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Sample records for vhl ret nf1

  1. Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Koch, Christian A; Brouwers, Frederieke M; Vortmeyer, Alexander O; Tannapfel, Andrea; Libutti, Steven K; Zhuang, Zhengping; Pacak, Karel; Neumann, Hartmut PH; Paschke, Ralf

    2006-01-01

    Germline mutations in RET are responsible for multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia/adenoma. Recent studies suggest a 'second hit' mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic VHL gene alterations are also important in the pathogenesis of MEN2-associated MTC. We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and RET germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and VHL mutation analysis. First, we searched for allelic imbalance between mutant and wild-type RET by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for RET amplification by this technique could be demonstrated in 3 of 6 MTCs. We then performed LOH analysis using D3S1038 and D3S1110 which map to the VHL gene locus at 3p25/26. VHL gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type RET. Mutation analysis of the VHL gene showed a somatic frameshift mutation in 1 MTC that also demonstrated LOH at 3p25/26. In the 2 other MTCs with allelic imbalance of RET and somatic VHL gene deletion, no somatic VHL mutation could be detected. The CCH specimen did neither reveal RET imbalance nor somatic VHL gene alterations. These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC

  2. NF1 Neuronal Genotype Phenotype Relationships

    Science.gov (United States)

    2017-06-01

    interesting results from the Drosophila functional assays, at present we have decided to focus our attention on selected NF1 patient missense mutations...complexity of NF1 disease phenotypes in different tissues, age and sex dependency of symptoms, impact of environmental factors and genetic heterogeneity...suggesting the role of modifier genes [12]. This work aims to shed light on this issue by studying the functional consequences of selected NF1

  3. Functional Analysis of Drosophila NF1

    National Research Council Canada - National Science Library

    Bernards, Andre

    2005-01-01

    ...) for Ras, yet homozygous loss of a highly conserved Drosophila NF1 ortholog results in several phenotypes that are insensitive to manipulating Ras signal transduction, but rescued by increasing...

  4. NF1 Signal Transduction and Vascular Dysfunction

    Science.gov (United States)

    2015-05-01

    microenvironment that promotes much of the pathology associated with the disease . Moreover we hypothesize that a mechanistic consequence of the loss...obliteration of the normal red pulp architecture. In addition, we found significant peri-aveolar and peri-vascular inflammatory infiltrates in the lung...the mouse model of NF1 disease in the endothelium we proposed and have done experiments investigating the loss of endothelial NF1 in the adult

  5. Identification of 3 novel VHL germ-line mutations in Danish VHL patients

    DEFF Research Database (Denmark)

    Dandanell, Mette; Friis-Hansen, Lennart Jan; Sunde, Lone

    2012-01-01

    von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene.......von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene....

  6. Chorionic gonadotropin regulates the transcript level of VHL, p53, and HIF-2alpha in human granulosa lutein cells.

    Science.gov (United States)

    Herr, D; Keck, C; Tempfer, C; Pietrowski, Detlef

    2004-12-01

    The ovarian corpus luteum plays a critical role in reproduction being the primary source of circulating progesterone. After ovulation the corpus luteum is build by avascular granulosa lutein cells through rapid vascularization regulated by gonadotropic hormones. The present study was performed to investigate whether this process might be influenced by the human chorionic gonadotropin (hCG)-dependent expression of different tumor suppressor genes and hypoxia dependent transcription factors. RNA was isolated from cultured granulosa lutein cells, transcribed into cDNA, and the transcript level of following genes were determined: RB-1, VHL, NF-1, NF-2, Wt-1, p53, APC, and hypoxia inducible factor-1 (HIF-1), -2, and -3alpha. Additionally, the influence of hCG on the expression of VHL, p53, and HIf2alpha were investigated. We demonstrate that in human granulosa lutein cells the tumor suppressor genes RB-1, VHL, NF-1, NF-2, Wt-1, p53, and APC and the hypoxia dependent transcription factors HIF-1alpha, -2alpha, and -3alpha are expressed. In addition, we showed that hCG regulates the expression of p53, VHL, and HIF-2alpha. Our results indicate that hCG may determine the growth and development of the corpus luteum by mediating hypoxic and apoptotic pathways in human granulosa lutein cells. Copyright 2004 Wiley-Liss, Inc.

  7. Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells

    International Nuclear Information System (INIS)

    Thomas, Stacey L.; Deadwyler, Gail D.; Tang, Jun; Stubbs, Evan B.; Muir, David; Hiatt, Kelly K.; Clapp, D. Wade; De Vries, George H.

    2006-01-01

    Schwann cells derived from peripheral nerve sheath tumors from individuals with Neurofibromatosis Type 1 (NF1) are deficient for the protein neurofibromin, which contains a GAP-related domain (NF1-GRD). Neurofibromin-deficient Schwann cells have increased Ras activation, increased proliferation in response to certain growth stimuli, increased angiogenic potential, and altered cell morphology. This study examined whether expression of functional NF1-GRD can reverse the transformed phenotype of neurofibromin-deficient Schwann cells from both benign and malignant peripheral nerve sheath tumors. We reconstituted the NF1-GRD using retroviral transduction and examined the effects on cell morphology, growth potential, and angiogenic potential. NF1-GRD reconstitution resulted in morphologic changes, a 16-33% reduction in Ras activation, and a 53% decrease in proliferation in neurofibromin-deficient Schwann cells. However, NF1-GRD reconstitution was not sufficient to decrease the in vitro angiogenic potential of the cells. This study demonstrates that reconstitution of the NF1-GRD can at least partially reverse the transformation of human NF1 tumor-derived Schwann cells

  8. Dicty_cDB: VHL434 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available VH (Link to library) VHL434 (Link to dictyBase) - - - Contig-U16336-1 VHL434P (Link... to Original site) VHL434F 546 VHL434Z 778 VHL434P 1304 - - Show VHL434 Library VH (Link to library) Clone ID VHL434 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U16336-1 Original site URL http://dict...EVMSCNKFSSKRIGYLAASQSFNEGTDVIVLATHQIRKDFLS SNQSEAYLALNCLSNICTTDLARELANDILTLLSTQKTHILKRAITVLYKIFLRYPES-- - --...GFDISWASFKIVEVMSCNKFSSKRIGYLAASQSFNEGTDVIVLATHQIRKDFLS SNQSEAYLALNCLSNICTTDLARELANDILTLLSTQKTHILKRAITVLYKIFL

  9. Dicty_cDB: VHL663 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available VH (Link to library) VHL663 (Link to dictyBase) - - - Contig-U15767-1 VHL663P (Link... to Original site) VHL663F 574 VHL663Z 702 VHL663P 1256 - - Show VHL663 Library VH (Link to library) Clone ID VHL663 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U15767-1 Original site URL http://dict...WPDGFKYFFVDNQAGDSESAKSGKNLPIQRDIELNWNGEAYEYSNSNYFPINGQG FNDVSYPV--- ---SYATGKCEPDSSLCNDNNICTIDICVHEGILDGLPQG...ik rqelvgqmvlsifl*itklviqnlpnlvkifqfkeiss*igmekhmniviqitsqltdkv smm*aiq--- ---SYATGKCEPDSSLCNDNNICTIDICVHEGI

  10. Genetic Factors that Affect Tumorigenesis in NF1

    National Research Council Canada - National Science Library

    Stephens, Karen

    2003-01-01

    ...) that flank the NF1 gene. We identified recombination hotspots where 69% of NF1 microdeletions occur and developed robust and sensitive assays to detect microdeletions in a patient blood sample...

  11. Genetic Factors that Affect Tumorigenesis in NF1

    National Research Council Canada - National Science Library

    Stephens, Karen G

    2004-01-01

    ...) that flank the NF1 gene. We identified recombination hotspots where 69% of NF1 microdeletions occur and developed robust and sensitive assays to detect microdeletions in a patient blood sample...

  12. A Functional Genomic Analysis of NF1-Associated Learning Disabilities

    National Research Council Canada - National Science Library

    Tang, Shao-Jun

    2008-01-01

    Learning disabilities severely deteriorate the life of many NF1 patients. However, the pathogenic process for NF1-associated learning disabilities has not been fully understood and an effective therapy is not available...

  13. A Functional Genomic Analysis of NF1-Associated Learning Disabilities

    National Research Council Canada - National Science Library

    Tang, Shao-Jun

    2007-01-01

    Learning disabilities severely deteriorate the life of many NF1 patients. However, the pathogenic process for NF1-associated learning disabilities has not been fully understood and an effective therapy is not available...

  14. A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A.

    Science.gov (United States)

    Bethanis, Sotirios; Koutsodontis, George; Palouka, Theodosia; Avgoustis, Christos; Yannoukakos, Drakoulis; Bei, Thalia; Papadopoulos, Savas; Linos, Dimitrios; Tsagarakis, Stylianos

    2007-01-01

    Multiple endocrine neoplasia type 2A (MEN2A) is a syndrome of familial neoplasias characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperplasia of the parathyroid glands. RET protooncogene mutations are responsible for MEN 2A. Mutations in exons 10 or 11 have been identified in more than 96% of patients with MEN 2A. We herein report for the first time a patient with MEN 2A harboring a mutation (Gly(533)Cys) in exon 8. A 66-year old male patient was referred to our department for bilateral adrenal nodules. The patient's family history was remarkable in that his mother had pheochromocytoma. Biochemical evaluation and findings of the magnetic resonance imaging of the adrenals were compatible with the diagnosis of bilateral pheochromocytomas. The patient underwent laparoscopic bilateral adrenalectomy and histological examination confirmed the preoperative diagnosis of pheochromocytoma. Absence of phenotypic characteristics of VHL or NF1 and elevated calcitonin levels both basal and post pentagastrin stimulation, raised the possibility of MEN 2A syndrome. Total thyroidectomy was performed and histological examination showed the presence of MTC. Direct sequencing of exon 8 from the patient's genomic DNA revealed the mutation c.1,597G-->T (Gly533Cys). Although this missense point mutation has been associated with familial MTC (FMTC), to the best of our knowledge mutations in exon 8 have not previously been identified in patients with MEN 2A. In conclusion, in patients with clinical suspicion of MEN 2A syndrome, analysis of RET exon 8 should be considered when the routine evaluation of MEN 2A-associated mutations is negative. Furthermore, patients with FMTC and exon 8 mutations should also be screened for pheochromocytoma.

  15. The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma.

    Science.gov (United States)

    Maranchie, Jodi K; Vasselli, James R; Riss, Joseph; Bonifacino, Juan S; Linehan, W Marston; Klausner, Richard D

    2002-04-01

    Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the alpha subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1alpha recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1alpha alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL.

  16. Clinical and Molecular Consequences of NF1 Microdeletion

    National Research Council Canada - National Science Library

    Stephens, Karen

    2007-01-01

    ... model of plexiform neurofibroma tunorigenesis and the conservation of recombination hotspots. Our hypothesis that genome instability occurs during NF1-tumorigenesis continues to be supported by our findings...

  17. NF-1 Dependent Gene Regulation in Drosophila Melanogaster

    Science.gov (United States)

    2004-04-01

    standard cornmeal medium at 25oC in a humidified incubator. Flies were collected and frozen in liquid nitrogen at the same time of day to minimize...melanogaster media, strains and heat-shock conditions Flies were raised at room temperature (22–248C) on standard cornmeal medium. The Nf1 mutants Nf1P1 and

  18. Anmeldelse : Howard Zehr: Genoprettende Ret

    DEFF Research Database (Denmark)

    Adrian, Lin

    2010-01-01

    Anmeldelse af Howard Zehr: Genoprettende ret, der udkom i 2008. Oversat fra engelsk: Restorative Justice Udgivelsesdato: august 2010......Anmeldelse af Howard Zehr: Genoprettende ret, der udkom i 2008. Oversat fra engelsk: Restorative Justice Udgivelsesdato: august 2010...

  19. Dicty_cDB: VHL364 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available VH (Link to library) VHL364 (Link to dictyBase) - - - Contig-U16205-1 - (Link to Or...iginal site) - - VHL364Z 668 - - - - Show VHL364 Library VH (Link to library) Clone ID VHL364 (Link to dicty...Base) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U16205-1 Original site URL http://dictycdb.b...mino Acid sequence ---KKVTIAEAKEIFEKQYRDLYTVSQDVTKLAIQSAEQNGIVFLDEIDKICTSRESIKN GGDASTDGVQRDLLPIVEGCMVSTKYGQ...itwyh*tyrrgykf*lxys*r*nscfrysrh*ktfk Frame B: ---KKVTIAEAKEIFEKQYRDLYTVSQDVTKLAIQSAEQNGIVFLDEIDKICTSRESIKN G

  20. NF-1 Dependent Gene Regulation in Drosophila Melanogaster

    National Research Council Canada - National Science Library

    Zhong, Yi

    2004-01-01

    .... We have used an Affymetrix whole genome chip, containing all 13,500 genes of the fruit fly Drosophila, to identify 93 genes with altered expression patterns in flies that have no NF1 protein compared...

