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Sample records for cbd involves deregulation

  1. The Profile of Immune Modulation by Cannabidiol (CBD) Involves Deregulation of Nuclear Factor of Activated T Cells (NFAT)

    PubMed Central

    Kaplan, Barbara L. F.; Springs, Alison E. B.; Kaminski, Norbert E.

    2009-01-01

    Cannabidiol (CBD) is a cannabinoid compound derived from Cannabis Sativa that does not possess high affinity for either the CB1 or CB2 cannabinoid receptors. Similar to other cannabinoids, we demonstrated previously that CBD suppressed interleukin-2 (IL-2) production from phorbol ester plus calcium ionophore (PMA/Io)-activated murine splenocytes. Thus, the focus of the present studies was to further characterize the effect of CBD on immune function. CBD also suppressed IL-2 and interferon-γ (IFN-γ) mRNA expression, proliferation, and cell surface expression of the IL-2 receptor alpha chain, CD25. While all of these observations support the fact that CBD suppresses T cell function, we now demonstrate that CBD suppressed IL-2 and IFN-γ production in purified splenic T cells. CBD also suppressed activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) transcriptional activity, which are critical regulators of IL-2 and IFN-γ. Furthermore, CBD suppressed the T cell-dependent anti-sheep red blood cell immunoglobulin M antibody forming cell (anti-sRBC IgM AFC) response. Finally, using splenocytes derived from CB1-/-/CB2-/- mice, it was determined that suppression of IL-2 and IFN-γ and suppression of the in vitro anti-sRBC IgM AFC response occurred independently of both CB1 and CB2. However, the magnitude of the immune response to sRBC was significantly depressed in CB1-/-/CB2-/- mice. Taken together, these data suggest that CBD suppresses T cell function and that CB1 and/or CB2 play a critical role in the magnitude of the in vitro anti-sRBC IgM AFC response. PMID:18656454

  2. Expression of 2-halobenzoate dioxygenase genes (cbdSABC) involved in the degradation of benzoate and 2-halobenzoate in Burkholderia sp. TH2.

    PubMed

    Suzuki, K; Ogawa, N; Miyashita, K

    2001-01-10

    Burkholderia sp. TH2, isolated from soil, utilizes 2-chlorobenzoate (2CB) and benzoate (BA) as its sole source of carbon and energy. The genes for 2-halobenzoate dioxygenase (cbdABC) from Burkholderia sp. TH2 were cloned and sequenced. The predicted amino acid sequences of all the gene products are highly similar to the cbd gene products of Pseudomonas sp. 2CBS. Disruption of the promoter region of cbdA resulted in loss of growth on 2CB and BA, indicating that these genes are involved in the growth of TH2 on these substrates. Expression of the cbd genes was analyzed by transcriptional fusion assay. The cbdS gene, a possible araC/xylS-type transcriptional regulatory gene, was shown to positively regulate the expression of cbdA. In addition, the effectors of CbdS were shown to be 2CB, 2-bromobenzoate, o-toluate (2-methylbenzoate), 2-iodobenzoate, and BA. Primer extension analysis showed that the cbdA mRNA started at two positions, 14 and 15 nucleotides upstream from the cbdA start codon, ATG. A pair of direct repeats, identical to that of the Pm promoter of the TOL plasmid, was found upstream of -35 hexamer of the cbdA promoter. PMID:11179677

  3. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation.

    PubMed

    Burstein, Sumner

    2015-04-01

    First isolated from Cannabis in 1940 by Roger Adams, the structure of CBD was not completely elucidated until 1963. Subsequent studies resulted in the pronouncement that THC was the 'active' principle of Cannabis and research then focused primarily on it to the virtual exclusion of CBD. This was no doubt due to the belief that activity meant psychoactivity that was shown by THC and not by CBD. In retrospect this must be seen as unfortunate since a number of actions of CBD with potential therapeutic benefit were downplayed for many years. In this review, attention will be focused on the effects of CBD in the broad area of inflammation where such benefits seem likely to be developed. Topics covered in this review are; the medicinal chemistry of CBD, CBD receptor binding involved in controlling Inflammation, signaling events generated by CBD, downstream events affected by CBD (gene expression and transcription), functional effects reported for CBD and combined THC plus CBD treatment. PMID:25703248

  4. Toward the Identification of Two Glycoproteins Involved in the Stomatal Deregulation of Downy Mildew-Infected Grapevine Leaves.

    PubMed

    Guillier, Christelle; Gamm, Magdalena; Lucchi, Géraldine; Truntzer, Caroline; Pecqueur, Delphine; Ducoroy, Patrick; Adrian, Marielle; Héloir, Marie-Claire

    2015-11-01

    Stomata remain abnormally opened and unresponsive to abscisic acid in grapevine leaves infected by downy mildew. This deregulation occurs from 3 days postinoculation and increases concomitantly with leaf colonization by the pathogen. Using epidermal peels, we demonstrated that the active compound involved in this deregulation is located in the apoplast. Biochemical assays showed that the active compound present in the apoplastic fluids isolated from Plasmopara viticola-infected grapevine leaves (IAF) is a CysCys bridge-independent, thermostable and glycosylated protein. Fractionation guided assays based on chromatography coupled to stomatal response and proteomic analysis allowed the identification of both plant and pathogen proteins in the active fraction obtained from IAF. Further in silico analysis and discriminant filtrations based on the comparison between predictions and experimental indications lead to the identification of two Vitis vinifera proteins as candidates for the observed stomatal deregulation. PMID:26106900

  5. Deregulated expression of DNA polymerase β is involved in the progression of genomic instability

    PubMed Central

    Luo, Qingying; Lai, Yanhao; Liu, Shukun; Wu, Mei; Liu, Yuan; Zhang, Zunzhen

    2013-01-01

    Deregulated expression of DNA polymerase beta (pol β) has been implicated in genomic instability that leads to tumorigenesis, yet the mechanisms underlying the pol β-mediated genetic instability remain elusive. In this study, we investigated the roles of deregulated expression of pol β in spontaneous and xenobiotic-induced genetic instability using mouse embryonic fibroblasts (MEFs) that express distinct pol β levels (wild-type, null and over-expression) as a model system. Three genetic instability endpoints, DNA strand breaks, chromosome breakage and gene mutation, were examined under various expression levels of pol β by comet assay, micronuclei test and hprt mutation assay. Our results demonstrate that neither pol β deficiency nor pol β over-expression is sufficient for accumulation of spontaneous DNA damage that promotes a hyper-proliferation phenotype. However, pol β null cells exhibit increased sensitivity to exogenous DNA damaging agents with increased genomic instability compared with pol β wild-type and over-expression cells. This finding suggests that a pol β deficiency may underlie genomic instability induced by exogenous DNA damaging agents. Interestingly, pol β over-expression cells exhibit less chromosomal or DNA damage, but display a higher hprt mutation frequency upon methyl methanesulfonate exposure compared with the other two cell types. Our results therefore indicate that an excessive amount of pol β may promote genomic instability, presumably through an error-prone repair response, although it enhances overall BER capacity for induced DNA damage. PMID:22576475

  6. Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice.

    PubMed

    Viatte, Lydie; Lesbordes-Brion, Jeanne-Claire; Lou, Dan-Qing; Bennoun, Myriam; Nicolas, Gaël; Kahn, Axel; Canonne-Hergaux, François; Vaulont, Sophie

    2005-06-15

    Evidence is accumulating that hepcidin, a liver regulatory peptide, could be the common pathogenetic denominator of all forms of iron overload syndromes including HFE-related hemochromatosis, the most prevalent genetic disorder characterized by inappropriate iron absorption. To understand the mechanisms whereby hepcidin controls iron homeostasis in vivo, we have analyzed the level of iron-related proteins by Western blot and immunohistochemistry in hepcidin-deficient mice, a mouse model of severe hemochromatosis. These mice showed important increased levels of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), and ferroportin compared with control mice. Interestingly, the level of ferroportin was coordinately up-regulated in the duodenum, the spleen, and the liver (predominantly in the Kupffer cells). Finally, we also evidenced a decrease of ceruloplasmin in the liver of hepcidin-deficient mice. We hypothesized that the deregulation of these proteins might be central in the pathogenesis of iron overload, providing key therapeutic targets for iron disorders. PMID:15713792

  7. Deregulation of mTOR signaling is involved in thymic lymphoma development in Atm-/- mice

    SciTech Connect

    Kuang, Xianghong; Shen, Jianjun; Wong, Paul K.Y.; Yan, Mingshan

    2009-06-05

    Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.

  8. Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis.

    PubMed

    Torres, R J; Puig, J G

    2015-11-01

    Neurological manifestations in Lesch-Nyhan disease (LND) are attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on the nervous system development. HPRT deficiency causes the excretion of increased amounts of hypoxanthine into the extracellular medium and we hypothesized that HPRT deficiency related to hypoxanthine excess may then lead, directly or indirectly, to transcriptional aberrations in a variety of genes essential for the function and development of striatal progenitor cells. We have examined the effect of hypoxanthine excess on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells differentiate along neuroectodermal lineages after exposure to retinoic acid (RA). Hypoxanthine effects on RA-differentiation were examined by the changes on the expression of various transcription factor genes essential to neuronal differentiation and by the changes in tyrosine hydroxylase (TH), dopamine, adenosine and serotonin receptors (DRD, ADORA, HTR). We report that hypoxanthine excess deregulate WNT4, from Wnt/β-catenin pathway, and engrailed homeobox 1 gene and increased TH and dopamine DRD1, adenosine ADORA2A and serotonin HTR7 receptors, whose over expression characterize early neuro-developmental processes. PMID:25940910

  9. The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation

    PubMed Central

    Maffei, Rossana; Bulgarelli, Jenny; Fiorcari, Stefania; Bertoncelli, Linda; Martinelli, Silvia; Guarnotta, Carla; Castelli, Ilaria; Deaglio, Silvia; Debbia, Giulia; De Biasi, Sara; Bonacorsi, Goretta; Zucchini, Patrizia; Narni, Franco; Tripodo, Claudio; Luppi, Mario; Cossarizza, Andrea; Marasca, Roberto

    2013-01-01

    Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792±86 cells/μL versus 485±46 cells/μL, P=0.003). Higher numbers of non-classical CD14+CD16++ and Tie-2-expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia-mediated “education” of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population. PMID:23349302

  10. Confronting Deregulation.

    ERIC Educational Resources Information Center

    Madget, James

    1997-01-01

    Discusses how schools can capitalize on new opportunities for cost savings and improved service in a deregulated electric industry. It discusses strategies for preparing to buy electrical power on the open market and examines two forms of purchasing called "wholesale-wheeling" and "retail-wheeling." Steps in conducting a utility audit are…

  11. Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.

    PubMed

    Alvarez-Mora, M I; Rodriguez-Revenga, L; Madrigal, I; Garcia-Garcia, F; Duran, M; Dopazo, J; Estivill, X; Milà, M

    2015-10-15

    FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways. PMID:26095811

  12. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation.

    PubMed

    Oktay, Yavuz; Ülgen, Ege; Can, Özge; Akyerli, Cemaliye B; Yüksel, Şirin; Erdemgil, Yiğit; Durası, I Melis; Henegariu, Octavian Ioan; Nanni, E Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Şevin; Özpınar, Aysel; Huse, Jason T; Sav, M Aydın; Flanagan, Adrienne; Günel, Murat; Sezerman, O Uğur; Yakıcıer, M Cengiz; Pamir, M Necmettin; Özduman, Koray

    2016-01-01

    The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94-27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association. PMID:27282637

  13. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation

    PubMed Central

    Oktay, Yavuz; Ülgen, Ege; Can, Özge; Akyerli, Cemaliye B.; Yüksel, Şirin; Erdemgil, Yiğit; Durası, İ. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Şevin; Özpınar, Aysel; Huse, Jason T.; Sav, M. Aydın; Flanagan, Adrienne; Günel, Murat; Sezerman, O. Uğur; Yakıcıer, M. Cengiz; Pamir, M. Necmettin; Özduman, Koray

    2016-01-01

    The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17–16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94–27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association. PMID:27282637

  14. A protocol for the delivery of cannabidiol (CBD) and combined CBD and ∆9-tetrahydrocannabinol (THC) by vaporisation

    PubMed Central

    2014-01-01

    Background Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with ∆9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis. Methods Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano® vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230°C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC. Results THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation. Conclusions While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD. Trial

  15. [Deregulation and Higher Education].

    ERIC Educational Resources Information Center

    Business Officer, 1982

    1982-01-01

    The extent to which the Reagan Administration has achieved its deregulation goals in the area of higher education is addressed in three articles: "Deregulation and Higher Education: The View a Year Later" (Sheldon Elliot Steinbach); "Student Financial Aid Deregulation: Rhetoric or Reality?" (Robin E. Jenkins); and "Administration Reform of Civil…

  16. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

    PubMed

    Elmes, Matthew W; Kaczocha, Martin; Berger, William T; Leung, KwanNok; Ralph, Brian P; Wang, Liqun; Sweeney, Joseph M; Miyauchi, Jeremy T; Tsirka, Stella E; Ojima, Iwao; Deutsch, Dale G

    2015-04-01

    Δ(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders. PMID:25666611

  17. Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)*

    PubMed Central

    Elmes, Matthew W.; Kaczocha, Martin; Berger, William T.; Leung, KwanNok; Ralph, Brian P.; Wang, Liqun; Sweeney, Joseph M.; Miyauchi, Jeremy T.; Tsirka, Stella E.; Ojima, Iwao; Deutsch, Dale G.

    2015-01-01

    Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders. PMID:25666611

  18. THC:CBD spray and MS spasticity symptoms: data from latest studies.

    PubMed

    Rekand, Tiina

    2014-01-01

    New clinical experience with 9-delta-tetrahydocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex®) involving more than an additional 1,000 patients with MS spasticity (approximately 150 in clinical studies and 900 in post-marketing surveillance studies) have become available in 2013 and are reviewed. A randomized, placebo controlled long-term follow-up clinical trial with THC:CBD spray versus placebo demonstrated that it was not associated with cognitive decline, depression or significant mood changes after 12 months of treatment. Furthermore, in a prospective observational pilot study involving 33 patients (60% female) aged 33-68 years and a mean disease duration of 6.6 years, THC:CBD oromucosal spray did not adversely influence standard driving ability in patients with moderate to severe MS spasticity. Other new long term observational data about the use of THC:CBD oromucosal spray in clinical practice are available from patient registries in the UK, Germany and Spain. Findings to date reinforce the efficacy and safety observed in Phase III clinical trials. It is of interest that in practice average dosages used by patients tended to be lower than those reported in clinical studies (5-6.4 vs. >8 sprays/day), and effectiveness was maintained in the majority of patients. Importantly, no additional safety concerns were identified in the registry studies which included findings from patients who have been treated for prolonged periods (in the German/UK registry 45% of patients had >2 years exposure). Thus, these new data support a positive benefit-risk relationship for THC:CBD oromucosal spray during longer-term use. PMID:24457846

  19. Deregulation of electric utilities

    SciTech Connect

    Zaccour, G.

    1998-07-01

    This volume is a collection of fourteen, mainly applied, economic papers examining electric utility deregulation in many parts of the world. These papers were presented at the International Workshop on Deregulation of Electric Utilities held in Montreal, Canada in September 1997. As the title suggests, these papers cover a broad range of topics. Despite the book's scattershot approach, a small subset of contributors asks a fundamental question: Is the industry sufficiently deregulated? This book succeeds in providing some concrete and well-analyzed examples that examine this important question.

  20. Apoptosis deregulation in myeloproliferative neoplasms

    PubMed Central

    Tognon, Raquel; Nunes, Natália de Souza; de Castro, Fabíola Attié

    2013-01-01

    ABSTRACT Philadelphia-chromosome negative chronic myeloproliferative neoplasms are clonal hematologic diseases characterized by hematopoietic progenitor independence from or hypersensitivity to cytokines. The cellular and molecular mechanisms involved in the pathophysiology of myeloproliferative neoplasms have not yet been fully clarified. Pathophysiologic findings relevant for myeloproliferative neoplasms are associated with genetic alterations, such as, somatic mutation in the gene that codifies JAK-2 (JAK V617F). Deregulation of the process of programmed cellular death, called apoptosis, seems to participate in the pathogenesis of these disorders. It is known that expression deregulation of pro- and anti-apoptotic genes promotes cell resistance to apoptosis, culminating with the accumulation of myeloid cells and establishing neoplasms. This review will focus on the alterations in apoptosis regulation in myeloproliferative neoplasms, and the importance of a better understanding of this mechanism for the development of new therapies for these diseases. PMID:24488400

  1. Corticobasal degeneration with olivopontocerebellar atrophy and TDP-43 pathology: an unusual clinicopathologic variant of CBD

    PubMed Central

    Kouri, Naomi; Oshima, Kenichi; Takahashi, Makio; Murray, Melissa E.; Ahmed, Zeshan; Parisi, Joseph E.; Yen, Shu-Hui C.; Dickson, Dennis W.

    2013-01-01

    CBD is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus was comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. Additionally, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology. PMID:23371366

  2. Deregulated transcription factors in leukemia.

    PubMed

    Shima, Yutaka; Kitabayashi, Issay

    2011-08-01

    Specific chromosomal translocations and other mutations associated with acute myeloblastic leukemia (AML) often involve transcription factors and transcriptional coactivators. Such target genes include AML1, C/EBPα, RARα, MOZ, p300/CBP, and MLL, all of which are important in the regulation of hematopoiesis. The resultant fusion or mutant proteins deregulate the transcription of the affected genes and disrupt their essential role in hematopoiesis, causing differentiation block and abnormal proliferation and/or survival. This review focuses on such transcription factors and coactivators, and describes their roles in leukemogenesis and hematopoiesis. PMID:21823042

  3. Next-Generation Sequencing Identifies Deregulation of MicroRNAs Involved in Both Innate and Adaptive Immune Response in ALK+ ALCL

    PubMed Central

    Steinhilber, Julia; Bonin, Michael; Walter, Michael; Fend, Falko; Bonzheim, Irina; Quintanilla-Martinez, Leticia

    2015-01-01

    Anaplastic large cell lymphoma (ALCL) is divided into two systemic diseases according to the expression of the anaplastic lymphoma kinase (ALK). We investigated the differential expression of miRNAs between ALK+ ALCL, ALK- ALCL cells and normal T-cells using next generation sequencing (NGS). In addition, a C/EBPβ-dependent miRNA profile was generated. The data were validated in primary ALCL cases. NGS identified 106 miRNAs significantly differentially expressed between ALK+ and ALK- ALCL and 228 between ALK+ ALCL and normal T-cells. We identified a signature of 56 miRNAs distinguishing ALK+ ALCL, ALK- ALCL and T-cells. The top candidates significant differentially expressed between ALK+ and ALK- ALCL included 5 upregulated miRNAs: miR-340, miR-203, miR-135b, miR-182, miR-183; and 7 downregulated: miR-196b, miR-155, miR-146a, miR-424, miR-503, miR-424*, miR-542-3p. The miR-17-92 cluster was also upregulated in ALK+ cells. Additionally, we identified a signature of 3 miRNAs significantly regulated by the transcription factor C/EBPβ, which is specifically overexpressed in ALK+ ALCL, including the miR-181 family. Of interest, miR-181a, which regulates T-cell differentiation and modulates TCR signalling strength, was significantly downregulated in ALK+ ALCL cases. In summary, our data reveal a miRNA signature linking ALK+ ALCL to a deregulated immune response and may reflect the abnormal TCR antigen expression known in ALK+ ALCL. PMID:25688981

  4. Overview: Tuition Deregulation

    ERIC Educational Resources Information Center

    Texas Higher Education Coordinating Board, 2009

    2009-01-01

    Prior to 2003, the Texas Legislature had the regulatory authority to set tuition rates, generally mandating that the same statutory and designated tuition rate be charged across the state. Tuition deregulation became effective September 1, 2003, and universities began increasing designated tuition in spring 2004. This article answers the following…

  5. Should antibacterials be deregulated?

    PubMed

    Rovira, J; Figueras, M; Segú, J L

    1998-05-01

    Deregulation of antibacterials is a recurrent topic in the debate on pharmaceutical policy. This article focuses on one aspect of pharmaceutical regulation, namely the requirement of a medical prescription for purchasing antibacterials. However, a strategy of deregulation should not only concern the switch from prescription-only status to nonprescription status for a given drug, but should consider some complementary measures to minimise potentially harmful effects on health and costs. Risk-benefit and economic evaluations, which are possible approaches to assess the convenience of antibacterial deregulation, force the empirical evidence, the assumptions, as well as the value judgements on which the options are evaluated, to be made explicit. We outline the basic traits of an economic-evaluation approach to assess the issues related to the public interest and the feasibility of a deregulation policy. However, the answer cannot be a generic one, but should address the question for each particular country, and for each antibacterial and indication. Given the limitations of existing evidence on that issue, a tentative research agenda is also proposed. PMID:10180749

  6. Impact of enzymatic and alkaline hydrolysis on CBD concentration in urine.

    PubMed

    Bergamaschi, Mateus M; Barnes, Allan; Queiroz, Regina H C; Hurd, Yasmin L; Huestis, Marilyn A

    2013-05-01

    A sensitive and specific analytical method for cannabidiol (CBD) in urine was needed to define urinary CBD pharmacokinetics after controlled CBD administration, and to confirm compliance with CBD medications including Sativex-a cannabis plant extract containing 1:1 ∆(9)-tetrahydrocannabinol (THC) and CBD. Non-psychoactive CBD has a wide range of therapeutic applications and may also influence psychotropic smoked cannabis effects. Few methods exist for the quantification of CBD excretion in urine, and no data are available for phase II metabolism of CBD to CBD-glucuronide or CBD-sulfate. We optimized the hydrolysis of CBD-glucuronide and/or -sulfate, and developed and validated a GC-MS method for urinary CBD quantification. Solid-phase extraction isolated and concentrated analytes prior to GC-MS. Method validation included overnight hydrolysis (16 h) at 37 °C with 2,500 units β-glucuronidase from Red Abalone. Calibration curves were fit by linear least squares regression with 1/x (2) weighting with linear ranges (r(2) > 0.990) of 2.5-100 ng/mL for non-hydrolyzed CBD and 2.5-500 ng/mL for enzyme-hydrolyzed CBD. Bias was 88.7-105.3 %, imprecision 1.4-6.4 % CV and extraction efficiency 82.5-92.7 % (no hydrolysis) and 34.3-47.0 % (enzyme hydrolysis). Enzyme-hydrolyzed urine specimens exhibited more than a 250-fold CBD concentration increase compared to alkaline and non-hydrolyzed specimens. This method can be applied for urinary CBD quantification and further pharmacokinetics characterization following controlled CBD administration. PMID:23494274

  7. Airline Deregulation and Public Policy

    NASA Astrophysics Data System (ADS)

    Morrison, Steven A.; Winston, Clifford

    1989-08-01

    An assessment of the effects of airline deregulation on travelers and carriers indicates that deregulation has provided travelers and carriers with 14.9 billion of annual benefits (1988 dollars). Airport congestion, airline safety, airline bankruptcy, and mergers are also analyzed and found in most cases to have reduced benefits. But, these costs should not be attributed to deregulation per se, but to failures by the government to pursue appropriate policies in these areas. Pursuit of policies that promote airline competition and efficient use of airport capacity would significantly increase the benefits from deregulation and would provide valuable guidance for other industries undergoing the transition to deregulation.

  8. Cannabis-based medicines--GW pharmaceuticals: high CBD, high THC, medicinal cannabis--GW pharmaceuticals, THC:CBD.

    PubMed

    2003-01-01

    GW Pharmaceuticals is undertaking a major research programme in the UK to develop and market distinct cannabis-based prescription medicines [THC:CBD, High THC, High CBD] in a range of medical conditions. The cannabis for this programme is grown in a secret location in the UK. It is expected that the product will be marketed in the US in late 2003. GW's cannabis-based products include selected phytocannabinoids from cannabis plants, including D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). The company is investigating their use in three delivery systems, including sublingual spray, sublingual tablet and inhaled (but not smoked) dosage forms. The technology is protected by patent applications. Four different formulations are currently being investigated, including High THC, THC:CBD (narrow ratio), THC:CBD (broad ratio) and High CBD. GW is also developing a specialist security technology that will be incorporated in all its drug delivery systems. This technology allows for the recording and remote monitoring of patient usage to prevent any potential abuse of its cannabis-based medicines. GW plans to enter into agreements with other companies following phase III development, to secure the best commercialisation terms for its cannabis-based medicines. In June 2003, GW announced that exclusive commercialisation rights for the drug in the UK had been licensed to Bayer AG. The drug will be marketed under the Sativex brand name. This agreement also provides Bayer with an option to expand their license to include the European Union and certain world markets. GW was granted a clinical trial exemption certificate by the Medicines Control Agency to conduct clinical studies with cannabis-based medicines in the UK. The exemption includes investigations in the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive

  9. Deregulation of NF-кB-miR-146a negative feedback loop may be involved in the pathogenesis of diabetic neuropathy.

    PubMed

    Yousefzadeh, Nasibeh; Alipour, Mohammad Reza; Soufi, Farhad Ghadiri

    2015-03-01

    The current study was designed to explore whether microRNA-146a and its adapter proteins (tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1)) are involved in the pathogenesis of diabetes neuropathy. Twelve male Sprague Dawley rats were randomized into control and diabetic groups (n = 6). Diabetes was induced by a single-dose injection of nicotinamide (110 mg/kg; i.p.), 15 min before injection of streptozotocin (50 mg/kg; i.p.) in 12-h-fasted rats. Diabetic neuropathy was evaluated by hot plate and tail emersion tests, 2 months after the injection of streptozotocin. The gene expression level of microRNA-146a (miR-146a), IRAK1, TRAF6, and nuclear factor kappa B (NF-κB) was measured in the sciatic nerve of rats using the real time-PCR method. Moreover, the activity of NF-κB and the concentration of pro-inflammatory cytokines were determined by the ELISA method. In comparison with the control group, a threefold increase in the expression of miR-146a and NF-κB, and a twofold decrease in the expression of TRAF6 were observed in the sciatic nerve of diabetic rats. Furthermore, the NF-κB activity and the concentration of TNF-α, interleukin 6 (IL-6), and interleukin 1β (IL-1β) in the sciatic nerve of diabetic rats were higher than in those of control counterparts. These results suggest that a defect in the NF-кB-miR-146a negative feedback loop may be involved in the pathogenesis of diabetic neuropathy. PMID:25567745

  10. Chromatin deregulation in disease.

    PubMed

    Mirabella, Anne C; Foster, Benjamin M; Bartke, Till

    2016-03-01

    The regulation of chromatin by epigenetic mechanisms plays a central role in gene expression and is essential for development and maintenance of cell identity and function. Aberrant chromatin regulation is observed in many diseases where it leads to defects in epigenetic gene regulation resulting in pathological gene expression programmes. These defects are caused by inherited or acquired mutations in genes encoding enzymes that deposit or remove DNA and histone modifications and that shape chromatin architecture. Chromatin deregulation often results in neurodevelopmental disorders and intellectual disabilities, frequently linked to physical and developmental abnormalities, but can also cause neurodegenerative diseases, immunodeficiency, or muscle wasting syndromes. Epigenetic diseases can either be of monogenic origin or manifest themselves as complex multifactorial diseases such as in congenital heart disease, autism spectrum disorders, or cancer in which mutations in chromatin regulators are contributing factors. The environment directly influences the epigenome and can induce changes that cause or predispose to diseases through risk factors such as stress, malnutrition or exposure to harmful chemicals. The plasticity of chromatin regulation makes targeting the enzymatic machinery an attractive strategy for therapeutic intervention and an increasing number of small molecule inhibitors against a variety of epigenetic regulators are in clinical use or under development. In this review, we will give an overview of the molecular lesions that underlie epigenetic diseases, and we will discuss the impact of the environment and prospects for epigenetic therapies. PMID:26188466

  11. Effects of sigmaS and the transcriptional activator AppY on induction of the Escherichia coli hya and cbdAB-appA operons in response to carbon and phosphate starvation.

    PubMed Central

    Atlung, T; Knudsen, K; Heerfordt, L; Brøndsted, L

    1997-01-01

    The transcriptional regulation of two energy metabolism operons, hya and cbdAB-appA, has been investigated during carbon and phosphate starvation. The hya operon encodes hydrogenase 1, and the cbdAB-appA operon encodes cytochrome bd-II oxidase and acid phosphatase, pH 2.5. Both operons are targets for the transcriptional activator AppY. In exponential growth, expression of the hya and cbd operons was reduced in an rpoS mutant lacking the RNA polymerase sigmaS factor, and the induction of the two operons by entry into stationary phase in rich medium was strongly dependent on sigmaS. Both operons were induced by carbon starvation, but only induction of the hya operon was dependent on sigmaS, whereas that of the cbd promoter was dependent on AppY. The appY gene also showed sigmaS-dependent induction by carbon starvation. The cbd and hya operons were also found to exhibit a sigmaS-dependent transient twofold induction by osmotic upshift. Like the cbd operon, the hya operon was highly induced by phosphate starvation. For both operons the induction was strongly dependent on AppY. The induction ratio of the two operons was the same in rpoS+ and rpoS mutant strains, indicating that the phosphate starvation-induced increase in sigmaS concentration is not involved in the phosphate regulation of these operons. PMID:9079897

  12. Effects of sigmaS and the transcriptional activator AppY on induction of the Escherichia coli hya and cbdAB-appA operons in response to carbon and phosphate starvation.

    PubMed

    Atlung, T; Knudsen, K; Heerfordt, L; Brøndsted, L

    1997-04-01

    The transcriptional regulation of two energy metabolism operons, hya and cbdAB-appA, has been investigated during carbon and phosphate starvation. The hya operon encodes hydrogenase 1, and the cbdAB-appA operon encodes cytochrome bd-II oxidase and acid phosphatase, pH 2.5. Both operons are targets for the transcriptional activator AppY. In exponential growth, expression of the hya and cbd operons was reduced in an rpoS mutant lacking the RNA polymerase sigmaS factor, and the induction of the two operons by entry into stationary phase in rich medium was strongly dependent on sigmaS. Both operons were induced by carbon starvation, but only induction of the hya operon was dependent on sigmaS, whereas that of the cbd promoter was dependent on AppY. The appY gene also showed sigmaS-dependent induction by carbon starvation. The cbd and hya operons were also found to exhibit a sigmaS-dependent transient twofold induction by osmotic upshift. Like the cbd operon, the hya operon was highly induced by phosphate starvation. For both operons the induction was strongly dependent on AppY. The induction ratio of the two operons was the same in rpoS+ and rpoS mutant strains, indicating that the phosphate starvation-induced increase in sigmaS concentration is not involved in the phosphate regulation of these operons. PMID:9079897

  13. Transcranial Magnetic Stimulation (TMS) as a Tool for Early Diagnosis and Prognostication in Cortico-Basal Ganglia Degeneration (CBD) Syndromes: Review of Literature and Case Report

    PubMed Central

    Issac, Thomas Gregor; Chandra, Sadanandavalli Retnaswami; Nagaraju, B. C.

    2016-01-01

    Background: Cortico basal degeneration (CBD) of the brain is a rare progressive neurodegenerative disease which encompasses unique neuropsychiatric manifestations. Early diagnosis is essential for initiating proper treatment and favorable outcome. Transcranial Magnetic Stimulation (TMS), a well-known technique for assessment of cortical excitatory and inhibitory properties. It was suggested that in a degenerative disease like CBD which involves the cortex as well as the subcortical structures, comparing both hemispheres, a differential pattern in TMS can be obtained which would help in early identification, prognostication and early therapeutic intervention. Case Report: We describe a case of CBD with corroborative clinical and imaging picture wherein single pulse TMS was used over both the hemispheres measuring the following parameters of interest which included: Motor Threshold (MT), Central Motor Conduction Time (CMCT) and Silent Period (SP). Results and Conclusion: Differential patterns of MT, CMCT and SP was obtained by stimulating over both the hemispheres with the affected hemisphere showing significantly reduced MT and prolonged CMCT implying early impairment of cortical and subcortical structures thereby revealing the potential application of TMS being utilized in a novel way for early detection and prognostication in CBD syndromes. PMID:27011412

  14. Success in a deregulated environment

    SciTech Connect

    Furlong, J.F. III

    1983-10-27

    The author sees numerous parallels in the experiences of industries which proceed from a highly regulated position to one of less regulation or complete deregulation, of which the natural gas industry is only one of the latest. Common elements and pattern formation can be detected. Managements of US gas companies may thus profit from the experiences of other industries which have made the transition to a deregulated mode earlier. The article points up some common elements in the success of those companies in other industries which have survived and prospered in a newly competitive environment.

  15. State Deregulation and Management Flexibility.

    ERIC Educational Resources Information Center

    Tancredo, Thomas G.; And Others

    1984-01-01

    The origin of deregulation of higher education in Colorado, its effects, and implications for other states are discussed. In "How and Why It Happened," Thomas G. Tancredo traces the development of a new budgeting process, called MOU (memorandum of understanding). Under MOU each governing board is responsible for setting the expenditure level for…

  16. Down the road to deregulation.

    PubMed

    Chenet, L; McKee, M

    1998-01-01

    A recent preliminary ruling by the European Court of Justice, that would have ended the Swedish state retail alcohol monopoly on grounds of European law on free movement of goods, highlights the international pressure on countries to deregulate further their alcohol markets. However, those countries that have recently taken the road to deregulation have not been able to prevent the alcohol industry encouraging people to drink more and they are experiencing increased alcohol-related problems. The international debates about tradeable commodities rarely take account of the consequences for public health. Alcohol is one such commodity that is also an important cause of premature death. It is essential that this is not overlooked in the race to promote free trade. PMID:9719390

  17. Compression-based distance (CBD): a simple, rapid, and accurate method for microbiota composition comparison

    PubMed Central

    2013-01-01

    Background Perturbations in intestinal microbiota composition have been associated with a variety of gastrointestinal tract-related diseases. The alleviation of symptoms has been achieved using treatments that alter the gastrointestinal tract microbiota toward that of healthy individuals. Identifying differences in microbiota composition through the use of 16S rRNA gene hypervariable tag sequencing has profound health implications. Current computational methods for comparing microbial communities are usually based on multiple alignments and phylogenetic inference, making them time consuming and requiring exceptional expertise and computational resources. As sequencing data rapidly grows in size, simpler analysis methods are needed to meet the growing computational burdens of microbiota comparisons. Thus, we have developed a simple, rapid, and accurate method, independent of multiple alignments and phylogenetic inference, to support microbiota comparisons. Results We create a metric, called compression-based distance (CBD) for quantifying the degree of similarity between microbial communities. CBD uses the repetitive nature of hypervariable tag datasets and well-established compression algorithms to approximate the total information shared between two datasets. Three published microbiota datasets were used as test cases for CBD as an applicable tool. Our study revealed that CBD recaptured 100% of the statistically significant conclusions reported in the previous studies, while achieving a decrease in computational time required when compared to similar tools without expert user intervention. Conclusion CBD provides a simple, rapid, and accurate method for assessing distances between gastrointestinal tract microbiota 16S hypervariable tag datasets. PMID:23617892

  18. MET deregulation in breast cancer

    PubMed Central

    Landi, Lorenza

    2015-01-01

    Background Mesenchymal-epithelial transition (MET) is an oncogene encoding for a trans-membrane tyrosine kinase receptor activated by the hepatocyte growth factor (HGF). MET has a normal function in organ development during embryogenesis and in tissue homeostasis during adult life. Deregulation of HGF/MET signaling pathway is frequently observed in many cancer types, conferring invasive growth and tendency to progression. MET deregulation is due to gene amplification or increased copy number, gene mutation, receptor over-expression or ligand autocrine loops activation. These events lead to migration, invasion, proliferation, metastatic spread and neo-angiogenesis of cancer cells, suggesting that anti-HGF/MET agents may represent a potential antitumor strategy. In breast cancer (BC), preclinical and clinical data demonstrated the role of HGF/MET signalling pathway in carcinogenesis, disease progression and resistance features. Methods For this review article, all published data on HGF/MET in BC were collected and analyzed. Results Several evidences underline that, in early BC, MET over-expression has an independent negative prognostic significance, regardless of method used for evaluation and BC subtypes. Available data suggest that MET is a relevant target particularly in basal-like (BL) and in triple negative BC. Moreover, preclinical and retrospective data support the critical role of MET deregulation in the development of resistance to target-agents, such as anti-HER2 strategies. Conclusions MET is a promising new target in BC. Several anti-MET agents are under investigation and ongoing clinical trials will clarify its relevance in BC treatment. PMID:26366398

  19. A comparative study of physico-chemical properties of CBD and SILAR grown ZnO thin films

    SciTech Connect

    Jambure, S.B.; Patil, S.J.; Deshpande, A.R.; Lokhande, C.D.

    2014-01-01

    Graphical abstract: Schematic model indicating ZnO nanorods by CBD (Z{sub 1}) and nanograins by SILAR (Z{sub 2}). - Highlights: • Simple methods for the synthesis of ZnO thin films. • Comparative study of physico-chemical properties of ZnO thin films prepared by CBD and SILAR methods. • CBD outperforms SILAR method. - Abstract: In the present work, nanocrystalline zinc oxide (ZnO) thin films have been successfully deposited onto glass substrates by simple and economical chemical bath deposition (CBD) and successive ionic layer adsorption reaction (SILAR) methods. These films were further characterized for their structural, optical, surface morphological and wettability properties. The X-ray diffraction (XRD) patterns for both CBD and SILAR deposited ZnO thin films reveal the highly crystalline hexagonal wurtzite structure. From optical studies, band gaps obtained are 2.9 and 3.0 eV for CBD and SILAR deposited thin films, respectively. The scanning electron microscope (SEM) patterns show growth of well defined randomly oriented nanorods and nanograins on the CBD and SILAR deposited samples, respectively. The resistivity of CBD deposited films (10{sup 2} Ω cm) is lower than that of SILAR deposited films (10{sup 5} Ω cm). Surface wettability studies show hydrophobic nature for both films. From the above results it can be concluded that CBD grown ZnO thin films show better properties as compared to SILAR method.

  20. Quantification of the CBD-FITC conjugates surface coating on cellulose fibres

    PubMed Central

    Pinto, Ricardo; Amaral, António L; Ferreira, Eugénio C; Mota, Manuel; Vilanova, Manuel; Ruel, Katia; Gama, Miguel

    2008-01-01

    Background Cellulose Binding Domains (CBD) were conjugated with fluorescein isothiocyanate (FITC). The surface concentration of the Binding Domains adsorbed on cellulose fibres was determined by fluorescence image analysis. Results For a CBD-FITC concentration of 60 mg/L, a coating fraction of 78% and 110% was estimated for Portucel and Whatman fibres, respectively. For a saturating CBD concentration, using Whatman CF11 fibres, a surface concentration of 25.2 × 10-13 mol/mm2 was estimated, the equivalent to 4 protein monolayers. This result does not imply the existence of several adsorbed protein layers. Conclusion It was verified that CBDs were able to penetrate the fibres, according to confocal microscopy and TEM-immunolabelling analysis. The surface concentration of adsorbed CBDs was greater on amorphous fibres (phosphoric acid swollen) than on more crystalline ones (Whatman CF11 and Sigmacell 20). PMID:18184429

  1. Primer on electric-utility deregulation

    SciTech Connect

    Not Available

    1982-08-01

    This primer on deregulation of the electric utility industry presents material on various subjects that are important for assessing the merits and weaknesses of alternative proposals and for generally understanding the meaning and implications of deregulation. It reviews: (a) the structure of the utility industry, its operation and its technology, with an emphasis placed on economies of scale and the benefits/problems of increased competition; (b) economic regulation, its criticisms and its prospects for improvement; and (c) the host of deregulation proposals and the few analytic studies of deregulation.

  2. Power Buying: Planning For Your Deregulated Future.

    ERIC Educational Resources Information Center

    Robertson, Wayne K.

    1997-01-01

    Colleges and universities can benefit from the coming deregulation of utilities. Deregulation creates opportunity for facility managers to aggressively negotiate agreements, implement changes to the physical plant to make the institution a more attractive customer, and explore new, less expensive energy supply options and alternatives. Some action…

  3. Deregulation: Implications for Community College Leaders.

    ERIC Educational Resources Information Center

    Bender, Louis W.

    1986-01-01

    Looks at the ways in which the deregulation of business and industry may affect community colleges in the years ahead, using the banking industry as an illustration. Argues that the deregulation of higher education requires that community college leadership programs examine past assumptions and develop new strategies. (LAL)

  4. miR deregulation in CLL

    PubMed Central

    Balatti, Veronica; Pekarky, Yuri; Rizzotto, Lara; Croce, Carlo M.

    2014-01-01

    B-cell chronic lymphocytic leukemia (CLL) is the most frequent human leukemia and it occurs in two forms, indolent and aggressive. Although clinical features and genetic abnormalities in CLL are well documented, molecular details underlying the disease are still under investigation. MicroRNAs are small non-coding RNAs involved in a variety of cellular processes and expressed in a tissue specific manner. MicroRNAs have the ability to regulate gene expression. In physiological conditions, microRNAs act as gene expression controllers by targeting the mRNA or inhibiting its translation. Their deregulation can lead to an alteration of the expression level of many genes which can induce the development or promote the progression of tumors. In CLL microRNAs can function as oncogenes, tumor suppressor genes or and can be used as markers for disease onset/progression. For example, in indolent CLL, 13q14 deletions targeting miR-15/16 initiate the disease, while in aggressive CLL miR-181 targets the critical TCL1 oncogene and can also be used as a progression marker. Here we discuss the foremost findings about the role of microRNAs in CLL pathogenesis, and how this knowledge can be used to identify new approaches to treat CLL. PMID:24014303

  5. Public health sector unions and deregulation in Europe.

    PubMed

    Lethbridge, Jane

    2004-01-01

    Deregulation and liberalization of health services take several forms in Europe: public-private partnerships; contracting out of services; and corporatization of health care institutions. The impact on health workers includes changes in terms and conditions of employment, breakup of collective bargaining agreements, and often more stressful working conditions. The author examines four types of trade union responses to deregulation. National health trade union action has used campaigning, awareness raising, and judicial review. Health workers' unions in alliance with other trade unions have taken part in wider campaigns against privatization and in promoting public services. Health workers' unions joining with social movements have become involved in wider alliances that link with broader public policy issues such as poverty reduction and urban/regional regeneration. European-wide action, seen through the work of the European Federation of Public Service Unions, has concentrated on the development of an alternative health policy, and the promotion of social dialogue at a European level. Trade unions must adopt a range of approaches to challenge the effects of deregulation. Increasingly, trade union members need to be aware of how to take action at both the national and European levels. PMID:15346679

  6. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.

    PubMed

    Campos, Alline C; Ortega, Zaira; Palazuelos, Javier; Fogaça, Manoela V; Aguiar, Daniele C; Díaz-Alonso, Javier; Ortega-Gutiérrez, Silvia; Vázquez-Villa, Henar; Moreira, Fabricio A; Guzmán, Manuel; Galve-Roperh, Ismael; Guimarães, Francisco S

    2013-07-01

    Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling. PMID:23298518

  7. High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect.

    PubMed

    Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

    2015-01-01

    The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy. PMID:26309534

  8. Deregulation holds key to power industry future

    SciTech Connect

    McComas, M.W.

    1996-10-01

    Deregulation and its accompanying regulatory and legislative changes are the keys to today`s widespread innovations in the electric utility industry. As deregulation saturates the market, utilities eager to gain customers are lowering prices and offering diversified services. These changes will continue to reverberate well into the 21st century. Just as AT and T and the Baby Bells struck out on their own, electric utilities are changing their way of thinking to stay in business and keep their customers happy. The result? Capital expenditures on power plants are down while alternatives to energy production are up.

  9. FAS system deregulation in T-cell lymphoblastic lymphoma

    PubMed Central

    Villa-Morales, M; Cobos, M A; González-Gugel, E; Álvarez-Iglesias, V; Martínez, B; Piris, M A; Carracedo, A; Benítez, J; Fernández-Piqueras, J

    2014-01-01

    The acquisition of resistance towards FAS-mediated apoptosis may be required for tumor formation. Tumors from various histological origins exhibit FAS mutations, the most frequent being hematological malignancies. However, data regarding FAS mutations or FAS signaling alterations are still lacking in precursor T-cell lymphoblastic lymphomas (T-LBLs). The available data on acute lymphoblastic leukemia, of precursor origin as well, indicate a low frequency of FAS mutations but often report a serious reduction in FAS-mediated apoptosis as well as chemoresistance, thus suggesting the occurrence of mechanisms able to deregulate the FAS signaling pathway, different from FAS mutation. Our aim at this study was to determine whether FAS-mediated apoptotic signaling is compromised in human T-LBL samples and the mechanisms involved. This study on 26 T-LBL samples confirms that the FAS system is impaired to a wide extent in these tumors, with 57.7% of the cases presenting any alteration of the pathway. A variety of mechanisms seems to be involved in such alteration, in order of frequency the downregulation of FAS, the deregulation of other members of the pathway and the occurrence of mutations at FAS. Considering these results together, it seems plausible to think of a cumulative effect of several alterations in each T-LBL, which in turn may result in FAS/FASLG system deregulation. Since defective FAS signaling may render the T-LBL tumor cells resistant to apoptotic cell death, the correct prognosis, diagnosis and thus the success of anticancer therapy may require such an in-depth knowledge of the complete scenario of FAS-signaling alterations. PMID:24603338

  10. FAS system deregulation in T-cell lymphoblastic lymphoma.

    PubMed

    Villa-Morales, M; Cobos, M A; González-Gugel, E; Álvarez-Iglesias, V; Martínez, B; Piris, M A; Carracedo, A; Benítez, J; Fernández-Piqueras, J

    2014-01-01

    The acquisition of resistance towards FAS-mediated apoptosis may be required for tumor formation. Tumors from various histological origins exhibit FAS mutations, the most frequent being hematological malignancies. However, data regarding FAS mutations or FAS signaling alterations are still lacking in precursor T-cell lymphoblastic lymphomas (T-LBLs). The available data on acute lymphoblastic leukemia, of precursor origin as well, indicate a low frequency of FAS mutations but often report a serious reduction in FAS-mediated apoptosis as well as chemoresistance, thus suggesting the occurrence of mechanisms able to deregulate the FAS signaling pathway, different from FAS mutation. Our aim at this study was to determine whether FAS-mediated apoptotic signaling is compromised in human T-LBL samples and the mechanisms involved. This study on 26 T-LBL samples confirms that the FAS system is impaired to a wide extent in these tumors, with 57.7% of the cases presenting any alteration of the pathway. A variety of mechanisms seems to be involved in such alteration, in order of frequency the downregulation of FAS, the deregulation of other members of the pathway and the occurrence of mutations at FAS. Considering these results together, it seems plausible to think of a cumulative effect of several alterations in each T-LBL, which in turn may result in FAS/FASLG system deregulation. Since defective FAS signaling may render the T-LBL tumor cells resistant to apoptotic cell death, the correct prognosis, diagnosis and thus the success of anticancer therapy may require such an in-depth knowledge of the complete scenario of FAS-signaling alterations. PMID:24603338

  11. Deregulation-restructuring: Evidence for individual industries

    SciTech Connect

    Costello, K.W.; Graniere, R.J.

    1997-05-01

    Several studies have measured the effects of regulation on a particular industry. These studies range widely in sophistication, from simple observation (comparison) of pre-transformation and post-transformation actual industry performance to econometric analysis that attempt to separate the effects of deregulation from other factors in explaining changes in an industry`s performance. The major problem with observation studies is that they are unable to measure the effect of one particular event, such as deregulation, on an industry`s performance. For example, at the same time that the United Kingdom privatized its electric power industry, it also radically restructured the industry to encourage competition and instituted a price-cap mechanism to regulate the prices of transmission, distribution, and bundled retail services. Subsequent to these changes in 1991, real prices for most UK electricity customers have fallen. It is not certain however, which of these factors was most important or even contributed to the decline in price. In any event, one must be cautious in interpreting the results of studies that attempt to measure the effect of deregulation per se for a specific industry. This report highlights major outcomes for five industries undergoing deregulation or major regulatory and restructuring reforms. These include the natural gas, transportation, UK electric power, financial, and telecommunications industries. Particular attention was given to the historical development of events in the telecommunications industry.

  12. What Energy Deregulation Means for Your District.

    ERIC Educational Resources Information Center

    Costello, Richard J.

    1999-01-01

    Provides advice on how school districts might reduce energy costs in an era of electric industry deregulation. The competitive environment is described along with suggestions about joining purchasing groups to achieve pricing discounts. Final comments reveal the importance of energy contract negotiation. (GR)

  13. Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis

    PubMed Central

    Zettl, Uwe K.; Rommer, Paulus; Hipp, Petra; Patejdl, Robert

    2016-01-01

    Spasticity, one of the main symptoms of multiple sclerosis (MS), can affect more than 80% of MS patients during the course of their disease and is often not treated adequately. δ-9-Tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray is a plant-derived, standardized cannabinoid-based oromucosal spray medicine for add-on treatment of moderate to severe, resistant multiple sclerosis-induced spasticity. This article reviews the current evidence for the efficacy and safety, with dizziness and fatigue as the most common treatment-related adverse events, being mostly mild to moderate in severity. Results from both randomized controlled phase III studies involving about,1600 MS patients or 1500 patient-years and recently published studies on everyday clinical practice involving more than 1000 patients or more than,1000 patient-years are presented. PMID:26788128

  14. Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis.

    PubMed

    Zettl, Uwe K; Rommer, Paulus; Hipp, Petra; Patejdl, Robert

    2016-01-01

    Spasticity, one of the main symptoms of multiple sclerosis (MS), can affect more than 80% of MS patients during the course of their disease and is often not treated adequately. δ-9-Tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray is a plant-derived, standardized cannabinoid-based oromucosal spray medicine for add-on treatment of moderate to severe, resistant multiple sclerosis-induced spasticity. This article reviews the current evidence for the efficacy and safety, with dizziness and fatigue as the most common treatment-related adverse events, being mostly mild to moderate in severity. Results from both randomized controlled phase III studies involving about,1600 MS patients or 1500 patient-years and recently published studies on everyday clinical practice involving more than 1000 patients or more than,1000 patient-years are presented. PMID:26788128

  15. Who benefits most from THC:CBD spray? Learning from clinical experience.

    PubMed

    Koehler, Jürgen

    2014-01-01

    Patients with multiple sclerosis (MS) represent a diverse and heterogeneous population varying in terms of disease type, its severity and variable progression/time-course, and with regard to the wide range of presenting symptoms. Consequently, detailed experience with individual patients is important to provide examples of therapy to specific patient types. In this article, real-life data from clinical practice showing specific aspects relating to use of 9-delta-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) in patients with moderate to severe spasticity resistant to usual therapy will be presented. Three common clinical scenarios will be considered: MS patients with resistance to usual spasticity therapies; patients with impairment in MS spasticity symptoms; MS patients with relevant impairment in quality of life/activities of daily living (QoL/ADL). These case reports highlight the diverse nature of the MS spasticity population and they show the possible usefulness of THC:CBD oromucosal spray in individual patients with moderate to severe spasticity resistant to existing therapies, within the frame of use approved after large clinical trial results. Perhaps the most important finding is the possibility of obtaining relevant improvements in QoL/ADL in some patients with resistant MS spasticity, allowing them to engage back in physical and social activities. PMID:24457847

  16. Pharmacokinetics in rats of a long-acting human parathyroid hormone-collagen binding domain (PTH-CBD) peptide construct

    PubMed Central

    Stratford, Robert; Vu, Christopher; Sakon, Joshua; Katikaneni, Ranjitha; Gensure, Robert; Ponnapakkam, Tulasi

    2014-01-01

    The pharmacokinetics of a hybrid peptide consisting of the N-terminal biologically active region of human parathyroid hormone (PTH) linked to a collagen binding domain (CBD) were evaluated in female Sprague-Dawley rats. The peptide, PTH-CBD, consists of the first 33 amino acids of PTH linked as an extension of the amino acid chain to the CBD peptide derived from ColH collagenase of Clostridium histolyticum. Serum concentrations arising from single dose administration by the subcutaneous and intravenous routes were compared to those measured following route specific mole equivalent doses of PTH(1-34). Population-based modeling demonstrated similar systemic absorption kinetics and bioavailability for both peptides. Exposure to PTH-CBD was 6-fold higher due to a systemic clearance of approximately 20% relative to PTH(1-34); however, these kinetics were consistent with >95% of a dose being eliminated from serum within 24 hours. Results obtained support continued investigation of PTH-CBD as a bone targeted anabolic agent for the treatment of post-menopausal osteoporosis. PMID:24399637

  17. Cell cycle deregulation by methyl isocyanate: Implications in liver carcinogenesis.

    PubMed

    Panwar, Hariom; Raghuram, Gorantla V; Jain, Deepika; Ahirwar, Alok K; Khan, Saba; Jain, Subodh K; Pathak, Neelam; Banerjee, Smita; Maudar, Kewal K; Mishra, Pradyumna K

    2014-03-01

    Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to methyl isocyanate (MIC), one of the most toxic isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis. PMID:22223508

  18. Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts.

    PubMed

    Kitamura, Hodaka; Ozono, Eiko; Iwanaga, Ritsuko; Bradford, Andrew P; Okuno, Junko; Shimizu, Emi; Kurayoshi, Kenta; Kugawa, Kazuyuki; Toh, Hiroyuki; Ohtani, Kiyoshi

    2015-09-01

    The transcription factor E2F is the principal target of the tumor suppressor pRB. E2F plays crucial roles not only in cell proliferation by activating growth-related genes but also in tumor suppression by activating pro-apoptotic and growth-suppressive genes. We previously reported that, in human normal fibroblasts, the tumor suppressor genes ARF, p27(Kip1) and TAp73 are activated by deregulated E2F activity induced by forced inactivation of pRB, but not by physiological E2F activity induced by growth stimulation. In contrast, growth-related E2F targets are activated by both E2F activities, underscoring the roles of deregulated E2F in tumor suppression in the context of dysfunctional pRB. In this study, to further understand the roles of deregulated E2F, we explored new targets that are specifically activated by deregulated E2F using DNA microarray. The analysis identified nine novel targets (BIM, RASSF1, PPP1R13B, JMY, MOAP1, RBM38, ABTB1, RBBP4 and RBBP7), many of which are involved in the p53 and RB tumor suppressor pathways. Among these genes, the BIM gene was shown to be activated via atypical E2F-responsive promoter elements and to contribute to E2F1-mediated apoptosis. Our results underscore crucial roles of deregulated E2F in growth suppression to counteract loss of pRB function. PMID:26201719

  19. Electric Deregulation: Don't Get the Cart before the Horse.

    ERIC Educational Resources Information Center

    Schaeffer, Statton C.

    1999-01-01

    Examines the development of a campus energy-monitoring system and three energy strategies to help control energy costs in a deregulated environment. Strategies discussed involve purchasing off-campus electric energy, modifying power-plant technology, and considering third-party ownership of the power plant. (GR)

  20. Transcriptional Control of Mitosis: Deregulation and Cancer

    PubMed Central

    Nath, Somsubhra; Ghatak, Dishari; Das, Pijush; Roychoudhury, Susanta

    2015-01-01

    Research over the past few decades has well established the molecular functioning of mitosis. Deregulation of these functions has also been attributed to the generation of aneuploidy in different tumor types. Numerous studies have given insight into the regulation of mitosis by cell cycle specific proteins. Optimum abundance of these proteins is pivotal to timely execution of mitosis. Aberrant expressions of these mitotic proteins have been reported in different cancer types. Several post-transcriptional mechanisms and their interplay have subsequently been identified that control the level of mitotic proteins. However, to date, infrequent incidences of cancer-associated mutations have been reported for the genes expressing these proteins. Therefore, altered expression of these mitotic regulators in tumor samples can largely be attributed to transcriptional deregulation. This review discusses the biology of transcriptional control for mitosis and evaluates its role in the generation of aneuploidy and tumorigenesis. PMID:25999914

  1. Deregulation of Cell Signaling in Cancer

    PubMed Central

    Giancotti, Filippo G.

    2014-01-01

    Summary Oncogenic mutations disrupt the regulatory circuits that govern cell function, enabling tumor cells to undergo de-regulated mitogenesis, to resist to proapoptotic insults, and to invade through tissue boundaries. Cancer cell biology has played a crucial role in elucidating the signaling mechanisms by which oncogenic mutations sustain these malignant behaviors and thereby in identifying rational targets for cancer drugs. The efficacy of such targeted therapies illustrate the power of a reductionist approach to the study of cancer. PMID:24561200

  2. Efficient economic dispatch in deregulated power systems

    NASA Astrophysics Data System (ADS)

    Sun, Xijian

    FERC has recently issued a Standard Market Design (SMD) document, which has given indication that the process of deregulating US electric power industry is not a fait accompli, but is an ongoing process with many crucial unsolved problems, some of them are discussed in this dissertation. The problems addressed in this dissertation are listed as below: for the deregulated power market, what kind of optima we could reach, what kind of optima we should reach and how these optima are reached. Moreover, how to solve "Seams" problem with the above information is also addressed. "Seams" problem is defined as the problem of enabling two ISOs to reach consistent Locational Marginal Prices along their boundary. Solving the above problems is extremely important for the design of electric power market, and for the success of deregulation. A new methodology is presented in this dissertation. With this methodology, the market equilibrium (Nash Equilibrium) and market optima (Pareto optima) have been calculated. The relations among them and the criterion of selecting an optimum are also discussed. Based on this methodology, a new inter-regional cooperation scheme is proposed, which could finally solve "Seams" problem. The proposed methodology is a market-oriented approach, which could be easily accepted by market participants. Also this methodology is based on traditional power flow methods, which makes it easier to be implemented and integrated into an Energy Management System (EMS) or other existing software of this kind. This methodology could easily incorporate contingency analysis, an essential requirement for a secure and reliable power system. Most importantly, this methodology is stable and fast-converged. With all the above advantages, the methodology proposed here is a good choice for the deregulated power market.

  3. Is Endoscopic Papillary Large Balloon Dilation Safe for Treating Large CBD Stones?

    PubMed Central

    Shim, Chan Sup; Kim, Ji Wan; Lee, Tae Yoon; Cheon, Young Koog

    2016-01-01

    In recent years, endoscopic papillary large balloon dilation (EPLBD) with endoscopic sphincterotomy (EST) has been shown to be an effective technique for the removal of large or difficult common bile duct (CBD) stones, as an alternative to EST. Reviewing the literature published since 2003, it is understood that EPLBD has fewer associated overall complications than EST. Bleeding occurred less frequently with EPLBD than with EST. There was no significant difference in postendoscopic retrograde cholangiopancreatography pancreatitis or perforation. Recent accumulated results of EPLBD with or even without EST suggest that it is a safe and effective procedure for the removal of large or difficult bile duct stones without any additional risk of severe adverse events, when performed under appropriate guidelines. Since use of a larger balloon can tear the sphincter as well as the bile duct, possibly resulting in bleeding and perforation, a balloon size that is equal to or smaller in diameter than the diameter of the native distal bile duct is recommended. The maximum transverse diameter of the stone and the balloon-stone diameter ratio have a tendency to affect the success or failure of complete removal of stones by large balloon dilation to prevent adverse effects such as perforation and bleeding. One should take into account the size of the native bile duct, the size and burden of stones, the presence of stricture of distal bile duct, and the presence of the papilla in or adjacent to a diverticulum. Even though the results of EPLBD indicate that it is a relatively safe procedure in patients with common duct stones with a dilated CBD, the recommended guidelines should be followed strictly for the prevention of major adverse events such as bleeding and perforation. PMID:27488319

  4. Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs

    PubMed Central

    Ludwig, Nicole; Kim, Yoo-Jin; Mueller, Sabine C.; Backes, Christina; Werner, Tamara V.; Galata, Valentina; Sartorius, Elke; Bohle, Rainer M.; Keller, Andreas; Meese, Eckart

    2015-01-01

    Background Micro (mi)RNAs are key regulators of gene expression and offer themselves as biomarkers for cancer development and progression. Meningioma is one of the most frequent primary intracranial tumors. As of yet, there are limited data on the role of miRNAs in meningioma of different histological subtypes and the affected signaling pathways. Methods In this study, we compared expression of 1205 miRNAs in different meningioma grades and histological subtypes using microarrays and independently validated deregulation of selected miRNAs with quantitative real-time PCR. Clinical utility of a subset of miRNAs as biomarkers for World Health Organization (WHO) grade II meningioma based on quantitative real-time data was tested. Potential targets of deregulated miRNAs were discovered with an in silico analysis. Results We identified 13 miRNAs deregulated between different subtypes of benign meningiomas, and 52 miRNAs deregulated in anaplastic meningioma compared with benign meningiomas. Known and putative target genes of deregulated miRNAs include genes involved in epithelial-to-mesenchymal transition for benign meningiomas, and Wnt, transforming growth factor–β, and vascular endothelial growth factor signaling for higher-grade meningiomas. Furthermore, a 4-miRNA signature (miR-222, -34a*, -136, and -497) shows promise as a biomarker differentiating WHO grade II from grade I meningiomas with an area under the curve of 0.75. Conclusions Our data provide novel insights into the contribution of miRNAs to the phenotypic spectrum in benign meningiomas. By deregulating translation of genes belonging to signaling pathways known to be important for meningioma genesis and progression, miRNAs provide a second in line amplification of growth promoting cellular signals. MiRNAs as biomarkers for diagnosis of aggressive meningiomas might prove useful and should be explored further in a prospective manner. PMID:25681310

  5. Streptococcus gordonii collagen-binding domain protein CbdA may enhance bacterial survival in instrumented root canals ex vivo

    PubMed Central

    Moses, Peter J.; Power, Daniel A.; Jesionowski, Amy M.; Jenkinson, Howard F.; Pantera, Eugene A.; Vickerman, M. Margaret

    2012-01-01

    Introduction The surface-associated collagen-binding protein Ace of Enterococcus faecalis has been implicated as a virulence factor that contributes to bacterial persistence in endodontic infections. The purpose of this study was to determine if proteins with amino acid sequence similarity to Ace found in more abundant oral streptococci could play a similar role in potentially enhancing endodontic infections. Methods A Streptococcus gordonii gene similar to ace was identified by genome sequence searches in silico. An isogenic derivative of strain DL1 with a disruption in the identified gene was constructed by allelic replacement. Parent and mutant strains were characterized for their ability to bind immobilized collagen type-1 in a microtiter plate binding assay. Survival of the strains in a human tooth ex vivo instrumented root canal model was compared by inoculating canals with parental or mutant bacteria and determining the CFUs recovered at various time points over a 12-day period. Results The S. gordonii gene, encoding a protein with a conserved collagen-binding domain similar to that of Ace, was designated cbdA. The cbdA-deficient cells were less able to bind collagen type-1 than parental cells (P <0.0001). Genetic complementation of the cbdA-deficient strain restored the collagen-binding phenotype. By day 12 significantly fewer (P =0.03) cbdA-deficient than parental CFUs were recovered from instrumented canals. Conclusion A gene encoding a putative collagen-binding protein was identified in S. gordonii. Fewer S. gordonii cbdA-deficient cells survived ex vivo compared with parental cells, suggesting that collagen-binding proteins may contribute to persistence of oral streptococci in instrumented root canals. PMID:23228255

  6. Deregulation of Rho GTPases in cancer

    PubMed Central

    Porter, Andrew P.; Papaioannou, Alexandra; Malliri, Angeliki

    2016-01-01

    ABSTRACT In vitro and in vivo studies and evidence from human tumors have long implicated Rho GTPase signaling in the formation and dissemination of a range of cancers. Recently next generation sequencing has identified direct mutations of Rho GTPases in human cancers. Moreover, the effects of ablating genes encoding Rho GTPases and their regulators in mouse models, or through pharmacological inhibition, strongly suggests that targeting Rho GTPase signaling could constitute an effective treatment. In this review we will explore the various ways in which Rho signaling can be deregulated in human cancers. PMID:27104658

  7. National policy in a deregulated marketplace

    SciTech Connect

    Jensen, V.

    1996-12-31

    This paper is one of three keynote presentations given at the conference. It briefly discusses government policy issues regarding electric utility deregulation. Three major questions are examined: (1) policies and institutions required to ensure a free market, (2) allocation of stranded assets and ensuring that consumers benefit from restructuring, and (3) continuation of collateral utility activities such as low income program investments, energy efficiency, and renewable energy use. Types of policy options under consideration are reviewed, and potential state and federal roles are described.

  8. Energy flow for electric power system deregulation

    NASA Astrophysics Data System (ADS)

    Lin, Chia-Hung

    Over the past few years, the electric power utility industry in North America and other countries has experienced a strong drive towards deregulation. People have considered the necessity of deregulation of electric utilities for higher energy efficiency and energy saving. The vertically integrated monopolistic industry is being transferred into a horizontally integrated competitive structure in some countries. Wheeling charges are a current high priority problem throughout the power industry, for independent power producers, as well as regulators. Nevertheless the present transmission pricing mechanism fails to be adjusted by a customer loading condition. Customer loading is dynamic, but the present wheeling charge method is fixed, not real-time. A real-time wheeling charge method is developed in this dissertation. This dissertation introduces a concept of a power flow network which can be used for the calculation of power contribution factors in a network. The contribution factor is defined as the ratio of the power contributed by a particular source to a line flow or bus load to the total output of the source. Generation, transmission, and distribution companies can employ contribution factors for the calculation of energy cost, wheeling charges, and loss compensation. Based on the concept of contribution factors, a proposed loss allocation method is developed in this dissertation. Besides, counterflow condition will be given a credit in the proposed loss allocation method. A simple 22-bus example was used for evaluating the contribution factors, proposed wheeling charge method, and loss allocation method.

  9. Deregulated expression of PAX5 in medulloblastoma.

    PubMed Central

    Kozmik, Z; Sure, U; Rüedi, D; Busslinger, M; Aguzzi, A

    1995-01-01

    Medulloblatoma is a pediatric brain tumor originating in the human cerebellum. A collection of 23 medulloblastomas was analyzed for expression of the developmental control genes of the PAX and EN gene families by RNase protection and in situ hybridization. Of all nine PAX genes investigated, only PAX5 and PAX6 were consistently expressed in most medulloblastomas (70 and 78% of all cases, respectively), as were the genes EN1 (57%) and EN2 (78%). EN1, EN2, and PAX6 genes were also expressed in normal cerebellar tissue, and their expression in medulloblastoma is consistent with the hypothesis that this tumor originates in the external granular layer of the developing cerebellum. PAX5 transcripts were, however, not detected in the neonatal cerebellum, indicating that this gene is deregulated in medulloblastoma. In the desmoplastic variant of medulloblastoma, PAX5 expression was restricted to the reticulin-producing proliferating tumor areas containing undifferentiated cells; PAX5 was not expressed in the reticulin-free nonproliferating islands undergoing neuronal differentiation. These data suggest that deregulated expression of PAX5 correlates positively with cell proliferation and inversely with neuronal differentiation in desmoplastic medulloblastoma. Images Fig. 1 Fig. 2 Fig. 3 PMID:7777574

  10. Heavy metal removal by novel CBD-EC20 sorbents immobilized on cellulose.

    PubMed

    Xu, Zhaohui; Bae, Weon; Mulchandani, Ashok; Mehra, Rajesh K; Chen, Wilfred

    2002-01-01

    Heavy metals are major contributors to pollution of the biosphere, and their efficient removal from contaminated water is required. Biosorption is an emerging technology that has been shown to be effective in removing very low levels of heavy metal from wastewater. Although peptides such as metallothioneins or phytotchelatins are known to immobilize heavy metals, peptide-based biosorbents have not been extensively investigated. In this paper, we describe the construction and expression of bifunctional fusion proteins consisting of synthetic phytochelatin (EC20) linked to a Clostridium-derived cellulose-binding domain (CBD(clos)), enabling purification and immobilization of the fusions onto different cellulose materials in essentially a single step. The immobilized sorbents were shown to be highly effective in removing cadmium at parts per million levels. Repeated removal of cadmium was demonstrated in an immobilized column. The ability to genetically engineer biosorbents with precisely defined properties could provide an attractive strategy for developing high-affinity bioadsorbents suitable for heavy metal removal. PMID:12005515

  11. Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics.

