibit synchronized oscillatory motions

    PubMed Central

    Ciszak, Marzena; Masi, Elisa; Baluška, František; Mancuso, Stefano

    2016-01-01

    ABSTRACT In animals, the ability to move has evolved as an important means of protection from predators and for enhancing nutrient uptake. In the animal kingdom, an individual's movements may become coordinated with those of other individuals that belong to the same group, which leads, for example, to the beautiful collective patterns that are observed in flocks of birds and schools of fish or in animal migration. Land plants, however, are fixed to the ground, which limits their movement and, apparently, their interactions and collective behaviors. We show that emergent maize plants grown in a group exhibit synchronized oscillatory motions that may be in-phase or anti-phase. These oscillations occur in short bursts and appear when the leaves rupture from the coleoptile tip. The appearance of these oscillations indicates an abrupt increase in the plant growth rate, which may be associated with a sudden change in the energy uptake for photosynthesis. Our results suggest that plant shoots behave as a complex network of biological oscillators, interacting through biophysical links, e.g. chemical substances or electric signals. PMID:27829981

  3. Agitated Honeybees Exhibit Pessimistic Cognitive Biases

    PubMed Central

    Bateson, Melissa; Desire, Suzanne; Gartside, Sarah E.; Wright, Geraldine A.

    2011-01-01

    Summary Whether animals experience human-like emotions is controversial and of immense societal concern [1–3]. Because animals cannot provide subjective reports of how they feel, emotional state can only be inferred using physiological, cognitive, and behavioral measures [4–8]. In humans, negative feelings are reliably correlated with pessimistic cognitive biases, defined as the increased expectation of bad outcomes [9–11]. Recently, mammals [12–16] and birds [17–20] with poor welfare have also been found to display pessimistic-like decision making, but cognitive biases have not thus far been explored in invertebrates. Here, we ask whether honeybees display a pessimistic cognitive bias when they are subjected to an anxiety-like state induced by vigorous shaking designed to simulate a predatory attack. We show for the first time that agitated bees are more likely to classify ambiguous stimuli as predicting punishment. Shaken bees also have lower levels of hemolymph dopamine, octopamine, and serotonin. In demonstrating state-dependent modulation of categorization in bees, and thereby a cognitive component of emotion, we show that the bees' response to a negatively valenced event has more in common with that of vertebrates than previously thought. This finding reinforces the use of cognitive bias as a measure of negative emotional states across species and suggests that honeybees could be regarded as exhibiting emotions. Video Abstract PMID:21636277

  4. Rotating pigment cells exhibit an intrinsic chirality.

    PubMed

    Yamanaka, Hiroaki; Kondo, Shigeru

    2015-01-01

    In multicellular organisms, cell properties, such as shape, size and function are important in morphogenesis and physiological functions. Recently, 'cellular chirality' has attracted attention as a cellular property because it can cause asymmetry in the bodies of animals. In recent in vitro studies, the left-right bias of cellular migration and of autonomous arrangement of cells under some specific culture conditions were discovered. However, it is difficult to identify the molecular mechanism underlying their intrinsic chirality because the left-right bias observed to date is subtle or is manifested in the stable orientation of cells. Here, we report that zebrafish (Danio rerio) melanophores exhibit clear cellular chirality by unidirectional counterclockwise rotational movement under isolated conditions without any special settings. The chirality is intrinsic to melanophores because the direction of the cellular rotation was not affected by the type of extracellular matrix. We further found that the cellular rotation was generated as a counter action of the clockwise movement of actin cytoskeleton. It suggested that the mechanism that directs actin cytoskeleton in the clockwise direction is pivotal for determining cellular chirality.

  5. Virtual Exhibition and Fruition of Archaeological Finds

    NASA Astrophysics Data System (ADS)

    Manferdini, A. M.; Garagnani, S.

    2011-09-01

    During the last two decades, since digital technologies have become more sophisticated in acquiring real data and building faithful copies of them, their improvements have suggested interesting applications in the field of valorisation of Historical, Cultural and Artistic Heritage, with significant consequences in the share and widespread of knowledge. But although several technologies and methodologies for 3d digitization have recently been developed and improved, the lack of a standard procedure and the costs connected to their use still doesn't encourage the systematic digital acquisition of wide collections and heritage. The aim of this paper is to show the state of the art of a project whose aim is to provide a methodology and a procedure to create digital reproductions of artefacts for Institutions called to preserve, manage and enhance the fruition of archaeological finds inside museums or through digital exhibitions. Our project's aim is to find the most suitable procedure to digitally acquire archaeo logical artefacts that usually have small dimensions and have very complex and detailed surfaces. Within our methodology, particular attention has been paid to the use of widely shared and open-source visualization systems that enhance the involvement of the user by emphasizing three-dimensional characteristics of artefacts through virtual reality.

  6. Plant shoots exhibit synchronized oscillatory motions.

    PubMed

    Ciszak, Marzena; Masi, Elisa; Baluška, František; Mancuso, Stefano

    2016-01-01

    In animals, the ability to move has evolved as an important means of protection from predators and for enhancing nutrient uptake. In the animal kingdom, an individual's movements may become coordinated with those of other individuals that belong to the same group, which leads, for example, to the beautiful collective patterns that are observed in flocks of birds and schools of fish or in animal migration. Land plants, however, are fixed to the ground, which limits their movement and, apparently, their interactions and collective behaviors. We show that emergent maize plants grown in a group exhibit synchronized oscillatory motions that may be in-phase or anti-phase. These oscillations occur in short bursts and appear when the leaves rupture from the coleoptile tip. The appearance of these oscillations indicates an abrupt increase in the plant growth rate, which may be associated with a sudden change in the energy uptake for photosynthesis. Our results suggest that plant shoots behave as a complex network of biological oscillators, interacting through biophysical links, e.g. chemical substances or electric signals.

  7. Quantum Nonlocal Boxes Exhibit Stronger Distillability

    NASA Astrophysics Data System (ADS)

    Høyer, Peter; Rashid, Jibran

    2013-06-01

    The hypothetical nonlocal box (NLB) proposed by Popescu and Rohrlich allows two spatially separated parties, Alice and Bob, to exhibit stronger than quantum correlations. If the generated correlations are weak, they can sometimes be distilled into a stronger correlation by repeated applications of the NLB. Motivated by the limited distillability of NLBs, we initiate here a study of the distillation of correlations for nonlocal boxes that output quantum states rather than classical bits (qNLBs). We propose a new protocol for distillation and show that it asymptotically distills a class of correlated quantum nonlocal boxes to the value (1)/(2)(3√ {3}+1) ≈ 3.098076, whereas in contrast, the optimal non-adaptive parity protocol for classical nonlocal boxes asymptotically distills only to the value 3.0. We show that our protocol is an optimal non-adaptive protocol for 1, 2 and 3 qNLB copies by constructing a matching dual solution for the associated primal semidefinite program (SDP). We conclude that qNLBs are a stronger resource for nonlocality than NLBs. The main premise that develops from this conclusion is that the NLB model is not the strongest resource to investigate the fundamental principles that limit quantum nonlocality. As such, our work provides strong motivation to reconsider the status quo of the principles that are known to limit nonlocal correlations under the framework of qNLBs rather than NLBs.

  8. Marine bacteria exhibit a bipolar distribution.

    PubMed

    Sul, Woo Jun; Oliver, Thomas A; Ducklow, Hugh W; Amaral-Zettler, Linda A; Sogin, Mitchell L

    2013-02-05

    The microbial cosmopolitan dispersion hypothesis often invoked to explain distribution patterns driven by high connectivity of oceanographic water masses and widespread dispersal ability has never been rigorously tested. By using a global marine bacterial dataset and iterative matrix randomization simulation, we show that marine bacteria exhibit a significantly greater dispersal limitation than predicted by our null model using the "everything is everywhere" tenet with no dispersal limitation scenario. Specifically, marine bacteria displayed bipolar distributions (i.e., species occurring exclusively at both poles and nowhere else) significantly less often than in the null model. Furthermore, we observed fewer taxa present in both hemispheres but more taxa present only in a single hemisphere than expected under the null model. Each of these trends diverged further from the null expectation as the compared habitats became more geographically distant but more environmentally similar. Our meta-analysis supported a latitudinal gradient in bacterial diversity with higher richness at lower latitudes, but decreased richness toward the poles. Bacteria in the tropics also demonstrated narrower latitudinal ranges at lower latitudes and relatively larger ranges in higher latitudes, conforming to the controversial macroecological pattern of the "Rapoport rule." Collectively, our findings suggest that bacteria follow biogeographic patterns more typical of macroscopic organisms, and that dispersal limitation, not just environmental selection, likely plays an important role. Distributions of microbes that deliver critical ecosystem services, particularly those in polar regions, may be vulnerable to the same impacts that environmental stressors, climate warming, and degradation in habitat quality are having on biodiversity in animal and plant species.

  9. Waves in geomaterials exhibiting negative stiffness behaviour

    NASA Astrophysics Data System (ADS)

    Esin, Maxim; Dyskin, Arcady; Pasternak, Elena

    2016-04-01

    Negative stiffness denotes the type of material behaviour when the force applied to the body decreases the body's deformation increases. Some geomaterials, for instance, rocks, demonstrate behaviour of this type at certain loads: during the compression tests the loading curves exhibit descending branch (post-peak softening). One of the possible mechanisms of the negative stiffness appearance in geomaterials is rotation of non-spherical grains. It is important to emphasize that in this case the descending branch may be reversible given that the testing machine is stiff enough (in general case it means an importance of boundary conditions). Existence of geomaterials with a negative modulus associated with rotations may have significant importance. In particular, important is understanding of the wave propagation in such materials. We study the stability of geomaterials with negative stiffness inclusions and wave propagation in it using two approaches: Cosserat continuum and discrete mass-spring models. In both cases we consider the rotational degrees of freedom in addition to the conventional translational ones. We show that despite non positiveness of the energy the materials with negative stiffness elements can be stable if certain conditions are met. In the case of Cosserat continuum the Cosserat shear modulus (the modulus relating the non-symmetrical part of shear stress and internal rotations) is allowed to assume negative values as long as its value does not exceed the value of the standard (positive) shear modulus. In the case of discrete mass-spring systems (with translational and rotational springs) the concentration of negative stiffness springs and the absolute values of negative spring stiffness are limited. The critical concentration when the system loses stability and the amplitude of the oscillations tends to infinity is equal to 1/2 and 3/5 for two- and three-dimensional cases respectively.

  10. Progastrin overexpression imparts tumorigenic/metastatic potential to embryonic epithelial cells: phenotypic differences between transformed and non-transformed stem cells

    PubMed Central

    Sarkar, Shubhashish; Kantara, Carla; Ortiz, Ixiu; Swiercz, Rafal; Kuo, Joyce; Davey, Robert; Escobar, Kenneth; Ullrich, Robert; Singh, Pomila

    2012-01-01

    We recently reported that overexpression of progastrin in embryonic epithelial cells (HEKmGAS-cells) increased proliferation of the cells, compared to that of control HEKC-cells. Here we report the novel finding that tumorigenic and metastatic potential of HEKmGAS cells is also increased significantly, compared to that of HEKC cells. Cell-surface associated annexinA2 (CS-ANXA2) binds progastrin and is over-expressed on cancer-cells, allowing us to successfully use fluorescently-labeled progastrin-peptide for enumerating metastatic lesions of transformed/cancer cells in vivo. Next, we examined the hypothesis that increased tumorigenic/metastatic potential of isogenic HEKmGAS vs HEKC cells maybe due to transformed-phenotype of stem-cells. FACSorting/FACScanning of cells demonstrated significant increases in percent DCLK1/Lgr5 positive stem-cells, co-expressing CD44/CS-ANXA2, in HEKmGAS vs HEKC-cells. Distinct differences were noted in morphology of HEKC vs HEKmGAS spheroidal growths on non-adherent cultures (selective for stem cells). HEKC-spheroids were rounded with distinct perimeters (basement membranes?), while HEKmGAS-spheroids were amorphous, with no perimeters. Relative levels of DCLK1/Lgr5/CD44 and AnnexinA2/β-catenin/pNFκBp65/metalloproteinases were significantly increased in HEKmGAS vs HEKC-cells, growing either as mono-layer cultures, 3D-spheroids (in vitro), or xenografts (in vivo). Interestingly, HEKC-cells enriched for CS-ANXA2, developed amorphous spheroids, while down-regulation of ANXA2 in HEKmGAS-clones, resulted in loss of matrixmetalloproteinases and re-formation of rounded spheroids, suggesting high levels of CS-ANXA2/matrixmetalloproteinases may impact spheroid morphology. Down-regulation of DCLK1 significantly attenuated activation of β-catenin, with loss of proliferation of HEKmGAS and HEKC-cells, suggesting DCLK1 is required for maintaining proliferation of cells. Conclusions Our results suggest the novel possibility that transformed stem

  11. Development of Exhibit on Arctic Climate Change Called The Arctic: A Friend Acting Strangely Exhibition

    SciTech Connect

    Stauffer, Barbara W.