  1. Angiogenesis and Therapeutic Approaches to NF1 Tumors

    National Research Council Canada - National Science Library

    Muir, David F

    2007-01-01

    .... Invivo and in vitro models were used to firmly conclude that Nf1 haploinsufficiency in endothelial cells results inexaggerated proliferation and angiogenesis in response to key pro-angiogenic factors...

  2. Pathogenesis of Germline and Somatic NF1 Rearrangements

    Science.gov (United States)

    1998-10-01

    tilt of the occlusal plane upwards to the left and severe malocclusion class II with left cross-bite. Eye examination documented visual acuities of 6...9 on the right and 6/12 on the left, mild hypermetropia, mild amblyopia , divergent strabismus and Lisch nodules. He had minor webbing of the neck... therapy -related myeloid leukemias in Nf +1- mice show both LOH and disomy at the NF1 locus (N. Mahgoub et al, submitted). How do the LOH regions

  3. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    These clinical guidelines outline the criteria and recommendations for diagnostic and genetic work-up of families suspected of von Hippel-Lindau disease (vHL), as well as recommendations for prophylactic surveillance for vHL patients. The guideline has been composed by the Danish Coordination Group...... for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations...... of the disease, and/or in individuals with a vHL-associated manifestation; i.e. a hemangioblastoma in the retina or the central nervous system, familial or bilateral pheochromocytomas, familial, multiple, or early onset renal cell carcinomas, and in individuals with an endolymphatic sac tumour in the inner ear...

  4. The handwriting performance of children with NF1.

    Science.gov (United States)

    Gilboa, Yafit; Josman, Naomi; Fattal-Valevski, Aviva; Toledano-Alhadef, Hagit; Rosenblum, Sara

    2010-01-01

    The objective of this study was to analyze the process and product of handwriting among children with Neurofibromatosis Type 1 (NF1) in comparison to those of Typically Developing (TD) children. Children with NF1 are at risk for some cognitive deficits, a wide range of deficits in perceptual skills and, motor and visual-motor integration skills which may interfere with handwriting competency, which is an essential ingredient for success at school. Participants were 30 NF1 children and 30 age and gender matched TD children, between the ages 8 and 16.08. The handwriting performance of children with NF1 was evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI), for copying text and free style writing tasks, using: (1) Computerized Penmanship Evaluation Tool (ComPET) to assess mechanical aspects of the writing process. (2) The Hebrew Handwriting Evaluation (HHE) to examine product legibility. (3) The Six-Trait Writing Model to judge the quality of the written product. Significant differences between the NF1 children and the control group were found in the process and product measures. Significant correlations were found between the VMI, the ComPET, the HHE and the Six-Trait Writing Model variables for both groups. We suggest a possible relationship between executive dysfunction and poor performance in handwriting.

  5. Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.

    Science.gov (United States)

    Pack, S D; Zbar, B; Pak, E; Ault, D O; Humphrey, J S; Pham, T; Hurley, K; Weil, R J; Park, W S; Kuzmin, I; Stolle, C; Glenn, G; Liotta, L A; Lerman, M I; Klausner, R D; Linehan, W M; Zhuang, Z

    1999-11-01

    von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W. M. Linehan et al., J. Am. Med. Assoc., 273: 564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76: 381-391, 1997; W. M. Linehan and R. D. Klausner, In: B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp. 455-473, McGraw-Hill, 1998]. The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. Germline mutations in the VHL gene have been detected in the majority of VHL kindreds. The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55: 1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4: 2233-2237, 1995; F. Chen et al., Hum. Mutat., 5: 66-75, 1995; E. R. Maher et al., J. Med. Genet., 33: 328-332, 1996; B. Zbar, Cancer Surv., 25: 219-232, 1995). Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12: 417-423, 1998). In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions. We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus. We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus. We then tested six phenotypically normal offspring from four of these VHL families: two were found to carry the deletion and the other four were deletion-free. In addition, germline mosaicism of the VHL gene was identified in

  6. Molecular Regulation of Endothelial Cells by NF-1

    Science.gov (United States)

    2013-01-01

    malformations, aneurysms, and hypertension. As a consequence these patients show a markedly elevated risk of cerebrovascular accidents [2]. Previous...associated cerebrovascular disease (Friedman, Arbiser et al. 2002). Thus, a better understanding of the role of NF1 in the vasculature is 2 an essential...vasculopathies including malformations, aneurysms, hypertension and consequently there is a markedly elevated risk of cerbrovascular accidents

  7. The Role of Cumulative Genetic Defeats in NF1 Tumorigenesis

    Science.gov (United States)

    2000-10-01

    without LOH of the NF1 tumors’ slow and limited growth, and lack of gene. Biochem Biophys Res Comm 234:346-350. Decker H-JH, Cannizzaro LA, Mendez MJ, Leong... Caro - lina; and the 4 Department of Pediatrics, Division of Genetics, University of Florida, Gaines- Center, Durham. ville, Florida L. Messiaen

  8. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations....../MRI of the abdomen, e) annual plasma-metanephrine, plasma-normetanephrine, and plasma-chromogranin A tests, and f) annual hearing examination at a department of audiology. It is advised that one doctor takes on the responsibility of coordination of and referral to the many examinations, and the communication...

  9. Konsulent året rundt

    DEFF Research Database (Denmark)

    Stenderup, Mogens Larsen; Næsby, Torben

    Udgangspunktet for indholdet i Konsulent året rundt har været konsulenttjenesten i Aalborg Kommunes Reggio Emilia projekt. Konsulenter spiller en væsentlig rolle i de pædagogiske analyser og fungerer som en helt integreret del af praksis i denne filosofi. Derfor får konsulentarbejdet en helt...

  10. Familial Non-VHL Clear Cell Renal Cell Carcinoma

    Science.gov (United States)

    ... from the mother and 1 inherited from the father. Although a specific gene has not been discovered, familial non-VHL CCRCC appears to follow an autosomal dominant inheritance pattern, in which a mutation happens in ...

  11. Clinical and Molecular Consequences of NF1 Microdeletion

    Science.gov (United States)

    2009-08-01

    intriguing possibility that MLH1 deficiency predisposes to NF1 and early onset extracolonic tumors.[120,121] Germline heterozygous inactivating mutations...in MLH1 cause inefficient DNA mismatch repair, with the consequent increase in mutation frequency and susceptibility to hereditary nonpolyposis...colorectal cancer (reviewed in Ref. [122]). Two rare and independent cases of con- sanguineous marriages between MLH1 heterozygous first cousins each

  12. Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.

    Science.gov (United States)

    Lanikova, Lucie; Lorenzo, Felipe; Yang, Chunzhang; Vankayalapati, Hari; Drachtman, Richard; Divoky, Vladimir; Prchal, Josef T

    2013-05-09

    Germline von Hippel-Lindau (VHL) gene mutations underlie dominantly inherited familial VHL tumor syndrome comprising a predisposition for renal cell carcinoma, pheochromocytoma/paraganglioma, cerebral hemangioblastoma, and endolymphatic sac tumors. However, recessively inherited congenital polycythemia, exemplified by Chuvash polycythemia, has been associated with 2 separate 3' VHL gene mutations in exon 3. It was proposed that different positions of loss-of-function VHL mutations are associated with VHL syndrome cancer predisposition and only C-terminal domain-encoding VHL mutations would cause polycythemia. However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors. We show that VHL(P138L) has perturbed interaction with hypoxia-inducible transcription factor (HIF)1α. Further, VHL(P138L) protein has decreased stability in vitro. Similarly to what was reported in Chuvash polycythemia and some other instances of HIFs upregulation, VHL(P138L) erythroid progenitors are hypersensitive to erythropoietin. Interestingly, the level of RUNX1/AML1 and NF-E2 transcripts that are specifically upregulated in acquired polycythemia vera were also upregulated in VHL(P138L) granulocytes.

  13. Motor dysfunction in NF1: Mediated by attention deficit or inherent to the disorder?

    Science.gov (United States)

    Haas-Lude, Karin; Heimgärtner, Magdalena; Winter, Sarah; Mautner, Victor-Felix; Krägeloh-Mann, Ingeborg; Lidzba, Karen

    2018-01-01

    Attention deficit and compromised motor skills are both prevalent in Neurofibromatosis type 1 (NF1), but the relationship is unclear. We investigated motor function in children with NF1 and in children with Attention Deficit/Hyperactivity Disorder (ADHD), and explored if, in patients with NF1, attention deficit influences motor performance. Motor performance was measured using the Movement Assessment Battery for Children (M-ABC) in 71 children (26 with NF1 plus ADHD, 14 with NF1 without ADHD, and 31 with ADHD without NF1) aged 6-12 years. There was a significant effect of group on motor performance. Both NF1 groups scored below children with ADHD without NF1. Attention performance mediated motor performance in children with ADHD without NF1, but not in children with NF1. Motor function is not mediated by attention performance in children with NF1. While in ADHD, attention deficit influences motor performance, motor problems in NF1 seem to be independent from attention deficit. This argues for different pathomechanisms in these two groups of developmental disorders. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  14. Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas

    Directory of Open Access Journals (Sweden)

    Christ Ordookhanian

    2017-08-01

    Full Text Available Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel–Lindau (VHL syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia-inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions.

  15. Drug Response and Resistance in Advanced NF-1-Associated Cancers

    Science.gov (United States)

    2015-07-01

    Neurofibromatosis 1: closing the GAP between mice and men. Current opinion in genetics & development. 2003;13(1):20-7. 3. Maris JM, Wiersma SR, Mahgoub N...13. Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M, Shannon K. Homozygous inactivation of the NF1 gene in bone marrow cells from children...1998;7(8):1261-8. 54. Bollag G, Adler F, elMasry N, McCabe PC, Conner E, Thompson P, McCormick F, Shannon K. Biochemical characterization of a novel KRAS

  16. pVHL's kryptonite: E2-EPF UCP.

    Science.gov (United States)

    Ohh, Michael

    2006-08-01

    E2-EPF ubiquitin carrier protein (UCP) is a member of an E2 family of enzymes that catalyzes the ligation of ubiquitin to proteins targeted for destruction by the proteasome. UCP is overexpressed in common human cancers, suggesting its involvement in oncogenesis, but a physiologic target of UCP has not been identified. In a recent report published in Nature Medicine, Jung et al. identified von Hippel-Lindau (VHL) tumor suppressor protein, which targets the alpha subunit of hypoxia-inducible factor (HIF) for ubiquitin-mediated destruction, as a bona fide substrate of UCP and demonstrated a potential pVHL-HIF pathway-dependent role for UCP in cancer development.

  17. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

    NARCIS (Netherlands)

    Koczkowska, M. (Magdalena); Chen, Y. (Yunjia); Callens, T. (Tom); Gomes, A. (Alicia); Sharp, A. (Angela); Johnson, S. (Sherrell); Hsiao, M.-C. (Meng-Chang); Chen, Z. (Zhenbin); Balasubramanian, M. (Meena); Barnett, C.P. (Christopher P.); Becker, T.A. (Troy A.); Ben-Shachar, S. (Shay); D.R. Bertola (Débora Romeo); J.O. Blakeley (Jaishri O.); Burkitt-Wright, E.M.M. (Emma M.M.); Callaway, A. (Alison); Crenshaw, M. (Melissa); Cunha, K.S. (Karin S.); Cunningham, M. (Mitch); M.D. D'Agostino (Maria Daniela); K. Dahan (Karin); De Luca, A. (Alessandro); A. Destrée (Anne); Dhamija, R. (Radhika); Eoli, M. (Marica); Evans, D.G.R. (D. Gareth R.); Galvin-Parton, P. (Patricia); George-Abraham, J.K. (Jaya K.); K.W. Gripp (Karen); Guevara-Campos, J. (Jose); Hanchard, N.A. (Neil A.); Hernández-Chico, C. (Concepcion); Immken, L. (LaDonna); S. Janssens (Sandra); K.J. Jones (Kristi); Keena, B.A. (Beth A.); Kochhar, A. (Aaina); Liebelt, J. (Jan); Martir-Negron, A. (Arelis); Mahoney, M.J. (Maurice J.); I. Maystadt (Isabelle); McDougall, C. (Carey); M. McEntagart (Meriel); N.J. Mendelsohn; Miller, D.T. (David T.); G. Mortier (Geert); J. Morton (Jenny); Pappas, J. (John); S.R. Plotkin (Scott R.); Pond, D. (Dinel); Rosenbaum, K. (Kenneth); Rubin, K. (Karol); Russell, L. (Laura); Rutledge, L.S. (Lane S.); Saletti, V. (Veronica); Schonberg, R. (Rhonda); Schreiber, A. (Allison); Seidel, M. (Meredith); Siqveland, E. (Elizabeth); D.W. Stockton (David); Trevisson, E. (Eva); N.J. Ullrich (Nicole J.); M. Upadhyaya (Meena); A.S. Thornton (Andrew); H. Verhelst (H.); M.R. Wallace (Margaret); Yap, Y.-S. (Yoon-Sim); Zackai, E. (Elaine); Zonana, J. (Jonathan); Zurcher, V. (Vickie); K. Claes (Kathleen); Martin, Y. (Yolanda); B. Korf (Bruce); E. Legius (Eric); L.M. Messiaen (Ludwine)

    2018-01-01

    textabstractNeurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations

  18. Von Hippel-Lindau (VHL inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.

    Directory of Open Access Journals (Sweden)

    Lee E Moore

    2011-10-01

    Full Text Available Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs. VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5. Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20-1.31 and current: OR = 0.56 (0.32-0.99; P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.