    PubMed

    Gatto, Francesco; Schulze, Almut; Nielsen, Jens

    2016-07-19

    Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network. PMID:27396332

  12. Combinatorial epigenetic deregulation by Helicobacter pylori and Epstein-Barr virus infections in gastric tumourigenesis.

    PubMed

    Wu, William Kk; Yu, Jun; Chan, Matthew Tv; To, Ka F; Cheng, Alfred Sl

    2016-07-01

    Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling and microRNAs, convert environmental signals to transcriptional outputs but are commonly hijacked by pathogenic microorganisms. Recent advances in cancer epigenomics have shed new light on the importance of epigenetic deregulation in Helicobacter pylori- and Epstein-Barr virus (EBV)-driven gastric tumourigenesis. Moreover, it is becoming apparent that epigenetic mechanisms interact through crosstalk and feedback loops, which modify global gene expression patterns. The SWI/SNF remodelling complexes are commonly involved in gastric cancers associated with H. pylori or EBV through different mechanisms, including microRNA-mediated deregulation and genetic mutations. While H. pylori causes epigenetic silencing of tumour-suppressor genes to deregulate cellular pathways, EBV-positive tumours exhibit a widespread and distinctive DNA hypermethylation profile. Given the early successes of epigenetic drugs in haematological malignancies, further studies are mandated to enrich and translate our understanding of combinatorial epigenetic deregulation in gastric cancers into interventional strategies in the clinic. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27102722

  13. Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model.

    PubMed

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert

    2014-01-01

    Alopecia is a psychologically devastating complication of chemotherapy for which there is currently no effective therapy. PTH-CBD is a collagen-targeted parathyroid hormone analog that has shown promise as a therapy for alopecia disorders. This study compared the efficacy of prophylactic versus therapeutic administration of PTH-CBD in chemotherapy-induced alopecia using a mouse model that mimics the cyclic chemotherapy dosing used clinically. C57BL/6J mice were treated with a single subcutaneous injection of PTH-CBD (320 mcg/kg) or vehicle control before or after hair loss developing from three courses of cyclophosphamide chemotherapy (50-150 mg/kg/week). Mice receiving chemotherapy alone developed hair loss and depigmentation over 6-12 months. Mice pretreated with PTH-CBD did not develop these changes and maintained a normal-appearing coat. Mice treated with PTH-CBD after development of hair loss showed a partial recovery. Observations of hair loss were confirmed quantitatively by gray scale analysis. Histological examination showed that in mice receiving chemotherapy alone, there were small, dystrophic hair follicles mostly in the catagen phase. Mice receiving PTH-CBD before chemotherapy showed a mix of normal-appearing telogen and anagen hair follicles with no evidence of dystrophy. Mice receiving PTH-CBD therapy after chemotherapy showed intermediate histological features. PTH-CBD was effective in both the prevention and the treatment of chemotherapy-induced alopecia in mice, but pretreatment appears to result in a better cosmetic outcome. PTH-CBD shows promise as an agent in the prevention of this complication of chemotherapy and improving the quality of life for cancer patients. PMID:24025564

  14. Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model

    PubMed Central

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert

    2014-01-01

    Alopecia is a psychologically devastating complication of chemotherapy for which there is currently no effective therapy. PTH-CBD is a collagen-targeted parathyroid hormone analog that has shown promise as a therapy for alopecia disorders. To compare the efficacy of prophylactic versus therapeutic administration of PTH-CBD in chemotherapy-induced alopecia using a mouse model that mimics the cyclic chemotherapy dosing used clinically. C57BL/6J mice were treated with a single subcutaneous injection of PTH-CBD (320 mcg/kg) or vehicle control before or after hair loss developing from three courses of cyclophosphamide chemotherapy (50–150 mg/kg/week). Mice receiving chemotherapy alone developed hair loss and depigmentation over 6–12 months. Mice pretreated with PTH-CBD did not develop these changes and maintained a normal-appearing coat. Mice treated with PTH-CBD after development of hair loss showed a partial recovery. Observations of hair loss were confirmed quantitatively by gray scale analysis. Histological examination showed that in mice receiving chemotherapy alone, there were small, dystrophic hair follicles mostly in the catagen phase. Mice receiving PTH-CBD before chemotherapy showed a mix of normal-appearing telogen and anagen hair follicles with no evidence of dystrophy. Mice receiving PTH-CBD therapy after chemotherapy showed intermediate histological features. PTH-CBD was effective in both the prevention and the treatment of chemotherapy-induced alopecia in mice, but pretreatment appears to result in a better cosmetic outcome. PTH-CBD shows promise as an agent in the prevention of this complication of chemotherapy and improving the quality of life for cancer patients. PMID:24025564

  15. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    PubMed Central

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  16. Ras-mediated deregulation of the circadian clock in cancer.

    PubMed

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  17. Comparative Study of Zn(O,S) Buffer Layers and CIGS Solar Cells Fabricated by CBD, ALD, and Sputtering: Preprint

    SciTech Connect

    Ramanathan, K.; Mann, J.; Glynn, S.; Christensen, S.; Pankow, J.; Li, J.; Scharf, J.; Mansfield, L. M.; Contreras, M. A.; Noufi, R.

    2012-06-01

    Zn(O,S) thin films were deposited by chemical bath deposition (CBD), atomic layer deposition, and sputtering. Composition of the films and band gap were measured and found to follow the trends described in the literature. CBD Zn(O,S) parameters were optimized and resulted in an 18.5% efficiency cell that did not require post annealing, light soaking, or an undoped ZnO layer. Promising results were obtained with sputtering. A 13% efficiency cell was obtained for a Zn(O,S) emitter layer deposited with 0.5%O2. With further optimization of process parameters and an analysis of the loss mechanisms, it should be possible to increase the efficiency.

  18. Telecommunications Policy Research Conference. Regulation, Deregulation & Competition Section. Papers.

    ERIC Educational Resources Information Center

    Telecommunications Policy Research Conference, Inc., Washington, DC.

    Three papers discuss aspects of telecommunications regulation in a deregulated environment. The first paper, "Implementing Telephone Deregulation: The Political Economy of State Regulation in the Post-Divestiture Era" (Paul E. Teske), analyzed the variation in state regulation of local telephone operating companies using regression analyses across…

  19. The Deregulation of U.S. Communication Policy.

    ERIC Educational Resources Information Center

    Meeske, Milan D.

    This analysis of government regulation of America's broadcast service provides: (1) a historical view of radio and television regulation, including the doctrines of scarcity and public trustee and other areas affected by deregulation in particular; (2) an analysis of the argument for deregulation; and (3) an assessment of the First Amendment, the…

  20. On the causes and consequences of US power retail deregulation

    NASA Astrophysics Data System (ADS)

    Mercado, Jorge E.

    As relevant research in power retail deregulation had identified, the point of departure to consider power markets reforms had been the comparison of state retail prices to those at the average national level as well as the behavior of natural gas prices as an indication of potential entrance of more efficient generation. As a way to have a final answer on the real causes and consequences of retail deregulation, I propose to use a structural model of price and effects of deregulation to show that the causes of deregulation go further than the difference with respect to average national prices and that competitive market reforms by themselves may not be the main reason behind price reduction in states that decided to deregulate their power retail. In particular, the sign on the price difference variable, contrary to what has been argued in the literature, strongly suggest that those states with lower prices tend to favor deregulation, hence obtaining even better electricity prices through reform. Results also suggest that a more complex process of decision to deregulate the power retail has occurred at the state level, since not only price differences mattered as has been the argument so far, but also income per capita, the ratio of small to big businesses, and the party composition of legislatures had played a determinant role on explaining decisions to deregulate as well as price behavior.

  1. 3D bioprinting of BMSC-laden methacrylamide gelatin scaffolds with CBD-BMP2-collagen microfibers.

    PubMed

    Du, Mingchun; Chen, Bing; Meng, Qingyuan; Liu, Sumei; Zheng, Xiongfei; Zhang, Cheng; Wang, Heran; Li, Hongyi; Wang, Nuo; Dai, Jianwu

    2015-01-01

    Three-dimensional (3D) bioprinting combines biomaterials, cells and functional components into complex living tissues. Herein, we assembled function-control modules into cell-laden scaffolds using 3D bioprinting. A customized 3D printer was able to tune the microstructure of printed bone mesenchymal stem cell (BMSC)-laden methacrylamide gelatin scaffolds at the micrometer scale. For example, the pore size was adjusted to 282 ± 32 μm and 363 ± 60 μm. To match the requirements of the printing nozzle, collagen microfibers with a length of 22 ± 13 μm were prepared with a high-speed crusher. Collagen microfibers bound bone morphogenetic protein 2 (BMP2) with a collagen binding domain (CBD) as differentiation-control module, from which BMP2 was able to be controllably released. The differentiation behaviors of BMSCs in the printed scaffolds were compared in three microenvironments: samples without CBD-BMP2-collagen microfibers in the growth medium, samples without microfibers in the osteogenic medium and samples with microfibers in the growth medium. The results indicated that BMSCs showed high cell viability (>90%) during printing; CBD-BMP2-collagen microfibers induced BMSC differentiation into osteocytes within 14 days more efficiently than the osteogenic medium. Our studies suggest that these function-control modules are attractive biomaterials and have potential applications in 3D bioprinting. PMID:26684899

  2. The transformation of ZnO submicron dumbbells into perfect hexagonal tubular structures using CBD: a post treatment route

    NASA Astrophysics Data System (ADS)

    Borade, P.; Joshi, K. U.; Gokarna, A.; Lerondel, G.; Jejurikar, S. M.

    2016-01-01

    In this paper, we report the synthesis of dumbbell-shaped ZnO structures and their subsequent transformation into perfect hexagonal tubes by the extended chemical bath deposition (CBD) method, retaining all advantages such as reproducibility, simplicity, quickness and economical aspect. Well-dispersed sub-micron-sized dumbbell-shaped ZnO structures were synthesized on a SiO2/Si substrate by the CBD method. As an extension of the CBD process the synthesized ZnO dumbbells were exposed to the evaporate coming out of the chemical bath for a few minutes (simply by adjusting the height of the deposit so that it remained just above the solution) to convert them into hexagonal tubes via the dissolution process. The possible dissolution mechanism responsible for the observed conversion is discussed. The optical properties (photo-luminescence) recorded at low temperature on both the structures showed an intense, sharp excitonic peak located at ∼370 nm. The improved intensity and low FWHM of the UV peak observed in the hexagonal tubular structures assures high optical quality, and hence can be used for optoelectronic applications.

  3. Deregulated proliferation and differentiation in brain tumors.

    PubMed

    Swartling, Fredrik J; Čančer, Matko; Frantz, Aaron; Weishaupt, Holger; Persson, Anders I

    2015-01-01

    Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment resistance, suppress tumor growth, and prevent recurrence in patients. PMID:25416506

  4. Deregulated proliferation and differentiation in brain tumors

    PubMed Central

    Swartling, Fredrik J; Čančer, Matko; Frantz, Aaron; Weishaupt, Holger; Persson, Anders I

    2014-01-01

    Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment-resistance, suppress tumor growth, and prevent recurrence in patients. PMID:25416506

  5. Steady state security assessment in deregulated power systems

    NASA Astrophysics Data System (ADS)

    Manjure, Durgesh Padmakar

    Power system operations are undergoing changes, brought about primarily due to deregulation and subsequent restructuring of the power industry. The primary intention of the introduction of deregulation in power systems was to bring about competition and improved customer focus. The underlying motive was increased economic benefit. Present day power system analysis is much different than what it was earlier, essentially due to the transformation of the power industry from being cost-based to one that is price-based and due to open access of transmission networks to the various market participants. Power is now treated as a commodity and is traded in an open market. The resultant interdependence of the technical criteria and the economic considerations has only accentuated the need for accurate analysis in power systems. The main impetus in security analysis studies is on efficient assessment of the post-contingency status of the system, accuracy being of secondary consideration. In most cases, given the time frame involved, it is not feasible to run a complete AC load flow for determining the post-contingency state of the system. Quite often, it is not warranted as well, as an indication of the state of the system is desired rather than the exact quantification of the various state variables. With the inception of deregulation, transmission networks are subjected to a host of multilateral transactions, which would influence physical system quantities like real power flows, security margins and voltage levels. For efficient asset utilization and maximization of the revenue, more often than not, transmission networks are operated under stressed conditions, close to security limits. Therefore, a quantitative assessment of the extent to which each transaction adversely affects the transmission network is required. This needs to be done accurately as the feasibility of the power transactions and subsequent decisions (execution, curtailment, pricing) would depend upon the

  6. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors.

    PubMed

    Campos, Alline Cristina; Ferreira, Frederico Rogério; Guimarães, Francisco Silveira

    2012-11-01

    Posttraumatic stress disorder (PTSD) is an incapacitating syndrome that follows a traumatic experience. Predator exposure promotes long-lasting anxiogenic effect in rodents, an effect related to symptoms found in PTSD patients. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa with anxiolytic effects. The present study investigated the anti-anxiety actions of CBD administration in a model of PTSD. Male Wistar rats exposed to a predator (cat) received, 1 h later, singled or repeated i.p. administration of vehicle or CBD. Seven days after the stress animals were submitted to the elevated plus maze. To investigate the involvement of 5HT1A receptors in CBD effects animals were pre-treated with WAY100635, a 5HT1A receptor antagonist. To explore possible neurobiological mechanisms involved in these effects, 5HT1A receptor mRNA and BDNF protein expression were measured in the hippocampus, frontal cortex, amygdaloid complex and dorsal periaqueductal gray. Repeated administration of CBD prevented long-lasting anxiogenic effects promoted by a single predator exposure. Pretreatment with WAY100635 attenuated CBD effects. Seven days after predator exposure 5HT1A mRNA expression was up regulated in the frontal cortex and hippocampus. CBD and paroxetine failed to prevent this effect. No change in BDNF expression was found. In conclusion, predator exposure promotes long-lasting up-regulation of 5HT1A receptor gene expression in the hippocampus and frontal cortex. Repeated CBD administration prevents the long-lasting anxiogenic effects observed after predator exposure probably by facilitating 5HT1A receptors neurotransmission. Our results suggest that CBD has beneficial potential for PTSD treatment and that 5HT1A receptors could be a therapeutic target in this disorder. PMID:22979992

  7. The influence of supramolecular structure of cellulose allomorphs on the interactions with cellulose-binding domain, CBD3b from Paenibacillus barcinonensis.

    PubMed

    Ciolacu, Diana; Chiriac, Alina Iulia; Pastor, F I Javier; Kokol, Vanja

    2014-04-01

    The interaction of recombinant cellulose-binding domains (CBDs) of endoglucanase Cel9B from Paenibacillus barcinonensis with different cotton cellulose allomorphs (I, II and III) has been investigated, in order to bring new insights regarding the CBD adsorption and desorption processes. The highest CBD adsorption capacity was recorded for cellulose I, confirming the affinity of proteins to the most crystalline substrate. The weakening and splitting of the hydrogen bonds within cellulose structure after CBD adsorption, as well as a decrease of the crystallinity degree were identified by ATR-FTIR spectroscopy and XRD. The CBD's adsorption kinetic was shown to be rendered by properties as, specific surface area and porosity, being confirmed by dynamic vapor sorption measurements. An important influence of temperature (25, 37 and 50°C) and/or pH medium (4, 5.5, 7 and 10) on the CBD desorption capacity was confirmed, being related to the hydrophobic interactions formed between the CBD and the cellulose allomorphs. PMID:24525243

  8. Epigenetic deregulation in pediatric acute lymphoblastic leukemia

    PubMed Central

    Chatterton, Zac; Morenos, Leah; Mechinaud, Francoise; Ashley, David M; Craig, Jeffrey M; Sexton-Oates, Alexandra; Halemba, Minhee S; Parkinson-Bates, Mandy; Ng, Jane; Morrison, Debra; Carroll, William L; Saffery, Richard; Wong, Nicholas C

    2014-01-01

    Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (>50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes. PMID:24394348

  9. Deregulation and Nuclear Training: Cost Effective Alternatives

    SciTech Connect

    Richard P. Coe; Patricia A. Lake

    2000-11-12

    Training is crucial to the success of any organization. It is also expensive, with some estimates exceeding $50 billion annually spent on training by U.S. corporations. Nuclear training, like that of many other highly technical organizations, is both crucial and costly. It is unlikely that the amount of training can be significantly reduced. If anything, current trends indicate that training needs will probably increase as the industry and workforce ages and changes. With the advent of energy deregulation in the United States, greater pressures will surface to make the costs of energy more cost-competitive. This in turn will drive businesses to more closely examine existing costs and find ways to do things in a more cost-effective way. The commercial nuclear industry will be no exception, and nuclear training will be equally affected. It is time for nuclear training and indeed the entire nuclear industry to begin using more aggressive techniques to reduce costs. This includes the need for nuclear training to find alternatives to traditional methods for the delivery of cost-effective high-quality training that meets regulatory requirements and produces well-qualified personnel capable of working in an efficient and safe manner. Computer-based and/or Web-based training are leading emerging technologies.

  10. Simultaneous quantification of delta-9-THC, THC-acid A, CBN and CBD in seized drugs using HPLC-DAD.

    PubMed

    Ambach, Lars; Penitschka, Franziska; Broillet, Alain; König, Stefan; Weinmann, Wolfgang; Bernhard, Werner

    2014-10-01

    An HPLC-DAD method for the quantitative analysis of Δ(9)-tetrahydrocannabinol (THC), Δ(9)-tetrahydrocannabinolic acid-A (THCA-A), cannabidiol (CBD), and cannabinol (CBN) in confiscated cannabis products has been developed, fully validated and applied to analyse seized cannabis products. For determination of the THC content of plant material, this method combines quantitation of THCA-A, which is the inactive precursor of THC, and free THC. Plant material was dried, homogenized and extracted with methanol by ultrasonication. Chromatographic separation was achieved with a Waters Alliance 2695 HPLC equipped with a Merck LiChrospher 60 RP-Select B (5μm) precolumn and a Merck LiChroCart 125-4 LiChrospher 60 RP-Select B (5μm) analytical column. Analytes were detected and quantified using a Waters 2996 photo diode array detector. This method has been accepted by the public authorities of Switzerland (Bundesamt für Gesundheit, Federal Office of Public Health), and has been used to analyse 9092 samples since 2000. Since no thermal decarboxylation of THCA-A occurs, the method is highly reproducible for different cannabis materials. Two calibration ranges are used, a lower one for THC, CBN and CBD, and a higher one for THCA-A, due to its dominant presence in fresh plant material. As provider of the Swiss proficiency test, the robustness of this method has been tested over several years, and homogeneity tests even in the low calibration range (1%) show high precision (RSD≤4.3%, except CBD) and accuracy (bias≤4.1%, except CBN). PMID:25005819

  11. Cellulose binding domain assisted immobilization of lipase (GSlip-CBD) onto cellulosic nanogel: characterization and application in organic medium.

    PubMed

    Kumar, Ashok; Zhang, Shaowei; Wu, Gaobing; Wu, Cheng Chao; Chen, JunPeng; Baskaran, R; Liu, Ziduo

    2015-12-01

    A cbd gene was cloned into the C-terminal region of a lip gene from Geobacillus stearothermophilus. The native lipase (43.5 kDa) and CBD-Lip fusion protein (60.2 kDa) were purified to homogeneity by SDS-PAGE. A highly stable cellulosic nanogel was prepared by controlled hydrolysis of microcrystalline cellulose onto which the CBD-lip fusion protein was immobilized through bio-affinity based binding. The nanogel-bound lipase showed optimum activity at 55 °C, and it remains stable and active at pH 10-10.5. Furthermore, the immobilized lipase showed an over two-fold increase of relative activity in the presence of DMSO, isopropanol, isoamyl alcohol and n-butanol, but a mild activity decrease at a low concentration of methanol and ethanol. The immobilized biocatalyst retained ~50% activity after eight repetitive hydrolytic cycles. Enzyme kinetic studies of the immobilized lipase showed a 1.24 fold increase in Vmax and 5.25 fold increase in kcat towards p-NPP hydrolysis. Additionally, the nanogel bound lipase was tested to synthesize a biodiesel ester, ethyl oleate in DMSO. Kinetic analysis showed the km 100.5 ± 4.3 mmol and Vmax 0.19 ± 0.015 mmolmin(-1) at varied oleic acid concentration. Also, the values of km and Vmax at varying concentration of ethanol were observed to be 95.9 ± 13.9 mmol and 0.22 ± 0.013 mmolmin(-1) respectively. The maximum yield of ethyl oleate 111.2 ± 1.24 mM was obtained under optimized reaction conditions in organic medium. These results suggest that this immobilized biocatalyst can be used as an efficient tool for the biotransformation reactions on an industrial scale. PMID:26590897

  12. The neuroprotection of cannabidiol against MPP⁺-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease.

    PubMed

    Santos, Neife Aparecida Guinaim; Martins, Nádia Maria; Sisti, Flávia Malvestio; Fernandes, Laís Silva; Ferreira, Rafaela Scalco; Queiroz, Regina Helena Costa; Santos, Antônio Cardozo

    2015-12-25

    Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa with potential to treat neurodegenerative diseases. Its neuroprotection has been mainly associated with anti-inflammatory and antioxidant events; however, other mechanisms might be involved. We investigated the involvement of neuritogenesis, NGF receptors (trkA), NGF, and neuronal proteins in the mechanism of neuroprotection of CBD against MPP(+) toxicity in PC12 cells. CBD increased cell viability, differentiation, and the expression of axonal (GAP-43) and synaptic (synaptophysin and synapsin I) proteins. Its neuritogenic effect was not dependent or additive to NGF, but it was inhibited by K252a (trkA inhibitor). CBD did not increase the expression of NGF, but protected against its decrease induced by MPP(+), probably by an indirect mechanism. We also evaluated the neuritogenesis in SH-SY5Y cells, which do not express trkA receptors. CBD did not induce neuritogenesis in this cellular model, which supports the involvement of trkA receptors. This is the first study to report the involvement of neuronal proteins and trkA in the neuroprotection of CBD. Our findings suggest that CBD has a neurorestorative potential independent of NGF that might contribute to its neuroprotection against MPP(+), a neurotoxin relevant to Parkinson's disease. PMID:26556726

  13. Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders*

    PubMed Central

    Mukerjee, Ruma; Chang, J. Robert; Del Valle, Luis; Bagashev, Asen; Gayed, Monika M.; Lyde, Randolph B.; Hawkins, Brian J.; Brailoiu, Eugen; Cohen, Eric; Power, Chris; Azizi, S. Ausim; Gelman, Benjamin B.; Sawaya, Bassel E.

    2011-01-01

    Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders. PMID:21816823

  14. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience.

    PubMed

    Fogaça, M V; Reis, F M C V; Campos, A C; Guimarães, F S

    2014-03-01

    The prelimbic medial prefrontal cortex (PL) is an important encephalic structure involved in the expression of emotional states. In a previous study, intra-PL injection of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, reduced the expression of fear conditioning response. Although its mechanism remains unclear, CBD can facilitate 5HT1A receptor-mediated neurotransmission when injected into several brain structures. This study was aimed at verifying if intra-PL CBD could also induce anxiolytic-like effect in a conceptually distinct animal model, the elevated plus maze (EPM). We also verified if CBD effects in the EPM and contextual fear conditioning test (CFC) depend on 5HT1A receptors and previous stressful experience. CBD induced opposite effects in the CFC and EPM, being anxiolytic and anxiogenic, respectively. Both responses were prevented by WAY100,635, a 5HT1A receptor antagonist. In animals that had been previously (24h) submitted to a stressful event (2h-restraint) CBD caused an anxiolytic, rather than anxiogenic, effect in the EPM. This anxiolytic response was abolished by previous injection of metyrapone, a glucocorticoid synthesis blocker. Moreover, restraint stress increased 5HT1A receptors expression in the dorsal raphe nucleus, an effect that was attenuated by injection of metyrapone before the restraint procedure. Taken together, these results suggest that CBD modulation of anxiety in the PL depend on 5HT1A-mediated neurotransmission and previous stressful experience. PMID:24321837

  15. Copper-induced deregulation of microRNA expression in the zebrafish olfactory system

    PubMed Central

    Wang, Lu; Bammler, Theo K.; Beyer, Richard P.; Gallagher, Evan P.

    2016-01-01

    Although environmental trace metals, such as copper (Cu), can disrupt normal olfactory function in fish, the underlying molecular mechanisms of metal-induced olfactory injury have not been elucidated. Current research has suggested the involvement of epigenetic modifications. To address this hypothesis, we analyzed microRNA (miRNA) profiles in the olfactory system of Cu-exposed zebrafish. Our data revealed 2, 10, and 28 differentially expressed miRNAs in a dose-response manner corresponding to three increasing Cu concentrations. Numerous deregulated miRNAs were involved in neurogenesis (e.g. let-7, miR-7a, miR-128 and miR-138), indicating a role for Cu-mediated toxicity via interference with neurogenesis processes. Putative gene targets of deregulated miRNAs were identified when interrogating our previously published microarray database, including those involved in cell growth and proliferation, cell death, and cell morphology. Moreover, several miRNAs (e.g. miR-203a, miR-199*, miR-16a, miR-16c, and miR-25) may contribute to decreased mRNA levels of their host genes involved in olfactory signal transduction pathways and other critical neurological processes via a post-transcriptional mechanism. Our findings provide novel insight into the epigenetic regulatory mechanisms of metal-induced neurotoxicity of the fish olfactory system, and identify novel miRNA biomarkers of metal exposures. PMID:23745839

  16. Copper-induced deregulation of microRNA expression in the zebrafish olfactory system.

    PubMed

    Wang, Lu; Bammler, Theo K; Beyer, Richard P; Gallagher, Evan P

    2013-07-01

    Although environmental trace metals, such as copper (Cu), can disrupt normal olfactory function in fish, the underlying molecular mechanisms of metal-induced olfactory injury have not been elucidated. Current research has suggested the involvement of epigenetic modifications. To address this hypothesis, we analyzed microRNA (miRNA) profiles in the olfactory system of Cu-exposed zebrafish. Our data revealed 2, 10, and 28 differentially expressed miRNAs in a dose-response manner corresponding to three increasing Cu concentrations. Numerous deregulated miRNAs were involved in neurogenesis (e.g., let-7, miR-7a, miR-128, and miR-138), indicating a role for Cu-mediated toxicity via interference with neurogenesis processes. Putative gene targets of deregulated miRNAs were identified when interrogating our previously published microarray database, including those involved in cell growth and proliferation, cell death, and cell morphology. Moreover, several miRNAs (e.g., miR-203a, miR-199*, miR-16a, miR-16c, and miR-25) may contribute to decreased mRNA levels of their host genes involved in olfactory signal transduction pathways and other critical neurological processes via a post-transcriptional mechanism. Our findings provide novel insight into the epigenetic regulatory mechanisms of metal-induced neurotoxicity of the fish olfactory system and identify novel miRNA biomarkers of metal exposures. PMID:23745839

  17. Deregulation of purine pathway in Bacillus subtilis and its use in riboflavin biosynthesis

    PubMed Central

    2014-01-01

    Background Purine nucleotides are essential metabolites for living organisms because they are involved in many important processes, such as nucleic acid synthesis, energy supply, and biosynthesis of several amino acids and riboflavin. Owing to the pivotal roles of purines in cell physiology, the pool of intracellular purine nucleotides must be maintained under strict control, and hence the de novo purine biosynthetic pathway is tightly regulated by transcription repression and inhibition mechanism. Deregulation of purine pathway is essential for this pathway engineering in Bacillus subtilis. Results Deregulation of purine pathway was attempted to improve purine nucleotides supply, based on a riboflavin producer B. subtilis strain with modification of its rib operon. To eliminate transcription repression, the pur operon repressor PurR and the 5’-UTR of pur operon containing a guanine-sensing riboswitch were disrupted. Quantitative RT-PCR analysis revealed that the relative transcription levels of purine genes were up-regulated about 380 times. Furthermore, site-directed mutagenesis was successfully introduced into PRPP amidotransferase (encoded by purF) to remove feedback inhibition by homologous alignment and analysis. Overexpression of the novel mutant PurF (D293V, K316Q and S400W) significantly increased PRPP amidotransferase activity and triggered a strong refractory effect on purine nucleotides mediated inhibition. Intracellular metabolite target analysis indicated that the purine nucleotides supply in engineered strains was facilitated by a stepwise gene-targeted deregulation. With these genetic manipulations, we managed to enhance the metabolic flow through purine pathway and consequently increased riboflavin production 3-fold (826.52 mg/L) in the purF-VQW mutant strain. Conclusions A sequential optimization strategy was applied to deregulate the rib operon and purine pathway of B. subtilis to create genetic diversities and to improve riboflavin production

  18. MYC Deregulation in Gastric Cancer and Its Clinicopathological Implications

    PubMed Central

    de Souza, Carolina Rosal Teixeira; Leal, Mariana Ferreira; Calcagno, Danielle Queiroz; Costa Sozinho, Eliana Kelly; Borges, Bárbara do Nascimento; Montenegro, Raquel Carvalho; dos Santos, Ândrea Kely Campos Ribeiro; dos Santos, Sidney Emanuel Batista; Ribeiro, Helem Ferreira; Assumpção, Paulo Pimentel; de Arruda Cardoso Smith, Marília; Burbano, Rommel Rodríguez

    2013-01-01

    Our study investigated the relationship between MYC alterations and clinicopathological features in gastric cancers. We evaluated the effect of MYC mRNA expression and its protein immunoreactivity, as well as copy number variation, promoter DNA methylation, and point mutations, in 125 gastric adenocarcinoma and 67 paried non-neoplastic tissues. We observed that 77% of the tumors presented MYC immunoreactivity which was significantly associated with increased mRNA expression (p<0.05). These observations were associated with deeper tumor extension and the presence of metastasis (p<0.05). MYC protein expression was also more frequently observed in intestinal-type than in diffuse-type tumors (p<0.001). Additionally, MYC mRNA and protein expression were significantly associated with its copy number (p<0.05). The gain of MYC copies was associated with late-onset, intestinal-type, advanced tumor stage, and the presence of distant metastasis (p<0.05). A hypomethylated MYC promoter was detected in 86.4% of tumor samples. MYC hypomethylation was associated with diffuse-type, advanced tumor stage, deeper tumor extension, and the presence of lymph node metastasis (p<0.05). Moreover, eighteen tumor samples presented at least one known mutation. The presence of MYC mutations was associated with diffuse-type tumor (p<0.001). Our results showed that MYC deregulation was mainly associated with poor prognostic features and also reinforced the presence of different pathways involved in intestinal-type and diffuse-type gastric carcinogenesis. Thus, our findings suggest that MYC may be a useful marker for clinical stratification and prognosis. PMID:23717612

  19. Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure

    PubMed Central

    van Loon, Ellen P.; van de Sluis, Bart; Vervloet, Mark G.; Hoenderop, Joost G.; Bindels, René J.

    2015-01-01

    Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca2+ and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca2+ excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca2+/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development. PMID:26566277

  20. Evidence of deregulated cholesterol efflux in abdominal aortic aneurysm.

    PubMed

    Mourmoura, Evanthia; Vasilaki, Anna; Giannoukas, Athanasios; Michalodimitrakis, Emmanouel; Pavlidis, Pavlos; Tsezou, Aspasia

    2016-03-01

    Previous studies indicated that lipids may be associated with abdominal aortic aneurysm (AAA); however the molecular mechanism involved is unclear. Our study aimed to investigate the expression pattern of cholesterol efflux related proteins in AAA. Liver X receptors (LXRα and LXRβ), ATP-binding-cassette transporter A1 (ABCA1), Apolipoprotein AI (ApoAI), smooth muscle α-actin (α-SM) and vimentin expression levels were evaluated in human AAA, atherosclerotic (ATH) and normal abdominal aortic tissues. We found significant differences in LXRα, LXRβ and ABCA1 mRNA expression levels between AAA, ATH and normal whole aortic tissues and also within the AAA, ATH and normal "intima-media" layers. Specifically, LXRα, LXRβ and ABCA1 mRNA levels were decreased in AAA compared to ATH-whole tissues, as well as in AAA "intima-media" compared to ATH and normal "intima-media" layers. Moreover, immunohistochemical evaluation revealed that LXRα and ABCA1 immunoreactivities (IR) were reduced in the AAA media compared to the normal and ATH media layers and that they were also reduced in the intima layer of AAA and ATH tissues, whereas ApoAI-IR was increased in the AAA and ATH aortic walls compared to normal pointing to possible deregulation of the cholesterol efflux mechanism in AAA. Furthermore, double staining for vimentin and α-SM showed vimentin expression in the intima and inner media layer of AAA with sparse vimentin positive SMCs designating possible SMCs phenotype switch from contractile to synthetic form. In addition, histochemical analysis showed excessive lipid accumulation in the AAA wall, while co-staining using Oil Red O with α-SM or CD68 revealed lipid accumulation in SMCs and macrophages, respectively. Our study provides novel evidence for impaired cholesterol efflux in AAA associated with lipid accumulation in SMCs and macrophages, as well as switch of SMCs phenotype from contractile to synthetic form. PMID:26725543

  1. Deregulation of Rab and Rab Effector Genes in Bladder Cancer

    PubMed Central

    Ho, Joel R.; Chapeaublanc, Elodie; Kirkwood, Lisa; Nicolle, Remy; Benhamou, Simone; Lebret, Thierry; Allory, Yves; Southgate, Jennifer; Radvanyi, François; Goud, Bruno

    2012-01-01

    Growing evidence indicates that Rab GTPases, key regulators of intracellular transport in eukaryotic cells, play an important role in cancer. We analysed the deregulation at the transcriptional level of the genes encoding Rab proteins and Rab-interacting proteins in bladder cancer pathogenesis, distinguishing between the two main progression pathways so far identified in bladder cancer: the Ta pathway characterized by a high frequency of FGFR3 mutation and the carcinoma in situ pathway where no or infrequent FGFR3 mutations have been identified. A systematic literature search identified 61 genes encoding Rab proteins and 223 genes encoding Rab-interacting proteins. Transcriptomic data were obtained for normal urothelium samples and for two independent bladder cancer data sets corresponding to 152 and 75 tumors. Gene deregulation was analysed with the SAM (significant analysis of microarray) test or the binomial test. Overall, 30 genes were down-regulated, and 13 were up-regulated in the tumor samples. Five of these deregulated genes (LEPRE1, MICAL2, RAB23, STXBP1, SYTL1) were specifically deregulated in FGFR3-non-mutated muscle-invasive tumors. No gene encoding a Rab or Rab-interacting protein was found to be specifically deregulated in FGFR3-mutated tumors. Cluster analysis showed that the RAB27 gene cluster (comprising the genes encoding RAB27 and its interacting partners) was deregulated and that this deregulation was associated with both pathways of bladder cancer pathogenesis. Finally, we found that the expression of KIF20A and ZWINT was associated with that of proliferation markers and that the expression of MLPH, MYO5B, RAB11A, RAB11FIP1, RAB20 and SYTL2 was associated with that of urothelial cell differentiation markers. This systematic analysis of Rab and Rab effector gene deregulation in bladder cancer, taking relevant tumor subgroups into account, provides insight into the possible roles of Rab proteins and their effectors in bladder cancer pathogenesis

  2. Homeobox Gene Deregulation: Impact on the Hallmarks of Cancer

    PubMed Central

    Haria, Dhwani; Naora, Honami

    2014-01-01

    Homeobox genes comprise a super-family of evolutionarily conserved genes that play essential roles in controlling body plan specification and cell fate determination. Substantial evidence indicates that leukemogenesis is driven by abnormal expression of homeobox genes that control hematopoiesis. In solid tumors, aberrant expression of homeobox genes has been increasingly found to modulate diverse processes such as cell proliferation, cell death, metastasis, angiogenesis and DNA repair. This review discusses how homeobox genes are deregulated in solid tumors and the functional significance of this deregulation in the hallmarks of cancer. PMID:24761365

  3. Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPARγ involvement.

    PubMed

    Scuderi, Caterina; Steardo, Luca; Esposito, Giuseppe

    2014-07-01

    The amyloidogenic cascade is regarded as a key factor at the basis of Alzheimer's disease (AD) pathogenesis. The aberrant cleavage of amyloid precursor protein (APP) induces an increased production and a subsequent aggregation of beta amyloid (Aβ) peptide in limbic and association cortices. As a result, altered neuronal homeostasis and oxidative injury provoke tangle formation with consequent neuronal loss. Cannabidiol (CBD), a Cannabis derivative devoid of psychotropic effects, has attracted much attention because it may beneficially interfere with several Aβ-triggered neurodegenerative pathways, even though the mechanism responsible for such actions remains unknown. In the present research, the role of CBD was investigated as a possible modulating compound of APP processing in SHSY5Y(APP+) neurons. In addition, the putative involvement of peroxisome proliferator-activated receptor-γ (PPARγ) was explored as a candidate molecular site responsible for CBD actions. Results indicated the CBD capability to induce the ubiquitination of APP protein which led to a substantial decrease in APP full length protein levels in SHSY5Y(APP+) with the consequent decrease in Aβ production. Moreover, CBD promoted an increased survival of SHSY5Y(APP+) neurons, by reducing their long-term apoptotic rate. Obtained results also showed that all, here observed, CBD effects were dependent on the selective activation of PPARγ. PMID:24288245

  4. Evaluating an Ice-Storage System in a Deregulated Environment.

    ERIC Educational Resources Information Center

    Staniewicz, Theodore J.; Watson, Joseph J.

    2001-01-01

    Examines the difficulties the electric industry's deregulation created for St. Joseph's University's (Philadelphia) development of a thermal ice-storage system as part of its HVAC design and the school's solution. A monthly equipment summary sheet with year-to-date figures is provided. (GR)

  5. Biomass in the Deregulated Marketplace: Current Issues for Biomass Power

    SciTech Connect

    Not Available

    1998-12-01

    This issue brief provides readers with a monthly review and analysis of electric utility deregulation as it impacts biomass power production and distribution. The topical areas to be routinely covered will include Federal activities, State activities, Current challenges, and Current opportunities. Additionally, a monthly highlighted topic will provide more in-depth analysis of current issue impacting biomass power.

  6. Deregulation of Television? A Base for Possible Consideration.

    ERIC Educational Resources Information Center

    Wollert, James A.; Wirth, Michael O.

    Anticipating government relaxation of guidelines for public affairs programing on television (the Federal Communications Commission--FCC--has already deregulated radio programing), researchers analyzed 1978 programing data for commercial television stations to determine percentages of informational (news plus public affairs), local, and…

  7. Electric Restructuring and Utilities Deregulation: A Facility Manager's Guide.

    ERIC Educational Resources Information Center

    Glazner, Steve, Ed.

    This volume presents 12 papers offering guidelines to higher education institutions on planning for the deregulation of the electric power industry. Following an introduction (by Dorsey D. Jacobs), the papers are organized into three parts which address: the changing market, identifying opportunities and challenges, and taking advantage of…

  8. Deregulation of University Education in Nigeria: Problems and Prospects

    ERIC Educational Resources Information Center

    Adeogun, A. A.; Subair, S. T.; Osifila, G. I.

    2009-01-01

    This paper focuses on the deregulation of university education in Nigeria, its problems and prospects. The paper commences with the recognition given to education all over the world, especially higher education. Nigeria as a country gives much credence to higher education as the means for social and economic mobility, social transformation, and as…

  9. The Deregulation Critique of the Federal Role in Education.

    ERIC Educational Resources Information Center

    Clune, William H., III

    The deregulation critique of the federal role in education asserts that education can be as productive with less federal intervention. This critique can be broken down into three groupings of separate criticisms. The first group denies the value or feasibility of federal goals. These criticisms insist either that federal goals are not worthwhile…

  10. Understanding electricity market reforms and the case of Philippine deregulation

    SciTech Connect

    Santiago, Andrea; Roxas, Fernando

    2010-03-15

    The experience of the Philippines offers lessons that should be relevant to any country seeking to deregulate its power industry. Regardless of structure, consumers must face the real price of electricity production and delivery that is closer to marginal cost. Politically motivated prices merely shift the burden from ratepayers to taxpayers. And any reform should work within a reasonable timetable. (author)

  11. Epigenetic deregulation of the COX pathway in cancer.

    PubMed

    Cebola, Inês; Peinado, Miguel A

    2012-10-01

    Inflammation is a major cause of cancer and may condition its progression. The deregulation of the cyclooxygenase (COX) pathway is implicated in several pathophysiological processes, including inflammation and cancer. Although, its targeting with nonsteroidal antiinflammatory drugs (NSAIDs) and COX-2 selective inhibitors has been investigated for years with promising results at both preventive and therapeutic levels, undesirable side effects and the limited understanding of the regulation and functionalities of the COX pathway compromise a more extensive application of these drugs. Epigenetics is bringing additional levels of complexity to the understanding of basic biological and pathological processes. The deregulation of signaling and biosynthetic pathways by epigenetic mechanisms may account for new molecular targets in cancer therapeutics. Genes of the COX pathway are seldom mutated in neoplastic cells, but a large proportion of them show aberrant expression in different types of cancer. A growing body of evidence indicates that epigenetic alterations play a critical role in the deregulation of the genes of the COX pathway. This review summarizes the current knowledge on the contribution of epigenetic processes to the deregulation of the COX pathway in cancer, getting insights into how these alterations may be relevant for the clinical management of patients. PMID:22580191

  12. Deregulation of genes related to iron and mitochondrial metabolism in refractory anemia with ring sideroblasts.

    PubMed

    del Rey, Mónica; Benito, Rocío; Fontanillo, Celia; Campos-Laborie, Francisco J; Janusz, Kamila; Velasco-Hernández, Talía; Abáigar, María; Hernández, María; Cuello, Rebeca; Borrego, Daniel; Martín-Zanca, Dionisio; De Las Rivas, Javier; Mills, Ken I; Hernández-Rivas, Jesús M

    2015-01-01

    The presence of SF3B1 gene mutations is a hallmark of refractory anemia with ring sideroblasts (RARS). However, the mechanisms responsible for iron accumulation that characterize the Myelodysplastic Syndrome with ring sideroblasts (MDS-RS) are not completely understood. In order to gain insight in the molecular basis of MDS-RS, an integrative study of the expression and mutational status of genes related to iron and mitochondrial metabolism was carried out. A total of 231 low-risk MDS patients and 81 controls were studied. Gene expression analysis revealed that iron metabolism and mitochondrial function had the highest number of genes deregulated in RARS patients compared to controls and the refractory cytopenias with unilineage dysplasia (RCUD). Thus mitochondrial transporters SLC25 (SLC25A37 and SLC25A38) and ALAD genes were over-expressed in RARS. Moreover, significant differences were observed between patients with SF3B1 mutations and patients without the mutations. The deregulation of genes involved in iron and mitochondrial metabolism provides new insights in our knowledge of MDS-RS. New variants that could be involved in the pathogenesis of these diseases have been identified. PMID:25955609

  13. Deregulation of Genes Related to Iron and Mitochondrial Metabolism in Refractory Anemia with Ring Sideroblasts

    PubMed Central

    del Rey, Mónica; Benito, Rocío; Fontanillo, Celia; Campos-Laborie, Francisco J.; Janusz, Kamila; Velasco-Hernández, Talía; Abáigar, María; Hernández, María; Cuello, Rebeca; Borrego, Daniel; Martín-Zanca, Dionisio; De Las Rivas, Javier; Mills, Ken I.; Hernández-Rivas, Jesús M.

    2015-01-01

    The presence of SF3B1 gene mutations is a hallmark of refractory anemia with ring sideroblasts (RARS). However, the mechanisms responsible for iron accumulation that characterize the Myelodysplastic Syndrome with ring sideroblasts (MDS-RS) are not completely understood. In order to gain insight in the molecular basis of MDS-RS, an integrative study of the expression and mutational status of genes related to iron and mitochondrial metabolism was carried out. A total of 231 low-risk MDS patients and 81 controls were studied. Gene expression analysis revealed that iron metabolism and mitochondrial function had the highest number of genes deregulated in RARS patients compared to controls and the refractory cytopenias with unilineage dysplasia (RCUD). Thus mitochondrial transporters SLC25 (SLC25A37 and SLC25A38) and ALAD genes were over-expressed in RARS. Moreover, significant differences were observed between patients with SF3B1 mutations and patients without the mutations. The deregulation of genes involved in iron and mitochondrial metabolism provides new insights in our knowledge of MDS-RS. New variants that could be involved in the pathogenesis of these diseases have been identified. PMID:25955609

  14. Deregulation of the miRNAs Expression in Cervical Cancer: Human Papillomavirus Implications

    PubMed Central

    Gómez-Gómez, Yazmín; Organista-Nava, Jorge; Gariglio, Patricio

    2013-01-01

    MicroRNAs (miRNAs) are a class of small non coding RNAs of 18–25 nucleotides in length. The temporal or short-lived expression of the miRNAs modulates gene expression post transcriptionally. Studies have revealed that miRNAs deregulation correlates and is involved with the initiation and progression of human tumors. Cervical cancer (CC) displays notably increased or decreased expression of a large number of cellular oncogenic or tumor suppressive miRNAs, respectively. However, understanding the potential role of miRNAs in CC is still limited. In CC, the high-risk human papillomaviruses (HR-HPVs) infection can affect the miRNAs expression through oncoprotein E6 and E7 that contribute to viral pathogenesis, although other viral proteins might also be involved. This deregulation in the miRNAs expression has an important role in the hallmarks of CC. Interestingly, the miRNA expression profile in CC can discriminate between normal and tumor tissue and the extraordinary stability of miRNAs makes it suitable to serve as diagnostic and prognostic biomarkers of cancer. In this review, we will summarize the role of the HR-HPVs in miRNA expression, the role of miRNAs in the hallmarks of CC, and the use of miRNAs as potential prognostic biomarkers in CC. PMID:24490161

  15. The detection of THC, CBD and CBN in the oral fluid of Sativex® patients using two on-site screening tests and LC-MS/MS.

    PubMed

    Molnar, Anna; Fu, Shanlin; Lewis, John; Allsop, David J; Copeland, Jan

    2014-05-01

    Sativex(®) is an oromucosal spray used to treat spasticity in multiple sclerosis sufferers in some European countries, the United Kingdom, Canada and New Zealand. The drug has also recently been registered by the Therapeutic Goods Administration (TGA) in Australia for treatment of multiple sclerosis. Sativex(®) contains high concentrations of Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with the former being the subject of random roadside drug tests across Australia to detect cannabis use. This pilot study aims to determine whether or not patients taking Sativex(®) will test positive to THC using these roadside screening tests. Detectable levels of THC, CBD and cannabinol (CBN) in their oral fluid were also confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study was a double-blind, placebo controlled design. Oral fluid was tested prior to and immediately after dosing with either Sativex(®) or placebo at intervals up to 2h after the dose. Two Sativex(®) doses were studied. The low dose contained 5.4mg THC, the high dose 21.6mg THC. Results indicate that the primary screening test used in Australian roadside drug testing, the DrugWipe(®) II Twin, often gave a false negative response for THC, even with high concentrations present. However, secondary screening test, Cozart(®) DDS (used by police after a DrugWipe test gives a positive result), gave true positive results in all cases where patients were being treated with Sativex(®). Confirmatory testing showed high concentrations of THC and CBD (>5356ng/mL THC and >3826ng/mL CBD) in the oral fluid shortly after dosing and also elevated concentrations of CBN. Levels dropped quickly but remained at detectable concentrations (>67.6ng/mL) two hours after drug administration. The average concentration ratio of THC/CBD across all positive samples was 1.10 (%RSD 19.9) reflecting the composition of the Sativex(®) spray. In conclusion, Sativex(®) users may test positive for THC by

  16. One-step diffusion membrane assisted CBD synthesis and characterization of Cu2SnS3 thin films

    NASA Astrophysics Data System (ADS)

    Becerra, R. A.; Correa, J. M.; Suarez, H.; Gordillo, G.

    2014-04-01

    This paper present a novel method for growing thin films of Cu2SnS3 (CTS) using a solution-based chemical route consisting of simultaneous precipitation of Cu2-xS and SnS2 performed by diffusion membranes assisted CBD technique. Diffusion membranes are used to optimize the kinetic growth through a moderate control of the releasing metal into the solution. The conditions in terms of concentration of metal species, sulfide anion and temperature required for the precipitation of the Cu2SnS3 compound were determined through a study of chemical equilibrium of the system SnCl2, Na3C6H5O7·2H2O, CuCl2 and Na2S2O3·5H2O. These conditions were obtained solving the equilibrium equations with the help of the Visual MINTEQ 3.0 package, supported on the program MINTEQA2. X-ray diffraction (XRD) and Raman spectroscopy were used to characterize the structural properties of the CTS films. Optical, morphological and electrical properties were also studied by spectral transmittance, atomic force microscopy (AFM) and resistivity vs temperature measurements. XRD and Raman measurements confirmed the formation of the Cu2SnS3 phase.

  17. Effects of pH on the characteristics of ZnS thin films grown by using the CBD method

    NASA Astrophysics Data System (ADS)

    Ahn, Heejin; Lee, Dongchan; Park, Sujung; Um, Youngho

    In CIGS-based thin film solar cells, a chemically deposited ZnS buffer layer with high resistivity is generally used between the absorber layer and transparent conducting oxide layer. In this work, we report a chemical process to prepare ZnS films by the CBD technique based on the typical bath deposition. The influences of ammonia (NH4OH) and Na2EDTA (Na2C10H16N2O8) as complexing agents on structural, morphological, and optical properties of ZnS thin films are investigated ranging pH concentration from 5 to 10. To investigate effects of pH on the characteristics of ZnS thin films, by using UV-visible transmittance, atomic force microscopy, and optical absorption were investigated. With changing the pH range, the ZnS thin films demonstrate high transmittance of 75~80% in the visible region, indicating the films are potentially useful in photovoltaic applications. The results will be presented in detail. This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (2011-0024709).

  18. A model for gene deregulation detection using expression data

    PubMed Central

    2015-01-01

    In tumoral cells, gene regulation mechanisms are severely altered. Genes that do not react normally to their regulators' activity can provide explanations for the tumoral behavior, and be characteristic of cancer subtypes. We thus propose a statistical methodology to identify the misregulated genes given a reference network and gene expression data. Our model is based on a regulatory process in which all genes are allowed to be deregulated. We derive an EM algorithm where the hidden variables correspond to the status (under/over/normally expressed) of the genes and where the E-step is solved thanks to a message passing algorithm. Our procedure provides posterior probabilities of deregulation in a given sample for each gene. We assess the performance of our method by numerical experiments on simulations and on a bladder cancer data set. PMID:26679516

  19. Deregulation of electric utilities in California and its effect on navy installations. Master`s thesis

    SciTech Connect

    O`Shea, P.J.

    1997-06-01

    On January 1, 1998, California will be the first state to deregulate its electricity industry. Deregulation is expected to reduce the high rates paid throughout the state by allowing competition, not regulators, to determine rates. Deregulation will dissolve the monopoly of the electricity industry by allowing customers to choose who will supply their electricity. Competition will emerge in the generation market, where transactions between consumers and suppliers will be free and open. Under regulation, most customers do not have a choice in their electricity supplier. Their supplier is usually determined by their geographic location. This thesis researches the differences between the regulated and deregulated rate structures and provides a cost comparison for a Navy organization classified as a large commercial/industrial user of electricity. There are many aspects of deregulation that are not yet determined, but the initial comparison indicates deregulation may save Navy installations money. If deregulation progresses as planned, additional future saving may occur.

  20. Managing an evolution: Deregulation of the electric utility industry

    SciTech Connect

    Skinner, S.K.

    1994-12-31

    The author discusses the emerging competitive situation in the electric power industry as deregulation of electric utilities looms on the horizon. The paper supports this change, and the competition it will bring, but urges caution as changes are instituted, and the regulatory bodies decide how and how much to free, and at what rates. The reason for his urge for caution comes from historical experience of other industries, which were smaller and had less direct impact on every American.

  1. Generation capacity expansion planning in deregulated electricity markets

    NASA Astrophysics Data System (ADS)

    Sharma, Deepak

    With increasing demand of electric power in the context of deregulated electricity markets, a good strategic planning for the growth of the power system is critical for our tomorrow. There is a need to build new resources in the form of generation plants and transmission lines while considering the effects of these new resources on power system operations, market economics and the long-term dynamics of the economy. In deregulation, the exercise of generation planning has undergone a paradigm shift. The first stage of generation planning is now undertaken by the individual investors. These investors see investments in generation capacity as an increasing business opportunity because of the increasing market prices. Therefore, the main objective of such a planning exercise, carried out by individual investors, is typically that of long-term profit maximization. This thesis presents some modeling frameworks for generation capacity expansion planning applicable to independent investor firms in the context of power industry deregulation. These modeling frameworks include various technical and financing issues within the process of power system planning. The proposed modeling frameworks consider the long-term decision making process of investor firms, the discrete nature of generation capacity addition and incorporates transmission network modeling. Studies have been carried out to examine the impact of the optimal investment plans on transmission network loadings in the long-run by integrating the generation capacity expansion planning framework within a modified IEEE 30-bus transmission system network. The work assesses the importance of arriving at an optimal IRR at which the firm's profit maximization objective attains an extremum value. The mathematical model is further improved to incorporate binary variables while considering discrete unit sizes, and subsequently to include the detailed transmission network representation. The proposed models are novel in the

  2. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma.

    PubMed

    Snijders, Antoine M; Schmidt, Brian L; Fridlyand, Jane; Dekker, Nusi; Pinkel, Daniel; Jordan, Richard C K; Albertson, Donna G

    2005-06-16

    Genomes of solid tumors are characterized by gains and losses of regions, which may contribute to tumorigenesis by altering gene expression. Often the aberrations are extensive, encompassing whole chromosome arms, which makes identification of candidate genes in these regions difficult. Here, we focused on narrow regions of gene amplification to facilitate identification of genetic pathways important in oral squamous cell carcinoma (SCC) development. We used array comparative genomic hybridization (array CGH) to define minimum common amplified regions and then used expression analysis to identify candidate driver genes in amplicons that spanned <3 Mb. We found genes involved in integrin signaling (TLN1), survival (YAP1, BIRC2), and adhesion and migration (TLN1, LAMA3, MMP7), as well as members of the hedgehog (GLI2) and notch (JAG1, RBPSUH, FJX1) pathways to be amplified and overexpressed. Deregulation of these and other members of the hedgehog and notch pathways (HHIP, SMO, DLL1, NOTCH4) implicates deregulation of developmental and differentiation pathways, cell fate misspecification, in oral SCC development. PMID:15824737

  3. Chromosomal translocations deregulating c-myc are associated with normal immune responses.

    PubMed

    Roschke, V; Kopantzev, E; Dertzbaugh, M; Rudikoff, S

    1997-06-26

    Plasmacytomas induced in BALB/c mice by pristane consistently evidence chromosomal translocations involving the c-myc gene and one of the Ig loci. This observation has lead to the suggestion that c-myc deregulation is a critical event in the generation of such tumors. However, it is not clear whether c-myc translocation is related to pristane treatment or occurs in normal lymphocyte populations nor whether such translocations occur normally, and at similar frequencies, in strains genetically resistant to plasmacytoma development, such as DBA/2. In order to address these questions, a Long Distance PCR assay with single copy sensitivity was employed to assess the frequency of c-myc/IgA translocations in normal and immunized mice of both plasmacytoma resistant and susceptible lineages in the absence of pristane treatment. Our data demonstrate that spontaneous translocations occur in normal DBA/2 and BALB/c mice with no significant differences in frequency. A 3-5-fold increase in translocation frequency was observed in mice immunized with cholera toxin, a strong stimulator of IgA responses. We conclude that c-myc deregulation by chromosomal translocation is associated with normal physiological processes of B-cell differentiation and, as such, can not be the determining factor leading to malignancy. PMID:9223664

  4. Choice of electricity provider in California after deregulation

    NASA Astrophysics Data System (ADS)

    Keanini, Rasa Ilze

    Surveys often ask consumers how much they are willing to pay for certain goods and services, without requiring the consumer to actually pay for the good or service. Such surveys, termed stated preference studies, find that consumers value renewable electricity. This result is in contrast to actual experiences in recently deregulated electricity markets in several states, including California. When given the opportunity to choose in California, only one to two percent of the population opted for renewable electricity products. This dissertation used data from residential customers who chose an alternative electricity product in California's deregulated electricity market to determine the value placed on the renewable attribute of electricity products. This dissertation begins by taking a historical look at the electricity market of the nation and specifically California. From 1998 through 2001, California's electricity market was deregulated to include retail competition. This dissertation used data from electric service providers to reveal the factors influencing residential customer's choice of electricity product. Discrete choice models were used to determine the factors influencing electricity product choice. The results indicated that both price and renewable content had an effect on choice of product. Additionally, a more complicated model jointly estimating the discrete choice of electricity product with the continuous choice of electricity consumption (kWh) was specified and estimated.

  5. Analysis of the Department of Defense deregulated electricity contract

    SciTech Connect

    Lin, R.E.

    1998-08-14

    This investigation of the first Department of Defense (DOD) energy contract in California`s deregulated electricity market with New Energy Ventures, Inc., of Los Angeles, California, is submitted as a Master of Science project under the advisement of Drs. C. C. Liu and M. Damborg, Professors of Electrical Engineering, University of Washington. The project stemmed from personal interest, professional commitment, and anticipated beneficial application to the United States Navy. The approach taken to evaluate the electricity contract is based on the current California market structure. Specifically considered are the contract specifications; the pricing elements of the contract and how they are related to the present deregulated market; a zero-risk versus shared-risk savings comparison; and concluding with strong points and disadvantages of the electricity contract as it relates to the Department of Defense (DOD). Included in section two is a brief history leading to the current deregulation, and a basic description of the current California market structure. Section three describes the electricity contract between the DOD and the power marketer, New Energy Ventures, Inc. The contract pricing elements are listed in section four. Section five examines the expected savings comparison between the government and an average commercial consumer. Conclusions on the advantages and disadvantages of this electricity contract are summarized in section six.

  6. Experiences with energy prices in a deregulated market

    SciTech Connect

    Rebellon, P.

    1999-11-01

    The energy market was deregulated in Colombia back in 1994. Since then, an increasing share of energy has been traded at prices dictated essentially by market considerations, not always coherent with sound technical and commercial practices. This paper is based on the author`s experiences with the negotiation of a number of contracts for energy purchase between 1994 and 1997. It starts with a brief presentation of the Colombian power system, the key players and the structure of energy prices before the market was deregulated. An overview of the conditions that led to power shortages in 1992 is included. The document continues with the description of the operation of the Colombian deregulated energy market, as well as the available contracts and energy transactions. Then, the evolution of the energy bid prices submitted by different generating companies during the period 1994--1997 is developed in detail. The final part of the paper discusses the effects of the energy prices in the operation of the system; the financial impact for IPPs; the economic signals given to the market; and the overall performance of the national power system.

  7. Long-Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients.

    PubMed

    Paolicelli, Damiano; Direnzo, Vita; Manni, Alessia; D'Onghia, Mariangela; Tortorella, Carla; Zoccolella, Stefano; Di Lecce, Valentina; Iaffaldano, Antonio; Trojano, Maria

    2016-07-01

    Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on therapy for spasticity in patients with multiple sclerosis (MS). We show our 40-week postmarketing experience regarding efficacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25-Foot Walk (T25-FW) at the beginning of treatment and then every 3 months. After 4 weeks, if a clinically significant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort, patients received an average of 6.5 ± 1.6 sprays each day. The mean reduction to the NRS spasticity score was 2.5 ± 1.2 points (P < .0001). Thirty-seven patients (36.2%) discontinued the treatment. The incidence of adverse events (AEs) was 40.2%. Fifty-eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunction were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a significant improvement in these scales (P = .011 and P = .001, respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory-to-treatment symptoms. PMID:26608223

  8. Altered metabolic pathways in clear cell renal cell carcinoma: A meta-analysis and validation study focused on the deregulated genes and their associated networks

    PubMed Central

    Zaravinos, Apostolos; Pieri, Myrtani; Mourmouras, Nikos; Anastasiadou, Natassa; Zouvani, Ioanna; Delakas, Dimitris; Deltas, Constantinos

    2014-01-01

    Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cell carcinoma (RCC). It is one of the most therapy-resistant carcinomas, responding very poorly or not at all to radiotherapy, hormonal therapy and chemotherapy. A more comprehensive understanding of the deregulated pathways in ccRCC can lead to the development of new therapies and prognostic markers. We performed a meta- analysis of 5 publicly available gene expression datasets and identified a list of co- deregulated genes, for which we performed extensive bioinformatic analysis coupled with experimental validation on the mRNA level. Gene ontology enrichment showed that many proteins are involved in response to hypoxia/oxygen levels and positive regulation of the VEGFR signaling pathway. KEGG analysis revealed that metabolic pathways are mostly altered in ccRCC. Similarly, Ingenuity Pathway Analysis showed that the antigen presentation, inositol metabolism, pentose phosphate, glycolysis/gluconeogenesis and fructose/mannose metabolism pathways are altered in the disease. Cellular growth, proliferation and carbohydrate metabolism, were among the top molecular and cellular functions of the co-deregulated genes. qRT-PCR validated the deregulated expression of several genes in Caki-2 and ACHN cell lines and in a cohort of ccRCC tissues. NNMT and NR3C1 increased expression was evident in ccRCC biopsies from patients using immunohistochemistry. ROC curves evaluated the diagnostic performance of the top deregulated genes in each dataset. We show that metabolic pathways are mostly deregulated in ccRCC and we highlight those being most responsible in its formation. We suggest that these genes are candidate predictive markers of the disease. PMID:25594006

  9. Development and validation of an LC-MS/MS method for quantification of Δ9-tetrahydrocannabinolic acid A (THCA-A), THC, CBN and CBD in hair.

    PubMed

    Roth, Nadine; Moosmann, Bjoern; Auwärter, Volker

    2013-02-01

    For analysis of hair samples derived from a pilot study ('in vivo' contamination of hair by sidestream marijuana smoke), an LC-MS/MS method was developed and validated for the simultaneous quantification of Δ9-tetrahydrocannabinolic acid A (THCA-A), Δ9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD). Hair samples were extracted in methanol for 4 h under occasional shaking at room temperature, after adding THC-D(3), CBN-D(3), CBD-D(3) and THCA-A-D(3) as an in-house synthesized internal standard. The analytes were separated by gradient elution on a Luna C18 column using 0.1% HCOOH and ACN + 0.1% HCOOH. Data acquisition was performed on a QTrap 4000 in electrospray ionization-multi reaction monitoring mode. Validation was carried out according to the guidelines of the German Society of Toxicological and Forensic Chemistry (GTFCh). Limit of detection and lower limit of quantification were 2.5 pg/mg for THCA-A and 20 pg/mg for THC, CBN and CBD. A linear calibration model was applicable for all analytes over a range of 2.5 pg/mg or 20 pg/mg to 1000 pg/mg, using a weighting factor 1/x. Selectivity was shown for 12 blank hair samples from different sources. Accuracy and precision data were within the required limits for all analytes (bias between -0.2% and 6.4%, RSD between 3.7% and 11.5%). The dried hair extracts were stable over a time period of one to five days in the dark at room temperature. Processed sample stability (maximum decrease of analyte peak area below 25%) was considerably enhanced by adding 0.25% lecithin (w/v) in ACN + 0.1% HCOOH for reconstitution. Extraction efficiency for CBD was generally very low using methanol extraction. Hence, for effective extraction of CBD alkaline hydrolysis is recommended. PMID:23378095

  10. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.

    PubMed

    Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

    2012-12-01

    Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects. PMID:23108553

  11. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

    PubMed Central

    Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

    2012-01-01

    Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ9-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca2+) increase, etc.), on CBD behavioural effects. PMID:23108553

  12. Power systems locational marginal pricing in deregulated markets

    NASA Astrophysics Data System (ADS)

    Wang, Hui-Fung Francis

    Since the beginning of the 1990s, the electricity business is transforming from a vertical integrating business to a competitive market operations. The generation, transmission, distribution subsystem of an electricity utility are operated independently as Genco (generation subsystem), Transco (transmission subsystem), and Distco (distribution subsystem). This trend promotes more economical inter- and intra regional transactions to be made by the participating companies and the users of electricity to achieve the intended objectives of deregulation. There are various types of electricity markets that are implemented in the North America in the past few years. However, transmission congestion management becomes a key issue in the electricity market design as more bilateral transactions are traded across long distances competing for scarce transmission resources. It directly alters the traditional concept of energy pricing and impacts the bottom line, revenue and cost of electricity, of both suppliers and buyers. In this research, transmission congestion problem in a deregulated market environment is elucidated by implementing by the Locational Marginal Pricing (LMP) method. With a comprehensive understanding of the LMP method, new mathematical tools will aid electric utilities in exploring new business opportunities are developed and presented in this dissertation. The dissertation focuses on the development of concept of (LMP) forecasting and its implication to the market participants in deregulated market. Specifically, we explore methods of developing fast LMP calculation techniques that are differ from existing LMPs. We also explore and document the usefulness of the proposed LMP in determining electricity pricing of a large scale power system. The developed mathematical tools use of well-known optimization techniques such as linear programming that are support by several flow charts. The fast and practical security constrained unit commitment methods are the

  13. Effect of deposition variables on properties of CBD ZnS thin films prepared in chemical bath of ZnSO4/SC(NH2)2/Na3C3H5O7/NH4OH

    NASA Astrophysics Data System (ADS)

    Liu, Wei-Long; Yang, Chang-Siao; Hsieh, Shu-Huei; Chen, Wen-Jauh; Fern, Chi-Lon

    2013-01-01

    The CBD ZnS thin films were prepared on substrates of soda lime glass in chemical bath. The effect of deposition variables including zinc sulfate, thiourea, tri-sodium citrate, ammoina water, bath temperature, and deposition time on the properties of CBD ZnS thin films were comprehensively studied. The CBD ZnS thin films were characterized by a field emission scanning electron microscope (FESEM) for the surface and cross section morphologies and thicknesses, an energy dispersive spectrometer equipped in FESEM for the atomic% of Zn and S, an ultraviolet-visible spectrometer (300-800 nm) for the transmittance and energy gap, and an atomic force microscope for the surface roughness. The results showed that the CBD ZnS thin films have a transmittance for ultraviolet-visible rays (300-800 nm) from 70.8 to 87.8%. The CBD ZnS thin films prepared in bath 5 have an energy gap from 3.881 to 3.980 eV. The CBD ZnS thin films prepared in bath 6 have a growth rate from 1.8 to 3.2 nm/min and activation energy of 59.8 kJ/mol for their growth.