    2006-04-01

    The exhibition, The Arctic: A Friend Acting Strangely, was developed at the Smithsonian Institution’s National Museum of Natural History (NMNH) as a part of the museum’s Forces of Change exhibit series on global change. It opened to the public in Spring 2006, in conjunction with another Forces of Change exhibit on the Earth’s atmosphere called Change Is in the Air. The exhibit was a 2000 square-foot presentation that explored the forces and consequences of the changing Arctic as documented by scientists and native residents alike. Native peoples of the Arctic have always lived with year-to-year fluctuations in weather and ice conditions. In recent decades, they have witnessed that the climate has become unpredictable, the land and sea unfamiliar. An elder in Arctic Canada recently described the weather as uggianaqtuq —an Inuit word that can suggest strange, unexpected behavior, sometimes described as that of “a friend acting strangely.” Scientists too have been documenting dramatic changes in the Arctic. Air temperatures have warmed over most—though not all—of the Arctic since the 1950s; Arctic precipitation may have increased by as much as 8%; seasonal melting of the Greenland Ice Sheet has increased on average by 16% since 1979; polar-orbiting satellites have measured a 15¬–20% decline in sea ice extent since the 1970s; aircraft reconnaissance and ship observations show a steady decrease in sea ice since the 1950s. In response to this warming, plant distributions have begun to shift and animals are changing their migration routes. Some of these changes may have beneficial effects while others may bring hardship or have costly implications. And, many scientists consider arctic change to be a ‘bell-weather’ for large-scale changes in other regions of the world. The exhibition included text, photos artifacts, hands-on interactives and other exhibitry that illustrated the changes being documented by indigenous people and scientists alike.

  12. 37 CFR 1.95 - Copies of exhibits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... COMMERCE GENERAL RULES OF PRACTICE IN PATENT CASES National Processing Provisions Models, Exhibits, Specimens § 1.95 Copies of exhibits. Copies of models or other physical exhibits will not ordinarily be furnished by the Office, and any model or exhibit in an application or patent shall not be taken from...

  13. 37 CFR 1.95 - Copies of exhibits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... COMMERCE GENERAL RULES OF PRACTICE IN PATENT CASES National Processing Provisions Models, Exhibits, Specimens § 1.95 Copies of exhibits. Copies of models or other physical exhibits will not ordinarily be furnished by the Office, and any model or exhibit in an application or patent shall not be taken from...

  14. 29 CFR 2204.202 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 9 2012-07-01 2012-07-01 false Net worth exhibit. 2204.202 Section 2204.202 Labor... COMMISSION Information Required From Applicants § 2204.202 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant as of the date specified by § 2204.105(c). The exhibit...

  15. 29 CFR 2204.202 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 9 2011-07-01 2011-07-01 false Net worth exhibit. 2204.202 Section 2204.202 Labor... COMMISSION Information Required From Applicants § 2204.202 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant as of the date specified by § 2204.105(c). The exhibit...

  16. 29 CFR 2204.202 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 9 2014-07-01 2014-07-01 false Net worth exhibit. 2204.202 Section 2204.202 Labor... COMMISSION Information Required From Applicants § 2204.202 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant as of the date specified by § 2204.105(c). The exhibit...

  17. 29 CFR 2204.202 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 9 2013-07-01 2013-07-01 false Net worth exhibit. 2204.202 Section 2204.202 Labor... COMMISSION Information Required From Applicants § 2204.202 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant as of the date specified by § 2204.105(c). The exhibit...

  18. EGCG-targeted p57/KIP2 reduces tumorigenicity of oral carcinoma cells: Role of c-Jun N-terminal kinase

    SciTech Connect

    Yamamoto, Tetsuya; Digumarthi, Hari; Aranbayeva, Zina; Wataha, John; Lewis, Jill; Messer, Regina; Qin, Haiyan; Dickinson, Douglas; Osaki, Tokio; Schuster, George S.; Hsu, Stephen

    2007-11-01

    The green tea polyphenol epigallocatechin-3-gallate (EGCG) regulates gene expression differentially in tumor and normal cells. In normal human primary epidermal keratinocytes (NHEK), one of the key mediators of EGCG action is p57/KIP2, a cyclin-dependent kinase (CDK) inhibitor. EGCG potently induces p57 in NHEK, but not in epithelial cancer cells. In humans, reduced expression of p57 often is associated with advanced tumors, and tumor cells with inactivated p57 undergo apoptosis when exposed to EGCG. The mechanism of p57 induction by EGCG is not well understood. Here, we show that in NHEK, EGCG-induces p57 via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. In p57-negative tumor cells, JNK signaling mediates EGCG-induced apoptosis, and exogenous expression of p57 suppresses EGCG-induced apoptosis via inhibition of c-Jun N-terminal kinase (JNK). We also found that restoration of p57 expression in tumor cells significantly reduced tumorigenicity in athymic mice. These results suggest that p57 expression may be an useful indicator for the clinical course of cancers, and could be potentially useful as a target for cancer therapies.

  19. Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor beta 1.

    PubMed Central

    Gerwin, B I; Spillare, E; Forrester, K; Lehman, T A; Kispert, J; Welsh, J A; Pfeifer, A M; Lechner, J F; Baker, S J; Vogelstein, B

    1992-01-01

    Loss of normal functions and gain of oncogenic functions when the p53 tumor suppressor gene is mutated are considered critical events in the development of the majority of human cancers. Human bronchial epithelial cells (BEAS-2B) provide an in vitro model system to study growth, differentiation, and neoplastic transformation of progenitor cells of lung carcinoma. When wild-type (WT) or mutant (MT; codon 143Val-Ala) human p53 cDNA was transfected into nontumorigenic BEAS-2B cells, we observed that (i) transfected WT p53 suppresses and MT p53 enhances the colony-forming efficiency of these cells, (ii) MT p53 increases resistance to transforming growth factor beta 1, and (iii) clones of MT p53 transfected BEAS-2B cells are tumorigenic when inoculated into athymic nude mice. These results are consistent with the hypothesis that certain mutations in p53 may function in multistage lung carcinogenesis by reducing the responsiveness of bronchial epithelial cells to negative growth factors. Images PMID:1557382

  20. Differential expression of thrombospondin (THBS1) in tumorigenic and nontumorigenic prostate epithelial cells in response to a chromatin-binding soy peptide.

    PubMed

    Galvez, Alfredo F; Huang, Liping; Magbanua, Mark M J; Dawson, Kevin; Rodriguez, Raymond L

    2011-01-01

    The chemopreventive properties of the chromatin-binding soy peptide, lunasin, are well documented, but its mechanism of action is unclear. To elucidate the mechanism by which lunasin reduces tumor foci formation in cultured mammalian cells, nontumorigenic (RWPE-1) and tumorigenic (RWPE-2) human prostate epithelial cells were treated with lunasin followed by gene expression profiling and characterization of the chromatin acetylation status for certain chemopreventive genes. The genes HIF1A, PRKAR1A, TOB1, and THBS1 were upregulated by lunasin in RWPE-1 but not in RWPE-2 cells. Using histone acetyltransferase (HAT) assays with acid-extracted histones as templates, we showed that lunasin specifically inhibited H4K8 acetylation while enhanced H4K16 acetylation catalyzed by HAT enzymes p300, PCAF, and HAT1A. These results suggest a novel mechanism for lunasin-dependent upregulation of gene expression. Chromatin immunoprecipitation (ChIP) revealed hypoacetylation of H4K16 in RWPE-2 cells, specifically at the 5' end of THBS1 containing a CpG island. Moreover, bisulfite PCR (BSP) and subsequent DNA sequencing indicated that this CpG island was hypomethylated in RWPE-1 but hypermethylated in RWPE-2 cells. Histone hypoacetylation and DNA hypermethylation in the 5' region of THBS1 may explain the inability of lunasin to upregulate this gene in RWPE-2 cells.

  1. Acquisition of multidrug resistance by L1210 leukemia cells decreases their tumorigenicity and enhances their susceptibility to the host immune response.

    PubMed

    Martín-Orozco, Elena; Ferragut, José Antonio; Garcia-Peñarrubia, Pilar; Ferrer-Montiel, Antonio

    2005-04-01

    The use of antineoplastic drugs for cancer treatment is frequently associated with the acquisition of a multidrug-resistant (MDR) phenotype that renders tumoural cells insensitive to antineoplastics. It remains elusive whether the acquisition of the MDR phenotype alters immunological parameters that could influence the cell sensitivity to an eventual host immune response. We report that immunisation of syngeneic mice with gamma-irradiated L1210S (parental line) and L1210R (MDR phenotype) cells results in a significant rejection of subsequently implanted L1210R-based tumours, but not of the L1210S ones. Notably, L1210R tumours display a twofold reduction in vivo proliferative capacity and are less aggressive in terms of mouse survival than their sensitive counterparts. Also, analysis of surface expression of molecules involved in antigen presentation and cytokine activity revealed a slight increase in IFN-gamma receptor expression, a decrease of Fas molecule, and a fourfold up-regulation of MHC class I molecules in L1210R cells. Nonetheless, both cell lines were able to induce a cytotoxic response in syngeneic mice and were equally susceptible to cytotoxicity by splenic cells. Together, these findings indicate that acquisition of drug resistance by L1210 cells is accompanied by pleiotropic changes that result in reduced tumour proliferative capacity and tumorigenicity in syngeneic mice. Hence, immunological studies of MDR tumours may assist in the design of specific therapeutic strategies that complement current chemotherapy treatments.

  2. The Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential

    PubMed Central

    Iglesias, Juan Manuel; Leis, Olatz; Pérez Ruiz, Estíbaliz; Gumuzio Barrie, Juan; Garcia-Garcia, Francisco; Aduriz, Ariane; Beloqui, Izaskun; Hernandez-Garcia, Susana; Lopez-Mato, Maria Paz; Dopazo, Joaquin; Pandiella, Atanasio; Menendez, Javier A.; Martin, Angel Garcia

    2014-01-01

    The striking similarity displayed at the mechanistic level between tumorigenesis and the generation of induced pluripotent stem cells and the fact that genes and pathways relevant for embryonic development are reactivated during tumor progression highlights the link between pluripotency and cancer. Based on these observations, we tested whether it is possible to use a pluripotency-associated transcriptional reporter, whose activation is driven by the SRR2 enhancer from the Sox2 gene promoter (named S4+ reporter), to isolate cancer stem cells (CSCs) from breast cancer cell lines. The S4+ pluripotency transcriptional reporter allows the isolation of cells with enhanced tumorigenic potential and its activation was switched on and off in the cell lines studied, reflecting a plastic cellular process. Microarray analysis comparing the populations in which the reporter construct is active versus inactive showed that positive cells expressed higher mRNA levels of cytokines (IL-8, IL-6, TNF) and genes (such as ATF3, SNAI2, and KLF6) previously related with the CSC phenotype in breast cancer. PMID:25414831

  3. Suppression of tumorigenicity of breast cancer cells by transfer of human chromosome 17 does not require transferred BRCA1 and p53 genes.

    PubMed

    Theile, M; Hartmann, S; Scherthan, H; Arnold, W; Deppert, W; Frege, R; Glaab, F; Haensch, W; Scherneck, S

    1995-02-02

    A number of candidate tumor suppressor genes located on the human chromosome 17 are thought to have a role to play in the development of breast cancer. In addition to the p53 gene on 17p13.1 and the BRCA1 gene mapped to 17q12-21, other chromosomal regions for tumor suppressor genes have been suggested to exist on 17p13.3 and both the central and the distal parts of 17q, although definitive functional proof of their involvement in breast cancer tumorigenesis is still lacking. In this report we show that microcell transfer of a human chromosome 17 into wild-type p53 breast cancer cells CAL51 results in loss of tumorigenicity and anchorage-independent growth, changes in cell morphology and a reduction of cell growth rates of the neo-selected microcell hybrids. In the hybrid cells, which express the p53 wild-type protein, only the p- and the distal parts of the q arm of donor chromosome 17 are transferred. Thus, our results provide functional evidence for the presence of one or more tumor suppressor gene(s) on chromosome 17, which are distinct from the p53 and the BRCA1 genes.