  19. Sediments of a retting yard

    Digital Repository Service at National Institute of Oceanography (India)

    Remani, K.N.; Venugopal, P.; Devi, K.S.; Unnithan, R.V.

    (av. 46.8 and 92.3 mg/g respectively) compared to the reference station (20.6 and 48.9 mg/g) and published data on estuarine sediments.C/N ratios were consistently higher in the retting yard. Organic nitrogen, however,did not show this trend. Annual...

  20. ret en daarna

    NARCIS (Netherlands)

    Dommering, E.; Geus, M.J.; Hins, A.W.; Kroes, Q.R.; Nieuwenhuis, A.J.; Pietermaat, E.C.; Turner, C.J.; Voorhoof, D.

    2013-01-01

    In de zaak Féret1 veroordeelde het EHRM de haatzaaiende politicus voor discriminatie en aanzetten tot racisme, zonder dat in concreto een daad tot aanzetten van geweld of discriminatie door de nationale rechter was vastgesteld. Dit blijft, ondanks interne discussie in het Hof, vaste jurisprudentie.

  1. Retort to Religious Critics of RET.

    Science.gov (United States)

    Nardi, Thomas J.

    This paper is concerned with people who contact clergymen for counseling who could benefit from the short-term directive therapeutic approach of Rational Emotive Therapy (RET) and the reluctance of clergymen to use RET. The integration of the precepts of Christianity and the concepts of RET is considered. This paper is specifically a response to…

  2. Comparative Evaluation of Physical and Structural Properties of Water Retted and Non-retted Flax Fibers

    Directory of Open Access Journals (Sweden)

    Vijaya Raghavan

    2013-10-01

    Full Text Available Flax stems of Modran variety were subjected to water retting under laboratory conditions and its physical properties were compared with non-retted fibers. Physical properties including percentage of impurities, weighted average length, linear density, tenacity and elongation were analyzed and the results were compared. The analysis of retted and non-retted flax fibers showed that retting is the most important step in the processing of flax fibers and it directly affects quality attributes like strength, fineness, and homogeneity. Scanning Electron microscope images of fibers were also analyzed and the retted fibers showed much cleaner surface when compared to decorticated non-retted fibers.

  3. Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only

    Directory of Open Access Journals (Sweden)

    D.G. Evans

    2016-05-01

    Interpretation: RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥6 CAL that they are unlikely to have NF1.

  4. A new nonsense mutation in the NF1 gene with neurofibromatosis-Noonan syndrome phenotype.

    Science.gov (United States)

    Yimenicioğlu, Sevgi; Yakut, Ayten; Karaer, Kadri; Zenker, Martin; Ekici, Arzu; Carman, Kürşat Bora

    2012-12-01

    Neurofibromatosis-Noonan syndrome is a rare autosomal dominant disorder which combines neurofibromatosis type 1 (NF1) features with Noonan syndrome. NF1 gene mutations are reported in the majority of these patients. Sequence analysis of the established genes for Noonan syndrome revealed no mutation; a heterozygous NF1 point mutation c.7549C>T in exon 51, creating a premature stop codon (p.R2517X), had been demonstrated. Neurofibromatosis-Noonan syndrome recently has been considered a subtype of NF1 and caused by different NF1 mutations. We report the case of a 14-year-old boy with neurofibromatosis type 1 with Noonan-like features, who complained of headache with triventricular hydrocephaly and a heterozygous NF1 point mutation c.7549C>T in exon 51.

  5. Phospholamban Is Downregulated by pVHL-Mediated Degradation through Oxidative Stress in Failing Heart

    Directory of Open Access Journals (Sweden)

    Shunichi Yokoe

    2017-10-01

    Full Text Available The E3 ubiquitin ligase, von Hippel–Lindau (VHL, regulates protein expression by polyubiquitination. Although the protein VHL (pVHL was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in hearts from two types of genetically dilated cardiomyopathy (DCM mice models. In comparison with the wild-type mouse, both DCM mice models showed a significant reduction in the expression of phospholamban (PLN, a potent inhibitor of sarco(endoplasmic reticulum Ca2+-ATPase, and enhanced interaction between pVHL and PLN. To clarify whether pVHL is involved in PLN degradation in failing hearts, we used carbonylcyanide m-chlorophenylhydrazone (CCCP, a mitochondrial membrane potential (MMP-lowering reagent, to mimic the heart failure condition in PLN-expressing HEK293 cells and found that CCCP treatment resulted in PLN degradation and increased interaction between PLN and pVHL. However, these effects were reversed with the addition of N-acetyl-l-cysteine. Furthermore, the co-transfection of VHL and PLN in HEK293 cells decreased PLN expression under oxidative stress, whereas knockdown of VHL increased PLN expression both under normal and oxidative stress conditions. Together, we propose that oxidative stress upregulates pVHL expression to induce PLN degradation in failing hearts.

  6. Forårets urter

    DEFF Research Database (Denmark)

    Jensen, Kirsten

    2016-01-01

    Om foråret kommer der liv i naturen. Planter og dyr får en ny begyndelse. Fugleæg, dyreunger, små nye træer i skovbunden og lysegrønne planter dukker op. Forårsmånederne hedder marts, april og maj. Her pibler alt det grønne op ad jorden. Meget af det kan faktisk spises, selvom vi kalder det ukrud...

  7. VHL type 2B mutations retain VBC complex form and function.

    Directory of Open Access Journals (Sweden)

    Kathryn E Hacker

    Full Text Available von Hippel-Lindau disease is characterized by a spectrum of hypervascular tumors, including renal cell carcinoma, hemangioblastoma, and pheochromocytoma, which occur with VHL genotype-specific differences in penetrance. VHL loss causes a failure to regulate the hypoxia inducible factors (HIF-1alpha and HIF-2alpha, resulting in accumulation of both factors to high levels. Although HIF dysregulation is critical to VHL disease-associated renal tumorigenesis, increasing evidence points toward gradations of HIF dysregulation contributing to the degree of predisposition to renal cell carcinoma and other manifestations of the disease.This investigation examined the ability of disease-specific VHL missense mutations to support the assembly of the VBC complex and to promote the ubiquitylation of HIF. Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF. We additionally demonstrated that Type 2B mutant pVHL forms a remnant VBC complex containing the active members ROC1 and Cullin-2 which retains the ability to ubiquitylate HIF-1alpha.Our results suggest that subtypes of VHL mutations support an intermediate level of HIF regulation via a remnant VBC complex. These findings provide a mechanism for the graded HIF dysregulation and genetic predisposition for cancer development in VHL disease.

  8. VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells.

    Science.gov (United States)

    Bindra, Ranjit S; Vasselli, James R; Stearman, Robert; Linehan, W Marston; Klausner, Richard D

    2002-06-01

    Renal cell carcinoma is associated with mutation of the von Hippel-Lindau (VHL) tumor suppressor gene. Cell lines derived from these tumors cannot exit the cell cycle when deprived of growth factors, and the ability to exit the cell cycle can be restored by the reintroduction of wild-type protein VHL (pVHL). Here, we report that cyclin D1 is overexpressed and remains inappropriately high in during contact inhibition in pVHL-deficient cell lines. In addition, hypoxia increased the expression of cyclin D1 specifically in pVHL-negative cell lines into which pVHL expression was restored. Hypoxic-induction of cyclin D1 was not observed in other pVHL-positive cell lines. This suggests a model whereby in some kidney cell types, pVHL may regulate a proliferative response to hypoxia, whereas the loss of pVHL leads to constitutively elevated cyclin D1 and abnormal proliferation under normal growth conditions.

  9. Modulation of Ras Signaling by NF1 and CRKL in Development

    National Research Council Canada - National Science Library

    Imamoto, Akira

    2003-01-01

    Mutations in the NF1 gene are the genetic basis of neurofibromatosis type I, a common genetic disorder which predisposes the patient to neoplasia in the peripheral nervous system as well as other tissues...

  10. Receptor Tyrosine Kinases as Targets for Treatment of Peripheral Nerve Sheath Tumors in NF 1 Patients

    National Research Council Canada - National Science Library

    Mautner, Victor-Felix

    2007-01-01

    .... The only available but unsatisfying therapy is surgical tumor resection. The purpose of this study is the preclinical testing of multiple available tyrosine kinase inhibitors for NF1-associated MPNST using in vitro and in vivo systems...

  11. Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors

    Science.gov (United States)

    2016-10-01

    development of the principal discipline(s) of the project? • We have learned that the drug PEGPH20, which degrades a component of connective tissue called...AWARD NUMBER: W81XWH-15-1-0114 TITLE: Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors PRINCIPAL INVESTIGATOR...14 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER NF140089 Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors 5b

  12. Progression of Epididymal Maldevelopment Into Hamartoma-like Neoplasia in VHL Disease

    Directory of Open Access Journals (Sweden)

    Gautam U. Mehta

    2008-10-01

    Full Text Available Inactivation of the von Hippel-Lindau (VHL gene and activation of the hypoxia-inducible factor (HIF in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes. Areas of interest were genetically analyzed by tissue microdissection, immunohistochemistry for HIF and markers for mesonephric differentiation, and in situ hybridization for HIF downstream target vascular endothelial growth factor. Structural analysis of the epididymides revealed marked deviations from the regular anatomic structure resulting from impaired organogenesis. Selected efferent ductules were represented by disorganized mesonephric cells, and the maldeveloped mesonephric material was VHL-deficient by allelic deletion analysis. Furthermore, we observed maldeveloped mesonephric material near cystic structures, which were also VHL-deficient and were apparent derivatives of maldeveloped material. Finally, a subset of VHL-deficient cells was structurally integrated in regular efferent ductules; proliferation of intraductular VHL-deficient cells manifests itself as papillary growth into the ductular lumen. Furthermore, we clarify that that there is a pathogenetic continuum between microscopic tumorlets and formation of tumor. In multiple locations, three-dimensional reconstruction revealed papillary growth to extend deeply into ductular lumina, indicative of progression into early hamartoma-like neoplasia. We conclude epididymal tumorigenesis in VHL disease to occur in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation.

  13. Retting of Flax by Aspergillus niger

    Science.gov (United States)

    De França, F. P.; Rosemberg, J. A.; De Jesus, A. M.

    1969-01-01

    In this study, retting was carried out by Aspergillus niger. The pH, galacturonic acid (GA), and total reducing sugar were determined; the end point was identified by the classic empirical processes and by the maximal GA content of the retting water. The process gave clear and resistent fibers, and the retting time was similar to that of current industrial processes with bacterial enzymes. Control of total acidity was not required, since the pH remained close to neutrality throughout the entire process. PMID:16349835

  14. RET is a potential tumor suppressor gene in colorectal cancer

    Science.gov (United States)

    Luo, Yanxin; Tsuchiya, Karen D.; Park, Dong Il; Fausel, Rebecca; Kanngurn, Samornmas; Welcsh, Piri; Dzieciatkowski, Slavomir; Wang, Jianping; Grady, William M.

    2012-01-01

    Cancer arises as the consequence of mutations and epigenetic alterations that activate oncogenes and inactivate tumor suppressor genes. Through a genome-wide screen for methylated genes in colon neoplasms, we identified aberrantly methylated RET in colorectal cancer. RET, a transmembrane receptor tyrosine kinase and a receptor for the GDNF-family ligands, was one of the first oncogenes to be identified and has been shown to be an oncogene in thyroid cancer and pheochromocytoma. However, unexpectedly, we found RET is methylated in 27% of colon adenomas and in 63% of colorectal cancers, and now provide evidence that RET has tumor suppressor activity in colon cancer. The aberrant methylation of RET correlates with decreased RET expression, whereas the restoration of RET in colorectal cancer cell lines results in apoptosis. Furthermore, in support of a tumor suppressor function of RET, mutant RET has also been found in primary colorectal cancer. We now show that these mutations inactivate RET, which is consistent with RET being a tumor suppressor gene in the colon. These findings suggest that the aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation and that RET can serve as a tumor suppressor gene in the colon. Moreover, the increased frequency of methylated RET in colon cancers compared to adenomas suggests RET inactivation is involved in the progression of colon adenomas to cancer. PMID:22751117

  15. The Roles of VHL-Dependent Ubiquitination in Signaling and Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qing [Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (United States); Yang, Haifeng, E-mail: qing_zhang@dfci.harvard.edu [Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH (United States); Haifeng Yang, E-mail: yangh2@ccf.org [Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, NB-40, 9500 Euclid Avenue, Cleveland, OH 44195 (United States)

    2012-04-12

    The function of tumor suppressor VHL is compromised in the vast majority of clear cell renal cell carcinoma, and its mutations or loss of expression was causal for this disease. pVHL was found to be a substrate recognition subunit of an E3 ubiquitin ligase, and most of the tumor-derived mutations disrupt this function. pVHL was found to bind to the alpha subunits of hypoxia-inducible factor (HIF) and promote their ubiquitination and proteasomal degradation. Proline hydroxylation on key sites of HIFα provides the binding signal for pVHL E3 ligase complex. Beside HIFα, several other VHL targets have been identified, including activated epidermal growth factor receptor (EGFR), RNA polymerase II subunits RPB1 and hsRPB7, atypical protein kinase C (PKC), Sprouty2, β-adrenergic receptor II, and Myb-binding protein p160. HIFα is the most well studied substrate and has been proven to be critical for pVHL’s tumor suppressor function, but the activated EGFR and PKC and other pVHL substrates might also be important for tumor growth and drug response. Their regulations by pVHL and their relevance to signaling and cancer are discussed.