  14. Economic deregulation and transport safety: a synthesis of evidence from evaluation studies.

    PubMed

    Elvik, Rune

    2006-07-01

    This paper presents a synthesis of evidence from studies that have evaluated the impacts of economic deregulation on transport safety. Most of these studies refer to aviation or road transport. Very few studies deal with deregulation of rail transport. There are no studies of maritime transport, which has never been regulated the same way as other modes of transport. The review includes studies that have attempted to quantify the impacts of transport deregulation on transport safety. Each study contains one or more estimates of the effect on transport safety of deregulation. Summary estimates of effect have been derived from the individual estimates of effect by means of meta-analysis. Airline deregulation, which has only been evaluated in the United States, does not appear to influence the safety of air travel. Deregulation of road transport has been evaluated in several countries. The summary estimate of effect indicates that no statistically significant changes in road safety have occurred as a result of deregulation. Deregulation of rail transport has only been evaluated in Great Britain and the United States. The experience so far suggests that deregulation of railways is associated with improved rail safety. This association does, however, not necessarily imply a causal relationship. PMID:16427020

  15. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

    PubMed Central

    Gañán-Gómez, I; Wei, Y; Starczynowski, DT; Colla, S; Yang, H; Cabrero-Calvo, M; Bohannan, ZS; Verma, A; Steidl, U; Garcia-Manero, G

    2016-01-01

    Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications. PMID:25761935

  16. Natural flavonoids targeting deregulated cell cycle progression in cancer cells.

    PubMed

    Singh, Rana Pratap; Agarwal, Rajesh

    2006-03-01

    The prolonged duration requiring alteration of multi-genetic and epigenetic molecular events for cancer development provides a strong rationale for cancer prevention, which is developing as a potential strategy to arrest or reverse carcinogenic changes before the appearance of the malignant disease. Cell cycle progression is an important biological event having controlled regulation in normal cells, which almost universally becomes aberrant or deregulated in transformed and neoplastic cells. In this regard, targeting deregulated cell cycle progression and its modulation by various natural and synthetic agents are gaining widespread attention in recent years to control the unchecked growth and proliferation in cancer cells. In fact, a vast number of experimental studies convincingly show that many phytochemicals halt uncontrolled cell cycle progression in cancer cells. Among these phytochemicals, natural flavonoids have been identified as a one of the major classes of natural anticancer agents exerting antineoplastic activity via cell cycle arrest as a major mechanism in various types of cancer cells. This review is focused at the modulatory effects of natural flavonoids on cell cycle regulators including cyclin-dependent kinases and their inhibitors, cyclins, p53, retinoblastoma family of proteins, E2Fs, check-point kinases, ATM/ATR and survivin controlling G1/S and G2/M check-point transitions in cell cycle progression, and discusses how these molecular changes could contribute to the antineoplastic effects of natural flavonoids. PMID:16515531

  17. Air pollution effects due to deregulation of the electric industry

    NASA Astrophysics Data System (ADS)

    Davoodi, Khojasteh Riaz

    The Energy Policy Act of 1992 introduced the concept of open-access into the electric utility industry which allows privately-owned utilities to transmit power produced by non-utility generators and independent power producers (IPPs). In April 1996, the Federal Energy Regulatory Commission (FERC) laid down the final rules (Orders No. 888 & No. 889), which required utilities to open their transmission lines to any power producer and charge them no more than what they pay for the use of their own lines. These rules set the stage for the retail sale of electricity to industrial, commercial and residential utility customers; non-utility generators (Nugs); and power marketers. These statutory, regulatory and administrative changes create for the electric utility industry two different forces that contradict each other. The first is the concept of competition among utility companies; this places a greater emphasis on electric power generation cost control and affects generation/fuel mix selection and demand side management (DSM) activities. The second force, which is converse to the first, is that utilities are major contributors to the air pollution burden in the United States and environmental concerns are forcing them to reduce emissions of air pollutants by using more environmentally friendly fuels and implementing energy saving programs. This study evaluates the impact of deregulation within the investor owned electric utilities and how this deregulation effects air quality by investigating the trend in demand side management programs and generation/fuel mix. A survey was conducted of investor owned utilities and independent power producers. The results of the survey were analyzed by analysis of variance and regression analysis to determine the impact to Air Pollution. An air Quality Impact model was also developed in this study. This model consists of six modules: (1) demand side management and (2) consumption of coal, (3) gas, (4) renewable, (5) oil and (6

  18. Deregulation/restructuring part I: reregulation will not fix the problems

    SciTech Connect

    Lave, Lester; Apt, Jay; Blumsack, Seth

    2007-10-15

    Electricity market restructuring is widely seen as having failed. Many of the same groups that pressed for deregulation now find themselves seeking reregulation. But reregulation will reintroduce the flaws and problems that led people to seek deregulation. Further, reregulation will introduce the additional problem of how to value competitive market assets for inclusion in the regulated rate base. (author)

  19. Market Model Considering Bilateral Transactions in the Deregulated Electricity Market

    NASA Astrophysics Data System (ADS)

    Ruiz Monroy, José Joaquín; Kita, Hiroyuki; Tanaka, Eiichi; Hasegawa, Jun

    This paper proposes an algorithm to simulate the transactions that take place in a free market of electricity. The algorithm presented is used for Bilateral Transaction Matrix (BTM) creation assuming that a day ahead load forecast is previously known. Bids can be made by both the generation side and the demand side to determine transaction prices, then the algorithm allocates the transactions according to market rules until the demand is satisfied. This creates feasible BTMs that can be used to study system security and to find future methods to regulate bilateral transactions through market mechanisms like the application of penalties to the transactions that affect the system’s security. Results show that the proposed algorithm is a good option for electricity market analysis. The proposed algorithm provides system planners with a practical tool for data creation to further study the effects of bilateral transactions in a deregulated electricity market.

  20. The vitamin D system is deregulated in pancreatic diseases

    PubMed Central

    Hummel, Doris; Aggarwal, Abhishek; Borka, Katalin; Bajna, Erika; Kállay, Enikö; Horváth, Henrik Csaba

    2014-01-01

    The vitamin D system is deregulated during development and progression of several cancer types. Data on the expression of the vitamin D system in the diseased pancreas are missing. The aim of this study was to investigate the expression of the vitamin D receptor (VDR), 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1), and the calcium-sensing receptor (CaSR), a vitamin D target gene, in the different regions of the pancreas in patients with chronic pancreatitis (n = 6) and pancreatic ductal adenocarcinomas (PDAC) (n = 17). We analyzed the expression of these genes at mRNA and protein level with quantitative real-time RT-PCR and immunostaining. mRNA expression of CYP24A1 and VDR was significantly increased in tumors compared with the adjacent non-tumorous tissue (p < 0.01), while CaSR mRNA expression decreased. Both the VDR and the CaSR protein were highly expressed in the endocrine compared with the exocrine pancreas. In CP the CYP24A1 expression was highest in the endocrine pancreas, while in PDACs in the transformed ducts. In the PDAC patients CYP24A1 expression in the islets was significantly lower than in CP patients. Our data suggest that during ductal adenocarcinoma development the vitamin D system in the pancreas becomes deregulated on two levels: in the islets CYP24A1 expression decreases weakening the negative feedback regulation of the vitamin D-dependent insulin synthesis/secretion. In the transformed ducts CYP24A1 expression increases, impairing the antiproliferative effect of vitamin D in these cells. PMID:25090635

  1. Deregulated tyrosine-phenylalanine metabolism in pulmonary tuberculosis patients.

    PubMed

    Das, Mrinal Kumar; Bishwal, Subasa Chandra; Das, Aleena; Dabral, Deepti; Badireddy, Vinod Kumar; Pandit, Bhaswati; Varghese, George M; Nanda, Ranjan Kumar

    2015-04-01

    Metabolic profiling of biofluids from tuberculosis (TB) patients would help us in understanding the disease pathophysiology and may also be useful for the development of novel diagnostics and host-directed therapy. In this pilot study we have compared the urine metabolic profiles of two groups of subjects having similar TB symptoms and categorized as active TB (ATB, n = 21) and non-TB (NTB, n = 21) based on GeneXpert test results. Silylation, gas chromatography mass spectrometry, and standard chemometric methods were employed to identify the important molecules and deregulated metabolic pathways. Eleven active TB patients were followed up on longitudinally for comparative urine metabolic profiling with healthy controls (n = 11). A set of 42 features qualified to have a variable importance parameter score of > 1.5 of a partial least-squares discriminate analysis model and fold change of > 1.5 at p value < 0.05 between ATB and NTB. Using these variables, a receiver operating characteristics curve was plotted and the area under the curve was calculated to be 0.85 (95% CI: 0.72-0.96). Several of these variables that represent norepinephrine, gentisic acid, 4-hydroxybenzoic acid, hydroquinone, and 4-hydroxyhippuric acid are part of the tyrosine-phenylalanine metabolic pathway. In the longitudinal study we observed a treatment-dependent trend in the urine metabolome of follow-up samples, and subjects declared as clinically cured showed similar metabolic profile as those of asymptomatic healthy subjects. The deregulated tyrosine-phenylalanine axis reveals a potential target for diagnostics and intervention in TB. PMID:25693719

  2. Voltage stability analysis in the new deregulated environment

    NASA Astrophysics Data System (ADS)

    Zhu, Tong

    Nowadays, a significant portion of the power industry is under deregulation. Under this new circumstance, network security analysis is more critical and more difficult. One of the most important issues in network security analysis is voltage stability analysis. Due to the expected higher utilization of equipment induced by competition in a power market that covers bigger power systems, this issue is increasingly acute after deregulation. In this dissertation, some selected topics of voltage stability analysis are covered. In the first part, after a brief review of general concepts of continuation power flow (CPF), investigations on various matrix analysis techniques to improve the speed of CPF calculation for large systems are reported. Based on these improvements, a new CPF algorithm is proposed. This new method is then tested by an inter-area transaction in a large inter-connected power system. In the second part, the Arnoldi algorithm, the best method to find a few minimum singular values for a large sparse matrix, is introduced into the modal analysis for the first time. This new modal analysis is applied to the estimation of the point of voltage collapse and contingency evaluation in voltage security assessment. Simulations show that the new method is very efficient. In the third part, after transient voltage stability component models are investigated systematically, a novel system model for transient voltage stability analysis, which is a logical-algebraic-differential-difference equation (LADDE), is offered. As an example, TCSC (Thyristor controlled series capacitors) is addressed as a transient voltage stabilizing controller. After a TCSC transient voltage stability model is outlined, a new TCSC controller is proposed to enhance both fault related and load increasing related transient voltage stability. Its ability is proven by the simulation.

  3. Evaluation of the Effects of Sativex (THC BDS: CBD BDS) on Inhibition of Spasticity in a Chronic Relapsing Experimental Allergic Autoimmune Encephalomyelitis: A Model of Multiple Sclerosis.

    PubMed

    Hilliard, A; Stott, C; Wright, S; Guy, G; Pryce, G; Al-Izki, S; Bolton, C; Giovannoni, G

    2012-01-01

    This study investigated the antispasticity potential of Sativex in mice. Chronic relapsing experimental allergic encephalomyelitis was induced in adult ABH mice resulting in hind limb spasticity development. Vehicle, Sativex, and baclofen (as a positive control) were injected intravenously and the "stiffness" of limbs assessed by the resistance force against hind limb flexion. Vehicle alone caused no significant change in spasticity. Baclofen (5 mg/kg) induced approximately a 40% peak reduction in spasticity. Sativex dose dependently reduced spasticity; 5 mg/kg THC + 5 mg/kg CBD induced approximately a 20% peak reduction; 10 mg/kg THC + 10 mg/kg CBD produced approximately a 40% peak reduction in spasticity. Sativex has the potential to reduce spasticity in an experimental mouse model of multiple sclerosis (MS). Baclofen reduced spasticity and served as a positive control. Sativex (10 mg/kg) was just as effective as baclofen, providing supportive evidence for Sativex use in the treatment of spasticity in MS. PMID:22928118

  4. Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.

    PubMed

    Di Marzo, Vincenzo; Centonze, Diego

    2015-03-01

    Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ(9) -tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale (NRS; ~-20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated. PMID:25475413

  5. Deregulation of miR-183 and KIAA0101 in Aggressive and Malignant Pituitary Tumors

    PubMed Central

    Roche, Magali; Wierinckx, Anne; Croze, Séverine; Rey, Catherine; Legras-Lachuer, Catherine; Morel, Anne-Pierre; Fusco, Alfredo; Raverot, Gérald; Trouillas, Jacqueline; Lachuer, Joel

    2015-01-01

    Changes in microRNAs (miRNAs) expression in many types of cancer suggest that they may be involved in crucial steps during tumor progression. Indeed, miRNAs deregulation has been described in pituitary tumorigenesis, but few studies have described their role in pituitary tumor progression toward aggressiveness and malignancy. To assess the role of miRNAs within the hierarchical cascade of events in prolactin (PRL) tumors during progression, we used an integrative genomic approach to associate clinical–pathological features, global miRNA expression, and transcriptomic profiles of the same human tumors. We describe the specific down-regulation of one principal miRNA, miR-183, in the 8 aggressive (A, grade 2b) compared to the 18 non-aggressive (NA, grades 1a, 2a) PRL tumors. We demonstrate that it acts as an anti-proliferative gene by directly targeting KIAA0101, which is involved in cell cycle activation and inhibition of p53–p21-mediated cell cycle arrest. Moreover, we show that miR-183 and KIAA0101 expression significantly correlate with the main markers of pituitary tumors aggressiveness, Ki-67 and p53. These results confirm the activation of proliferation in aggressive and malignant PRL tumors compared to non-aggressive ones. Importantly, these data also demonstrate the ability of such an integrative genomic strategy, applied in the same human tumors, to identify the molecular mechanisms responsible for tumoral progression even from a small cohort of patients. PMID:26322309

  6. Internet-based wide area measurement applications in deregulated power systems

    NASA Astrophysics Data System (ADS)

    Khatib, Abdel-Rahman Amin

    Since the deregulation of power systems was started in 1989 in the UK, many countries have been motivated to undergo deregulation. The United State started deregulation in the energy sector in California back in 1996. Since that time many other states have also started the deregulation procedures in different utilities. Most of the deregulation market in the United States now is in the wholesale market area, however, the retail market is still undergoing changes. Deregulation has many impacts on power system network operation and control. The number of power transactions among the utilities has increased and many Independent Power Producers (IPPs) now have a rich market for competition especially in the green power market. The Federal Energy Regulatory Commission (FERC) called upon utilities to develop the Regional Transmission Organization (RTO). The RTO is a step toward the national transmission grid. RTO is an independent entity that will operate the transmission system in a large region. The main goal of forming RTOs is to increase the operation efficiency of the power network under the impact of the deregulated market. The objective of this work is to study Internet based Wide Area Information Sharing (WAIS) applications in the deregulated power system. The study is the first step toward building a national transmission grid picture using information sharing among utilities. Two main topics are covered as applications for the WAIS in the deregulated power system, state estimation and Total Transfer Capability (TTC) calculations. As a first step for building this national transmission grid picture, WAIS and the level of information sharing of the state estimation calculations have been discussed. WAIS impacts to the TTC calculations are also covered. A new technique to update the TTC using on line measurements based on WAIS created by sharing state estimation is presented.

  7. Parathyroid hormone linked to a collagen binding domain (PTH-CBD) promotes hair growth in a mouse model of chemotherapy-induced alopecia in a dose-dependent manner

    PubMed Central

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Seymour, Andrew; Sakon, Joshua; Gensure, Robert

    2014-01-01

    Chemotherapy-induced alopecia is a major source of psychological stress in patients undergoing cancer chemotherapy, and can influence treatment decisions. While there is currently no therapy, PTH-CBD, a fusion protein of parathyroid hormone and collagen binding domain, has shown promise in animal models. Objective To determine if there are dose-dependent effects of PTH-CBD on chemotherapy-induced alopecia in a mouse model. Methods C57BL/6J mice were waxed to synchronize hair follicles; treated on day 7 with vehicle or PTH-CBD (100, 320 and 1000 mcg/kg subcutaneous injection); treated on day 9 with vehicle or cyclophosphamide (150 mg/kg i.p.). Mice were photographed every 3–4 days and sacrificed on day 63 for histological analysis. Photographs were quantified by grey scale analysis to assess hair content. Results Mice not receiving chemotherapy showed regrowth of hair 2 weeks following waxing, and normal histology after 2 months. Mice receiving chemotherapy alone showed marked hair loss after chemotherapy, which was sustained for 10 days and was followed by rapid regrowth of a normal coat. Histology revealed rapid cycling dystrophic anagen/catagen follicles. Animals receiving chemotherapy and PTH-CBD showed decreased hair loss and more rapid regrowth of hair than that seen with chemotherapy alone (increased hair growth by grey scale analysis, p<0.05), and the effects were dose dependent. Histologically, hair follicles in animals receiving the highest dose of PTH-CBD were in a quiescent phase, similar to mice which did not receive chemotherapy. Conclusions Single dose subcutaneous administration of PTH-CBD showed dose-dependent effects in minimizing hair loss and speeding recovery from chemotherapy-induced alopecia. PMID:24710191

  8. Neural network based load and price forecasting and confidence interval estimation in deregulated power markets

    NASA Astrophysics Data System (ADS)

    Zhang, Li

    With the deregulation of the electric power market in New England, an independent system operator (ISO) has been separated from the New England Power Pool (NEPOOL). The ISO provides a regional spot market, with bids on various electricity-related products and services submitted by utilities and independent power producers. A utility can bid on the spot market and buy or sell electricity via bilateral transactions. Good estimation of market clearing prices (MCP) will help utilities and independent power producers determine bidding and transaction strategies with low risks, and this is crucial for utilities to compete in the deregulated environment. MCP prediction, however, is difficult since bidding strategies used by participants are complicated and MCP is a non-stationary process. The main objective of this research is to provide efficient short-term load and MCP forecasting and corresponding confidence interval estimation methodologies. In this research, the complexity of load and MCP with other factors is investigated, and neural networks are used to model the complex relationship between input and output. With improved learning algorithm and on-line update features for load forecasting, a neural network based load forecaster was developed, and has been in daily industry use since summer 1998 with good performance. MCP is volatile because of the complexity of market behaviors. In practice, neural network based MCP predictors usually have a cascaded structure, as several key input factors need to be estimated first. In this research, the uncertainties involved in a cascaded neural network structure for MCP prediction are analyzed, and prediction distribution under the Bayesian framework is developed. A fast algorithm to evaluate the confidence intervals by using the memoryless Quasi-Newton method is also developed. The traditional back-propagation algorithm for neural network learning needs to be improved since MCP is a non-stationary process. The extended Kalman

  9. Electricity generation and transmission planning in deregulated power markets

    NASA Astrophysics Data System (ADS)

    He, Yang

    This dissertation addresses the long-term planning of power generation and transmission facilities in a deregulated power market. Three models with increasing complexities are developed, primarily for investment decisions in generation and transmission capacity. The models are presented in a two-stage decision context where generation and transmission capacity expansion decisions are made in the first stage, while power generation and transmission service fees are decided in the second stage. Uncertainties that exist in the second stage affect the capacity expansion decisions in the first stage. The first model assumes that the electric power market is not constrained by transmission capacity limit. The second model, which includes transmission constraints, considers the interactions between generation firms and the transmission network operator. The third model assumes that the generation and transmission sectors make capacity investment decisions separately. These models result in Nash-Cournot equilibrium among the unregulated generation firms, while the regulated transmission network operator supports the competition among generation firms. Several issues in the deregulated electric power market can be studied with these models such as market powers of generation firms and transmission network operator, uncertainties of the future market, and interactions between the generation and transmission sectors. Results deduced from the developed models include (a) regulated transmission network operator will not reserve transmission capacity to gain extra profits; instead, it will make capacity expansion decisions to support the competition in the generation sector; (b) generation firms will provide more power supplies when there is more demand; (c) in the presence of future uncertainties, the generation firms will add more generation capacity if the demand in the future power market is expected to be higher; and (d) the transmission capacity invested by the

  10. Exploring and exploiting the systemic effects of deregulated replication licensing.

    PubMed

    Petrakis, Theodoros G; Komseli, Eirini-Stavroula; Papaioannou, Marilena; Vougas, Kostas; Polyzos, Alexandros; Myrianthopoulos, Vassilios; Mikros, Emmanuel; Trougakos, Ioannis P; Thanos, Dimitris; Branzei, Dana; Townsend, Paul; Gorgoulis, Vassilis G

    2016-06-01

    Maintenance and accurate propagation of the genetic material are key features for physiological development and wellbeing. The replication licensing machinery is crucial for replication precision as it ensures that replication takes place once per cell cycle. Thus, the expression status of the components comprising the replication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress that leads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basis of replication licensing deregulation, which leads to systemic effects, exemplified by its role in carcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above a particular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outlining new lines of exploration. The role of the putative replication licensing factor ChlR1/DDX11, mutated in the Warsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on the potential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, are discussed. PMID:26707000

  11. Price-elastic demand in deregulated electricity markets

    SciTech Connect

    Siddiqui, Afzal S.

    2003-05-01

    The degree to which any deregulated market functions efficiently often depends on the ability of market agents to respond quickly to fluctuating conditions. Many restructured electricity markets, however, experience high prices caused by supply shortages and little demand-side response. We examine the implications for market operations when a risk-averse retailer's end-use consumers are allowed to perceive real-time variations in the electricity spot price. Using a market-equilibrium model, we find that price elasticity both increases the retailers revenue risk exposure and decreases the spot price. Since the latter induces the retailer to reduce forward electricity purchases, while the former has the opposite effect, the overall impact of price responsive demand on the relative magnitudes of its risk exposure and end-user price elasticity. Nevertheless, price elasticity decreases cumulative electricity consumption. By extending the analysis to allow for early settlement of demand, we find that forward stage end-user price responsiveness decreases the electricity forward price relative to the case with price-elastic demand only in real time. Moreover, we find that only if forward stage end-user demand is price elastic will the equilibrium electricity forward price be reduced.

  12. Issues in the deregulation of the electric industry

    NASA Astrophysics Data System (ADS)

    Tyler, Cleve Brent

    The electric industry is undergoing a major restructuring which allows competition in the generation portion of the industry. This dissertation explores several pricing issues relevant to this restructuring. First, an extensive overview examines the industry's history, discusses major regulation theories, and relays the major issues of deregulation. Second, a literature review recounts major works in the economics literature on price discrimination, pricing efficiency, and cost estimation. Then, customer specific generation, transmission, distribution, and general and administration costs are estimated for each company. The customer classes are residential, general service, large general service, and large industrial, representing a finer division of customer classes than found in previous studies. Average prices are compiled and marginal prices are determined from a set of utility schedules. Average and marginal price/cost ratios are computed for each customer class. These ratios show that larger use customers face relative price discrimination but operate under more efficient price structures than small use consumers. Finally, issues in peak load pricing are discussed using a model which predicts inefficient capital choice by regulated utilities. Efficiency losses are estimated to be $620 million dollars a year from the lack of peak load prices under regulation. This result is based on the time-of-use pricing predictions from the Department of Energy.

  13. Deregulation of lipid metabolism pathway genes in nasopharyngeal carcinoma cells.

    PubMed

    Daker, Maelinda; Bhuvanendran, Saatheeyavaane; Ahmad, Munirah; Takada, Kenzo; Khoo, Alan Soo-Beng

    2013-03-01

    Nasopharyngeal carcinoma (NPC) is a unique tumour of epithelial origin with a distinct geographical distribution, closely associated with the Epstein‑Barr virus (EBV). EBV‑encoded RNAs (EBERs) are small non‑polyadenylated RNAs that are abundantly expressed in latent EBV‑infected NPC cells. To study the role of EBERs in NPC, we established stable expression of EBERs in HK1, an EBV‑negative NPC cell line. Cells expressing EBERs consistently exhibited an increased growth rate. However, EBERs did not confer resistance towards cisplatin‑induced apoptosis or promote migration or invasion ability in the cells tested. Using microarray gene expression profiling, we identified potential candidate genes that were deregulated in NPC cells expressing EBERs. Gene Ontology analysis of the data set revealed that EBERs upregulate the cellular lipid metabolic process. Upregulation of low‑density lipoprotein receptor (LDLR) and fatty acid synthase (FASN) was observed in EBER‑expressing cells. NPC cells exhibited LDL‑dependent cell proliferation. In addition, a polyphenolic flavonoid compound, quercetin, known to inhibit FASN, was found to inhibit proliferation of NPC cells. PMID:23292678

  14. Navigating market transformation through New England's minefield of deregulation

    SciTech Connect

    Albert, S.

    1998-07-01

    Massachusetts is now six months into its first year of implementing a number of regional market transformation initiatives in a restructured electric utility industry environment. Recently, the future of utility-subsidized energy efficiency programs has been one of many issues addressed by key parties to the ongoing industry restructuring debates. Straight from the front-lines of the scarred Massachusetts deregulation battlegrounds, this paper provides a retrospective on Boston Edison Company's efforts to design and deliver some innovative new energy efficiency initiatives. Although veteran readers may be able to relate and share war stories, it is hoped that this paper will provide a small glimpse of the future to new recruits so that they are better prepared to recognize and navigate their energy efficiency program soldiers through the restructuring landmines laid before them. This paper first provides a short introduction to set the stage regarding the evolving situation on various fronts (i.e. the status of industry restructuring in Massachusetts, potential directions for energy efficiency, key parties engaged in the debate). Readers will then be guided through some major issues encountered and how they were addressed to procure regional support and regulatory approval (i.e. market transformation definitions, collaboration, exit strategies, etc.). A sampling of some innovative and regional energy efficiency initiatives follows along with discussion of their market barriers, evaluation metrics, delivery mechanisms, and any unique administrative approaches. Finally, the paper ends with some thoughts on what worked, what didn't, and how things could have been done better or differently.

  15. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.

    PubMed

    Langford, R M; Mares, J; Novotna, A; Vachova, M; Novakova, I; Notcutt, W; Ratcliffe, S

    2013-04-01

    Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically

  16. Effects of the Deregulation on the Concentration of the Brazilian Air Transportation Industry

    NASA Technical Reports Server (NTRS)

    Guterres, Marcelo Xavier; Muller, Carlos

    2003-01-01

    This paper addresses the effects of the deregulation of the Brazilian air transportation industry in terms of the concentration of the market. We will show some metrics that are commonly used to study the concentration of the industry. This paper uses the Herfindhal- Hirschman Index. This index tends to zero in the competitive scenario, with a large number of small firms, and to one in case of a monopolistic scenario. The paper analyses the dynamics of the concentration of the Brazilian domestic air transportation market, in order to evaluate the effects of deregulation. We conclude that the Brazilian market presents oligopoly characteristics and aspects in its current structure that maintain the market concentrated in spite of the Deregulation measures adopted by the aeronautical authority. Keywords: Herfindhal-Hirschman Index, concentration, Deregulation

  17. Recessive genetic deregulation abrogates c-myc suppression by interferon and is implicated in oncogenesis

    SciTech Connect

    Kimchi, A.; Resnitzky, D.; Ber, R.; Gat, G.

    1988-07-01

    Previously the authors demonstrated that many hematopoietic tumor cells are resistant to the inhibitory effects that interferon exerts on c-myc mRNA expression without losing other receptor-mediated intracellular responses. They report here that this partial resistance was overridden in two independent stable somatic cell hybrids prepared by fusion between sensitive and resistant cells. The c-myc mRNA transcribed from the active allele of the resistant parent cell was reduced by interferon within the context of the cell hybrid. It was therefore concluded that changes in the cis-acting sequences of c-myc were not involved in this type of relaxed regulation and that resistance resulted rather from inactivation or loss of postreceptor elements which operate in trans. The growth-stimulating effect that this genetic deregulation might have on cells was tested in experimental systems of cell differentiation in which an autocrine interferon is produced. For that purpose the authors isolated variant clones of M1 myeloid cells which were partially resistant to alpha and beta interferons and tested their growth behaviour during in vitro-induced differentiation. The resistant clones displayed higher proliferative activity on days 2 and 3 of differentiation than did the sensitive clones, which stopped proliferating. The loss of c-myc responses to the self-produced interferon disrupted the normal cessation of growth during differentiation and therefore might lead cells along the pathway of neoplasia.

  18. Average Rank-Based Score to Measure Deregulation of Molecular Pathway Gene Sets

    PubMed Central

    Zhang, Wei

    2011-01-01

    Background Deregulation of biological pathways has been shown to be involved in the turmorigenesis of a variety of cancers. The co-regulation of pathways in tumor and normal tissues has not been studied in a systematic manner. Results In this study we propose a novel statistic named AR-score (average rank based score) to measure pathway activities based on microarray gene expression profiles. We calculate and compare the AR-scores of pathways in microarray datasets containing expression profiles for a wide range of cancer types as well as the corresponding normal tissues. We find that many pathways undergo significant activity changes in tumors with respect to normal tissues. AR-scores for a small subset of pathways are capable of distinguishing tumor from normal tissues or classifying tumor subtypes. In normal tissues many pathways are highly correlated in their activities, whereas their correlations reduce significantly in tumors and cancer cell lines. The co-expression of genes in the same pathways was also significantly perturbed in tumors. Conclusions The co-regulation of genes in the same pathways and co-regulation of different pathways are significantly perturbed in tumors versus normal tissues. Our method provides a useful tool for better understanding the mechanistic changes in tumors, which can also be used for exploring other biological problems. PMID:22096597

  19. Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling.

    PubMed

    Osorio, Fernando G; Soria-Valles, Clara; Santiago-Fernández, Olaya; Bernal, Teresa; Mittelbrunn, María; Colado, Enrique; Rodríguez, Francisco; Bonzon-Kulichenko, Elena; Vázquez, Jesús; Porta-de-la-Riva, Montserrat; Cerón, Julián; Fueyo, Antonio; Li, Juan; Green, Anthony R; Freije, José M P; López-Otín, Carlos

    2016-01-01

    AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias. PMID:26692333

  20. Image is all: Deregulation, restructuring and reputation in the natural gas industry

    SciTech Connect

    1997-09-01

    Does image affect how one views his local utility company--or energy supplier? Does one value his utility companies more if one sees a lot of image advertising and public relations stories about community involvement, environmental action and charitable work? Or does one view utilities as faceless and anonymous entities that provide necessary services one thinks little about until there`s a problem? And, more important, what is the role of utility image in an era of deregulation, as companies begin a new scramble for customers? To find an answer to these questions, American Gas and Christopher Bonner Consultants conducted a survey of A.G.A. member companies to learn what, if anything, utility companies are doing in the areas of image assessment and change. The survey was sent to more than 200 A.G.A. member companies; written responses were received from 35. In addition, 13 follow-up telephone interviews were conducted, including four with companies that had not responded in writing. The picture that emerges if of an industry that is starting to pay greater and greater attention to image. And, as utilities reorganize and redefine themselves, they are also reexamining the ways they communicate with key audiences, including employees, customers, legislators, the financial community and the news media.

  1. hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions

    PubMed Central

    2012-01-01

    Background Gastric cancer is a serious public health problem in Northern Brazil and in the world due to its high incidence and mortality. Despite the severity of the disease, more research is needed to better understand the molecular events involved in this intestinal-type gastric carcinogenesis process. Since precancerous lesions precede intestinal-type gastric cancer, here, we evaluated the hTERT, MYC, and TP53 mRNA and protein expression, as well as TP33 copy number, in gastric preneoplastic lesions. Methods We evaluated 19 superficial gastritis, 18 atrophic gastritis, and 18 intestinal metaplasia from cancer-free individuals of Northern Brazil. Quantitative reverse transcription PCR was used to analyze the mRNA expression and immunohistochemical methods were used to assess protein immunoreactivity in tissue samples. The number of TP53 gene copies was investigated in gastric diseases by quantitative PCR. Results We observed hTERT, MYC, and p53 immunoreactivity only in intestinal metaplasia samples. The immunoreactivity of these proteins was strongly associated with each other. A significantly higher MYC mRNA expression was observed in intestinal metaplasia compared to gastritis samples. Loss of TP53 was also only detected in intestinal metaplasia specimens. Conclusions We demonstrated that hTERT, MYC, and TP53 are deregulated in intestinal metaplasia of individuals from Northern Brazil and these alterations may facilitate tumor initiation. PMID:22768805

  2. Epigenetic Deregulation of MicroRNAs in Rhabdomyosarcoma and Neuroblastoma and Translational Perspectives

    PubMed Central

    Romania, Paolo; Bertaina, Alice; Bracaglia, Giorgia; Locatelli, Franco; Fruci, Doriana; Rota, Rossella

    2012-01-01

    Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, such as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal precursors, respectively, blocked at different stages of differentiation. Consistently, tumor cells express tissue markers of origin but are unable to terminally differentiate. Several microRNAs playing a key role during tissue differentiation are often epigenetically downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has provided encouraging results causing re-expression of anti-tumor master gene pathways. Thus, a similar approach could be used to correct the aberrant epigenetic regulation of microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and neuroblastoma and their role in tumorigenesis and developmental pathways. The translational clinical implications and challenges regarding modulation of epigenetic chromatin remodeling/microRNAs interconnections are also discussed. PMID:23443118

  3. Tungstate, a Molybdate Analog Inactivating Nitrate Reductase, Deregulates the Expression of the Nitrate Reductase Structural Gene

    PubMed Central

    Deng, Mingde; Moureaux, Thérèse; Caboche, Michel

    1989-01-01

    Nitrate reductase (NR, EC 1.6.6.1) from higher plants is a homodimeric enzyme carrying a molybdenum cofactor at the catalytic site. Tungsten can be substituted for molybdenum in the cofactor structure, resulting in an inactive enzyme. When nitratefed Nicotiana tabacum plants were grown on a nutrient solution in which tungstate was substituted for molybdate, NR activity in the leaves decreased to a very low level within 24 hours while NR protein accumulated progressively to a level severalfold higher than the control after 6 days. NR mRNA level in molybdate-grown plants exhibited a considerable day-night fluctuation. However, when plants were treated with tungstate, NR mRNA level remained very high. NR activity and protein increased over a 24-hour period when nitrate was added back to N-starved molybdate-grown plants. NR mRNA level increased markedly during the first 2 hours and then decreased. In the presence of tungstate, however, the induction of NR activity by nitrate was totally abolished while high levels of NR protein and mRNA were both induced, and the high level of NR mRNA was maintained over a 10-hour period. These results suggest that the substitution of tungsten for molybdenum in NR complex leads to an overexpression of the NR structural gene. Possible mechanisms involved in this deregulation are discussed. Images Figure 2 Figure 3 Figure 5 PMID:16667015

  4. Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability.

    PubMed

    Herrero, Ana B; San Miguel, Jesús; Gutierrez, Norma C

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy characterized by frequent chromosome abnormalities. However, the molecular basis for this genome instability remains unknown. Since both impaired and hyperactive double strand break (DSB) repair pathways can result in DNA rearrangements, we investigated the functionality of DSB repair in MM cells. Repair kinetics of ionizing-radiation (IR)-induced DSBs was similar in MM and normal control lymphoblastoid cell lines, as revealed by the comet assay. However, four out of seven MM cell lines analyzed exhibited a subset of persistent DSBs, marked by γ-H2AX and Rad51 foci that elicited a prolonged G2/M DNA damage checkpoint activation and hypersensitivity to IR, especially in the presence of checkpoint inhibitors. An analysis of the proteins involved in DSB repair in MM cells revealed upregulation of DNA-PKcs, Artemis and XRCC4, that participate in non-homologous end joining (NHEJ), and Rad51, involved in homologous recombination (HR). Accordingly, activity of both NHEJ and HR were elevated in MM cells compared to controls, as determined by in vivo functional assays. Interestingly, levels of proteins involved in a highly mutagenic, translocation-promoting, alternative NHEJ subpathway (Alt-NHEJ) were also increased in all MM cell lines, with the Alt-NHEJ protein DNA ligase IIIα, also overexpressed in several plasma cell samples isolated from MM patients. Overactivation of the Alt-NHEJ pathway was revealed in MM cells by larger deletions and higher sequence microhomology at repair junctions, which were reduced by chemical inhibition of the pathway. Taken together, our results uncover a deregulated DSB repair in MM that might underlie the characteristic genome instability of the disease, and could be therapeutically exploited. PMID:25790254

  5. Fuel, environmental, and transmission pricing considerations in a deregulated environment

    NASA Astrophysics Data System (ADS)

    Obessis, Emmanouil Vlassios

    The 1992 National Energy Policy Act drastically changed the traditional structure of the vertically integrated utility. To facilitate increased competition in the power utility sector, all markets related to power generation have been opened to free competition and trading. To survive in the new competitive environment, power producers need to reduce costs and increase efficiency. Fuel marketing strategies are thus, getting more aggressive and fuel markets are becoming more competitive, offering more options regarding fuel supplies and contracts. At the same time, the 1990 Clean Air Act Amendments are taking effect. Although tightening the emission standards, this legislation offers utilities a wider flexibility in choosing compliance strategies. It also set maximum annual allowable levels replacing the traditional uniform maximum emission rates. The bill also introduced the concept of marketable emission allowances and provided for the establishment of nationwide markets where allowances may be traded, sold, or purchased. Several fuel- and emission-constrained algorithms have been historically presented, but those two classes of constraints, in general, were handled independently. The multiobjective optimization model developed in this research work, concurrently satisfies sets of detailed fuel and emission limits, modeling in a more accurate way the fuel supply and environmental limitations and their complexities in the new deregulated operational environment. Development of the implementation software is an integral part of this research project. This software may be useful for both daily scheduling activities and short-term operational planning. A Lagrangian multipliers-based variant is used to solve the problem. Single line searches are used to update the multipliers, thus offering attractive execution times. This work also investigates the applicability of cooperative games to the problem of transmission cost allocation. Interest in game theory as a powerful

  6. Global Profiling in Vestibular Schwannomas Shows Critical Deregulation of MicroRNAs and Upregulation in Those Included in Chromosomal Region 14q32

    PubMed Central

    Torres-Martin, Miguel; Lassaletta, Luis; de Campos, Jose M.; Isla, Alberto; Gavilan, Javier; Pinto, Giovanny R.; Burbano, Rommel R.; Latif, Farida; Melendez, Barbara; Castresana, Javier S.; Rey, Juan A.

    2013-01-01

    Background Vestibular schwannomas are benign tumors that arise from Schwann cells in the VIII cranial pair and usually present NF2 gene mutations and/or loss of heterozygosity on chromosome 22q. Deregulation has also been found in several genes, such as ERBB2 and NRG1. MicroRNAs are non-coding RNAs approximately 21 to 23 nucleotides in length that regulate mRNAs, usually by degradation at the post-transcriptional level. Methods We used microarray technology to test the deregulation of miRNAs and other non-coding RNAs present in GeneChip miRNA 1.0 (Affymetrix) over 16 vestibular schwannomas and 3 control-nerves, validating 10 of them by qRT-PCR. Findings Our results showed the deregulation of 174 miRNAs, including miR-10b, miR-206, miR-183 and miR-204, and the upregulation of miR-431, miR-221, miR-21 and miR-720, among others. The results also showed an aberrant expression of other non-coding RNAs. We also found a general upregulation of the miRNA cluster located at chromosome 14q32. Conclusion Our results suggest that several miRNAs are involved in tumor formation and/or maintenance and that global upregulation of the 14q32 chromosomal site contains miRNAs that may represent a therapeutic target for this neoplasm. PMID:23776562

  7. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol.

    PubMed

    Gomes, Felipe V; Llorente, Ricardo; Del Bel, Elaine A; Viveros, Maria-Paz; López-Gallardo, Meritxell; Guimarães, Francisco S

    2015-05-01

    NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and glial cells, such as microglia and astrocytes, have been related to the pathogenesis of schizophrenia. Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa with anti-inflammatory and neuroprotective properties induces antipsychotic-like effects. The present study evaluated if repeated treatment with CBD (30 and 60 mg/kg) would attenuate the behavioral and glial changes observed in an animal model of schizophrenia based on the NMDA receptor hypofunction (chronic administration of MK-801, an NMDA receptor antagonist, for 28 days). The behavioral alterations were evaluated in the social interaction and novel object recognition (NOR) tests. These tests have been widely used to study changes related to negative symptoms and cognitive deficits of schizophrenia, respectively. We also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Repeated MK-801 administration impaired performance in the social interaction and NOR tests. It also increased the number of GFAP-positive astrocytes in the mPFC and the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. No change in the number of NeuN-positive cells was observed. Both the behavioral disruptions and the changes in expression of glial markers induced by MK-801 treatment were attenuated by repeated treatment with CBD or clozapine. These data reinforces the proposal

  8. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract.

    PubMed

    Nadulski, Thomas; Pragst, Fritz; Weinberg, Gordon; Roser, Patrik; Schnelle, Martin; Fronk, Eva-Maria; Stadelmann, Andreas Michael

    2005-12-01

    Cannabidiol (CBD) is known to modify the effects of Delta-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. As a reason, pharmacodynamic as well as pharmacokinetic mechanisms were suggested. In context of the use of cannabis-based medicine extracts for therapeutic purposes, a study was performed in a double-blind and placebo-controlled cross-over design in which each of 24 volunteers (12 male and 12 female, age 18-45 years) obtained soft-gelatin capsules with 10 mg THC (THC-set), cannabis extract containing 10 mg THC +5.4 mg CBD (CAN-set) or placebo in weekly intervals. Blood samples were taken 30 minutes before and 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours and 24 hours after the intake. The concentrations of THC, of its metabolites 11-OH-THC, THC-COOH and of CBD in the plasma samples were determined by automatic solid phase extraction, derivatization with N,O-bis(trimethylsilyl)triflouroacetamide and gas chromatography-mass spectrometry. The concentration versus time curves (maximum concentrations Cmax, corresponding time tmax and areas under the curves AUC) were evaluated by statistical methods with respect to equivalence or differences between the CAN-set and the THC-set. Furthermore, the intra-individual ratios of Cmax and AUC for 11-OH-THC/THC, THC-COOH/THC and THC-COOH/11-OH-THC were compared between the THC-set and the CAN-set. Despite the large variation of the data, evidence emerged from the total of the results that CBD partially inhibits the CYP 2C catalyzed hydroxylation of THC to 11-OH-THC. The probability for this inhibition is particularly high for oral intake because THC and CBD attain relatively high concentrations in the liver and because of the high first-pass metabolism of THC. However, the effect of CBD is small in comparison to the variability caused by other factors. Therefore, a pharmacokinetic reason for the differences determined between pure THC and cannabis extract is improbable at

  9. Effects of air annealing on CdS quantum dots thin film grown at room temperature by CBD technique intended for photosensor applications

    SciTech Connect

    Shaikh, Shaheed U.; Desale, Dipalee J.; Siddiqui, Farha Y.; Ghosh, Arindam; Birajadar, Ravikiran B.; Ghule, Anil V.; Sharma, Ramphal

    2012-11-15

    Graphical abstract: The effect of different intensities (40, 60 100 and 200 W) of light on CdS quantum dots thin film annealed at 350 °C indicating enhancement in (a) photo-current and (b) photosensitivity. Highlights: ► The preparation of CdS nanodot thin film at room temperature by M-CBD technique. ► Study of air annealing on prepared CdS nanodots thin film. ► The optimized annealing temperature for CdS nanodot thin film is 350 °C. ► Modified CdS thin films can be used in photosensor application. -- Abstract: CdS quantum dots thin-films have been deposited onto the glass substrate at room temperature using modified chemical bath deposition technique. The prepared thin films were further annealed in air atmosphere at 150, 250 and 350 °C for 1 h and subsequently characterized by scanning electron microscopy, ultraviolet–visible spectroscopy, electrical resistivity and I–V system. The modifications observed in morphology and opto-electrical properties of the thin films are presented.

  10. Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia.

    PubMed

    Takahashi, Ryutaro; Yamagishi, Makoto; Nakano, Kazumi; Yamochi, Toshiko; Yamochi, Tadanori; Fujikawa, Dai; Nakashima, Makoto; Tanaka, Yuetsu; Uchimaru, Kaoru; Utsunomiya, Atae; Watanabe, Toshiki

    2014-09-01

    One of the hallmarks of cancer, global gene expression alteration, is closely associated with the development and malignant characteristics associated with adult T-cell leukemia (ATL) as well as other cancers. Here, we show that aberrant overexpression of the Ellis Van Creveld (EVC) family is responsible for cellular Hedgehog (HH) activation, which provides the pro-survival ability of ATL cells. Using microarray, quantitative RT-PCR and immunohistochemistry we have demonstrated that EVC is significantly upregulated in ATL and human T-cell leukemia virus type I (HTLV-1)-infected cells. Epigenetic marks, including histone H3 acetylation and Lys4 trimethylation, are specifically accumulated at the EVC locus in ATL samples. The HTLV-1 Tax participates in the coordination of EVC expression in an epigenetic fashion. The treatment of shRNA targeting EVC, as well as the transcription factors for HH signaling, diminishes the HH activation and leads to apoptotic death in ATL cell lines. We also showed that a HH signaling inhibitor, GANT61, induces strong apoptosis in the established ATL cell lines and patient-derived primary ATL cells. Therefore, our data indicate that HH activation is involved in the regulation of leukemic cell survival. The epigenetically deregulated EVC appears to play an important role for HH activation. The possible use of EVC as a specific cell marker and a novel drug target for HTLV-1-infected T-cells is implicated by these findings. The HH inhibitors are suggested as drug candidates for ATL therapy. Our findings also suggest chromatin rearrangement associated with active histone markers in ATL. PMID:24996003

  11. Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model.

    PubMed

    Bhatta, Anil; Sangani, Rajnikumar; Kolhe, Ravindra; Toque, Haroldo A; Cain, Michael; Wong, Abby; Howie, Nicole; Shinde, Rahul; Elsalanty, Mohammed; Yao, Lin; Chutkan, Norman; Hunter, Monty; Caldwell, Ruth B; Isales, Carlos; Caldwell, R William; Fulzele, Sadanand

    2016-02-15

    A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of l-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of l-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases. PMID:26704078

  12. Microarray analysis of gene expression in vestibular schwannomas reveals SPP1/MET signaling pathway and androgen receptor deregulation

    PubMed Central

    TORRES-MARTIN, MIGUEL; LASSALETTA, LUIS; SAN-ROMAN-MONTERO, JESUS; DE CAMPOS, JOSE M.; ISLA, ALBERTO; GAVILAN, JAVIER; MELENDEZ, BARBARA; PINTO, GIOVANNY R.; BURBANO, ROMMEL R.; CASTRESANA, JAVIER S.; REY, JUAN A.

    2013-01-01

    Vestibular schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of neurofibromin 2 (NF2). Transcriptomic alterations, such as the neuregulin 1 (NRG1)/ErbB2 pathway, have been described in schwannomas. In this study, we performed a whole transcriptome analysis in 31 vestibular schwannomas and 9 control nerves in the Affymetrix Gene 1.0 ST platform, validated by quantitative real-time PCR (qRT-PCR) using TaqMan Low Density arrays. We performed a mutational analysis of NF2 by PCR/denaturing high-performance liquid chromatography (dHPLC) and multiplex ligation-dependent probe amplification (MLPA), as well as a microsatellite marker analysis of the loss of heterozygosity (LOH) of chromosome 22q. The microarray analysis demonstrated that 1,516 genes were deregulated and 48 of the genes were validated by qRT-PCR. At least 2 genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed 1 hit and 8 tumors showed no NF2 alteration. MET and associated genes, such as integrin, alpha 4 (ITGA4)/B6, PLEXNB3/SEMA5 and caveolin-1 (CAV1) showed a clear deregulation in vestibular schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in schwannoma merlin depletion. Finally, no major differences were observed among tumors of different size, histological type or NF2 status, which suggests that, at the mRNA level, all schwannomas, regardless of their molecular and clinical characteristics, may share common features that can be used in their treatment. PMID:23354516

  13. MiR-9, -31, and -182 Deregulation Promote Proliferation and Tumor Cell Survival in Colon Cancer12

    PubMed Central

    Cekaite, Lina; Rantala, Juha K; Bruun, Jarle; Guriby, Marianne; Ågesen, Trude H; Danielsen, Stine A; Lind, Guro E; Nesbakken, Arild; Kallioniemi, Olli; Lothe, Ragnhild A; Skotheim, Rolf I

    2012-01-01

    Several microRNAs (miRNAs) are known to be deregulated in colon cancer, but the mechanisms behind their potential involvement on proliferation and tumor cell survival are unclear. The present study aimed to identify miRNAs with functional implications for development of colon cancer. The cell proliferation and apoptosis were examined following perturbations of miRNA levels by employing a comprehensive miRNA library screen. miRNAs nominated for relevance to colon cancer were validated on expression and functional levels. By integrating the effect of miRNA up-regulation with the endogenous miRNA expression levels within the HT29, HCT116, and SW480 colon cancer cell lines, we identified miRNAs controlling cell proliferation (n = 53) and apoptosis (n = 93). From these functionally nominated miRNAs, we narrowed the list to 10 oncogene- and 20 tumor suppressor-like miRNAs that were also differentially expressed between colon cancer (n = 80) and normal colonic mucosa (n = 20). The differential expressions of miR-9, miR-31, and miR-182 were successfully validated in a series of colon carcinomas (n = 30) and polyps (n = 10) versus normal colonic mucosa (n = 10), whereas the functional effect was confirmed in an in-depth validation using different cell viability and apoptotic markers. Several transcription factors and genes regulating cell proliferation were identified as putative target genes by integrative miRNA/mRNA expression analysis obtained from the same colon cancer patient samples. This study suggests that deregulated expression of miR-9, miR-31, and miR-182 during carcinogenesis plays a significant role in the development of colon cancer by promoting proliferation and tumor cell survival. PMID:23019418

  14. 26 CFR 1.168(i)-3 - Treatment of excess deferred income tax reserve upon disposition of deregulated public utility...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... upon disposition of deregulated public utility property. 1.168(i)-3 Section 1.168(i)-3 Internal Revenue... (CONTINUED) Itemized Deductions for Individuals and Corporations § 1.168(i)-3 Treatment of excess deferred... of section 168(i)(10)) that ceases, whether by disposition, deregulation, or otherwise, to be...

  15. 26 CFR 1.168(i)-3 - Treatment of excess deferred income tax reserve upon disposition of deregulated public utility...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... upon disposition of deregulated public utility property. 1.168(i)-3 Section 1.168(i)-3 Internal Revenue... (CONTINUED) Itemized Deductions for Individuals and Corporations § 1.168(i)-3 Treatment of excess deferred... of section 168(i)(10)) that ceases, whether by disposition, deregulation, or otherwise, to be...

  16. Behavior of Photocarriers in the Light-Induced Metastable State in the p-n Heterojunction of a Cu(In,Ga)Se2 Solar Cell with CBD-ZnS Buffer Layer.

    PubMed

    Lee, Woo-Jung; Yu, Hye-Jung; Wi, Jae-Hyung; Cho, Dae-Hyung; Han, Won Seok; Yoo, Jisu; Yi, Yeonjin; Song, Jung-Hoon; Chung, Yong-Duck

    2016-08-31

    We fabricated Cu(In,Ga)Se2 (CIGS) solar cells with a chemical bath deposition (CBD)-ZnS buffer layer grown with varying ammonia concentrations in aqueous solution. The solar cell performance was degraded with increasing ammonia concentration, due to actively dissolved Zn atoms during CBD-ZnS precipitation. These formed interfacial defect states, such as hydroxide species in the CBD-ZnS film, and interstitial and antisite Zn defects at the p-n heterojunction. After light/UV soaking, the CIGS solar cell performance drastically improved, with a rise in fill factor. With the Zn-based buffer layer, the light soaking treatment containing blue photons induced a metastable state and enhanced the CIGS solar cell performance. To interpret this effect, we suggest a band structure model of the p-n heterojunction to explain the flow of photocarriers under white light at the initial state, and then after light/UV soaking. The determining factor is a p+ defect layer, containing an amount of deep acceptor traps, located near the CIGS surface. The p+ defect layer easily captures photoexcited electrons, and then when it becomes quasi-neutral, attracts photoexcited holes. This alters the barrier height and controls the photocurrent at the p-n junction, and fill factor values, determining the solar cell performance. PMID:27494649

  17. Internationalization, Deregulation and the Extension of Higher Education in Korea: A Further Note

    ERIC Educational Resources Information Center

    Jin, Jang C.

    2015-01-01

    The Korean government implemented several educational policies to enhance internationalization of higher education such as deregulation of higher education, classroom instructions in English, and faculty publications in international refereed journals. However, the speed of globalization has been lagging behind (Green, 2015). Alternatively, this…

  18. Short-Term Effects of State Deregulation on the Adequacy and Equity of School Facility Projects.

    ERIC Educational Resources Information Center

    Kowalski, Theodore J.; Decman, John C.

    2002-01-01

    In 1995, the Indiana Legislature deregulated state controls over public-school construction projects by reducing the status of required specifications to guidelines. Also, local taxpayers were given greater authority to prevent proposed projects. This study examines the short-term effects of this policy shift. (Contains 5 tables and 16…

  19. The Italian Middle School in a Deregulation Era: Modernity through Path-Dependency and Global Models

    ERIC Educational Resources Information Center

    Mincu, Monica E.

    2015-01-01

    In the current context of intensified moves towards educational deregulation, the configuration of the Italian middle school and its relationship to education governance is an interesting case. Historically, it represents a unique example of the successful "decision-making" model of the welfarist era. Despite some internal constraints,…

  20. The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication

    PubMed Central

    Ou, Horng D.; May, Andrew P.

    2010-01-01

    One of the greatest challenges in biomedicine is to define the critical targets and network interactions that are subverted to elicit growth deregulation in human cells. Understanding and developing rational treatments for cancer requires a definition of the key molecular targets and how they interact to elicit the complex growth deregulation phenotype. Viral proteins provide discerning and powerful probes to understand both how cells work and how they can be manipulated using a minimal number of components. The small DNA viruses have evolved to target inherent weaknesses in cellular protein interaction networks to hijack the cellular DNA and protein replication machinery. In the battle to escape the inevitability of senescence and programmed cell death, cancers have converged on similar mechanisms, through the acquisition and selection of somatic mutations that drive unchecked cellular replication in tumors. Understanding the dynamic mechanisms through which a minimal number of viral proteins promote host cells to undergo unscheduled and pathological replication is a powerful strategy to identify critical targets that are also disrupted in cancer. Viruses can therefore be used as tools to probe the system-wide protein-protein interactions and structures that drive growth deregulation in human cells. Ultimately this can provide a path for developing system context-dependent therapeutics. This review will describe ongoing experimental approaches using viruses to study pathways deregulated in cancer, with a particular focus on viral cellular protein-protein interactions and structures. PMID:21061422

  1. Deregulation and the Structure of Rural Financial Markets. Rural Development Research Report Number 75.

    ERIC Educational Resources Information Center

    Milkove, Daniel L.; Sullivan, Patrick J.

    Changes in rural financial markets as affected by bank deregulation have a potential impact on rural educational finance, specifically, financial aid programs for students and schools. Banking legislation and regulation changes have aimed to strengthen the industry and to provide consumers with more services and more choices among providers.…

  2. Ruling Out Rules: The Evolution of Deregulation in State Education Policy.

    ERIC Educational Resources Information Center

    Fuhrman, Susan H.; Elmore, Richard F.

    In the late 1980s and 1990s, states began working to decrease the level of regulation of public education, using a variety of approaches to regulatory flexibility. This paper examines the evolution of deregulation, from limited waiver programs to charter-school plans and new performance-based accountability systems that include broad-scale…

  3. The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication.

    PubMed

    Ou, Horng D; May, Andrew P; O'Shea, Clodagh C

    2011-01-01

    One of the greatest challenges in biomedicine is to define the critical targets and network interactions that are subverted to elicit growth deregulation in human cells. Understanding and developing rational treatments for cancer requires a definition of the key molecular targets and how they interact to elicit the complex growth deregulation phenotype. Viral proteins provide discerning and powerful probes to understand both how cells work and how they can be manipulated using a minimal number of components. The small DNA viruses have evolved to target inherent weaknesses in cellular protein interaction networks to hijack the cellular DNA and protein replication machinery. In the battle to escape the inevitability of senescence and programmed cell death, cancers have converged on similar mechanisms, through the acquisition and selection of somatic mutations that drive unchecked cellular replication in tumors. Understanding the dynamic mechanisms through which a minimal number of viral proteins promote host cells to undergo unscheduled and pathological replication is a powerful strategy to identify critical targets that are also disrupted in cancer. Viruses can therefore be used as tools to probe the system-wide protein-protein interactions and structures that drive growth deregulation in human cells. Ultimately this can provide a path for developing system context-dependent therapeutics. This review will describe ongoing experimental approaches using viruses to study pathways deregulated in cancer, with a particular focus on viral cellular protein-protein interactions and structures. PMID:21061422

  4. Job Placement in Germany: Developments before and after Deregulation. IAB Labour Market Research Topics No. 31.

    ERIC Educational Resources Information Center

    Walwei, Ulrich

    Since 1994, the German public employment service has not had a monopoly on placement. A new law permits private job placement as an independent activity, but only with a license from the public employment service. Since deregulation, the number of job placement licenses has increased continuously, but the number of placements made by private…

  5. Internationalization, Deregulation and the Expansion of Higher Education in Korea: An Historical Overview

    ERIC Educational Resources Information Center

    Green, Christopher

    2015-01-01

    The purpose of this article is to provide an overview of internationalization policies in Korean higher education since 1993. Deregulation was a key strategy of Korean governments, but this strategy has led to an increasing oversupply of enrolment capacity. In response, the current government is implementing a system of reregulation to reduce the…

  6. 75 FR 68321 - Forage Genetics International; Supplemental Request for Partial Deregulation of Roundup Ready...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-05

    ...The Animal and Plant Inspection Service has received a supplemental request for ``partial deregulation'' from Forage Genetics International for the planting, harvesting, and movement interstate of Roundup Ready[reg] alfalfa under measures designed to ensure any risks posed by cultivation are mitigated. This notice seeks to inform interested or affected persons of the availability of the......

  7. Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

    PubMed Central

    Nath, Somsubhra; Chowdhury, Abhishek; Dey, Sanjib; Roychoudhury, Anirban; Ganguly, Abira; Bhattacharyya, Dibyendu

    2014-01-01

    The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to the UBCH10 promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression of UBCH10, leading to chromosomal instability in cancer cells. PMID:25368385

  8. MiR-424 and miR-155 deregulated expression in cytogenetically normal acute myeloid leukaemia: correlation with NPM1 and FLT3 mutation status

    PubMed Central

    2012-01-01

    Background MicroRNA have a central role in normal haematopoiesis and are deregulated in acute myeloid leukaemia (AML). The purpose of the study was to investigate by qRT-PCR the expression of miRNAs involved in myeloid differentiation (miR-424, miR-155, miR-223, miR-17-5p) in 48 patients with cytogenetically normal AML well characterized for NPM1 and/or FLT3 mutations. Three types of normalization were used for the data validation. Findings We found that miR-424 was down-modulated in AMLs with NPM1mutA regardless of FLT3 status. On the contrary, miR-155 showed up-regulation in patients with FLT3 internal tandem duplications (ITD) with or without NPM1 mutations. No significant associations were found by analyzing miR-223 and miR-17-5p in relation to FLT3 and NPM1 status. Conclusions This study supports the view that major genetic subsets of CN-AML are associated with distinct miRNA signatures and suggests that miR-424 and miR-155 deregulation is involved in the pathogenesis of CN-AML with NPM1 and FLT3-ITD mutations, respectively. PMID:22681934

  9. Progression of mouse skin carcinogenesis is associated with the orchestrated deregulation of mir-200 family members, mir-205 and their common targets.

    PubMed

    Skourti, Elena; Logotheti, Stella; Kontos, Christos K; Pavlopoulou, Athanasia; Dimoragka, Paraskevi T; Trougakos, Ioannis P; Gorgoulis, Vassilis; Scorilas, Andreas; Michalopoulos, Ioannis; Zoumpourlis, Vassilis

    2016-08-01

    MicroRNAs are small, non-coding RNAs which regulate post-transcriptionally hundreds of target mRNAs. Given that their expression is deregulated in several cancer types, they represent potential diagnostic, prognostic, and predictive biomarkers, as well as next-generation therapeutic targets. Nevertheless, the involvement of miRNAs in non-melanoma skin cancer, a cancer type with increasing prevalence, is not extensively studied, and their comprehensive characterization as regard to the initiation, promotion, and progression stages is missing. To this end, we exploited a well-established multistage mouse skin carcinogenesis model in order to identify miRNAs consistently implicated in different stages of skin carcinogenesis. The cell lines comprising this model were subjected to miRNA expression profiling using microarrays, followed by bioinformatics analysis and validation with Q-PCR, as well as treatment with miRNA modulators. We showed that among all deregulated miRNAs in our system, only a functionally coherent group consisting of the miR-200 family members and miR-205-5p displays a pattern of progressive co-downregulation from the early toward the most aggressive stages of carcinogenesis. Their overlapping, co-regulated putative targets are potentially inter-associated and, of these, the EMT-related Rap1a is overexpressed toward aggressive stages. Ectopic expression of miR-205-5p in spindle cancer cells reduces Rap1a, mitigates cell invasiveness, decreases proliferation, and delays tumor onset. We conclude that deregulation of this miRNA group is primarily associated with aggressive phenotypes of skin cancer cells. Restoration of the miR-205-5p member of this group in spindle cells reduces the expression of critical, co-regulated targets that favor cancer progression, thus reversing the EMT characteristics. © 2015 Wiley Periodicals, Inc. PMID:26527515

  10. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

    SciTech Connect

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

    2015-05-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common biological

  11. Analysis of Deregulated microRNAs and Their Target Genes in Gastric Cancer

    PubMed Central

    Kupcinskas, Juozas; Link, Alexander; Kiudelis, Gediminas; Jonaitis, Laimas; Jarmalaite, Sonata; Kupcinskas, Limas; Malfertheiner, Peter; Skieceviciene, Jurgita

    2015-01-01

    Background MicroRNAs (miRNAs) are widely studied non-coding RNAs that modulate gene expression. MiRNAs are deregulated in different tumors including gastric cancer (GC) and have potential diagnostic and prognostic implications. The aim of our study was to determine miRNA profile in GC tissues, followed by evaluation of deregulated miRNAs in plasma of GC patients. Using available databases and bioinformatics methods we also aimed to evaluate potential target genes of confirmed differentially expressed miRNA and validate these findings in GC tissues. Methods The study included 51 GC patients and 51 controls. Initially, we screened miRNA expression profile in 13 tissue samples of GC and 12 normal gastric tissues with TaqMan low density array (TLDA). In the second stage, differentially expressed miRNAs were validated in a replication cohort using qRT-PCR in tissue and plasma samples. Subsequently, we analyzed potential target genes of deregulated miRNAs using bioinformatics approach, determined their expression in GC tissues and performed correlation analysis with targeting miRNAs. Results Profiling with TLDA revealed 15 deregulated miRNAs in GC tissues compared to normal gastric mucosa. Replication analysis confirmed that miR-148a-3p, miR-204-5p, miR-223-3p and miR-375 were consistently deregulated in GC tissues. Analysis of GC patients’ plasma samples showed significant down-regulation of miR-148a-3p, miR-375 and up-regulation of miR-223-3p compared to healthy subjects. Further, using bioinformatic tools we identified targets of replicated miRNAs and performed disease-associated gene enrichment analysis. Ultimately, we evaluated potential target gene BCL2 and DNMT3B expression by qRT-PCR in GC tissue, which correlated with targeting miRNA expression. Conclusions Our study revealed miRNA profile in GC tissues and showed that miR-148a-3p, miR-223-3p and miR-375 are deregulated in GC plasma samples, but these circulating miRNAs showed relatively weak diagnostic

  12. Properties of the static NMR response of a confined thin nematic film of 5CB-d2 under crossed electric and magnetic fields: theory and experiments.

    PubMed

    Véron, A; Sugimura, A; Luckhurst, G R; Martins, A F

    2012-11-01

    This work describes an investigation of the static (or quasistatic) nuclear magnetic resonance (NMR) response in a nematic liquid crystal confined between two planar conducting plates and subject to a magnetic field and an electric field produced by a difference of voltage applied on the plates. Deuterium NMR spectroscopy of 4-pentyl-d(2)-4'-cyanobiphenyl (5CB-d(2)) under these conditions has revealed a voltage dependent inhomogeneous director distribution for a particular narrow range of voltages and for a fixed magnetic field (that of the spectrometer). In the ideal setup the two plates are assumed to be rigorously parallel, so that a difference of voltage applied on the plates leads to a constant electric field normal to them. When the magnetic field is parallel to the plates (orthogonal geometry) there exists a threshold value of the electric field for which the effect of both fields exactly compensate; moreover, for stronger electric field the director aligns with the electric field while for weaker electric field the director aligns with the magnetic field. If there is a lack of parallelism between the two plates, the electric field becomes inhomogeneous so that it may be larger than the threshold value in some region of the sample and smaller in the remaining part of the sample. In that case the director will adopt essentially two orientations within the sample, namely, parallel or perpendicular to the magnetic field, and the position of the frontier between the two domains depends on the voltage. This feature is clearly shown by deuterium NMR spectra that exhibit a transfer of intensity between two quadrupolar doublets with increase in the applied voltage. The coexistence of two director populations occurs for a range of voltages that depends on the degree of nonparallelism; accordingly, an estimation of this range by NMR yields an experimental estimation of the lack of parallelism. A tiny tilt of the magnetic field (nonorthogonal geometry) entrains a

  13. Properties of the static NMR response of a confined thin nematic film of 5CB-d2 under crossed electric and magnetic fields: Theory and experiments

    NASA Astrophysics Data System (ADS)

    Véron, A.; Sugimura, A.; Luckhurst, G. R.; Martins, A. F.