  4. Elimination of Tumorigenic Stem Cells from Differentiated Progeny and Selection of Definitive Endoderm Reveals a Pdx1+ Foregut Endoderm Stem Cell Lineage

    PubMed Central

    Kahan, Brenda; Magliocca, Joseph; Merriam, Fabiola; Treff, Nathan; Budde, Melisa; Nelson, Jeffrey; Browning, Victoria; Ziehr, Benjamin; Odorico, Jon

    2011-01-01

    Embryonic stem cell (ESC) derivatives offer promise for generating clinically useful tissues for transplantation, yet the specter of producing tumors in patients remains a significant concern. We have developed a simple method that eliminates the tumorigenic potential from differentiated ESC cultures of murine and human origin while purifying lineage-restricted, definitive endoderm-committed cells. A three-stage scheme utilizing magnetic bead sorting and specific antibodies to remove undifferentiated ESCs and extraembryonic endoderm cells, followed by positive selection of definitive endoderm cells on the basis of epithelial cell adhesion molecule (EpCAM) expression, was used to isolate a population of EpCAM+SSEA1−SSEA3− cells. Sorted cells do not form teratomas after transplantation into immunodeficient mice, but display gene and protein expression profiles indicative of definitive endoderm cells. Sorted cells could be subsequently expanded in vitro and further differentiated to express key pancreas specification proteins. In vivo transplantation of sorted cells resulted in small, benign tissues that uniformly express PDX1. These studies describe a straightforward method without genetic manipulation that eliminates the risk of teratoma formation from ESC differentiated derivatives. Significantly, enriched populations isolated by this method appear to be lineage-restricted definitive endoderm cells with limited proliferation capacity. PMID:21130058

  5. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signaling

    PubMed Central

    Chandler, Ronald L.; Damrauer, Jeffrey S.; Raab, Jesse R.; Schisler, Jonathan C.; Wilkerson, Matthew D.; Didion, John P.; Starmer, Joshua; Serber, Daniel; Yee, Della; Xiong, Jessie; Darr, David B.; Pardo-Manuel de Villena, Fernando; Kim, William Y.; Magnuson, Terry

    2014-01-01

    Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis. PMID:25625625

  6. Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer

    PubMed Central

    Thakur, Ravi; Trivedi, Rachana; Rastogi, Namrata; Singh, Manisha; Mishra, Durga Prasad

    2015-01-01

    Cancer stem cells (CSCs) are responsible for aggressive tumor growth, metastasis and therapy resistance. In this study, we evaluated the effects of Shikonin (Shk) on breast cancer and found its anti-CSC potential. Shk treatment decreased the expression of various epithelial to mesenchymal transition (EMT) and CSC associated markers. Kinase profiling array and western blot analysis indicated that Shk inhibits STAT3, FAK and Src activation. Inhibition of these signaling proteins using standard inhibitors revealed that STAT3 inhibition affected CSCs properties more significantly than FAK or Src inhibition. We observed a significant decrease in cell migration upon FAK and Src inhibition and decrease in invasion upon inhibition of STAT3, FAK and Src. Combined inhibition of STAT3 with Src or FAK reduced the mammosphere formation, migration and invasion more significantly than the individual inhibitions. These observations indicated that the anti-breast cancer properties of Shk are due to its potential to inhibit multiple signaling proteins. Shk also reduced the activation and expression of STAT3, FAK and Src in vivo and reduced tumorigenicity, growth and metastasis of 4T1 cells. Collectively, this study underscores the translational relevance of using a single inhibitor (Shk) for compromising multiple tumor-associated signaling pathways to check cancer metastasis and stem cell load. PMID:25973915

  7. A network of clinically and functionally relevant genes is involved in the reversion of the tumorigenic phenotype of MDA-MB-231 breast cancer cells after transfer of human chromosome 8.

    PubMed

    Seitz, Susanne; Frege, Renate; Jacobsen, Anja; Weimer, Jörg; Arnold, Wolfgang; von Haefen, Clarissa; Niederacher, Dieter; Schmutzler, Rita; Arnold, Norbert; Scherneck, Siegfried

    2005-01-27

    Several investigations have supposed that tumor suppressor genes might be located on human chromosome 8. We used microcell-mediated transfer of chromosome 8 into MDA-MB-231 breast cancer cells and generated independent hybrids with strongly reduced tumorigenic potential. Loss of the transferred chromosome results in reappearance of the malignant phenotype. Expression analysis identified a set of 109 genes (CT8-ps) differentially expressed in microcell hybrids as compared to the tumorigenic MDA-MB-231 and rerevertant cells. Of these, 44.9% are differentially expressed in human breast tumors. The expression pattern of CT8-ps was associated with prognostic factors such as tumor size and grading as well as loss of heterozygosity at the short arm of chromosome 8. We identified CT8-ps networks suggesting that these genes act cooperatively to cause reversion of tumorigenicity in MDA-MB-231 cells. Our findings provide a conceptual basis and experimental system to identify and evaluate genes and gene networks involved in the development and/or progression of breast cancer.

  8. A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene.

    PubMed Central

    Markowitz, S D; Myeroff, L; Cooper, M J; Traicoff, J; Kochera, M; Lutterbaugh, J; Swiriduk, M; Willson, J K

    1994-01-01

    We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation. Images PMID:8132740

  9. Frequent Attenuation of the WWOX Tumor Suppressor in Osteosarcoma is Associated with Increased Tumorigenicity and Aberrant RUNX2 Expression

    PubMed Central

    Kurek, Kyle; Del Mare, Sara; Salah, Zaidoun; Abdeen, Suhaib; Sadiq, Hussain; Lee, Sukhee; Gaudio, Eugenio; Zanesi, Nicola; Jones, Kevin B.; DeYoung, Barry; Amir, Gail; Gebhardt, Mark; Warman, Matthew; Stein, Gary S.; Stein, Janet L.; Lian, Jane B.; Aqeilan, Rami I.

    2011-01-01

    The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P< 0.0001). Compared to the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels, relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorgenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas Runx2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease. PMID:20530675

  10. Numb-like (NumbL) downregulation increases tumorigenicity, cancer stem cell-like properties and resistance to chemotherapy

    PubMed Central

    García-Heredia, José M.; Sivianes, Eva M. Verdugo; Lucena-Cacace, Antonio; Molina-Pinelo, Sonia; Carnero, Amancio

    2016-01-01

    NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool. PMID:27613838

  11. 7 CFR Exhibit C to Subpart C of... - Checklist of Visual Exhibits and Documentation for RRH, RCH, and LH Proposals

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false Checklist of Visual Exhibits and Documentation for... Part 1924—Checklist of Visual Exhibits and Documentation for RRH, RCH, and LH Proposals U.S. Department... exhibit lists visual exhibits and documentation necessary for FmHA or its successor agency under...

  12. 48 CFR 204.7105 - Contract exhibits and attachments.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... attachments. 204.7105 Section 204.7105 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS... 204.7105 Contract exhibits and attachments. Follow the procedures at PGI 204.7105 for use and numbering of contract exhibits and attachments....

  13. 32 CFR 705.25 - Navy Exhibit Center.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... AND OFFICIAL RECORDS PUBLIC AFFAIRS REGULATIONS § 705.25 Navy Exhibit Center. (a) The center is a... mission is to produce, transport and display U.S. Navy exhibits throughout the United States. It...

  14. 32 CFR 705.25 - Navy Exhibit Center.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... AND OFFICIAL RECORDS PUBLIC AFFAIRS REGULATIONS § 705.25 Navy Exhibit Center. (a) The center is a... mission is to produce, transport and display U.S. Navy exhibits throughout the United States. It...

  15. 32 CFR 705.25 - Navy Exhibit Center.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... AND OFFICIAL RECORDS PUBLIC AFFAIRS REGULATIONS § 705.25 Navy Exhibit Center. (a) The center is a... mission is to produce, transport and display U.S. Navy exhibits throughout the United States. It...

  16. Weight lifting can facilitate appreciative comprehension for museum exhibits.

    PubMed

    Yamada, Yuki; Harada, Shinya; Choi, Wonje; Fujino, Rika; Tokunaga, Akinobu; Gao, Yueyun; Miura, Kayo

    2014-01-01

    Appreciation of exhibits in a museum can be equated to a virtual experience of lives in the contexts originally surrounding the exhibits. Here we focus on the importance of weight information, and hence tested whether experiencing a weight during museum exhibit appreciation affects the beholders' satisfaction and recognition memory for the exhibits. An experiment was performed at a museum exhibiting skeletal preparations of animals. We used nine preparations and prepared four weight stimuli as weight cues in accordance with the actual weight of four of the preparations: Remaining five preparations was displayed without weight stimuli. In the cued condition, participants were asked to lift up the weight stimuli during their observation of the four exhibits. In the uncued condition, participants observed the exhibits without touching the weight stimuli. After observation of the exhibits, the participants responded to a questionnaire that measured their impressions of the exhibits and the museum, and performed a recognition test on the exhibits. Results showed that memory performance was better and viewing duration was longer with weight lifting instruction than without instruction. A factor analysis on the questionnaires revealed four factors (likeability, contentment, value, and quality). A path analysis showed indirect effects of viewing duration on memory performance and willingness-to-pay (WTP) for the museum appreciation through the impression factors. Our findings provide insight into a new interactive exhibition that enables long appreciation producing positive effects on visitors' impression, memory, and value estimation for exhibits.

  17. 14 CFR Appendix to Part 1274 - Listing of Exhibits

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Listing of Exhibits Appendix to Part 1274 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION COOPERATIVE AGREEMENTS WITH COMMERCIAL FIRMS Pt. 1274, App. Appendix to Part 1274—Listing of Exhibits Exhibit A to Part...

  18. 14 CFR Appendix to Part 1274 - Listing of Exhibits

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Listing of Exhibits Appendix to Part 1274 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION COOPERATIVE AGREEMENTS WITH COMMERCIAL FIRMS Pt. 1274, App. Appendix to Part 1274—Listing of Exhibits Exhibit A to Part...

  19. 14 CFR Appendix to Subpart A of... - Listing of Exhibits

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Listing of Exhibits Appendix to Subpart A of Part 1260 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS General Pt. 1260, Subpt. A, App. Appendix to Subpart A of Part 1260—Listing of Exhibits Exhibit...

  20. A Phenomenological Investigation of Science Center Exhibition Developers' Expertise Development

    ERIC Educational Resources Information Center

    Young, Denise L.

    2012-01-01

    The purpose of this study was to examine the exhibition developer role in the context of United States (U.S.) science centers, and more specifically, to investigate the way science center exhibition developers build their professional expertise. This research investigated how successfully practicing exhibition developers described their current…

  1. African Past: Migrant Present. A Guide to the Exhibition.

    ERIC Educational Resources Information Center

    Twining, Mary Arnold; Roark-Calnek, Sue

    This exhibit guide describes an exhibition of African folk arts produced by seasonal migrant farmworkers in western New York State. Workers come from the American South, Haiti, Puerto Rico, and Jamaica. The exhibition pieces were collected through the BOCES Geneseo Migrant Center's Folk Arts Program and Creative Artists Migrant Program Services…

  2. A Major Children's Educational Art Exhibit: An Evaluative Case Study.

    ERIC Educational Resources Information Center

    Schlenk, George W.; Shrock, Sharon A.

    Results of a case study of an exhibit of art and artifacts designed for children are presented. The focus of the study was to apply the principles of instructional-message design to the evaluation of the exhibit. The exhibit, "Art Inside Out: Exploring Art and Culture through Time," was displayed at the Art Institute of Chicago. Textual…

  3. 76 FR 68808 - Culturally Significant Objects Imported for Exhibition

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-07

    ... Exhibition Determinations: ``Transition to Christianity: Art of Late Antiquity, 3rd-7th Century AD'' SUMMARY... objects to be included in the exhibition ``Transition to Christianity: Art of Late Antiquity, 3rd-7th Century AD,'' imported from abroad for temporary exhibition within the United States, are of...

  4. 49 CFR 826.22 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 7 2013-10-01 2013-10-01 false Net worth exhibit. 826.22 Section 826.22... Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of the applicant...

  5. 49 CFR 6.19 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Net worth exhibit. 6.19 Section 6.19... PROCEEDINGS Information Required from Applicants § 6.19 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant and any affiliates (as defined in this part) when...

  6. 45 CFR 13.11 - Net worth exhibits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false Net worth exhibits. 13.11 Section 13.11 Public... TO JUSTICE ACT IN AGENCY PROCEEDINGS Information Required from Applicants § 13.11 Net worth exhibits. (a) Each applicant must provide with its application a detailed exhibit showing the net worth of...

  7. 31 CFR 6.9 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false Net worth exhibit. 6.9 Section 6.9... EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 6.9 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  8. 17 CFR 201.42 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 2 2013-04-01 2013-04-01 false Net worth exhibit. 201.42... Regulations Pertaining to the Equal Access to Justice Act § 201.42 Net worth exhibit. (a) Each applicant... a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  9. 17 CFR 201.42 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 3 2014-04-01 2014-04-01 false Net worth exhibit. 201.42... Regulations Pertaining to the Equal Access to Justice Act § 201.42 Net worth exhibit. (a) Each applicant... a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  10. 31 CFR 6.9 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Net worth exhibit. 6.9 Section 6.9... EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 6.9 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  11. 45 CFR 13.11 - Net worth exhibits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Net worth exhibits. 13.11 Section 13.11 Public... TO JUSTICE ACT IN AGENCY PROCEEDINGS Information Required from Applicants § 13.11 Net worth exhibits. (a) Each applicant must provide with its application a detailed exhibit showing the net worth of...