  16. Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression.

    Directory of Open Access Journals (Sweden)

    Marta Miró-Murillo

    Full Text Available Von Hippel Lindau (Vhl gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs, have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquitous tamoxifen-inducible recombinase Cre-ER(T2. Here, we characterize a widespread reduction in Vhl gene expression in Vhl(floxed-UBC-Cre-ER(T2 adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O(2 tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2 mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice.

  17. Compromised JMJD6 histone demethylase activity impacts on VHL gene repression in preeclampsia.

    Science.gov (United States)

    Alahari, Sruthi; Post, Martin; Rolfo, Alessandro; Weksberg, Rosanna; Caniggia, Isabella

    2018-01-24

    The von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5-7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive. We examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia. Placentae were obtained from early-onset (E-PE: n=56; <34 weeks of gestation) and late onset preeclampsia (L-PE: n=19; ≥ 34 weeks of gestation). Placentae from healthy normotensive age-matched preterm and term pregnancies (PTC: n=43; TC: n=23) were included as controls. We measured the activity of Jumonji domain containing protein 6 (JMJD6), a Fe2+ and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL. JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592 treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592-treated mice. Our study uncovers novel epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia. Copyright © 2018 Endocrine Society

  18. Øret i skyen

    DEFF Research Database (Denmark)

    Søndergaard, Morten

    2015-01-01

    Da Etisk Råd afholder sit årlige møde på Utzon Centret i Ålborg i oktober 2010 er ingen af deltagerne på mødet klar over, at et bioteknologisk øre lytter med. Det er et resultat af flere ret utrolige tilfældigheder og sammenfald: Nogen har ved en fejl tændt højttalersystemet i udstillingsrummene...... under den smukke konferencesal med udsigt ud over Limfjorden. I udstillingsrummene står et værk af den Australske kunstner Stelarc, Internet Ear, som er en del af udstillingen BIOTOPIA – Art in the Wet Zone. Internet Ear er, rent skulpturelt, en eksakt kopi af kunstnerens egen arm, hvorpå han for ca. 4...... år siden fik et ekstra øre indopereret. Situationen der udspiller sig i Utzon Centret er på flere måder symptomatisk for en række aktuelle kulturelle og samfundsmæssige tendenser. Den er endvidere emblematisk for de udfordringer, en cyber-museologi står overfor....

  19. VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.

    LENUS (Irish Health Repository)

    Nyhan, Michelle J

    2012-01-31

    BACKGROUND: von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-alpha (HIF-alpha), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP) A2\\/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue. METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by real-time RT-PCR. Expression of pVHL\\'s protein targets were determined by Western blotting in 17 paired patient samples. RESULTS: VHL genetic alterations were identified in 43.5% (10\\/23) of CCRCCs. HIF-1alpha, HIF-2alpha and CAIX were up-regulated in 88.2% (15\\/17), 100% (17\\/17) and 88.2% (15\\/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2\\/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status. CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), these data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

  20. Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions

    Directory of Open Access Journals (Sweden)

    Mußotter Tanja

    2012-10-01

    Full Text Available Abstract Background Neurofibromatosis type-1 (NF1 is caused by mutations of the NF1 gene at 17q11.2. In 95% of non-founder NF1 patients, NF1 mutations are identifiable by means of a comprehensive mutation analysis. 5-10% of these patients harbour microdeletions encompassing the NF1 gene and its flanking regions. NF1 is characterised by tumours of the peripheral nerve sheaths, the pathognomonic neurofibromas. Considerable inter- and intra-familial variation in expressivity of the disease has been observed which is influenced by genetic modifiers unrelated to the constitutional NF1 mutation. The number of plexiform neurofibromas (PNF in NF1 patients is a highly heritable genetic trait. Recently, SNP rs2151280 located within the non-coding RNA gene ANRIL at 9p21.3, was identified as being strongly associated with PNF number in a family-based association study. The T-allele of rs2151280, which correlates with reduced ANRIL expression, appears to be associated with higher PNF number. ANRIL directly binds to the SUZ12 protein, an essential component of polycomb repressive complex 2, and is required for SUZ12 occupancy of the CDKN2A/CDKN2B tumour suppressor genes as well as for their epigenetic silencing. Methods Here, we explored a potential association of PNF number and PNF volume with SNP rs2151280 in 29 patients with constitutional NF1 microdeletions using the exact Cochran-Armitage test for trends and the exact Mann–Whitney–Wilcoxon test. Both the PNF number and total tumour volume in these 29 NF1 patients were assessed by whole-body MRI. The NF1 microdeletions observed in these 29 patients encompassed the NF1 gene as well as its flanking regions, including the SUZ12 gene. Results In the 29 microdeletion patients investigated, neither the PNF number nor PNF volume was found to be associated with the T-allele of rs2151280. Conclusion Our findings imply that, at least in patients with NF1 microdeletions, PNF susceptibility is not associated with

  1. VHL-dependent regulation of a β-dystroglycan glycoform and glycogene expression in renal cancer.

    Science.gov (United States)

    Aggelis, Vassilis; Craven, Rachel A; Peng, Jianhe; Harnden, Patricia; Schaffer, Lana; Hernandez, Gilberto E; Head, Steven R; Maher, Eamonn R; Tonge, Robert; Selby, Peter J; Banks, Rosamonde E

    2013-11-01

    Identification of novel biomarkers and targets in renal cell carcinoma (RCC) remains a priority and one cellular compartment that is a rich potential source of such molecules is the plasma membrane. A shotgun proteomic analysis of cell surface proteins enriched by cell surface biotinylation and avidin affinity chromatography was explored using the UMRC2- renal cancer cell line, which lacks von Hippel-Lindau (VHL) tumour suppressor gene function, to determine whether proteins of interest could be detected. Of the 814 proteins identified ~22% were plasma membrane or membrane-associated, including several with known associations with cancer. This included β-dystroglycan, the transmembrane subunit of the DAG1 gene product. VHL-dependent changes in the form of β-dystroglycan were detected in UMRC2-/+VHL transfectants. Deglycosylation experiments showed that this was due to differential sialylation. Analysis of normal kidney cortex and conventional RCC tissues showed that a similar change also occurred in vivo. Investigation of the expression of genes involved in glycosylation in UMRC2-/+VHL cells using a focussed microarray highlighted a number of enzymes involved in sialylation; upregulation of bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) was validated in UMRC2- cells compared with their +VHL counterparts and also found in conventional RCC tissue. These results implicate VHL in the regulation of glycosylation and raise interesting questions regarding the extent and importance of such changes in RCC.

  2. Gonosomal mosaicism for an NF1 deletion in a sperm donor

    DEFF Research Database (Denmark)

    Callum, P; Messiaen, L M; Bower, P V

    2012-01-01

    Screening of gamete donors can reduce but cannot eliminate the risks for medical problems in donor-conceived offspring. We present a case of gonosomal mosaicism discovered in an anonymous sperm donor after receiving two reports of neurofibromatosis type 1 (NF1) in donor-conceived offspring...

  3. Do hormonal contraceptives stimulate growth of neurofibromas? A survey on 59 NF1 patients

    International Nuclear Information System (INIS)

    Lammert, Marge; Mautner, Victor-Felix; Kluwe, Lan

    2005-01-01

    Neurofibromas are benign tumors of the peripheral nerves and hallmark of neurofibromatosis type 1 (NF1), a tumor suppressor gene syndrome. Neurofibromas mostly start developing at puberty and can increase in size and number during pregnancy. Expression of progesterone receptors has been found in 75% of the tumors. Many female NF1 patients are thus concerned about the possibility that hormonal contraceptives may stimulate the growth of their neurofibromas. A survey was carried out on 59 female NF1 patients who are practicing or have practiced hormonal contraception to examine the effect of the various contraceptives on the growth of neurofibromas. Majority (53 out of 58) of patients who received oral estrogen-progestogen or pure progestogen preparations reported no associated tumor growth. In contrast, significant tumor growth was reported by two patients who received depot contraceptive containing high dose of synthetic progesterone. Oral contraceptives do not seem to stimulate the growth of neurofibromas in NF1 patients. High doses of progesterone might stimulate the growth of neurofibromas and deserve more caution

  4. Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1)

    NARCIS (Netherlands)

    Eijk, S. (S.); S.E. Mous (Sabine); G.C. Dieleman (Gwen); B. Dierckx (Bram); A.B. Rietman (André); P.F.A. de Nijs (Pieter); L.W. ten Hoopen (Leontine); A.S. Thornton (Andrew); Y. Elgersma (Ype); C.E. Catsman-Berrevoets (Coriene); R. Oostenbrink (Rianne); J.S. Legerstee (Jeroen)

    2018-01-01

    textabstractIn a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)—and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The

  5. The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W).

    Science.gov (United States)

    Tomasic, Nikica Ljubas; Piterkova, Lucie; Huff, Chad; Bilic, Ernest; Yoon, Donghoon; Miasnikova, Galina Y; Sergueeva, Adelina I; Niu, Xiaomei; Nekhai, Sergei; Gordeuk, Victor; Prchal, Josef T

    2013-04-01

    Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ∼six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations.

  6. La retórica en Internet

    Directory of Open Access Journals (Sweden)

    Roberto Gamonal Arroyo

    2012-04-01

    Full Text Available La Retórica, una disciplina antigua que data del siglo V a.C., está muy presente enInternet, un medio de comunicación social que nació en el siglo XX. La AntigüedadClásica renace para esclarecer este fenómeno de las nuevas tecnologías de lainformación. La Retórica ayuda a explicar el intrincado concepto de Internet, afacilitar su práctica cotidiana y a su construcción de una forma ordenada y sistemática.

  7. Injury Signals Cooperate with Nf1 Loss to Relieve the Tumor-Suppressive Environment of Adult Peripheral Nerve

    Directory of Open Access Journals (Sweden)

    Sara Ribeiro

    2013-10-01

    Full Text Available Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1−/− mSCs redifferentiate normally, whereas at the wound site Nf1−/− mSCs give rise to neurofibromas in both Nf1+/+ and Nf1+/− backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.

  8. Byggeri hele året 1

    DEFF Research Database (Denmark)

    Den voksende byggeaktivitet har medført, at både betydningen af og interessen for vinterbyggeri stadig øges. Denne tendens har været kraftigt understøttet af Boligministeriet, og Statens Byggeforskningsinstitut har derfor fundet det naturligt at sammenfatte tidligere anvisninger og de seneste års...

  9. Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression

    International Nuclear Information System (INIS)

    Woodfield, Sarah E.; Zhang, Linna; Scorsone, Kathleen A.; Liu, Yin; Zage, Peter E.

    2016-01-01

    Novel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models. Levels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes. Both primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC 50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib. Neuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify

  10. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I

    Directory of Open Access Journals (Sweden)

    Kairong Li

    2016-07-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681* and a missense mutation (c.2542G>C; p.Gly848Arg. The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681* allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F/Arg681*; DhhCre display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  11. Comparison of traditional field retting and Phlebia radiata Cel 26 retting of hemp fibres for fibre-reinforced composites

    DEFF Research Database (Denmark)

    Liu, Ming; Ale, Marcel Tutor; Kołaczkowski, Bartłomiej

    2017-01-01

    Classical field retting and controlled fungal retting of hemp using Phlebia radiata Cel 26 (a mutant with low cellulose degrading ability) were compared with pure pectinase treatment with regard to mechanical properties of the produced fibre/epoxy composites. For field retting a classification...