    2012-11-01

    This work describes an investigation of the static (or quasistatic) nuclear magnetic resonance (NMR) response in a nematic liquid crystal confined between two planar conducting plates and subject to a magnetic field and an electric field produced by a difference of voltage applied on the plates. Deuterium NMR spectroscopy of 4-pentyl-d2-4'-cyanobiphenyl (5CB-d2) under these conditions has revealed a voltage dependent inhomogeneous director distribution for a particular narrow range of voltages and for a fixed magnetic field (that of the spectrometer). In the ideal setup the two plates are assumed to be rigorously parallel, so that a difference of voltage applied on the plates leads to a constant electric field normal to them. When the magnetic field is parallel to the plates (orthogonal geometry) there exists a threshold value of the electric field for which the effect of both fields exactly compensate; moreover, for stronger electric field the director aligns with the electric field while for weaker electric field the director aligns with the magnetic field. If there is a lack of parallelism between the two plates, the electric field becomes inhomogeneous so that it may be larger than the threshold value in some region of the sample and smaller in the remaining part of the sample. In that case the director will adopt essentially two orientations within the sample, namely, parallel or perpendicular to the magnetic field, and the position of the frontier between the two domains depends on the voltage. This feature is clearly shown by deuterium NMR spectra that exhibit a transfer of intensity between two quadrupolar doublets with increase in the applied voltage. The coexistence of two director populations occurs for a range of voltages that depends on the degree of nonparallelism; accordingly, an estimation of this range by NMR yields an experimental estimation of the lack of parallelism. A tiny tilt of the magnetic field (nonorthogonal geometry) entrains a notably

  14. Golden Indica and Japonica rice lines amenable to deregulation.

    PubMed

    Hoa, Tran Thi Cuc; Al-Babili, Salim; Schaub, Patrick; Potrykus, Ingo; Beyer, Peter

    2003-09-01

    As an important step toward free access and, thus, impact of GoldenRice, a freedom-to-operate situation has been achieved for developing countries for the technology involved. Specifically, to carry the invention beyond its initial "proof-of-concept" status in a Japonica rice (Oryza sativa) cultivar, we report here on two transformed elite Indica varieties (IR64 and MTL250) plus one Japonica variety Taipei 309. Indica varieties are predominantly consumed in the areas with vitamin A deficiency. To conform with regulatory constraints, we changed the vector backbone, investigated the absence of beyond-border transfer, and relied on Agrobacterium tumefaciens-mediated transformation to obtain defined integration patterns. To avoid an antibiotic selection system, we now rely exclusively on phosphomannose isomerase as the selectable marker. Single integrations were given a preference to minimize potential epigenetic effects in subsequent generations. These novel lines, now in the T(3) generation, are highly valuable because they are expected to more readily receive approval for follow-up studies such as nutritional and risk assessments and for breeding approaches leading to locally adapted variety development. PMID:12970483

  15. Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

    PubMed Central

    Carroll, Patrick A.; Diolaiti, Daniel; McFerrin, Lisa; Gu, Haiwei; Djukovic, Danijel; Du, Jianhai; Cheng, Pei Feng; Anderson, Sarah; Ulrich, Michelle; Hurley, James B.; Raftery, Daniel; Ayer, Donald E.; Eisenman, Robert N.

    2014-01-01

    SUMMARY Deregulated Myc transcriptionally reprograms cell metabolism to promote neoplasia. Here we show that oncogenic Myc requires the Myc superfamily member MondoA, a nutrient-sensing transcription factor, for tumorigenesis. Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways resulting in apoptosis. Identification, and knockdown, of genes co-regulated by Myc and MondoA has allowed us to define metabolic functions required by deregulated Myc and demonstrate a critical role for lipid biosynthesis in survival of Myc-driven cancer. Furthermore, overexpression of a subset of Myc and MondoA co-regulated genes correlates with poor outcome of patients with diverse cancers. Co-regulation of cancer metabolism by Myc and MondoA provides the potential for therapeutics aimed at inhibiting MondoA and its target genes. PMID:25640402

  16. Electricity for the CPI: Free wheeling in a deregulated market. [Chemical Processing Industry

    SciTech Connect

    Parkinson, G.

    1995-01-01

    US process plant operators who think that they're paying too much for electric power may soon have a new option: buying power from a less-expensive supplier and having it delivered through local utility power lines. Known as retail wheeling, the prospective open-market purchase of electricity reflects a deregulation in the electrical power industry that has already taken place in the US telecommunications and natural gas businesses. Epact, the US Energy Policy Act of 1992, has already opened up the nation's transmission lines to wholesale competition, and offers a way to open up retail competition as well. Implementation at the retail level is up to each state, as regulations must be approved by state utility regulatory commissions. The paper describes deregulation, how wheeling works in other countries, and implementation of retail wheeling by some of the states.

  17. Psychology of change: Models and implications for nuclear plants in an era of deregulation

    SciTech Connect

    Gates, W.G.; Stark, J.A.

    1999-09-01

    This presentation explores the psychology of change in the implications that it has for nuclear plants during this era of deregulation. The authors analyze models that work, models that have failed in the past, and specific findings and applications based on 2 yr of research, as well as the results regarding the impact of the psychology of change on the Fort Calhoun nuclear station in Nebraska.

  18. Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen.

    PubMed

    Phung, Thu-Ha; Jung, Sunyo

    2015-04-01

    This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, Fv/Fm, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H2O2 production and greater increases in H2O2-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage. PMID:25735982

  19. Landscape of Transcriptional Deregulations in the Preeclamptic Placenta

    PubMed Central

    Vaiman, Daniel; Calicchio, Rosamaria; Miralles, Francisco

    2013-01-01

    Preeclampsia is a pregnancy disease affecting 5 to 8% of pregnant women and a leading cause of both maternal and fetal mortality and morbidity. Because of a default in the process of implantation, the placenta of preeclamptic women undergoes insufficient vascularization. This results in placental ischemia, inflammation and subsequent release of placental debris and vasoactive factors in the maternal circulation causing a systemic endothelial activation. Several microarray studies have analyzed the transcriptome of the preeclamptic placentas to identify genes which could be involved in placental dysfunction. In this study, we compared the data from publicly available microarray analyses to obtain a consensus list of modified genes. This allowed to identify consistently modified genes in the preeclamptic placenta. Of these, 67 were up-regulated and 31 down-regulated. Assuming that changes in the transcription level of co-expressed genes may result from the coordinated action of a limited number of transcription factors, we looked for over-represented putative transcription factor binding sites in the promoters of these genes. Indeed, we found that the promoters of up-regulated genes are enriched in putative binding sites for NFkB, CREB, ANRT, REEB1, SP1, and AP-2. In the promoters of down-regulated genes, the most prevalent putative binding sites are those of MZF-1, NFYA, E2F1 and MEF2A. These transcriptions factors are known to regulate specific biological pathways such as cell responses to inflammation, hypoxia, DNA damage and proliferation. We discuss here the molecular mechanisms of action of these transcription factors and how they can be related to the placental dysfunction in the context of preeclampsia. PMID:23785430

  20. Regulation and deregulation of natural gas in the US: 1938-1985

    SciTech Connect

    Merrill, Peter R.

    1980-06-01

    Public policy towards natural gas has swung first towards, and then away from regulation in this century. In 1906, the Congress specifically excluded natural gas from the jurisdiction of the Interstate Commerce Commission. Three decades later, a New Deal Congress passed the Natural Gas Act of 1938 bringing pipelines under the control of the Federal Power Commission (FDC). Forty years thereafter, the Congress passed a phased decontrol bill, the Natural Gas Policy Act (NGPA) of 1978, as part of the Carter Administration's National Energy Plan. Recently, the Congress has backed off from New Deal legislation in other markets - notably aviation and trucking. In this study, the rise and fall of economic regulation in the natural gas industry are examined to understand: (1) why public policy has followed a pendulum's path, and (2) the economic consequences of regulation and deregulation. The main part of the analysis is directed toward the Natural Gas Policy Act of 1978. Widely viewed as a deregulation measure, the author finds that the Act is more restrictive and burdensome than the pricing policies it superceded. The path toward deregulation in natural gas and perhaps other markets is not as direct or simple as might be expected.

  1. Multi-objective Decision Based Available Transfer Capability in Deregulated Power System Using Heuristic Approaches

    NASA Astrophysics Data System (ADS)

    Pasam, Gopi Krishna; Manohar, T. Gowri

    2015-07-01

    Determination of available transfer capability (ATC) requires the use of experience, intuition and exact judgment in order to meet several significant aspects in the deregulated environment. Based on these points, this paper proposes two heuristic approaches to compute ATC. The first proposed heuristic algorithm integrates the five methods known as continuation repeated power flow, repeated optimal power flow, radial basis function neural network, back propagation neural network and adaptive neuro fuzzy inference system to obtain ATC. The second proposed heuristic model is used to obtain multiple ATC values. Out of these, a specific ATC value will be selected based on a number of social, economic, deregulated environmental constraints and related to specific applications like optimization, on-line monitoring, and ATC forecasting known as multi-objective decision based optimal ATC. The validity of results obtained through these proposed methods are scrupulously verified on various buses of the IEEE 24-bus reliable test system. The results presented and derived conclusions in this paper are very useful for planning, operation, maintaining of reliable power in any power system and its monitoring in an on-line environment of deregulated power system. In this way, the proposed heuristic methods would contribute the best possible approach to assess multiple objective ATC using integrated methods.

  2. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer.

    PubMed

    Ekholm-Reed, Susanna; Spruck, Charles H; Sangfelt, Olle; van Drogen, Frank; Mueller-Holzner, Elisabeth; Widschwendter, Martin; Zetterberg, Anders; Reed, Steven I; Reed, Susanna Ekholm

    2004-02-01

    hCDC4, the gene that encodes the F-box protein responsible for targeting cyclin E for ubiquitin-mediated proteolysis, has been found to be mutated in a number of primary cancers and cancer-derived cell lines. We have observed that functional inactivation of hCDC4 does not necessarily correlate with elevated levels of cyclin E in tumors. Here we show, however, that hCDC4 mutation in primary tumors correlates strongly with loss of cell cycle regulation of cyclin E. Similarly, a breast carcinoma-derived cell line mutated for hCDC4 exhibits cell cycle deregulation of cyclin E, but periodic expression is restored by reintroducing hCDC4 via retroviral transduction. Conversely, small interfering RNA-mediated silencing of hCdc4 deregulates cyclin E with respect to the cell cycle. These results indicate that hCdc4 function is an absolute prerequisite for cell cycle regulation of cyclin E levels, and loss of hCdc4 function is sufficient to deregulate cyclin E. PMID:14871801

  3. Exploration of Deregulated Long Non-Coding RNAs in Association with Hepatocarcinogenesis and Survival

    PubMed Central

    Shen, Jing; Siegel, Abby B.; Remotti, Helen; Wang, Qiao; Shen, Yueyue; Santella, Regina M.

    2015-01-01

    Long non-coding RNAs (lncRNAs) are larger than 200 nucleotides in length and pervasively expressed across the genome. An increasing number of studies indicate that lncRNA transcripts play integral regulatory roles in cellular growth, division, differentiation and apoptosis. Deregulated lncRNAs have been observed in a variety of human cancers, including hepatocellular carcinoma (HCC). We determined the expression profiles of 90 lncRNAs for 65 paired HCC tumor and adjacent non-tumor tissues, and 55 lncRNAs were expressed in over 90% of samples. Eight lncRNAs were significantly down-regulated in HCC tumor compared to non-tumor tissues (p < 0.05), but no lncRNA achieved statistical significance after Bonferroni correction for multiple comparisons. Within tumor tissues, carrying more aberrant lncRNAs (6–7) was associated with a borderline significant reduction in survival (HR = 8.5, 95% CI: 1.0–72.5). The predictive accuracy depicted by the AUC was 0.93 for HCC survival when using seven deregulated lncRNAs (likelihood ratio test p = 0.001), which was similar to that combining the seven lncRNAs with tumor size and treatment (AUC = 0.96, sensitivity = 87%, specificity = 87%). These data suggest the potential association of deregulated lncRNAs with hepatocarcinogenesis and HCC survival. PMID:26378581

  4. Deregulated Direct Targets of the Hepatitis B Virus (HBV) Protein, HBx, Identified through Chromatin Immunoprecipitation and Expression Microarray Profiling*

    PubMed Central

    Sung, Wing-Kin; Lu, Yiwei; Lee, Charlie W. H.; Zhang, Dongwei; Ronaghi, Mostafa; Lee, Caroline G. L.

    2009-01-01

    The hepatitis B-X (HBx) protein is strongly associated with hepatocellular carcinoma. It is implicated not to directly cause cancer but to play a role in hepatocellular carcinoma as a co-factor. The oncogenic potential of HBx primarily lies in its interaction with transcriptional regulators resulting in aberrant gene expression and deregulated cellular pathways. Utilizing ultraviolet irradiation to simulate a tumor-initiating event, we integrated chip-based chromatin immunoprecipitation (ChIP-chip) with expression microarray profiling and identified 184 gene targets directly deregulated by HBx. One-hundred forty-four transcription factors interacting with HBx were computationally inferred. We experimentally validated that HBx interacts with some of the predicted transcription factors (pTF) as well as the promoters of the deregulated target genes of these pTFs. Significantly, we demonstrated that the pTF interacts with the promoters of the deregulated HBx target genes and that deregulation by HBx of these HBx target genes carrying the pTF consensus sequences can be reversed using pTF small interfering RNAs. The roles of these deregulated direct HBx target genes and their relevance in cancer was inferred via querying against biogroup/cancer-related microarray databases using web-based NextBioTM software. Six pathways, including the Jak-STAT pathway, were predicted to be significantly deregulated when HBx binds indirectly to direct target gene promoters. In conclusion, this study represents the first ever demonstration of the utilization of ChIP-chip to identify deregulated direct gene targets from indirect protein-DNA binding as well as transcriptional factors directly interacting with HBx. Increased knowledge of the gene/transcriptional factor targets of HBx will enhance our understanding of the role of HBx in hepatocellular carcinogenesis and facilitate the design of better strategies in combating hepatitis B virus-associated hepatocellular carcinoma. PMID:19439406

  5. Deregulated direct targets of the hepatitis B virus (HBV) protein, HBx, identified through chromatin immunoprecipitation and expression microarray profiling.

    PubMed

    Sung, Wing-Kin; Lu, Yiwei; Lee, Charlie W H; Zhang, Dongwei; Ronaghi, Mostafa; Lee, Caroline G L

    2009-08-14

    The hepatitis B-X (HBx) protein is strongly associated with hepatocellular carcinoma. It is implicated not to directly cause cancer but to play a role in hepatocellular carcinoma as a co-factor. The oncogenic potential of HBx primarily lies in its interaction with transcriptional regulators resulting in aberrant gene expression and deregulated cellular pathways. Utilizing ultraviolet irradiation to simulate a tumor-initiating event, we integrated chip-based chromatin immunoprecipitation (ChIP-chip) with expression microarray profiling and identified 184 gene targets directly deregulated by HBx. One-hundred forty-four transcription factors interacting with HBx were computationally inferred. We experimentally validated that HBx interacts with some of the predicted transcription factors (pTF) as well as the promoters of the deregulated target genes of these pTFs. Significantly, we demonstrated that the pTF interacts with the promoters of the deregulated HBx target genes and that deregulation by HBx of these HBx target genes carrying the pTF consensus sequences can be reversed using pTF small interfering RNAs. The roles of these deregulated direct HBx target genes and their relevance in cancer was inferred via querying against biogroup/cancer-related microarray databases using web-based NextBio(TM) software. Six pathways, including the Jak-STAT pathway, were predicted to be significantly deregulated when HBx binds indirectly to direct target gene promoters. In conclusion, this study represents the first ever demonstration of the utilization of ChIP-chip to identify deregulated direct gene targets from indirect protein-DNA binding as well as transcriptional factors directly interacting with HBx. Increased knowledge of the gene/transcriptional factor targets of HBx will enhance our understanding of the role of HBx in hepatocellular carcinogenesis and facilitate the design of better strategies in combating hepatitis B virus-associated hepatocellular carcinoma. PMID

  6. 76 FR 6759 - Monsanto Company and KWS SAAT AG; Decision With Respect to the Petition for Partial Deregulation...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-08

    ...We are advising the public of our decision to ``partially deregulate'' Roundup Ready[supreg] sugar beets developed by the Monsanto Company (Monsanto) and KWS SAAT AG (KWS), designated as event H7-1, in response to a supplemental Monsanto/KWS petition requesting partial deregulation of event H7-1. APHIS has determined that it will, for an interim period of time, grant the petition in part.......

  7. Hair analysis for delta(9)-THC, delta(9)-THC-COOH, CBN and CBD, by GC/MS-EI. Comparison with GC/MS-NCI for delta(9)-THC-COOH.

    PubMed

    Baptista, Maria João; Monsanto, Paula Verâncio; Pinho Marques, Estela Gouveia; Bermejo, Ana; Avila, Sofia; Castanheira, Alice Martelo; Margalho, Cláudia; Barroso, Mário; Vieira, Duarte Nuno

    2002-08-14

    A sensitive analytical method was developed for quantitative analysis of delta(9)-tetrahydrocannabinol (delta(9)-THC), 11-nor-delta(9)-tetrahydrocannabinol-carboxylic acid (delta(9)-THC-COOH), cannabinol (CBN) and cannabidiol (CBD) in human hair. The identification of delta(9)-THC-COOH in hair would document Cannabis use more effectively than the detection of parent drug (delta(9)-THC) which might have come from environmental exposure. Ketamine was added to hair samples as internal standard for CBN and CBD. Ketoprofen was added to hair samples as internal standard for the other compounds. Samples were hydrolyzed with beta-glucuronidase/arylsulfatase for 2h at 40 degrees C. After cooling, samples were extracted with a liquid-liquid extraction procedure (with chloroform/isopropyl alcohol, after alkalinization, and n-hexane/ethyl acetate, after acidification), which was developed in our laboratory. The extracts were analysed before and after derivatization with pentafluoropropionic anhydride (PFPA) and pentafluoropropanol (PFPOH) using a Hewlett Packard gas chromatographer/mass spectrometer detector, in electron impact mode (GC/MS-EI). Derivatized delta(9)-THC-COOH was also analysed using a Hewlett Packard gas chromatographer/mass spectrometer detector, in negative ion chemical ionization mode (GC/MS-NCI) using methane as the reagent gas. Responses were linear ranging from 0.10 to 5.00 ng/mg hair for delta(9)-THC and CBN, 0.10-10.00 ng/mg hair for CBD, 0.01-5.00 ng/mg for delta(9)-THC-COOH (r(2)>0.99). The intra-assay precisions ranged from <0.01 to 12.40%. Extraction recoveries ranged from 80.9 to 104.0% for delta(9)-THC, 85.9-100.0% for delta(9)-THC-COOH, 76.7-95.8% for CBN and 71.0-94.0% for CBD. The analytical method was applied to 87 human hair samples, obtained from individuals who testified in court of having committed drug related crimes. Quantification of delta(9)-THC-COOH using GC/MS-NCI was found to be more convenient than GC/MS-EI. The latter may give rise

  8. Deep sequencing identifies deregulation of microRNAs involved with vincristine drug-resistance of colon cancer cells

    PubMed Central

    Dong, Wei-Hua; Li, Qin; Zhang, Xiao-Yan; Guo, Qing; Li, Huizheng; Wang, Tian-Yun

    2015-01-01

    Background: Vincristine (VCR) is a chemical that is widely used in tumor therapy. While long-term use can make tumor cells resistant to VCR, the underlying mechanisms of this resistance are still unclear. Objective: This study aimed at investigating the role of microRNA (miRNA) in colon cancer drug resistance. Methods: HCT-8 colon carcinoma cells were cultured and treated with different VCR concentrations to establish an HCT-8/VCR resistant cell line. Whole-genome screens, HiSeq 2500 sequencing, and bioinformatics methods were used to detect and analyze differences in miRNA expression between the drug-resistant HCT-8/VCR cells and non-resistant HCT-8 cells. Differential expression profiles of miRNAs were constructed based on sequencing result. Results: The HCT-8/VCR resistant colon carcinoma cell line was established. With regard to the difference in drug resistance between HCT-8/VCR and HCT-8 cells, 24 miRNAs showed statistically significant differences in their expression (fold change > 4), of which 17 were up-regulated. Seven miRNAs were down-regulated. Conclusion: As abnormal expression of miRNAs was associated with VCR resistance of colon carcinoma cells, differences in miRNA expression may play a key role in VCR resistance of colon cancer cells. PMID:26617885

  9. Multiple myeloma–related deregulation of bone marrow–derived CD34+ hematopoietic stem and progenitor cells

    PubMed Central

    Cadeddu, Ron-Patrick; Brueckmann, Ines; Fröbel, Julia; Geyh, Stefanie; Büst, Sebastian; Fischer, Johannes C.; Roels, Frederik; Wilk, Christian Matthias; Schildberg, Frank A.; Hünerlitürkoglu, Ali-Nuri; Zilkens, Christoph; Jäger, Marcus; Steidl, Ulrich; Zohren, Fabian; Fenk, Roland; Kobbe, Guido; Brors, Benedict; Czibere, Akos; Schroeder, Thomas; Trumpp, Andreas; Haas, Rainer

    2012-01-01

    Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGFβ signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGFβ signaling. In accordance, TGFβ levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGFβ signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations. PMID:22517906

  10. Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet

    PubMed Central

    Asfa, Alli Shaik; Qiu, Beiying; Wee, Sheena; Choi, Hyungwon; Gunaratne, Jayantha; Tergaonkar, Vinay

    2016-01-01

    Despite efforts in the last decade, signaling aberrations associated with obesity remain poorly understood. To dissect molecular mechanisms that define this complex metabolic disorder, we carried out global phosphoproteomic analysis of white adipose tissue (WAT) from mice fed on low-fat diet (LFD) and high-fat diet (HFD). We quantified phosphorylation levels on 7696 peptides, and found significant differential phosphorylation levels in 282 phosphosites from 191 proteins, including various insulin-responsive proteins and metabolic enzymes involved in lipid homeostasis in response to high-fat feeding. Kinase-substrate prediction and integrated network analysis of the altered phosphoproteins revealed underlying signaling modulations during HFD-induced obesity, and suggested deregulation of lipogenic and lipolytic pathways. Mutation of the differentially-regulated novel phosphosite on cytoplasmic acetyl-coA forming enzyme ACSS2 (S263A) upon HFD-induced obesity led to accumulation of serum triglycerides and reduced insulin-responsive AKT phosphorylation as compared to wild type ACSS2, thus highlighting its role in obesity. Altogether, our study presents a comprehensive map of adipose tissue phosphoproteome in obesity and reveals many previously unknown candidate phosphorylation sites for future functional investigation. PMID:27180971

  11. Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet.

    PubMed

    Asfa, Alli Shaik; Qiu, Beiying; Wee, Sheena; Choi, Hyungwon; Gunaratne, Jayantha; Tergaonkar, Vinay

    2016-01-01

    Despite efforts in the last decade, signaling aberrations associated with obesity remain poorly understood. To dissect molecular mechanisms that define this complex metabolic disorder, we carried out global phosphoproteomic analysis of white adipose tissue (WAT) from mice fed on low-fat diet (LFD) and high-fat diet (HFD). We quantified phosphorylation levels on 7696 peptides, and found significant differential phosphorylation levels in 282 phosphosites from 191 proteins, including various insulin-responsive proteins and metabolic enzymes involved in lipid homeostasis in response to high-fat feeding. Kinase-substrate prediction and integrated network analysis of the altered phosphoproteins revealed underlying signaling modulations during HFD-induced obesity, and suggested deregulation of lipogenic and lipolytic pathways. Mutation of the differentially-regulated novel phosphosite on cytoplasmic acetyl-coA forming enzyme ACSS2 (S263A) upon HFD-induced obesity led to accumulation of serum triglycerides and reduced insulin-responsive AKT phosphorylation as compared to wild type ACSS2, thus highlighting its role in obesity. Altogether, our study presents a comprehensive map of adipose tissue phosphoproteome in obesity and reveals many previously unknown candidate phosphorylation sites for future functional investigation. PMID:27180971

  12. Deregulation of Protein Phosphatase 2A and Hyperphosphorylation of τ Protein Following Onset of Diabetes in NOD Mice

    PubMed Central

    Papon, Marie-Amélie; El Khoury, Noura B.; Marcouiller, François; Julien, Carl; Morin, Françoise; Bretteville, Alexis; Petry, Franck R.; Gaudreau, Simon; Amrani, Abdelaziz; Mathews, Paul M.; Hébert, Sébastien S.; Planel, Emmanuel

    2013-01-01

    The histopathological hallmarks of Alzheimer disease (AD) include intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated τ protein. Insulin dysfunction might influence AD pathology, as population-based and cohort studies have detected higher AD incidence rates in diabetic patients. But how diabetes affects τ pathology is not fully understood. In this study, we investigated the impact of insulin dysfunction on τ phosphorylation in a genetic model of spontaneous type 1 diabetes: the nonobese diabetic (NOD) mouse. Brains of young and adult female NOD mice were examined, but young NOD mice did not display τ hyperphosphorylation. τ phosphorylation at τ-1 and pS422 epitopes was slightly increased in nondiabetic adult NOD mice. At the onset of diabetes, τ was hyperphosphorylated at the τ-1, AT8, CP13, pS262, and pS422. A subpopulation of diabetic NOD mice became hypothermic, and τ hyperphosphorylation further extended to paired helical filament-1 and TG3 epitopes. Furthermore, elevated τ phosphorylation correlated with an inhibition of protein phosphatase 2A (PP2A) activity. Our data indicate that insulin dysfunction in NOD mice leads to AD-like τ hyperphosphorylation in the brain, with molecular mechanisms likely involving a deregulation of PP2A. This model may be a useful tool to address further mechanistic association between insulin dysfunction and AD pathology. PMID:22961084

  13. Multi-Objective Differential Evolution for Voltage Security Constrained Optimal Power Flow in Deregulated Power Systems

    NASA Astrophysics Data System (ADS)

    Roselyn, J. Preetha; Devaraj, D.; Dash, Subhransu Sekhar

    2013-11-01

    Voltage stability is an important issue in the planning and operation of deregulated power systems. The voltage stability problems is a most challenging one for the system operators in deregulated power systems because of the intense use of transmission line capabilities and poor regulation in market environment. This article addresses the congestion management problem avoiding offline transmission capacity limits related to voltage stability by considering Voltage Security Constrained Optimal Power Flow (VSCOPF) problem in deregulated environment. This article presents the application of Multi Objective Differential Evolution (MODE) algorithm to solve the VSCOPF problem in new competitive power systems. The maximum of L-index of the load buses is taken as the indicator of voltage stability and is incorporated in the Optimal Power Flow (OPF) problem. The proposed method in hybrid power market which also gives solutions to voltage stability problems by considering the generation rescheduling cost and load shedding cost which relieves the congestion problem in deregulated environment. The buses for load shedding are selected based on the minimum eigen value of Jacobian with respect to the load shed. In the proposed approach, real power settings of generators in base case and contingency cases, generator bus voltage magnitudes, real and reactive power demands of selected load buses using sensitivity analysis are taken as the control variables and are represented as the combination of floating point numbers and integers. DE/randSF/1/bin strategy scheme of differential evolution with self-tuned parameter which employs binomial crossover and difference vector based mutation is used for the VSCOPF problem. A fuzzy based mechanism is employed to get the best compromise solution from the pareto front to aid the decision maker. The proposed VSCOPF planning model is implemented on IEEE 30-bus system, IEEE 57 bus practical system and IEEE 118 bus system. The pareto optimal

  14. Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.

    PubMed

    El-Remessy, Azza B; Khalil, Ibrahim E; Matragoon, Suraporn; Abou-Mohamed, Gamal; Tsai, Nai-Jer; Roon, Penny; Caldwell, Ruth B; Caldwell, Robert W; Green, Keith; Liou, Gregory I

    2003-11-01

    In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma. PMID:14578199

  15. Simultaneous analysis of several synthetic cannabinoids, THC, CBD and CBN, in hair by ultra-high performance liquid chromatography tandem mass spectrometry. Method validation and application to real samples.

    PubMed

    Salomone, A; Gerace, E; D'Urso, F; Di Corcia, D; Vincenti, M

    2012-05-01

    A simple procedure for the quantitative detection of JWH-018, JWH-073, JWH 200, JWH-250, HU-210, Δ(9)-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) in hair has been developed and fully validated. After digestion with NaOH and liquid-liquid extraction, the separation was performed with an ultra-high performance liquid chromatography system coupled to a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode. The absence of matrix interferents, together with excellent repeatability of both retention times and relative abundances of diagnostic transitions, allowed the correct identification of all analytes tested. The method was linear in two different intervals at low and high concentration, with correlation coefficient values between 0.9933 and 0.9991. Quantitation limits ranged from 0.07 pg/mg for JWH-200 up to 18 pg/mg for CBD The present method for the determination of several cannabinoids in hair proved to be simple, fast, specific and sensitive. The method was successfully applied to the analysis of 179 real samples collected from proven consumers of Cannabis, among which 14 were found positive to at least one synthetic cannabinoid. PMID:22576873

  16. Implications of deregulation in natural gas industry on utility risks and returns

    NASA Astrophysics Data System (ADS)

    Addepalli, Rajendra P.

    This thesis examines the changes in risk and required return on capital for local distribution utility companies in the increasingly competitive natural gas industry. The deregulation in the industry impacts the LDCs in several ways. First, with the introduction of competition consumers have been given choices among suppliers besides the traditional monopoly, the local utility, for purchasing their natural gas supply needs. Second, with the introduction of competition, some of the interstate pipelines were stuck with 'Take Or Pay' contracts and other costs that resulted in 'stranded costs', which have been passed on to customers of the pipeline including the LDCs. Third, the new obligation for the LDCs to purchase gas from the market, as opposed to buying it from pipelines and passing on the costs to its customers, brought opportunities and risks as well. Finally, with the introduction of competition, in some states LDCs have been allowed to enter into unregulated ventures to increase their profits. In the thesis we first develop a multifactor model (MFM) to explain historical common stock returns of individual utilities and of utility portfolios. We use 'rolling regression' analysis to analyze how different variables explain the variation in stock returns over time. Second, we conduct event studies to analyze the events in the deregulation process that had significant impacts on the LDC returns. Finally we assess the changes in risk and required return on capital for the LDCs over a 15 year time frame, covering the deregulation period. We employ four aspects in the examination of risk and return profile of the utilities: measuring (a) changes in required return on common equity and Weighted Average Cost of Capital, (b) changes in risk premium (WACC less an interest rate proxy), (c) changes in utility bond ratings, and (d) changes in dividend payments, new debt and equity issuances. We perform regression analysis to explain the changes in the required WACC using

  17. Policy and research on health manpower regulation: never too late to deregulate?

    PubMed

    Begun, J W; Feldman, R

    1990-01-01

    Research on health manpower regulation has reached a consistent conclusion for the last two decades that is likely to carry into the 1990s: deregulate. Research has progressed in recent years, however, and research in the 1990s will be quite different from that of the past two decades. While the battle cry "never too late to deregulate" will continue to be heard, the "easy" targets, those markets with the least extensive or least important information asymmetry, have already been attacked. What is (or should be) finally emerging in the 1990s is a more challenging appraisal of health manpower regulation, one that recognizes greater complexity in health care markets and consumer preferences than has been recognized in past research. Lessons for the 1990s include the need to recognize, accept, and study information asymmetry and its consequences, and to more closely analyze the hypothesis that occupational interest groups, while meeting their self-interest, also may be serving the commonwealth. Such a reorientation leads us to ask different questions of regulation in future research, all directing attention to the informational attributes of markets: (1) How much information asymmetry exists in different health care markets, and how important is it? In which information-asymmetric markets is manpower regulation most likely to benefit consumers? (2) How can information asymmetry between consumers and providers be reduced, thereby facilitating deregulation? (3) How many regulations, of what type, are consumers willing to eliminate, for what benefits? Simplistic policy recommendations are less likely with this new orientation, and there is a great deal of interesting research awaiting health services researchers. PMID:10123015

  18. AGC System after Deregulation Considering TCPS in Series with the Tie-Line

    NASA Astrophysics Data System (ADS)

    Abraham, Rajesh Joseph; Das, D.; Patra, A.

    2015-06-01

    This paper presents the study of automatic generation control (AGC) of two area interconnected power system after deregulation, considering a thyristor controlled phase shifter (TCPS) in series with the tie-line. It is possible to minimize the system frequency and tie-power oscillations by controlling the phase angle of TCPS which is expected to provide a new ancillary service for the future power system. Effect of TCPS is examined for three different cases, i.e. (1) unilateral contract, (2) bilateral contract and (3) contract violation. Analysis reveals that a TCPS is quite capable of suppressing the frequency and tie-power oscillations effectively as compared to that obtained without TCPS.

  19. Feasibility Study of Scheduling Work of System Operation in Deregulated Environment

    NASA Astrophysics Data System (ADS)

    Sugihara, Toshio; Yokoyama, Akihiko; Sasaki, Tetsuo

    This paper presents the results of work flow analysis of generation scheduling and power system operation on the assumption that further deregulation is introduced into Japanese electric utility. California system and PJM system are tested as they are introduced into Japan. It was made clear that the time required for making the plan to operate the grid for the next day is acceptable for the Japanese system when a spot market is founded. Flow simulation of jobs of the power system operation is done based on IDEF0 method using flow charts similar to Petri net.

  20. The relationship between cellular ion deregulation and acute and chronic toxicity.

    PubMed

    Trump, B F; Berezesky, I K; Smith, M W; Phelps, P C; Elliget, K A

    1989-01-01

    Cell injury proceeds through a predictable series of stages as it progresses from reversible to irreversible injury (or "point of no return") and ends eventually in cell death. Ion deregulation is strongly implicated in this process and, in particular, the deregulation of cytosolic Ca2+ ([Ca2+]i) which is thought by most to be a critical step in the transition from reversible to irreversible injury. [Ca2+]i is normally maintained at approximately 100 microM, a level 10,000 times lower than for extracellular Ca2+ [( Ca2+]e). Deregulation may affect any of three Ca2+ buffering systems: the plasma membrane, the mitochondria, and the endoplasmic reticulum. Perturbation of [Ca2+]i is intimately related to perturbation of other ions, including, H+, Na+, and K+. In normal cells, [Ca2+]i elevation is also linked to activation of oncogenes as well as cell division, initiation, wound repair, differentiation, and possibly tumor promotion. In all models of acute injury for which we have measured [Ca2+]i, including ischemia, HgCl2 and calcium inophores, [Ca2+]i always became elevated. This elevation results from influx of [Ca2+]e (ionomycin), redistribution from intracellular stores (NEM, KCN), or from both sources (HgCl2). The degree of [Ca2+]i elevation is correlated with the degree of injury (as determined by blebbing and morphological changes) and cell killing. More recently, much work has been focused on the role of [Ca2+]i in neoplasia. Many stimuli, including the promoter TPA and transforming growth factor beta have been shown to affect normal and transformed cells differently. Both cause differentiation in normal human bronchial epithelial cells but stimulate growth in transformed cells. We propose that deregulation of ions, especially [Ca2+]i, plays an important role, if not a key role, in the initiation of acute and chronic cell injury, including neoplasia. Increases in [Ca2+]i appear to accelerate degradative processes and, unless regulated, lead to cell death. PMID

  1. Genetics and metabolic deregulation following cancer initiation: A world to explore.

    PubMed

    Araldi, Rodrigo Pinheiro; Módolo, Diego Grando; de Sá Júnior, Paulo Luiz; Consonni, Sílvio Roberto; de Carvalho, Rodrigo Franco; Roperto, Franco Peppino; Beçak, Willy; de Cassia Stocco, Rita

    2016-08-01

    Cancer is a group of highly complex and heterogeneous diseases with several causes. According to the stochastic model, cancer initiates from mutation in somatic cells, leading to genomic instability and cell transformation. This canonical pathway of carcinogenesis is related to the discovery of important mechanisms that regulate cancer initiation. However, there are few studies describing genetic and metabolic alterations that deregulate transformed cells, resulting in epithelial-mesenchymal transition (EMT) and its most dramatic consequence, the metastasis. This review summarizes the main genetics and metabolic changes induced by reactive oxygen species (ROS) that lead to EMT. PMID:27470384

  2. Out of the frying pan: New York City hospitals in an age of deregulation.

    PubMed

    Salit, Sharon; Fass, Steven; Nowak, Mark

    2002-01-01

    For several decades New York City hospitals had been distinguished by their tightly regulated environment, chronically weak finances, high occupancy rates, teaching intensity, dependency on public payers, low managed care penetration, and minimal merger activity. Then in the late 1990s a rapid convergence of forces--the Balanced Budget Act, managed care growth, state deregulation of commercial rates, escalating costs, and plunging hospital occupancy rates--threw the city's hospital industry into turmoil. In this paper we describe this period of turbulent change that has left most of the city's safety-net and small community hospitals near bankruptcy. PMID:11900065

  3. Effect of plasmid replication deregulation via inc mutations on E. coli proteome & simple flux model analysis.

    PubMed

    Meade, Jonathan; Bartlow, Patrick; Trivedi, Ram Narayan; Akhtar, Parvez; Ataai, Mohammad M; Khan, Saleem A; Domach, Michael M

    2015-01-01

    When the replication of a plasmid based on sucrose selection is deregulated via the inc1 and inc2 mutations, high copy numbers (7,000 or greater) are attained while the growth rate on minimal medium is negligibly affected. Adaptions were assumed to be required in order to sustain the growth rate. Proteomics indicated that indeed a number of adaptations occurred that included increased expression of ribosomal proteins and 2-oxoglutarate dehydrogenase. The operating space prescribed by a basic flux model that maintained phenotypic traits (e.g. growth, byproducts, etc.) within typical bounds of resolution was consistent with the flux implications of the proteomic changes. PMID:25890349

  4. Cerulenin-mediated apoptosis is involved in adenine metabolic pathway

    SciTech Connect

    Chung, Kyung-Sook; Sun, Nam-Kyu; Lee, Seung-Hee; Lee, Hyun-Jee; Choi, Shin-Jung; Kim, Sun-Kyung; Song, Ju-Hyun; Jang, Young-Joo; Song, Kyung-Bin; Yoo, Hyang-Sook; Simon, Julian . E-mail: jsimon@fhcrc.org; Won, Misun . E-mail: misun@kribb.re.kr

    2006-10-27

    Cerulenin, a fatty acid synthase (FAS) inhibitor, induces apoptosis of variety of tumor cells. To elucidate mode of action by cerulenin, we employed the proteomics approach using Schizosaccharomyces pombe. The differential protein expression profile of S. pombe revealed that cerulenin modulated the expressions of proteins involved in stresses and metabolism, including both ade10 and adk1 proteins. The nutrient supplementation assay demonstrated that cerulenin affected enzymatic steps transferring a phosphoribosyl group. This result suggests that cerulenin accumulates AMP and p-ribosyl-s-amino-imidazole carboxamide (AICAR) and reduces other necessary nucleotides, which induces feedback inhibition of enzymes and the transcriptional regulation of related genes in de novo and salvage adenine metabolic pathway. Furthermore, the deregulation of adenine nucleotide synthesis may interfere ribonucleotide reductase and cause defects in cell cycle progression and chromosome segregation. In conclusion, cerulenin induces apoptosis through deregulation of adenine nucleotide biosynthesis resulting in nuclear division defects in S. pombe.

  5. Coevolutionary analysis enabled rational deregulation of allosteric enzyme inhibition in Corynebacterium glutamicum for lysine production.

    PubMed

    Chen, Zhen; Meyer, Weiqian; Rappert, Sugima; Sun, Jibin; Zeng, An-Ping

    2011-07-01

    Product feedback inhibition of allosteric enzymes is an essential issue for the development of highly efficient microbial strains for bioproduction. Here we used aspartokinase from Corynebacterium glutamicum (CgAK), a key enzyme controlling the biosynthesis of industrially important aspartate family amino acids, as a model to demonstrate a fast and efficient approach to the deregulation of allostery. In the last 50 years many researchers and companies have made considerable efforts to deregulate this enzyme from allosteric inhibition by lysine and threonine. However, only a limited number of positive mutants have been identified so far, almost exclusively by random mutation and selection. In this study, we used statistical coupling analysis of protein sequences, a method based on coevolutionary analysis, to systematically clarify the interaction network within the regulatory domain of CgAK that is essential for allosteric inhibition. A cluster of interconnected residues linking different inhibitors' binding sites as well as other regions of the protein have been identified, including most of the previously reported positions of successful mutations. Beyond these mutation positions, we have created another 14 mutants that can partially or completely desensitize CgAK from allosteric inhibition, as shown by enzyme activity assays. The introduction of only one of the inhibition-insensitive CgAK mutations (here Q298G) into a wild-type C. glutamicum strain by homologous recombination resulted in an accumulation of 58 g/liter L-lysine within 30 h of fed-batch fermentation in a bioreactor. PMID:21531824

  6. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

    PubMed Central

    Pearson, Helen B.; Perez-Mancera, Pedro A.; Dow, Lukas E.; Ryan, Andrew; Tennstedt, Pierre; Bogani, Debora; Elsum, Imogen; Greenfield, Andy; Tuveson, David A.; Simon, Ronald; Humbert, Patrick O.

    2011-01-01

    Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention. PMID:21965329

  7. And deregulation shall lead me to lie down in green pastures

    SciTech Connect

    Weidinger, G.

    1995-06-01

    This presentation briefly reviews the history of the IPP industry, the current state of competition, and potential opportunities for IPPs in a deregulated environment. Since the beginning of the PURPA created IPP industry, we have experienced many market phases. These began with {open_quotes}beat avoided cost,{close_quotes} followed by {open_quotes}find a need and fill it,{close_quotes} followed by {open_quotes}the bid fest,{close_quotes} to today`s {open_quotes}anything goes.{close_quotes} During this time, market clearing prices have declined from over 80/KwHr to 2-40/KwHr. Today`s partially deregulated electric market includes fierce competition and several new players in the game. Where surplus capacity exists, IPPs must compete with subsidized power. Long-term contracts are no longer widely available. Access to markets is constrained by less than open transmission. Even with these challenges, opportunities remain for the IPP supplier. Opportunities for advanced coal-fired power systems will be explored.

  8. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains

    PubMed Central

    Ren, Tong; Takahashi, Yoshinori; Liu, Xin; Loughran, Thomas P.; Sun, Shao-Cong; Wang, Hong-Gang; Cheng, Hua

    2014-01-01

    The retroviral oncoprotein Tax from Human T cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T cell leukemia and lymphoma, plays a crucial role in initiating T lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating IκB kinase complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IκB kinase complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells. PMID:24362528

  9. Exposure to Endocrine Disruptor Induces Transgenerational Epigenetic Deregulation of MicroRNAs in Primordial Germ Cells

    PubMed Central

    Brieño-Enríquez, Miguel A.; García-López, Jesús; Cárdenas, David B.; Guibert, Sylvain; Cleroux, Elouan; Děd, Lukas; Hourcade, Juan de Dios; Pěknicová, Jana; Weber, Michael; del Mazo, Jesús

    2015-01-01

    In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs) during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation. PMID:25897752

  10. Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers.

    PubMed

    Kaczkowski, Bogumil; Tanaka, Yuji; Kawaji, Hideya; Sandelin, Albin; Andersson, Robin; Itoh, Masayoshi; Lassmann, Timo; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R

    2016-01-15

    Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression profiles from 225 different cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the The Cancer Genome Atlas and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer RNAs, which are upregulated in cancer, defining promoters that overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall, our genome-wide expression profiling approach identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective and pathogenic significance of repetitive elements that are frequently activated during cancer progression. PMID:26552699

  11. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.

    PubMed

    Galanos, Panagiotis; Vougas, Konstantinos; Walter, David; Polyzos, Alexander; Maya-Mendoza, Apolinar; Haagensen, Emma J; Kokkalis, Antonis; Roumelioti, Fani-Marlen; Gagos, Sarantis; Tzetis, Maria; Canovas, Begoña; Igea, Ana; Ahuja, Akshay K; Zellweger, Ralph; Havaki, Sofia; Kanavakis, Emanuel; Kletsas, Dimitris; Roninson, Igor B; Garbis, Spiros D; Lopes, Massimo; Nebreda, Angel; Thanos, Dimitris; Blow, J Julian; Townsend, Paul; Sørensen, Claus Storgaard; Bartek, Jiri; Gorgoulis, Vassilis G

    2016-07-01

    The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs. PMID:27323328

  12. Deregulation of keratinocyte differentiation and activation: a hallmark of venous ulcers

    PubMed Central

    Stojadinovic, Olivera; Pastar, Irena; Vukelic, Sasa; Mahoney, Mỹ G; Brennan, Donna; Krzyzanowska, Agata; Golinko, Michael; Brem, Harold; Tomic-Canic, Marjana

    2008-01-01

    Epidermal morphology of chronic wounds differs from that of normal epidermis. Biopsies of non-healing edges obtained from patients with venous ulcers show thick and hyperproliferative epidermis with mitosis present in suprabasal layers. This epidermis is also hyper-keratotic and parakeratotic. This suggests incomplete activation and differentiation of keratinocytes. To identify molecular changes that lead to pathogenic alterations in keratinocyte activation and differentiation pathways we isolated mRNA from non-healing edges deriving from venous ulcers patients and determined transcriptional profiles using Affymetrix chips. Obtained transcriptional profiles were compared to those from healthy, unwounded skin. As previously indicated by histology, we found deregulation of differentiation and activation markers. We also found differential regulation of signalling molecules that regulate these two processes. Early differentiation markers, keratins K1/K10 and a subset of small proline-rich proteins, along with the late differentiation marker filaggrin were suppressed, whereas late differentiation markers involucrin, transgultaminase 1 and another subset of small proline-rich proteins were induced in ulcers when compared to healthy skin. Surprisingly, desomosomal and tight junction components were also deregulated. Keratinocyte activation markers keratins K6/K16/K17 were induced. We conclude that keratinocytes at the non-healing edges of venous ulcers do not execute either activation or differentiation pathway, resulting in thick callus-like formation at the edge of a venous ulcers. PMID:18373736

  13. BPA-Induced Deregulation Of Epigenetic Patterns: Effects On Female Zebrafish Reproduction

    PubMed Central

    Santangeli, Stefania; Maradonna, Francesca; Gioacchini, Giorgia; Cobellis, Gilda; Piccinetti, Chiara Carla; Dalla Valle, Luisa; Carnevali, Oliana

    2016-01-01

    Bisphenol A (BPA) is one of the commonest Endocrine Disruptor Compounds worldwide. It interferes with vertebrate reproduction, possibly by inducing deregulation of epigenetic mechanisms. To determine its effects on female reproductive physiology and investigate whether changes in the expression levels of genes related to reproduction are caused by histone modifications, BPA concentrations consistent with environmental exposure were administered to zebrafish for three weeks. Effects on oocyte growth and maturation, autophagy and apoptosis processes, histone modifications, and DNA methylation were assessed by Real-Time PCR (qPCR), histology, and chromatin immunoprecipitation combined with qPCR analysis (ChIP-qPCR). The results showed that 5 μg/L BPA down-regulated oocyte maturation-promoting signals, likely through changes in the chromatin structure mediated by histone modifications, and promoted apoptosis in mature follicles. These data indicate that the negative effects of BPA on the female reproductive system may be due to its upstream ability to deregulate epigenetic mechanism. PMID:26911650

  14. BPA-Induced Deregulation Of Epigenetic Patterns: Effects On Female Zebrafish Reproduction.

    PubMed

    Santangeli, Stefania; Maradonna, Francesca; Gioacchini, Giorgia; Cobellis, Gilda; Piccinetti, Chiara Carla; Dalla Valle, Luisa; Carnevali, Oliana

    2016-01-01

    Bisphenol A (BPA) is one of the commonest Endocrine Disruptor Compounds worldwide. It interferes with vertebrate reproduction, possibly by inducing deregulation of epigenetic mechanisms. To determine its effects on female reproductive physiology and investigate whether changes in the expression levels of genes related to reproduction are caused by histone modifications, BPA concentrations consistent with environmental exposure were administered to zebrafish for three weeks. Effects on oocyte growth and maturation, autophagy and apoptosis processes, histone modifications, and DNA methylation were assessed by Real-Time PCR (qPCR), histology, and chromatin immunoprecipitation combined with qPCR analysis (ChIP-qPCR). The results showed that 5 μg/L BPA down-regulated oocyte maturation-promoting signals, likely through changes in the chromatin structure mediated by histone modifications, and promoted apoptosis in mature follicles. These data indicate that the negative effects of BPA on the female reproductive system may be due to its upstream ability to deregulate epigenetic mechanism. PMID:26911650

  15. The impact of deregulation on the board structure of electric utilities

    NASA Astrophysics Data System (ADS)

    Wollan, Patricia L.

    This study analyzes the impact of deregulation on board structure by comparing the boards of electric utilities before and after the passage of the Energy Policy Act (EPACT). In addition, the study assesses whether board structure has an impact on firm performance during the period of transition. I find that electric utilities do change their board structure in response to their new operating environment. Boards are smaller and more independent in the later period. Also, even though the number of outside directors stays the same, there are notable changes in the character of these directors. The number of executives from large firms and the number of directors with political backgrounds are both significantly greater after the passage of EPACT. These results are consistent with Williamson's hypothesis that firms will change the composition and character of their board in response to a change in the firm's operating environment. Further investigation reveals that even though utilities' boards change following deregulation, the pace of change is slow, and during the four-year period immediately following the passage of EPACT firm performance is related to board character. These results suggest that while firms reconfigure their boards in response to a change in their operating environment, there may be impediments that prevent them from adjusting their boards too quickly.

  16. Effect of neurotrophin-3 precursor on glutamate-induced calcium homeostasis deregulation in rat cerebellum granule cells.

    PubMed

    Safina, Dina R; Surin, Alexander M; Pinelis, Vsevolod G; Kostrov, Sergey V

    2015-12-01

    Neurotrophin-3 (NT-3) belongs to the family of highly conserved dimeric growth factors that controls the differentiation and activity of various neuronal populations. Mammals contain both the mature (NT-3) and the precursor (pro-NT-3) forms of neurotrophin. Members of the neurotrophin family are involved in the regulation of calcium homeostasis in neurons; however, the role of NT-3 and pro-NT-3 in this process remains unclear. The current study explores the effects of NT-3 and pro-NT-3 on disturbed calcium homeostasis and decline of mitochondrial potential induced by a neurotoxic concentration of glutamate (Glu; 100 µM) in the primary culture of rat cerebellar granule cells. In this Glu excitotoxicity model, mature NT-3 had no effect on the induced changes in Ca²⁺ homeostasis. In contrast, pro-NT-3 decreased the period of delayed calcium deregulation (DCD) and concurrent strong mitochondrial depolarization. According to the amplitude of the increase in the intracellular free Ca²⁺ concentration ([Ca²⁺]i ) and Fura-2 fluorescence quenching by Mn²⁺ within the first 20 sec of exposure to Glu, pro-NT-3 had no effect on the initial rate of Ca²⁺ entry into neurons. During the lag period preceding DCD, the mean amplitude of [Ca²⁺]i rise was 1.2-fold greater in the presence of pro-NT-3 than in the presence of Glu alone (1.67 ±  0.07 and 1.39 ± 0.04, respectively, P < 0.05). The Glu-induced changes in Са²⁺ homeostasis in the presence of pro-NT-3 likely are due to the decreased rate of Са²⁺ removal from the cytosol during the DCD latency period. PMID:26346533

  17. Phenotypic impact of deregulated expression of class I histone deacetylases in urothelial cell carcinoma of the bladder.

    PubMed

    Junqueira-Neto, Susana; Vieira, Filipa Q; Montezuma, Diana; Costa, Natália R; Antunes, Luís; Baptista, Tiago; Oliveira, Ana Isabel; Graça, Inês; Rodrigues, Ângelo; Magalhães, José S; Oliveira, Jorge; Henrique, Rui; Jerónimo, Carmen

    2015-07-01

    Deregulated expression of histone deacetylases (HDACs) has been implicated in tumorigenesis. Herein, we investigated class I HDACs expression in bladder urothelial cell carcinoma (BUCC), its prognostic value and biological significance. Significantly increased transcript levels of all HDACs were found in BUCC compared to 20 normal mucosas, and these were higher in lower grade and stage tumors. Increased HDAC3 levels were associated with improved patient survival. SiRNA experiments showed decrease cell viability and motility, and increased apoptosis. We concluded that class I HDACs play an important role in bladder carcinogenesis through deregulation of proliferation, migration and apoptosis, constituting putative therapeutic targets. PMID:24293253

  18. Deregulation of miRNA-181c potentially contributes to the pathogenesis of AD by targeting collapsin response mediator protein 2 in mice.

    PubMed

    Zhou, Huimin; Zhang, Rui; Lu, Kang; Yu, Wenjun; Xie, Bing; Cui, Dongsheng; Jiang, Lei; Zhang, Qingfu; Xu, Shunjiang

    2016-08-15

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is usually accompanied by abnormal gene expression. The 20 to 25 nucleotide (nt) tiny regulators, known as micro ribonucleic acids (miRNAs), have been found to play important roles in the etiology and pathogenesis of various biological processes. The purpose of the current study was to identify the aberrant expression of microRNAs in the hippocampus of an AD mouse model and to investigate its potential role during the progression of AD. The results from microarray analysis showed that several miRNAs were deregulated in the hippocampus tissue of SAMP8 mice compared to SAMR1 mice. Among the deregulated miRNAs, a significant decrease in miR-181c was validated by quantitative real-time PCR. Bioinformatic analysis revealed that miR-181c might be involved in the regulation of axon guidance, MAPK signaling, dorso-ventral axis formation and long-term depression. Moreover, the results of a luciferase activity assay, western blot analysis and immunofluorescent staining showed that over-expression of miR-181c targets the 3'-untranslated region (3'-UTR) of collapsin response mediator protein 2 (crmp2) through its binding sites and down-regulates crmp2 protein abundance at the post-transcriptional level. Taken together, these findings suggested that crmp2 is a target of miR-181c and that the abnormally low expression of miR-181c in the hippocampus of SAMP8 mice could lead to an increase of the crmp2 protein level in AD mice, which might potentially play a role in the pathogenesis of Alzheimer's disease. PMID:27423553

  19. Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen

    SciTech Connect

    Phung, Thu-Ha; Jung, Sunyo

    2015-04-03

    This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, F{sub v}/F{sub m}, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H{sub 2}O{sub 2} production and greater increases in H{sub 2}O{sub 2}-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage. - Highlights: • We employ two different types of photodynamic stress, white and brown necrosis. • We examine molecular mechanisms of antioxidative and detoxification systems. • ALA and OF develop differential actions of antioxidant and detoxification systems. • Coordinated mechanism of antioxidants and detoxification works against toxic ROS. • Detoxification system plays critical roles in protection against photodynamic stress.

  20. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water1

    PubMed Central

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

    2015-01-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50–1000 µg/ L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic’s possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. PMID:25759245

  1. Parent Involvement.

    ERIC Educational Resources Information Center

    LaCrosse, Ed

    The paper discusses the rationale and guidelines for parent involvement in HCEEP (Handicapped Children's Early Education Program) projects. Ways of assessing parents' needs are reviewed, as are four types of services to meet the identified needs: parent education, direct participation, parent counseling, and parent provided programs. Materials and…

  2. Hearing on the Impact of Deregulation on the American Workers. Hearing before the Committee on Education and Labor. House of Representatives, One Hundredth Congress, First Session (Miami, Florida).

    ERIC Educational Resources Information Center

    Congress of the U.S., Washington, DC. House Committee on Education and Labor.

    This congressional report includes testimony pertaining to the impact of the Reagan administration's policy of increased deregulation on American workers. Particular emphasis is placed on the impact that deregulation has had on specific occupations, industries (including plant closings), wage structures, and organized labor. The following…

  3. Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

    PubMed Central

    Eisinger-Mathason, T. S. Karin; Mucaj, Vera; Biju, Kevin M.; Nakazawa, Michael S.; Gohil, Mercy; Cash, Timothy P.; Yoon, Sam S.; Skuli, Nicolas; Park, Kyung Min; Gerecht, Sharon; Simon, M. Celeste

    2015-01-01

    Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes. PMID:26080399

  4. A Deregulated Intestinal Cell Cycle Program Disrupts Tissue Homeostasis without Affecting Longevity in Drosophila*

    PubMed Central

    Petkau, Kristina; Parsons, Brendon D.; Duggal, Aashna; Foley, Edan

    2014-01-01

    Recent studies illuminate a complex relationship between the control of stem cell division and intestinal tissue organization in the model system Drosophila melanogaster. Host and microbial signals drive intestinal proliferation to maintain an effective epithelial barrier. Although it is widely assumed that proliferation induces dysplasia and shortens the life span of the host, the phenotypic consequences of deregulated intestinal proliferation for an otherwise healthy host remain unexplored. To address this question, we genetically isolated and manipulated the cell cycle programs of adult stem cells and enterocytes. Our studies revealed that cell cycle alterations led to extensive cell death and morphological disruptions. Despite the extensive tissue damage, we did not observe an impact on longevity, suggesting a remarkable degree of plasticity in intestinal function. PMID:25170078

  5. Allocation of Transaction Cost to Market Participants Using an Analytical Method in Deregulated Market

    NASA Astrophysics Data System (ADS)

    Jeyasankari, S.; Jeslin Drusila Nesamalar, J.; Charles Raja, S.; Venkatesh, P.

    2014-04-01

    Transmission cost allocation is one of the major challenges in transmission open access faced by the electric power sector. The purpose of this work is to provide an analytical method for allocating transmission transaction cost in deregulated market. This research work provides a usage based transaction cost allocation method based on line-flow impact factor (LIF) which relates the power flow in each line with respect to transacted power for the given transaction. This method provides the impact of line flows without running iterative power flow solution and is well suited for real time applications. The proposed method is compared with the Newton-Raphson (NR) method of cost allocation on sample six bus and practical Indian utility 69 bus systems by considering multilateral transaction.

  6. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer

    PubMed Central

    Knudsen, Karen E.; Penning, Trevor

    2010-01-01

    Prostate cancer remains a leading cause of cancer death, as there are no durable means to treat advanced disease. Treatment of non-organ confined prostate cancer hinges on its androgen dependence. First line therapeutic strategies suppress androgen receptor (AR) activity, via androgen ablation and direct AR antagonists. While initially effective, incurable, "castration-resistant" tumors arise due to resurgent AR activity. Alterations of AR and/or associated regulatory networks are known to restore receptor activity and support resultant therapy-resistant tumor progression. However, recent evidence also reveals an unexpected contribution of AR ligand, wherein alterations in pathways controlling androgen synthesis support castrate-resistant AR activity. Herein, mechanisms underlying the lethal pairing of AR deregulation and aberrant androgen synthesis in prostate cancer progression will be discussed. PMID:20138542

  7. The future of America's electric utilities: Reconciling deregulation and least-cost planning

    SciTech Connect

    Cavanagh, R. )

    1991-05-01

    For more than a decade, two dynamic reform movements have been reshaping the utility industry. One camp follows the banner of least-cost of integrated-resource planning and investment; it puts special emphasis on previously neglectetd improvements in the efficiency of energy use, enlisting both public and private sectors in a search for cost-effective ways to get more services out of less energy. The other vision is rooted in the ideology and practice of deregulation; it seeks to reduce costs and boost supplies by spurring increased competition in the sale of kilowatt-hours. This article seeks a reconciliation of these views, whose proponents often have not yet paused even to acknowledge each others; existence. Yet the best of both ideals can be realized under proper regulatory and management regimes.

  8. CCT`s in a deregulated environment: A producer`s perspective

    SciTech Connect

    Edmonds, R.F. Jr.; Fayssoux, J.O.

    1997-12-31

    The US electric industry will be deregulated (or substantially re-regulated) within 5 years. Several states, including California, Rhode Island, and New Hampshire, already have passed legislation to introduce competition into the electric markets before the year 2000. As this trend sweeps across the country, the resulting competitive market for generation will reward the lowest cost producers and force high cost producers out of the market. As a result, at least in the short run, it may be very difficult for new power plants employing Clean Coal Technologies (CCTs) to compete. This paper discusses a producer`s perspective of the new competitive market, and suggests several short and long term strategies and niches for CCTs.

  9. Amplification of Distant Estrogen Response Elements Deregulates Target Genes Associated with Tamoxifen Resistance in Breast Cancer

    PubMed Central

    Hsu, Pei-Yin; Hsu, Hang-Kai; Lan, Xun; Juan, Liran; Yan, Pearlly S.; Labanowska, Jadwiga; Heerema, Nyla; Hsiao, Tzu-Hung; Chiu, Yu-Chiao; Chen, Yidong; Liu, Yunlong; Li, Lang; Li, Rong; Thompson, Ian M.; Nephew, Kenneth P.; Sharp, Zelton D.; Kirma, Nameer B.; Jin, Victor X.; Huang, Tim H.-M.

    2013-01-01

    SUMMARY A causal role of gene amplification in tumorigenesis is well-known, while amplification of DNA regulatory elements as an oncogenic driver remains unclear. In this study, we integrated next-generation sequencing approaches to map distant estrogen response elements (DEREs) that remotely control transcription of target genes through chromatin proximity. Two densely mapped DERE regions located on chromosomes 17q23 and 20q13 were frequently amplified in ERα-positive luminal breast cancer. These aberrantly amplified DEREs deregulated target gene expression potentially linked to cancer development and tamoxifen resistance. Progressive accumulation of DERE copies was observed in normal breast progenitor cells chronically exposed to estrogenic chemicals. These findings may extend to other DNA regulatory elements, the amplification of which can profoundly alter target transcriptome during tumorigenesis. PMID:23948299

  10. Prognostic and predictive value of MET deregulation in non-small cell lung cancer

    PubMed Central

    Toschi, Luca; Gianoncelli, Letizia; Baretti, Marina; Santoro, Armando

    2015-01-01

    Recent progress in cancer biology has led to the discovery of increasing number of oncogene alterations that have dramatically changed the paradigm of lung cancer treatment. MET is a tyrosine kinase receptor for the hepatocyte growth factor (HGF) that is deregulated in several malignancies, including non-small cell lung cancer (NSCLC). Abnormal MET-HGF signaling pathway activation can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. MET protein overexpression and increased MET gene number have been identified as poor prognostic factors in several series of surgically resected NSCLC making this receptor an attractive target for cancer treatment. Several clinical trials have recently evaluated the activity of a variety of anti-MET strategies in NSCLC patients with or without molecular selection with a variable degree of success, underscoring the need of establishing the best predictive biomarker for the identification of responding patients. PMID:25992382

  11. Modeling hydro power plants in deregulated electricity markets : integration and application of EMCAS and VALORAGUA.

    SciTech Connect

    Thimmapuram, P.; Veselka, T.; Koritarov, V.; Vilela, S.; Pereira, R.; Silva, R.

    2008-01-01

    In this paper, we present details of integrating an agent-based model, Electricity Market Complex Adaptive System (EMCAS) with a hydro-thermal coordination model, VALORAGUA. EMCAS provides a framework for simulating deregulated markets with flexible regulatory structure along with bidding strategies for supply offers and demand bids. VALORAGUA provides longer-term operation plans by optimizing hydro and thermal power plant operation for the entire year. In addition, EMCAS uses the price forecasts and weekly hydro schedules from VALORAGUA to provide intra-week hydro plant optimization for hourly supply offers. The integrated model is then applied to the Iberian electricity market which includes about 111 thermal plants and 38 hydro power plants. We then analyze the impact of hydro plant supply offers on the market prices and ways to minimize the Gencospsila exposure to price risk.

  12. A deregulated intestinal cell cycle program disrupts tissue homeostasis without affecting longevity in Drosophila.

    PubMed

    Petkau, Kristina; Parsons, Brendon D; Duggal, Aashna; Foley, Edan

    2014-10-10

    Recent studies illuminate a complex relationship between the control of stem cell division and intestinal tissue organization in the model system Drosophila melanogaster. Host and microbial signals drive intestinal proliferation to maintain an effective epithelial barrier. Although it is widely assumed that proliferation induces dysplasia and shortens the life span of the host, the phenotypic consequences of deregulated intestinal proliferation for an otherwise healthy host remain unexplored. To address this question, we genetically isolated and manipulated the cell cycle programs of adult stem cells and enterocytes. Our studies revealed that cell cycle alterations led to extensive cell death and morphological disruptions. Despite the extensive tissue damage, we did not observe an impact on longevity, suggesting a remarkable degree of plasticity in intestinal function. PMID:25170078

  13. A Novel Approach of Battery Energy Storage for Improving Value of Wind Power in Deregulated Markets

    NASA Astrophysics Data System (ADS)

    Nguyen, Y. Minh; Yoon, Yong Tae

    2013-06-01

    Wind power producers face many regulation costs in deregulated environment, which remarkably lowers the value of wind power in comparison with the conventional sources. One of these costs is associated with the real-time variation of power output and being paid in frequency control market according to the variation band. In this regard, this paper presents a new approach to the scheduling and operation of battery energy storage installed in wind generation system. This approach depends on the statistic data of wind generation and the prediction of frequency control market prices to determine the optimal charging and discharging of batteries in real-time, which ultimately gives the minimum cost of frequency regulation for wind power producers. The optimization problem is formulated as the trade-off between the decrease in regulation payment and the increase in the cost of using battery energy storage. The approach is illustrated in the case study and the results of simulation show its effectiveness.

  14. The role of clean coal technologies in a deregulated rural utility market

    SciTech Connect

    Neal, J.W.

    1997-12-31

    The nation`s rural electric cooperatives own a high proportion of coal-fired generation, in excess of 80 percent of their generating capacity. As the electric utility industry moves toward a competitive electricity market, the generation mix for electric cooperatives is expected to change. Distributed generation will likely serve more customer loads than is now the case, and that will lead to an increase in gas-fired generation capacity. But, clean low-cost central station coal-fired capacity is expected to continue to be the primary source of power for growing rural electric cooperatives. Gasification combined cycle could be the lowest cost coal based generation option in this new competitive market if both capital cost and electricity production costs can be further reduced. This paper presents anticipated utility business scenarios for the deregulated future and identifies combined cycle power plant configurations that might prove most competitive.

  15. Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis.

    PubMed

    Taymans, Jean-Marc; Nkiliza, Aurore; Chartier-Harlin, Marie-Christine

    2015-08-01

    Protein translation is one of the most fundamental and exquisitely controlled processes in biology, and is energetically demanding. The deregulation of this process is deleterious to cells, as demonstrated by several diseases caused by mutations in protein translation machinery. Emerging evidence now points to a role for protein translation in the pathogenesis of Parkinson's disease (PD); a debilitating neurodegenerative movement disorder. In this paper, we propose a hypothesis that protein translation machinery, PD-associated proteins and PD pathology are connected in a functional network linking cell survival to protein translation control. This hypothesis is a potential game changer in the field of the molecular pathogenesis of PD, with implications for the development of PD diagnostics and disease-modifying therapies. PMID:26091824

  16. Integrated Computing, Communication, and Distributed Control of Deregulated Electric Power Systems

    SciTech Connect

    Bajura, Richard; Feliachi, Ali

    2008-09-24

    Restructuring of the electricity market has affected all aspects of the power industry from generation to transmission, distribution, and consumption. Transmission circuits, in particular, are stressed often exceeding their stability limits because of the difficulty in building new transmission lines due to environmental concerns and financial risk. Deregulation has resulted in the need for tighter control strategies to maintain reliability even in the event of considerable structural changes, such as loss of a large generating unit or a transmission line, and changes in loading conditions due to the continuously varying power consumption. Our research efforts under the DOE EPSCoR Grant focused on Integrated Computing, Communication and Distributed Control of Deregulated Electric Power Systems. This research is applicable to operating and controlling modern electric energy systems. The controls developed by APERC provide for a more efficient, economical, reliable, and secure operation of these systems. Under this program, we developed distributed control algorithms suitable for large-scale geographically dispersed power systems and also economic tools to evaluate their effectiveness and impact on power markets. Progress was made in the development of distributed intelligent control agents for reliable and automated operation of integrated electric power systems. The methodologies employed combine information technology, control and communication, agent technology, and power systems engineering in the development of intelligent control agents for reliable and automated operation of integrated electric power systems. In the event of scheduled load changes or unforeseen disturbances, the power system is expected to minimize the effects and costs of disturbances and to maintain critical infrastructure operational.