  12. 39 CFR 960.10 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 39 Postal Service 1 2013-07-01 2013-07-01 false Net worth exhibit. 960.10 Section 960.10 Postal... JUSTICE ACT IN POSTAL SERVICE PROCEEDINGS Information Required From Applicants § 960.10 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  13. 12 CFR 1071.201 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 8 2013-01-01 2013-01-01 false Net worth exhibit. 1071.201 Section 1071.201... Information Required from Applicants § 1071.201 Net worth exhibit. (a) The application shall also include a detailed exhibit showing that the applicant's net worth did not exceed $2 million (if an individual) or...

  14. 12 CFR 625.11 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 6 2011-01-01 2011-01-01 false Net worth exhibit. 625.11 Section 625.11 Banks... EXPENSES UNDER THE EQUAL ACCESS TO JUSTICE ACT Applicant Information Required § 625.11 Net worth exhibit... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  15. 49 CFR 826.22 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 7 2010-10-01 2010-10-01 false Net worth exhibit. 826.22 Section 826.22... Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of the applicant...

  16. 45 CFR 13.11 - Net worth exhibits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 1 2011-10-01 2011-10-01 false Net worth exhibits. 13.11 Section 13.11 Public... TO JUSTICE ACT IN AGENCY PROCEEDINGS Information Required from Applicants § 13.11 Net worth exhibits. (a) Each applicant must provide with its application a detailed exhibit showing the net worth of...

  17. 5 CFR 2610.202 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Net worth exhibit. 2610.202 Section 2610... THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 2610.202 Net worth exhibit. (a... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  18. 10 CFR 12.202 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Net worth exhibit. 12.202 Section 12.202 Energy NUCLEAR... Required From Applicants § 12.202 Net worth exhibit. (a) Each applicant, except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  19. 17 CFR 201.42 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 2 2012-04-01 2012-04-01 false Net worth exhibit. 201.42... Regulations Pertaining to the Equal Access to Justice Act § 201.42 Net worth exhibit. (a) Each applicant... a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  20. 7 CFR 1.191 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 1 2012-01-01 2012-01-01 false Net worth exhibit. 1.191 Section 1.191 Agriculture... § 1.191 Net worth exhibit. (a) An applicant, except a qualified tax-exempt organization or cooperative association, must provide with its application a detailed exhibit showing the net worth of the applicant...

  1. 17 CFR 201.42 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 2 2011-04-01 2011-04-01 false Net worth exhibit. 201.42... Regulations Pertaining to the Equal Access to Justice Act § 201.42 Net worth exhibit. (a) Each applicant... a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  2. 17 CFR 148.12 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Net worth exhibit. 148.12... Required from Applicants § 148.12 Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  3. 39 CFR 960.10 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Net worth exhibit. 960.10 Section 960.10 Postal... JUSTICE ACT IN POSTAL SERVICE PROCEEDINGS Information Required From Applicants § 960.10 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  4. 7 CFR 1.191 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 1 2014-01-01 2014-01-01 false Net worth exhibit. 1.191 Section 1.191 Agriculture... § 1.191 Net worth exhibit. (a) An applicant, except a qualified tax-exempt organization or cooperative association, must provide with its application a detailed exhibit showing the net worth of the applicant...

  5. 31 CFR 6.9 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false Net worth exhibit. 6.9 Section 6.9... EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 6.9 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  6. 45 CFR 13.11 - Net worth exhibits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Net worth exhibits. 13.11 Section 13.11 Public... TO JUSTICE ACT IN AGENCY PROCEEDINGS Information Required from Applicants § 13.11 Net worth exhibits. (a) Each applicant must provide with its application a detailed exhibit showing the net worth of...

  7. 19 CFR 212.11 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 3 2012-04-01 2012-04-01 false Net worth exhibit. 212.11 Section 212.11 Customs... IMPLEMENTATION OF THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 212.11 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  8. 49 CFR 6.19 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Net worth exhibit. 6.19 Section 6.19... PROCEEDINGS Information Required from Applicants § 6.19 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant and any affiliates (as defined in this part) when...

  9. 12 CFR 1071.201 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 9 2014-01-01 2014-01-01 false Net worth exhibit. 1071.201 Section 1071.201... Information Required from Applicants § 1071.201 Net worth exhibit. (a) The application shall also include a detailed exhibit showing that the applicant's net worth did not exceed $2 million (if an individual) or...

  10. 7 CFR 1.191 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false Net worth exhibit. 1.191 Section 1.191 Agriculture... § 1.191 Net worth exhibit. (a) An applicant, except a qualified tax-exempt organization or cooperative association, must provide with its application a detailed exhibit showing the net worth of the applicant...

  11. 49 CFR 826.22 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 7 2014-10-01 2014-10-01 false Net worth exhibit. 826.22 Section 826.22... Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of the applicant...

  12. 12 CFR 625.11 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Net worth exhibit. 625.11 Section 625.11 Banks... EXPENSES UNDER THE EQUAL ACCESS TO JUSTICE ACT Applicant Information Required § 625.11 Net worth exhibit... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  13. 5 CFR 2610.202 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Net worth exhibit. 2610.202 Section 2610... THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 2610.202 Net worth exhibit. (a... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  14. 39 CFR 960.10 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 39 Postal Service 1 2014-07-01 2014-07-01 false Net worth exhibit. 960.10 Section 960.10 Postal... JUSTICE ACT IN POSTAL SERVICE PROCEEDINGS Information Required From Applicants § 960.10 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  15. 10 CFR 12.202 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Net worth exhibit. 12.202 Section 12.202 Energy NUCLEAR... Required From Applicants § 12.202 Net worth exhibit. (a) Each applicant, except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  16. 5 CFR 2610.202 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Net worth exhibit. 2610.202 Section 2610... THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 2610.202 Net worth exhibit. (a... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  17. 12 CFR 625.11 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 7 2013-01-01 2013-01-01 false Net worth exhibit. 625.11 Section 625.11 Banks... EXPENSES UNDER THE EQUAL ACCESS TO JUSTICE ACT Applicant Information Required § 625.11 Net worth exhibit... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  18. 39 CFR 960.10 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 39 Postal Service 1 2012-07-01 2012-07-01 false Net worth exhibit. 960.10 Section 960.10 Postal... JUSTICE ACT IN POSTAL SERVICE PROCEEDINGS Information Required From Applicants § 960.10 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  19. 7 CFR 1.191 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Net worth exhibit. 1.191 Section 1.191 Agriculture... § 1.191 Net worth exhibit. (a) An applicant, except a qualified tax-exempt organization or cooperative association, must provide with its application a detailed exhibit showing the net worth of the applicant...

  20. 49 CFR 826.22 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 7 2011-10-01 2011-10-01 false Net worth exhibit. 826.22 Section 826.22... Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of the applicant...

  1. 17 CFR 148.12 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 1 2012-04-01 2012-04-01 false Net worth exhibit. 148.12... Required from Applicants § 148.12 Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  2. 49 CFR 1016.202 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 8 2011-10-01 2011-10-01 false Net worth exhibit. 1016.202 Section 1016.202... BY PARTIES TO BOARD ADJUDICATORY PROCEEDINGS Information Required From Applicants § 1016.202 Net worth exhibit. (a) Each applicant must provide with its application a detailed exhibit showing the...

  3. 49 CFR 1016.202 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 8 2014-10-01 2014-10-01 false Net worth exhibit. 1016.202 Section 1016.202... BY PARTIES TO BOARD ADJUDICATORY PROCEEDINGS Information Required From Applicants § 1016.202 Net worth exhibit. (a) Each applicant must provide with its application a detailed exhibit showing the...

  4. 14 CFR § 1262.202 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Net worth exhibit. § 1262.202 Section Â... ACT IN AGENCY PROCEEDINGS Information Required From Applicants § 1262.202 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defiined...

  5. 12 CFR 625.11 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 7 2012-01-01 2012-01-01 false Net worth exhibit. 625.11 Section 625.11 Banks... EXPENSES UNDER THE EQUAL ACCESS TO JUSTICE ACT Applicant Information Required § 625.11 Net worth exhibit... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  6. 49 CFR 1016.202 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Net worth exhibit. 1016.202 Section 1016.202... BY PARTIES TO BOARD ADJUDICATORY PROCEEDINGS Information Required From Applicants § 1016.202 Net worth exhibit. (a) Each applicant must provide with its application a detailed exhibit showing the...

  7. 49 CFR 826.22 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 7 2012-10-01 2012-10-01 false Net worth exhibit. 826.22 Section 826.22... Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of the applicant...

  8. 19 CFR 212.11 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 3 2013-04-01 2013-04-01 false Net worth exhibit. 212.11 Section 212.11 Customs... IMPLEMENTATION OF THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 212.11 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  9. 19 CFR 212.11 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 3 2014-04-01 2014-04-01 false Net worth exhibit. 212.11 Section 212.11 Customs... IMPLEMENTATION OF THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 212.11 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  10. 49 CFR 6.19 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Net worth exhibit. 6.19 Section 6.19... PROCEEDINGS Information Required from Applicants § 6.19 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant and any affiliates (as defined in this part) when...

  11. 49 CFR 1016.202 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 8 2012-10-01 2012-10-01 false Net worth exhibit. 1016.202 Section 1016.202... BY PARTIES TO BOARD ADJUDICATORY PROCEEDINGS Information Required From Applicants § 1016.202 Net worth exhibit. (a) Each applicant must provide with its application a detailed exhibit showing the...

  12. 19 CFR 212.11 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 3 2011-04-01 2011-04-01 false Net worth exhibit. 212.11 Section 212.11 Customs... IMPLEMENTATION OF THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 212.11 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  13. 17 CFR 201.42 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Net worth exhibit. 201.42... Regulations Pertaining to the Equal Access to Justice Act § 201.42 Net worth exhibit. (a) Each applicant... a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  14. 31 CFR 6.9 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false Net worth exhibit. 6.9 Section 6.9... EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 6.9 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  15. 31 CFR 6.9 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false Net worth exhibit. 6.9 Section 6.9... EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 6.9 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  16. 49 CFR 6.19 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Net worth exhibit. 6.19 Section 6.19... PROCEEDINGS Information Required from Applicants § 6.19 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant and any affiliates (as defined in this part) when...

  17. 5 CFR 2610.202 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Net worth exhibit. 2610.202 Section 2610... THE EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 2610.202 Net worth exhibit. (a... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  18. 49 CFR 1016.202 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 8 2013-10-01 2013-10-01 false Net worth exhibit. 1016.202 Section 1016.202... BY PARTIES TO BOARD ADJUDICATORY PROCEEDINGS Information Required From Applicants § 1016.202 Net worth exhibit. (a) Each applicant must provide with its application a detailed exhibit showing the...

  19. 47 CFR 1.1512 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 1 2013-10-01 2013-10-01 false Net worth exhibit. 1.1512 Section 1.1512... Applicants § 1.1512 Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of...

  20. 14 CFR 1262.202 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Net worth exhibit. 1262.202 Section 1262... AGENCY PROCEEDINGS Information Required From Applicants § 1262.202 Net worth exhibit. (a) Each applicant... detailed exhibit showing the net worth of the applicant and any affiliates (as defiined in §...

  1. 12 CFR 625.11 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 7 2014-01-01 2014-01-01 false Net worth exhibit. 625.11 Section 625.11 Banks... EXPENSES UNDER THE EQUAL ACCESS TO JUSTICE ACT Applicant Information Required § 625.11 Net worth exhibit... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  2. 47 CFR 1.1512 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 1 2014-10-01 2014-10-01 false Net worth exhibit. 1.1512 Section 1.1512... Applicants § 1.1512 Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of...

  3. 14 CFR 1262.202 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Net worth exhibit. 1262.202 Section 1262.202... PROCEEDINGS Information Required From Applicants § 1262.202 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant and any affiliates (as defiined in § 1262.104(f) when...

  4. 10 CFR 1023.311 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Net worth exhibit. 1023.311 Section 1023.311 Energy... Access to Justice Act Information Required from Applicants § 1023.311 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  5. 17 CFR 148.12 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 1 2011-04-01 2011-04-01 false Net worth exhibit. 148.12... Required from Applicants § 148.12 Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  6. 17 CFR 148.12 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 1 2013-04-01 2013-04-01 false Net worth exhibit. 148.12... Required from Applicants § 148.12 Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  7. 10 CFR 1023.311 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Net worth exhibit. 1023.311 Section 1023.311 Energy... Access to Justice Act Information Required from Applicants § 1023.311 Net worth exhibit. (a) Each... application a detailed exhibit showing the net worth of the applicant and any affiliates (as defined in §...