  12. Relationship between child epilepsy and MRI findings in von Recklinghausen Neurofibromatosis (NF 1)

    International Nuclear Information System (INIS)

    Yasujima, Hidehiro; Komatsu, Mikio; Sakurai, Takashi; Kodama, Soichi

    1994-01-01

    Fourteen children meeting the NIH consensus diagnostic criteria for NF 1 were evaluated at the Department of Pediatrics, Himeji Red Cross Hospital. MRI and EEG were examined in all patients, respectively. Four of 14 patients had a history of epilepsy, two had suffered West syndrome, one had complex partial seizures and one had secondary generalized partial epilepsy. Seven (50%) of 14 patients showed abnormal MRI; three (75%) of 4 patients with epilepsy and four (40%) of 10 patients with epilepsy showed low intensity on T 1 -weighted images and hyperintensity on T 2 -weighted images in the globus pallidus and brain stem. These results suggest that children with NF 1 have a spectrum of MRI abnormalities, irrespective of existence of epilepsy. (author)

  13. The mTORC1 Complex Is Significantly Overactivated in SDHX-Mutated Paragangliomas

    NARCIS (Netherlands)

    Oudijk, Lindsey; Papathomas, Thomas; de Krijger, Ronald; Korpershoek, Esther; Gimenez-Roqueplo, Anne Paule; Favier, Judith; Canu, Letizia; Mannelli, Massimo; Rapa, Ida; Currás-Freixes, Maria; Robledo, Mercedes; Smid, Marcel; Papotti, Mauro; Volante, Marco

    2017-01-01

    AIM: We aimed at exploring the activation pattern of the mTOR pathway in sporadic and hereditary pheochromocytomas (PCCs) and paragangliomas (PGLs). METHODS: A total of 178 PCCs and 44 PGLs, already characterized for the presence of germline mutations in VHL, RET, NF1, MAX, SDHA, SDHB, SDHC, and

  14. Identifying Neurofibromin Specific Regulatory Nodes for Therapeutic Targeting in NF1

    Science.gov (United States)

    2017-10-01

    suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704...imatinib, an approved BCR-ABL inhibitor. Given the robustness of these results, we believe K562 is an ideal cancer cell line system to interrogate ...fusion gene partner NOL4L greatly increased viability in the NF1 knockout cells, suggesting that these genes normally suppress growth through

  15. Genotyping of PCR-based polymorphisms and linkage-disequilibrium analysis at the NF1 locus

    Energy Technology Data Exchange (ETDEWEB)

    Purandare, S.M.; Viskochil, D.H.; Cawthon, R. [Univ. of Utah, Salt Lake City, UT (United States)] [and others

    1996-07-01

    Six polymorphism across the NF1 gene have been adapted for genotyping through application of PCR-based assays. Three exon-based polymorphisms - at positions 702, 2034, and 10647 in the NF1 cDNA - were genotyped by mutagenically separated PCR (MS-PCR). A fourth polymorphism, DV1.9, is an L1 insertion element in intron 30, and the other two polymorphisms, GXAlu and EVI-20, are short tandem repeats in intron 27b. All the polymorphisms were evaluated in a cohort of 110 CEPH individuals who previously had been analyzed by use of eight RFLPs at the NF1 locus. Pairwise linkage-disequilibrium analyses with the six PCR-based polymorphisms and their flanking markers demonstrated disequilibrium between all tested loci. Genotypes of the four diallelic polymorphisms (702, 2034, 10647, and DV1.9) were also evaluated in cohorts from the CEPH, African, and Japanese populations. The CEPH and Japanese cohorts showed similar heterozygosities and linkage-disequilibrium coefficients. The African cohort showed a higher degree of heterozygosity and lower linkage-disequilibrium values, compared with the CEPH and Japanese cohorts. 36 refs., 2 figs., 3 tabs.

  16. Drosophila Cancer Models Identify Functional Differences between Ret Fusions.

    Science.gov (United States)

    Levinson, Sarah; Cagan, Ross L

    2016-09-13

    We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Genetic analyses of the NF1 gene in Turkish neurofibromatosis type I patients and definition of three novel variants

    Directory of Open Access Journals (Sweden)

    Ulusal SD

    2017-06-01

    Full Text Available Neurofibromatosis Type I (NF1 is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. Loss of function mutations or deletions of the NF1 gene is responsible for NF1 disease. Involvement of various pathogenic variants, the size of the gene and presence of pseudogenes makes it difficult to analyze. We aimed to report the results of 2 years of multiplex ligation-dependent probe amplification (MLPA and next generation sequencing (NGS for genetic diagnosis of NF1 applied at our genetic diagnosis center. The MLPA, semiconductor sequencing and Sanger sequencing were performed in genomic DNA samples from 24 unrelated patients and their affected family members referred to our center suspected of having NF1. In total, three novel and 12 known pathogenic variants and a whole gene deletion were determined. We suggest that next generation sequencing is a practical tool for genetic analysis of NF1. Deletion/duplication analysis with MLPA may also be helpful for patients clinically diagnosed to carry NF1 but do not have a detectable mutation in NGS.

  18. Multiscale, Converging Defects of Macro-Porosity, Microstructure and Matrix Mineralization Impact Long Bone Fragility in NF1

    Science.gov (United States)

    Kühnisch, Jirko; Seto, Jong; Lange, Claudia; Schrof, Susanne; Stumpp, Sabine; Kobus, Karolina; Grohmann, Julia; Kossler, Nadine; Varga, Peter; Osswald, Monika; Emmerich, Denise; Tinschert, Sigrid; Thielemann, Falk; Duda, Georg; Seifert, Wenke; el Khassawna, Thaqif; Stevenson, David A.; Elefteriou, Florent; Kornak, Uwe; Raum, Kay; Fratzl, Peter; Mundlos, Stefan; Kolanczyk, Mateusz

    2014-01-01

    Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions. PMID:24465906

  19. Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Galanakis, Michael Carter Bisgaard; Budtz-Jørgensen, Esben

    2017-01-01

    the international diagnostic criteria. We found an overall penetrance of 87% at age 60 years. When considering only vHL patients who have not attended surveillance, 20% will still be asymptomatic at age 60 years. This should be considered in the context of genetic counselling, especially when assessing the risk...... of vHL in asymptomatic adult first-degree relatives who are often not genetically tested.European Journal of Human Genetics advance online publication, 14 December 2016; doi:10.1038/ejhg.2016.173....

  20. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

    DEFF Research Database (Denmark)

    Fisher, Rosalie; Horswell, Stuart; Rowan, Andrew

    2014-01-01

    are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient...... a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity....

  1. Retting effect of kenaf bast fiber by electron beam irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Hye Kyoung; Kangm Hyo Kyoung; Jeun, Joon Pyo; Kang, Phil Hyun [Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of)

    2010-06-15

    Kenaf (Hibiscus cannabinus) retting were separated from a kenaf bast fiber by a combination of Electron beam irradiation (EBI) and NaOH solution treatment. The methods were based on a 6% NaOH solution treatment after various doses of EBI. FT-IR spectroscopy demonstrated that the content of lignin and hemicellulose in the retted kenaf fibers decreased as the EBI dose increased. Specifically, the lignin in the retted kenaf fiber treated with 300 kGy of EBI was almost completely removed. The morphology of retted kenaf fibers were characterized by SEM image, and the studies showed that the fibrillated degree of retted kenaf fibers treated with various EBI doses and was increased as EBI dose increased. The retted kenaf fibers treated with the EBI at 300 kGy was uniformly fibrillated with 10 {approx} 30 {mu}m diameters.

  2. Retting effect of kenaf bast fiber by electron beam irradiation

    International Nuclear Information System (INIS)

    Shin, Hye Kyoung; Kangm Hyo Kyoung; Jeun, Joon Pyo; Kang, Phil Hyun

    2010-01-01

    Kenaf (Hibiscus cannabinus) retting were separated from a kenaf bast fiber by a combination of Electron beam irradiation (EBI) and NaOH solution treatment. The methods were based on a 6% NaOH solution treatment after various doses of EBI. FT-IR spectroscopy demonstrated that the content of lignin and hemicellulose in the retted kenaf fibers decreased as the EBI dose increased. Specifically, the lignin in the retted kenaf fiber treated with 300 kGy of EBI was almost completely removed. The morphology of retted kenaf fibers were characterized by SEM image, and the studies showed that the fibrillated degree of retted kenaf fibers treated with various EBI doses and was increased as EBI dose increased. The retted kenaf fibers treated with the EBI at 300 kGy was uniformly fibrillated with 10 ∼ 30 μm diameters

  3. Neurofibromatosis Type 1 (Nf1 and Pregnancy - Case With Positive Outcomes

    Directory of Open Access Journals (Sweden)

    Astrit M. Gashi

    2018-01-01

    Full Text Available Apregnancy is categorized as with high-risk when the life of the mother or the fetus becomes fragile due to various diseases. Many health problems can be manifested in women before pregnancy, during and after pregnancy. Some health problems can also begin in early adolescence with very light clinical signs, but during pregnancy because of the hormonal changes that may occur, lead to intensification of the disease. We report the management of a 26-year-old woman patient diagnosed with neurofibromatosis 1 (NF1, without any complications during pregnancy and childbirth.

  4. NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies.

    Science.gov (United States)

    Ponti, Giovanni; Martorana, Davide; Pellacani, Giovanni; Ruini, Cristel; Loschi, Pietro; Baccarani, Alessio; De Santis, Giorgio; Pollio, Annamaria; Neri, Tauro Maria; Mandel, Victor Desmond; Maiorana, Antonio; Maccio, Livia; Maccaferri, Monia; Tomasi, Aldo

    2014-06-01

    Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. Prognostic and predictive value of VHL gene alteration in renal cell carcinoma: a meta-analysis and review.

    Science.gov (United States)

    Kim, Bum Jun; Kim, Jung Han; Kim, Hyeong Su; Zang, Dae Young

    2017-02-21

    The von Hippel-Lindau (VHL) gene is often inactivated in sporadic renal cell carcinoma (RCC) by mutation or promoter hypermethylation. The prognostic or predictive value of VHL gene alteration is not well established. We conducted this meta-analysis to evaluate the association between the VHL alteration and clinical outcomes in patients with RCC. We searched PUBMED, MEDLINE and EMBASE for articles including following terms in their titles, abstracts, or keywords: 'kidney or renal', 'carcinoma or cancer or neoplasm or malignancy', 'von Hippel-Lindau or VHL', 'alteration or mutation or methylation', and 'prognostic or predictive'. There were six studies fulfilling inclusion criteria and a total of 633 patients with clear cell RCC were included in the study: 244 patients who received anti-vascular endothelial growth factor (VEGF) therapy in the predictive value analysis and 419 in the prognostic value analysis. Out of 663 patients, 410 (61.8%) had VHL alteration. The meta-analysis showed no association between the VHL gene alteration and overall response rate (relative risk = 1.47 [95% CI, 0.81-2.67], P = 0.20) or progression free survival (hazard ratio = 1.02 [95% CI, 0.72-1.44], P = 0.91) in patients with RCC who received VEGF-targeted therapy. There was also no correlation between the VHL alteration and overall survival (HR = 0.80 [95% CI, 0.56-1.14], P = 0.21). In conclusion, this meta-analysis indicates that VHL gene alteration has no prognostic or predictive value in patients with clear cell RCC.

  6. E2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis.

    Science.gov (United States)

    Park, Kyeong-Su; Kim, Ju Hee; Shin, Hee Won; Chung, Kyung-Sook; Im, Dong-Soo; Lim, Jung Hwa; Jung, Cho-Rok

    2015-10-26

    Missense mutation of VHL gene is frequently detected in type 2 VHL diseases and linked to a wide range of pVHL functions and stability. Certain mutant pVHLs retain ability to regulate HIFs but lose their function by instability. In this case, regulating of degradation of mutant pVHLs, can be postulated as therapeutic method. The stability and cellular function of missense mutant pVHLs were determine in HEK293T transient expressing cell and 786-O stable cell line. Ubiquitination assay of mutant VHL proteins was performed in vitro system. Anticancer effect of adenovirus mediated shUCP expressing was evaluated using ex vivo mouse xenograft assay. Three VHL missense mutants (V155A, L158Q, and Q164R) are directly ubiquitinated by E2-EPF UCP (UCP) in vitro. Mutant pVHLs are more unstable than wild type in cell. Missense mutant pVHLs interact with UCP directly in both in vitro and cellular systems. Lacking all of lysine residues of pVHL result in resistance to ubiquitination thereby increase its stability. Missense mutant pVHLs maintained the function of E3 ligase to ubiquitinate HIF-1α in vitro. In cells expressing mutant pVHLs, Glut-1 and VEGF were relatively upregulated compared to their levels in cells expressing wild-type. Depletion of UCP restored missense mutant pVHLs levels and inhibited cell growth. Adenovirus-mediated shUCP RNA delivery inhibited tumor growth in ex vivo mouse xenograft model. These data suggest that targeting of UCP can be one of therapeutic method in type 2 VHL disease caused by unstable but functional missense mutant pVHL.