  17. Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation

    PubMed Central

    Hasumi, Yukiko; Baba, Masaya; Hasumi, Hisashi; Huang, Ying; Lang, Martin; Reindorf, Rachel; Oh, Hyoung-bin; Sciarretta, Sebastiano; Nagashima, Kunio; Haines, Diana C.; Schneider, Michael D.; Adelstein, Robert S.; Schmidt, Laura S.; Sadoshima, Junichi; Marston Linehan, W.

    2014-01-01

    Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK–mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK–mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model. PMID:24908670

  18. Aberrantly Expressed OTX Homeobox Genes Deregulate B-Cell Differentiation in Hodgkin Lymphoma

    PubMed Central

    Nagel, Stefan; Ehrentraut, Stefan; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G.; MacLeod, Roderick A. F.

    2015-01-01

    In Hodgkin lymphoma (HL) we recently reported that deregulated homeobox gene MSX1 mediates repression of the B-cell specific transcription factor ZHX2. In this study we investigated regulation of MSX1 in this B-cell malignancy. Accordingly, we analyzed expression and function of OTX homeobox genes which activate MSX1 transcription during embryonal development in the neural plate border region. Our data demonstrate that OTX1 and OTX2 are aberrantly expressed in both HL patients and cell lines. Moreover, both OTX loci are targeted by genomic gains in overexpressing cell lines. Comparative expression profiling and subsequent pathway modulations in HL cell lines indicated that aberrantly enhanced FGF2-signalling activates the expression of OTX2. Downstream analyses of OTX2 demonstrated transcriptional activation of genes encoding transcription factors MSX1, FOXC1 and ZHX1. Interestingly, examination of the physiological expression profile of ZHX1 in normal hematopoietic cells revealed elevated levels in T-cells and reduced expression in B-cells, indicating a discriminatory role in lymphopoiesis. Furthermore, two OTX-negative HL cell lines overexpressed ZHX1 in correlation with genomic amplification of its locus at chromosomal band 8q24, supporting the oncogenic potential of this gene in HL. Taken together, our data demonstrate that deregulated homeobox genes MSX1 and OTX2 respectively impact transcriptional inhibition of (B-cell specific) ZHX2 and activation of (T-cell specific) ZHX1. Thus, we show how reactivation of a specific embryonal gene regulatory network promotes disturbed B-cell differentiation in HL. PMID:26406991

  19. Obtaining operational flexibility during power plant permitting in a deregulated market

    SciTech Connect

    Head, S.J.; Kelly, J,; Welch, A.C.; Fraser, R.

    1999-07-01

    According to the Wall Street Journal, California is one of the most aggressive states in pursuing deregulation of the power industry. The High Desert Power Project (HDPP) is one of the first merchant power plants to undergo permitting in California's deregulated energy market. HDPP requires air permits from the California Energy Commission, EPA Region IX, and Mojave Desert Air Quality Management District for the power plant. As a merchant plant, HDPP will be solely responsible for efficient, reliable production of energy. Neither electricity customers nor utility companies will bear any financial risk of operation of HDPP. This changing risk profile has affected the permitting process for power plants in California. This paper will discuss how HDPP is endeavoring to obtain operational flexibility within this changing market place through the permitting process. Some of the strategies being pursued, and the impact on the permitting process and schedule, that will be discussed include: Use of conceptual vs. final plant design and engineering; Permitting of multiple plant configurations (both simple and combined cycle) and multiple natural gas pipelines to maximize market opportunities; The emissions envelope approach and inclusion of multiple gas turbine vendors; Determination of the Lowest Achievable Emission Rate for NO{sub x} and VOC in the midst of new developments for control technology options; Investigation of interbasin and interpollutant emission reduction credits for offsets; and Development of flexible permit conditions and requirements. The HDPP is currently in the permit processing stage and expects to be issued permits by EPA and MDAQMD in early-1999 and be licensed by the CEC by mid-1999.

  20. MMPs/TIMPs and inflammatory signalling de-regulation in human incisional hernia tissues

    PubMed Central

    Guillen-Marti, Jordi; Diaz, Ramon; Quiles, Maria T; Lopez-Cano, Manuel; Vilallonga, Ramon; Huguet, Pere; Ramon-y-Cajal, Santiago; Sanchez-Niubo, Albert; Reventós, Jaume; Armengol, Manel; Arbos, Maria A

    2009-01-01

    Background: Incisional hernia is a common and important complication of laparotomies. Epidemiological studies allude to an underlying biological cause, at least in a subset of population. Interest has mainly focused on abnormal collagen metabolism. However, the role played by other determinants of extracellular matrix (ECM) composition is unknown. To date, there are few laboratory studies investigating the importance of biological factors contributing to incisional hernia development. We performed a descriptive tissue-based analysis to elucidate the possible relevance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in association with local cytokine induction in human incisional hernia tissues. The expression profiles of MMPs, TIMPs and pro-inflammatory cytokine signalling were investigated in aponeurosis and skeletal muscle specimens taken intraoperatively from incisional hernia (n= 10) and control (n= 10) patients. Semiquantitative RT-PCR, zymography and immunoblotting analyses were done. Incisional hernia samples displayed alterations in the microstructure and loss of ECM, as assessed by histological analyses. Moreover, incisional hernia tissues showed increased MMP/TIMP ratios and de-regulated inflammatory signalling (tumor necrosis factor [TNFA] and interleukin [IL]-6 tended to increase, whereas aponeurosis TNFA receptors decreased). The changes were tissue-specific and were detectable at the mRNA and/or protein level. Statistical analyses showed several associations between individual MMPs, TIMPs, interstitial collagens and inflammatory markers. The increment of MMPs in the absence of a counterbalance by TIMPs, together with an ongoing de-regulated inflammatory signalling, may contribute in inducing a functional defect of the ECM network by post-translational mechanisms, which may trigger abdominal wall tissue loss and eventual rupture. The notable TIMP3 protein down-regulation in incisional hernia fascia may be of pathophysiological

  1. The implications of deregulation for biomass and renewable energy in California

    SciTech Connect

    Morris, G

    1998-07-01

    California has been leading the nation down the path of electric utility deregulation, beginning with the April 1994, California Public Utilities Commission`s (CPUC) Blue Book restructuring proposal. The road for renewable energy producers has been particularly rocky, leaving the future of renewable energy production very much in doubt. The original CPUC proposal provided for competition among generating sources on the basis of price alone, without regard for environmental considerations. The California legislature took up electric utility deregulation legislation during 1996, culminating in AB 1890, California`s landmark restructuring legislation, which was passed unanimously by the Senate and Assembly, and signed into law by the governor on September 28, 1996. AB 1890 assigned to the California Energy Commission (CEC) the task of determining how to allocate the renewables transition funds between existing and new renewable generating sources, and among the various renewable energy technologies that are available for deployment in California. The California Environmental Protection Agency (Cal/EPA) was assigned the task of reporting to the legislature about the specific benefits provided by biomass energy production in California, and about policies that could shift some of the cost of biomass energy production away from the electric ratepayer, on to beneficiaries of the environmental benefits of biomass energy production. This study describes the development of the CEC and Cal/EPA reports to the California legislature, and provides an analysis of the major issues that were encountered during the course of their development. The study concludes with a consideration of the future prospects for biomass and renewable energy production in the state.

  2. 26 CFR 1.168(i)-3 - Treatment of excess deferred income tax reserve upon disposition of deregulated public utility...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 2 2012-04-01 2012-04-01 false Treatment of excess deferred income tax reserve... INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES... income tax reserve upon disposition of deregulated public utility property. (a) Scope—(1) In...

  3. 26 CFR 1.168(i)-3 - Treatment of excess deferred income tax reserve upon disposition of deregulated public utility...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 2 2013-04-01 2013-04-01 false Treatment of excess deferred income tax reserve... INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES... income tax reserve upon disposition of deregulated public utility property. (a) Scope—(1) In...

  4. 26 CFR 1.168(i)-3 - Treatment of excess deferred income tax reserve upon disposition of deregulated public utility...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Treatment of excess deferred income tax reserve... INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES... income tax reserve upon disposition of deregulated public utility property. (a) Scope—(1) In...

  5. Deregulating School Aid in California: How 10 Districts Responded to Fiscal Flexibility, 2009-2010. Research Report Number 2

    ERIC Educational Resources Information Center

    Fuller, Bruce; Marsh, Julie A.; Stecher, Brian M.; Timar, Tom

    2011-01-01

    In 2009, California state legislators freed local educators from the specific guidelines that previously regulated spending on 40 categorical-aid programs known as Tier 3 programs. This Tier 3 flexibility reform, which deregulates $4.5 billion in education funding, was enacted at the same time the legislature made cuts in education spending in…

  6. MicroRNA involvement in glioblastoma pathogenesis

    SciTech Connect

    Novakova, Jana; Slaby, Ondrej; Vyzula, Rostislav; Michalek, Jaroslav

    2009-08-14

    MicroRNAs are endogenously expressed regulatory noncoding RNAs. Altered expression levels of several microRNAs have been observed in glioblastomas. Functions and direct mRNA targets for these microRNAs have been relatively well studied over the last years. According to these data, it is now evident, that impairment of microRNA regulatory network is one of the key mechanisms in glioblastoma pathogenesis. MicroRNA deregulation is involved in processes such as cell proliferation, apoptosis, cell cycle regulation, invasion, glioma stem cell behavior, and angiogenesis. In this review, we summarize the current knowledge of miRNA functions in glioblastoma with an emphasis on its significance in glioblastoma oncogenic signaling and its potential to serve as a disease biomarker and a novel therapeutic target in oncology.

  7. The effects of deregulation on rural electric distribution cooperatives: An empirical analysis

    NASA Astrophysics Data System (ADS)

    Greer, Monica Lynne

    In 1996, the Federal Energy Regulatory Commission ("FERC") issued Orders 888 and 889, which were designed to promote competition in wholesale markets for electricity. While these Orders were predominantly meant to apply to vertically integrated investor-owned utilities ("IOUs"), FERC recently issued a Notice of Proposed Rulemaking that indicates its intent to make all transmission-owning entities, including those of cooperatively-owned utilities and the federal power administrations subject to FERC jurisdiction. Cooperatively owned utilities ("coops"), the focus of this paper, are organized as either generation and transmission ("G&T") or distribution only. And, although there are typically long-term contracts between the G&T and the distribution coops (thus rendering them quasi-vertically-integrated), they are very different from their investor-owned counterparts. It is because of these differences that the economic viability of these entities is being questioned in a deregulated environment. This dissertation examines the ability of coops to continue operating in their present form in a restructured electricity market. More specifically, using 1996 data for 831 distribution coops I estimate both quadratic and translogarithmic cost specifications so as to ascertain whether these firms are operating in such a fashion as to minimize costs. I find evidence that they are not. When delivered power is modeled as a single-output translogarithmic cost equation, I find that the majority of firms in the sample were operating in the increasing returns to scale portion of the average cost curve in 1996. This result reveals that coops delivered far less electricity to all customer classes than was necessary to attain the minimum efficient scale. And, upon estimating a multiple-output quadratic cost function, I find that there are ray economies, product specific returns to scale, and economies of scope in the distribution of electricity to the various customer classes that are

  8. The MAPK1/3 pathway is essential for the deregulation of autophagy observed in G2019S LRRK2 mutant fibroblasts

    PubMed Central

    Bravo-San Pedro, José M.; Gómez-Sánchez, Rubén; Niso-Santano, Mireia; Pizarro-Estrella, Elisa; Aiastui-Pujana, Ana; Gorostidi, Ana; Climent, Vicente; López de Maturana, Rakel; Sanchez-Pernaute, Rosario; López de Munain, Adolfo; Fuentes, José M.; González-Polo, Rosa A.

    2012-01-01

    The link between the deregulation of autophagy and cell death processes can be essential in the development of several neurodegenerative diseases, such as Parkinson disease (PD). However, the molecular mechanism of deregulation of this degradative process in PD patients is unknown. The leucine-rich repeat kinase 2 (LRRK2) gene is related to PD and its implication in autophagy regulation has been described. Our recent work shows that the presence of the G2019S LRRK2 mutation, one of the most prevalent in LRRK2, is accompanied by a deregulation of autophagy basal levels dependent on the MAPK1/3 (ERK2/1) pathway. PMID:22914360

  9. Truncated tau deregulates synaptic markers in rat model for human tauopathy

    PubMed Central

    Jadhav, Santosh; Katina, Stanislav; Kovac, Andrej; Kazmerova, Zuzana; Novak, Michal; Zilka, Norbert

    2015-01-01

    Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer’s disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology. PMID:25755633

  10. SOD2 deregulation enhances migration, invasion and has poor prognosis in salivary adenoid cystic carcinoma

    PubMed Central

    Chang, Boyang; Yang, Hang; Jiao, Yuan; Wang, Kefeng; Liu, Zhonghua; Wu, Peihong; Li, Su; Wang, Anxun

    2016-01-01

    This study aimed to investigate the role of SOD2 in the progression and metastasis of salivary adenoid cystic carcinoma (SACC). We analyzed the expression of SOD2 in 50 SACC patients. Then, the effects and mechanism of SOD2 on cell metastasis in a pair of different metastatic potential cell lines was investigated. SOD2 was deregulated in patients with SACC. Up-regulation of SOD2 was associated with distant metastasis and reduced overall survival and disease free - survival. Compared to SACC-83 cells (lower metastasis ability), SACC-LM cells (higher metastasis ability) had higher SOD2 activity and intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug, but had similar catalase protein level and activity. In SACC-LM, reducing the expression of SOD2 by SiRNA inhibited the metastasis ability and reduced the SOD2 activities, intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug. These effects were revised in SACC-83 after SOD2 overexpression. Moreover, in SACC-83, treated with H2O2, the metastasis was enhanced accompanied by increased protein levels of pERK1/2 and Slug. We confirmed that SOD2 play an important role in the development and prognosis of SACC and SOD2-dependent production of H2O2 contributes to metastasis of SACC through the ERK-Slug signaling pathway. PMID:27181103

  11. Deregulation of feedback inhibition of phosphoenolpyruvate carboxylase for improved lysine production in Corynebacterium glutamicum.

    PubMed

    Chen, Zhen; Bommareddy, Rajesh Reddy; Frank, Doinita; Rappert, Sugima; Zeng, An-Ping

    2014-02-01

    Allosteric regulation of phosphoenolpyruvate carboxylase (PEPC) controls the metabolic flux distribution of anaplerotic pathways. In this study, the feedback inhibition of Corynebacterium glutamicum PEPC was rationally deregulated, and its effect on metabolic flux redistribution was evaluated. Based on rational protein design, six PEPC mutants were designed, and all of them showed significantly reduced sensitivity toward aspartate and malate inhibition. Introducing one of the point mutations (N917G) into the ppc gene, encoding PEPC of the lysine-producing strain C. glutamicum LC298, resulted in ∼37% improved lysine production. In vitro enzyme assays and (13)C-based metabolic flux analysis showed ca. 20 and 30% increases in the PEPC activity and corresponding flux, respectively, in the mutant strain. Higher demand for NADPH in the mutant strain increased the flux toward pentose phosphate pathway, which increased the supply of NADPH for enhanced lysine production. The present study highlights the importance of allosteric regulation on the flux control of central metabolism. The strategy described here can also be implemented to improve other oxaloacetate-derived products. PMID:24334667

  12. Non-enzymatic post-translational protein modifications and proteostasis network deregulation in carcinogenesis.

    PubMed

    Trougakos, Ioannis P; Sesti, Fabiola; Tsakiri, Eleni; Gorgoulis, Vassilis G

    2013-10-30

    Organisms are constantly challenged by stressors and thus the maintenance of biomolecules functionality is essential for the assurance of cellular homeostasis. Proteins carry out the vast majority of cellular functions by mostly participating in multimeric protein assemblies that operate as protein machines. Cells have evolved a complex proteome quality control network for the rescue, when possible, or the degradation of damaged polypeptides. Nevertheless, despite these proteostasis ensuring mechanisms, new protein synthesis, and the replication-mediated dilution of proteome damage in mitotic cells, the gradual accumulation of stressors during aging (or due to lifestyle) results in increasingly damaged proteome. Non-enzymatic post-translational protein modifications mostly arise by unbalanced redox homeostasis and/or high glucose levels and may cause disruption of proteostasis as they can alter protein function. This outcome may then increase genomic instability due to reduced fidelity in processes like DNA replication or repair. Herein, we present a synopsis of the major non-enzymatic post-translation protein modifications and of the proteostasis network deregulation in carcinogenesis. We propose that activation of the proteostasis ensuring mechanisms in premalignant cells has tumor-preventive effects, whereas considering that over-activation of these mechanisms represents a hallmark of advanced tumors, their inhibition provides a strategy for the development of anti-tumor therapies. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID:23500136

  13. Head lice surveillance on a deregulated OTC-sales market: a study using web query data.

    PubMed

    Lindh, Johan; Magnusson, Måns; Grünewald, Maria; Hulth, Anette

    2012-01-01

    The head louse, Pediculus humanus capitis, is an obligate ectoparasite that causes infestations of humans. Studies have demonstrated a correlation between sales figures for over-the-counter (OTC) treatment products and the number of humans with head lice. The deregulation of the Swedish pharmacy market on July 1, 2009, decreased the possibility to obtain complete sale figures and thereby the possibility to obtain yearly trends of head lice infestations. In the presented study we wanted to investigate whether web queries on head lice can be used as substitute for OTC sales figures. Via Google Insights for Search and Vårdguiden medical web site, the number of queries on "huvudlöss" (head lice) and "hårlöss" (lice in hair) were obtained. The analysis showed that both the Vårdguiden series and the Google series were statistically significant (p<0.001) when added separately, but if the Google series were already included in the model, the Vårdguiden series were not statistically significant (p = 0.5689). In conclusion, web queries can detect if there is an increase or decrease of head lice infested humans in Sweden over a period of years, and be as reliable a proxy as the OTC-sales figures. PMID:23144923

  14. A deregulated immune response to gliadin causes a decreased villus height in DQ8 transgenic mice.

    PubMed

    D'Arienzo, Rossana; Stefanile, Rosita; Maurano, Francesco; Luongo, Diomira; Bergamo, Paolo; Mazzarella, Giuseppe; Troncone, Riccardo; Auricchio, Salvatore; David, Chella; Rossi, Mauro

    2009-12-01

    Celiac disease (CD) is an enteropathy triggered by gluten and mediated by CD4+ T cells. A complete understanding of CD immunopathogenesis has been hindered due to the lack of adequate in vivo models. Here, we explored the effect of the inhibition of COX by indomethacin in wheat gliadin-sensitized transgenic mice expressing the HLA-DQ8 heterodimer, a molecule associated with CD. Treated mice showed a gliadin-specific immune response with a significant reduction of villus height, not linked to crypt hyperplasia and to expansion of intraepithelial T cells. Notably, treated mice showed increased numbers of CD25+ and apoptotic cells in the lamina propria, whereas high basal levels of IFN-gamma secretion, along with a reduced gliadin-specific IL-2 expression were detected in MLN. Biochemical assessment of the lesion revealed increased mRNA of Lamb3 and Adamts2, encoding for ECM proteins, and enhanced activities of metalloproteinases MMP1, 2 and 7. We conclude that an intestinal sensitivity to gliadin, in connection with COX inhibition, caused a decreased villus height in DQ8 tg mice. The lesion was induced by a deregulated mucosal cell immunity to gliadin, thus triggering activation of a specific ECM protein pathway responsible for lamina propria remodeling. PMID:19795413

  15. Wrecked regulation of intrinsically disordered proteins in diseases: pathogenicity of deregulated regulators

    PubMed Central

    Uversky, Vladimir N.

    2014-01-01

    Biologically active proteins without stable tertiary structure are common in all known proteomes. Functions of these intrinsically disordered proteins (IDPs) are typically related to regulation, signaling, and control. Cellular levels of these important regulators are tightly regulated by a variety mechanisms ranging from firmly controlled expression to precisely targeted degradation. Functions of IDPs are controlled by binding to specific partners, alternative splicing, and posttranslational modifications among other means. In the norm, right amounts of precisely activated IDPs have to be present in right time at right places. Wrecked regulation brings havoc to the ordered world of disordered proteins, leading to protein misfolding, misidentification, and missignaling that give rise to numerous human diseases, such as cancer, cardiovascular disease, neurodegenerative diseases, and diabetes. Among factors inducing pathogenic transformations of IDPs are various cellular mechanisms, such as chromosomal translocations, damaged splicing, altered expression, frustrated posttranslational modifications, aberrant proteolytic degradation, and defective trafficking. This review presents some of the aspects of deregulated regulation of IDPs leading to human diseases. PMID:25988147

  16. Deregulation of paralogous 13 HOX genes in oral squamous cell carcinoma

    PubMed Central

    Aquino, Gabriella; Franco, Renato; Sabatino, Rocco; Mantia, Elvira La; Scognamiglio, Giosuè; Collina, Francesca; Longo, Francesco; Ionna, Franco; Losito, Nunzia S; Liguori, Giuseppina; Botti, Gerardo; Cantile, Monica

    2015-01-01

    Many oncogenic drivers related to the pathogenesis of OSCC have identified, but the discovery of new molecular markers for early detection of this cancer, remains one the main goals of clinical research. HOX genes regulate normal embryonic development, cell differentiation and other critical processes in eukaryotic cell life. Several studies have demonstrated that the deregulation of HOX genes play a significant role in cancer development and progression. In this study, we built a prognostic TMA with 119 OSCC samples, representative of deep and superficial part of the tumour, to investigate, the paralogous 13 HOX proteins expression, correlating them with clinicpathological parameters, outcomes and therapy information. Our results show an aberrant expression of HOX A13 and HOX D13 in OSCC pathogenesis and tumour progression. HOX A13 overexpression is related to an OSCC better prognosis (P=0.029) and better therapy response in patients treated with both radiotherapy and chemotherapy (P=0.015). HOX D13 overexpression is inversely related to an overall survival (P=0.004). These data highlight the potential prognostic role of HOX paralogous group 13 genes in OSCC. PMID:26693058

  17. Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression.

    PubMed

    Forno, Irene; Ferrero, Stefano; Russo, Maria Veronica; Gazzano, Giacomo; Giangiobbe, Sara; Montanari, Emanuele; Del Nero, Alberto; Rocco, Bernardo; Albo, Giancarlo; Languino, Lucia R; Altieri, Dario C; Vaira, Valentina; Bosari, Silvano

    2015-01-01

    Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the "stemness" marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease. PMID:26107383

  18. Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression

    PubMed Central

    Russo, Maria Veronica; Gazzano, Giacomo; Giangiobbe, Sara; Montanari, Emanuele; Del Nero, Alberto; Rocco, Bernardo; Albo, Giancarlo; Languino, Lucia R.; Altieri, Dario C.; Vaira, Valentina; Bosari, Silvano

    2015-01-01

    Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the “stemness” marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease. PMID:26107383

  19. The implications of deregulation for biomass and renewable energy in California. Revision

    SciTech Connect

    Morris, G.

    1998-08-01

    The California legislature took up electric utility deregulation legislation during 1996, culminating in AB 1890, California`s landmark restructuring legislation. The legislation created a transition funding program for renewables. No permanent program for the support of renewable energy production extending beyond the end of the transition period (2002) is included in AB 1890. AB 1890 assigned to the California Energy Commission (CEC) the task of determining how to allocate the renewables transition funds between existing and new renewable generating sources, and among the various renewable energy technologies that are available for deployment in California. The California Environmental Protection Agency (Cal/EPA) was assigned the task of reporting to the legislature about the specific benefits provided by biomass energy production in California, and about policies that could shift some of the cost of biomass energy production away from the electric ratepayer, on to beneficiaries of the environmental benefits of biomass energy production. This study describes the development of the CEC and Cal/EPA reports to the California legislature, and provides an analysis of the major issues that were encountered during the course of their development. The study concludes with a consideration of the future prospects for biomass and renewable energy production in the state.

  20. Calpain-mediated cleavage of Beclin-1 and autophagy deregulation following retinal ischemic injury in vivo

    PubMed Central

    Russo, R; Berliocchi, L; Adornetto, A; Varano, G P; Cavaliere, F; Nucci, C; Rotiroti, D; Morrone, L A; Bagetta, G; Corasaniti, M T

    2011-01-01

    Autophagy is the major intracellular degradation pathway that regulates long-lived proteins and organelles turnover. This process occurs at basal levels in all cells but it is rapidly upregulated in response to starvation and cellular stress. Although being recently implicated in neurodegeneration, it remains still unclear whether autophagy has a detrimental or protective role. In this study, we investigated the dynamics of the autophagic process in retinal tissue that has undergone transient ischemia, an experimental model that recapitulates features of ocular pathologies, including glaucoma, anterior ischemic optic neuropathy and retinal vessels occlusion. Retinal ischemia, induced in adult rats by increasing the intraocular pressure, was characterized by a reduction in the phosphatidylethanolamine-modified form of LC3 (LC3II) and by a significant decrease in Beclin-1. The latter event was associated with a proteolytic cleavage of Beclin-1, leading to the accumulation of a 50-kDa fragment. This event was prevented by intravitreal treatment with the non-competitive N-methyl-D-aspartate antagonist MK801 and calpain inhibitors or by calpain knockdown. Blockade of autophagy by pharmacological inhibition or Beclin-1 silencing in RGC-5 increased cell death, suggesting a pro-survival role of the autophagic process in this neuronal cell type. Altogether, our results provide original evidence for calpain-mediated cleavage of Beclin-1 and deregulation of basal autophagy in the rat retina that has undergone ocular ischemia/reperfusion injury. PMID:21490676

  1. SOD2 deregulation enhances migration, invasion and has poor prognosis in salivary adenoid cystic carcinoma.

    PubMed

    Chang, Boyang; Yang, Hang; Jiao, Yuan; Wang, Kefeng; Liu, Zhonghua; Wu, Peihong; Li, Su; Wang, Anxun

    2016-01-01

    This study aimed to investigate the role of SOD2 in the progression and metastasis of salivary adenoid cystic carcinoma (SACC). We analyzed the expression of SOD2 in 50 SACC patients. Then, the effects and mechanism of SOD2 on cell metastasis in a pair of different metastatic potential cell lines was investigated. SOD2 was deregulated in patients with SACC. Up-regulation of SOD2 was associated with distant metastasis and reduced overall survival and disease free - survival. Compared to SACC-83 cells (lower metastasis ability), SACC-LM cells (higher metastasis ability) had higher SOD2 activity and intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug, but had similar catalase protein level and activity. In SACC-LM, reducing the expression of SOD2 by SiRNA inhibited the metastasis ability and reduced the SOD2 activities, intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug. These effects were revised in SACC-83 after SOD2 overexpression. Moreover, in SACC-83, treated with H2O2, the metastasis was enhanced accompanied by increased protein levels of pERK1/2 and Slug. We confirmed that SOD2 play an important role in the development and prognosis of SACC and SOD2-dependent production of H2O2 contributes to metastasis of SACC through the ERK-Slug signaling pathway. PMID:27181103

  2. Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis

    PubMed Central

    IFERE, GODWIN O.; DESMOND, RENEE; DEMARK-WAHNEFRIED, WENDY; NAGY, TIM R.

    High circulating cholesterol and its deregulated homeostasis may facilitate prostate cancer progression. Genetic polymorphism in Apolipoprotein (Apo) E, a key cholesterol regulatory protein may effect changes in systemic cholesterol levels. In this investigation, we determined whether variants of the Apo E gene can trigger defective intracellular cholesterol efflux, which could promote aggressive prostate cancer. ApoE genotypes of weakly (non-aggressive), moderate and highly tumorigenic (aggressive) prostate cancer cell lines were characterized, and we explored whether the ApoE variants were associated with tumor aggressiveness generated by intra cellular cholesterol imbalance, using the expression of caveolin-1 (cav-1), a pro-malignancy surrogate of cholesterol overload. Restriction isotyping of ApoE isoforms revealed that the non-aggressive cell lines carried ApoE ε3/ε3 or ε3/ε4 alleles, while the aggressive cell lines carried the Apoε2/ε4 alleles. Our data suggest a contrast between the non-aggressive and the aggressive prostate cancer cell lines in the pattern of cholesterol efflux and cav-1 expression. Our exploratory results suggest a relationship between prostate aggressiveness, ApoE isoforms and cholesterol imbalance. Further investigation of this relationship may elucidate the molecular basis for considering cholesterol as a risk factor of aggressive prostate tumors, and underscore the potential of the dysfunctional ApoE2/E4 isoform as a biomarker of aggressive disease. PMID:23934233

  3. [Effects of pharmacy market deregulation regarding patient-centred drug care in Germany from a health economics perspecitve].

    PubMed

    Rumm, R; Böcking, W

    2013-03-01

    This article analyses the impact of a potential deregulation Germany's pharmacy market by allowing foreign ownership of pharmacies and removing the limit of the number pharmacies that can be owned by a pharmacist. Based on a mathematical model and empirical values of foreign countries, scenarios for the German market are calculated and the impact on all participants of the health care system analysed. The key outcomes are:- A deregulation would enables the creation of pharmacy chains- In all simulated scenarios the total number of pharmacies would drastically grow- The increased pharmacy density improves patient centred drug care- The competition among pharmacies increases and leads to the closure of many independently owned and operated pharmacies. PMID:23423941

  4. E2Fs mediate a fundamental cell-cycle deregulation in high-grade serous ovarian carcinomas.

    PubMed

    De Meyer, T; Bijsmans, I T G W; Van de Vijver, K K; Bekaert, S; Oosting, J; Van Criekinge, W; van Engeland, M; Sieben, N L G

    2009-01-01

    Several studies described a role for the E2F/Rb pathway in ovarian serous carcinomas (SCAs). Since E2F/Rb pathway deregulation is a general hallmark of human cancer, it remains unclear whether this deregulation is of particular importance in SCAs or whether it reflects a common oncological feature. Here, we have clarified this issue by the examination of microarray expression profiles of SCAs and particularly by the comparison with another, less malignant, ovarian cancer type, serous borderline tumours (SBTs). Results were validated by quantitative RT-PCR, both on the microarray samples and on an independent panel, and TP53 mutation analysis was performed. This integrated analysis revealed a significant increase in the expression of the transcription factors E2F1 and E2F3 in SCAs, when compared to SBTs. This was associated with vast overexpression of E2F target genes in SCAs compared to SBTs. High-grade SCAs in particular exhibited a major deregulated E2F target expression pattern. Generally, overexpression of E2F targets in SCAs appeared to be well structured since those targets considered negative regulators of the cell cycle or promoters of apoptosis were usually not overexpressed in SCAs. Similar to E2F target deregulation, TP53 mutations were identified in SCA3s, to a lesser extent in SCA1s, and not in SBTs. These results suggest that a structured, generally up-regulated E2F transcription factor activity is associated with a global cell-cycle disturbance in high-grade SCAs and exceeds typical E2F/Rb pathway disruption in tumours, at least compared with SBTs. PMID:18991331

  5. An optimization-based approach for facility energy management with uncertainties, and, Power portfolio optimization in deregulated electricity markets with risk management

    NASA Astrophysics Data System (ADS)

    Xu, Jun

    Topic 1. An Optimization-Based Approach for Facility Energy Management with Uncertainties. Effective energy management for facilities is becoming increasingly important in view of the rising energy costs, the government mandate on the reduction of energy consumption, and the human comfort requirements. This part of dissertation presents a daily energy management formulation and the corresponding solution methodology for HVAC systems. The problem is to minimize the energy and demand costs through the control of HVAC units while satisfying human comfort, system dynamics, load limit constraints, and other requirements. The problem is difficult in view of the fact that the system is nonlinear, time-varying, building-dependent, and uncertain; and that the direct control of a large number of HVAC components is difficult. In this work, HVAC setpoints are the control variables developed on top of a Direct Digital Control (DDC) system. A method that combines Lagrangian relaxation, neural networks, stochastic dynamic programming, and heuristics is developed to predict the system dynamics and uncontrollable load, and to optimize the setpoints. Numerical testing and prototype implementation results show that our method can effectively reduce total costs, manage uncertainties, and shed the load, is computationally efficient. Furthermore, it is significantly better than existing methods. Topic 2. Power Portfolio Optimization in Deregulated Electricity Markets with Risk Management. In a deregulated electric power system, multiple markets of different time scales exist with various power supply instruments. A load serving entity (LSE) has multiple choices from these instruments to meet its load obligations. In view of the large amount of power involved, the complex market structure, risks in such volatile markets, stringent constraints to be satisfied, and the long time horizon, a power portfolio optimization problem is of critical importance but difficulty for an LSE to serve the

  6. Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo.

    PubMed

    Duan, Quanlu; Ni, Li; Wang, Peihua; Chen, Chen; Yang, Lei; Ma, Ben; Gong, Wei; Cai, Zhejun; Zou, Ming-Hui; Wang, Dao Wen

    2016-08-01

    Endoplasmic reticulum (ER) stress has been reported to be involved in many cardiovascular diseases such as atherosclerosis, diabetes, myocardial ischemia, and hypertension that ultimately result in heart failure. XBP1 is a key ER stress signal transducer and an important pro-survival factor of the unfolded protein response (UPR) in mammalian cells. The aim of this study was to establish a role for XBP1 in the deregulation of pro-angiogenic factor VEGF expression and potential regulatory mechanisms in hypertrophic and failing heart. Western blots showed that myocardial XBP1s protein was significantly increased in both isoproterenol (ISO)-induced and pressure-overload-induced hypertrophic and failing heart compared to normal control. Furthermore, XBP1 silencing exacerbates ISO-induced cardiac dysfunction along with a reduction of myocardial capillary density and cardiac expression of pro-angiogenic factor VEGF-A in vivo. Consistently, experiments in cultured cardiomyocytes H9c2 (2-1) cells showed that UPR-induced VEGF-A upregulation was determined by XBP1 expression level. Importantly, VEGF-A expression was increased in failing human heart tissue and blood samples and was correlated with the levels of XBP1. These results suggest that XBP1 regulates VEGF-mediated cardiac angiogenesis, which contributes to the progression of adaptive hypertrophy, and might provide novel targets for prevention and treatment of heart failure. PMID:27133203

  7. MicroRNAs in cervical cancer: evidences for a miRNA profile deregulated by HPV and its impact on radio-resistance.

    PubMed

    Pedroza-Torres, Abraham; López-Urrutia, Eduardo; García-Castillo, Verónica; Jacobo-Herrera, Nadia; Herrera, Luis A; Peralta-Zaragoza, Oscar; López-Camarillo, César; De Leon, David Cantú; Fernández-Retana, Jorge; Cerna-Cortés, Jorge F; Pérez-Plasencia, Carlos

    2014-01-01

    Cervical carcinoma (CC) is one of the most common cancers and a leading cause of mortality in women worldwide. Epidemiologic and experimental data have clearly demonstrated a causal role of high-risk Human Papillomavirus (HR-HPV) types in CC initiation and progression, affecting the cellular processes by targeting and inactivating p53 and pRB host proteins. HR-HPV E5, E6 and E7 oncoproteins have the ability to deregulate several cellular processes, mostly apoptosis, cell cycle control, migration, immune evasion, and induction of genetic instability, which promote the accumulation of mutations and aneuploidy. In this scenario, genomic profiles have shown that aberrant expression of cellular oncogenic and tumor suppressive miRNAs have an important role in CC carcinogenesis. It has been stated that HPV infection and E6/E7 expression are essential but not sufficient to lead to CC development; hence other genetic and epigenetic factors have to be involved in this complex disease. Recent evidence suggests an important level of interaction among E6/E7 viral proteins and cellular miRNA, and other noncoding RNAs. The aim of the current review is to analyze recent data that mainly describe the interaction between HR-HPV established infections and specific cellular miRNAs; moreover, to understand how those interactions could affect radio-therapeutic response in tumor cells. PMID:24840898

  8. HTLV-1 positive and negative T cells cloned from infected individuals display telomerase and telomere genes deregulation that predominate in activated but untransformed CD4+ T cells.

    PubMed

    Zane, Linda; Sibon, David; Capraro, Valérie; Galia, Perrine; Karam, Maroun; Delfau-Larue, Marie-Hélène; Gilson, Eric; Gessain, Antoine; Gout, Olivier; Hermine, Olivier; Mortreux, Franck; Wattel, Eric

    2012-08-15

    Untransformed HTLV-1 positive CD4(+) cells from infected individuals are selected for expressing tax and displaying morphological features consistent with telomere dysfunctions. We show that in resting HTLV-1 positive CD4(+) cells cloned from patients, hTERT expression parallels tax expression and cell cycling. Upon activation, these cells dramatically augment tax expression, whereas their increase in telomerase activity is about 20 times lower than that of their uninfected counterpart. Activated HTLV-1 positive CD4(+) but not uninfected CD4(+) or CD8(+) clones also repress the transcription of TRF1, TPP1, TANK1, POT1, DNA-PKc and Ku80. Both infected and uninfected lymphocytes from infected individuals shared common telomere gene deregulations toward a pattern consistent with premature senescence. ATLL cells displayed the highest telomerase activity (TA) whereas recovered a telomere gene transcriptome close to that of normal CD4(+) cells. In conclusion HTLV-1-dependent telomere modulations seem involved in clonal expansion, immunosuppression, tumor initiation and progression. PMID:21717459

  9. UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1).

    PubMed

    Kemp, Michael G; Lindsey-Boltz, Laura A; Sancar, Aziz

    2015-05-01

    The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders. PMID:25792739

  10. Reduction of coproporphyrinogen oxidase level by antisense RNA synthesis leads to deregulated gene expression of plastid proteins and affects the oxidative defense system.

    PubMed Central

    Kruse, E; Mock, H P; Grimm, B

    1995-01-01

    A full-length cDNA sequence encoding coproporphyrinogen oxidase was inserted in inverse orientation behind a CaMV promoter and transferred to tobacco (Nicotiana tabacum) by standard transformation techniques. Transformants showed reduced coproporphyrinogen oxidase activity and accumulation of photosensitive coproporphyrin(ogen), indicating antisense RNA expression. An inverse correlation was observed between the level of coproporphyrinogen oxidase and transformant phenotype. The latter is characterized by a broad range of growth retardation and necrosis, indicating oxidative leaf damage. Coproporphyrinogen is an apparent chromophore and its excitation finally leads to the production of reactive oxygen. Evidence is presented that indicates a direct correlation between the accumulation of non-metabolized coproporphyrinogen and oxidative damage to cellular structural components. Enzymatic and non-enzymatic antioxidants were investigated. Whereas superoxide dismutase activity increased in transgenic plants, catalase and ascorbate peroxidase activity remained constant. Tocopherol, rather than carotene or zeaxanthin, seemed to be involved in detoxification, indicating the putative localization and allocation of coproporphyrinogen. Expression of coproporphyrinogen oxidase antisense RNA did not significantly influence the level of other enzymes in the chlorophyll metabolic pathway, but deregulated gene expression of nuclear encoded plastid proteins. Accumulation of coproporphyrinogen and/or the resulting effects, such as oxidative stress, impairs a plastid/nuclear signal which may adapt gene expression to the plastid state. Images PMID:7641690

  11. Targeting the oncogene B lymphoma deregulator IgH 3' regulatory region does not impede the in vivo inflammatory response in mice.

    PubMed

    Saad, Faten; Saintamand, Alexis; Rouaud, Pauline; Denizot, Yves

    2014-01-01

    The IgH 3' regulatory region (3'RR), encompassing the four transcriptional enhancers hs3a-hs1,2-hs3b-hs4, is a potent lymphoma oncogene deregulator but its role in B cell-mediated inflammatory responses is unknown. We investigated the 3'RR involvement in the in vivo pristane-induced inflammatory response in BALB/c mice. The lack of the 3'RR in BALB/c mice had no wide effect on the incidence, the kinetic of development and the cellular composition of peritoneal ascites. Ascite pro-inflammatory cytokines levels (IL-6, IL-21, IL-12/23, TNF-α) were unchanged while anti-inflammatory cytokines levels (IL-10, interferon-γ) were slightly increased in 3'RR-deficient BALB/c mice as compared to wt BALB/c mice. In conclusion, the 3'RR is dispensable for the efficient recruitment of immune cells and the normal development of an inflammatory response in the in vivo pristane-induced inflammatory model. The 3'RR might be considered as a potential suitable target for anti-lymphoma pharmacological therapy without potent adverse effect on normal immune and inflammatory responses. PMID:25594069

  12. Targeting the oncogene B lymphoma deregulator IgH 3′ regulatory region does not impede the in vivo inflammatory response in mice

    PubMed Central

    Saad, Faten; Saintamand, Alexis; Rouaud, Pauline; Denizot, Yves

    2014-01-01

    The IgH 3′ regulatory region (3′RR), encompassing the four transcriptional enhancers hs3a-hs1,2-hs3b-hs4, is a potent lymphoma oncogene deregulator but its role in B cell-mediated inflammatory responses is unknown. We investigated the 3′RR involvement in the in vivo pristane-induced inflammatory response in BALB/c mice. The lack of the 3′RR in BALB/c mice had no wide effect on the incidence, the kinetic of development and the cellular composition of peritoneal ascites. Ascite pro-inflammatory cytokines levels (IL-6, IL-21, IL-12/23, TNF-α) were unchanged while anti-inflammatory cytokines levels (IL-10, interferon-γ) were slightly increased in 3′RR-deficient BALB/c mice as compared to wt BALB/c mice. In conclusion, the 3′RR is dispensable for the efficient recruitment of immune cells and the normal development of an inflammatory response in the in vivo pristane-induced inflammatory model. The 3′RR might be considered as a potential suitable target for anti-lymphoma pharmacological therapy without potent adverse effect on normal immune and inflammatory responses. PMID:25594069

  13. A deregulated expression of estrogen-target genes is associated with an altered response to estradiol in aged rats perinatally exposed to bisphenol A.

    PubMed

    Vigezzi, Lucía; Ramos, Jorge G; Kass, Laura; Tschopp, María V; Muñoz-de-Toro, Mónica; Luque, Enrique H; Bosquiazzo, Verónica L

    2016-05-01

    Here we assessed the effects of perinatal exposure to bisphenol A (BPA) on the uterine response to 17β-estradiol (E2) in aged rats. Pregnant rats were orally exposed to 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. On postnatal day (PND) 360, the rats were ovariectomized and treated with E2 for three months. The uterine tissue of BPA50 and BPA0.5 rats showed increased density of glands with squamous metaplasia (GSM) and glands with daughter glands respectively. Wnt7a expression was lower in GSM of BPA50 rats than in controls. The expression of estrogen receptor 1 (ESR1) and its 5'- untranslated exons ESR1-O and ESR1-OT was lower in BPA50 rats. Both doses of BPA modified the expression of coactivator proteins and epigenetic regulatory enzymes. Thus, perinatal BPA-exposed rats showed different glandular abnormalities associated with deregulated expression of E2-target genes. Different mechanisms would be involved depending on the BPA dose administered. PMID:26898831

  14. Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease

    PubMed Central

    2016-01-01

    Chronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The “omics” techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other “omics” methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients. PMID:27419142

  15. IRF4 Is a Critical Gene in Retinoic Acid-Mediated Plasma Cell Formation and Is Deregulated in Common Variable Immunodeficiency-Derived B Cells.

    PubMed

    Indrevær, Randi L; Moskaug, Jan Ø; Paur, Ingvild; Bøhn, Siv K; Jørgensen, Silje F; Blomhoff, Rune; Aukrust, Pål; Fevang, Børre; Blomhoff, Heidi K

    2015-09-15

    In the present study, we aimed at identifying the mechanisms whereby the vitamin A metabolite all-trans retinoic acid (RA) promotes the formation of plasma cells upon stimulation of B cells via the innate immunity receptors TLR9 and RP105. Most often, differentiation of B cells involves the sequential events of class switch recombination and somatic hypermutations characteristic of germinal center reactions, followed by plasma cell formation. By studying the regulatory networks known to drive these reactions, we revealed that RA enhances the expression of the plasma cell-generating transcription factors IFN regulatory factor (IRF)4 and Blimp1, and paradoxically also activation-induced deaminase (AID) involved in somatic hypermutations/class switch recombination, in primary human B cells. IRF4 was identified as a particularly important protein involved in the RA-mediated production of IgG in TLR9/RP105-stimulated B cells. Based on kinetic studies, we present a model suggesting that the initial induction of IRF4 by RA favors AID expression. According to this model, the higher level of IRF4 that eventually arises results in sustained elevated levels of Blimp1. Regarded as a master regulator of plasma cell development, Blimp1 will in turn suppress AID expression and drive the formation of IgG-secreting plasma cells. Notably, we demonstrated IRF4 to be deregulated in B cells from common variable immunodeficiency patients, contributing to the observed aberrant expression of AID in these patients. Taken together, the present study both provides new insight into the mechanisms whereby RA induces differentiation of B cells and identifies IRF4 as a key to understand the defective functions of B cells in common variable immunodeficiency patients. PMID:26276871

  16. Gene expression analysis in patients with traumatic anterior shoulder instability suggests deregulation of collagen genes.

    PubMed

    Belangero, Paulo Santoro; Leal, Mariana Ferreira; Figueiredo, Eduardo Antônio; Cohen, Carina; Pochini, Alberto de Castro; Smith, Marília Cardoso; Andreoli, Carlos Vicente; Belangero, Sintia Iole; Ejnisman, Benno; Cohen, Moises

    2014-10-01

    Shoulder dislocation occurs in 1-2% of the population. Capsular deformation is a key factor in shoulder dislocation; however, little is known about capsule biology. We evaluated, for the first time in literature, the expression of COL1A1, COL1A2, COL3A1 and COL5A1 in the antero-inferior, antero-superior and posterior regions of the glenohumeral capsule of 31 patients with anterior shoulder instability and eight controls. The expression of collagen genes was evaluated by quantitative reverse transcription-PCR. The expression of COL1A1, COL3A1 and the ratio of COL1A1/COL1A2 were increased in all three portions of the capsule in patients compared to controls (p < 0.05). COL1A2 expression was upregulated in the antero-superior and posterior sites of the capsule of patients (p < 0.05). The ratio of COL1A2/COL3A1 expression was reduced in capsule antero-inferior and posterior sites of patients compared to controls (p < 0.05). In the capsule antero-inferior site of patients, the ratios of COL1A1/COL5A1, CO1A2/COL5A1 and COL3A1/COL5A1 expression were increased (p < 0.05). In patients, COL1A1/COL5A1 was also increased in the posterior site (p < 0.05). We found deregulated expression of collagen genes across the capsule of shoulder instability patients. These molecular alterations may lead to modifications of collagen fibril structure and impairment of the healing process, possibly with a role in capsular deformation. PMID:25042113

  17. Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance.

    PubMed

    Maciag, Anna E; Holland, Ryan J; Robert Cheng, Y-S; Rodriguez, Luis G; Saavedra, Joseph E; Anderson, Lucy M; Keefer, Larry K

    2013-01-01

    JS-K is a nitric oxide (NO)-releasing prodrug of the O (2)-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion) spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action. PMID:24024144

  18. Expression of the Retrotransposon Helena Reveals a Complex Pattern of TE Deregulation in Drosophila Hybrids.

    PubMed

    Romero-Soriano, Valèria; Garcia Guerreiro, Maria Pilar

    2016-01-01

    Transposable elements (TEs), repeated mobile sequences, are ubiquitous in the eukaryotic kingdom. Their mobilizing capacity confers on them a high mutagenic potential, which must be strongly regulated to guarantee genome stability. In the Drosophila germline, a small RNA-mediated silencing system, the piRNA (Piwi-interacting RNA) pathway, is the main responsible TE regulating mechanism, but some stressful conditions can destabilize it. For instance, during interspecific hybridization, genomic stress caused by the shock of two different genomes can lead, in both animals and plants, to higher transposition rates. A recent study in D. buzatii-D. koepferae hybrids detected mobilization of 28 TEs, yet little is known about the molecular mechanisms explaining this transposition release. We have characterized one of the mobilized TEs, the retrotransposon Helena, and used quantitative expression to assess whether its high transposition rates in hybrids are preceded by increased expression. We have also localized Helena expression in the gonads to see if cellular expression patterns have changed in the hybrids. To give more insight into changes in TE regulation in hybrids, we analysed Helena-specific piRNA populations of hybrids and parental species. Helena expression is not globally altered in somatic tissues, but male and female gonads have different patterns of deregulation. In testes, Helena is repressed in F1, increasing then its expression up to parental values. This is linked with a mislocation of Helena transcripts along with an increase of their specific piRNA levels. Ovaries have additive levels of Helena expression, but the ping-pong cycle efficiency seems to be reduced in F1 hybrids. This could be at the origin of new Helena insertions in hybrids, which would be transmitted to F1 hybrid female progeny. PMID:26812285

  19. Expression of the Retrotransposon Helena Reveals a Complex Pattern of TE Deregulation in Drosophila Hybrids

    PubMed Central

    Romero-Soriano, Valèria; Garcia Guerreiro, Maria Pilar

    2016-01-01

    Transposable elements (TEs), repeated mobile sequences, are ubiquitous in the eukaryotic kingdom. Their mobilizing capacity confers on them a high mutagenic potential, which must be strongly regulated to guarantee genome stability. In the Drosophila germline, a small RNA-mediated silencing system, the piRNA (Piwi-interacting RNA) pathway, is the main responsible TE regulating mechanism, but some stressful conditions can destabilize it. For instance, during interspecific hybridization, genomic stress caused by the shock of two different genomes can lead, in both animals and plants, to higher transposition rates. A recent study in D. buzatii—D. koepferae hybrids detected mobilization of 28 TEs, yet little is known about the molecular mechanisms explaining this transposition release. We have characterized one of the mobilized TEs, the retrotransposon Helena, and used quantitative expression to assess whether its high transposition rates in hybrids are preceded by increased expression. We have also localized Helena expression in the gonads to see if cellular expression patterns have changed in the hybrids. To give more insight into changes in TE regulation in hybrids, we analysed Helena-specific piRNA populations of hybrids and parental species. Helena expression is not globally altered in somatic tissues, but male and female gonads have different patterns of deregulation. In testes, Helena is repressed in F1, increasing then its expression up to parental values. This is linked with a mislocation of Helena transcripts along with an increase of their specific piRNA levels. Ovaries have additive levels of Helena expression, but the ping-pong cycle efficiency seems to be reduced in F1 hybrids. This could be at the origin of new Helena insertions in hybrids, which would be transmitted to F1 hybrid female progeny. PMID:26812285

  20. Molecular Pathways: Deregulation of Histone 3 Lysine 27 Methylation in Cancer—Different Paths, Same Destination

    PubMed Central

    Ezponda, Teresa; Licht, Jonathan D.

    2014-01-01

    Methylation of lysine 27 on histone 3 (H3K27me), a modification associated with gene repression, plays a critical role in regulating the expression of genes that determine the balance between cell differentiation and proliferation. Alteration of the level of this histone modification has emerged as a recurrent theme in many types of cancer, demonstrating that either excess or lack of H3K27 methylation can have oncogenic effects. Cancer genome sequencing has revealed the genetic basis of H3K27me deregulation, including mutations of the components of the H3K27 methyltransferase complex PRC2 and accessory proteins, and deletions and inactivating mutations of the H3K27 demethylase UTX in a wide variety of neoplasms. More recently, mutations of lysine 27 on histone 3 itself were shown to prevent H3K27me in pediatric glioblastomas. Aberrant expression or mutations in proteins that recognize H3K27me3 also occur in cancer and may result in misinterpretation of this mark. Additionally, due to the crosstalk between different epigenetic modifications, alterations of chromatin modifiers controlling H3K36me, or even mutations of this residue, can ultimately regulate H3K27me levels and distribution across the genome. The significance of mutations altering H3K27me is underscored by the fact that many tumors harboring such lesions often have a poor clinical outcome. New therapeutic approaches targeting aberrant H3K27 methylation include small molecules that block the action of mutant EZH2 in germinal center-derived lymphoma. Understanding the biological consequences and gene expression pathways affected by aberrant H3K27 methylation may also lead to other new therapeutic strategies. PMID:24987060

  1. Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance☆

    PubMed Central

    Maciag, Anna E.; Holland, Ryan J.; Robert Cheng, Y.-S.; Rodriguez, Luis G.; Saavedra, Joseph E.; Anderson, Lucy M.; Keefer, Larry K.

    2013-01-01

    JS-K is a nitric oxide (NO)-releasing prodrug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion) spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action. PMID:24024144

  2. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.

    PubMed

    Dolatshad, H; Pellagatti, A; Fernandez-Mercado, M; Yip, B H; Malcovati, L; Attwood, M; Przychodzen, B; Sahgal, N; Kanapin, A A; Lockstone, H; Scifo, L; Vandenberghe, P; Papaemmanuil, E; Smith, C W J; Campbell, P J; Ogawa, S; Maciejewski, J P; Cazzola, M; Savage, K I; Boultwood, J

    2015-05-01

    The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34(+) cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link. PMID:25428262

  3. Retraction: "Inactivation of Ink4a/Arf Leads to Deregulated Expression of miRNAs in K-Ras Transgenic Mouse Model of Pancreatic Cancer" by Ali et al.

    PubMed

    2016-10-01

    The above article, published online on June 21, 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 5A to be inappropriately manipulated. Literature Cited Ali S, Banerjee S, Logna F, Bao B, Philip PA, Korc M, Sarkar FH. 2012. Inactivation of Ink4a/Arf leads to deregulated expression of miRNAs in K-Ras transgenic mouse model of pancreatic cancer. J Cell Physiol 227:3373-3380; doi: 10.1002/jcp.24036. PMID:27315161

  4. Competition and deregulation in the electric industry. A study of organizational change: The New York State Public Service Commission

    NASA Astrophysics Data System (ADS)

    Ashley, Deborah J. Cordaro

    2000-11-01

    Public organizations are formed in response to societal needs. They collect taxes, educate children, enforce laws and provide protection to the environment, the nation and consumers. One such organization is the New York State Public Service Commission. In 1907, legislation was passed to form the New York State Public Service Commission the first regulatory body of its kind in the United States. Its mission was to provide safe, reliable and reasonably priced electricity. Subsequently, this became the model that was implemented in every state in the nation. The past decade heralds an era of competition and a lessening of regulatory control. The telephone, natural gas and airline industries are in various stages of deregulation, and the electric industry is beginning down this path as well. In an environment such as this, are regulatory organizations necessary, and if they are, how can they organize to meet the new societal requirements? The case of the New York State Public Service Commission at this point in time offers a real time study of a regulatory body immersed in an environment that is calling for competition and an end to big government. Utilizing case studies of industries that have deregulated, or are in the process of deregulating, indicates a future societal need for regulations. This result does not lead to a conclusion that organizational change is unnecessary. This Dissertation will lay out the current organizational structure of the Public Service Commission, give an overview of the environmental signals, describe the mission/core values, and illustrate general political and employee factors that are indigenous to public service. Utilizing both classic and current organizational theory, an evaluation will be made of the Commission's need for change, their ability to change, and obstacles they may encounter.

  5. Massive deregulation of miRNAs from nuclear reprogramming errors during trophoblast differentiation for placentogenesis in cloned pregnancy

    PubMed Central

    2014-01-01

    Background Low efficiency of Somatic Cell Nuclear Transfer (NT) has been widely addressed with high incidence of placental abnormalities due to genetic and epigenetic modifications. MiRNAs are shown to be major regulators of such modifications. The present study has been carried out to identify the expression patterns of 377 miRNAs, their functional associations and mechanism of regulation in bovine placentas derived from artificial insemination (AI), in vitro production (IVP) and NT pregnancies. Results This study reveals a massive deregulation of miRNAs as chromosomal cluster or miRNA families without sex-linkage in NT and in-vitro derived IVP placentas. Cell specific localization miRNAs in blastocysts and expression profiling of embryos and placentas at different developmental stages identified that the major deregulation of miRNAs exhibited in placentas at day 50 of pregnancies is found to be less dependent on global DNA methylation, rather than on aberrant miRNA biogenesis molecules. Among them, aberrant AGO2 expression due to hypermethylation of its promoter was evident. Along with other factors, aberrant AGO2 expression was observed to be associated with multiple defects in trophoblast differentiation through deregulation of miRNAs mediated mechanisms. Conclusion These aberrant miRNA activities might be associated with genetic and epigenetic modifications in abnormal placentogenesis due to maldifferentiation of early trophoblast cell lineage in NT and IVP pregnancies. This study provides the first insight into genome wide miRNA expression, their role in regulation of trophoblast differentiation as well as abnormal placental development in Somatic Cell Nuclear Transfer pregnancies to pave the way to improve the efficiency of cloning by nuclear transfer. PMID:24438674

  6. Combination of ascorbate/epigallocatechin-3-gallate/gemcitabine synergistically induces cell cycle deregulation and apoptosis in mesothelioma cells

    SciTech Connect

    Martinotti, Simona; Ranzato, Elia; Parodi, Monica; Vitale, Massimo; Burlando, Bruno

    2014-01-01

    Malignant mesothelioma (MMe) is a poor-prognosis tumor in need of innovative therapies. In a previous in vivo study, we showed synergistic anti-MMe properties of the ascorbate/epigallocatechin-3-gallate/gemcitabine combination. We have now focused on the mechanism of action, showing the induction of apoptosis and cell cycle arrest through measurements of caspase 3, intracellular Ca{sup 2+}, annexin V, and DNA content. StellArray™ PCR technology and Western immunoblotting revealed DAPK2-dependent apoptosis, upregulation of cell cycle promoters, downregulation of cell cycle checkpoints and repression of NFκB expression. The complex of data indicates that the mixture is synergistic in inducing cell cycle deregulation and non-inflammatory apoptosis, suggesting its possible use in MMe treatment. - Highlights: • Ascorbate/epigallocathechin-gallate/gemcitabine has been tested on mesothelioma cells • A synergistic mechanism has been shown for cell cycle arrest and apoptosis • PCR-array analysis has revealed the de-regulation of apoptosis and cell cycle genes • Maximum upregulation has been found for the Death-Associated Protein Kinase-2 gene • Data suggest that the mixture could be used as a clinical treatment.

  7. Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle.

    PubMed

    Búa, Sabela; Sotiropoulou, Peggy; Sgarlata, Cecilia; Borlado, Luis R; Eguren, Manuel; Domínguez, Orlando; Ortega, Sagrario; Malumbres, Marcos; Blanpain, Cedric; Méndez, Juan

    2015-01-01

    Cdc6 encodes a key protein for DNA replication, responsible for the recruitment of the MCM helicase to replication origins during the G1 phase of the cell division cycle. The oncogenic potential of deregulated Cdc6 expression has been inferred from cellular studies, but no mouse models have been described to study its effects in mammalian tissues. Here we report the generation of K5-Cdc6, a transgenic mouse strain in which Cdc6 expression is deregulated in tissues with stratified epithelia. Higher levels of CDC6 protein enhanced the loading of MCM complexes to DNA in epidermal keratinocytes, without affecting their proliferation rate or inducing DNA damage. While Cdc6 overexpression did not promote skin tumors, it facilitated the formation of papillomas in cooperation with mutagenic agents such as DMBA. In addition, the elevated levels of CDC6 protein in the skin extended the resting stage of the hair growth cycle, leading to better fur preservation in older mice. PMID:26697840

  8. Injury, death, and the deregulation fetish: the politics of occupational safety regulation in U.K. manufacturing industries.

    PubMed

    Tombs, S

    1996-01-01

    The author examines some of the more recent developments in the social and political environments within which the "deregulation fetish" is crucial, but of which it remains only one element. This fetish, as part of a broader assault on the legitimacy of the external regulation of business activity, will not go away; its effects are already being felt in the context of the regulation of occupational safety in the United Kingdom. After outlining recent trends in recorded injuries in U.K. workplaces, with particular reference to manufacturing industries, the author charts the nature and effects of the social and political contexts of the work of U.K. safety regulators in the 1980s. While Thatcher governments withdrew from any direct deregulatory assault on occupational safety, what transpired was a gradual but continual undermining of the ability of these agencies to fulfill their mandated functions. The nature and effects of a new politics of deregulation are examined and this new politics is related to U.K. governmental opposition to European Union influence in domestic social policy, which stands in a symbiotic relationship with the re-emergence of a sustained deregulatory discourse in the United Kingdom. PMID:9132377

  9. Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology

    PubMed Central

    Marcuzzi, Annalisa; Piscianz, Elisa; Zweyer, Marina; Bortul, Roberta; Loganes, Claudia; Girardelli, Martina; Baj, Gabriele; Monasta, Lorenzo; Celeghini, Claudio

    2016-01-01

    Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related. PMID:26978350

  10. Loss of c-Met accelerates development of liver fibrosis in response to CCl(4) exposure through deregulation of multiple molecular pathways.

    PubMed

    Marquardt, Jens U; Seo, Daekwan; Gómez-Quiroz, Luis E; Uchida, Koichi; Gillen, Matthew C; Kitade, Mitsuteru; Kaposi-Novak, Pal; Conner, Elizabeth A; Factor, Valentina M; Thorgeirsson, Snorri S

    2012-06-01

    HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. HGF treatment accelerates resolution of fibrosis in experimental animal models. Here, we utilized Met(fl/fl);Alb-Cre(+/-) conditional knockout mice and a carbon tetrachloride(CCl(4))-induced liver fibrosis model to formally address the role of c-Met signaling in hepatocytes in the context of chronic tissue injury. Histological changes during injury (4weeks) and healing phase (4weeks) were monitored by immunohistochemistry; expression levels of selected key fibrotic molecules were evaluated by western blotting, and time-dependent global transcriptomic changes were examined using a microarray platform. Loss of hepatocyte c-Met signaling altered hepatic microenvironment and aggravated hepatic fibrogenesis. Greater liver damage was associated with decreased hepatocyte proliferation, excessive stellate cell activation and rapid dystrophic calcification of necrotic areas. Global transcriptome analysis revealed a broad impact of c-Met on critical signaling pathways associated with fibrosis. Loss of hepatocyte c-Met caused a strong deregulation of chemotactic and inflammatory signaling (MCP-1, RANTES, Cxcl10) in addition to modulation of genes involved in reorganization of the cytoskeletal network (Actb, Tuba1a, Tuba8), intercellular communications and adhesion (Adam8, Icam1, Itgb2), control of cell proliferation (Ccng2, Csnk2a, Cdc6, cdk10), DNA damage and stress response (Rad9, Rad52, Ercc4, Gsta1 and 2, Jun). Our study demonstrates that deletion of c-Met receptor in hepatocytes results in pronounced changes in hepatic metabolism and microenvironment, and establishes an essential role for c-Met in maintaining the structural integrity and adaptive plasticity of the liver under adverse conditions. PMID:22386877

  11. MicroRNA deregulation in triple negative breast cancer reveals a role of miR-498 in regulating BRCA1 expression

    PubMed Central

    Matamala, Nerea; Vargas, Maria Teresa; González-Cámpora, Ricardo; Arias, Jose Ignacio; Menéndez, Primitiva; Andrés-León, Eduardo; Yanowsky, Kira; Llaneza-Folgueras, Ana; Miñambres, Rebeca; Martínez-Delgado, Beatriz; Benítez, Javier

    2016-01-01

    Emerging evidence suggests that BRCA1 pathway contributes to the behavior of sporadic triple negative breast cancer (TNBC), but little is known about the mechanisms underlying this association. Considering the central role that microRNAs (miRNAs) play in gene expression regulation, the aim of this study was to identify miRNAs specifically deregulated in TNBC and investigate their involvement in BRCA1 regulation. Using locked nucleic acid (LNA)-based microarrays, expression levels of 1919 miRNAs were measured in paraffin-embedded tissues from 122 breast tumors and 11 healthy breast tissue samples. Differential miRNA expression was explored among the main subtypes of breast cancer, and 105 miRNAs were identified as specific for triple negative tumors. In silico prediction revealed that miR-498 and miR-187-5p target BRCA1, and these results were confirmed by luciferase reporter assay. While miR-187-5p was found overexpressed in a luminal B cell line, miR-498 was highly expressed in a triple negative cell line, Hs578T, and its expression was negatively correlated with the levels of BRCA1. We functionally demonstrated that miR-498 inhibits BRCA1 in breast cancer cell lines, and showed that inhibition of miR-498 led to reduced proliferation in the triple negative cell line Hs578T. Our results indicate that miR-498 regulates BRCA1 expression in breast cancer and its overexpression could contribute to the pathogenesis of sporadic TNBC via BRCA1 downregulation. PMID:26933805

  12. Involvement of deregulated epiregulin expression in tumorigenesis in vivo through activated Ki-Ras signaling pathway in human colon cancer cells.