  8. 49 CFR 6.19 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false Net worth exhibit. 6.19 Section 6.19... PROCEEDINGS Information Required from Applicants § 6.19 Net worth exhibit. (a) Each applicant except a... exhibit showing the net worth of the applicant and any affiliates (as defined in this part) when...

  9. 10 CFR 12.202 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Net worth exhibit. 12.202 Section 12.202 Energy NUCLEAR... Required From Applicants § 12.202 Net worth exhibit. (a) Each applicant, except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  10. 47 CFR 1.1512 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 1 2012-10-01 2012-10-01 false Net worth exhibit. 1.1512 Section 1.1512... Applicants § 1.1512 Net worth exhibit. (a) Each applicant except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the net worth of...

  11. 10 CFR 12.202 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Net worth exhibit. 12.202 Section 12.202 Energy NUCLEAR... Required From Applicants § 12.202 Net worth exhibit. (a) Each applicant, except a qualified tax-exempt organization or cooperative association must provide with its application a detailed exhibit showing the...

  12. 14 CFR 1262.202 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Net worth exhibit. 1262.202 Section 1262... AGENCY PROCEEDINGS Information Required From Applicants § 1262.202 Net worth exhibit. (a) Each applicant... detailed exhibit showing the net worth of the applicant and any affiliates (as defiined in §...

  13. 39 CFR 960.10 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 39 Postal Service 1 2011-07-01 2011-07-01 false Net worth exhibit. 960.10 Section 960.10 Postal... JUSTICE ACT IN POSTAL SERVICE PROCEEDINGS Information Required From Applicants § 960.10 Net worth exhibit... with its application a detailed exhibit showing the net worth of the applicant and any affiliates...

  14. Online Cultural Heritage Exhibitions: A Survey of Strategic Issues

    ERIC Educational Resources Information Center

    Liew, Chern Li

    2006-01-01

    Purpose: This paper seeks to report findings from a study that looked at a range of strategic issues faced in the development, management and maintenance of online cultural heritage exhibitions. The study examined exhibitions from different types of cultural agencies and asked questions about whether, for instance, the exhibitions are part of the…

  15. Weight lifting can facilitate appreciative comprehension for museum exhibits

    PubMed Central

    Yamada, Yuki; Harada, Shinya; Choi, Wonje; Fujino, Rika; Tokunaga, Akinobu; Gao, YueYun; Miura, Kayo

    2014-01-01

    Appreciation of exhibits in a museum can be equated to a virtual experience of lives in the contexts originally surrounding the exhibits. Here we focus on the importance of weight information, and hence tested whether experiencing a weight during museum exhibit appreciation affects the beholders' satisfaction and recognition memory for the exhibits. An experiment was performed at a museum exhibiting skeletal preparations of animals. We used nine preparations and prepared four weight stimuli as weight cues in accordance with the actual weight of four of the preparations: Remaining five preparations was displayed without weight stimuli. In the cued condition, participants were asked to lift up the weight stimuli during their observation of the four exhibits. In the uncued condition, participants observed the exhibits without touching the weight stimuli. After observation of the exhibits, the participants responded to a questionnaire that measured their impressions of the exhibits and the museum, and performed a recognition test on the exhibits. Results showed that memory performance was better and viewing duration was longer with weight lifting instruction than without instruction. A factor analysis on the questionnaires revealed four factors (likeability, contentment, value, and quality). A path analysis showed indirect effects of viewing duration on memory performance and willingness-to-pay (WTP) for the museum appreciation through the impression factors. Our findings provide insight into a new interactive exhibition that enables long appreciation producing positive effects on visitors' impression, memory, and value estimation for exhibits. PMID:24782807

  16. FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma

    PubMed Central

    Zhou, Haiping; He, Feng; Mendelsohn, Cathy L.; Tang, Moon-shong; Huang, Chuanshu; Wu, Xue-Ru

    2016-01-01

    Missense mutations of fibroblast growth factor receptor 3 (FGFR3) occur in up to 80% of low-grade papillary urothelial carcinoma of the bladder (LGP-UCB) suggesting that these mutations are tumor drivers, although direct experimental evidence is lacking. Here we show that forced expression of FGFR3b-S249C, the most prevalent FGFR3 mutation in human LGP-UCB, in cultured urothelial cells resulted in slightly reduced surface translocation than wild-type FGFR3b, but nearly twice as much proliferation. When we expressed a mouse equivalent of this mutant (FGFR3b-S243C) in urothelia of adult transgenic mice in a tissue-specific and inducible manner, we observed significant activation of AKT and MAPK pathways. This was, however, not accompanied by urothelial proliferation or tumorigenesis over 12 months, due to compensatory tumor barriers in p16-pRB and p19-p53-p21 axes. Indeed, expressing FGFR3b-S249C in cultured human urothelial cells expressing SV40T, which functionally inactivates pRB/p53, markedly accelerated proliferation and cell-cycle progression. Furthermore, expressing FGFR3b-S243C in transgenic mouse urothelium expressing SV40T converted carcinoma-in-situ to high-grade papillary urothelial carcinoma. Together, our study provides new experimental evidence indicating that the FGFR3 mutations have very limited urothelial tumorigenicity and that these mutations must collaborate with other genetic events to drive urothelial tumorigenesis. PMID:27157475

  17. ET-11RESVERATROL REGULATES GLIOBLASTOMA AND GLIOBLASTOMA STEM-LIKE CELLS VIA ANTI-TUMORIGENIC AKT DEPHOSPHORYLATION AND p53 ACTIVATION

    PubMed Central

    Clark, Paul; Bhattacharya, Saswati; van Ginkel, Paul; Darjatmoko, Soesiawati; Elmayam, Ardem; Polans, Arthur; Kuo, John

    2014-01-01

    Resveratrol (RES), a natural non-toxic plant product, exerts broad anti-cancer effects. RES was investigated for efficacy against glioblastoma (GBM) and therapeutically resistant GBM stem-like cells (GSC) hypothesized to drive tumor recurrence. Patient-derived GSC lines (12.1, 22, 33, 44) isolated via marker-neutral sphere cultures in stem cell medium, and U87 glioma were treated with RES. Low RES (25 µM) achieved significant inhibition of U87 cell proliferation after 4 days compared to control vehicle (DMSO) treatment. RES also inhibited GSC sphere-forming ability, with 50% inhibitory concentrations (IC50) from 5-25 µM. Interestingly, both 12.1 and 22 GSC lines highly express stem cell markers and initiate focal orthotopic GBM xenografts in brains of immunodeficient mice, and were most sensitive to RES compared to 33 and 44 GSC lines that cause highly infiltrative xenografts. This suggests differential RES response by various GBM/GSC subtypes. In a Matrigel transwell assay, 50 µM RES significantly inhibited invasion (>50%) of both U87 and 44 GSCs. RES also altered GSC progenitor marker expression, with 50 µM RES inducing increased expression of neural differentiation markers GFAP (astrocyte) and βIII-tubulin (neuron) after 3 days on western immunoblotting. We observed the broad anti-tumorigenic RES effects against GBM/GSC by dephosphorylating oncogenic AKT and activating tumor suppressor p53. Quantitative PCR revealed RES activates a large p53 tumor suppressive gene network (PIGG8, CD95, TP53, and NOXA). In U87 flank xenografts, oral RES (50 mg/kg daily) significantly inhibited xenograft growth, and single intra-tumoral 1mg injections reduced tumor volume by >60% compared to injection of vehicle control. In conclusion, RES causes broad anti-GBM and anti-GSC effects via AKT dephosphorylation and p53 activation, and warrants further study as a non-toxic adjuvant GBM therapy.

  18. Cyclin D1 silencing suppresses tumorigenicity, impairs DNA double strand break repair and thus radiosensitizes androgen-independent prostate cancer cells to DNA damage

    PubMed Central

    Ju, Xiaoming; Vetuschi, Antonella; Sferra, Roberta; Casimiro, Mathew C.; Pompili, Simona; Festuccia, Claudio; Colapietro, Alessandro; Gaudio, Eugenio; Di Cesare, Ernesto; Tombolini, Vincenzo; Pestell, Richard G.

    2016-01-01

    Patients with hormone-resistant prostate cancer (PCa) have higher biochemical failure rates following radiation therapy (RT). Cyclin D1 deregulated expression in PCa is associated with a more aggressive disease: however its role in radioresistance has not been determined. Cyclin D1 levels in the androgen-independent PC3 and 22Rv1 PCa cells were stably inhibited by infecting with cyclin D1-shRNA. Tumorigenicity and radiosensitivity were investigated using in vitro and in vivo experimental assays. Cyclin D1 silencing interfered with PCa oncogenic phenotype by inducing growth arrest in the G1 phase of cell cycle and reducing soft agar colony formation, migration, invasion in vitro and tumor formation and neo-angiogenesis in vivo. Depletion of cyclin D1 significantly radiosensitizes PCa cells by increasing the RT-induced DNA damages by affecting the NHEJ and HR pathways responsible of the DNA double-strand break repair. Following treatment of cells with RT the abundance of a biomarker of DNA damage, γ-H2AX, was dramatically increased in sh-cyclin D1 treated cells compared to shRNA control. Concordant with these observations DNA-PKcs-activation and RAD51-accumulation, part of the DNA double-strand break repair machinery, were reduced in shRNA-cyclin D1 treated cells compared to shRNA control. We further demonstrate the physical interaction between CCND1 with activated-ATM, -DNA-PKcs and RAD51 is enhanced by RT. Finally, siRNA-mediated silencing experiments indicated DNA-PKcs and RAD51 are downstream targets of CCND1-mediated PCa cells radioresistance. In summary, these observations suggest that CCND1 is a key mediator of PCa radioresistance and could represent a potential target for radioresistant hormone-resistant PCa. PMID:26689991

  19. The CRISPR/Cas9 system efficiently reverts the tumorigenic ability of BCR/ABL in vitro and in a xenograft model of chronic myeloid leukemia.

    PubMed

    García-Tuñón, Ignacio; Hernández-Sánchez, María; Ordoñez, José Luis; Alonso-Pérez, Veronica; Álamo-Quijada, Miguel; Benito, Rocio; Guerrero, Carmen; Hernández-Rivas, Jesús María; Sánchez-Martín, Manuel

    2017-02-09

    CRISPR/Cas9 technology was used to abrogate p210 oncoprotein expression in the Boff-p210 cell line, a pro-B line derived from interlukin-3-dependent Baf/3, that shows IL-3-independence arising from the constitutive expression of BCR-ABL p210. Using this approach, pools of Boff-p210-edited cells and single edited cell-derived clones were obtained and functionally studied in vitro. The loss of p210 expression in Boff-p210 cells resulted in the loss of ability to grow in the absence of IL-3, as the Baf/3 parental line, showing significantly increased apoptosis levels. Notably, in a single edited cell-derived clone carrying a frame-shift mutation that prevents p210 oncoprotein expression, the effects were even more drastic, resulting in cell death. These edited cells were injected subcutaneously in immunosuppressed mice and tumor growth was followed for three weeks. BCR/ABL-edited cells developed smaller tumors than those originating from unedited Boff-p210 parental cells. Interestingly, the single edited cell-derived clone was unable to develop tumors, similar to what is observed with the parental Baf/3 cell line.CRISPR/Cas9 genomic editing technology allows the ablation of the BCR/ABL fusion gene, causing an absence of oncoprotein expression, and blocking its tumorigenic effects in vitro and in the in vivo xenograft model of CML. The future application of this approach in in vivo models of CML will allow us to more accurately assess the value of CRISPR/Cas9 technology as a new therapeutic tool that overcomes resistance to the usual treatments for CML patients.

  20. Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase

    PubMed Central

    Ormazábal, Cristina; Santos-Roncero, Matilde; Galán-Díez, Marta; Steegmann, Juan Luis; Figuera, Ángela; Arranz, Eva; Vizmanos, José Luis; Bueren, Juan A.; Río, Paula; Fernández-Ruiz, Elena

    2012-01-01

    Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2 in vivo. Together these findings suggest that adult and pediatric patients with BCR-ABL-negative leukemia and JAK2 overexpression may benefit from targeted therapies. PMID:22384256

  1. Cyclin D1 silencing suppresses tumorigenicity, impairs DNA double strand break repair and thus radiosensitizes androgen-independent prostate cancer cells to DNA damage.