  7. A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL syndrome type 2C

    Directory of Open Access Journals (Sweden)

    Rinkes Inne

    2007-10-01

    Full Text Available Abstract Background Von Hippel-Lindau (VHL disease is an autosomal dominant inherited disease. It is relatively recent that type 2C was identified as a separate group solely presenting with pheochromocytomas. As an illustration, an interesting case is presented of a pregnant woman with refractory hypertension. It proved to be the first manifestation of bilateral pheochromocytomas. The family history may indicate the diagnosis, but only identification of a germ line mutation in the DNA of a patient will confirm carriership. Case presentation A 27 year pregnant patient with intra uterine growth retardation presented with hypertension and pre-eclampsia. Magnetic resonance imaging revealed bilateral adrenal pheochromocytoma. She underwent laparoscopic adrenelectomy and a missense mutation (Gly93Ser in exon 1 of the VHL gene on chromosome 3 (p25 – p26 was shown in the patient, her father and her daughter confirming the diagnosis of VHL. Conclusion In almost all VHL families molecular genetic analysis of DNA will demonstrate an inherited mutation. Because of the involvement in several organs, periodic clinical evaluation should take place in a well coordinated, multidisciplinary setting. VHL disease can be classified into several subtypes. VHL type 2C patients present with pheochromocytomas without evidence of haemangioblastomas in the central nervous system and/or retina and a low risk of renal cell carcinoma. Therefore, in such families, periodic clinical screening can be focussed on pheochromocytomas.

  8. Computed tomography (CT) findings in 88 neurofibromatosis 1 (NF1) patients: Prevalence rates and correlations of thoracic findings

    Energy Technology Data Exchange (ETDEWEB)

    Ueda, Ken, E-mail: k-ueda@radiol.med.osaka-u.ac.jp [Department of Radiology, Osaka University Graduate School of Medicine (Japan); Honda, Osamu [Department of Radiology, Osaka University Graduate School of Medicine (Japan); Satoh, Yukihisa [Department of Diagnostic Radiology, Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan); Kawai, Misa; Gyobu, Tomoko; Kanazawa, Toru; Hidaka, Shojiro; Yanagawa, Masahiro [Department of Radiology, Osaka University Graduate School of Medicine (Japan); Sumikawa, Hiromitsu [Department of Diagnostic Radiology, Osaka Rosai Hospital (Japan); Tomiyama, Noriyuki [Department of Radiology, Osaka University Graduate School of Medicine (Japan)

    2015-06-15

    Highlights: • Various thoracic CT findings, including cysts, mediastinal masses, etc. were found. • Cysts show upper and peripheral dominant distribution. • The number, size, and distribution of the pulmonary cysts in NF-1 revealed significant correlation. • It is suspected that thoracic CT findings in NF-1 occur independently. - Abstract: Purpose: To evaluate the prevalence rates and the correlations of thoracic computed tomography (CT) findings of neurofibromatosis 1 (NF1) in 88 patients. Materials and methods: Chest CT images of 88 NF1 patients were independently reviewed by three observers, and the CT findings were evaluated. If abnormal findings were present, their number, size, and distribution were recorded. The prevalence rate of each CT finding was calculated, and the correlations between CT findings were analyzed. Results: Of the 88 cases, 13 were positive for cysts, 16 for emphysema, 8 for nodules, 8 for GGNs (ground glass nodules), 13 for mediastinal masses, 20 for scoliosis, 44 for subcutaneous nodules, and 34 for skin nodules. Cysts showed upper and peripheral dominant distributions. Regarding 13 mediastinal masses, 2 were diagnosed as malignant peripheral nerve sheath tumors (MPNSTs), 1 was diagnosed as primary lung cancer, 2 were diagnosed as lateral meningocele, 3 were diagnosed as neurofibromas, and the remaining 7 were considered neurofibromas. There was a significant correlation between the prevalence of subcutaneous nodules and that of skin nodules. Significant positive correlations were also seen between size and number, size and rate of central distribution, and number and rate of central distribution of cysts. Conclusion: Various CT findings were found in NF-1 patients, and the prevalence rates of subcutaneous and skin nodules were higher than other findings. Though the prevalence rates of subcutaneous nodules and skin nodules were significantly correlated, the other CT findings in NF-1 occurred independently. The number, size, and

  9. Computed tomography (CT) findings in 88 neurofibromatosis 1 (NF1) patients: Prevalence rates and correlations of thoracic findings

    International Nuclear Information System (INIS)

    Ueda, Ken; Honda, Osamu; Satoh, Yukihisa; Kawai, Misa; Gyobu, Tomoko; Kanazawa, Toru; Hidaka, Shojiro; Yanagawa, Masahiro; Sumikawa, Hiromitsu; Tomiyama, Noriyuki

    2015-01-01

    Highlights: • Various thoracic CT findings, including cysts, mediastinal masses, etc. were found. • Cysts show upper and peripheral dominant distribution. • The number, size, and distribution of the pulmonary cysts in NF-1 revealed significant correlation. • It is suspected that thoracic CT findings in NF-1 occur independently. - Abstract: Purpose: To evaluate the prevalence rates and the correlations of thoracic computed tomography (CT) findings of neurofibromatosis 1 (NF1) in 88 patients. Materials and methods: Chest CT images of 88 NF1 patients were independently reviewed by three observers, and the CT findings were evaluated. If abnormal findings were present, their number, size, and distribution were recorded. The prevalence rate of each CT finding was calculated, and the correlations between CT findings were analyzed. Results: Of the 88 cases, 13 were positive for cysts, 16 for emphysema, 8 for nodules, 8 for GGNs (ground glass nodules), 13 for mediastinal masses, 20 for scoliosis, 44 for subcutaneous nodules, and 34 for skin nodules. Cysts showed upper and peripheral dominant distributions. Regarding 13 mediastinal masses, 2 were diagnosed as malignant peripheral nerve sheath tumors (MPNSTs), 1 was diagnosed as primary lung cancer, 2 were diagnosed as lateral meningocele, 3 were diagnosed as neurofibromas, and the remaining 7 were considered neurofibromas. There was a significant correlation between the prevalence of subcutaneous nodules and that of skin nodules. Significant positive correlations were also seen between size and number, size and rate of central distribution, and number and rate of central distribution of cysts. Conclusion: Various CT findings were found in NF-1 patients, and the prevalence rates of subcutaneous and skin nodules were higher than other findings. Though the prevalence rates of subcutaneous nodules and skin nodules were significantly correlated, the other CT findings in NF-1 occurred independently. The number, size, and

  10. Trichloroethylene exposure and somatic mutations of the VHL gene in patients with Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Fevotte Joelle

    2007-11-01

    Full Text Available Abstract Background We investigated the association between exposure to trichloroethylene (TCE and mutations in the von Hippel-Lindau (VHL gene and the subsequent risk for renal cell carcinoma (RCC. Methods Cases were recruited from a case-control study previously carried out in France that suggested an association between exposures to high levels of TCE and increased risk of RCC. From 87 cases of RCC recruited for the epidemiological study, 69 were included in the present study. All samples were evaluated by a pathologist in order to identify the histological subtype and then be able to focus on clear cell RCC. The majority of the tumour samples were fixed either in formalin or Bouin's solutions. The majority of the tumours were of the clear cell RCC subtype (48 including 2 cystic RCC. Mutation screening of the 3 VHL coding exons was carried out. A descriptive analysis was performed to compare exposed and non exposed cases of clear cell RCC in terms of prevalence of mutations in both groups. Results In the 48 cases of RCC, four VHL mutations were detected: within exon 1 (c.332G>A, p.Ser111Asn, at the exon 2 splice site (c.463+1G>C and c.463+2T>C and within exon 3 (c.506T>C, p.Leu169Pro. No difference was observed regarding the frequency of mutations in exposed versus unexposed groups: among the clear cell RCC, 25 had been exposed to TCE and 23 had no history of occupational exposure to TCE. Two patients with a mutation were identified in each group. Conclusion This study does not confirm the association between the number and type of VHL gene mutations and exposure to TCE previously described.

  11. Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia-like Bone Phenotype.

    Science.gov (United States)

    Kamiya, Nobuhiro; Yamaguchi, Ryosuke; Aruwajoye, Olumide; Kim, Audrey J; Kuroyanagi, Gen; Phipps, Matthew; Adapala, Naga Suresh; Feng, Jian Q; Kim, Harry Kw

    2017-08-01

    Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi-system abnormalities, including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1-promoter. The conditional knockout (Nf1 cKO) mice displayed serum profile of a metabolic bone disorder with an osteomalacia-like bone phenotype. Serum FGF23 levels were 4 times increased in cKO mice compared with age-matched controls. In addition, calcium-phosphorus metabolism was significantly altered (calcium reduced; phosphorus reduced; parathyroid hormone [PTH] increased; 1,25(OH) 2 D decreased). Bone histomorphometry showed dramatically increased osteoid parameters, including osteoid volume, surface, and thickness. Dynamic bone histomorphometry revealed reduced bone formation rate and mineral apposition rate in the cKO mice. TRAP staining showed a reduced osteoclast number. Micro-CT demonstrated thinner and porous cortical bones in the cKO mice, in which osteocyte dendrites were disorganized as assessed by electron microscopy. Interestingly, the cKO mice exhibited spontaneous fractures in long bones, as found in NF1 patients. Mechanical testing of femora revealed significantly reduced maximum force and stiffness. Immunohistochemistry showed significantly increased FGF23 protein in the cKO bones. Moreover, primary osteocytes from cKO femora showed about eightfold increase in FGF23 mRNA levels compared with control cells. The upregulation of FGF23 was specifically and significantly inhibited by PI3K inhibitor Ly294002, indicating upregulation of FGF23 through PI3K in Nf1-deficient osteocytes. Taken together, these results indicate that Nf1 deficiency in osteocytes dramatically increases FGF23 production and causes a mineralization

  12. Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex.

    Science.gov (United States)

    Cardote, Teresa A F; Gadd, Morgan S; Ciulli, Alessio

    2017-06-06

    Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2 VHL complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL. The structure traps a closed state of full-length Cul2 and a new pose of Rbx1 in a trajectory from closed to open conformation. We characterize hotspots and binding thermodynamics at the interface between Cul2 and pVHL-EloBC and identify mutations that contribute toward a selectivity switch for Cul2 versus Cul5 recognition. Our findings provide structural and biophysical insights into the whole Cul2 complex that could aid future drug targeting. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  13. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo.

    Science.gov (United States)

    Ingram, D A; Yang, F C; Travers, J B; Wenning, M J; Hiatt, K; New, S; Hood, A; Shannon, K; Williams, D A; Clapp, D W

    2000-01-03

    Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's "two hit" model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1-/- murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W(41) mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras-mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W(41)) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types.

  14. Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells.

    Science.gov (United States)

    Chintalapudi, Mastan R; Markiewicz, Margaret; Kose, Nurgun; Dammai, Vincent; Champion, Kristen J; Hoda, Rana S; Trojanowska, Maria; Hsu, Tien

    2008-04-01

    The von Hippel-Lindau (VHL) protein serves as a negative regulator of hypoxia-inducible factor (HIF)-alpha subunits. Since HIF regulates critical angiogenic factors such as vascular endothelial growth factor (VEGF) and lesions in VHL gene are present in a majority of the highly vascularized renal cell carcinoma (RCC), it is believed that deregulation of the VHL-HIF pathway is crucial for the proangiogenic activity of RCC. Although VEGF has been confirmed as a critical angiogenic factor upregulated in VHL-mutant cells, the efficacy of antiangiogenic therapy specifically targeting VEGF signaling remains modest. In this study, we developed a three-dimensional in vitro assay to evaluate the ability of RCC cells to promote cord formation by the primary human dermal microvascular endothelial cells (HDMECs). Compared with VHL wild-type cells, VHL-mutant RCC cells demonstrated a significantly increased proangiogenic activity, which correlated with increased secretion of cysteine-rich 61 (Cyr61)/cysteine-rich 61-connective tissue growth factor-nephroblastoma overexpressed (CCN) 1, connective tissue growth factor (CTGF)/CCN2 and VEGF in conditioned culture medium. Both CCN proteins are required for HDMEC cord formation as shown by RNA interference knockdown experiments. Importantly, the proangiogenic activities conferred by the CCN proteins and VEGF are additive, suggesting non-overlapping functions. Expression of the CCN proteins is at least partly dependent on the HIF-2alpha function, the dominant HIF-alpha isoform expressed in RCC. Finally, immunohistochemical staining of Cyr61/CCN1 and CTGF/CCN2 in RCC tissue samples showed that increased expression of these proteins correlates with the loss of VHL protein expression. These findings strengthened the notion that the hypervascularized phenotype of RCC is afforded by multiple proangiogenic factors that function in parallel pathways.

  15. Epithelioid hemangioendothelioma and multiple thoraco-lumbar lateral meningoceles: two rare pathological entities in a patient with NF-1

    International Nuclear Information System (INIS)

    Reis, C.; Carneiro, E.; Fonseca, J.; Salgado, A.; Pereira, P.; Vaz, R.; Pinto, R.; Capelinha, A.F.; Lopes, J.M.

    2005-01-01

    Epithelioid hemangioendothelioma (EHE) is a rare vascular soft-tissue tumour of intermediate malignancy. Neurofibromatosis type I (NF-1) is a genetic syndrome associated with soft tissue sarcoma and higher risk of developing neoplasia. Lateral meningoceles are uncommon entities, being mostly associated with NF-1. We report a case of a 31-year-old woman, with NF-1 and past history of right thalamic/peduncular astrocytoma WHO grade II, admitted to the Neurosurgery Department in December 2003 due to severe low back pain, irradiating to the left leg without a radicular pattern. Thoraco-lumbar magnetic resonance imaging (MRI) showed a large left posterior paravertebral expansive lesion, bilateral and multiple thoraco-lumbar lateral meningoceles and dural ectasias with scalloping of the vertebral bodies. Biopsy of the paravertebral mass lesion disclosed EHE. We present this case because of the novel association between NF-1 and EHE, and the unusual aggressiveness of the neoplasia. Additionally, we highlight the co-existence of bilateral and multiple lateral meningoceles. (orig.)