    PubMed

    Baba, I; Shirasawa, S; Iwamoto, R; Okumura, K; Tsunoda, T; Nishioka, M; Fukuyama, K; Yamamoto, K; Mekada, E; Sasazuki, T

    2000-12-15

    To identify the genes located downstream of the activated Ki-Ras signaling pathways in human colon cancer cells, a PCR-based cDNA subtraction library was constructed between HCT116 cells and HCT116-derived activated Ki-ras-disrupted cells (HKe3). One of the genes in HCT116 that was evidently up-regulated was epiregulin, a member of the epidermal growth factor family that is expressed in many kinds of human cancer cells. HKe3-stable transfectants expressing activated Ki-Ras regained over-expression of epiregulin. To further elucidate the biochemical structure and significance of epiregulin expression in tumorigenesis, HKe3-stable transfectants expressing epiregulin (e3-pSE cells) were established. Epiregulin existed as highly glycosylated membrane-bound forms, and TPA rapidly induced ectodomain shedding of epiregulin. Furthermore, the conditioned medium of e3-pSE cells showed more DNA synthesis for 32D cells expressing epidermal growth factor receptor (DER) cells than that of HKe3. Although anchorage-independent growth in soft agar was not observed for e3-pSE cells, tumorigenicity in nude mice was observed evidently, and their growth rate was correlated with each amount of exogenous epiregulin expression. These results suggested that activated Ki-Ras will be one of the factors contributing to the overexpression of epiregulin in human colon cancer cells, and that epiregulin will play a critical role in human tumorigenesis in vivo. PMID:11156386

  13. Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

    PubMed Central

    Marsollier, Nicolas; Masseboeuf, Myriam; Payros, Gaëlle; Kabani, Catherine; Denom, Jessica; Lacombe, Amélie; Thiers, Jean-Claude; Negre-Salvayre, Anne; Luquet, Serge; Burcelin, Rémy; Cruciani-Guglielmacci, Céline; Magnan, Christophe

    2011-01-01

    Background Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. Methodology/Principal Findings An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. Conclusions/Significance Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity. PMID:21698161

  14. Loss of DDB1 Leads to Transcriptional p53 Pathway Activation in Proliferating Cells, Cell Cycle Deregulation, and Apoptosis in Zebrafish Embryos

    PubMed Central

    Hu, Zhilian; Holzschuh, Jochen; Driever, Wolfgang

    2015-01-01

    DNA damage-binding protein 1 (DDB1) is a large subunit of the heterodimeric DDB complex that recognizes DNA lesions and initiates the nucleotide excision repair process. DDB1 is also a component of the CUL4 E3 ligase complex involved in a broad spectrum of cellular processes by targeted ubiquitination of key regulators. Functions of DDB1 in development have been addressed in several model organisms, however, are not fully understood so far. Here we report an ENU induced mutant ddb1 allele (ddb1m863) identified in zebrafish (Danio rerio), and analyze its effects on development. Zebrafish ddb1 is expressed broadly, both maternally and zygotically, with enhanced expression in proliferation zones. The (ddb1m863 mutant allele affects the splice acceptor site of exon 20, causing a splicing defect that results in truncation of the 1140 amino acid protein after residue 800, lacking part of the β-propeller domain BPC and the C-terminal helical domain CTD. ddb1m863 zygotic mutant embryos have a pleiotropic phenotype, including smaller and abnormally shaped brain, head skeleton, eyes, jaw, and branchial arches, as well as reduced dopaminergic neuron groups. However, early forming tissues develop normally in zygotic ddb1m863 mutant embryos, which may be due to maternal rescue. In ddb1m863 mutant embryos, pcna-expressing proliferating cell populations were reduced, concurrent with increased apoptosis. We also observed a concomitant strong up-regulation of transcripts of the tumor suppressor p53 (tp53) and the cell cycle inhibitor cdkn1a (p21a/bCIP1/WAF1) in proliferating tissues. In addition, transcription of cyclin genes ccna2 and ccnd1 was deregulated in ddb1m863 mutants. Reduction of p53 activity by anti-sense morpholinos alleviated the apoptotic phenotype in ddb1m863 mutants. These results imply that Ddb1 may be involved in maintaining proper cell cycle progression and viability of dividing cells during development through transcriptional mechanisms regulating genes

  15. An integrated genome-wide approach to discover deregulated microRNAs in non-small cell lung cancer: Clinical significance of miR-23b-3p deregulation.

    PubMed

    Begum, Shahnaz; Hayashi, Masamichi; Ogawa, Takenori; Jabboure, Fayez J; Brait, Mariana; Izumchenko, Evgeny; Tabak, Sarit; Ahrendt, Steven A; Westra, William H; Koch, Wayne; Sidransky, David; Hoque, Mohammad O

    2015-01-01

    In spite of significant technical advances, genesis and progression of non-small cell lung cancer (NSCLC) remain poorly understood. We undertook an integrated genetic approach to discover novel microRNAs that were deregulated in NSCLCs. A total 119 primary NSCLCs with matched normal were analyzed for genome-wide copy number changes. We also tested a subset of matched samples by microRNA expression array, and integrated them to identify microRNAs positioned in allelic imbalance area. Our findings support that most of the identified deregulated microRNAs (miR-21, miR-23b, miR-31, miR-126, miR-150, and miR-205) were positioned in allelic imbalance areas. Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32-4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30-4.19) in multivariable analysis. In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time. In summary, integration of genomic analysis and microRNA expression profiling could identify novel cancer-related microRNAs, and miR-23b could be a potential prognostic marker for early stage NSCLCs. Further biological studies of miR-23b are warranted for the potential development of targeted therapy. PMID:26314549

  16. An integrated genome-wide approach to discover deregulated microRNAs in non-small cell lung cancer: Clinical significance of miR-23b-3p deregulation

    PubMed Central

    Begum, Shahnaz; Hayashi, Masamichi; Ogawa, Takenori; Jabboure, Fayez J.; Brait, Mariana; Izumchenko, Evgeny; Tabak, Sarit; Ahrendt, Steven A.; Westra, William H.; Koch, Wayne; Sidransky, David; Hoque, Mohammad O.

    2015-01-01

    In spite of significant technical advances, genesis and progression of non-small cell lung cancer (NSCLC) remain poorly understood. We undertook an integrated genetic approach to discover novel microRNAs that were deregulated in NSCLCs. A total 119 primary NSCLCs with matched normal were analyzed for genome-wide copy number changes. We also tested a subset of matched samples by microRNA expression array, and integrated them to identify microRNAs positioned in allelic imbalance area. Our findings support that most of the identified deregulated microRNAs (miR-21, miR-23b, miR-31, miR-126, miR-150, and miR-205) were positioned in allelic imbalance areas. Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32–4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30–4.19) in multivariable analysis. In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time. In summary, integration of genomic analysis and microRNA expression profiling could identify novel cancer-related microRNAs, and miR-23b could be a potential prognostic marker for early stage NSCLCs. Further biological studies of miR-23b are warranted for the potential development of targeted therapy. PMID:26314549

  17. De-regulation of gene expression and alternative splicing affects distinct cellular pathways in the aging hippocampus

    PubMed Central

    Stilling, Roman M.; Benito, Eva; Gertig, Michael; Barth, Jonas; Capece, Vincenzo; Burkhardt, Susanne; Bonn, Stefan; Fischer, Andre

    2014-01-01

    Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing. PMID:25431548

  18. Effects of ZnO nanoparticles in plants: Cytotoxicity, genotoxicity, deregulation of antioxidant defenses, and cell-cycle arrest.

    PubMed

    Ghosh, Manosij; Jana, Aditi; Sinha, Sonali; Jothiramajayam, Manivannan; Nag, Anish; Chakraborty, Anirban; Mukherjee, Amitava; Mukherjee, Anita

    2016-09-01

    Cytotoxicity, genotoxicity, and biochemical effects were evaluated in the plants Allium cepa, Nicotiana tabacum, and Vicia faba following exposure to ZnO nanoparticles (np; diameter, ∼85nm). In the root meristems of Allium cepa cells, we observed loss of membrane integrity, increased chromosome aberrations, micronucleus formation, DNA strand breaks, and cell-cycle arrest at the G2/M checkpoint. In Vicia faba and Nicotiana tabacum, we observed increased intracellular ROS production, lipid peroxidation, and activities of some antioxidant enzymes. TEM images revealed gross morphological alterations and internalization of the np. Our findings provide evidence of ZnO np toxicity, characterized by deregulation of components of ROS-antioxidant machinery, leading to DNA damage, cell-cycle arrest, and cell death. These plants, especially Allium cepa, are reliable systems for assessment of np toxicology. PMID:27542712

  19. Conserved Region 3 of Human Papillomavirus 16 E7 Contributes to Deregulation of the Retinoblastoma Tumor Suppressor

    PubMed Central

    Todorovic, Biljana; Hung, Katherine; Massimi, Paola; Avvakumov, Nikita; Dick, Frederick A.; Shaw, Gary S.; Banks, Lawrence

    2012-01-01

    The human papillomavirus (HPV) E7 oncoprotein binds cellular factors, preventing or retargeting their function and thereby making the infected cell conducive for viral replication. A key target of E7 is the product of the retinoblastoma susceptibility locus (pRb). This interaction results in the release of E2F transcription factors and drives the host cell into the S phase of the cell cycle. E7 binds pRb via a high-affinity binding site in conserved region 2 (CR2) and also targets a portion of cellular pRb for degradation via the proteasome. Evidence suggests that a secondary binding site exists in CR3, and that this interaction influences pRb deregulation. Additionally, evidence suggests that CR3 also participates in the degradation of pRb. We have systematically analyzed the molecular mechanisms by which CR3 contributes to deregulation of the pRb pathway by utilizing a comprehensive series of mutations in residues predicted to be exposed on the surface of HPV16 E7 CR3. Despite differences in the ability to interact with cullin 2, all CR3 mutants degrade pRb comparably to wild-type E7. We identified two specific patches of residues on the surface of CR3 that contribute to pRb binding independently of the high-affinity CR2 binding site. Mutants within CR3 that affect pRb binding are less effective than the wild-type E7 in overcoming pRb-induced cell cycle arrest. This demonstrates that the interaction between HPV16 E7 CR3 and pRb is functionally important for alteration of the cell cycle. PMID:23015707

  20. HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance

    PubMed Central

    Van Damme, Michaël; Crompot, Emerence; Meuleman, Nathalie; Mineur, Philippe; Bron, Dominique; Lagneaux, Laurence; Stamatopoulos, Basile

    2012-01-01

    Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an underexpression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0–1–2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively (HR = 4.03, p < 0.0001). For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo (HR = 6.38, p < 0.0001). However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course. PMID:23108383

  1. The influence of market deregulation on fast food consumption and body mass index: a cross-national time series analysis

    PubMed Central

    Kouvonen, Anne; Gimeno, David

    2014-01-01

    Abstract Objective To investigate the effect of fast food consumption on mean population body mass index (BMI) and explore the possible influence of market deregulation on fast food consumption and BMI. Methods The within-country association between fast food consumption and BMI in 25 high-income member countries of the Organisation for Economic Co-operation and Development between 1999 and 2008 was explored through multivariate panel regression models, after adjustment for per capita gross domestic product, urbanization, trade openness, lifestyle indicators and other covariates. The possible mediating effect of annual per capita intake of soft drinks, animal fats and total calories on the association between fast food consumption and BMI was also analysed. Two-stage least squares regression models were conducted, using economic freedom as an instrumental variable, to study the causal effect of fast food consumption on BMI. Findings After adjustment for covariates, each 1-unit increase in annual fast food transactions per capita was associated with an increase of 0.033 kg/m2 in age-standardized BMI (95% confidence interval, CI: 0.013–0.052). Only the intake of soft drinks – not animal fat or total calories – mediated the observed association (β: 0.030; 95% CI: 0.010–0.050). Economic freedom was an independent predictor of fast food consumption (β: 0.27; 95% CI: 0.16–0.37). When economic freedom was used as an instrumental variable, the association between fast food and BMI weakened but remained significant (β: 0.023; 95% CI: 0.001–0.045). Conclusion Fast food consumption is an independent predictor of mean BMI in high-income countries. Market deregulation policies may contribute to the obesity epidemic by facilitating the spread of fast food. PMID:24623903

  2. ASSAY FOR DETECTION AD ENUMERATION OF GENETICALLY ENGINEERED MICROORGANISMS WHICH IS BASED ON THE ACTIVITY OF A DEREGULATED 2,4-DICHLOROPHENOXYACETATE MONOOXYGENASE

    EPA Science Inventory

    An assay system was developed for the enumeration of genetically engineered microorganisms expressing a deregulated 2,4-dichlorophenoxyacetate (TFD) monooxygenase, which coverts phenoxyacetate (PAA) to phenol. n PAA-amended cultures of Pseudomonas aeruginosa PAO1C (pRO103) and Ps...

  3. Regulation and Deregulation of Telecommunications: The Economic and Political Realities. Part I: The United States and Part II. The United Kingdom and Other Western European Countries.

    ERIC Educational Resources Information Center

    Philip, George; Tsoi, Shao Hing

    1988-01-01

    These two articles explore the arguments for and against the liberalization of natural monopolies in general and the privatization of the telecommunications industry in particular. The discussion covers the reasons for and consequences of deregulation of telecommunications in the United States, United Kingdom, and other Western European countries.…

  4. Cadmium, cobalt and lead cause stress response, cell cycle deregulation and increased steroid as well as xenobiotic metabolism in primary normal human bronchial epithelial cells which is coordinated by at least nine transcription factors.

    PubMed

    Glahn, Felix; Schmidt-Heck, Wolfgang; Zellmer, Sebastian; Guthke, Reinhard; Wiese, Jan; Golka, Klaus; Hergenröder, Roland; Degen, Gisela H; Lehmann, Thomas; Hermes, Matthias; Schormann, Wiebke; Brulport, Marc; Bauer, Alexander; Bedawy, Essam; Gebhardt, Rolf; Hengstler, Jan G; Foth, Heidi

    2008-08-01

    Workers occupationally exposed to cadmium, cobalt and lead have been reported to have increased levels of DNA damage. To analyze whether in vivo relevant concentrations of heavy metals cause systematic alterations in RNA expression patterns, we performed a gene array study using primary normal human bronchial epithelial cells. Cells were incubated with 15 microg/l Cd(II), 25 microg/l Co(II) and 550 microg/l Pb(II) either with individual substances or in combination. Differentially expressed genes were filtered out and used to identify enriched GO categories as well as KEGG pathways and to identify transcription factors whose binding sites are enriched in a given set of promoters. Interestingly, combined exposure to Cd(II), Co(II) and Pb(II) caused a coordinated response of at least seven stress response-related transcription factors, namely Oct-1, HIC1, TGIF, CREB, ATF4, SRF and YY1. A stress response was further corroborated by up regulation of genes involved in glutathione metabolism. A second major response to heavy metal exposure was deregulation of the cell cycle as evidenced by down regulation of the transcription factors ELK-1 and the Ets transcription factor GABP, as well as deregulation of genes involved in purine and pyrimidine metabolism. A third and surprising response was up regulation of genes involved in steroid metabolism, whereby promoter analysis identified up regulation of SRY that is known to play a role in sex determination. A forth response was up regulation of xenobiotic metabolising enzymes, particularly of dihydrodiol dehydrogenases 1 and 2 (AKR1C1, AKR1C2). Incubations with individual heavy metals showed that the response of AKR1C1 and AKR1C2 was predominantly caused by lead. In conclusion, we have shown that in vivo relevant concentrations of Cd(II), Co(II) and Pb(II) cause a complex and coordinated response in normal human bronchial epithelial cells. This study gives an overview of the most responsive genes. PMID:18654764

  5. Deregulated expression of TCL1 causes T cell leukemia in mice

    PubMed Central

    Virgilio, Laura; Lazzeri, Cristina; Bichi, Roberta; Nibu, Ken-ichi; Narducci, Maria Grazia; Russo, Giandomenico; Rothstein, Jay L.; Croce, Carlo M.

    1998-01-01

    The TCL1 oncogene on human chromosome 14q32.1 is involved in the development of T cell leukemia in humans. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. The TCL1 oncogene is activated in these leukemias by juxtaposition to the α or β locus of the T cell receptor, caused by chromosomal translocations t(14:14)(q11:q32), t(7:14)(q35:q32), or by inversions inv(14)(q11:q32). To show that transcriptional alteration of TCL1 is causally involved in the generation of T cell neoplasia we have generated transgenic mice that carry the TCL1 gene under the transcriptional control of the p56lck promoter element. The lck-TCL1 transgenic mice developed mature T cell leukemias after a long latency period. Younger mice presented preleukemic T cell expansions expressing TCL1, and leukemias developed only at an older age. The phenotype of the murine leukemias is CD4−CD8+, in contrast to human leukemias, which are predominantly CD4+CD8−. These studies demonstrate that transcriptional activation of the TCL1 protooncogene can cause malignant transformation of T lymphocytes, indicating the role of TCL1 in the initiation of malignant transformation in T prolymphocytic leukemias and T chronic lymphocytic leukemias. PMID:9520462

  6. Anticonvulsants attenuate amyloid beta-peptide neurotoxicity, Ca2+ deregulation, and cytoskeletal pathology.

    PubMed

    Mark, R J; Ashford, J W; Goodman, Y; Mattson, M P

    1995-01-01

    Increasing evidence supports the involvement of amyloid beta-peptide (A beta) and an excitotoxic mechanism of neuronal injury in the pathogenesis of Alzheimer's disease. However, approaches aimed at preventing A beta toxicity and neurofibrillary degeneration are undeveloped. We now report that anticonvulsants (carbamazepine, phenytoin, and valproic acid) can protect cultured rat hippocampal neurons against A beta- and glutamate-induced injury. Each of the anticonvulsants attenuated the elevation of intracellular free calcium levels [(Ca2+)i] elicited by A beta or glutamate suggesting that their neuroprotective mechanism of action involved stabilization of [Ca2+]i. These compounds were effective at clinically relevant concentrations (carbamazepine, 100 nM-10 microM; phenytoin, 100 nM-1 microM; valproic acid, 100 nM-100 microM). The anticonvulsants suppressed glutamate-induced alterations in tau and buiquitin immunoreactivities. Compounds that stabilize [Ca2+]i may afford protection against the kinds of insults believed to underlie neuronal injury in Alzheimer's disease. PMID:7777136

  7. Deregulated semantic cognition contributes to object-use deficits in Alzheimer's disease: A comparison with semantic aphasia and semantic dementia.

    PubMed

    Corbett, Faye; Jefferies, Elizabeth; Burns, Alistair; Lambon Ralph, Matthew A

    2015-09-01

    Executive control is impaired from the early stages of Alzheimer's Disease (AD) and this produces deregulated semantic cognition (Corbett, Jefferies, Burns, & Lambon Ralph, ; Perry, Watson, & Hodges, ). While control deficits should affect semantic retrieval across all modalities, previous studies have typically focused on verbal semantic tasks. Even when non-verbal semantic tasks have been used, these have typically employed simple picture-matching tasks, which may be influenced by abnormalities in covert naming. Therefore, in the present study, we examined 10 patients with AD on a battery of object-use tasks, in order to advance our understanding of the origins of non-verbal semantic deficits in this population. The AD patients' deficits were contrasted with previously published performance on the same tasks within two additional groups of patients, displaying either semantic degradation (semantic dementia) or deregulation of semantic retrieval (semantic aphasia; Corbett, Jefferies, Ehsan, & Lambon Ralph, ). While overall accuracy was comparable to the scores in both other groups, the AD patients' object-use impairment most closely resembled that observed in SA; they exhibited poorer performance on comprehension tasks that placed strong demands on executive control. A similar pattern was observed in the expressive domain: the AD and SA groups were relatively good at straightforward object use compared to executively demanding, mechanical puzzles. Error types also differed: while all patients omitted essential actions, the SA and AD groups' demonstrations also featured unrelated intrusions. An association between AD patients' object use and their scores on standard executive measures suggested that control deficits contributed to their non-verbal semantic deficits. Moreover, in a task specifically designed to manipulate executive demand, patients with AD (and SA) exhibited difficulty in thinking flexibly about the non-canonical uses of everyday objects, especially

  8. Home Fires Involving Grills

    MedlinePlus

    ... fires were fueled by gas while 13% used charcoal or other solid fuel. Gas grills were involved ... structure fires and 4,300 outdoor fires annually. Charcoal or other solid-fueled grills were involved in ...

  9. Evidence that the familial adenomatous polyposis gene is involved in a subset of colon cancers with a complementable defect in c-myc regulation

    SciTech Connect

    Erisman, M.D.; Scott, J.K.; Astrin, S.M. )

    1989-06-01

    Human colorectal carcinomas frequently express elevated levels of c-myc mRNA in the absence of a gross genetic change at the c-myc locus. To test the hypothesis that these tumors are defective in a gene function necessary for the regulation of c-myc expression, the authors fused an osteosarcoma cell line that exhibits normal c-myc regulation with two colon carcinoma cell lines that express deregulated levels of c-myc mRNA. Since rates of c-myc mRNA turnover in the colon carcinoma cells were found to be comparable to those in normal cells, increased message stability cannot account for the increased steady-state levels of transcripts. These finding suggest that loss of function of a trans-acting regulator is responsible for the deregulation of c-myc expression in a major fraction of colorectal carcinomas. Analysis of restriction fragment length polymorphisms in tumor/normal tissue pairs from patients with primary colorectal lesions indicated that deregulation of c-myc expression in the tumors is correlated with frequent loss of alleles of syntenic markers on chromosome 5q. Chromosome 5q is the region known to contain the gene for familial adenomatous polyposis, an inherited predisposition to colon cancer. These findings, together with the arlier finding that the colonic distribution of tumors exhibiting deregulated c-myc expression is similar to that reported for familial polyposis, provide evidence that loss of function of the familial adenomatous polyposis gene is involved in a subset of colorectal cancers in which c-myc expression is deregulated.

  10. Involving Latino Parents.

    ERIC Educational Resources Information Center

    Quezada, Reyes L.; Diaz, Delia M.; Sanchez, Maria

    2003-01-01

    Describes barriers to Latino parent involvement in educational activities, factors to consider when involving Latino parents, and two examples of Latino involvement programs in California: Family Literacy Workshop at James Monroe Elementary School, Madera Unified School District, and Parents Take P.A.R.T. (Parent Assisted Reading Training) at…

  11. Affective Involvement Instrument.

    ERIC Educational Resources Information Center

    Lemlech, Johanna K.

    1970-01-01

    The Affective Involvement Instrument (AII) describes and classifies affective involvement in the process of decision-making as it occurs during classroom activities such as role-playing or group discussions. The thirty-celled instrument behaviorizes the six processes involved in decision-making and combines them with the taxonomic levels of the…

  12. Importance of maternal diabetes on the chronological deregulation of the intrauterine development: an experimental study in rat.

    PubMed

    Salazar García, Marcela; Reyes Maldonado, Elba; Revilla Monsalve, María Cristina; Villavicencio Guzmán, Laura; Reyes López, Alfonso; Sánchez-Gómez, Concepción

    2015-01-01

    We investigated whether maternal diabetes induced in rats using streptozotocin (STZ) on Day 5 of pregnancy affects the intrauterine developmental timeline. A total of 30 pregnant Sprague-Dawley diabetic rats (DRs) and 20 control rats (CRs) were used to obtain 21-day fetuses (F21) and newborn (NB) pups. Gestational age, weight, and body size were recorded as were the maxillofacial morphometry and morphohistological characteristics of the limbs. In DRs, pregnancy continued for ∼1.7 days, and delivery occurred 23 days postcoitus (DPC). In this group, the number of pups was lower, and 13% had maxillofacial defects. F21 in the DR group had lower weights and were smaller; moreover, the morphological characteristics of the maxillofacial structures, derived from the neural crest, were discordant with their chronological gestational age, resembling 18- to 19-day-old fetuses. These deficiencies were counterbalanced in NB pups. We conclude that hyperglycemia, which results from maternal diabetes and precedes embryo implantation, deregulates the intrauterine developmental timeline, restricts embryo-fetal growth, and primarily delays the remodeling and maturation of the structures derived from neural crest cells. PMID:25756053

  13. Importance of Maternal Diabetes on the Chronological Deregulation of the Intrauterine Development: An Experimental Study in Rat

    PubMed Central

    Salazar García, Marcela; Reyes Maldonado, Elba; Revilla Monsalve, María Cristina; Villavicencio Guzmán, Laura; Reyes López, Alfonso; Sánchez-Gómez, Concepción

    2015-01-01

    We investigated whether maternal diabetes induced in rats using streptozotocin (STZ) on Day 5 of pregnancy affects the intrauterine developmental timeline. A total of 30 pregnant Sprague-Dawley diabetic rats (DRs) and 20 control rats (CRs) were used to obtain 21-day fetuses (F21) and newborn (NB) pups. Gestational age, weight, and body size were recorded as were the maxillofacial morphometry and morphohistological characteristics of the limbs. In DRs, pregnancy continued for ∼1.7 days, and delivery occurred 23 days postcoitus (DPC). In this group, the number of pups was lower, and 13% had maxillofacial defects. F21 in the DR group had lower weights and were smaller; moreover, the morphological characteristics of the maxillofacial structures, derived from the neural crest, were discordant with their chronological gestational age, resembling 18- to 19-day-old fetuses. These deficiencies were counterbalanced in NB pups. We conclude that hyperglycemia, which results from maternal diabetes and precedes embryo implantation, deregulates the intrauterine developmental timeline, restricts embryo-fetal growth, and primarily delays the remodeling and maturation of the structures derived from neural crest cells. PMID:25756053

  14. SERCA and PMCA pumps contribute to the deregulation of Ca2+ homeostasis in human CF epithelial cells.

    PubMed

    Philippe, Réginald; Antigny, Fabrice; Buscaglia, Paul; Norez, Caroline; Becq, Frédéric; Frieden, Maud; Mignen, Olivier

    2015-05-01

    Cystic Fibrosis (CF) disease is caused by mutations in the CFTR gene (CF transmembrane conductance regulator). F508 deletion is the most represented mutation, and F508del-CFTR is absent of plasma membrane and accumulates into the endoplasmic reticulum (ER) compartment. Using specific Ca2+ genetics cameleon probes, we showed in the human bronchial CF epithelial cell line CFBE that ER Ca2+ concentration was strongly increased compared to non-CF (16HBE) cells, and normalized by the F508del-CFTR corrector agent, VX-809. We also showed that ER F508del-CFTR retention increases SERCA (Sarcoplasmic/Reticulum Ca2+ ATPase) pump activity whereas PMCA (Plasma Membrane Ca2+ ATPase) activities were reduced in these CF cells compared to corrected CF cells (VX-809) and non-CF cells. We are showing for the first time CFTR/SERCA and CFTR/PMCA interactions that are modulated in CF cells and could explain part of Ca2+ homeostasis deregulation due to mislocalization of F508del-CFTR. Using ER or mitochondria genetics Ca2+ probes, we are showing that ER Ca2+ content, mitochondrial Ca2+ uptake, SERCA and PMCA pump, activities are strongly affected by the localization of F508del-CFTR protein. PMID:25661196

  15. Formation of Mallory Body-like Inclusions and Cell Death Induced by Deregulated Expression of Keratin 18

    PubMed Central

    Nakamichi, Ikuo; Hatakeyama, Shigetsugu; Nakayama, Keiichi I.

    2002-01-01

    Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia. Mice fed long term with griseofulvin are an animal model of MB formation. However, the lack of a cellular model has impeded understanding of the molecular mechanism of this process. Culture of HepG2 cells with griseofulvin has now been shown to induce both the formation of intracellular aggregates containing K18 as well as an increase in the abundance of K18 mRNA. Overexpression of K18 in HepG2, HeLa, or COS-7 cells also induced the formation of intracellular aggregates that stained with antibodies to ubiquitin and with rhodamine B (characteristics of MBs formed in vivo), eventually leading to cell death. The MB-like aggregates were deposited around centrosomes and disrupted the microtubular array. Coexpression of K8 with K18 restored the normal fibrous pattern of keratin distribution and reduced the toxicity of K18. In contrast, an NH2-terminal deletion mutant of K8 promoted the formation of intracellular aggregates even in the absence of K18 overexpression. Deregulated expression of K18, or an imbalance between K8 and K18, may thus be an important determinant of MB formation, which compromises the function of centrosomes and the microtubule network and leads to cell death. PMID:12388748

  16. Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring.

    PubMed

    Lee, Kuan-I; Chiang, Chin-Wei; Lin, Hui-Ching; Zhao, Jin-Feng; Li, Cheng-Ta; Shyue, Song-Kun; Lee, Tzong-Shyuan

    2016-05-01

    Long-term exposure to di-(2-ethylhexyl) phthalate (DEHP) is highly associated with carcinogenicity, fetotoxicity, psychological disorders and metabolic diseases, but the detrimental effects and mechanisms are not fully understood. We investigated the effect of exposing mouse mothers to DEHP, and the underlying mechanism, on blood pressure, obesity and cholesterol metabolism as well as psychological and learning behaviors in offspring. Tail-cuff plethysmography was used for blood pressure measurement; Western blot used was for phosphorylation and expression of protein; hematoxylin and eosin staining, Nissl staining and Golgi staining were used for histological examination. The serum levels of cholesterol, triglycerides and glucose were measured by blood biochemical analysis. Hepatic cholesterol and triglyceride levels were assessed by colorimetric assay kits. Offspring behaviors were evaluated by open-field activity, elevated plus maze, social preference test and Morris water maze. Maternal DEHP exposure deregulated the phosphorylation of endothelial nitric oxide synthase and upregulated angiotensin type 1 receptor in offspring, which led to increased blood pressure. It led to obesity in offspring by increasing the size of adipocytes in white adipose tissue and number of adipocytes in brown adipose tissue. It increased the serum level of cholesterol in offspring by decreasing the hepatic capacity for cholesterol clearance. The impaired social interaction ability induced by maternal DEHP exposure might be due to abnormal neuronal development. Collectively, our findings provide new evidence that maternal exposure to DEHP has a lasting effect on the physiological functions of the vascular system, adipose tissue and nerve system in offspring. PMID:25995009

  17. New Methodology for Evaluating Optimal Pricing for Primary Regulation of Deregulated Power Systems under Steady State Condition

    NASA Astrophysics Data System (ADS)

    Satyaramesh, P. V.; RadhaKrishna, C.

    2013-06-01

    A generalized pricing structure for procurement of power under frequency ancillary service is developed in this paper. It is a frequency linked-price model and suitable for deregulation market environment. This model takes into consideration: governor characteristics and frequency characteristics of generator as additional parameters in load flow method. The main objective of the new approach proposed in this paper is to establish bidding price structure for frequency regulation services in competitive ancillary electrical markets under steady state condition. Lot of literatures are available for calculating the frequency deviations with respect to load changes by using dynamic simulation methods. But in this paper, the model computes the frequency deviations for additional requirements of power under steady state with considering power system network topology. An attempt is also made in this paper to develop optimal bidding price structure for the frequency-regulated systems. It gives a signal to traders or bidders that the power demand can be assessed more accurately much closer to real time and helps participants bid more accurate quantities on day-ahead market. The recent trends of frequency linked-price model existing in Indian power systems issues required for attention are also dealt in this paper. Test calculations have been performed on 30-bus system. The paper also explains adoptability of 33 this model to practical Indian power system. The results presented are analyzed and useful conclusions are drawn.

  18. JNK is constitutively active in mantle cell lymphoma: cell cycle deregulation and polyploidy by JNK inhibitor SP600125.

    PubMed

    Wang, Miao; Atayar, Cigdem; Rosati, Stefano; Bosga-Bouwer, Anneke; Kluin, Philip; Visser, Lydia

    2009-05-01

    Mantle cell lymphoma (MCL) is characterized by genetic instability and a poor prognosis. Many blastoid variants are (hypo)tetraploid and have an even worse prognosis. We investigated the role of signalling by mitogen-activated protein kinases (MAPKs) in MCL. As compared to normal tonsil B cells, MCL cells showed higher activation of the JNK MAPK in both an MAPK array and a sandwich ELISA assay. Immunohistochemistry showed overexpression of phospho (p)-JNK (Thr183/Tyr185) in 30 of 37 MCL cases. Inhibition of p-JNK with SP600125 resulted in growth arrest in all four MCL cell lines (Jeko-1, HBL-2, UPN-1, Granta-519), which could be partly reversed by the addition of CD40L and IL-4. Furthermore, SP600125 led to G2/M phase arrest on day 1 and a striking increase in endoreduplication on day 2 and day 3, which was confirmed by karyotype analysis. G2/M arrest was associated with down-regulation of EGR1 and p21 protein expression. SP600125-induced polyploidy could be blocked by the BCL-2 inhibitor YC137. These data suggest that constitutive JNK activity is necessary to promote proliferation and maintain diploidy in MCL. JNK inhibition leads to cell cycle deregulation and endoreduplication, mimicking the tetraploid state seen in a subset of MCL cases. Thus, our data also provide an experimental model to study polyploid MCL cells. PMID:19206150

  19. Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression

    PubMed Central

    Benavente, Claudia A.; Finkelstein, David; Johnson, Dianna A.; Marine, Jean-Christophe; Ashery-Padan, Ruth; Dyer, Michael A.

    2014-01-01

    The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK. PMID:25338120

  20. The class-specific BCR tonic signal modulates lymphomagenesis in a c-myc deregulation transgenic model

    PubMed Central

    Amin, Rada; Marfak, Abdelghafour; Pangault, Céline; Oblet, Christelle; Chanut, Aurélie; Tarte, Karin; Denizot, Yves; Cogné, Michel

    2014-01-01

    Deregulation of c-myc by translocation onto immunoglobulin (Ig) loci can promote B cell malignant proliferations with phenotypes as diverse as acute lymphoid leukemia, Burkitt lymphoma, diffuse large B cell lymphoma, myeloma… The B cell receptor (BCR) normally providing tonic signals for cell survival and mitogenic responses to antigens, can also contribute to lymphomagenesis upon sustained ligand binding or activating mutations. BCR signaling varies among cell compartments and BCR classes. For unknown reasons, some malignancies associate with expression of either IgM or class-switched Ig. We explored whether an IgA BCR, with strong tonic signaling, would affect lymphomagenesis in c-myc IgH 3′RR transgenic mice prone to lymphoproliferations. Breeding c-myc transgenics in a background where IgM expression was replaced with IgA delayed lymphomagenesis. By comparison to single c-myc transgenics, lymphomas from double mutant animals were more differentiated and less aggressive, with an altered transcriptional program. Larger tumor cells more often expressed CD43 and CD138, which culminated in a plasma cell phenotype in 10% of cases. BCR class-specific signals thus appear to modulate lymphomagenesis and may partly explain the observed association of specific Ig classes with human B cell malignancies of differential phenotype, progression and prognosis. PMID:25229630

  1. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

    PubMed Central

    Irvine, David A.; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L.; Moka, Hothri A.; Ho, Yinwei; Nixon, Colin; Manley, Paul W.; Wheadon, Helen; Goodlad, John R.; Holyoake, Tessa L.; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  2. Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia

    PubMed Central

    Mansouri, Larry; Sutton, Lesley-Ann; Ljungström, Viktor; Bondza, Sina; Arngården, Linda; Bhoi, Sujata; Larsson, Jimmy; Cortese, Diego; Kalushkova, Antonia; Plevova, Karla; Young, Emma; Gunnarsson, Rebeqa; Falk-Sörqvist, Elin; Lönn, Peter; Muggen, Alice F.; Yan, Xiao-Jie; Sander, Birgitta; Enblad, Gunilla; Smedby, Karin E.; Juliusson, Gunnar; Belessi, Chrysoula; Rung, Johan; Chiorazzi, Nicholas; Strefford, Jonathan C.; Langerak, Anton W.; Pospisilova, Sarka; Davi, Frederic; Hellström, Mats; Jernberg-Wiklund, Helena; Ghia, Paolo; Söderberg, Ola; Stamatopoulos, Kostas; Nilsson, Mats

    2015-01-01

    NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis. PMID:25987724

  3. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.

    PubMed

    Irvine, David A; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L; Moka, Hothri A; Ho, Yinwei; Nixon, Colin; Manley, Paul W; Wheadon, Helen; Goodlad, John R; Holyoake, Tessa L; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  4. Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

    PubMed Central

    Clarke, Julia R; Lyra e Silva, Natalia M; Figueiredo, Claudia P; Frozza, Rudimar L; Ledo, Jose H; Beckman, Danielle; Katashima, Carlos K; Razolli, Daniela; Carvalho, Bruno M; Frazão, Renata; Silveira, Marina A; Ribeiro, Felipe C; Bomfim, Theresa R; Neves, Fernanda S; Klein, William L; Medeiros, Rodrigo; LaFerla, Frank M; Carvalheira, Jose B; Saad, Mario J; Munoz, Douglas P; Velloso, Licio A; Ferreira, Sergio T; De Felice, Fernanda G

    2015-01-01

    Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD. PMID:25617315

  5. Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma.

    PubMed

    Wang, Pei; Zhuang, Chunbo; Huang, Da; Xu, Keshu

    2016-07-01

    Iroquois homeobox (IRX) gene family, which plays essential roles in embryonic development, has recently been reported to be involved in tumor progression. However, the association of IRX3, a member of the IRX family, with hepatocellular carcinoma (HCC) has not previously been studied. In the present study, we found that IRX3 was upregulated in HCC cell lines (HepG2 and SMMC7721). We investigated the regulatory mechanism of IRX3 in HCC cells. Western blot and luciferase reporter assays identified that IRX3 is a direct target of miR-377. In addition, miR-377 was downregulated in HepG2 and SMMC7721 cell lines, and overexpression of miR-377 inhibited HepG2 cell proliferation, migration and invasion. Moreover, miR-377 restoration significantly abrogated IRX3-induced proliferation, migration and invasion of SMMC7721 cells. These findings demonstrate the tumor-promoting potential of IRX3, and that downregulation of miR-377 may contribute to the upregulation of IRX3 in HCC. The present study provides insights into HCC progression and a novel potential therapeutic target of HCC treatment. PMID:27222047

  6. FACTS Devices Cost Recovery During Congestion Management in Deregulated Electricity Markets

    NASA Astrophysics Data System (ADS)

    Sharma, Ashwani Kumar; Mittapalli, Ram Kumar; Pal, Yash

    2015-07-01

    In future electricity markets, flexible alternating current transmission system (FACTS) devices will play key role for providing ancillary services. Since huge cost is involved for the FACTS devices placement in the power system, the cost invested has to be recovered in their life time for the replacement of these devices. The FACTS devices in future electricity markets can act as an ancillary services provider and have to be remunerated. The main contributions of the paper are: (1) investment recovery of FACTS devices during congestion management such as static VAR compensator and unified power flow controller along with thyristor controlled series compensator using non-linear bid curves, (2) the impact of ZIP load model on the FACTS cost recovery of the devices, (3) the comparison of results obtained without ZIP load model for both pool and hybrid market model, (4) secure bilateral transactions incorporation in hybrid market model. An optimal power flow based approach has been developed for maximizing social welfare including FACTS devices cost. The optimal placement of the FACTS devices have been obtained based on maximum social welfare. The results have been obtained for both pool and hybrid electricity market for IEEE 24-bus RTS.

  7. Significant Deregulated Pathways in Diabetes Type II Complications Identified through Expression Based Network Biology

    NASA Astrophysics Data System (ADS)

    Ukil, Sanchaita; Sinha, Meenakshee; Varshney, Lavneesh; Agrawal, Shipra

    Type 2 Diabetes is a complex multifactorial disease, which alters several signaling cascades giving rise to serious complications. It is one of the major risk factors for cardiovascular diseases. The present research work describes an integrated functional network biology approach to identify pathways that get transcriptionally altered and lead to complex complications thereby amplifying the phenotypic effect of the impaired disease state. We have identified two sub-network modules, which could be activated under abnormal circumstances in diabetes. Present work describes key proteins such as P85A and SRC serving as important nodes to mediate alternate signaling routes during diseased condition. P85A has been shown to be an important link between stress responsive MAPK and CVD markers involved in fibrosis. MAPK8 has been shown to interact with P85A and further activate CTGF through VEGF signaling. We have traced a novel and unique route correlating inflammation and fibrosis by considering P85A as a key mediator of signals. The next sub-network module shows SRC as a junction for various signaling processes, which results in interaction between NF-kB and beta catenin to cause cell death. The powerful interaction between these important genes in response to transcriptionally altered lipid metabolism and impaired inflammatory response via SRC causes apoptosis of cells. The crosstalk between inflammation, lipid homeostasis and stress, and their serious effects downstream have been explained in the present analyses.

  8. A single amino acid substitution deregulates a bacterial lactate dehydrogenase and stabilizes its tetrameric structure.

    PubMed

    Clarke, A R; Wigley, D B; Barstow, D A; Chia, W N; Atkinson, T; Holbrook, J J

    1987-05-27

    We have engineered a variant of the lactate dehydrogenase enzyme from Bacillus stearothermophilus in which arginine-173 at the proposed regulatory site has been replaced by glutamine. Like the wild-type enzyme, this mutant undergoes a reversible, protein-concentration-dependent subunit assembly, from dimer to tetramer. However, the mutant tetramer is much more stable (by a factor of 400) than the wild type and is destabilized rather than stabilized by binding the allosteric regulator, fructose 1,6-biphosphate (Fru-1,6-P2). The mutation has not significantly changed the catalytic properties of the dimer (Kd NADH, Km pyruvate, Ki oxamate and kcat), but has weakened the binding of Fru-1,6-P2 to both the dimeric and tetrameric forms of the enzyme and has almost abolished any stimulatory effect. We conclude that the Arg-173 residue in the wild-type enzyme is directly involved in the binding of Fru-1,6-P2, is important for allosteric communication with the active site, and, in part, regulates the state of quaternary structure through a charge-repulsion mechanism. PMID:3580377

  9. RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS.

    PubMed

    Xiao, Shangxi; Sanelli, Teresa; Dib, Samar; Sheps, David; Findlater, Joseph; Bilbao, Juan; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Robertson, Janice

    2011-07-01

    TDP-43 is a predominantly nuclear DNA/RNA binding protein involved in transcriptional regulation and RNA processing. TDP-43 is also a component of the cytoplasmic inclusion bodies characteristic of amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). We have investigated the premise that abnormalities of TDP-43 in disease would be reflected by changes in processing of its target RNAs. To this end, we have firstly identified RNA targets of TDP-43 using UV-Cross-Linking and Immunoprecipitation (UV-CLIP) of SHSY5Y cells, a human neuroblastoma cell line. We used conventional cloning strategies to identify, after quality control steps, 127 targets. Results show that TDP-43 binds mainly to introns at UG/TG repeat motifs (49%) and polypyrimidine rich sequences (17.65%). To determine if the identified RNA targets of TDP-43 were abnormally processed in ALS versus control lumbar spinal cord RNA, we performed RT-PCR using primers designed according to the location of TDP-43 binding within the gene, and prior evidence of alternative splicing of exons adjacent to this site. Of eight genes meeting these criteria, five were differentially spliced in ALS versus control. This supports the premise that abnormalities of TDP-43 in ALS are reflected in changes of RNA processing. PMID:21421050

  10. Proteomics Based Identification of Proteins with Deregulated Expression in B Cell Lymphomas.

    PubMed

    Wu, Rui; Nijland, Marcel; Rutgers, Bea; Veenstra, Rianne; Langendonk, Myra; van der Meeren, Lotte E; Kluin, Philip M; Li, Guanwu; Diepstra, Arjan; Chiu, Jen-Fu; van den Berg, Anke; Visser, Lydia

    2016-01-01

    Follicular lymphoma and diffuse large B cell lymphomas comprise the main entities of adult B cell malignancies. Although multiple disease driving gene aberrations have been identified by gene expression and genomic studies, only a few studies focused at the protein level. We applied 2 dimensional gel electrophoresis to compare seven GC B cell non Hodgkin lymphoma (NHL) cell lines with a lymphoblastoid cell line (LCL). An average of 130 spots were at least two folds different in intensity between NHL cell lines and the LCL. We selected approximately 38 protein spots per NHL cell line and linked them to 145 unique spots based on the location in the gel. 34 spots that were found altered in at least three NHL cell lines when compared to LCL, were submitted for LC-MS/MS. This resulted in 28 unique proteins, a substantial proportion of these proteins were involved in cell motility and cell metabolism. Loss of expression of B2M, and gain of expression of PRDX1 and PPIA was confirmed in the cell lines and primary lymphoma tissue. Moreover, inhibition of PPIA with cyclosporine A blocked cell growth of the cell lines, the effect size was associated with the PPIA expression levels. In conclusion, we identified multiple differentially expressed proteins by 2-D proteomics, and showed that some of these proteins might play a role in the pathogenesis of NHL. PMID:26752561

  11. Deregulation of the IL-1β axis in chronic recurrent multifocal osteomyelitis

    PubMed Central

    2014-01-01

    Background This study aims to investigate the inflammasome response in peripheral blood mononuclear cells (PBMCs) and the expression of inflammasome components in bone biopsies from patients with chronic recurrent multifocal osteomyelitis (CRMO). Methods The expression of inflammasome components mRNAs was evaluated in PBMCs isolated from 15 CRMO patients and 13 healthy controls by quantitative real-time PCR. The Interleukin (IL)-1β released in the medium of PBMC cultures after treatment with lipopolysaccharides (LPS) alone or LPS and ATP was measured by ELISA. Immunohistochemical staining for Apoptosis-associated Speck-like protein (ASC), caspase-1 (CASP-1), Nod-like receptor protein-3 (NLRP3) and IL-1β expression was performed in bone biopsies from CRMO patients. Results mRNA levels of ASC, CASP-1 and IL-1β were significantly higher in freshly isolated PBMCs from CRMO patients in active disease than in healthy controls. CASP-1 and IL-1β transcript levels were significantly higher also in PBMCs from CRMO patients in remission compared to healthy controls. PBMCs from CRMO patients in active disease stimulated in vitro with LPS showed a significant increase in IL-1β release compared to healthy control cells. Immunohistochemistry staining of bone tissue revealed the expression of inflammasome components in CRMO osteoclasts. Conclusions Our data suggest that an abnormal regulation of IL-1β axis may be involved in CRMO pathogenesis. PMID:25061439

  12. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

    PubMed Central

    Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T.; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

    2015-01-01

    Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20–30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. PMID:26113417

  13. Epigenetic deregulation of the anaplastic lymphoma kinase gene modulates mesenchymal characteristics of oral squamous cell carcinomas

    PubMed Central

    Huang, Tim Hui-Ming

    2013-01-01

    DNA hypermethylation of promoter CpG islands is associated with epigenetic silencing of tumor suppressor genes in oral squamous cell carcinomas (OSCCs). We used a methyl-CpG-binding domain protein capture method coupled with next-generation sequencing (MBDCap-seq) to survey global DNA methylation patterns in OSCCs with and without nodal metastasis and normal mucosa (total n = 58). Of 1462 differentially methylated CpG islands identified in OSCCs relative to normal controls, MBDCap-seq profiling uncovered 359 loci linked to lymph node metastasis. Interactive network analysis revealed a subset of these loci (n = 23), including the anaplastic lymphoma kinase (ALK) gene, are potential regulators and effectors of invasiveness and metastatic progression. Promoter methylation of ALK was preferentially observed in OSCCs without node metastasis, whereas relatively lower methylation levels were present in metastatic tumors, implicating an active state of ALK transcription in the latter group. The OSCC cell line, SCC4, displayed reduced ALK expression that corresponded to extensive promoter CpG island methylation. SCC4 treatment with demethylating agents induced ALK expression and increased invasion and migration characteristics. Inhibition of ALK activity in OSCC cells with high ALK expression (CAL27, HSC3 and SCC25), decreased cell growth and resulted in changes in invasive potential and mesenchymal marker expression that were cell-line dependent. Although ALK is susceptible to epigenetic silencing during oral tumorigenesis, overwriting this default state may be necessary for modulating invasive processes involved in nodal metastases. Given the complex response of OSCC cells to ALK inhibition, future studies are required to assess the feasibility of targeting ALK to treat invasive OSCCs. PMID:23568951

  14. Chronic lymphocytic leukemia-associated chromosomal abnormalities and miRNA deregulation

    PubMed Central

    Kiefer, Yvonne; Schulte, Christoph; Tiemann, Markus; Bullerdiek, Joern

    2012-01-01

    Chronic lymphocytic leukemia is the most common leukemia in adults. By cytogenetic investigations major subgroups of the disease can be identified that reflect different routes of tumor development. Of these chromosomal deviations, trisomy 12 and deletions of parts of either the long arm of chromosome 13, the long arm of chromosome 11, or the short arm of chromosome 17 are most commonly detected. In some of these aberrations the molecular target has been identified as eg, ataxia telangiectasia mutated (ATM) in case of deletions of chromosomal region 11q22~23 and the genes encoding microRNAs miR-15a/16-1 as likely targets of deletions of chromosomal band 13q14.3. Of note, these aberrations do not characterize independent subgroups but often coexist within the metaphases of one tumor. Generally, complex aberrations are associated with a worse prognosis than simple karyotypic alterations. Due to smaller sizes of the missing segment the detection of recurrent deletions is not always possible by means of classical cytogenetics but requires more advanced techniques as in particular fluorescence in situ hybridization (FISH). Nevertheless, at this time it is not recommended to replace classical cytogenetics by FISH because this would miss additional information given by complex or secondary karyotypic alterations. However, the results of cytogenetic analyses allow the stratification of prognostic and predictive groups of the disease. Of these, the group characterized by deletions involving TP53 is clinically most relevant. In the future refined methods as eg, array-based comparative genomic hybridization will supplement the existing techniques to characterize CLL. PMID:23776377

  15. Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma.

    PubMed

    Arab, Khelifa; Smith, Laura T; Gast, Andreas; Weichenhan, Dieter; Huang, Joseph Po-Hsien; Claus, Rainer; Hielscher, Thomas; Espinosa, Allan V; Ringel, Matthew D; Morrison, Carl D; Schadendorf, Dirk; Kumar, Rajiv; Plass, Christoph

    2011-10-01

    Metastatic melanoma is a fatal disease due to the lack of successful therapies and biomarkers for early detection and its incidence has been increasing. Genetic studies have defined recurrent chromosomal aberrations, suggesting the location of either tumor suppressor genes or oncogenes. Transcription factor 21 (TCF21) belongs to the class A of the basic helix-loop-helix family with reported functions in early lung and kidney development as well as tumor suppressor function in the malignancies of the lung and head and neck. In this study, we combined quantitative DNA methylation analysis in patient biopsies and in their derived cell lines to demonstrate that TCF21 expression is downregulated in metastatic melanoma by promoter hypermethylation and TCF21 promoter DNA methylation is correlated with decreased survival in metastatic skin melanoma patients. In addition, the chromosomal location of TCF21 on 6q23-q24 coincides with the location of a postulated metastasis suppressor in melanoma. Functionally, TCF21 binds the promoter of the melanoma metastasis-suppressing gene, KiSS1, and enhances its gene expression through interaction with E12, a TCF3 isoform and with TCF12. Loss of TCF21 expression results in loss of KISS1 expression through loss of direct interaction of TCF21 at the KISS1 promoter. Finally, overexpression of TCF21 inhibits motility of C8161 melanoma cells. These data suggest that epigenetic downregulation of TCF21 is functionally involved in melanoma progression and that it may serve as a biomarker for aggressive tumor behavior. PMID:21771727

  16. Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma

    PubMed Central

    Arab, Khelifa; Smith, Laura T.; Gast, Andreas; Weichenhan, Dieter; Huang, Joseph Po-Hsien; Claus, Rainer; Hielscher, Thomas; Espinosa, Allan V.; Ringel, Matthew D.; Morrison, Carl D.; Schadendorf, Dirk; Kumar, Rajiv; Plass, Christoph

    2011-01-01

    Metastatic melanoma is a fatal disease due to the lack of successful therapies and biomarkers for early detection and its incidence has been increasing. Genetic studies have defined recurrent chromosomal aberrations, suggesting the location of either tumor suppressor genes or oncogenes. Transcription factor 21 (TCF21) belongs to the class A of the basic helix-loop-helix family with reported functions in early lung and kidney development as well as tumor suppressor function in the malignancies of the lung and head and neck. In this study, we combined quantitative DNA methylation analysis in patient biopsies and in their derived cell lines to demonstrate that TCF21 expression is downregulated in metastatic melanoma by promoter hypermethylation and TCF21 promoter DNA methylation is correlated with decreased survival in metastatic skin melanoma patients. In addition, the chromosomal location of TCF21 on 6q23–q24 coincides with the location of a postulated metastasis suppressor in melanoma. Functionally, TCF21 binds the promoter of the melanoma metastasis-suppressing gene, KiSS1, and enhances its gene expression through interaction with E12, a TCF3 isoform and with TCF12. Loss of TCF21 expression results in loss of KISS1 expression through loss of direct interaction of TCF21 at the KISS1 promoter. Finally, overexpression of TCF21 inhibits motility of C8161 melanoma cells. These data suggest that epigenetic downregulation of TCF21 is functionally involved in melanoma progression and that it may serve as a biomarker for aggressive tumor behavior. PMID:21771727

  17. Deregulation of MYC and TP53 through genetic and epigenetic alterations in gallbladder carcinomas.

    PubMed

    Ishak, Geraldo; Leal, Mariana Ferreira; Dos Santos, Ney Pereira Carneiro; Demachki, Samia; Nunes, Caroline Aquino Moreira; do Nascimento Borges, Barbara; Calcagno, Danielle Queiroz; Smith, Marília Cardoso; Assumpção, Paulo Pimentel; Burbano, Rommel Rodríguez

    2015-08-01

    Gallbladder cancer is a rare malignancy and presents a poor prognosis. MYC and p53 have been implicated in gallbladder carcinogenesis. However, little is known about the molecular mechanisms involved in their regulation in this neoplasia. Here, we evaluated the MYC and TP53 copy numbers in gallbladder tumors and their possible association with protein expression. We also investigated whether MYC may be controlled by mutations and DNA promoter methylation. In the present study, 15 samples of invasive gallbladder carcinomas and six control samples were analyzed. On the other hand, the expression of MYC and p53 was more frequent in gallbladder carcinomas than in control samples (p = 0.002, p = 0.046, respectively). Gain of copies of the MYC and TP53 genes was detected in 86.7 and 50 % of gallbladder carcinomas, respectively. MYC and TP53 amplifications were associated with immunoreactivity of their protein (p = 0.029, p = 0.001, respectively). MYC hypomethylation was only detected in tumoral samples and was associated with its protein expression (p = 0.029). MYC mutations were detected in 80 % of tumor samples. The G allele at rs117856857 was associated with the presence of gallbladder tumors (p = 0.019) and with MYC expression (p = 0.044). Moreover, two tumors presented a pathogenic mutation in MYC exon 2 (rs28933407). Our study highlights that the gain of MYC and TP53 copies seems to be a frequent finding in gallbladder cancer. In addition, gain of copies, hypomethylation and point mutations at MYC may contribute to overexpression of its protein in this type of cancer. PMID:25200035

  18. Deregulation of Mitochondria-Shaping Proteins Opa-1 and Drp-1 in Manganese-Induced Apoptosis

    PubMed Central

    Alaimo, Agustina; Gorojod, Roxana M.; Beauquis, Juan; Muñoz, Manuel J.; Saravia, Flavia; Kotler, Mónica L.

    2014-01-01

    Mitochondria are dynamic organelles that undergo fusion and fission processes. These events are regulated by mitochondria-shaping proteins. Changes in the expression and/or localization of these proteins lead to a mitochondrial dynamics impairment and may promote apoptosis. Increasing evidence correlates the mitochondrial dynamics disruption with the occurrence of neurodegenerative diseases. Therefore, we focused on this topic in Manganese (Mn)-induced Parkinsonism, a disorder associated with Mn accumulation preferentially in the basal ganglia where mitochondria from astrocytes represent an early target. Using MitoTracker Red staining we observed increased mitochondrial network fission in Mn-exposed rat astrocytoma C6 cells. Moreover, Mn induced a marked decrease in fusion protein Opa-1 levels as well as a dramatic increase in the expression of fission protein Drp-1. Additionally, Mn provoked a significant release of high MW Opa-1 isoforms from the mitochondria to the cytosol as well as an increased Drp-1 translocation to the mitochondria. Both Mdivi-1, a pharmacological Drp-1 inhibitor, and rat Drp-1 siRNA reduced the number of apoptotic nuclei, preserved the mitochondrial network integrity and prevented cell death. CsA, an MPTP opening inhibitor, prevented mitochondrial Δψm disruption, Opa-1 processing and Drp-1 translocation to the mitochondria therefore protecting Mn-exposed cells from mitochondrial disruption and apoptosis. The histological analysis and Hoechst 33258 staining of brain sections of Mn-injected rats in the striatum showed a decrease in cellular mass paralleled with an increase in the occurrence of apoptotic nuclei. Opa-1 and Drp-1 expression levels were also changed by Mn-treatment. Our results demonstrate for the first time that abnormal mitochondrial dynamics is implicated in both in vitro and in vivo Mn toxicity. In addition we show that the imbalance in fusion/fission equilibrium might be involved in Mn-induced apoptosis. This knowledge may

  19. Deregulation of mitochondria-shaping proteins Opa-1 and Drp-1 in manganese-induced apoptosis.

    PubMed

    Alaimo, Agustina; Gorojod, Roxana M; Beauquis, Juan; Muñoz, Manuel J; Saravia, Flavia; Kotler, Mónica L

    2014-01-01

    Mitochondria are dynamic organelles that undergo fusion and fission processes. These events are regulated by mitochondria-shaping proteins. Changes in the expression and/or localization of these proteins lead to a mitochondrial dynamics impairment and may promote apoptosis. Increasing evidence correlates the mitochondrial dynamics disruption with the occurrence of neurodegenerative diseases. Therefore, we focused on this topic in Manganese (Mn)-induced Parkinsonism, a disorder associated with Mn accumulation preferentially in the basal ganglia where mitochondria from astrocytes represent an early target. Using MitoTracker Red staining we observed increased mitochondrial network fission in Mn-exposed rat astrocytoma C6 cells. Moreover, Mn induced a marked decrease in fusion protein Opa-1 levels as well as a dramatic increase in the expression of fission protein Drp-1. Additionally, Mn provoked a significant release of high MW Opa-1 isoforms from the mitochondria to the cytosol as well as an increased Drp-1 translocation to the mitochondria. Both Mdivi-1, a pharmacological Drp-1 inhibitor, and rat Drp-1 siRNA reduced the number of apoptotic nuclei, preserved the mitochondrial network integrity and prevented cell death. CsA, an MPTP opening inhibitor, prevented mitochondrial Δψm disruption, Opa-1 processing and Drp-1 translocation to the mitochondria therefore protecting Mn-exposed cells from mitochondrial disruption and apoptosis. The histological analysis and Hoechst 33258 staining of brain sections of Mn-injected rats in the striatum showed a decrease in cellular mass paralleled with an increase in the occurrence of apoptotic nuclei. Opa-1 and Drp-1 expression levels were also changed by Mn-treatment. Our results demonstrate for the first time that abnormal mitochondrial dynamics is implicated in both in vitro and in vivo Mn toxicity. In addition we show that the imbalance in fusion/fission equilibrium might be involved in Mn-induced apoptosis. This knowledge may

  20. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer

    PubMed Central

    Chattopadhyay, Esita; Singh, Richa; Ray, Anindita; Roy, Roshni; De Sarkar, Navonil; Paul, Ranjan Rashmi; Pal, Mousumi; Aich, Ritesh; Roy, Bidyut

    2016-01-01

    Oral cancer generally progresses from precancerous lesions such as leukoplakia (LK), lichen planus (LP) and oral submucous fibrosis (OSMF). Since few of these precancers progress to cancers; it is worth to identify biological molecules that may play important roles in progression. Here, expression deregulation of 7 miRNAs (mir204, mir31, mir31*, mir133a, mir7, mir206 and mir1293) and their possible target genes in 23 cancers, 18 LK, 12 LP, 23 OSMF tissues compared to 20 healthy tissues was determined by qPCR method. Expression of mir7, mir31, mir31* and mir1293 was upregulated and that of mir133a, mir204 and mir206 was downregulated in cancer. Expression of most of these miRNAs was also upregulated in LK and LP tissues but not in OSMF. Expression deregulation of some of the target genes was also determined in cancer, LK and LP tissues. Significant upregulation of mir31 and downregulation of its target gene, CXCL12, in cancer, LK and LP tissues suggest their importance in progression of precancer to cancer. Expression upregulation of mir31 was also validated using GEO data sets. Although sample size is low, novelty of this work lies in studying expression deregulation of miRNAs and target genes in oral cancer and three types of precancerous lesions. PMID:27597234

  1. Deregulation Impact in Negotiating a New Electrical Contract Between NASA Glenn Research Center at Lewis Field and FirstEnergy Corp., Cleveland, Ohio, USA

    NASA Technical Reports Server (NTRS)

    Quach, Quyen T.; Zala, Laszlo F.

    2002-01-01

    The governor of the State of Ohio signed amended substitute Senate bill 3 on July 6, 1999, requiring Ohio's electric industry to change from a monopoly environment to a competitive electric environment for generation services. The start date for competitive retail generation services was set for January 1, 2001. This new deregulation law allowed all Ohioans to choose the supplier of generation service, but the transmission and distribution would remain regulated. It also required electric utilities to unbundle the three main components (generation, transmission, and distribution) and make other changes designed to produce a competitive electric generation market. While deregulation was taking shape, the NASA Glenn Research Center electrical contract with FirstEnergy Corp. of Cleveland, Ohio, was to expire on September 7, 1999. Glenn strategically evaluated and incorporated the impacts of electric deregulation in the negotiations. Glenn and FirstEnergy spent over a year in negotiations until the Glenn utility team and the FirstEnergy negotiating team came to an agreement in the fall of 2000, and a new contract became effective on January 1, 2001.

  2. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer.

    PubMed

    Chattopadhyay, Esita; Singh, Richa; Ray, Anindita; Roy, Roshni; De Sarkar, Navonil; Paul, Ranjan Rashmi; Pal, Mousumi; Aich, Ritesh; Roy, Bidyut

    2016-01-01

    Oral cancer generally progresses from precancerous lesions such as leukoplakia (LK), lichen planus (LP) and oral submucous fibrosis (OSMF). Since few of these precancers progress to cancers; it is worth to identify biological molecules that may play important roles in progression. Here, expression deregulation of 7 miRNAs (mir204, mir31, mir31*, mir133a, mir7, mir206 and mir1293) and their possible target genes in 23 cancers, 18 LK, 12 LP, 23 OSMF tissues compared to 20 healthy tissues was determined by qPCR method. Expression of mir7, mir31, mir31* and mir1293 was upregulated and that of mir133a, mir204 and mir206 was downregulated in cancer. Expression of most of these miRNAs was also upregulated in LK and LP tissues but not in OSMF. Expression deregulation of some of the target genes was also determined in cancer, LK and LP tissues. Significant upregulation of mir31 and downregulation of its target gene, CXCL12, in cancer, LK and LP tissues suggest their importance in progression of precancer to cancer. Expression upregulation of mir31 was also validated using GEO data sets. Although sample size is low, novelty of this work lies in studying expression deregulation of miRNAs and target genes in oral cancer and three types of precancerous lesions. PMID:27597234

  3. The impossible dream? How Nuclear Electric, Ltd. pulled itself out of the ashes of government ownership and became highly competitive in a privatized and deregulating British power market

    SciTech Connect

    Maycock, P.

    1998-12-31

    The day was dark for Nuclear Electric plc. when the British government decided it would privatize and deregulate the electric utility industry. For years, Nuclear Electric and other UK-based fossil power producers had been operating in a regulated market where the state set and guaranteed the price of electricity. All that was changing in Britain as the government introduced competition and as customers looked forward to purchasing power from the lowest bidder. Essentially the situation in England was much the same as it is now in the US: there was major momentum toward deregulation. The reality of competition in Britain came as good news to many power producers--in particular those who kept the lights on cost effectively. Others, However, weren`t so optimistic, especially nuclear plants that traditionally bear higher safety and maintenance costs than their fossil counterparts. Taking its cues from the City (Britain`s Wall Street), the British government simply considered nuclear generators to be unreliable, high cost, unprofitable organizations incapable of surviving in a privatized environment. It therefore left its nuclear power plants off the docket when selling (privatizing) its generating capacity. This paper describes how Nuclear Electric Ltd. became competitive in a deregulated environment.

  4. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma

    PubMed Central

    Özata, Deniz M; Caramuta, Stefano; Velázquez-Fernández, David; Akçakaya, Pinar; Xie, Hong; Höög, Anders; Zedenius, Jan; Bäckdahl, Martin; Larsson, Catharina; Lui, Weng-Onn

    2011-01-01

    Adrenocortical carcinoma (ACC) is an aggressive tumor showing frequent metastatic spread and poor survival. Although recent genome-wide studies of ACC have contributed to our understanding of the disease, major challenges remain for both diagnostic and prognostic assessments. The aim of this study was to identify specific microRNAs (miRNAs) associated with malignancy and survival of ACC patients. miRNA expression profiles were determined in a series of ACC, adenoma, and normal cortices using microarray. A subset of miRNAs showed distinct expression patterns in the ACC compared with adrenal cortices and adenomas. Among others, miR-483-3p, miR-483-5p, miR-210, and miR-21 were found overexpressed, while miR-195, miR-497, and miR-1974 were underexpressed in ACC. Inhibition of miR-483-3p or miR-483-5p and overexpression of miR-195 or miR-497 reduced cell proliferation in human NCI-H295R ACC cells. In addition, downregulation of miR-483-3p, but not miR-483-5p, and increased expression of miR-195 or miR-497 led to significant induction of cell death. Protein expression of p53 upregulated modulator of apoptosis (PUMA), a potential target of miR-483-3p, was significantly decreased in ACC, and inversely correlated with miR-483-3p expression. In addition, high expression of miR-503, miR-1202, and miR-1275 were found significantly associated with shorter overall survival among patients with ACC (P values: 0.006, 0.005, and 0.042 respectively). In summary, we identified additional miRNAs associated with ACC, elucidated the functional role of four miRNAs in the pathogenesis of ACC cells, demonstrated the potential involvement of the pro-apoptotic factor PUMA (a miR-483-3p target) in adrenocortical tumors, and found novel miRNAs associated with survival in ACC. PMID:21859927

  5. Current perspectives of molecular pathways involved in chronic inflammation-mediated breast cancer.

    PubMed

    Suman, Shankar; Sharma, Pradeep Kumar; Rai, Girish; Mishra, Sanjay; Arora, Deepika; Gupta, Prachi; Shukla, Yogeshwer

    2016-04-01

    Inflammation has multifaceted role in cancer progression including initiation, promotion and invasion by affecting the immune surveillance and associated signaling pathways. Inflammation facilitates the over-expression of cytokines, chemokines and growth factors involved in progression of different cancers including breast cancer progression. Deregulation of biological processes such as oxidative stress, angiogenesis, and autophagy elicit favorable immune response towards chronic inflammation. Apart from the role in carcinogenesis, chronic inflammation also favors the emergence of drug resistance clones by inducing the growth of breast cancer stem-like cells. Immunomodulation mediated by cytokines, chemokines and several other growth factors present in the tumor microenvironment regulate chronic inflammatory response and alter crosstalk among various signaling pathways such as NF-κB, Nrf-2, JAK-STAT, Akt and MAPKs involved in the progression of breast cancer. In this review, we focused on cellular and molecular processes involved in chronic inflammation, crosstalk among different signaling pathways and their association in breast cancer pathogenesis. PMID:26522220

  6. Emissions markets, power markets and market power: A study of the interactions between contemporary emissions markets and deregulated electricity markets

    NASA Astrophysics Data System (ADS)

    Dormady, Noah Christopher

    Chapter 1: A Monte Carlo Approach. The use of auctions to distribute tradeable property rights to firms in already heavily concentrated markets may further exacerbate the problems of market power that exist within those markets. This chapter provides a model of a two-stage emissions market modeled after a contemporary regional permit trading market in the United States, the Regional Greenhouse Gas Initiative, Inc. (RGGI). It then introduces Oligopsony 1.0, a C# software package constructed in the .NET environment that simulates uniform-price auctions using stochastic Monte Carlo simulation for modeling market power in tradeable property rights auctions. Monte Carlo methods add a probabilistic element to standard auction theoretic equilibria. The results of these simulations indicate that there can be significant non-linearities between profit and market power as exercised through strategic demand reduction. This analysis finds the optimum point of strategic demand reduction that enables the firm to exploit these non-linearities, and it determines the probability distributions of these optima using kernel density analysis. Chapter 2: An Experimental Approach. How will emerging auction-based emissions markets function within the context of today's deregulated auction-based electricity markets? This chapter provides an experimental analysis of a joint energy-emissions market. The impact of market power and collusion among dominant firms is evaluated to determine the extent to which an auction-based tradeable permit market influences performance in an adjacent electricity market. The experimental treatment design controls for a variety of real-world institutional features, including variable demand, permit banking, inter-temporal (multi-round) dynamics, a tightening cap, and resale. Results suggest that the exercise of market power significantly increases electricity auction clearing prices, without significantly increasing emissions

  7. High Involvement Work Teams.

    ERIC Educational Resources Information Center

    1996

    These three papers were presented at a symposium on high-involvement work teams moderated by Michael Leimbach at the 1996 conference of the Academy of Human Resource Development. "Beyond Training to the New Learning Environment: Workers on the High-Involvement Frontline" (Joseph Anthony Ilacqua, Carol Ann Zulauf) shows the link between an…

  8. Parent Involvement Handbook.

    ERIC Educational Resources Information Center

    Caplan, Arna

    This handbook on parent involvement, designed to be used with preschool programs, was developed by the Jefferson County Public Schools in Lakewood, Colorado. Included are: (1) a general statement about parent involvement in an early childhood program, (2) a description of the Jefferson County Early Childhood Program, (3) a description of the…

  9. Commericial Involvement in Intramurals.

    ERIC Educational Resources Information Center

    Maas, Gerry

    Sport in general has long had ties with commercial interests, the most popular and widespread involving publicity. Intramural sports programs, however, have not cultivated many commercial involvements in publicity. The approach in intramural sports advertising is simple. A commercial interest pays for space or time in a given communication media…

  10. [Families Involved in Learning.