    PubMed

    Marampon, Francesco; Gravina, Giovanni; Ju, Xiaoming; Vetuschi, Antonella; Sferra, Roberta; Casimiro, Mathew C; Pompili, Simona; Festuccia, Claudio; Colapietro, Alessandro; Gaudio, Eugenio; Di Cesare, Ernesto; Tombolini, Vincenzo; Pestell, Richard G

    2016-02-02

    Patients with hormone-resistant prostate cancer (PCa) have higher biochemical failure rates following radiation therapy (RT). Cyclin D1 deregulated expression in PCa is associated with a more aggressive disease: however its role in radioresistance has not been determined. Cyclin D1 levels in the androgen-independent PC3 and 22Rv1 PCa cells were stably inhibited by infecting with cyclin D1-shRNA. Tumorigenicity and radiosensitivity were investigated using in vitro and in vivo experimental assays. Cyclin D1 silencing interfered with PCa oncogenic phenotype by inducing growth arrest in the G1 phase of cell cycle and reducing soft agar colony formation, migration, invasion in vitro and tumor formation and neo-angiogenesis in vivo. Depletion of cyclin D1 significantly radiosensitizes PCa cells by increasing the RT-induced DNA damages by affecting the NHEJ and HR pathways responsible of the DNA double-strand break repair. Following treatment of cells with RT the abundance of a biomarker of DNA damage, γ-H2AX, was dramatically increased in sh-cyclin D1 treated cells compared to shRNA control. Concordant with these observations DNA-PKcs-activation and RAD51-accumulation, part of the DNA double-strand break repair machinery, were reduced in shRNA-cyclin D1 treated cells compared to shRNA control. We further demonstrate the physical interaction between CCND1 with activated-ATM, -DNA-PKcs and RAD51 is enhanced by RT. Finally, siRNA-mediated silencing experiments indicated DNA-PKcs and RAD51 are downstream targets of CCND1-mediated PCa cells radioresistance. In summary, these observations suggest that CCND1 is a key mediator of PCa radioresistance and could represent a potential target for radioresistant hormone-resistant PCa.

  2. Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells

    SciTech Connect

    Spink, Barbara C.; Bennett, James A.; Pentecost, Brian T.; Lostritto, Nicole; Englert, Neal A.; Benn, Geoffrey K.; Goodenough, Angela K.; Turesky, Robert J.; Spink, David C.

    2009-11-01

    The cumulative exposure to estrogens is an important determinant in the risk of breast cancer, yet the full range of mechanisms involving estrogens in the genesis and progression of breast cancer remains a subject of debate. Interactions of estrogens and environmental toxicants have received attention as putative factors contributing to carcinogenesis. Mechanistic studies have demonstrated interactions between estrogen receptor alpha (ERalpha) and the aryl hydrocarbon receptor (AhR), with consequences on the genes that they regulate. Many studies of ERalpha and AhR-mediated effects and crosstalk between them have focused on the initial molecular events. In this study, we investigated ERalpha- and AhR-mediated effects in long-term estrogen exposed (LTEE) MCF-7 human breast cancer cells, which were obtained by continuous culturing for at least 12 weeks in medium supplemented with 1 nM of 17beta-estradiol (E{sub 2}). With these LTEE cells and with parallel control cells cultured without E{sub 2} supplementation, we performed an extensive study of cytochrome P450 (CYP) induction, carcinogen bioactivation, global gene expression, and tumorigenicity in immunocompromised mice. We found that LTEE cells, in comparison with control cells, had higher levels of AhR mRNA and protein, greater responsiveness for AhR-regulated CYP1A1 and CYP1B1 induction, a 6-fold higher initial level of benzo(a)pyrene-DNA adducts as determined by liquid chromatography tandem mass spectrometry, marked differences in the expression of numerous genes, and a higher rate of E{sub 2}-dependent tumor growth as xenografts. These studies indicate that LTEE causes adaptive responses in MCF-7 cells, which may reflect processes that contribute to the overall carcinogenic effect of E{sub 2}.

  3. C-terminal truncated hepatitis B virus X protein regulates tumorigenicity, self-renewal and drug resistance via STAT3/Nanog signaling pathway.

    PubMed

    Ching, Rachel Hiu Ha; Sze, Karen Man Fong; Lau, Eunice Yuen Ting; Chiu, Yung-Tuen; Lee, Joyce Man Fong; Ng, Irene Oi Lin; Lee, Terence Kin Wah

    2017-02-08

    Hepatitis B virus (HBV) is a major risk factor of chronic liver disease and hepatocellular carcinoma (HCC). Random integration of HBV DNA into the host genome is frequent in HCC leading to truncation of the HBV DNA, particularly at the C-terminal end of the HBV X protein (HBx). C-terminally truncated HBx (HBx-ΔC) has been implicated in playing a pro-oncogenic role in hepatocarcinogenesis. However, the mechanism whereby HBx-ΔC1 contributes to hepatocarcinogenesis remains unclear. In this study, we investigated the functional role of HBx-ΔC1 in regulating liver cancer stem cell (CSC) properties. Using Tet-on inducible system, we found that HBx-ΔC1 enhanced CSC properties including self-renewal, tumorigenicity, chemoresistance, migration and expression of liver CSC markers, when compared with the full-length HBx counterpart and vector control. Interestingly, HBx-ΔC1 conferred resistance in HCC cells towards sorafenib treatment through suppression of apoptotic cascade. In addition, HBx-ΔC1 upregulated a panel of stemness genes, in which Nanog was found to be among the most significant one in both trasnfected cell lines. Consistently, Nanog was upregulated in human HCC samples which had HBx-ΔC1 expression. Furthermore, the induction of CSC properties by HBx-ΔC1 was via the Stat3/Nanog pathway, as administration of Stat3 inhibitor abolished the HBx-ΔC1-induced self-renewing capacity. In conclusion, our data suggest that HBx-ΔC1 enhances liver CSCs properties through Stat3/Nanog cascade, and provide a new insight for the therapeutic intervention for HBV-related HCC.

  4. Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing's sarcoma cells.

    PubMed

    Tirado, Oscar M; Mateo-Lozano, Silvia; Villar, Joaquín; Dettin, Luis E; Llort, Anna; Gallego, Soledad; Ban, Jozef; Kovar, Heinrich; Notario, Vicente

    2006-10-15

    Tumors of the Ewing's sarcoma family (ESFT), such as Ewing's sarcoma (EWS) and primitive neuroectodermal tumors (PNET), are highly aggressive malignancies predominantly affecting children and young adults. ESFT express chimeric transcription factors encoded by hybrid genes fusing the EWS gene with several ETS genes, most commonly FLI-1. EWS/FLI-1 proteins are responsible for the malignant phenotype of ESFT, but only few of their transcriptional targets are known. Using antisense and short hairpin RNA-mediated gene expression knockdown, array analyses, chromatin immunoprecipitation methods, and reexpression studies, we show that caveolin-1 (CAV1) is a new direct target of EWS/FLI-1 that is overexpressed in ESFT cell lines and tumor specimens and is necessary for ESFT tumorigenesis. CAV1 knockdown led to up-regulation of Snail and the concomitant loss of E-cadherin expression. Consistently, loss of CAV1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of EWS cell-derived tumors in nude mice xenografts, indicating that CAV1 promotes the malignant phenotype in EWS carcinogenesis. Reexpression of CAV1 or E-cadherin in CAV1 knockdown EWS cells rescued the oncogenic phenotype of the original EWS cells, showing that the CAV1/Snail/E-cadherin pathway plays a central role in the expression of the oncogenic transformation functions of EWS/FLI-1. Overall, these data identify CAV1 as a key determinant of the tumorigenicity of ESFT and imply that targeting CAV1 may allow the development of new molecular therapeutic strategies for ESFT patients.

  5. Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells

    PubMed Central

    Spink, Barbara C.; Bennett, James A.; Pentecost, Brian T.; Lostritto, Nicole; Englert, Neal A.; Benn, Geoffrey K.; Goodenough, Angela K.; Turesky, Robert J.; Spink, David C.

    2009-01-01

    The cumulative exposure to estrogens is an important determinant in the risk of breast cancer, yet the full range of mechanisms involving estrogens in the genesis and progression of breast cancer remains a subject of debate. Interactions of estrogens and environmental toxicants have received attention as putative factors contributing to carcinogenesis. Mechanistic studies have demonstrated interactions between estrogen receptor α (ERα) and the aryl hydrocarbon receptor (AhR), with consequences on the genes that they regulate. Many studies of ERα and AhR-mediated effects and crosstalk between them have focused on the initial molecular events. In this study, we investigated ERα- and AhR-mediated effects in long-term estrogen exposed (LTEE) MCF-7 human breast cancer cells, which were obtained by continuous culturing for at least 12 weeks in medium supplemented with 1 nM of 17β-estradiol (E2). With these LTEE cells and with parallel control cells cultured without E2 supplementation, we performed an extensive study of cytochrome P450 (CYP) induction, carcinogen bioactivation, global gene expression, and tumorigenicity in immunocompromised mice. We found that LTEE cells, in comparison with control cells, had higher levels of AhR mRNA and protein, greater responsiveness for AhR-regulated CYP1A1 and CYP1B1 induction, a 6-fold higher initial level of benzo(a)pyrene-DNA adducts as determined by liquid chromatography tandem mass spectrometry, marked differences in the expression of numerous genes, and a higher rate of E2-dependent tumor growth as xenografts. These studies indicate that LTEE causes adaptive responses in MCF-7 cells, which may reflect processes that contribute to the overall carcinogenic effect of E2. PMID:19619570

  6. Pig-a gene mutation and micronucleated reticulocyte induction in rats exposed to tumorigenic doses of the leukemogenic agents chlorambucil, thiotepa, melphalan, and 1,3-propane sultone.

    PubMed

    Dertinger, Stephen D; Phonethepswath, Souk; Avlasevich, Svetlana L; Torous, Dorothea K; Mereness, Jared; Cottom, John; Bemis, Jeffrey C; Macgregor, James T

    2014-05-01

    To evaluate whether blood-based genotoxicity endpoints can provide temporal and dose-response data within the low-dose carcinogenic range that could contribute to carcinogenic mode of action (MoA) assessments, we evaluated the sensitivity of flow cytometry-based micronucleus and Pig-a gene mutation assays at and below tumorigenic dose rate 50 (TD50) levels. The incidence of micronucleated reticulocytes (MN-RET) was used to evaluate chromosomal damage, and the frequency of CD59-negative reticulocytes (RET(CD59-) ) and erythrocytes (RBC(CD59-) ) served as phenotypic reporters of mutation at the X-linked Pig-a gene. Several leukemogenic agents with a presumed genotoxic MoA were studied. Specifically, male Sprague Dawley rats were treated via oral gavage for 28 days with chlorambucil, thiotepa, melphalan, and 1,3-propane sultone at doses corresponding to 0.33x, 1x, and 3x TD50, as well as at the maximum tolerated dose. Frequencies of MN-RET were determined at Days 4 and 29, and RET(CD59-) and RBC(CD59-) data were collected pretreatment as well as Days 15/16, 29, and 56/57. Dose-related increases were observed for each endpoint, and time to maximal effect was consistently: MN-RET < RET(CD59-)  < RBC(CD59-) . For each of the chemicals studied, the genotoxic events occurred long before tumors or preneoplastic lesions would be expected. Furthermore, in the case of Pig-a gene mutation, the responses were observed at or below the TD50 dose for three out of the four chemicals studied. These data illustrate the potential for quantitative blood-based analyses to provide dose-response and temporality information that relates genetic damage to cancer induction.

  7. [Review of the pharmaceutical exhibitions in the Meiji Era (Supplement)].

    PubMed

    Koyama, T

    1994-01-01

    The author described (Jpn. J. History Pharm. 16(1), 9-20 (1981) the Review of the Pharmaceutical Exhibitions in the Meiji era. But afterwards the author found there were omissions of three exhibitions. These are the Nagaoka, the Osaka, and the Akita Exhibitions. The Nagaoka Exhibition was organized by the Nagaoka Pharmacists Association in June, 1890. The Osaka Exhibition opened on Jan. 18, 1891 by Osaka Branch of the Pharmaceutical Society of Japan. The Akita Pharmaceutical Exhibition was held on Sept. 24-26, 1892, as the chief event of the opening ceremony of the Akita Drug-Trader Association, united pharmacists, druggists, and drug-manufacturers throughout Akita Prefecture. It is the most large-scaled of the three. The exhibits were 1,419, and the visitors were above 8,830. The planning originated with a young pharmacist Masayasu Hanyu.

  8. [Energy education exhibits for Insights El Paso Science Museum

    SciTech Connect

    Shubinski, R.

    1998-05-27

    The grant in question, DE-FG03-94ER75954, was awarded to Insights El Paso Science Museum to build key exhibits. These exhibits helped the Museum fulfill its mission to ``promote curiosity and stimulate interest by exploratory, entertaining, exciting, and participatory learning in a broad range of scientific disciplines to persons of all ages regionally and internationally.`` There are several current Board of Directors members who also were Board members during the grant period and who helped construct some of the exhibits. Through speaking with them and reviewing minutes of Board meetings during 1994, it has been determined that seven of the ten proposed exhibits were constructed, with an eighth exhibit constructed as an alternative. Photos of seven of the exhibits and preliminary sketches of some are attached. Following is a list of the constructed exhibits: Hot or Cold, Give and Take, Conduction, Convection, Sources of Energy, Wind Generator, Solar Tracker, and Perpetual Motion.