  16. Nf1 Loss and Ras Hyperactivation in Oligodendrocytes Induce NOS-Driven Defects in Myelin and Vasculature

    Directory of Open Access Journals (Sweden)

    Debra A. Mayes

    2013-09-01

    Full Text Available Patients with neurofibromatosis type 1 (NF1 and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB developed, implicating a soluble mediator. Nitric oxide (NO can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3 were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients.

  17. Somatic RET mutation in a patient with pigmented adrenal pheochromocytoma

    NARCIS (Netherlands)

    Maison, Nicole; Korpershoek, Esther; Eisenhofer, Graeme; Robledo, Mercedes; de Krijger, Ronald; Beuschlein, Felix

    UNLABELLED: Pheochromocytomas (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest. Mutations in the RET-proto-oncogene are associated with sporadic pheochromocytoma, familial or sporadic medullary thyroid carcinoma (MTC) and multiple

  18. LOSS OF JAK2 REGULATION VIA VHL-SOCS1 E3 UBIQUITIN HETEROCOMPLEX UNDERLIES CHUVASH POLYCYTHEMIA

    Science.gov (United States)

    Russell, Ryan C.; Sufan, Roxana I.; Zhou, Bing; Heir, Pardeep; Bunda, Severa; Sybingco, Stephanie S.; Greer, Samantha N.; Roche, Olga; Heathcote, Samuel A.; Chow, Vinca W.K.; Boba, Lukasz M.; Richmond, Terri D.; Hickey, Michele M.; Barber, Dwayne L.; Cheresh, David A.; Simon, M. Celeste; Irwin, Meredith S.; Kim, William Y.; Ohh, Michael

    2011-01-01

    SUMMARY Chuvash polycythemia (CP) is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the von Hippel-Lindau (VHL) gene whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark features of CP such as hypersensitivity to erythropoietin are unclear. Here, we show that VHL directly binds suppressor of cytokine signalling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated (p)JAK2 for ubiquitin-mediated destruction. In contrast, CP-associated VHL mutants have altered affinity for SOCS1 and fail to engage and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reverses the disease phenotype in vhlR200W/R200W knock-in mice, a model that faithfully recapitulates human CP. These results reveal VHL as a SOCS1-cooperative negative regulator of JAK2 and provide compelling biochemical and preclinical evidence for JAK2- targeted therapy in CP patients. PMID:21685897

  19. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis.

    Science.gov (United States)

    Jung, Cho-Rok; Hwang, Kyung-Sun; Yoo, Jinsang; Cho, Won-Kyung; Kim, Jin-Man; Kim, Woo Ho; Im, Dong-Soo

    2006-07-01

    The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including hypoxia-inducible factor-1alpha (HIF-1alpha), which is involved in tumor progression and angiogenesis. It remains unclear, however, how pVHL is destabilized. Here we show that E2-EPF ubiquitin carrier protein (UCP) associates with and targets pVHL for ubiquitin-mediated proteolysis in cells, thereby stabilizing HIF-1alpha. UCP is detected coincidently with HIF-1alpha in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells. UCP level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway. Our results suggest that UCP helps stabilize HIF-1alpha and may be a new molecular target for therapeutic intervention in human cancers.

  20. Improvement of organoleptic quality of retted cassava products by alkali pretreatment of roots and addition of sodium nitrate during retting.

    Science.gov (United States)

    Ogbo, Frank C

    2003-12-15

    Alkali pretreatment of cassava roots before retting and addition of sodium nitrate during retting were used to manipulate the metabolism of microorganisms involved in cassava (Manihot esculenta Crantz) retting, as a method for removing the characteristic offensive odour of retted cassava products. Odour was assessed by organoleptic methods. The characteristics of fermentation of cassava by the traditional method (control) were as follows; aerobic mesophilic count (APC) on nutrient agar (NA) at 30 degrees C/48 h, attained a maximum of 2.3 x 10(7)/ml retting juice while counts on de Man Rogosa and Sharpe agar (MRS) at 30 degrees C/48 h were 1.6 x 10(8)/ml. Maximum titrable acidity was 0.062% lactic acid by weight of retting juice. Cassava was retted in 3 days and the product exhibited characteristic offensive odour. Addition of NaNO3 into retting water effectively removed odour at a concentration of 0.3 g/l. Maximum APC on NA/30 degrees C/48 h was 6.8 x 10(6)/ml. Counts on MRS/30 degrees C/48 h exceeded 2.4 x 10(9)/ml. Retting was complete in 3 days with a final titrable acidity of 0.068% of retting juice. Removal of odour likely resulted from selection of homo-fermentative lactic acid bacteria, thus producing mostly odourless lactic acid. Alkali pretreatment of roots before retting was efficacious in removing odour at a concentration of 10 g/l for 30 min. This fermentation was characterized by APC on NA/30 degrees C/48 h of 5.4 x 10(6)/ml; MRS/30 degrees C/48 h reached a maximum of only 10 x 10(4)/ml and correspondingly low titrable acidity of 0.003%. Low counts of lactic acid bacteria correlate well with the absence of odour in this sample. Both treatments did not adversely affect the detoxification process, yielding "foo-foo" with HCN levels lower than 10 mg/kg. Residual nitrates and nitrites of 30 mg/kg in the sodium nitrate-treated sample were also within the safe limits of 156 mg/kg allowed in many countries. Organoleptically improved samples were acceptable to

  1. A Phase 2 Trial on the Effect of Low-Dose Versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1)

    Science.gov (United States)

    2015-10-01

    versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1) 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1...regulatory processes have taken more time than anticipated in the Statement of Work. An IND from the FDA to use high-dose vitamin D in the NF1

  2. pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma

    DEFF Research Database (Denmark)

    Struckmann, K; Mertz, Kd; Steu, S

    2008-01-01

    Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to...

  3. An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots and Freckling. Part II. Other Skin Manifestations Characteristic of NF1. NF1 and Cancer.

    Science.gov (United States)

    Hernández-Martín, A; Duat-Rodríguez, A

    2016-01-01

    Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still based primarily on clinical observations. The 7 diagnostic criteria of the National Institutes of Health, which were established in 1988, include 3 skin manifestations (café-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas). The age at which these diagnostic lesions appear is variable: onset can be late in some patients while others never develop certain symptoms. Definitive diagnosis may therefore be delayed by years. Although the appearance of the characteristic café-au-lait spots and freckling in the early years of childhood are very suggestive of the disease, these signs are not pathognomonic and, in isolation, do not constitute sufficient evidence to establish a definitive diagnosis. Thus, other diagnoses should be considered in patients whose only symptoms are café-au-lait spots and freckling. By contrast, the presence of multiple cutaneous neurofibromas or at least 1 plexiform neurofibroma is a very specific indication of NF1. Identification of the different types of neurofibroma allows us to confirm the diagnosis and initiate appropriate management. Copyright © 2016 AEDV. Published by Elsevier España, S.L.U. All rights reserved.

  4. The homozygous VHL(D126N) missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.

    Science.gov (United States)

    Sarangi, Susmita; Lanikova, Lucie; Kapralova, Katarina; Acharya, Suchitra; Swierczek, Sabina; Lipton, Jeffrey M; Wolfe, Lawrence; Prchal, Josef T

    2014-11-01

    von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated. © 2014 Wiley Periodicals, Inc.

  5. Microtubular stability affects pVHL-mediated regulation of HIF-1alpha via the p38/MAPK pathway in hypoxic cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Miao Teng

    Full Text Available BACKGROUND: Our previous research found that structural changes of the microtubule network influence glycolysis in cardiomyocytes by regulating the hypoxia-inducible factor (HIF-1α during the early stages of hypoxia. However, little is known about the underlying regulatory mechanism of the changes of HIF-1α caused by microtubule network alternation. The von Hippel-Lindau tumor suppressor protein (pVHL, as a ubiquitin ligase, is best understood as a negative regulator of HIF-1α. METHODOLOGY/PRINCIPAL FINDINGS: In primary rat cardiomyocytes and H9c2 cardiac cells, microtubule-stabilization was achieved by pretreating with paclitaxel or transfection of microtubule-associated protein 4 (MAP4 overexpression plasmids and microtubule-depolymerization was achieved by pretreating with colchicine or transfection of MAP4 siRNA before hypoxia treatment. Recombinant adenovirus vectors for overexpressing pVHL or silencing of pVHL expression were constructed and transfected in primary rat cardiomyocytes and H9c2 cells. With different microtubule-stabilizing and -depolymerizing treaments, we demonstrated that the protein levels of HIF-1α were down-regulated through overexpression of pVHL and were up-regulated through knockdown of pVHL in hypoxic cardiomyocytes. Importantly, microtubular structure breakdown activated p38/MAPK pathway, accompanied with the upregulation of pVHL. In coincidence, we found that SB203580, a p38/MAPK inhibitor decreased pVHL while MKK6 (Glu overexpression increased pVHL in the microtubule network altered-hypoxic cardiomyocytes and H9c2 cells. CONCLUSIONS/SIGNIFICANCE: This study suggests that pVHL plays an important role in the regulation of HIF-1α caused by the changes of microtubular structure and the p38/MAPK pathway participates in the process of pVHL change following microtubule network alteration in hypoxic cardiomyocytes.

  6. Characteristics of scientific production in Special Education in Virtual Health Library (VHL: a bibliometric study

    Directory of Open Access Journals (Sweden)

    Luciana Pizzani

    2010-12-01

    Full Text Available Objective: To characterize, through bibliometric approach, the scientific literature in this Special Education in the databases of the Virtual Health Library (VHL. The VHL is coordinated by BIREME - Specialized Center of the Pan American Health Organization whose objective is to promote the dissemination and use of scientific information in health. Method: The research methodology was performed by observing the following steps: a literature review on education special and bibliometrics, data collection from the site of BIREME about the presence of special education in the databases, organization, processing and bibliometric analysis of data collected using the software MS Excel and Vantage Point. Results: indicators produced allow signal that the predominant language of scientific production was the Portuguese and the majority of records were written individually, the themes addressed were psychology and developmental psychology. Conclusion: These bibliometric indicators characterizing the state of the art of scientific literature in Special Education at the various bases Data Bireme and also showed a field of interconnections between Health Sciences and Special Education.

  7. Integrated proteomics identified novel activation of dynein IC2-GR-COX-1 signaling in neurofibromatosis type I (NF1) disease model cells.

    Science.gov (United States)

    Hirayama, Mio; Kobayashi, Daiki; Mizuguchi, Souhei; Morikawa, Takashi; Nagayama, Megumi; Midorikawa, Uichi; Wilson, Masayo M; Nambu, Akiko N; Yoshizawa, Akiyasu C; Kawano, Shin; Araki, Norie

    2013-05-01

    Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up- or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural

  8. NF1, Sp1 and HSF1 are synergistically involved in sulfide-induced sqr activation in echiuran worm Urechis unicinctus

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiaolong; Qin, Zhenkui; Li, Xueyu; Ma, Xiaoyu; Gao, Beibei; Zhang, Zhifeng, E-mail: zzfp107@ouc.edu.cn

    2016-06-15

    Highlights: • Sulfide activates sqr transcription against respiratory toxicity in Urechis unicinctus. • Sulfide increases expressions and activities of NF1, Sp1 and HSF1 in a time-dependent manner. • NF1 and Sp1 participate in both basal and early sulfide-induced sqr transcription. • HSF1 functions more significantly than NF1 and Sp1 in sulfide-induced sqr transcription. • Transcription factors NF1, Sp1 and HSF1 enhance sqr promoter activity synergistically. - Abstract: Background: Sulfide is a well-known environmental toxic substance. Mitochondrial sulfide oxidation is a main mechanism of sulfide detoxification in organisms, and sulfide: quinone oxidoreductase (SQR) is a key enzyme which is involved in transferring electrons from sulfide to ubiquinone and converting sulfide into thiosulfate. Previous studies have revealed the SQR-mediated mitochondrial sulfide oxidation exists in the echiuran worm Urechis unicinctus, and its sqr mRNA level increased significantly when the worm is exposed to sulfide. In this study, we attempt to reveal the synergistic regulation of transcription factors on sulfide-induced sqr transcription in U. unicinctus. Methods: ChIP and EMSA were used to identify the interactions between sqr proximal promoter (from −391 to +194 bp) and transcription factors NF1 (nuclear factor 1) and Sp1 (specificity protein 1). Site-directed mutation and transfection assays further revealed their binding sites and synergistic roles of HSF1, NF1 and Sp1 in the sqr transcription. When U. unicinctus were exposed to 150 μM sulfide, the expression levels and nuclear contents of NF1 and Sp1 were examined by Western blotting, and the binding contents between NF1 or Sp1 and the sqr promoter were also detected by ChIP. Results: Transcription factors NF1 and Sp1 were confirmed to interact with the sqr proximal promoter, and their binding sites were identified in −75 to −69 bp for NF1 and −210 to −201 bp for Sp1. Transfection assays showed mutation

  9. Når politik og journalistik, ret og krig blandes

    DEFF Research Database (Denmark)

    Harste, Gorm

    2007-01-01

    Artiklen analyserer den manglende politiske dømmekraft som er opstået i debatten om Christoffer Guldbrandsens tv'dokumentar 'Den hemmelige krig'. Den offentlige og politiske debat herom er en erstatningsdebat for den kommisionsdomstol, der burde nedsættes om de løgne, der har været fremsat 2002 -...