    ERIC Educational Resources Information Center

    Ashby, Nicole, Ed.

    2001-01-01

    This issue of "Community Update" focuses on families involved in learning. The first article briefly discusses the "Ready to Read, Ready to Learn" White House summit that highlighted new research on early childhood learning. The center spread of this issue offers "Priming the Primary Educator: A Look at L. A. County's Parent Involvement Programs"…

  11. Conversational Involvement and Loneliness.

    ERIC Educational Resources Information Center

    Bell, Robert A.

    1985-01-01

    Assessed the relationship of conversational involvement and loneliness among college students. Found that lonely participants in this study had lower rates of talkativeness, interruptions, and attention than the nonlonely; they were also perceived as less involved and less interpersonally attractive. (PD)

  12. Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells

    PubMed Central

    Umazume, Takeshi; Thomas, William M.; Campbell, Sabrina; Aluri, Hema; Thotakura, Suharika; Zoukhri, Driss; Makarenkova, Helen P.

    2015-01-01

    Purpose The adult lacrimal gland (LG) is highly regenerative and is able to repair itself even after substantial damage; however, this ability to regenerate is lost with the development of dry eye conditions in chronically inflamed LGs.This study compares changes in the cell adhesion and cell matrix molecules and stem cell transcription factors in the LGs of healthy mice and of two mouse models of Sjögren's syndrome: nonobese diabetic (NOD) and MRL-lpr/lpr (MRL/lpr) mice during the early stage of inflammation. Methods The LGs from 12- to 13-week-old female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for quantitative (q) RT-PCR and qRT-PCR Arrays, histology, immunohistochemistry, and Western blotting. Results The extracellular matrix (ECM) and adhesion molecules RT2-PCR array combined with protein expression data revealed changes in the expression of integrins, matrix metalloproteinases, and other molecules, which are associated largely with invasion, attachment, and expansion of the lymphocytic cells, whereas changes in the stem cell transcription factors revealed substantial decrease in expression of transcription factors associated with epithelial stem/progenitor cell lineage. Conclusions We concluded that the expression of several important ECM components is significantly deregulated in the LG of two murine models of Sjögren's syndrome, suggesting an alteration of the epithelial stem/progenitor cell niche. This may result in profound effects on localization, activation, proliferation, and differentiation of the LG stem/progenitor cells and, therefore, LG regeneration. PMID:26747770

  13. Significance of TGFBR3 allelic loss in the deregulation of TGFβ signaling in primary human endometrial carcinomas.

    PubMed

    Zakrzewski, Piotr K; Nowacka-Zawisza, Maria; Semczuk, Andrzej; Rechberger, Tomasz; Gałczyński, Krzysztof; Krajewska, Wanda M

    2016-02-01

    Downregulation of betaglycan (β-glycan) [transforming growth factor β receptor type III (TGFβR3)], which belongs to co-receptors of the TGFβ pathway, occurs in a broad spectrum of primary human malignancies. However, in the case of endometrial cancer (EC), the mechanisms responsible for genetic alterations are still unknown. Therefore, we investigated allelic imbalance at the TGFBR3 locus (1p33‑p32) in the context of β-glycan mRNA and protein expression, as a possible genetic event determining β-glycan deregulation in EC patients. Study of β-glycan allelic imbalance in 48 primary human ECs was performed with the use of three different microsatellite markers, spanned within or in direct proximity to the TGFBR3 locus. Real‑time PCR and western blotting were used for β-glycan mRNA and protein quantification methods, respectively. Altogether, 25 of 39 (64%) informative cases and 25 of 48 (52%) of all specimens showed allelic imbalance in at least one microsatellite marker, concomitantly with decrease at both the β-glycan transcript and protein levels. Interestingly, 54% (15/28), 36% (8/22) and 35% (7/20) of informative ECs displayed allelic loss in D1S188, D1S435 and D1S1588 microsatellite markers, respectively. It is worth pointing out that 5 out of 39 (13%) informative cases showed loss of heterozygosity (LOH) at two microsatellite markers. Microsatellite instability (MSI) was found in two markers, but to a very strictly limited extent. None of the clinicoprognostic features was found to be of significance. Our results suggest that LOH in the TGFBR3 locus may be one of the mechanisms responsible for loss of β-glycan expression. No correlation of LOH at the TGFBR3 locus with clinicopathological parameters suggests that allelic imbalance may be an early genetic event during neoplastic transformation of human endometrium. PMID:26548418

  14. Deregulated expression of annexin-A2 and galectin-3 is associated with metastasis in gastric cancer patients.

    PubMed

    Leal, Mariana Ferreira; Calcagno, Danielle Queiroz; Chung, Janete; de Freitas, Vanessa Morais; Demachki, Samia; Assumpção, Paulo Pimentel; Chammas, Roger; Burbano, Rommel Rodríguez; Smith, Marília Cardoso

    2015-08-01

    Gastric cancer (GC) is the second highest cause of cancer mortality worldwide. However, nowadays, most of the studies aiming to understand the gastric carcinogenesis analyzed tumors of individuals from Asian population and, thus, may not reflect the distinct biological and clinical behaviors among GC processes. Since several membrane proteins have been implicated in carcinogenesis, we aimed to evaluate ANXA2 and GAL3 role in gastric tumors and GC cell lines of individuals from northern Brazil. The cellular localization of ANXA2 and GAL3 in the GC cell lines was evaluated by immunofluorescence. Gene expression was evaluated by real-time reverse-transcription PCR and protein expression by Western blot in gastric adenocarcinomas and non-neoplastic gastric samples, as well as in GC cell lines. ANXA2 and GAL3 were presented as dots in the plasma membrane and cytoplasm in ACP02 and ACP03 cell lines. ANXA2 mRNA expression was up-regulated in 32.14 % of gastric tumors compared to non-neoplastic tissues. ANXA2 up-regulation was associated with the metastasis process in vivo and with cell line invasive behavior. GAL3 protein expression was at least 1.5-fold reduced in 50 % of gastric tumors. The reduced GAL3 expression was associated with the presence of distant metastasis and with a higher invasive phenotype in vitro. Our study shows that ANXA2 and GAL3 deregulated expression was associated with an invasive phenotype in GC cell lines and may contribute to metastasis in GC patients. Therefore, these proteins may have potential prognostic relevance for GC of individuals from northern Brazil. PMID:25034653

  15. Influence of microRNA deregulation on chaperone-mediated autophagy and α-synuclein pathology in Parkinson's disease

    PubMed Central

    Alvarez-Erviti, L; Seow, Y; Schapira, A HV; Rodriguez-Oroz, M C; Obeso, J A; Cooper, J M

    2013-01-01

    The presence of α-synuclein aggregates in the characteristic Lewy body pathology seen in idiopathic Parkinson's disease (PD), together with α-synuclein gene mutations in familial PD, places α-synuclein at the center of PD pathogenesis. Decreased levels of the chaperone-mediated autophagy (CMA) proteins LAMP-2A and hsc70 in PD brain samples suggests compromised α-synuclein degradation by CMA may underpin the Lewy body pathology. Decreased CMA protein levels were not secondary to the various pathological changes associated with PD, including mitochondrial respiratory chain dysfunction, increased oxidative stress and proteasomal inhibition. However, decreased hsc70 and LAMP-2A protein levels in PD brains were associated with decreases in their respective mRNA levels. MicroRNA (miRNA) deregulation has been reported in PD brains and we have identified eight miRNAs predicted to regulate LAMP-2A or hsc70 expression that were reported to be increased in PD. Using a luciferase reporter assay in SH-SY5Y cells, four and three of these miRNAs significantly decreased luciferase activity expressed upstream of the lamp-2a and hsc70 3′UTR sequences respectively. We confirmed that transfection of these miRNAs also decreased endogenous LAMP-2A and hsc70 protein levels respectively and resulted in significant α-synuclein accumulation. The analysis of PD brains confirmed that six and two of these miRNAs were significantly increased in substantia nigra compacta and amygdala respectively. These data support the hypothesis that decreased CMA caused by miRNA-induced downregulation of CMA proteins plays an important role in the α-synuclein pathology associated with PD, and opens up a new avenue to investigate PD pathogenesis. PMID:23492776

  16. Nash equilibrium strategy in the deregulated power industry and comparing its lost welfare with Iran wholesale electricity market

    NASA Astrophysics Data System (ADS)

    Mousavi, Seyed Hosein; Nazemi, Ali; Hafezalkotob, Ashkan

    2016-07-01

    With the increasing use of different types of auctions in market designing, modeling of participants' behaviors to evaluate the market structure is one of the main discussions in the studies related to the deregulated power industries. In this article, we apply an approach of the optimal bidding behavior to the Iran wholesale electricity market as a restructured electric power industry and model how the participants of the market bid in the spot electricity market. The problem is formulated analytically using the Nash equilibrium concept composed of large numbers of players having discrete and very large strategy spaces. Then, we compute and draw supply curve of the competitive market in which all generators' proposed prices are equal to their marginal costs and supply curve of the real market in which the pricing mechanism is pay-as-bid. We finally calculate the lost welfare or inefficiency of the Nash equilibrium and the real market by comparing their supply curves with the competitive curve. We examine 3 cases on November 24 (2 cases) and July 24 (1 case), 2012. It is observed that in the Nash equilibrium on November 24 and demand of 23,487 MW, there are 212 allowed plants for the first case (plants are allowed to choose any quantity of generation except one of them that should be equal to maximum Power) and the economic efficiency or social welfare of Nash equilibrium is 2.77 times as much as the real market. In addition, there are 184 allowed plants for the second case (plants should offer their maximum power with different prices) and the efficiency or social welfare of Nash equilibrium is 3.6 times as much as the real market. On July 24 and demand of 42,421 MW, all 370 plants should generate maximum energy due to the high electricity demand that the economic efficiency or social welfare of the Nash equilibrium is about 2 times as much as the real market.

  17. Expression Analysis of Genes Involved in the RB/E2F Pathway in Astrocytic Tumors

    PubMed Central

    Ferreira, Wallax Augusto Silva; Araújo, Mariana Diniz; de Oliveira, Edivaldo Herculano Correa; Brito, José Reginaldo Nascimento; Burbano, Rommel Rodriguez; Harada, Maria Lúcia; Borges, Bárbara do Nascimento

    2015-01-01

    Astrocytic gliomas, which are derived from glial cells, are considered the most common primary neoplasias of the central nervous system (CNS) and are histologically classified as low grade (I and II) or high grade (III and IV). Recent studies have shown that astrocytoma formation is the result of the deregulation of several pathways, including the RB/E2F pathway, which is commonly deregulated in various human cancers via genetic or epigenetic mechanisms. On the basis of the assumption that the study of the mechanisms controlling the INK4/ARF locus can help elucidate the molecular pathogenesis of astrocytic tumors, identify diagnostic and prognostic markers, and help select appropriate clinical treatments, the present study aimed to evaluate and compare methylation patterns using bisulfite sequencing PCR and evaluate the gene expression profile using real-time PCR in the genes CDKN2A, CDKN2B, CDC6, Bmi-1, CCND1, and RB1 in astrocytic tumors. Our results indicate that all the evaluated genes are not methylated independent of the tumor grade. However, the real-time PCR results indicate that these genes undergo progressive deregulation as a function of the tumor grade. In addition, the genes CDKN2A, CDKN2B, and RB1 were underexpressed, whereas CDC6, Bmi-1, and CCND1 were overexpressed; the increase in gene expression was significantly associated with decreased patient survival. Therefore, we propose that the evaluation of the expression levels of the genes involved in the RB/E2F pathway can be used in the monitoring of patients with astrocytomas in clinical practice and for the prognostic indication of disease progression. PMID:26317630

  18. Expression Analysis of Genes Involved in the RB/E2F Pathway in Astrocytic Tumors.

    PubMed

    Ferreira, Wallax Augusto Silva; Araújo, Mariana Diniz; Anselmo, Nilson Praia; de Oliveira, Edivaldo Herculano Correa; Brito, José Reginaldo Nascimento; Burbano, Rommel Rodriguez; Harada, Maria Lúcia; Borges, Bárbara do Nascimento

    2015-01-01

    Astrocytic gliomas, which are derived from glial cells, are considered the most common primary neoplasias of the central nervous system (CNS) and are histologically classified as low grade (I and II) or high grade (III and IV). Recent studies have shown that astrocytoma formation is the result of the deregulation of several pathways, including the RB/E2F pathway, which is commonly deregulated in various human cancers via genetic or epigenetic mechanisms. On the basis of the assumption that the study of the mechanisms controlling the INK4/ARF locus can help elucidate the molecular pathogenesis of astrocytic tumors, identify diagnostic and prognostic markers, and help select appropriate clinical treatments, the present study aimed to evaluate and compare methylation patterns using bisulfite sequencing PCR and evaluate the gene expression profile using real-time PCR in the genes CDKN2A, CDKN2B, CDC6, Bmi-1, CCND1, and RB1 in astrocytic tumors. Our results indicate that all the evaluated genes are not methylated independent of the tumor grade. However, the real-time PCR results indicate that these genes undergo progressive deregulation as a function of the tumor grade. In addition, the genes CDKN2A, CDKN2B, and RB1 were underexpressed, whereas CDC6, Bmi-1, and CCND1 were overexpressed; the increase in gene expression was significantly associated with decreased patient survival. Therefore, we propose that the evaluation of the expression levels of the genes involved in the RB/E2F pathway can be used in the monitoring of patients with astrocytomas in clinical practice and for the prognostic indication of disease progression. PMID:26317630

  19. Eye Involvement in TSC

    MedlinePlus

    ... what we see to the brain via the optic nerve. Retinal and optic nerve involvement in TSC are well known today, ... hamartomas (non-cancerous tumors) of the retina or optic nerve. The most common type of retinal hamartoma ...

  20. Deregulating mandatory medical prescription.

    PubMed

    Mitchell, C N

    1986-01-01

    This Article links the legal evolution of mandatory medical prescription since 1900 to the police-power's prohibition of alcohol and the opiates as well as to the self-interested monopolization of new drugs by physicians. The Article advances a theory of professionalization consistent with the evidence that mandatory prescription is not in the public interest. The Article suggests that the supremacy of self-medication is consistent with competition policy, the medical profession's fiduciary duty to clients, reduced medical costs and improved health. The author analyzes the consequences of regulating drug production, testing, marketing and consumtion by granting decision-making authority to the lowest-cost risk avoider, suggesting this as a plausible basis for legal reform. PMID:3327377

  1. Deregulation and Station Trafficking.

    ERIC Educational Resources Information Center

    Bates, Benjamin J.

    To test whether the revocation of the Federal Communications Commission's "Anti-Trafficking" rule (requiring television station owners to keep a station for three years before transferring its license to another party) impacted station owner behavior, a study compared the behavior of television station "traffickers" (owners seeking quick turnovers…

  2. Functional Characterization of FLT3 Receptor Signaling Deregulation in Acute Myeloid Leukemia by Single Cell Network Profiling (SCNP)

    PubMed Central

    Rosen, David B.; Minden, Mark D.; Kornblau, Steven M.; Cohen, Aileen; Gayko, Urte; Putta, Santosh; Woronicz, John; Evensen, Erik; Fantl, Wendy J.; Cesano, Alessandra

    2010-01-01

    Background Molecular characterization of the FMS-like tyrosine kinase 3 receptor (FLT3) in cytogenetically normal acute myeloid leukemia (AML) has recently been incorporated into clinical guidelines based on correlations between FLT3 internal tandem duplications (FLT3-ITD) and decreased disease-free and overall survival. These mutations result in constitutive activation of FLT3, and FLT3 inhibitors are currently undergoing trials in AML patients selected on FLT3 molecular status. However, the transient and partial responses observed suggest that FLT3 mutational status alone does not provide complete information on FLT3 biological activity at the individual patient level. Examination of variation in cellular responsiveness to signaling modulation may be more informative. Methodology/Principal Findings Using single cell network profiling (SCNP), cells were treated with extracellular modulators and their functional responses were quantified by multiparametric flow cytometry. Intracellular signaling responses were compared between healthy bone marrow myeloblasts (BMMb) and AML leukemic blasts characterized as FLT3 wild type (FLT3-WT) or FLT3-ITD. Compared to healthy BMMb, FLT3-WT leukemic blasts demonstrated a wide range of signaling responses to FLT3 ligand (FLT3L), including elevated and sustained PI3K and Ras/Raf/Erk signaling. Distinct signaling and apoptosis profiles were observed in FLT3-WT and FLT3-ITD AML samples, with more uniform signaling observed in FLT3-ITD AML samples. Specifically, increased basal p-Stat5 levels, decreased FLT3L induced activation of the PI3K and Ras/Raf/Erk pathways, decreased IL-27 induced activation of the Jak/Stat pathway, and heightened apoptotic responses to agents inducing DNA damage were observed in FLT3-ITD AML samples. Preliminary analysis correlating these findings with clinical outcomes suggests that classification of patient samples based on signaling profiles may more accurately reflect FLT3 signaling deregulation and

  3. Intrinsic Deregulation of Vascular Smooth Muscle and Myofibroblast Differentiation in Mesenchymal Stromal Cells from Patients with Systemic Sclerosis

    PubMed Central

    Hegner, Björn; Schaub, Theres; Catar, Rusan; Kusch, Angelika; Wagner, Philine; Essin, Kirill; Lange, Claudia; Riemekasten, Gabriela; Dragun, Duska

    2016-01-01

    Introduction Obliterative vasculopathy and fibrosis are hallmarks of systemic sclerosis (SSc), a severe systemic autoimmune disease. Bone marrow-derived mesenchymal stromal cells (MSCs) from SSc patients may harbor disease-specific abnormalities. We hypothesized disturbed vascular smooth muscle cell (VSMC) differentiation with increased propensity towards myofibroblast differentiation in response to SSc-microenvironment defining growth factors and determined responsible mechanisms. Methods We studied responses of multipotent MSCs from SSc-patients (SSc-MSCs) and healthy controls (H-MSCs) to long-term exposure to CTGF, b-FGF, PDGF-BB or TGF-β1. Differentiation towards VSMC and myofibroblast lineages was analyzed on phenotypic, biochemical, and functional levels. Intracellular signaling studies included analysis of TGF-β receptor regulation, SMAD, AKT, ERK1/2 and autocrine loops. Results VSMC differentiation towards both, contractile and synthetic VSMC phenotypes in response to CTGF and b-FGF was disturbed in SSc-MSCs. H-MSCs and SSc-MSCs responded equally to PDGF-BB with prototypic fibroblastic differentiation. TGF-β1 initiated myofibroblast differentiation in both cell types, yet with striking phenotypic and functional differences: In relation to H-MSC-derived myofibroblasts induced by TGF-β1, those obtained from SSc-MSCs expressed more contractile proteins, migrated towards TGF-β1, had low proliferative capacity, and secreted higher amounts of collagen paralleled by reduced MMP expression. Higher levels of TGF-β receptor 1 and enhanced canonical and noncanonical TGF-β signaling in SSc-MSCs accompanied aberrant differentiation response of SSc-MSCs in comparison to H-MSCs. Conclusions Deregulated VSMC differentiation with a shift towards myofibroblast differentiation expands the concept of disturbed endogenous regenerative capacity of MSCs from SSc patients. Disease related intrinsic hyperresponsiveness to TGF-β1 with increased collagen production may

  4. Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation

    PubMed Central

    2010-01-01

    appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation. PMID:20860828

  5. Deregulated expression of cytoskeleton related genes in the spinal cord and sciatic nerve of presymptomatic SOD1G93A Amyotrophic Lateral Sclerosis mouse model

    PubMed Central

    Maximino, Jessica R.; de Oliveira, Gabriela P.; Alves, Chrystian J.; Chadi, Gerson

    2014-01-01

    Early molecular events related to cytoskeleton are poorly described in Amyotrophic Lateral Sclerosis (ALS), especially in the Schwann cell (SC), which offers strong trophic support to motor neurons. Database for Annotation, Visualization and Integrated Discovery (DAVID) tool identified cytoskeleton-related genes by employing the Cellular Component Ontology (CCO) in a large gene profiling of lumbar spinal cord and sciatic nerve of presymptomatic SOD1G93A mice. One and five CCO terms related to cytoskeleton were described from the spinal cord deregulated genes of 40 days (actin cytoskeleton) and 80 days (microtubule cytoskeleton, cytoskeleton part, actin cytoskeleton, neurofilament cytoskeleton, and cytoskeleton) old transgene mice, respectively. Also, four terms were depicted from the deregulated genes of sciatic nerve of 60 days old transgenes (actin cytoskeleton, cytoskeleton part, microtubule cytoskeleton and cytoskeleton). Kif1b was the unique deregulated gene in more than one studied region or presymptomatic age. The expression of Kif1b [quantitative polymerase chain reaction (qPCR)] elevated in the lumbar spinal cord (40 days old) and decreased in the sciatic nerve (60 days old) of presymptomatic ALS mice, results that were in line to microarray findings. Upregulation (24.8 fold) of Kif1b was seen in laser microdissected enriched immunolabeled motor neurons from the spinal cord of 40 days old presymptomatic SOD1G93A mice. Furthermore, Kif1b was dowregulated in the sciatic nerve Schwann cells of presymptomatic ALS mice (60 days old) that were enriched by means of cell microdissection (6.35 fold), cell sorting (3.53 fold), and primary culture (2.70 fold) technologies. The gene regulation of cytoskeleton molecules is an important occurrence in motor neurons and Schwann cells in presymptomatic stages of ALS and may be relevant in the dying back mechanisms of neuronal death. Furthermore, a differential regulation of Kif1b in the spinal cord and sciatic nerve cells

  6. ‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine

    DOE PAGESBeta

    Gardeux, Vincent; Achour, Ikbel; Li, Jianrong; Maienschein-Cline, Mark; Li, Haiquan; Pesce, Lorenzo; Parinandi, Gurunadh; Bahroos, Neil; Winn, Robert; Garcia, Joe G. N.; et al

    2014-11-01

    Background: The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. This research entails, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery. Method: ‘N-of-1-pathways’ is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodulesmore » assesses commonality and differences, within-study and cross-studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient. Results: Cross-patient N-of-1-pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03). Conclusions: The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies.« less

  7. ‘N-of-1-pathways’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: towards precision medicine

    PubMed Central

    Gardeux, Vincent; Achour, Ikbel; Li, Jianrong; Maienschein-Cline, Mark; Li, Haiquan; Pesce, Lorenzo; Parinandi, Gurunadh; Bahroos, Neil; Winn, Robert; Foster, Ian; Garcia, Joe G N; Lussier, Yves A

    2014-01-01

    Background The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. Indeed, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery. Method ‘N-of-1-pathways’ is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodules assesses commonality and differences, within-study and cross-studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient. Results Cross-patient N-of-1-pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03). Conclusions The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies. Software http://lussierlab.org/publications/N-of-1-pathways

  8. ‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine

    SciTech Connect

    Gardeux, Vincent; Achour, Ikbel; Li, Jianrong; Maienschein-Cline, Mark; Li, Haiquan; Pesce, Lorenzo; Parinandi, Gurunadh; Bahroos, Neil; Winn, Robert; Garcia, Joe G. N.; Foster, Ian; Lussier, Yves A.

    2014-11-01

    Background: The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. This research entails, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery. Method: ‘N-of-1-pathways’ is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodules assesses commonality and differences, within-study and cross-studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient. Results: Cross-patient N-of-1-pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03). Conclusions: The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies.

  9. Musculoskeletal involvement in sarcoidosis*, **

    PubMed Central

    Nessrine, Akasbi; Zahra, Abourazzak Fatima; Taoufik, Harzy

    2014-01-01

    Sarcoidosis is a multisystem inflammatory disorder of unknown cause. It most commonly affects the pulmonary system but can also affect the musculoskeletal system, albeit less frequently. In patients with sarcoidosis, rheumatic involvement is polymorphic. It can be the presenting symptom of the disease or can appear during its progression. Articular involvement is dominated by nonspecific arthralgia, polyarthritis, and Löfgren's syndrome, which is defined as the presence of lung adenopathy, arthralgia (or arthritis), and erythema nodosum. Skeletal manifestations, especially dactylitis, appear mainly as complications of chronic, multiorgan sarcoidosis. Muscle involvement in sarcoidosis is rare and usually asymptomatic. The diagnosis of rheumatic sarcoidosis is based on X-ray findings and magnetic resonance imaging findings, although the definitive diagnosis is made by anatomopathological study of biopsy samples. Musculoskeletal involvement in sarcoidosis is generally relieved with nonsteroidal anti-inflammatory drugs or corticosteroids. In corticosteroid-resistant or -dependent forms of the disease, immunosuppressive therapy, such as treatment with methotrexate or anti-TNF-α, is employed. The aim of this review was to present an overview of the various types of osteoarticular and muscle involvement in sarcoidosis, focusing on their diagnosis and management. PMID:24831403

  10. Why Parental Involvement?

    ERIC Educational Resources Information Center

    Manno, Bruno V.

    Analysis of values, values transmission, human development, and Catholic social theory can increase effectiveness of parental involvement in Catholic education. Values are interpreted to include fundamental criteria which give meaning and order to life. Although values are transmitted by numerous sources including the family, social groups,…

  11. Involvement or Engagement?

    ERIC Educational Resources Information Center

    Ferlazzo, Larry

    2011-01-01

    To create the kinds of school-family partnerships that raise student achievement, improve local communities, and increase public support, schools need to understand the difference between family involvement and family engagement. Schools that emphasize the latter tend toward doing with families, rather than doing to families. These schools do more…

  12. Getting Parents Involved.

    ERIC Educational Resources Information Center

    Butts, Vickie; Finch, Patty A.

    1985-01-01

    Describes a parental involvement program in reading, writing, and human education. The project consists of caring for Clifford, a stuffed toy dog, on a rotated basis by first grade students. Books and pet care items accompany Clifford and provide an opportunity for parent and child to work together. (ML)

  13. Job Involvement of Teachers.

    ERIC Educational Resources Information Center

    Knoop, Robert

    This study investigated the relationship between job involvement and three sets of variables: nine personal (age, sex, marital status, education, overall experience, nonteaching experience, present school experience, income, and locus of control), three structural (size of school, location of school, and hierarchical position), and eight job…

  14. Strengthening Parent Involvement.

    ERIC Educational Resources Information Center

    Williams, David L., Jr.; Chavkin, Nancy Feyl

    1986-01-01

    Recent studies have verified Secretary of Education William Bennett's observation on the importance of home and family life. The most successful students are those whose parents become actively engaged in the educational process at home and at school. To capitalize on potential parent involvement, principals need to understand the kinds of…

  15. Evaluation on Influence of Unstable Primary-Energy Price in a Deregulated Electric Power Market—Analysis based on a simulation model approach—

    NASA Astrophysics Data System (ADS)

    Maitani, Tatsuyuki; Tezuka, Tetsuo

    The electric power market of Japan has been locally monopolized for a long time. But, like many countries, Japan is moving forward with the deregulation of its electric power industry so that any power generation company could sell electric power in the market. The power price, however, will fluctuate inevitably to balance the power supply and demand. A new appropriate market design is indispensable when introducing new market mechanisms in the electric power market to avoid undesirable results of the market. The first stage of deregulation will be the competition between an existing large-scaled power utility and a new power generation company. In this paper we have investigated the wholesale market with competition of these two power companies based on a simulation model approach. Under the competitive situation the effects of exogenous disturbance may bring serious results and we estimated the influence on the market when the price of fossil fuel rises. The conclusion of this study is that several types of Nash equilibriums have been found in the market: the larger the new power generation company becomes, the higher the electricity price under the Nash equilibriums rises. Because of the difference in their structure of generation capacity, the existing large-scaled power utility gets more profit while the new power generation company loses its profit when the price of fossil fuel rises.

  16. Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment

    PubMed Central

    Finkernagel, Florian; Lieber, Sonja; Schnitzer, Evelyn; Legrand, Nathalie; Schober, Yvonne; Nockher, W. Andreas; Toth, Philipp M.; Diederich, Wibke E.; Nist, Andrea; Stiewe, Thorsten; Wagner, Uwe; Reinartz, Silke; Müller-Brüsselbach, Sabine; Müller, Rolf

    2015-01-01

    The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma. PMID:25968567

  17. Deregulated miR-296/S100A4 axis promotes tumor invasion by inducing epithelial-mesenchymal transition in human ovarian cancer

    PubMed Central

    Yan, Wang; Chen, Jiaqi; Chen, Zhaoying; Chen, Huimin

    2016-01-01

    S100A4 represents an important member of the S100 family of small calcium-binding proteins. Increased expression of S100A4 has been observed in chronic inflammatory and autoimmune diseases, such as idiopathic inflammatory myopathies. The majority of studies of S100A4 are focused on cancer research; however, the oncogenic roles of S100A4 in epithelial ovarian cancer (EOC) remain largely unexplored. In this study, S100A4 expression is significantly up-regulated in ovarian cancer and associated with the clinical stage of EOC patients. Attenuation of S100A4 expression results in decreased cell mobility and metastatic capacity, whereas overexpression of S100A4 enhanced the invasive ability of EOC cells. Then by an integrated informatics analysis and luciferase reporter assay, we identify that miR-296 is a critical upstream regulator of S100A4. In addition, deregulated miR-296/S100A4 axis facilitates epithelial-mesenchymal transition (EMT) process as demonstrated by altered expression of EMT-related markers. In conclusion, our study reveals that deregulated miR-296/S100A4 promotes tumor progression in EOC, and provides evidence that miR-296/S100A4 axis-related signaling may represent a potential target for EOC therapy. PMID:27186401

  18. Getting involved in research.

    PubMed

    Banner, Davina; Grant, Lyle G

    2011-01-01

    The need for quality nursing research to promote evidence-based practice and optimize patient care is well recognized. This is particularly pertinent in cardiovascular nursing, where cardiovascular disease continues to be the leading cause of morbidity and mortality worldwide (World Health Organization, 2007). Across the spectrum of academic, clinical, and health care administration nursing roles, research remains fundamental to bridging theory, practice, and education (LoBiondo-Wood, Haber, Cameron, & Singh, 2009). Despite recognition of the importance of nursing research, the gap between research and practice continues to be an ongoing issue (Funk, Tornquist, & Champagne, 1995; Pettengill, Gillies, & Clark, 1994; Rizzuto, Bostrom, Suterm, & Chenitz, 1994; Rolfe, 1998). Nurses are appropriately situated to contribute to research that improves clinical outcomes and health service delivery. However, the majority of nurses in clinical practice do not have a significant research component structured into their nursing role. In this research column, the authors outline the importance of nurses being engaged in research and present some different levels of involvement that nurses may assume. A continuum of nursing research involvement includes asking researchable questions, being a savvy consumer of research evidence, finding your own level of research involvement, and aspiring to lead. PMID:21361237

  19. Deregulation of PAX-5 by translocation of the Emu enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma.

    PubMed

    Busslinger, M; Klix, N; Pfeffer, P; Graninger, P G; Kozmik, Z

    1996-06-11

    Analyses of the human PAX-5 locus and of the 5' region of the mouse Pax-5 gene revealed that transcription from two distinct promoters results in splicing of two alternative 5' exons to the common coding sequences of exons 2-10. Transcription from the upstream promoter initiates downstream of a TATA box and occurs predominantly in B-lymphocytes, whereas the TATA-less downstream promoter is active in all Pax-5-expressing tissues. The human PAX-5 gene is located on chromosome 9 in region p13, which is involved in t(9;14)(pl3;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype and in derived large-cell lymphomas. A previous molecular analysis of a t(9;14) breakpoint from a diffuse large-cell lymphoma (KIS-1) demonstrated that the immunoglobulin heavy-chain (IgH) locus on 14q32 was juxtaposed to chromosome 9p13 sequences of unknown function [Ohno, H., Furukawa, T., Fukuhara, S., Zong, S. Q., Kamesaki, H., Shows, T. B., Le Beau, M. M., McKeithan, T. W., Kawakami, T. & Honjo, T. (1990) Proc. Natl. Acad. Sci. USA 87,628-632]. Here we show that the KIS-1 translocation breakpoint is located 1807 base pairs upstream of exon 1A of PAX-5, thus bringing the potent Emu enhancer of the IgH gene into close proximity of the PAX-5 promoters. These data suggest that deregulation of PAX-5 gene transcription by the t(9;14)(pl3;q32) translocation contributes to the pathogenesis of small lymphocytic lymphomas with plasmacytoid differentiation. PMID:8650231

  20. MicroRNAs Involved in Anti-Tumour Immunity

    PubMed Central

    Yu, Hong W. H.; Sze, Daniel M. Y.; Cho, William C. S.

    2013-01-01

    MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a number of cancers. miRNAs have been found to participate in cell transformation and multiplication by acting as tumour oncogenes or suppressors; therefore, harnessing miRNAs may provide promising cancer therapeutics. Another major function of miRNAs is their activity as critical regulatory vehicles eliciting important regulatory processes in anti-tumour immunity through their influence on the development, differentiation and activation of various immune cells of both innate and adaptive immunity. This review aims to summarise recent findings focusing on the regulatory mechanisms of the development, differentiation, and proliferative aspects of the major immune populations by a diverse profile of miRNAs and may enrich our current understanding of the involvement of miRNAs in anti-tumour immunity. PMID:23478435

  1. Promoting vital involvement.

    PubMed

    Kivnick, Helen Q; Stoffel, Sharon A

    2002-09-01

    Health care for the elderly generally focuses on health problems. This approach ignores the strengths and resources that maximize a person's autonomy, integrity, and ability to make contributions to society; and it exacerbates poor health. Vital involvement practice (VIP) is an approach to caring for the elderly that emphasizes an individual's capabilities by exploring factors both internal and external to the individual. VIP is identified as a model for health care providers that will improve the health and quality of life of elderly patients. PMID:12387120

  2. Endocannabinoid involvement in endometriosis

    PubMed Central

    Dmitrieva, Natalia; Nagabukuro, Hiroshi; Resuehr, David; Zhang, Guohua; McAllister, Stacy L.; McGinty, Kristina A.; Mackie, Ken; Berkley, Karen J.

    2010-01-01

    Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain. Here, using a rat model, we found that CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis’s abnormal growths. We further found that CB1 receptor agonists decrease, whereas CB1 receptor antagonists increase, endometriosis-associated hyperalgesia. Together these findings suggest that the endocannabinoid system contributes to mechanisms underlying both the peripheral innervation of the abnormal growths and the pain associated with endometriosis, thereby providing a novel approach for the development of badly-needed new treatments. PMID:20833475

  3. Deregulation of the California electric power industry: An analysis of electric and natural gas corporate mergers and their effect on the California electric power market

    NASA Astrophysics Data System (ADS)

    Hornbuckle, James Dixon

    Deregulation of the electric utility industry in California is moving in a direction that places greater reliance on the market forces of competition. Investor owned utilities (IOU's) are using mergers and acquisitions to improve their ability to compete in this new environment. Two large mergers were proposed in 1996 that could affect the California market. The first is between Enron Corporation, a large power marketer and Portland General Corporation, owner of Portland General Electric. The second is between Pacific Enterprises Inc., owner of Southern California Gas Company, the largest natural gas utility in the U. S., and Enova Corporation, owner of San Diego Gas and Electric Company. Understanding the impact of these mergers on the California electric power market is the focus of this study. This study examines hypotheses dealing with: (1) Merger Strategy, (2) Efficiency, and (3) Market Power. Using the Miles and Snow (1978) typology, I develop a strategic orientation model for the merger participants and their competitors. The results suggest a two-stage strategic orientation: (1) regulated core business stage, where the firms follow a Defender strategy, and (2) unregulated business stage, where the firms follow a Prospector strategy. Further, the results show the mergers are consistent with the strategy of Enron and Pacific Enterprises. Event study methodology, dollar gains/losses and market value weighted returns are used to determine if the mergers support the efficiency hypothesis. The evidence suggests the mergers lead to increased competitive advantage through improved efficiency for the participants. The results also suggest the mergers do not harm the rivals. The results of structural changes made by the California Public Utilities Commission (CPUC) in deregulation of the California market and analysis of the mergers by the CPUC and the Public Utility Commission of Oregon suggest that the exercise of market power is not a significant issue. Finally

  4. A negative element involved in Kaposi's sarcoma-associated herpesvirus-encoded ORF11 gene expression

    SciTech Connect

    Chen, Lei

    2009-01-01

    The ORF11 of the Kaposi's sarcoma-associated herpesvirus (KSHV) is a lytic viral gene with delayed-early expression kinetics. How the ORF11 gene expression is regulated in the KSHV lytic cascade is largely unknown. Here we report that the deletion of the KSHV viral IL-6 gene from the viral genome leads to deregulated ORF11 gene expression. The KSHV-encoded viral IL-6 protein was found not to be essentially involved in the regulation of ORF11, suggesting a potential transcriptional cis-regulation. A negative element was identified downstream of the ORF11 gene, which suppresses the ORF11 basal promoter activity in a position-independent manner.

  5. The IgG Fc receptor, FcγRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma

    PubMed Central

    Callanan, Mary B.; Le Baccon, Patricia; Mossuz, Pascal; Duley, Samuel; Bastard, Christian; Hamoudi, Rifat; Dyer, Martin J.; Klobeck, Gustav; Rimokh, Ruth; Sotto, Jean Jacques; Leroux, Dominique

    2000-01-01

    Rearrangement of chromosomal bands 1q21–23 is one of the most frequent chromosomal aberrations observed in hematological malignancy. The genes affected by these rearrangements remain poorly characterized. Typically, 1q21–23 rearrangements arise during tumor evolution and accompany disease-specific chromosomal rearrangements such as t(14;18) (BCL2) and t(8;14) (MYC), where they are thus thought to play an important role in tumor progression. The pathogenetic basis of this 1q21–23-associated disease progression is currently unknown. In this setting, we surveyed our series of follicular lymphoma for evidence of recurring 1q21–23 breaks and identified three cases in which a t(14;18)(q32;q21) was accompanied by a novel balanced t(1;22)(q22;q11). Molecular cloning of the t(1;22) in a cell line (B593) derived from one of these cases and detailed fluorescent in situ hybridization mapping in the two remaining cases identified the FCGR2B gene, which encodes the immunoreceptor tyrosine-based inhibition motif-bearing IgG Fc receptor, FcγRIIB, as the target gene of the t(1;22)(q22;q11). We demonstrate deregulation of FCGR2B leading to hyperexpression of FcγRIIb2 as the principal consequence of the t(1;22). This is evidence that IgG Fc receptors can be targets for deregulation through chromosomal translocation in lymphoma. It suggests that dysregulation of FCGR2B may play a role in tumor progression in follicular lymphoma. PMID:10618414

  6. Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel–Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects

    PubMed Central

    Abdelhamed, Zakia A.; Wheway, Gabrielle; Szymanska, Katarzyna; Natarajan, Subaashini; Toomes, Carmel; Inglehearn, Chris; Johnson, Colin A.

    2013-01-01

    The ciliopathies are a group of heterogeneous diseases with considerable variations in phenotype for allelic conditions such as Meckel–Gruber syndrome (MKS) and Joubert syndrome (JBTS) even at the inter-individual level within families. In humans, mutations in TMEM67 (also known as MKS3) cause both MKS and JBTS, with TMEM67 encoding the orphan receptor meckelin (TMEM67) that localizes to the ciliary transition zone. We now describe the Tmem67tm1(Dgen/H) knockout mouse model that recapitulates the brain phenotypic variability of these human ciliopathies, with categorization of Tmem67 mutant animals into two phenotypic groups. An MKS-like incipient congenic group (F6 to F10) manifested very variable neurological features (including exencephaly, and frontal/occipital encephalocele) that were associated with the loss of primary cilia, diminished Shh signalling and dorsalization of the caudal neural tube. The ‘MKS-like’ group also had high de-regulated canonical Wnt/β-catenin signalling associated with hyper-activated Dishevelled-1 (Dvl-1) localized to the basal body. Conversely, a second fully congenic group (F > 10) had less variable features pathognomonic for JBTS (including cerebellar hypoplasia), and retention of abnormal bulbous cilia associated with mild neural tube ventralization. The ‘JBTS-like’ group had de-regulated low levels of canonical Wnt signalling associated with the loss of Dvl-1 localization to the basal body. Our results suggest that modifier alleles partially determine the variation between MKS and JBTS, implicating the interaction between Dvl-1 and meckelin, or other components of the ciliary transition zone. The Tmem67tm1(Dgen/H) line is unique in modelling the variable expressivity of phenotypes in these two ciliopathies. PMID:23283079

  7. Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer’s disease

    PubMed Central

    2014-01-01

    Background The accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer’s disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling. Results Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P. Conclusions Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor. PMID:24468113

  8. The expression of miR-21 and miR-143 is deregulated by the HPV16 E7 oncoprotein and 17β-estradiol.

    PubMed

    Gómez-Gómez, Yazmín; Organista-Nava, Jorge; Ocadiz-Delgado, Rodolfo; García-Villa, Enrique; Leyva-Vazquez, Marco Antonio; Illades-Aguiar, Berenice; Lambert, Paul F; García-Carrancá, Alejandro; Gariglio, Patricio

    2016-08-01

    MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively regulate their target mRNAs at a posttranscriptional level, thereby affecting crucial processes in cancer development. However, little is known about the molecular events that control expression of miRNAs in cervical cancer (CC). HPV16 E7 oncoprotein in conjunction with estrogen are sufficient to produce high grade cervical dysplasia and invasive cervical malignancies in a mouse model. In the present study, we determined the potential role that the E7 oncoprotein and 17β-estradiol (E2) play in the deregulation of miR-21 and miR-143 expression levels by these two risk factors. We found that, while the expression of miR-21 was upregulated and the expression of miR-143 was downregulated by the HPV16 E7 oncoprotein in vivo, and in vitro and that E2 treatment is also implicated in the deregulation of these important miRNAs in vivo. Sustained upregulation of miR-21 resulted in suppression of PTEN expression, and repression of miR-143 increased the mRNA and protein levels from Bcl-2. These results suggested that HPV type 16 E7 oncoprotein and E2 play an important role in regulating miR-21 and miR-143 expression. We have observed similar results in CC patients containing HPV16 sequences, suggesting that these miRNAs could serve as diagnostic biomarkers in CC. The present study highlights the roles of miRNAs in cervical tissue and implicates these important molecules in cervical carcinogenesis. PMID:27278606

  9. Correlation Network Analysis Reveals Relationships between MicroRNAs, Transcription Factor T-bet, and Deregulated Cytokine/Chemokine-Receptor Network in Pulmonary Sarcoidosis

    PubMed Central

    Dyskova, Tereza; Fillerova, Regina; Novosad, Tomas; Kudelka, Milos; Zurkova, Monika; Gajdos, Petr; Kolek, Vitezslav; Kriegova, Eva

    2015-01-01

    Sarcoidosis is an inflammatory granulomatous disease with unknown etiology driven by cytokines and chemokines. There is limited information regarding the regulation of cytokine/chemokine-receptor network in bronchoalveolar lavage (BAL) cells in pulmonary sarcoidosis, suggesting contribution of miRNAs and transcription factors. We therefore investigated gene expression of 25 inflammation-related miRNAs, 27 cytokines/chemokines/receptors, and a Th1-transcription factor T-bet in unseparated BAL cells obtained from 48 sarcoidosis patients and 14 control subjects using quantitative RT-PCR. We then examined both miRNA-mRNA expressions to enrich relevant relationships. This first study on miRNAs in sarcoid BAL cells detected deregulation of miR-146a, miR-150, miR-202, miR-204, and miR-222 expression comparing to controls. Subanalysis revealed higher number of miR-155, let-7c transcripts in progressing (n = 20) comparing to regressing (n = 28) disease as assessed by 2-year follow-up. Correlation network analysis revealed relationships between microRNAs, transcription factor T-bet, and deregulated cytokine/chemokine-receptor network in sarcoid BAL cells. Furthermore, T-bet showed more pronounced regulatory capability to sarcoidosis-associated cytokines/chemokines/receptors than miRNAs, which may function rather as “fine-tuners” of cytokine/chemokine expression. Our correlation network study implies contribution of both microRNAs and Th1-transcription factor T-bet to the regulation of cytokine/chemokine-receptor network in BAL cells in sarcoidosis. Functional studies are needed to confirm biological relevance of the obtained relationships. PMID:26696750

  10. Cardiac involvement in hemochromatosis.

    PubMed

    Gulati, Vinay; Harikrishnan, Prakash; Palaniswamy, Chandrasekar; Aronow, Wilbert S; Jain, Diwakar; Frishman, William H

    2014-01-01

    Cardiac hemochromatosis or primary iron-overload cardiomyopathy is an important and potentially preventable cause of heart failure. This is initially characterized by diastolic dysfunction and arrhythmias and in later stages by dilated cardiomyopathy. Diagnosis of iron overload is established by elevated transferrin saturation (>55%) and elevated serum ferritin (>300 ng/mL). Genetic testing for mutations in the HFE (high iron) gene and other proteins, such as hemojuvelin, transferrin receptor, and ferroportin, should be performed if secondary causes of iron overload are ruled out. Patients should undergo comprehensive 2D and Doppler echocardiography to evaluate their systolic and diastolic function. Newer modalities like strain imaging and speckle-tracking echocardiography hold promise for earlier detection of cardiac involvement. Cardiac magnetic resonance imaging with measurement of T2* relaxation times can help quantify myocardial iron overload. In addition to its value in diagnosis of cardiac iron overload, response to iron reduction therapy can be assessed by serial imaging. Therapeutic phlebotomy and iron chelation are the cornerstones of therapy. The average survival is less than a year in untreated patients with severe cardiac impairment. However, if treated early and aggressively, the survival rate approaches that of the regular heart failure population. PMID:24503941

  11. Applying Employee Involvement in Schools.

    ERIC Educational Resources Information Center

    Mohrman, Susan Albers; And Others

    1992-01-01

    The applicability of employee-involvement approaches to the management of schools is explored, describing three approaches (parallel-suggestion involvement, job involvement, and high involvement). Design issues (technology; organizational structure; leadership; organizational boundaries, customer definition, and relation to stakeholder; measures;…

  12. Multidrug toxicity involving sumatriptan.

    PubMed

    Knittel, Jessica L; Vorce, Shawn P; Levine, Barry; Hughes, Rhome L; Bosy, Thomas Z

    2015-01-01

    A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident. PMID:25324526

  13. Nigral involvement in atypical parkinsonisms: evidence from a pilot study with ultra-high field MRI.

    PubMed

    Frosini, Daniela; Ceravolo, Roberto; Tosetti, Michela; Bonuccelli, Ubaldo; Cosottini, Mirco

    2016-05-01

    Ten healthy subjects (HS) and 15 patients with atypical parkinsonisms underwent 7-T susceptibility-weighted-imaging MR to evaluate substantia nigra (SN). All HS were judged "normal". Twelve out of 15 patients exhibited bilateral abnormal SN while three patients with corticobasal degeneration (CBD) showed bilateral normal aspect of SN. Anatomical changes of SN at 7 T occur in multiple system atrophy and progressive supranuclear palsy as previously reported in Parkinson's disease. Preserved SN in CBD confirms the pathological heterogeneity of this disease. PMID:26943945

  14. Foundation for PSP/CBD and Related Brain Diseases

    MedlinePlus

    ... for CurePSP without even having to leave your computer! Take a minute and sign up for Goodsearch ... We also coordinate online groups that meet via computer or telephone - all you have to do is ...

  15. The Principal and Community Involvement.

    ERIC Educational Resources Information Center

    Carnes, Leslie L.

    1983-01-01

    Describes an effective community education program for Pearl High School in Nashville (TN) that involved the consideration of five factors (community involvement, personal needs, organizational needs, perceptions, and expectations) in a successful effort to unify the school. (SB)

  16. Regulatory trends involving pumps and valves

    SciTech Connect

    Thadani, A.C.

    1996-12-01

    The long-standing inservice testing program is well established, but there are a number of activities that are creating dynamics in the program that could change the way it is developed and implemented by licensees: (1) the move toward risk-informed and performance-based regulation, (2) proposed changes to the governing regulations, and (3) the Maintenance Rule. Underlying all of the activities is the imminent deregulation of the electric utility industry of which everyone must be aware, but for which one cannot sacrifice safety for costs. The author discusses some of these factors in light of the changing environment.

  17. Families Get Involved! Learning Partners.

    ERIC Educational Resources Information Center

    Office of Educational Research and Improvement (ED), Washington, DC. Media and Information Services.

    Noting that families who are involved in their children's education make a difference in their child's performance, this two-page information sheet encourages families to get involved by listing the benefits of family involvement on one side and the ways adult family members can help in the school on the other. As a result of family participation:…

  18. Measuring Involvement with Social Issues.

    ERIC Educational Resources Information Center

    Nowak, Glen J.; Salmon, Charles T.

    A study applied research concepts from consumer product involvement to test a model for research on involvement with social issues. Issue involvement was defined as the state or level of perceived importance and/or interest evoked by a stimulus (issue) within a specific situation. Attitudes on four social issues--abortion, pornography, the…

  19. Temperature-dependent electrical characteristics of CBD/CBD grown n-ZnO nanowire/p-Si heterojunction diodes

    NASA Astrophysics Data System (ADS)

    Das, Avishek; Kushwaha, Ajay; Kajen Sivasayan, Rasanayagam; Chakraborty, Sandipan; Sekhar Dutta, Himadri; Karmakar, Anupam; Chattopadhyay, Sanatan; Chi, Dongzhi; Dalapati, Goutam Kumar

    2016-04-01

    Heterojunction diodes are fabricated using a low-temperature chemical bath deposition of oriented and crystalline ZnO nanowires on a  <1 1 1>  p-silicon substrate. The electrical transport properties of the heterojunction are investigated at various temperatures by measuring current-voltage (I-V) characteristics in the range of 90-390 K. A thermionic emission (TE) model is used to analyze the transport behavior. The deviation in the experimental value of Richardson’s constant for ZnO nanowires is obtained from I-V-T measurement. The temperature dependence of the effective barrier height and ideality factor is attributed to the inhomogeneous barrier height distribution at the n-ZnO NW/p-Si hetero-interface. The TE and barrier inhomogeneity model are simultaneously used to extract the appropriate value of the Richardson’s constants in three different temperature regions. Linear fittings for three different temperature regions suggest multiple Gaussian distributions of barrier heights at the junction.

  20. Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion.

    PubMed

    Wang, Huabo; Sharma, Lokendra; Lu, Jie; Finch, Paul; Fletcher, Steven; Prochownik, Edward V

    2015-06-30

    The c-Myc (Myc) oncoprotein is deregulated in a large proportion of diverse human cancers. Considerable effort has therefore been directed at identifying pharmacologic inhibitors as potential anti-neoplastic agents. Three such groups of small molecule inhibitors have been described. The first is comprised of so-called "direct" inhibitors, which perturb Myc's ability to form productive DNA-binding heterodimers in association with its partner, Max. The second group is comprised of indirect inhibitors, which largely function by targeting the BET-domain protein BRD4 to prevent the proper formation of transcriptional complexes that assemble in response to Myc-Max DNA binding. Thirdly, synthetic lethal inhibitors cause the selective apoptosis of Myc over-expressing either by promoting mitotic catastrophe or altering Myc protein stability. We report here a common mechanism by which all Myc inhibitors, irrespective of class, lead to eventual cellular demise. This involves the depletion of ATP stores due to mitochondrial dysfunction and the eventual down-regulation of Myc protein. The accompanying metabolic de-regulation causes neutral lipid accumulation, cell cycle arrest, and an attempt to rectify the ATP deficit by up-regulating AMP-activated protein kinase (AMPK). These responses are ultimately futile due to the lack of functional Myc to support the requisite anabolic response. Finally, the effects of Myc depletion on ATP levels, cell cycle arrest, differentiation and AMPK activation can be mimicked by pharmacologic inhibition of the mitochondrial electron transport chain without affecting Myc levels. Thus, all Myc inhibitors promote a global energy collapse that appears to underlie many of their phenotypic consequences. PMID:26036281

  1. Deregulated E2F5/p38/SMAD3 Circuitry Reinforces the Pro-Tumorigenic Switch of TGFβ Signaling in Prostate Cancer.

    PubMed

    Majumder, Subhadipa; Bhowal, Ankur; Basu, Sanmitra; Mukherjee, Pritha; Chatterji, Urmi; Sengupta, Sanghamitra

    2016-11-01

    Transforming growth factor-β signaling exerts divergent effects on normal and cancer cells, although mechanism underlying this differential behavior remains unclear. In this study, expression of 94 genes pertaining to the TGF-β signaling pathway was compared between tumor and benign tissue samples from the human prostate gland to identify major discriminators driving prostate carcinogenesis. E2F5 was identified as one of the most deregulated genes in prostate cancer tissues, predominantly in samples with Gleason-score 6. Expression of other deregulated components of TGF-β signaling was examined by qRT-PCR, Western blot, and immune-staining. Function of E2F5 and p38 in prostate cancer was investigated using siRNA-treatment of PC3 cell-line followed by analyses of associated components and cell cycle. Observations revealed that E2F5 overexpression was accompanied by significantly higher phosphorylation of SMAD3 at Ser-208 in the linker region (pSMAD3L) and p38 in tumor tissue. A striking difference in SMAD3 phosphorylation, marked by preponderance of pSMAD3L and pSMAD3C (Ser-423 and 425) in tumor and benign tissues, respectively was noted. Co-localization of E2F5 with pSMAD3L in the nuclei of tumor and PC3 cells indicated a functional interface between the proteins. Downregulation of E2F5 and p38 in PC3 cells resulted in marked reduction of phosphorylation of SMAD3 and perturbation of cell cycle with an arrest of cells in G1 . Our findings unearthed that E2F5/p38 axis played a cardinal role in uncontrolled cellular proliferation in prostate cancer through pSMAD3L activation. It also underscores a strong potential for E2F5 to be incorporated as a tool in early detection of prostate cancer. J. Cell. Physiol. 231: 2482-2492, 2016. © 2016 Wiley Periodicals, Inc. PMID:26919443

  2. Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3.

    PubMed

    Wang, Hai-Qiang; Yu, Xiao-Dong; Liu, Zhi-Heng; Cheng, Xin; Samartzis, Dino; Jia, Lin-Tao; Wu, Sheng-Xi; Huang, Jing; Chen, Jing; Luo, Zhuo-Jing

    2011-10-01

    The role of apoptosis in the pathogenesis of intervertebral disc degeneration (IDD) remains enigmatic. Accumulating evidence has shown that the apoptotic machinery is regulated by miRNAs. We hypothesized that miRNAs might contribute to apoptosis in IDD. We have found that 29 miRNAs were differentially expressed and miR-155 was down-regulated in degenerative nucleus pulposus (NP). The deregulation of miR-155 was further verified using real-time PCR (0.56 fold, p < 0.05). Bioinformatics target prediction identified FADD and caspase-3 as putative targets of miR-155. Furthermore, miR-155 inhibited FADD and caspase-3 expression by directly targeting their 3'-UTRs, which was abolished by mutation of the miR-155 binding sites. In vitro up-regulation of miR-155 in human NP cells by transfection with lentiviral pre-miR-155 resulted in repression of FADD and caspase-3; whereas knockdown of miR-155 with lentiviral antigomiR-155 led to over-expression of FADD and caspase-3. Also, Fas-mediated apoptosis was increased when antagonizing miR-155 and decreased when using pre-miR-155 in human NP cells. In addition, we presented direct evidence of NP cells undergoing apoptosis in IDD tissues using transmission electron microscopy analysis. Moreover, a combination of in situ hybridization (ISH) and immunohistochemistry (IHC) revealed that miR-155 expressed in the cytoplasm of human NP cells with reverse correlation with FADD and caspase-3. In summary, this is the first study addressing the underlying mechanisms of IDD in terms of apoptosis and miRNAs. Furthermore, caspase-3 is identified as a novel target of miR-155. Our results suggest that deregulated miR-155 promotes Fas-mediated apoptosis in human IDD by targeting FADD and caspase-3, implicating an aetiological and therapeutic role of miR-155 in IDD. PMID:21706480

  3. Deregulation of the circadian clock constitutes a significant factor in tumorigenesis: a clockwork cancer. Part I: clocks and clocking machinery

    PubMed Central

    Uth, Kristin; Sleigh, Roger

    2014-01-01

    Many physiological processes occur in a rhythmic fashion, consistent with a 24-h cycle. The central timing of the day/night rhythm is set by a master clock, located in the suprachiasmatic nucleus (a tiny region in the hypothalamus), but peripheral clocks exist in different tissues, adjustable by cues other than light (temperature, food, hormone stimulation, etc.), functioning autonomously to the master clock. Presence of unrepaired DNA damage may adjust the circadian clock so that the phase in which checking for damage and DNA repair normally occurs is advanced or extended. The expression of many of the genes coding for proteins functioning in DNA damage-associated response pathways and DNA repair is directly or indirectly regulated by the core clock proteins. Setting up the normal rhythm of the circadian cycle also involves oscillating changes in the chromatin structure, allowing differential activation of various chromatin domains within the 24-h cycle. PMID:26019503

  4. Altered Signaling in the G1 Phase Deregulates Chondrocyte Growth in a Mouse Model With Proteoglycan Undersulfation

    PubMed Central

    Leonardis, Fabio De; Monti, Luca; Gualeni, Benedetta; Tenni, Ruggero; Forlino, Antonella; Rossi, Antonio

    2014-01-01

    In several skeletal dysplasias defects in extracellular matrix molecules affect not only the structural and mechanical properties of cartilage, but also the complex network of signaling pathways involved in cell proliferation and differentiation. Sulfated proteoglycans, besides playing an important structural role in cartilage, are crucial in modulating the transport, diffusion, and interactions of growth factors with their specific targets, taking part in the regulation of signaling pathways involved in skeletal development and growth. In this work, we investigated by real time PCR and Western blots of the microdissected growth plate and by immunohistochemistry the molecular basis of reduced chondrocyte proliferation in the growth plate of the dtd mouse, a chondrodysplastic model with defective chondroitin sulfate proteoglycan sulfation of articular and growth plate cartilage. We detected activation of the Wnt pathway, leading to an increase in the non-phosphorylated form of nuclear β-catenin and subsequent up-regulation of cyclin D1 expression in the G1 phase of the cell cycle. β-Catenin was further stabilized by up-regulation of Smad3 expression through TGF-β pathway synergistic activation. We demonstrate that notwithstanding cyclin D1 expression increase, cell cycle progression is compromised in the G1 phase due to reduced phosphorylation of the pocket protein p130 leading to inhibition of transcription factors of the E2F family which are crucial for cell cycle progression and DNA replication. These data, together with altered Indian hedgehox signaling detected previously, explain at the molecular level the reduced chondrocyte proliferation rate of the dtd growth plate leading to reduced skeletal growth. J. Cell. Biochem. 115: 1779–1786, 2014. PMID:24820054

  5. E2F1 expression is deregulated and plays an oncogenic role in sporadic Burkitt’s lymphoma

    PubMed Central

    Molina-Privado, Irene; Rodríguez-Martínez, María; Rebollo, Patricia; Martín-Pérez, Daniel; Artiga, María-Jesús; Menárguez, Javier; Flemington, Erik K.; Piris, Miguel A.; Campanero, Miguel R.

    2009-01-01

    Current treatments of sBL are associated with severe toxicities. A better understanding of sBL formation would facilitate development of less toxic therapies. The etiology of sporadic Burkitt’s lymphoma (sBL) remains however largely unknown, being C-MYC up-regulation the only lesion known to occur in all sBL cases. Several studies examining the role of C-MYC in the pathogenesis of BL have concluded that C-MYC translocation is not the only critical event and that additional unidentified factors are expected to be involved in the formation of this tumor. We herein report that a gene distinct from C-MYC, E2F1, is involved in the formation of all or most sBL tumors. We found that E2F1 is highly expressed in Burkitt’s lymphoma cell lines and sBL lymphoma specimens. Our data indicate that its elevated expression is not merely the consequence of the presence of more cycling cells in this tumor relative to other cell lines or to other neoplasias. In fact, we show that reduction of its expression in sBL cells inhibits tumor formation and decreases their proliferation rate. We also provide data suggesting that E2F1 collaborates with C-MYC in sBL formation. E2F1 expression down-regulation did not affect, however, proliferation of human primary diploid fibroblasts. Since E2F1 is not needed for cell proliferation of normal cells, our results reveal E2F1 as a promising therapeutic target for sBL. PMID:19406837

  6. Associations of deregulation of mir-365 and its target mRNA TTF-1 and survival in patients with NSCLC

    PubMed Central

    Sun, Ruifang; Liu, Zhigang; Ma, Gang; Lv, Weidong; Zhao, Xinliang; Lei, Guangyan; Xu, Changfu

    2015-01-01

    microRNA (mir)-365 exerts tumor suppressor function by targeting thyroid transcription factor-1 (TTF-1) in lung cancer cells. The purpose of the present study was to assess mir-365 and its target mRNA TTF-1 in lung cancer and their correlations with patients’ survival. Quantitative real-time PCR was used to examine the expression levels of mir-365 and TTF-1 in tumor tissue and its adjacent noncancerous tissue of 126 patients with non-small cell lung cancer (NSCLC). Our results showed that mir-365 was significantly decreased in tumor tissue than that in normal tissue (P=0.006), however, TTF-1 was significantly increased in tumor tissue than in normal tissue (P<0.001). Besides, significant correlations between decreased mir-365 and advanced tumor-node-metastasis (TNM) stage (P=0.001) and regional lymph node involvement (P=0.037) was observed. The similar result was also found between increased TTF-1 and TNM stage (P=0.003). Furthermore, mir-365 downregulation or TTF-1 upregulation were associated with poor outcome of patients than mir-365 upregulation or TTF-1 downregulation (for mir-365: P<0.001; for TTF-1: P=0.002). Of note, combination of decreased mir-365 and increased TTF-1 had worst overall survival (P<0.001). In conclusion, aberrant expression of mir-365/TTF-1 may be involved in the tumor development in patients with NSCLC. Moreover, mir-365 and TTF-1 could jointly predict the prognosis of patients and their combination may serve as a biomarker to predict risk of poor survival in NSCLC patients. Mir-365/TTF-1 might serve as a potential therapeutic target for clinical treatment of NSCLC. PMID:26045746

  7. Involvement of microRNAs in epileptogenesis.

    PubMed

    Cattani, Adriano A; Allene, Camille; Seifert, Volker; Rosenow, Felix; Henshall, David C; Freiman, Thomas M

    2016-07-01

    Patients who have sustained brain injury or had developmental brain lesions present a non-negligible risk for developing delayed epilepsy. Finding therapeutic strategies to prevent development of epilepsy in at-risk patients represents a crucial medical challenge. Noncoding microRNA molecules (miRNAs) are promising candidates in this area. Indeed, deregulation of diverse brain-specific miRNAs has been observed in animal models of epilepsy as well as in patients with epilepsy, mostly in temporal lobe epilepsy (TLE). Herein we review deregulated miRNAs reported in epilepsy with potential roles in key molecular and cellular processes underlying epileptogenesis, namely neuroinflammation, cell proliferation and differentiation, migration, apoptosis, and synaptic remodeling. We provide an up-to-date listing of miRNAs altered in epileptogenesis and assess recent functional studies that have interrogated their role in epilepsy. Last, we discuss potential applications of these findings for the future development of disease-modifying therapeutic strategies for antiepileptogenesis. PMID:27207608

  8. Genomic deregulation of the E2F/Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer.

    PubMed

    Coe, Bradley P; Thu, Kelsie L; Aviel-Ronen, Sarit; Vucic, Emily A; Gazdar, Adi F; Lam, Stephen; Tsao, Ming-Sound; Lam, Wan L

    2013-01-01

    Small cell lung cancer (SCLC) is a highly aggressive lung neoplasm with extremely poor clinical outcomes and no approved targeted treatments. To elucidate the mechanisms responsible for driving the SCLC phenotype in hopes of revealing novel therapeutic targets, we studied copy number and methylation profiles of SCLC. We found disruption of the E2F/Rb pathway was a prominent feature deregulated in 96% of the SCLC samples investigated and was strongly associated with increased expression of EZH2, an oncogene and core member of the polycomb repressive complex 2 (PRC2). Through its catalytic role in the PRC2 complex, EZH2 normally functions to epigenetically silence genes during development, however, it aberrantly silences genes in human cancers. We provide evidence to support that EZH2 is functionally active in SCLC tumours, exerts pro-tumourigenic functions in vitro, and is associated with aberrant methylation profiles of PRC2 target genes indicative of a "stem-cell like" hypermethylator profile in SCLC tumours. Furthermore, lentiviral-mediated knockdown of EZH2 demonstrated a significant reduction in the growth of SCLC cell lines, suggesting EZH2 has a key role in driving SCLC biology. In conclusion, our data confirm the role of EZH2 as a critical oncogene in SCLC, and lend support to the prioritization of EZH2 as a potential therapeutic target in clinical disease. PMID:23967231

  9. Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation.