  9. MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells.

    PubMed

    Kwon, Yoojung; Kim, Youngmi; Eom, Sangkyung; Kim, Misun; Park, Deokbum; Kim, Hyuna; Noh, Kyeonga; Lee, Hansoo; Lee, Yun Sil; Choe, Jongseon; Kim, Young Myeong; Jeoung, Dooil

    2015-05-29

    Cyclooxgenase-2 (COX-2) knock-out mouse experiments showed that COX-2 was necessary for in vivo allergic inflammation, such as passive cutaneous anaphylaxis, passive systemic anaphylaxis, and triphasic cutaneous allergic reaction. TargetScan analysis predicted COX-2 as a target of miR-26a and miR-26b. miR-26a/-26b decreased luciferase activity associated with COX-2-3'-UTR. miR-26a/-26b exerted negative effects on the features of in vitro and in vivo allergic inflammation by targeting COX-2. ChIP assays showed the binding of HDAC3 and SNAIL, but not COX-2, to the promoter sequences of miR-26a and miR-26b. Cytokine array analysis showed that the induction of chemokines, such as MIP-2, in the mouse passive systemic anaphylaxis model occurred in a COX-2-dependent manner. ChIP assays showed the binding of HDAC3 and COX-2 to the promoter sequences of MIP-2. In vitro and in vivo allergic inflammation was accompanied by the increased expression of MIP-2. miR-26a/-26b negatively regulated the expression of MIP-2. Allergic inflammation enhanced the tumorigenic and metastatic potential of cancer cells and induced positive feedback involving cancer cells and stromal cells, such as mast cells, macrophages, and endothelial cells. miR-26a mimic and miR-26b mimic negatively regulated the positive feedback between cancer cells and stromal cells and the positive feedback among stromal cells. miR-26a/-26b negatively regulated the enhanced tumorigenic potential by allergic inflammation. COX-2 was necessary for the enhanced metastatic potential of cancer cells by allergic inflammation. Taken together, our results indicate that the miR26a/-26b-COX-2-MIP-2 loop regulates allergic inflammation and the feedback relationship between allergic inflammation and the enhanced tumorigenic and metastatic potential.

  10. Evolutionary Dynamics of Influenza A Viruses in US Exhibition Swine.

    PubMed

    Nelson, Martha I; Wentworth, David E; Das, Suman R; Sreevatsan, Srinand; Killian, Mary L; Nolting, Jacqueline M; Slemons, Richard D; Bowman, Andrew S

    2016-01-15

    The role of exhibition swine in influenza A virus transmission was recently demonstrated by >300 infections with influenza A(H3N2) variant viruses among individuals who attended agricultural fairs. Through active influenza A virus surveillance in US exhibition swine and whole-genome sequencing of 380 isolates, we demonstrate that exhibition swine are actively involved in the evolution of influenza A viruses, including zoonotic strains. First, frequent introduction of influenza A viruses from commercial swine populations provides new genetic diversity in exhibition pigs each year locally. Second, genomic reassortment between viruses cocirculating in exhibition swine increases viral diversity. Third, viral migration between exhibition swine in neighboring states demonstrates that movements of exhibition pigs contributes to the spread of genetic diversity. The unexpected frequency of viral exchange between commercial and exhibition swine raises questions about the understudied interface between these populations. Overall, the complexity of viral evolution in exhibition swine indicates that novel viruses are likely to continually reemerge, presenting threats to humans.

  11. 18. INTERIOR OF CIVIL RIGHTS INSTITUTE, MILESTONE GALLERY EXHIBITION OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. INTERIOR OF CIVIL RIGHTS INSTITUTE, MILESTONE GALLERY EXHIBITION OF THE SIXTEENTH STREET CHURCH, LOOKING NORTHWEST - Sixteenth Street Baptist Church, 1530 Sixth Avenue North, Birmingham, Jefferson County, AL

  12. Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2-epoxide isomers of dibenz[a,h]anthracene.

    PubMed

    Chang, Richard L; Wood, Alexander W; Huang, Mou Tuan; Xie, Jian Guo; Cui, Xiao Xing; Reuhl, Kenneth R; Boyd, D R; Lin, Yong; Shih, Weichung Joe; Balani, Suresh K; Yagi, Haruhiko; Jerina, Donald M; Conney, Allan H

    2013-09-01

    Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of Salmonella typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V-79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide-2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide-1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity. In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)-3β,4α-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin, whereas (+)-(3S,4S)-3α,4β-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice.

  13. HPV E7 contributes to the telomerase activity of immortalized and tumorigenic cells and augments E6-induced hTERT promoter function.

    PubMed

    Liu, Xuefeng; Roberts, Jeffrey; Dakic, Aleksandra; Zhang, Yiyu; Schlegel, Richard

    2008-06-05

    The E6 and E7 proteins of high-risk HPVs are both required for the immortalization of primary human keratinocytes and the maintenance of the malignant phenotype of HPV-positive cancer cell lines. Our previous studies have shown that E6 protein binds Myc protein and that both E6 and Myc associate with and cooperatively activate the hTERT promoter, thereby increasing cellular telomerase activity. In this study, we evaluated the role of E7 in the maintenance and activation of telomerase in immortalized and tumorigenic cells. siRNA knockdown of either E6 or E7 (or both) in HPV-immortalized cells or an HPV-positive cancer cell line reduced hTERT transcription and telomerase activity. Since telomerase was inhibited by E7 siRNA in cells that independently expressed the E6 and E7 genes, our results reveal an independent role for E7 in the maintenance of telomerase activity. However, E7 alone was insufficient to increase endogenous hTERT mRNA or telomerase activity, although it significantly augmented E6-induced hTERT transcription and telomerase activity. To further explore this apparent E7-induced promoter augmentation, we analyzed an exogenous hTERT core promoter in transduced keratinocytes. E7 alone induced the wt hTERT promoter and augmented E6-induced hTERT promoter activity. Mutation of the E2F site in the hTERT promoter abrogated the ability of E7 to induce the hTERT promoter or to enhance the ability of E6 to induce the promoter. Correspondingly, keratinocytes expressing E6 and a mutant E7 (defective for binding pRb pocket proteins) showed lower telomerase activity than cells expressing wt E6 and wt E7. Thus, HPV E7 plays a role in the maintenance of telomerase activity in stable cell lines and augments acute, E6-induced hTERT promoter activity.

  14. 7 CFR Exhibit A to Subpart A of... - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false A Exhibit A to Subpart A of Part 1902 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... SUPERVISED BANK ACCOUNTS Supervised Bank Accounts of Loan, Grant, and Other Funds Exhibit A to Subpart A...

  15. 7 CFR Exhibit A to Subpart A of... - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 12 2014-01-01 2013-01-01 true A Exhibit A to Subpart A of Part 1902 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... SUPERVISED BANK ACCOUNTS Supervised Bank Accounts of Loan, Grant, and Other Funds Exhibit A to Subpart A...

  16. 7 CFR Exhibits A-F to Subpart A... - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 14 2013-01-01 2013-01-01 false A Exhibits A-F to Subpart A of Part 1955 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Real and Chattel Property Exhibits A-F to Subpart A of Part 1955...

  17. 7 CFR Exhibits A-F to Subpart A... - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 14 2012-01-01 2012-01-01 false A Exhibits A-F to Subpart A of Part 1955 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Real and Chattel Property Exhibits A-F to Subpart A of Part 1955...

  18. 7 CFR Exhibit A to Subpart A of... - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 12 2011-01-01 2011-01-01 false A Exhibit A to Subpart A of Part 1902 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... SUPERVISED BANK ACCOUNTS Supervised Bank Accounts of Loan, Grant, and Other Funds Exhibit A to Subpart A...

  19. 7 CFR Exhibits A-F to Subpart A... - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 14 2014-01-01 2014-01-01 false A Exhibits A-F to Subpart A of Part 1955 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Real and Chattel Property Exhibits A-F to Subpart A of Part 1955...

  20. 7 CFR Exhibit A to Subpart A of... - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 12 2012-01-01 2012-01-01 false A Exhibit A to Subpart A of Part 1902 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... SUPERVISED BANK ACCOUNTS Supervised Bank Accounts of Loan, Grant, and Other Funds Exhibit A to Subpart A...

  1. 7 CFR Exhibits A-F to Subpart A... - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 14 2010-01-01 2009-01-01 true A Exhibits A-F to Subpart A of Part 1955 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Real and Chattel Property Exhibits A-F to Subpart A of Part 1955...

  2. 7 CFR Exhibit A to Subpart A of... - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 12 2013-01-01 2013-01-01 false A Exhibit A to Subpart A of Part 1902 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... SUPERVISED BANK ACCOUNTS Supervised Bank Accounts of Loan, Grant, and Other Funds Exhibit A to Subpart A...

  3. 7 CFR Exhibits A-F to Subpart A... - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 14 2011-01-01 2011-01-01 false A Exhibits A-F to Subpart A of Part 1955 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Real and Chattel Property Exhibits A-F to Subpart A of Part 1955...

  4. Data Collection Methods for Evaluating Museum Programs and Exhibitions

    ERIC Educational Resources Information Center

    Nelson, Amy Crack; Cohn, Sarah

    2015-01-01

    Museums often evaluate various aspects of their audiences' experiences, be it what they learn from a program or how they react to an exhibition. Each museum program or exhibition has its own set of goals, which can drive what an evaluator studies and how an evaluation evolves. When designing an evaluation, data collection methods are purposefully…

  5. Exhibitions: Connecting Classroom Assessment with Culminating Demonstrations of Mastery

    ERIC Educational Resources Information Center

    Davidson, Jill

    2009-01-01

    Exhibitions are public demonstrations of mastery that occur at culminating moments, such as at the conclusion of a unit of study, the transition from one level of schooling to the next, and graduation. Exhibitions require students to speak publicly, use evidence, present engaging visual displays, and otherwise demonstrate mastery to educators,…

  6. 7 CFR Exhibit C to Subpart N of... - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 13 2010-01-01 2009-01-01 true C Exhibit C to Subpart N of Part 1944 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... REGULATIONS (CONTINUED) HOUSING Housing Preservation Grants Exhibit C to Subpart N of Part 1944...

  7. 7 CFR Exhibit C to Subpart N of... - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 13 2014-01-01 2013-01-01 true C Exhibit C to Subpart N of Part 1944 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... REGULATIONS (CONTINUED) HOUSING Housing Preservation Grants Exhibit C to Subpart N of Part 1944...

  8. 7 CFR Exhibit C to Subpart N of... - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 13 2012-01-01 2012-01-01 false C Exhibit C to Subpart N of Part 1944 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... REGULATIONS (CONTINUED) HOUSING Housing Preservation Grants Exhibit C to Subpart N of Part 1944...

  9. 7 CFR Exhibit C to Subpart N of... - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 13 2013-01-01 2013-01-01 false C Exhibit C to Subpart N of Part 1944 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... REGULATIONS (CONTINUED) HOUSING Housing Preservation Grants Exhibit C to Subpart N of Part 1944...

  10. 7 CFR Exhibit G to Subpart A of... - Performance Bond

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 12 2011-01-01 2011-01-01 false Performance Bond G Exhibit G to Subpart A of Part.... 1924, Subpt. A, Exh. G Exhibit G to Subpart A of Part 1924—Performance Bond KNOW ALL PERSONS BY THESE... and faithful performance of the CONTRACT as so amended. The term “Amendment”, wherever used in...

  11. 7 CFR Exhibit A to Subpart L of... - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 13 2014-01-01 2013-01-01 true A Exhibit A to Subpart L of Part 1940 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Exhibit A to Subpart L of Part 1940...

  12. 7 CFR Exhibit A to Subpart L of... - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 13 2012-01-01 2012-01-01 false A Exhibit A to Subpart L of Part 1940 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Exhibit A to Subpart L of Part 1940...

  13. 7 CFR Exhibit A to Subpart L of... - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 13 2011-01-01 2009-01-01 true A Exhibit A to Subpart L of Part 1940 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Exhibit A to Subpart L of Part 1940...

  14. 7 CFR Exhibit A to Subpart L of... - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 13 2010-01-01 2009-01-01 true A Exhibit A to Subpart L of Part 1940 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Exhibit A to Subpart L of Part 1940...

  15. 7 CFR Exhibit A to Subpart L of... - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 13 2013-01-01 2013-01-01 false A Exhibit A to Subpart L of Part 1940 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... Exhibit A to Subpart L of Part 1940...