    PubMed

    Fung, Tsun Ming; Ng, Kai Yu; Tong, Man; Chen, Jin-Na; Chai, Stella; Chan, Kin-Tak; Law, Simon; Lee, Nikki P; Choi, Mei Yuk; Li, Bin; Cheung, Annie L; Tsao, Sai Wah; Qin, Yan-Ru; Guan, Xin-Yuan; Chan, Kwok Wah; Ma, Stephanie

    2016-07-01

    Oesophageal squamous cell carcinoma (ESCC) is the most common histological subtype of oesophageal cancer. The disease is particularly prevalent in southern China. The incidence of the disease is on the rise and its overall survival rate remains dismal. Identification and characterization of better molecular markers for early detection and therapeutic targeting are urgently needed. Here, we report levels of transmembrane and soluble neuropilin-2 (NRP2) to be significantly up-regulated in ESCC, and to correlate positively with advanced tumour stage, lymph node metastasis, less favourable R category and worse overall patient survival. NRP2 up-regulation in ESCC was in part a result of gene amplification at chromosome 2q. NRP2 overexpression promoted clonogenicity, angiogenesis and metastasis in ESCC in vitro, while NRP2 silencing by lentiviral knockdown or neutralizing antibody resulted in a contrary effect. This observation was extended in vivo in animal models of subcutaneous tumourigenicity and tail vein metastasis. Mechanistically, overexpression of NRP2 induced expression of ERK MAP kinase and the transcription factor ETV4, leading to enhanced MMP-2 and MMP-9 activity and, as a consequence, suppression of E-cadherin. In summary, NRP2 promotes tumourigenesis and metastasis in ESCC through deregulation of ERK-MAPK-ETV4-MMP-E-cadherin signalling. NRP2 represents a potential diagnostic or prognostic biomarker and therapeutic target for ESCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27063000

  10. Lamin A deregulation in human mesenchymal stem cells promotes an impairment in their chondrogenic potential and imbalance in their response to oxidative stress.

    PubMed

    Mateos, Jesús; De la Fuente, Alexandre; Lesende-Rodriguez, Iván; Fernández-Pernas, Pablo; Arufe, María C; Blanco, Francisco J

    2013-11-01

    In the present study, we examined the effect of the over-expression of LMNA, or its mutant form progerin (PG), on the mesoderm differentiation potential of mesenchymal stem cells (MSCs) from human umbilical cord (UC) stroma using a recently described differentiation model employing spheroid formation. Accumulation of lamin A (LMNA) was previously associated with the osteoarthritis (OA) chondrocyte phenotype. Mutations of this protein are linked to laminopathies and specifically to Hutchinson-Gilford Progeria Syndrome (HGPS), an accelerated aging disease. Some authors have proposed that a deregulation of LMNA affects the differentiation potential of stem cells. The chondrogenic potential is defective in PG-MSCs, although both PG and LMNA transduced MSCs, have an increase in hypertrophy markers during chondrogenic differentiation. Furthermore, both PG and LMNA-MSCs showed a decrease in manganese superoxide dismutase (MnSODM), an increase of mitochondrial MnSODM-dependent reactive oxygen species (ROS) and alterations in their migration capacity. Finally, defects in chondrogenesis are partially reversed by periodic incubation with ROS-scavenger agent that mimics MnSODM effect. Our results indicate that over-expression of LMNA or PG by lentiviral gene delivery leads to defects in chondrogenic differentiation potential partially due to an imbalance in oxidative stress. PMID:23994728

  11. Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage

    PubMed Central

    Halaby, Marie-Jo; Harris, Benjamin R. E.; Miskimins, W. Keith; Cleary, Margot P.

    2015-01-01

    Synthesis of the p53 tumor suppressor and its subsequent activation following DNA damage are critical for its protection against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) at the 5′ untranslated region of the p53 mRNA. However, the connection between IRES-mediated p53 translation and p53's tumor suppressive function is unknown. In this study, we identified two p53 IRES trans-acting factors, translational control protein 80 (TCP80), and RNA helicase A (RHA), which positively regulate p53 IRES activity. Overexpression of TCP80 and RHA also leads to increased expression and synthesis of p53. Furthermore, we discovered two breast cancer cell lines that retain wild-type p53 but exhibit defective p53 induction and synthesis following DNA damage. The levels of TCP80 and RHA are extremely low in both cell lines, and expression of both proteins is required to significantly increase the p53 IRES activity in these cells. Moreover, we found cancer cells transfected with a shRNA against TCP80 not only exhibit decreased expression of TCP80 and RHA but also display defective p53 induction and diminished ability to induce senescence following DNA damage. Therefore, our findings reveal a novel mechanism of p53 inactivation that links deregulation of IRES-mediated p53 translation with tumorigenesis. PMID:26391949

  12. A Probabilistic Boolean Network Approach for the Analysis of Cancer-Specific Signalling: A Case Study of Deregulated PDGF Signalling in GIST

    PubMed Central

    Wiesinger, Monique; Bahlawane, Christelle; Haan, Serge; Sauter, Thomas

    2016-01-01

    Background Signal transduction networks are increasingly studied with mathematical modelling approaches while each of them is suited for a particular problem. For the contextualisation and analysis of signalling networks with steady-state protein data, we identified probabilistic Boolean network (PBN) as a promising framework which could capture quantitative changes of molecular changes at steady-state with a minimal parameterisation. Results and Conclusion In our case study, we successfully applied the PBN approach to model and analyse the deregulated Platelet-Derived Growth Factor (PDGF) signalling pathway in Gastrointestinal Stromal Tumour (GIST). We experimentally determined a rich and accurate dataset of steady-state profiles of selected downstream kinases of PDGF-receptor-alpha mutants in combination with inhibitor treatments. Applying the tool optPBN, we fitted a literature-derived candidate network model to the training dataset consisting of single perturbation conditions. Model analysis suggested several important crosstalk interactions. The validity of these predictions was further investigated experimentally pointing to relevant ongoing crosstalk from PI3K to MAPK signalling in tumour cells. The refined model was evaluated with a validation dataset comprising multiple perturbation conditions. The model thereby showed excellent performance allowing to quantitatively predict the combinatorial responses from the individual treatment results in this cancer setting. The established optPBN pipeline is also widely applicable to gain a better understanding of other signalling networks at steady-state in a context-specific fashion. PMID:27232499

  13. Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice

    PubMed Central

    Bruscoli, Stefano; Biagioli, Michele; Sorcini, Daniele; Frammartino, Tiziana; Cimino, Monica; Sportoletti, Paolo; Mazzon, Emanuela; Bereshchenko, Oxana

    2015-01-01

    Glucocorticoids (GC) are widely used as antiinflammatory/immunosuppressive drugs and antitumor agents in several types of lymphoma and leukemia. Therapeutic doses of GC induce growth-suppressive and cytotoxic effects on various leukocytes including B cells. Molecular mechanisms of GC action include induction of GC target genes. Glucocorticoid-induced leucine zipper (GILZ) is a rapidly, potently, and invariably GC-induced gene. It mediates a number of GC effects, such as control of cell proliferation, differentiation, and apoptosis. Here we show that deletion of GILZ in mice leads to an accumulation of B lymphocytes in the bone marrow, blood, and lymphoid tissues. Gilz knockout (KO) mice develop a progressive nonlethal B lymphocytosis, with expansion of B220+ cells in the bone marrow and in the periphery, dependent on increased B-cell survival. Decreased B-cell apoptosis in mice lacking GILZ correlates with increased NF-κB transcriptional activity and Bcl-2 expression. B cell–specific gilz KO mice confirmed that the effect of GILZ deletion is B-cell self-intrinsic. These results establish GILZ as an important regulator of B-cell survival and suggest that the deregulation of GILZ expression could be implicated in the pathogenesis of B-cell disorders. PMID:26276664

  14. Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling.

    PubMed

    Kumar, S; Pan, C C; Bloodworth, J C; Nixon, A B; Theuer, C; Hoyt, D G; Lee, N Y

    2014-07-24

    Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell-cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis. PMID:24077288

  15. Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling

    PubMed Central

    Kumar, S; Pan, C C; Bloodworth, J C; Nixon, A B; Theuer, C; Hoyt, D G; Lee, N Y

    2014-01-01

    Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell–cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis. PMID:24077288

  16. Deregulation of the circadian clock constitutes a significant factor in tumorigenesis: a clockwork cancer. Part II. In vivo studies

    PubMed Central

    Uth, Kristin; Sleigh, Roger

    2014-01-01

    The uneventful progression through the cell cycle is closely associated with the rhythm set by the circadian clock machinery, with the S-phase of the cell cycle typically occurring at night. Presence of unrepaired DNA damage may reset the phase of the circadian clock, providing opportunities for damage assessment, repair and/or the induction of pro-apoptotic pathways. The core proteins of the circadian clock regulate directly or indirectly a significant number of genes coding for proteins involved in checkpoint transition, cell proliferation and programmed cell death. Disruption of the circadian rhythm may increase the risk for some multifactorial diseases and conditions, including glucose intolerance, cardiovascular disease and various common cancers. In patients with cancer, chronic circadian misalignment may stimulate the growth of tumours and may modify the outcomes of anticancer therapy. Knowledge about the role of physiological rhythms in human disease may contribute to the field of individualized medicine, specifically, in risk assessment and prognostication of the outcomes in patients with multifactorial disease. PMID:26019524

  17. Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy

    PubMed Central

    Caruso, Nathalie; Herberth, Balàzs; Bartoli, Marc; Puppo, Francesca; Dumonceaux, Julie; Zimmermann, Angela; Denadai, Simon; Lebossé, Marie; Roche, Stephane; Geng, Linda; Magdinier, Frederique; Attarian, Shahram; Bernard, Rafaelle; Maina, Flavio; Levy, Nicolas; Helmbacher, Françoise

    2013-01-01

    Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD. PMID:23785297

  18. Deregulation of Maize C4 Photosynthetic Development in a Mesophyll Cell-Defective Mutant1[C][W][OA

    PubMed Central

    Covshoff, Sarah; Majeran, Wojciech; Liu, Peng; Kolkman, Judith M.; van Wijk, Klaas J.; Brutnell, Thomas P.

    2008-01-01

    During maize (Zea mays) C4 differentiation, mesophyll (M) and bundle sheath (BS) cells accumulate distinct sets of photosynthetic enzymes, with very low photosystem II (PSII) content in BS chloroplasts. Consequently, there is little linear electron transport in the BS and ATP is generated by cyclic electron flow. In contrast, M thylakoids are very similar to those of C3 plants and produce the ATP and NADPH that drive metabolic activities. Regulation of this differentiation process is poorly understood, but involves expression and coordination of nuclear and plastid genomes. Here, we identify a recessive allele of the maize high chlorophyll fluorescence (Hcf136) homolog that in Arabidopsis (Arabidopsis thaliana) functions as a PSII stability or assembly factor located in the thylakoid lumen. Proteome analysis of the thylakoids and electron microscopy reveal that Zmhcf136 lacks PSII complexes and grana thylakoids in M chloroplasts, consistent with the previously defined Arabidopsis function. Interestingly, hcf136 is also defective in processing the full-length psbB-psbT-psbH-petB-petD polycistron specifically in M chloroplasts. To determine whether the loss of PSII in M cells affects C4 differentiation, we performed cell-type-specific transcript analysis of hcf136 and wild-type seedlings. The results indicate that M and BS cells respond uniquely to the loss of PSII, with little overlap in gene expression changes between data sets. These results are discussed in the context of signals that may drive differential gene expression in C4 photosynthesis. PMID:18258693

  19. Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis

    PubMed Central

    Annunziata, Ida; Patterson, Annette; Helton, Danielle; Hu, Huimin; Moshiach, Simon; Gomero, Elida; Nixon, Ralph; d’Azzo, Alessandra

    2013-01-01

    Alzheimer’s disease (AD) belongs to a category of adult neurodegenerative conditions which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of intensive research, but so far no preventive or curative therapy for AD is available and clinical trials have been largely unsuccessful. Here we show that deficiency of the lysosomal sialidase NEU1 leads to the spontaneous occurrence of an AD-like amyloidogenic process in mice. This involves two consecutive events linked to NEU1 loss-of-function – accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein in lysosomes, and extracellular release of Aβ-peptides by excessive lysosomal exocytosis. Furthermore, cerebral injection of NEU1 in an established AD mouse model substantially reduces β-amyloid plaques. Our findings identify an additional pathway for the secretion of Aβ and define NEU1 as a potential therapeutic molecule for AD. PMID:24225533

  20. Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion.

    PubMed

    Tervonen, T A; Belitškin, D; Pant, S M; Englund, J I; Marques, E; Ala-Hongisto, H; Nevalaita, L; Sihto, H; Heikkilä, P; Leidenius, M; Hewitson, K; Ramachandra, M; Moilanen, A; Joensuu, H; Kovanen, P E; Poso, A; Klefström, J

    2016-04-01

    Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination. PMID:26165838

  1. Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.

    PubMed

    Karthikeyan, Swathi; Potter, James J; Geschwind, Jean-Francois; Sur, Surojit; Hamilton, James P; Vogelstein, Bert; Kinzler, Kenneth W; Mezey, Esteban; Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-15

    Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis. PMID:26525850

  2. Parental Involvement in the Classroom

    ERIC Educational Resources Information Center

    Machen, Sandra M.; Wilson, Janell D.; Notar, Charles E.

    2005-01-01

    Improving parental involvement with public schools can improve schools. Parental involvement is highly important for pushing the public school systems to higher standards. Also, research reports that engaging parents in an active role in the school curriculum can open alternative opportunities for children to succeed in academics. This report will…

  3. Parental Involvement and Academic Achievement

    ERIC Educational Resources Information Center

    Goodwin, Sarah Christine

    2015-01-01

    This research study examined the correlation between student achievement and parent's perceptions of their involvement in their child's schooling. Parent participants completed the Parent Involvement Project Parent Questionnaire. Results slightly indicated parents of students with higher level of achievement perceived less demand or invitations…

  4. Involving Families in School Events

    ERIC Educational Resources Information Center

    Barrera, John M.; Warner, Laverne

    2006-01-01

    The relationship of schools to diverse communities demands attention by administrators, teachers, staff members, and volunteers. How well the three constructs mesh depends on the abilities and sensitivities of all constituencies involved. Three components are essential to successful programs that involve families in an educational setting:…

  5. A Handbook for Community Involvement.

    ERIC Educational Resources Information Center

    Georgia State Dept. of Education, Atlanta. Office of Administrative Services.

    To help Georgia school administrators, educators, and community members, this handbook suggests ideas and plans for strengthening school-community relations and increasing community involvement in schools. The first section lays out the four steps district administrators should take in developing a systemwide community involvement program,…

  6. Parent Involvement: The Critical Link.

    ERIC Educational Resources Information Center

    Oregon State Dept. of Education, Salem.

    Parent involvement in a child's education consists of schools and parents working together to achieve maximum educational growth for their children. Parents are the critical link between their children and school, and research demonstrates that parent attitudes and behavior influence children's school achievement. Parent involvement occurs when…

  7. Preparing Teachers for Parent Involvement.

    ERIC Educational Resources Information Center

    Safran, Daniel

    This paper examines the potential impact of parent involvement in the formal education of their children and suggests ways that teacher education can be restructured to prepare teachers to work with parents. This paper attempts to answer five questions: (1) Why should parents be involved in the formal education of their children? (2) Why should…

  8. Transcriptional deregulation in hereditary disorders and cancer: the 12th annual CABM symposium, October 21-22, 1998, Piscataway, NJ.

    PubMed

    Rabson, A B

    1999-07-29

    As can be seen from the above descriptions, the presentations at the CABM symposium provided an extraordinarily rich and diverse panorama of some of the most exciting science in current molecular biology. The presentations provided both a general overview and a detailed analysis of multiple biological systems, which despite their specific differences, also generated insights into important common themes. The success of any meeting is most appropriately measured by the kinds of questions that are provoked for future study, not merely by the recitation of past discoveries. In fact, the different presentations often raised highly similar questions for future study. At the most fundamental levels of transcriptional regulation, what are the signals that provide specificity of gene expression? What is the structural basis of specific protein-protein interactions, such as those between homeodomain proteins and beta-catenin-Lef1 interactions, and how are these determinants altered in transcriptional regulation in oncogenesis and in genetic diseases? How is specificity achieved in transcriptional repression, given that the fundamental biochemical reactions often involve modifications of relatively ubiquitous components such as histones? To what extent do changes in specificity of gene activation and repression or in chromosomal architecture mediate the kinds of developmental and oncogenic signals mediated through transcriptional regulators such as Myc, BCL6 and other basic helix-loop-helix proteins and the HMGI proteins? How do altered signaling pathways affect diseases of development and differentiation such as cardiovascular disorders and aging itself? What are the pathways that integrate extracellular signals and transcription during the process of organogenesis? How do fundamental cellular structures such as adhesion junctions, and the interactions of a cell with other cells and extracellular matrix impact on normal and abnormal development and on malignancy, and how do

  9. Gangliogliomas involving the optic chiasm.

    PubMed

    Liu, G T; Galetta, S L; Rorke, L B; Bilaniuk, L T; Vojta, D D; Molloy, P T; Phillips, P C; Needle, M; Duhaime, A C; Sutton, L N; Volpe, N J

    1996-06-01

    We report three patients with gangliogliomas involving the optic chiasm via distinct mechanisms. The ganglioglioma in one patient likely originated in the temporal lobe and spread medially to involve the chiasm, and diffuse spinal cord dissemination also occurred. Chiasmal involvement in this manner and dissemination at presentation are unusual for gangliogliomas. The tumor in a second patient was intrinsic to the hypothalmus and chiasm, while in the third patient, it involved both optic tracts, and a cyst compressed the chiasm laterally. Two patients developed severe bilateral visual loss, while the other had a stable bitemporal hemianopsia. Two patients received radiotherapy, but one continued to lose vision. Although gangliogliomas rarely involve chiasm, the mechanisms by which they produce chiasmal visual loss may be diverse, and the long-term visual prognosis is variable. PMID:8649567

  10. MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia

    PubMed Central

    2010-01-01

    Background Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). Over time, however, virtually all CLL patients become fludarabine-refractory. To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria. Results By comparing the expression profiles of these two groups of patients, we identified a microRNA signature able to distinguish refractory from sensitive CLLs. The expression of some microRNAs was also able to predict fludarabine resistance of 12 independent CLL patients. Among the identified microRNAs, miR-148a, miR-222 and miR-21 exhibited a significantly higher expression in non-responder patients either before and after fludarabine treatment. After performing messenger RNA expression profile of the same patients, the activation of p53-responsive genes was detected in fludarabine responsive cases only, therefore suggesting a possible mechanism linked to microRNA deregulation in non-responder patients. Importantly, inhibition of miR-21 and miR-222 by anti-miRNA oligonucleotides induced a significant increase in caspase activity in fludarabine-treated p53-mutant MEG-01 cells, suggesting that miR-21 and miR-222 up-regulation may be involved in the establishment of fludarabine resistance. Conclusions This is the first report that reveals the existence of a microRNA profile that differentiate refractory and sensitive CLLs, either before and after fludarabine mono-therapy. A p53 dysfunctional pathway emerged in refractory CLLs and could contribute in explaining the observed miRNA profile. Moreover, this work indicates that specific microRNAs can be used to predict fludarabine resistance and may potentially be used as therapeutic targets, therefore establishing an important

  11. [Physiology and molecular biology of extracellular peroxidases, H{sub 2}O{sub 2}-generating system and deregulated mutants of Phanerochaete chrysosporium]. Progress report

    SciTech Connect

    Not Available

    1992-07-01

    We have expanded the work on the LIP genes to Trametes versicolor, the second most studied white-rot fungus after P. chrysosporium. Six LIP genes have been cloned from this organism and one of these has been completely sequenced and compared to the known LIP genes that have been described to date. Our studies gave us further insights into the novel non-integrative transformation system of P. chrysosporium. Our recombinant plasmid pUGLGl-kan, which contains a LIP gene disrupted by the insertion of kan{sup r} determinant, also failed to integrate into the chromosome. Instead, it was maintained as a circular extrachromosomal element and was recoverable as a plasmid both from the meiotic and mitotic progeny. Basic characterization of the lignin peroxidase-negative mutant (lip mutant) and nitrogen-deregulated mutant has been completed. We also investigated the question whether carbon, nitrogen, and Mn(II) regulate LIP expression coordinately or independently. Results indicate that these three environmental controls independently regulate LIP and MNP gene expression. Furthermore, an idiophasic protease has been shown to be responsible for the sharp decline in LIP activity after day 6 of incubation in low nitrogen cultures and addition of glucose to these day 6 cultures has been shown to suppress the protease levels and maintain high levels of LIP. The results further indicated that this protease is synthesized de novo during the idiophase. Additional studies showed that MNPs play a dominant role in the decolorization of chlorolignols in bleached kraft pulp effluents and that LIPs play a relatively minor role in this process. These studies have since been confirmed independently by an Austrian group.

  12. (Physiology and molecular biology of extracellular peroxidases, H sub 2 O sub 2 -generating system and deregulated mutants of Phanerochaete chrysosporium)

    SciTech Connect

    Not Available

    1992-01-01

    We have expanded the work on the LIP genes to Trametes versicolor, the second most studied white-rot fungus after P. chrysosporium. Six LIP genes have been cloned from this organism and one of these has been completely sequenced and compared to the known LIP genes that have been described to date. Our studies gave us further insights into the novel non-integrative transformation system of P. chrysosporium. Our recombinant plasmid pUGLGl-kan, which contains a LIP gene disrupted by the insertion of kan{sup r} determinant, also failed to integrate into the chromosome. Instead, it was maintained as a circular extrachromosomal element and was recoverable as a plasmid both from the meiotic and mitotic progeny. Basic characterization of the lignin peroxidase-negative mutant (lip mutant) and nitrogen-deregulated mutant has been completed. We also investigated the question whether carbon, nitrogen, and Mn(II) regulate LIP expression coordinately or independently. Results indicate that these three environmental controls independently regulate LIP and MNP gene expression. Furthermore, an idiophasic protease has been shown to be responsible for the sharp decline in LIP activity after day 6 of incubation in low nitrogen cultures and addition of glucose to these day 6 cultures has been shown to suppress the protease levels and maintain high levels of LIP. The results further indicated that this protease is synthesized de novo during the idiophase. Additional studies showed that MNPs play a dominant role in the decolorization of chlorolignols in bleached kraft pulp effluents and that LIPs play a relatively minor role in this process. These studies have since been confirmed independently by an Austrian group.

  13. Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression

    PubMed Central

    2011-01-01

    Background As cell-free circulating DNA exists predominantly as mono- and oligonucleosomes, the focus of the current study was to examine the interplay of circulating nucleosomes, DNA, proteases and caspases in blood of patients with benign and malignant breast diseases. Methods The concentrations of cell-free DNA and nucleosomes as well as the protease and caspase activities were measured in serum of patients with benign breast disease (n = 20), primary breast cancer (M0, n = 31), metastatic breast cancer (M1, n = 32), and healthy individuals (n = 28) by PicoGreen, Cell Death Detection ELISA, Protease Fluorescent Detection Kit and Caspase-Glo®3/7 Assay, respectively. Results Patients with benign and malignant tumors had significantly higher levels of circulating nucleic acids in their blood than healthy individuals (p = 0.001, p = 0.0001), whereas these levels could not discriminate between benign and malignant lesions. Our analyses of all serum samples revealed significant correlations of circulating nucleosome with DNA concentrations (p = 0.001), nucleosome concentrations with caspase activities (p = 0.008), and caspase with protease activities (p = 0.0001). High serum levels of protease and caspase activities associated with advanced tumor stages (p = 0.009). Patients with lymph node-positive breast cancer had significantly higher nucleosome levels in their blood than node-negative patients (p = 0.004). The presence of distant metastases associated with a significant increase in serum nucleosome (p = 0.01) and DNA levels (p = 0.04), and protease activities (p = 0.008). Conclusion Our findings demonstrate that high circulating nucleic acid concentrations in blood are no indicators of a malignant breast tumor. However, the observed changes in apoptosis-related deregulation of proteolytic activities along with the elevated serum levels of nucleosomes and DNA in blood are linked to breast cancer progression. PMID:21211028

  14. PRAS40 deregulates apoptosis in Ewing sarcoma family tumors by enhancing the insulin receptor/Akt and mTOR signaling pathways

    PubMed Central

    Lv, Dan; Liu, Jinye; Guo, Lianying; Wu, Dawei; Matsumoto, Ken; Huang, Lin

    2016-01-01

    EWS expression in Ewing sarcoma family tumors (ESFTs) is decreased due to the haploinsufficiency elicited by chromosomal translocation. The abnormal expression levels of EWS and its downstream factors contribute to the manifestation of ESFTs. Previously, we reported that increased Proline-rich Akt substrate of 40 kDa (PRAS40), which is encoded by an EWS mRNA target, promotes the development of ESFTs. However, the mechanism remains elusive. To clarify the role of PRAS40 in ESFTs, we silenced PRAS40 expression in ESFT cells using siRNAs and found increased levels of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Cleaved caspase 3 levels and cytochrome C release were increased simultaneously. Furthermore, with PRAS40 knockdown, the phosphorylation of Akt and mTOR downstream factors, i.e., S6K and S6, was attenuated notably. Ectopic expression of PRAS40 increased Akt and S6 phosphorylation. Activation of Akt only partially reversed the apoptosis induced by PRAS40 knockdown, and downregulation of S6 phosphorylation by PRAS40 silencing could not be sufficiently restored via Akt activation. Searching the upstream factors in this pathway, the autophosphorylation of insulin receptor (IR) was found to be inhibited significantly by PRAS40 silencing but increased by PRAS40 overexpression. Therefore, PRAS40 may enhance IR phosphorylation to facilitate Akt and mTOR signaling leading to the apoptosis deregulation in ESFTs. Moreover, in vivo results confirmed that PRAS40 deletion suppressed the growth of ESFT xenografts and downregulated IR and S6 phosphorylation. Our findings suggest a novel functioning model for PRAS40, which represents a novel therapeutic target for ESFTs. PMID:27186418

  15. Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues

    PubMed Central

    Ulisse, Salvatore; Baldini, Enke; Toller, Matteo; Delcros, Jean-Guy; Guého, Aurélie; Curcio, Francesco; De Antoni, Enrico; Giacomelli, Laura; Ambesi-Impiombato, Francesco S; Bocchini, Sarah; D'Armiento, Massimino; Arlot-Bonnemains, Yannick

    2007-01-01

    Aurora-A kinase has recently been shown to be deregulated in thyroid cancer cells and tissues. Among the Aurora-A substrates identified, transforming acidic coiled-coil (TACC3), a member of the TACC family, plays an important role in cell cycle progression and alterations of its expression occur in different cancer tissues. In this study, we demonstrated the expression of the TACC3 gene in normal human thyroid cells (HTU5), and its modulation at both mRNA and protein levels during cell cycle. Its expression was found, with respect to HTU5 cells, unchanged in cells derived from a benign thyroid follicular tumor (HTU42), and significantly reduced in cell lines derived from follicular (FTC-133), papillary (B-CPAP), and anaplastic thyroid carcinomas (CAL-62 and 8305C). Moreover, in 16 differentiated thyroid cancer tissues, TACC3 mRNA levels were found, with respect to normal matched tissues, reduced by twofold in 56% of cases and increased by twofold in 44% of cases. In the same tissues, a correlation between the expression of the TACC3 and Aurora-A mRNAs was observed. TACC3 and Aurora-A interact in vivo in thyroid cells and both proteins localized onto the mitotic structure of thyroid cells. Finally, TACC3 localization on spindle microtubule was no more observed following the inhibition of Aurora kinase activity by VX-680. We propose that Aurora-A and TACC3 interaction is important to control the mitotic spindle organization required for proper chromosome segregation. PMID:17914111

  16. Epigenetic Deregulation of the LMP1/LMP2 Locus of Epstein-Barr Virus by Mutation of a Single CTCF-Cohesin Binding Site

    PubMed Central

    Chen, Horng-Shen; Martin, Kayla A.; Lu, Fang; Lupey, Lena N.; Mueller, Joshua M.

    2014-01-01

    The chromatin regulatory factors CTCF and cohesin have been implicated in the coordinated control of multiple gene loci in Epstein-Barr virus (EBV) latency. We have found that CTCF and cohesin are highly enriched at the convergent and partially overlapping transcripts for the LMP1 and LMP2A genes, but it is not yet known how CTCF and cohesin may coordinately regulate these transcripts. We now show that genetic disruption of this CTCF binding site (EBVΔCTCF166) leads to a deregulation of LMP1, LMP2A, and LMP2B transcription in EBV-immortalized B lymphocytes. EBVΔCTCF166 virus-immortalized primary B lymphocytes showed a decrease in LMP1 and LMP2A mRNA and a corresponding increase in LMP2B mRNA. The reduction of LMP1 and LMP2A correlated with a loss of euchromatic histone modification H3K9ac and a corresponding increase in heterochromatic histone modification H3K9me3 at the LMP2A promoter region in EBVΔCTCF166. Chromosome conformation capture (3C) revealed that DNA loop formation with the origin of plasmid replication (OriP) enhancer was eliminated in EBVΔCTCF166. We also observed that the EBV episome copy number was elevated in EBVΔCTCF166 and that this was not due to increased lytic cycle activity. These findings suggest that a single CTCF binding site controls LMP2A and LMP1 promoter selection, chromatin boundary function, DNA loop formation, and episome copy number control during EBV latency. PMID:24257606

  17. Epigenetic deregulation of the LMP1/LMP2 locus of Epstein-Barr virus by mutation of a single CTCF-cohesin binding site.

    PubMed

    Chen, Horng-Shen; Martin, Kayla A; Lu, Fang; Lupey, Lena N; Mueller, Joshua M; Lieberman, Paul M; Tempera, Italo

    2014-02-01

    The chromatin regulatory factors CTCF and cohesin have been implicated in the coordinated control of multiple gene loci in Epstein-Barr virus (EBV) latency. We have found that CTCF and cohesin are highly enriched at the convergent and partially overlapping transcripts for the LMP1 and LMP2A genes, but it is not yet known how CTCF and cohesin may coordinately regulate these transcripts. We now show that genetic disruption of this CTCF binding site (EBVΔCTCF166) leads to a deregulation of LMP1, LMP2A, and LMP2B transcription in EBV-immortalized B lymphocytes. EBVΔCTCF166 virus-immortalized primary B lymphocytes showed a decrease in LMP1 and LMP2A mRNA and a corresponding increase in LMP2B mRNA. The reduction of LMP1 and LMP2A correlated with a loss of euchromatic histone modification H3K9ac and a corresponding increase in heterochromatic histone modification H3K9me3 at the LMP2A promoter region in EBVΔCTCF166. Chromosome conformation capture (3C) revealed that DNA loop formation with the origin of plasmid replication (OriP) enhancer was eliminated in EBVΔCTCF166. We also observed that the EBV episome copy number was elevated in EBVΔCTCF166 and that this was not due to increased lytic cycle activity. These findings suggest that a single CTCF binding site controls LMP2A and LMP1 promoter selection, chromatin boundary function, DNA loop formation, and episome copy number control during EBV latency. PMID:24257606

  18. Elk1 and AP-1 sites in the TBP promoter mediate alcohol-induced deregulation of Pol III-dependent genes

    PubMed Central

    Zhong, Qian; Shi, Ganggang; Zhang, Yanmei; Levy, Daniel; Zhong, Shuping

    2013-01-01

    The major risk factors for hepatocellular carcinoma (HCC) are chronic liver diseases that include hepatitis B, hepatitis C, alcoholic liver disease and non-alcoholic steatohepatitis. However, the mechanisms of alcohol-associated HCC remain to be elucidated. The products of RNA Pol III (RNA polymerase III) dependent genes are elevated in both transformation cells and tumor cells. TBP (TATA-box binding protein) is a central transcription factor, which regulates Pol I, Pol II and Pol III gene activity. Our studies have demonstrated that alcohol increases TBP expression and Pol III gene transcription to promote liver tumor formation. We continue to investigate how ethanol mediates TBP expression. Here, we report that ethanol induces TBP promoter activity and the induction is ethanol dose dependent. Blocking the JNK1 pathway by a chemical inhibitor and siRNA reduce this ethanol-induced activity. Furthermore, mutating G>A at a −46bp Elk1 binding site of the TBP promoter or mutating AP-1 binding site at −37bp (A>G) and −38bp (C>T) reduces the TBP promoter activity. Mutation of both Elk1 and AP-1 binding sites dramatically represses this induction. Together, these studies demonstrate that, for the first time, alcohol increases Pol III gene transcription through a response element, which is composed of the overlapping the Elk1 and AP-1 binding sites of the TBP promoter. It suggests that these binding sites may play a critical role in alcohol-induced deregulation of Pol III genes in liver tumor development. PMID:23454483

  19. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness

    PubMed Central

    Bao, Bin; Azmi, Asfar S.; Ali, Shadan; Ahmad, Aamir; Li, Yiwei; Banerjee, Sanjeev; Kong, Dejuan; Sarkar, Fazlul H.

    2013-01-01

    Hypoxia is one of the fundamental biological phenomena that are intricately associated with the development and aggressiveness of a variety of solid tumors. Hypoxia-inducible factors (HIF) function as a master transcription factor, which regulates hypoxia responsive genes and has been recognized to play critical roles in tumor invasion, metastasis, and chemo-radiation resistance, and contributes to increased cell proliferation, survival, angiogenesis and metastasis. Therefore, tumor hypoxia with deregulated expression of HIF and its biological consequence lead to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. It has been well recognized that cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotypic cells are associated with therapeutic resistance and contribute to aggressive tumor growth, invasion, metastasis and believed to be the cause of tumor recurrence. Interestingly, hypoxia and HIF signaling pathway are known to play an important role in the regulation and sustenance of CSCs and EMT phenotype. However, the molecular relationship between HIF signaling pathway with the biology of CSCs and EMT remains unclear although NF-κB, PI3K/Akt/mTOR, Notch, Wnt/β-catenin, and Hedgehog signaling pathways have been recognized as important regulators of CSCs and EMT. In this article, we will discuss the state of our knowledge on the role of HIF-hypoxia signaling pathway and its kinship with CSCs and EMT within the tumor microenvironment. We will also discuss the potential role of hypoxia-induced microRNAs (miRNAs) in tumor development and aggressiveness, and finally discuss the potential effects of nutraceuticals on the biology of CSCs and EMT in the context of tumor hypoxia. PMID:22579961

  20. Deregulation of MicroRNA-375 inhibits cancer proliferation migration and chemosensitivity in pancreatic cancer through the association of HOXB3

    PubMed Central

    Yang, Dejun; Yan, Ronglin; Zhang, Xin; Zhu, Zhenxin; Wang, Changming; Liang, Chao; Zhang, Xin

    2016-01-01

    Background: The expression pattern and regulatory effect of microRNA-375 (miR-375) in human pancreatic cancer was explored. Methods: Gene expression of miR-375 was compared between pancreatic tumors and non-tumorous pancreatic tissues, as well as pancreatic cancer cell lines and normal epithelial cells. MiR-375 was downregulated in pancreatic cancer cell lines, Capan-1 and PANC-1 cells, to assess possible tumor suppressive effects on cancer proliferation, migration, cisplatin chemosensitivity and in vivo growth of tumor explant. The regulation of miR-375 on its target gene, homeobox B3 (HOXB3) gene, was assessed though luciferase activity assay and qRT-PCR. HOXB3 was also downregulated in Capan-1 and PANC-1 cells to assess its functional correlation with miR-375 on cancer regulation. Results: MiR-375 was upregulated in pancreatic tumors and pancreatic cancer cell lines. MiR-375 downregulation had tumor suppressive effects in Capan-1 and PANC-1 cells by reducing cancer proliferation & migration, increasing cisplatin sensitivity and inhibiting in vivo tumor explant growth. HOXB3 was directly bound by miR-375, and was negatively regulated by miR-375 in pancreatic cancer cells. Subsequent HOXB3 downregulation reversed the suppression of miR-375 downregulation on cancer proliferation, migration and cisplatin chemosensitivity in pancreatic cancer. Conclusion: MiR-375 is an oncogene in pancreatic cancer. Deregulation of miR-375 is inhibitory to the development of pancreatic cancer, and reversely regulated by HOXB3. PMID:27186281

  1. A Few Problems Involving Scale.

    ERIC Educational Resources Information Center

    McKillip, William D.; Kay, Cynthia Stinnette

    1985-01-01

    Some applications of ratio and proportion to scale drawing involving geometric figures are given. The activities or problems concern the earth and space, scale speeds, and the earth-moon system. (MNS)

  2. Maternal Competence, Expectation, and Involvement

    ERIC Educational Resources Information Center

    Heath, Douglas H.

    1977-01-01

    Presents a study of maternal competence, expectations and involvement in child rearing decisions in relation to paternal personality and marital characteristics. Subjects were 45 thirty-year-old mothers. (BD)

  3. Cervicobrachial involvement in diabetic radiculoplexopathy.

    PubMed

    Katz, J S; Saperstein, D S; Wolfe, G; Nations, S P; Alkhersam, H; Amato, A A; Barohn, R J

    2001-06-01

    Diabetic radiculoplexopathy is commonly viewed as a condition affecting the lower extremities. However, other regions may also be affected and the presence of upper extremity involvement has rarely been emphasized. Our goal was to illustrate the clinical features of arm involvement in this condition. Of 60 patients with diabetic lumbosacral radiculoplexopathy, we identified 9 who also had upper extremity involvement. The study included 8 men and 1 woman, ranging in age from 36 to 71 years. Upper limb involvement developed simultaneously with the onset of lower limb disorder in 1 patient, preceded it by 2 months in another patient, and occurred between 3 weeks and 15 months later in the remaining 7. In 5 cases, arm involvement developed after symptoms in the legs began to improve. The upper extremity weakness affected the hands and forearms most severely. It was unilateral in 5 patients and bilateral but asymmetric in 4. Pain was often present, but it was not a prominent feature. In most patients, neurologic deficits in the arms improved spontaneously after 2-9 months. We conclude that diabetic radiculoplexopathy may involve the cervical region before, after, or simultaneously with the lumbosacral syndrome. The upper limb process is similar to that in the legs, with subacutely progressive weakness and pain followed by spontaneous recovery. PMID:11360263

  4. RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma

    PubMed Central

    Laugier, Florence; Finet-Benyair, Adeline; André, Jocelyne; Rachakonda, P. Sivaramakrishna; Kumar, Rajiv; Bensussan, Armand; Dumaz, Nicolas

    2015-01-01

    Several studies have highlighted the importance of the PI3K pathway in melanocytes and its frequent over-activation in melanoma. However, little is known about regulation of the PI3K pathway in melanocytic cells. We showed that normal human melanocytes are less sensitive to selective PI3K or mTOR inhibitors than to dual PI3K/mTOR inhibitors. The resistance to PI3K inhibitor was due to a rapid AKT reactivation limiting the inhibitor effect on proliferation. Reactivation of AKT was linked to a feedback mechanism involving the mTORC2 complex and in particular its scaffold protein RICTOR. RICTOR overexpression in melanocytes disrupted the negative feedback, activated the AKT pathway and stimulated clonogenicity highlighting the importance of this feedback to restrict melanocyte proliferation. We found that the RICTOR locus is frequently amplified and overexpressed in melanoma and that RICTOR over-expression in NRAS-transformed melanocytes stimulates their clonogenicity, demonstrating that RICTOR amplification can cooperate with NRAS mutation to stimulate melanoma proliferation. These results show that RICTOR plays a central role in PI3K pathway negative feedback in melanocytes and that its deregulation could be involved in melanoma development. PMID:26356562

  5. The University Reform in Korea: A Deregulation To Be Deregulated?

    ERIC Educational Resources Information Center

    Chung, Bong Gun

    This paper explores the current situation of universities in Korea in an era of reform. University reform was initiated by the government in the 1980s and brought to the universities in the 1990s. In the interval, there have been many social, economic, and political changes in Korean society. The current approach to university reform in Korea…

  6. Cardiac involvement in Wegener's granulomatosis.

    PubMed Central

    Goodfield, N. E.; Bhandari, S.; Plant, W. D.; Morley-Davies, A.; Sutherland, G. R.

    1995-01-01

    Wegener's granulomatosis is a systemic inflammatory disorder of unknown aetiology. The protean clinical presentations depend on the organ(s) involved and the degree of progression from a local to a systemic arteritis. The development of serological tests (antieutrophil cytoplasmic antibodies) allows easier diagnosis of a disease whose incidence is increasing. This is particularly helpful where the presentation is not classic--for example "overlap syndromes"--or where the disease presents early in a more localised form. This is true of cardiac involvement, which is traditionally believed to be rare, but may not be as uncommon as has hitherto been thought (< or = 44%). This involvement may be subclinical or the principal source of symptoms either in the form of localised disease or as part of a systemic illness. Pericarditis, arteritis, myocarditis, valvulitis, and arrhythmias are all recognised. Wegener's granulomatosis should therefore be considered in the differential diagnosis of any non-specific illness with cardiac involvement. This includes culture negative endocarditis, because Wegener's granulomatosis can produce systemic upset with mass lesions and vasculitis. Echocardiography and particularly transoesophageal echocardiography can easily identify and delineate cardiac and proximal aortic involvement and may also be used to assess response to treatment. Images PMID:7696016

  7. Getting Involved: The Parent, School, and Community Involvement Guide

    ERIC Educational Resources Information Center

    Mississippi Department of Education, 2004

    2004-01-01

    The Mississippi Board of Education adopted the School/Community Involvement initiative in 2003 as a part of the Mississippi School Level Accountability Model Evaluation Instruments. This guide provides the components of those standards along with ideas and suggestions to assist parents, community members and school staff with the development or…

  8. Systemic mastocytosis involving the mandible.

    PubMed

    Medina, R; Faecher, R S; Stafford, D S; Zander, D S; Baughman, R A

    1994-07-01

    Systemic mastocytosis is a rare and clinically fascinating disorder that usually involves the skin and hematopoietic tissues. We report a patient with systemic mastocytosis involving the mandible who had no other presenting bone lesions on scintigraphic exam. After noting the radiographic emergence of this osteolytic jaw lesion over a 6-month interval, a biopsy of the lesion was performed, and histologic and electron microscopic studies completed. It is believed that this is the first documented case of mastocytosis to involve an oral-maxillofacial bone. Careful preoperative evaluation and clinical management were conducted to avoid potentially life-threatening complications. A discussion of this condition and strategies for diagnosis and patient management are presented. PMID:8078658

  9. Gastrointestinal involvement in systemic sclerosis.

    PubMed

    Savarino, Edoardo; Furnari, Manuele; de Bortoli, Nicola; Martinucci, Irene; Bodini, Giorgia; Ghio, Massimo; Savarino, Vincenzo

    2014-10-01

    Systemic sclerosis is an autoimmune chronic disease characterised by microvascular, muscular and immunologic abnormalities that lead to progressive and systemic deposition of connective tissue in the skin and internal organs. The gastrointestinal tract is often overlooked by physicians but it is the most affected organ after the skin, from the mouth to the anus. Indeed, 80% of SSc patients may present with gastrointestinal involvement. Gastrointestinal manifestations range from bloating and heartburn to dysphagia and anorectal dysfunction to severe weight loss and malabsorption. However, the gastrointestinal involvement is rarely the direct cause of death, but has great impact on quality of life and leads to several comorbidities that subsequently affect patients' survival. Treatments, including nutritional support and prokinetics provide limited benefits and do not arrest the progressive course of the disease, but earlier detection of gastrointestinal involvement may reduce the risk of complications such as malnutrition. PMID:25179275

  10. [Heart involvement in Friedreich's ataxia].

    PubMed

    Weidemann, F; Scholz, F; Florescu, C; Liu, D; Hu, K; Herrmann, S; Ertl, G; Störk, S

    2015-03-01

    Friedreich's ataxia is a rare hereditary disease and although the gene defect has already been identified as a deficiency of the mitochondrial protein frataxin, the pathophysiology is still unknown. Although a multisystem disorder organ involvement is predominantly neurological. Besides the characteristic features of spinocerebellar ataxia the heart is frequently also affected. Cardiac involvement typically manifests as hypertrophic cardiomyopathy, which can progress to heart failure and death. So far most research has focused on the neurological aspects and cardiac involvement in Friedreich's ataxia has not been systematically investigated. Thus, a better understanding of the progression of the cardiomyopathy, cardiac complications and long-term cardiac outcome is warranted. Although no specific treatment is available general cardiac therapeutic options for cardiomyopathy should be considered. The current review focuses on clinical and diagnostic features of cardiomyopathy and discusses potential therapeutic developments for Friedreich's ataxia. PMID:24848865

  11. Liver involvement in systemic infection

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2014-01-01

    The liver is often involved in systemic infections, resulting in various types of abnormal liver function test results. In particular, hyperbilirubinemia in the range of 2-10 mg/dL is often seen in patients with sepsis, and several mechanisms for this phenomenon have been proposed. In this review, we summarize how the liver is involved in various systemic infections that are not considered to be primarily hepatotropic. In most patients with systemic infections, treatment for the invading microbes is enough to normalize the liver function tests. However, some patients may show severe liver injury or fulminant hepatic failure, requiring intensive treatment of the liver. PMID:25276279

  12. Musculoskeletal involvement in systemic sclerosis.

    PubMed

    Lóránd, Veronika; Czirják, László; Minier, Tünde

    2014-10-01

    Musculoskeletal (MSK) involvement is a very frequent manifestation of patients with systemic sclerosis (SSc). There are several reports about clinical trials assessing musculoskeletal involvement in SSc. However, only few controlled studies have been conducted. The prevalence of musculoskeletal symptoms, clinical and radiographic findings has been assessed. The most important articular (arthralgia, synovitis, contractures), tendon (tendon friction rubs, tenosynovitis) and muscular manifestations (myalgia, muscle weakness, myositis) should be carefully evaluated during the assessment of SSc patients, because these are not only common, but substantially influence the quality of life and some of them also have predictive value concerning disease activity and severity. PMID:25179276

  13. Deregulating Low-Risk Research

    ERIC Educational Resources Information Center

    Shamoo, Adil E.

    2007-01-01

    In the past few decades, with the explosion of biotechnology and the aging of the population, the use of human subjects in research has increased significantly. The United States has done much to protect human research subjects, and no one can deny the importance of keeping them safe. But at the same time, researchers whose work poses no threat to…

  14. Railroad deregulation: impact on coal

    SciTech Connect

    Tukenmez, E.

    1983-08-01

    Recent railroad legislation exemplified by the Staggers Rail Act has aimed generally at improving the profitability of the railroads through pricing flexibility and operating changes. The evolution of railroad legislation through the 1970's has indicated a concern about the revenue adequacy of the railroads and the regulatory burden under which the railroads were forced to operate for many years. Over the past two-and-a-half years the railroads generally have been pleased with the results of the Staggers Act. Coal producers and consumers, however, are dissatisfied with the ICC's implementation of the Act. In April 1982, bills were introduced in Congress to clarify provisions of the Staggers Act dealing with market dominance, revenue adequacy, and establishment of coal rate guidelines, in order to protect captive shippers.

  15. Fiber Optics: Deregulate and Deploy.

    ERIC Educational Resources Information Center

    Suwinski, Jan H.

    1993-01-01

    Describes fiber optic technology, explains its use in education and commercial settings, and recommends regulations and legislation that will speed its use to create broadband information networks. Topics discussed include distance learning; interactive video; costs; and the roles of policy makers, lawmakers, public advocacy groups, and consumers.…

  16. Involvement in Subject Learning Scale.

    ERIC Educational Resources Information Center

    Bujold, Neree; Saint-Pierre, Henri; Bhushan, Vidya

    1997-01-01

    The Involvement in Subject Learning Scale (ISLS) was developed and validated as an educational outcome measure to be used in assessing higher education quality. The origins and development of the scale, its factor analysis, potential applications, limitations, and pilot use in France and Quebec (Canada) are described. The instrument is appended.…

  17. Malignant haemangioendothelioma involving the liver

    PubMed Central

    Pollard, Stella M.; Millward-Sadler, G. H.

    1974-01-01

    The features of four cases of malignant haemangioendothelioma involving the liver and other organs are described. Two cases were associated with a microangiopathic haemolytic anaemia. The nature of the tumours and possible pathogenesis for the anaemias are discussed. Images PMID:4832301

  18. Predictors of Residence Hall Involvement

    ERIC Educational Resources Information Center

    Arboleda, Ana; Wang, Yongyi; Shelley, Mack C., II; Whalen, Donald F.

    2003-01-01

    Residence hall students' (N = 1,186, 52% male, 90% White, 66% freshmen) involvement in their living community is influenced significantly by precollege student characteristics (gender, ethnicity), classification, attitudes (toward hall director, house cabinet, academic comfort, social environment, group study), and environmental variables (noise,…

  19. Multicultural Learning through Family Involvement.

    ERIC Educational Resources Information Center

    Swick, Kevin J.; And Others

    1994-01-01

    Presents a framework for initiating multicultural learning during early childhood through active family involvement. This framework includes the rationale for multicultural education, opportunities for multicultural learning, sensitive issues, specific educational strategies, and resources. Each aspect of the framework is examined in relation to…

  20. Veterinary involvement in poultry production.

    PubMed

    Parker, Daniel

    2016-01-16

    The worldwide poultry sector is expected to grow substantially over the next few decades, as the world looks to feed a rapidly expanding population. In a further article in Veterinary Record's series looking at the state of different sectors of the veterinary profession, Daniel Parker looks at veterinary involvement in the poultry sector. PMID:26769809

  1. Teaching Cases on Family Involvement

    ERIC Educational Resources Information Center

    Harvard Family Research Project, 2010

    2010-01-01

    Teaching cases are a valuable tool in preparing teachers and school administrators to engage effectively with families. Because the case method presents a story in practice, it offers students an active learning opportunity. Teaching cases involve real world situations and consider the perspectives of various stakeholders, including teachers,…

  2. Parental Involvement through Better Communication

    ERIC Educational Resources Information Center

    Reilly, Edel

    2008-01-01

    Building strong bonds between home and school is one of National Middle School Association's (2003) 14 characteristics for successful middle schools set forth in "This We Believe". Getting teachers to actually believe in the value of parental involvement is not always easy. This article examines a range of key issues in the literature on parental…

  3. Severe Pulmonary Involvement in Leptospirosis

    PubMed Central

    Jayakrishnan, B; Ben Abid, Fatma; Balkhair, Abdullah; Alkaabi, Juma K.; Al-Rawas, Omar A.; George, Jojy; Al-Zeedy, Khalfan

    2013-01-01

    Pulmonary complications in leptospirosis, though common, are often unrecognized in a non-endemic area. We report here a patient with leptospirosis and severe pulmonary involvement who was treated with meropenem (1 g every 8 hours), moxifloxacin (400 mg once daily), and high doses of corticosteroids. Systemic steroids were continued for 3 months because of persistent pulmonary lesions. PMID:23862041

  4. Parental Involvement in Norwegian Schools

    ERIC Educational Resources Information Center

    Paulsen, Jan Merok

    2012-01-01

    This article examines findings on key challenges of school-parent relations in Norway. The review is based on recent large-scale studies on several issues, including formalized school-parent cooperation, parental involvement in the pedagogical discourse, and teacher perspectives on the parents' role in the school community. Findings suggest a…

  5. Parent Involvement as Ritualized Practice

    ERIC Educational Resources Information Center

    Doucet, Fabienne

    2011-01-01

    This article examines parent involvement (PI) as a ritual system using Turner's concept of root paradigms. Through a twofold analysis, I argue that the highly ritualized nature of PI practices creates a group identity among mainstream parents and schools that marginalizes diverse families. First, I point out three root paradigms in the ritual…

  6. Drug Involvement and Academic Striving.

    ERIC Educational Resources Information Center

    Kahn, Malcolm; Holroyd, Kenneth

    This study attempted to clarify the relationship between drug involvement and academic accomplishments. Unlike other studies, it was controlled for aptitude and sex. In a structured interview, the College Behavior Questionnaire (CBQ) was administered to 77 male and 67 female student subjects. Based on the CBQ results three groups were identified:…

  7. Managing Parent Involvement during Crisis

    ERIC Educational Resources Information Center

    Merriman, Lynette S.

    2008-01-01

    In the wake of 9/11, Hurricane Katrina, and the Virginia Tech shooting tragedy, it is no surprise that concern for students' safety is the primary reason attributed to parents' increased involvement. Parents and university administrators share in their commitment to student safety. However, college and university staff who assume responsibility…

  8. Prostate Field Cancerization: Deregulated Expression of Macrophage Inhibitory Cytokine 1 (MIC-1) and Platelet Derived Growth Factor A (PDGF-A) in Tumor Adjacent Tissue

    PubMed Central

    Jones, Anna C.; Shoshan, Dor S.; Fischer, Edgar G.; Trujillo, Kristina A.; Bisoffi, Marco

    2015-01-01

    Prostate field cancerization denotes molecular alterations in histologically normal tissues adjacent to tumors. Such alterations include deregulated protein expression, as we have previously shown for the key transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS). Here we add the two secreted factors macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) to the growing list of protein markers of prostate field cancerization. Expression of MIC-1 and PDGF-A was measured quantitatively by immunofluorescence and comprehensively analyzed using two methods of signal capture and several groupings of data generated in human cancerous (n = 25), histologically normal adjacent (n = 22), and disease-free (n = 6) prostate tissues. A total of 208 digitized images were analyzed. MIC-1 and PDGF-A expression in tumor tissues were elevated 7.1x to 23.4x and 1.7x to 3.7x compared to disease-free tissues, respectively (p<0.0001 to p = 0.08 and p<0.01 to p = 0.23, respectively). In support of field cancerization, MIC-1 and PDGF-A expression in adjacent tissues were elevated 7.4x to 38.4x and 1.4x to 2.7x, respectively (p<0.0001 to p<0.05 and p<0.05 to p = 0.51, respectively). Also, MIC-1 and PDGF-A expression were similar in tumor and adjacent tissues (0.3x to 1.0x; p<0.001 to p = 0.98 for MIC-1; 0.9x to 2.6x; p<0.01 to p = 1.00 for PDGF-A). All analyses indicated a high level of inter- and intra-tissue heterogeneity across all types of tissues (mean coefficient of variation of 86.0%). Our data shows that MIC-1 and PDGF-A expression is elevated in both prostate tumors and structurally intact adjacent tissues when compared to disease-free specimens, defining field cancerization. These secreted factors could promote tumorigenesis in histologically normal tissues and lead to tumor multifocality. Among several clinical applications, they could also be exploited as indicators of disease in false negative

  9. Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall

    PubMed Central

    2012-01-01

    Background The cancer stem cell (CSC) hypothesis posits that deregulated neural stem cells (NSCs) form the basis of brain tumors such as glioblastoma multiforme (GBM). GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall. Methods We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques. Results The patient’s MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and −2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice. Conclusions This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer stem cells, which are likely

  10. Differential impact of immediate total deregulation of wellhead prices of natural gas on minority and low-income homeowners: a general review and a case study in the Washington, DC area

    SciTech Connect

    Green, R.D.; Gilbert, H.R.

    1983-01-01

    In this study, the authors evaluate the impact of total deregulation of wellhead prices of natural gas on various strata of the residential consuming population, and compare it to the baseline impact of a continuation of the Natural Gas Policy Act of 1978. They found that minority and poverty homeowners will suffer greater relative welfare losses than their white and non-poverty counterparts. They developed quantitative estimates of the extent of these differentials, and offered some policy proposals suggested by these findings. 54 refs., 8 figs., 68 tabs.

  11. [Cardiac involvement in Fabry's disease].

    PubMed

    Weidemann, Frank; Breunig, Frank

    2008-03-15

    Fabry's disease is a rare X-linked lysosomal storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of all tissues. The disease is characterized by a progressive involvement of important vital organs like the kidneys, the cerebrovascular system and the heart. Within the scope of this article an overview of Fabry's cardiomyopathy, the necessary cardiac diagnostic tests and, in addition, the new concept of enzyme replacement therapy is given. PMID:18344066

  12. Ethics in research involving prisoners.

    PubMed

    Pont, Jörg

    2008-01-01

    Research involving prisoners repeatedly went astray during the last century, culminating in the cruel medical experiments inside the Nazi concentration camps that gave rise to the Nuremberg Code. However, prisoners continued to become victims of scientific exploitation by the rapidly evolving biomedical research industry. The common roots of these abuses were the flawed philosophy that the needs of the society outweigh the needs of the individual and the researchers' view that prisoners are cheap, easy to motivate and stable research subjects. Prisoners are vulnerable to exploitation and abuse by research because their freedom for consent can easily be undermined, and because of learning disabilities, illiteracy and language barriers prevailing within prisoner populations. Therefore, penal laws of some countries supported by a number of internationally agreed documents prohibit research involving prisoners completely. However, prisoners must also be regarded as vulnerable to the specific health problems in prisons, e.g. transmissible diseases, mental disorders and suicide - problems that need to be addressed by research involving prisoners. Additionally, the participation of prisoner patients in research they directly can benefit from should be provided. Hence, it must be a common objective to find the right balance between protection from exploitation and access to research beneficial to prisoners. PMID:19061061

  13. Macrophages: are they involved in endometriosis, abortion and preeclampsia and how?

    PubMed

    Hutter, Stefan; Heublein, Sabine; Knabl, Julia; Andergassen, Ulrich; Vrekoussis, Thomas; Makrigiannakis, Antonis; Friese, Klaus; Mayr, Doris; Jeschke, Udo

    2013-01-01

    Macrophages hold a key role in both regulating and executing the body's own immune response under various conditions. Hence, although endometriosis, preeclampsia and abortions are clinically different, all three are regarded to involve highly complex immunological processes. The aim of our current work was to evaluate the role of macrophages within these gynaecological disorders. Macrophages have been shown to invade endometriosis lesions and to mediate propagation of endometriotic cyst growth. However this is the first time that significant GPER up-regulation in macrophages is demonstrated. This highlights a potential alternative way through which estrogen may modulate immune response of macrophages in endometriosis. In addition, during spontaneous miscarriages the macrophage population increases significantly. This deregulation may possibly support an inflammatory scheme further triggering abortive procedures. Macrophage-mediated apoptosis of extravillous trophoblasts (EVT) has been associated with preeclampsia. Larger numbers of apoptotic EVT were detected in preeclamptic placentas compared with normal. In preeclamptic placentas, decidual macrophages were found to be Fas ligand (FasL)-positive. Our results highlight a new aspect of macrophage biology in endometriosis and pregnancy physiology and patho-physiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact. Our data strongly indicate that macrophages hold key roles in various gynaecological disorders and might be crucial to further elucidate their patho-physiology. PMID:23657062

  14. Proteomic Approaches Identify Members of Cofilin Pathway Involved in Oral Tumorigenesis

    PubMed Central

    Polachini, Giovana M.; Sobral, Lays M.; Mercante, Ana M. C.; Paes-Leme, Adriana F.; Xavier, Flávia C. A.; Henrique, Tiago; Guimarães, Douglas M.; Vidotto, Alessandra; Fukuyama, Erica E.; Góis-Filho, José F.; Cury, Patricia M.; Curioni, Otávio A.; Michaluart Jr, Pedro; Silva, Adriana M. A.; Wünsch-Filho, Victor; Nunes, Fabio D.; Leopoldino, Andréia M.; Tajara, Eloiza H.

    2012-01-01

    The prediction of tumor behavior for patients with oral carcinomas remains a challenge for clinicians. The presence of lymph node metastasis is the most important prognostic factor but it is limited in predicting local relapse or survival. This highlights the need for identifying biomarkers that may effectively contribute to prediction of recurrence and tumor spread. In this study, we used one- and two-dimensional gel electrophoresis, mass spectrometry and immunodetection methods to analyze protein expression in oral squamous cell carcinomas. Using a refinement for classifying oral carcinomas in regard to prognosis, we analyzed small but lymph node metastasis-positive versus large, lymph node metastasis-negative tumors in order to contribute to the molecular characterization of subgroups with risk of dissemination. Specific protein patterns favoring metastasis were observed in the “more-aggressive” group defined by the present study. This group displayed upregulation of proteins involved in migration, adhesion, angiogenesis, cell cycle regulation, anti-apoptosis and epithelial to mesenchymal transition, whereas the “less-aggressive” group was engaged in keratinocyte differentiation, epidermis development, inflammation and immune response. Besides the identification of several proteins not yet described as deregulated in oral carcinomas, the present study demonstrated for the first time the role of cofilin-1 in modulating cell invasion in oral carcinomas. PMID:23227181

  15. t(11;14)(q23;q32) involving IGH and DDX6 in nodal marginal zone lymphoma.

    PubMed

    Stary, Susanne; Vinatzer, Ursula; Müllauer, Leonhard; Raderer, Markus; Birner, Peter; Streubel, Berthold

    2013-01-01

    Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell lymphoma that shares morphological and immunophenotypic characteristics with extranodal and splenic marginal zone lymphoma. Data on altered genes and signaling pathways are scarce in this rare tumor entity. To gain further insights into the genetic background of NMZL, seven cases were investigated by microarray analysis, G-banding, and FISH. Chromosomal imbalances were observed in 3/7 cases (43%) with gains of chromosome arms 1q, 8q, and 12q being the most frequent findings. Furthermore, we identified a translocation t(11;14)(q23;q32) involving IGH and DDX6. Chromosomal walking, expression analysis, siRNA-mediated gene knockdown and a yeast two hybrid screen were performed for further characterization of the translocation in vitro. In siRNA experiments, DDX6 appeared not to be involved in NF-κB activation as frequently observed for genes promoting lymphomagenesis but was found to interfere with the expression of BCL6 and BCL2 in an NF-κB independent manner. In conclusion, we identified several unbalanced aberrations and a t(11;14) involving IGH and DDX6 providing evidence for a contribution of DDX6 to lymphomagenesis by deregulation of BCL6 in NMZL. PMID:22965301

  16. Vestibular pathways involved in cognition

    PubMed Central

    Hitier, Martin; Besnard, Stephane; Smith, Paul F.

    2014-01-01

    Recent discoveries have emphasized the role of the vestibular system in cognitive processes such as memory, spatial navigation and bodily self-consciousness. A precise understanding of the vestibular pathways involved is essential to understand the consequences of vestibular diseases for cognition, as well as develop therapeutic strategies to facilitate recovery. The knowledge of the “vestibular cortical projection areas”, defined as the cortical areas activated by vestibular stimulation, has dramatically increased over the last several years from both anatomical and functional points of view. Four major pathways have been hypothesized to transmit vestibular information to the vestibular cortex: (1) the vestibulo-thalamo-cortical pathway, which probably transmits spatial information about the environment via the parietal, entorhinal and perirhinal cortices to the hippocampus and is associated with spatial representation and self-versus object motion distinctions; (2) the pathway from the dorsal tegmental nucleus via the lateral mammillary nucleus, the anterodorsal nucleus of the thalamus to the entorhinal cortex, which transmits information for estimations of head direction; (3) the pathway via the nucleus reticularis pontis oralis, the supramammillary nucleus and the medial septum to the hippocampus, which transmits information supporting hippocampal theta rhythm and memory; and (4) a possible pathway via the cerebellum, and the ventral lateral nucleus of the thalamus (perhaps to the parietal cortex), which transmits information for spatial learning. Finally a new pathway is hypothesized via the basal ganglia, potentially involved in spatial learning and spatial memory. From these pathways, progressively emerges the anatomical network of vestibular cognition. PMID:25100954

  17. Skeletal muscle involvement in cardiomyopathies.

    PubMed

    Limongelli, Giuseppe; D'Alessandro, Raffaella; Maddaloni, Valeria; Rea, Alessandra; Sarkozy, Anna; McKenna, William J

    2013-12-01

    The link between heart and skeletal muscle disorders is based on similar molecular, anatomical and clinical features, which are shared by the 'primary' cardiomyopathies and 'primary' neuromuscular disorders. There are, however, some peculiarities that are typical of cardiac and skeletal muscle disorders. Skeletal muscle weakness presenting at any age may indicate a primary neuromuscular disorder (associated with creatine kinase elevation as in dystrophinopathies), a mitochondrial disease (particularly if encephalopathy, ocular myopathy, retinitis, neurosensorineural deafness, lactic acidosis are present), a storage disorder (progressive exercise intolerance, cognitive impairment and retinitis pigmentosa, as in Danon disease), or metabolic disorders (hypoglycaemia, metabolic acidosis, hyperammonaemia or other specific biochemical abnormalities). In such patients, skeletal muscle weakness usually precedes the cardiomyopathy and dominates the clinical picture. Nevertheless, skeletal involvement may be subtle, and the first clinical manifestation of a neuromuscular disorder may be the occurrence of heart failure, conduction disorders or ventricular arrhythmias due to cardiomyopathy. ECG and echocardiogram, and eventually, a more detailed cardiovascular evaluation may be required to identify early cardiac involvement. Paediatric and adult cardiologists should be proactive in screening for neuromuscular and related disorders to enable diagnosis in probands and evaluation of families with a focus on the identification of those at risk of cardiac arrhythmia and emboli who may require specific prophylactic treatments, for example, pacemaker, implantable cardioverter-defibrillator and anticoagulation. PMID:24149064

  18. [Immunological mechanisms involved in pregnancy].

    PubMed

    Rico-Rosillo, María Guadalupe; Vega-Robledo, Gloria Bertha

    2012-05-01

    Pregnancy progresses through mechanisms that allow the embryo implantation and its development during gestation. Those mechanisms involve the immune cells that participate in the regulation of immune tolerance and response, as well as the protection conferred by Th2 cytokines and molecules expressed on trophoblast cells. Local factors expressed in the fetal interface as HLA-G, which inhibits the cytotoxicity of uterine natural killer cells and induces apoptosis of activated CD8 cells; transforming growth factor-beta, that induces tolerance, and uterine natural killer cells that are functionally different to the peripheral, as well as circulating progesterone and the glicodeline molecules that are important regulators of the immune response, also intervene in the process. From the conventional immunological point of view, pregnancy is a unique immune condition in which the fetus, semiallogenic, avoids being rejected immunologically by the mother, apparently by inducing a tolerance more than a sensitization PMID:23301425

  19. Diet, Obesity, and Political Involvement

    PubMed Central

    2015-01-01

    The views expressed are those of the author and may not necessarily reflect the views of the Editorial Board. Abstract: This essay is an opinion article addressed to the busy practitioner. It provides information on nutrition, diet, nutritional science, and obesity to serve as a reference in teaching his patients on these issues. It is composed by a gastroenterologist who has been engaged in clinical gastroenterology and nutrition, research, and teaching in an academic medical center for 35 years. It also relates the information to conclusions on reasonable involvement of the national government in these topics. Finally, its audience might include the interested, well-educated, lay public. Hence, excessive scientific parlance and referencing have been avoided. PMID:26106846

  20. Hirayama Disease with Proximal Involvement.

    PubMed

    Kim, Jinil; Kim, Yuntae; Kim, Sooa; Oh, Kiyoung

    2016-10-01

    Hirayama disease is a slowly progressing benign motor neuron disease that affects the distal upper limb. A 29-year-old man visited the hospital with a 1-year history of weakened left proximal upper limb. He was diagnosed with Hirayama disease 9 years ago, while there was no further progression of the muscle weakness afterward. Atrophy and weakness was detected in proximal upper limb muscles. Magnetic resonance imaging and somatosensory evoked potentials were normal. Needle electromyography showed abnormal findings in proximal upper limb muscles. Our patient had Hirayama disease involving the proximal portion through secondary progression. Clinical manifestation and accurate electromyography may be useful for diagnosis. Rare cases with progression patterns as described here are helpful and have clinical meaning for clinicians. PMID:27550499