  16. Modelling the Future: Exhibitions and the Materiality of Education

    ERIC Educational Resources Information Center

    Lawn, Martin, Ed.

    2009-01-01

    The role of World Exhibitions in the 19th and early 20th centuries was to confirm a relation between the nation state and modernity. As a display about industries, inventions and identities, the Exhibition, in a sense, put entire nations into an elevated, viewable space. It is a significant element in modernity as comparisons can be made, progress…

  17. 76 FR 61472 - Culturally Significant Objects Imported for Exhibition

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-04

    ... Culturally Significant Objects Imported for Exhibition Determinations: ``The Game of Kings: Medieval Ivory... Kings: Medieval Ivory Chessmen from the Isle of Lewis,'' imported from abroad for temporary exhibition..., Fifth Floor (Suite 5H03), Washington, DC 20522-0505. Dated: September 27, 2011. J. Adam Ereli,...

  18. Champions of American Sport--A Major Exhibition.

    ERIC Educational Resources Information Center

    Sorani, Bob

    1981-01-01

    An exhibit of 100 photographs, portraits, and sculptures, entitled "Champions of American Sport", is the first major art exhibit ever devoted to outstanding American sports personalities and to the aesthetic qualities of sport and human movement. The Smithsonian Institution is sponsoring the traveling collection, which includes works from the…

  19. Outreach to Science Faculty and Students through Research Exhibitions

    ERIC Educational Resources Information Center

    Chan, Tina; Hebblethwaite, Chris

    2014-01-01

    Penfield Library at the State University of New York at Oswego (SUNY Oswego) has a gallery exhibit space near the front entrance that is used to showcase student-faculty research and art class projects. This article features the library's outreach efforts to science faculty and students through research exhibitions. The library held an exhibition…

  20. Designing Art Exhibitions in an Educational Virtual World

    ERIC Educational Resources Information Center

    Julian, June; Crooks, Julian

    2011-01-01

    Demonstrating the multiple features of the Cerulean Gallery in Second Life, this research report showcases several exemplar exhibits created by students, artists, and museums. Located in The Educational Media Center, a Second Life teaching and social space, the Cerulean Gallery exhibits functioned as case studies that tested its effectiveness as…

  1. A Commemorative History of the George Rogers Clark Bicentennial Exhibit.

    ERIC Educational Resources Information Center

    Indiana State Museum Society, Inc., Indianapolis.

    This pamphlet provides an illustrated narrative history of the George Rogers Clark Bicentennial Exhibit at the Indiana State Museum. George Rogers Clark was a frontier hero of the American Revolution who explored and conquered territory in Kentucky, Ohio, and Illinois. The multimedia exhibit is open to the public from February 25, 1976 through…

  2. 14 CFR 14.11 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Net worth exhibit. 14.11 Section 14.11... IMPLEMENTING THE EQUAL ACCESS TO JUSTICE ACT OF 1980 Information Required From Applicants § 14.11 Net worth... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  3. 28 CFR 24.202 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Net worth exhibit. 24.202 Section 24.202... DEPARTMENT OF JUSTICE ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 24.202 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  4. 47 CFR 1.1512 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 1 2011-10-01 2011-10-01 false Net worth exhibit. 1.1512 Section 1.1512... Access to Justice Act (EAJA) in Agency Proceedings Information Required from Applicants § 1.1512 Net... must provide with its application a detailed exhibit showing the net worth of the applicant and...

  5. 29 CFR 16.202 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 1 2012-07-01 2012-07-01 false Net worth exhibit. 16.202 Section 16.202 Labor Office of the Secretary of Labor EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 16.202 Net... must provide with its application a detailed exhibit showing the net worth of the applicant and...

  6. 28 CFR 24.202 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 1 2014-07-01 2014-07-01 false Net worth exhibit. 24.202 Section 24.202... DEPARTMENT OF JUSTICE ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 24.202 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  7. 24 CFR 14.205 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 1 2011-04-01 2011-04-01 false Net worth exhibit. 14.205 Section... Required From Applicants § 14.205 Net worth exhibit. (a) Each applicant except a qualified tax-exempt... the net worth of the applicant and any affiliates (as defined in § 14.120(f) of this part) when...

  8. 40 CFR 17.12 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Net worth exhibit. 17.12 Section 17.12... JUSTICE ACT IN EPA ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 17.12 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  9. 22 CFR 134.12 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Net worth exhibit. 134.12 Section 134.12... Information Required From Applicants § 134.12 Net worth exhibit. (a) Each applicant except a qualifed tax... showing the net worth of the applicant and any affiliates (as defined in § 960.4(f)) when the...

  10. 24 CFR 14.205 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 1 2013-04-01 2013-04-01 false Net worth exhibit. 14.205 Section... Required From Applicants § 14.205 Net worth exhibit. (a) Each applicant except a qualified tax-exempt... the net worth of the applicant and any affiliates (as defined in § 14.120(f) of this part) when...

  11. 28 CFR 24.202 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 1 2012-07-01 2012-07-01 false Net worth exhibit. 24.202 Section 24.202... DEPARTMENT OF JUSTICE ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 24.202 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  12. 22 CFR 134.12 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Net worth exhibit. 134.12 Section 134.12... Information Required From Applicants § 134.12 Net worth exhibit. (a) Each applicant except a qualifed tax... showing the net worth of the applicant and any affiliates (as defined in § 960.4(f)) when the...

  13. 28 CFR 24.202 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 1 2013-07-01 2013-07-01 false Net worth exhibit. 24.202 Section 24.202... DEPARTMENT OF JUSTICE ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 24.202 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  14. 12 CFR 1203.11 - Confidentiality of net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 7 2011-01-01 2011-01-01 false Confidentiality of net worth exhibit. 1203.11... INFORMATION ACT Information Required From Applicants § 1203.11 Confidentiality of net worth exhibit. Unless otherwise ordered by the Director, or required by law, the statement of net worth will be for...

  15. 14 CFR 14.11 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Net worth exhibit. 14.11 Section 14.11... IMPLEMENTING THE EQUAL ACCESS TO JUSTICE ACT OF 1980 Information Required From Applicants § 14.11 Net worth... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  16. 28 CFR 24.202 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 1 2011-07-01 2011-07-01 false Net worth exhibit. 24.202 Section 24.202... DEPARTMENT OF JUSTICE ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 24.202 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  17. 29 CFR 16.202 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 1 2013-07-01 2013-07-01 false Net worth exhibit. 16.202 Section 16.202 Labor Office of the Secretary of Labor EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 16.202 Net... must provide with its application a detailed exhibit showing the net worth of the applicant and...

  18. 12 CFR 1203.11 - Confidentiality of net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 10 2014-01-01 2014-01-01 false Confidentiality of net worth exhibit. 1203.11... TO JUSTICE ACT Information Required From Applicants § 1203.11 Confidentiality of net worth exhibit. Unless otherwise ordered by the Director, or required by law, the statement of net worth will be for...

  19. 24 CFR 14.205 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 1 2012-04-01 2012-04-01 false Net worth exhibit. 14.205 Section... Required From Applicants § 14.205 Net worth exhibit. (a) Each applicant except a qualified tax-exempt... the net worth of the applicant and any affiliates (as defined in § 14.120(f) of this part) when...

  20. 22 CFR 134.12 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Net worth exhibit. 134.12 Section 134.12... Information Required From Applicants § 134.12 Net worth exhibit. (a) Each applicant except a qualifed tax... showing the net worth of the applicant and any affiliates (as defined in § 960.4(f)) when the...

  1. 40 CFR 17.12 - Net worth exhibit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Net worth exhibit. 17.12 Section 17.12... JUSTICE ACT IN EPA ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 17.12 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  2. 29 CFR 16.202 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 1 2014-07-01 2013-07-01 true Net worth exhibit. 16.202 Section 16.202 Labor Office of the Secretary of Labor EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 16.202 Net worth... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  3. 29 CFR 16.202 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 1 2011-07-01 2011-07-01 false Net worth exhibit. 16.202 Section 16.202 Labor Office of the Secretary of Labor EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 16.202 Net... must provide with its application a detailed exhibit showing the net worth of the applicant and...

  4. 22 CFR 134.12 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Net worth exhibit. 134.12 Section 134.12... Information Required From Applicants § 134.12 Net worth exhibit. (a) Each applicant except a qualifed tax... showing the net worth of the applicant and any affiliates (as defined in § 960.4(f)) when the...

  5. 47 CFR 1.1512 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Net worth exhibit. 1.1512 Section 1.1512... Access to Justice Act (EAJA) in Agency Proceedings Information Required from Applicants § 1.1512 Net... must provide with its application a detailed exhibit showing the net worth of the applicant and...

  6. 14 CFR 14.11 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Net worth exhibit. 14.11 Section 14.11... IMPLEMENTING THE EQUAL ACCESS TO JUSTICE ACT OF 1980 Information Required From Applicants § 14.11 Net worth... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  7. 29 CFR 16.202 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Net worth exhibit. 16.202 Section 16.202 Labor Office of the Secretary of Labor EQUAL ACCESS TO JUSTICE ACT Information Required From Applicants § 16.202 Net worth... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  8. 17 CFR 148.12 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 2 2014-04-01 2014-04-01 false Net worth exhibit. 148.12... Information Required from Applicants § 148.12 Net worth exhibit. (a) Each applicant except a qualified tax... showing the net worth of the applicant and any affiliates (as defined in § 148.4(f) of this part) when...

  9. 40 CFR 17.12 - Net worth exhibit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Net worth exhibit. 17.12 Section 17.12... JUSTICE ACT IN EPA ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 17.12 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  10. 24 CFR 14.205 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 1 2014-04-01 2014-04-01 false Net worth exhibit. 14.205 Section... Required From Applicants § 14.205 Net worth exhibit. (a) Each applicant except a qualified tax-exempt... the net worth of the applicant and any affiliates (as defined in § 14.120(f) of this part) when...

  11. 40 CFR 17.12 - Net worth exhibit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Net worth exhibit. 17.12 Section 17.12... JUSTICE ACT IN EPA ADMINISTRATIVE PROCEEDINGS Information Required From Applicants § 17.12 Net worth... submit with its application a detailed exhibit showing its net worth at the time the proceeding...

  12. 14 CFR 14.11 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Net worth exhibit. 14.11 Section 14.11... IMPLEMENTING THE EQUAL ACCESS TO JUSTICE ACT OF 1980 Information Required From Applicants § 14.11 Net worth... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  13. 12 CFR 1203.11 - Confidentiality of net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 9 2013-01-01 2013-01-01 false Confidentiality of net worth exhibit. 1203.11... TO JUSTICE ACT Information Required From Applicants § 1203.11 Confidentiality of net worth exhibit. Unless otherwise ordered by the Director, or required by law, the statement of net worth will be for...

  14. 24 CFR 14.205 - Net worth exhibit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Net worth exhibit. 14.205 Section... Required From Applicants § 14.205 Net worth exhibit. (a) Each applicant except a qualified tax-exempt... the net worth of the applicant and any affiliates (as defined in § 14.120(f) of this part) when...

  15. 14 CFR 14.11 - Net worth exhibit.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Net worth exhibit. 14.11 Section 14.11... IMPLEMENTING THE EQUAL ACCESS TO JUSTICE ACT OF 1980 Information Required From Applicants § 14.11 Net worth... provide with its application a detailed exhibit showing the net worth of the applicant and any...

  16. Using Museum Exhibits: An Innovation in Experiential Learning

    ERIC Educational Resources Information Center

    Das, Satarupa

    2015-01-01

    Museum exhibits can be a tool in experiential learning. While instructors have documented various methods of experiential learning, they have not sufficiently explored such learning from museum exhibits. Museum researchers, however, have long found a satisfying cognitive component to museum visits. This paper narrates the author's design to…

  17. 18 CFR 385.508 - Exhibits (Rule 508).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Exhibits (Rule 508). 385.508 Section 385.508 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY PROCEDURAL RULES RULES OF PRACTICE AND PROCEDURE Hearings § 385.508 Exhibits (Rule...

  18. 18 CFR 385.508 - Exhibits (Rule 508).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Exhibits (Rule 508). 385.508 Section 385.508 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY PROCEDURAL RULES RULES OF PRACTICE AND PROCEDURE Hearings § 385.508 Exhibits (Rule...

  19. 18 CFR 385.508 - Exhibits (Rule 508).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Exhibits (Rule 508). 385.508 Section 385.508 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY PROCEDURAL RULES RULES OF PRACTICE AND PROCEDURE Hearings § 385.508 Exhibits (Rule...

  20. 7 CFR Exhibit G to Subpart G of... - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 13 2010-01-01 2009-01-01 true G Exhibit G to Subpart G of Part 1940 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, RURAL BUSINESS-COOPERATIVE... REGULATIONS (CONTINUED) GENERAL Environmental Program Exhibit G to Subpart G of Part 1940...