  10. Forårets konflikter godt for den danske model

    DEFF Research Database (Denmark)

    Scheuer, Steen

    2008-01-01

    Den store vinder ved forårets konflikter var den danske model for aftaler på arbejdsmarkedet. De offentlige fagforeninger fik sig en lærestreg, da regeringen og Folketinget til de flestes overraskelse lod de lovlige konflikter løbe i ugevis. For hermed tvang man parterne, og især forbundene, til...

  11. Effektivitet af naturligt drevne radontiltag året rundt

    DEFF Research Database (Denmark)

    Haker Høegh, Britt; Rasmussen, Torben Valdbjørn

    Denne rapport omhandler projektet Effektivitet af naturligt drevne radontiltag året rundt. Projektet er et spireprojekt finansieret af Innovationsnetværket InnoBYG og Forsknings- og Innovationsstyrelsen. Projektet er gennemført af Teknologisk Institut i samarbejde med Statens Byggeforskningsinsti...

  12. Four-year follow-up study in a NF1 boy with a focal pontine hamartoma.

    Science.gov (United States)

    Parisi, Pasquale; Persechino, Severino; Paolino, Maria Chiara; Nicita, Francesco; Torrente, Isabella; Bozzao, Alessandro; Villa, Maria Pia

    2013-02-11

    Neurofibromatosis is a collective name for a group of genetic conditions in which benign tumours affect the nervous system. Type 1 is caused by a genetic mutation in the NF1 gene (OMIM 613113) and symptoms can vary dramatically between individuals, even within the same family. Some people have very mild skin changes, whereas others suffer severe medical complications. The condition usually appears in childhood and is diagnosed if two of the following are present: six or more café-au-lait patches larger than 1.5 cm in diameter, axillary or groin freckling, 2 or more Lisch nodules (small pigmented areas in the iris of the eye), 2 or more neurofibromas, optic pathway gliomas, bone dysplasia, and a first-degree family relative with Neurofibromatosis type 1. The pattern of inheritance is autosomal dominant, however, half of all NF1 cases are 'sporadic' and there is no family history. Neurofibromatosis type 1 is an extremely variable condition whose morbidity and mortality is largely dictated by the occurrence of the many complications that may involve any of the body systems. We describe a family affected by NF1 in whom genetic molecular analysis identified the same mutation in the son and father. Routine MRI showed pontine focal lesions in the eight-year-old son, though not in the father. We performed a four years follow-up study and at follow-up pontine hamartoma size remained unchanged in the son, and the father showed still no brain lesions, confirming thus an intra-familial phenotype variability.

  13. Four-year follow-up study in a NF1 Boy with a focal pontine hamartoma

    Directory of Open Access Journals (Sweden)

    Parisi Pasquale

    2013-02-01

    Full Text Available Abstract Neurofibromatosis is a collective name for a group of genetic conditions in which benign tumours affect the nervous system. Type 1 is caused by a genetic mutation in the NF1 gene (OMIM 613113 and symptoms can vary dramatically between individuals, even within the same family. Some people have very mild skin changes, whereas others suffer severe medical complications. The condition usually appears in childhood and is diagnosed if two of the following are present: six or more café-au-lait patches larger than 1.5 cm in diameter, axillary or groin freckling, 2 or more Lisch nodules (small pigmented areas in the iris of the eye, 2 or more neurofibromas, optic pathway gliomas, bone dysplasia, and a first-degree family relative with Neurofibromatosis type 1. The pattern of inheritance is autosomal dominant, however, half of all NF1 cases are ‘sporadic’ and there is no family history. Neurofibromatosis type 1 is an extremely variable condition whose morbidity and mortality is largely dictated by the occurrence of the many complications that may involve any of the body systems. We describe a family affected by NF1 in whom genetic molecular analysis identified the same mutation in the son and father. Routine MRI showed pontine focal lesions in the eight-year-old son, though not in the father. We performed a four years follow-up study and at follow-up pontine hamartoma size remained unchanged in the son, and the father showed still no brain lesions, confirming thus an intra-familial phenotype variability.

  14. Zebrafish Model of NF1 for Structure-Function Analysis, Mechanisms of Glial Tumorigenesis, and Chemical Biology

    Science.gov (United States)

    2015-08-01

    models. Zinc-finger nucleases (ZFNs) are chimeric fusions between a zinc-finger protein (ZFP) and the nuclease domain of FokI (Urnov et al., 2010). ZFNs...reference line. Once a target site is chosen, the user can click on the ZFN entry (QueryID; see Fig. 4B) for details about each construct (Fig. 4C...Zhong, Y. (1997). Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuro- peptides . Science 276, 795–798.ports 8, 1265

  15. Developing a Zebrafish Model of NF1 for Structure-Function Analysis and Identification of Modifier Genes

    Science.gov (United States)

    2012-04-01

    protein of 2,800 aa. It contains a small region homologous to yeast IRA proteins that includes a Ras-GTPase-activating domain (GAP) capable of...NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859. 6. Xu, G.F., O’Connell, P., Viskochil, D...J.W., Glass, J.O., Brewer , V.R., Reddick, W.E., Mages, R. and Pivnick, E.K. (2001) Prospective evaluation of the brain in asymptomatic children with

  16. Generation of KCL025 research grade human embryonic stem cell line carrying a mutation in NF1 gene

    Directory of Open Access Journals (Sweden)

    Heema Hewitson

    2016-03-01

    Full Text Available The KCL025 human embryonic stem cell line was derived from an embryo donated for research that carried an autosomal dominant mutation in the NF1 gene encoding neurofibromin (c.3739–3742 ΔTTTG. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The ICM was isolated using laser microsurgery and plated on γ-irradiated human foreskin fibroblasts. Both the derivation and cell line propagation were performed in an animal product-free environment. Pluripotent state and differentiation potential were confirmed by in vitro assays.

  17. Efficacy of rational emotive therapy (RET) with children: a critical re-appraisal.

    Science.gov (United States)

    Gossette, R L; O'Brien, R M

    1993-03-01

    Proponents of rational-emotive therapy (RET) advocate its use within the school curriculum to forestall future maladjustment through the early detection and eradication of irrational beliefs. A review of 33 unpublished dissertations and four published reports found RET effective in about 25% of comparisons with wait-list, placebo, and other treatment conditions. The major effects of RET were changes in scores on self-report measures of irrational beliefs, less on emotional distress, and little or no change in behavior; essentially the same pattern of effects previously found in a similar analysis of RET in adult populations. Little justification was found for continued use of RET in schools.

  18. Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors

    OpenAIRE

    Giovanni Minervini; Raffaele Lopreiato; Raissa Bortolotto; Antonella Falconieri; Geppo Sartori; Silvio C. E. Tosatto

    2017-01-01

    Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor predisposes patients to develop different highly vascularized cancers. pVHL targets the hypoxia-inducible transcription factor (HIF-1?) for degradation, modulating the activation of various genes involved in hypoxia response. Hypoxia plays a relevant role in regulating cell cycle progression, inducing growth arrest in cells exposed to prolonged oxygen deprivation. However, the exact molecular details driving this transition...

  19. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

    Science.gov (United States)

    Moura, M M; Cavaco, B M; Pinto, A E; Domingues, R; Santos, J R; Cid, M O; Bugalho, M J; Leite, V

    2009-01-01

    Screening of REarranged during Transfection (RET) gene mutations has been carried out in different series of sporadic medullary thyroid carcinomas (MTC). RET-positive tumours seem to be associated to a worse clinical outcome. However, the correlation between the type of RET mutation and the patients' clinicopathological data has not been evaluated yet. We analysed RET exons 5, 8, 10–16 in fifty-one sporadic MTC, and found somatic mutations in thirty-three (64.7%) tumours. Among the RET-positive cases, exon 16 was the most frequently affected (60.6%). Two novel somatic mutations (Cys630Gly, c.1881del18) were identified. MTC patients were divided into three groups: group 1, with mutations in RET exons 15 and 16; group 2, with other RET mutations; group 3, having no RET mutations. Group 1 had higher prevalence (P=0.0051) and number of lymph node metastases (P=0.0017), and presented more often multifocal tumours (P=0.037) and persistent disease at last control (P=0.0242) than group 2. Detectable serum calcitonin levels at last screening (P=0.0119) and stage IV disease (P=0.0145) were more frequent in group 1, than in the other groups. Our results suggest that, among the sporadic MTC, cases with RET mutations in exons 15 and 16 are associated with the worst prognosis. Cases with other RET mutations have the most indolent course, and those with no RET mutations have an intermediate risk. PMID:19401695

  20. SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients.

    Science.gov (United States)

    Mei, Zhu; Shao, Yang W; Lin, Peinan; Cai, Xiaomin; Wang, Biao; Ding, Yan; Ma, Xiangyuan; Wu, Xue; Xia, Yewei; Zhu, Dongqin; Shu, Yongqian; Fu, Zan; Gu, Yanhong

    2018-04-27

    Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. Patients carrying SMAD4 mutations (SMAD4 mut , n = 8) or NF1 mutations (NF1 mut , n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4 wt , n = 25) (P = 0.0081) or wildtype NF1 (NF1 wt , n = 29) (P = 0.0028), respectively. None of the SMAD4 mut or NF1 mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4 mut and NF1 mut showed the shortest PFS among all the patients. Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.

  1. Radiological Effluent Technical Specifications (RETS) implementation, Kewaunee Nuclear Power Plant

    International Nuclear Information System (INIS)

    Serrano, W.; Akers, D.W.

    1985-06-01

    A review of the Radiological Effluent Technical Specifications (RETS) for the Kewaunee Nuclear Power Plant was performed. The principal review guidelines used were NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants,'' and Draft 7'' of NUREG-0472, Revision 3, ''Radiological Effluent Technical Specifications for Pressurized Water Reactors.'' Draft submittals were discussed with the Licensee by the NRC staff until all items requiring changes to the Technical Specifications were resolved. The Licensee then submitted final proposed RETS to the NRC which were evaluated and found to be in compliance with the NRC review guidelines. The proposed Offsite Dose Calculation Manual and the Radiological Environmental Monitoring Manual were reviewed and generally found to be in compliance with the NRC review guidelines

  2. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

    Science.gov (United States)

    Frost, Julianty; Galdeano, Carles; Soares, Pedro; Gadd, Morgan S.; Grzes, Katarzyna M.; Ellis, Lucy; Epemolu, Ola; Shimamura, Satoko; Bantscheff, Marcus; Grandi, Paola; Read, Kevin D.; Cantrell, Doreen A.; Rocha, Sonia; Ciulli, Alessio

    2016-11-01

    Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

  3. Replication pattern of the pericentromeric region of chromosome 10q and expression of the RET protooncogene.

    Science.gov (United States)

    Cinti, R; Schena, F; Passalacqua, M; Ceccherini, I; Ravazzolo, R

    2004-08-15

    Regulation of the RET gene is highly specific during embryo development and is strictly tissue-specific. Control of transcription depends on mechanisms influenced by epigenetic processes, in particular, histone acetylation at regions flanking the 5' end of the gene. Since the RET gene is mapped in the pericentromeric region of the human chromosome 10, the implication of epigenetic processes is even more striking and worth to be investigated in an extended chromosomal tract. One experimental approach to study the chromatin status in relationship with gene transcription is to assess the replication timing, which we did by using fluorescent in situ hybridization in cells expressing or not expressing the RET gene. By using probes spanning a 700-kb genomic region from the RET locus toward the centromere, we found a relationship between RET expression and early replication. Different patterns were observed between cells naturally expressing RET and cells induced to expression of RET by treatment with sodium butyrate, an inhibitor of histone deacetylases. Three-dimensional analysis of the nuclear localization of fluorescent signals by confocal microscopy showed difference of localization between the RET probe and a probe for a housekeeping gene, G3PDH, located at 12p13.3, in cells that do not express RET, in accordance with previous data for other genes and chromosomal regions. However, RET-expressing cells showed a localization of signals which was not consistent with that expected for expressed genes.

  4. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

    Energy Technology Data Exchange (ETDEWEB)

    Verhaak, Roel GW; Hoadley, Katherine A; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D; Miller, C Ryan; Ding, Li; Golub, Todd; Mesirov, Jill P; Alexe, Gabriele; Lawrence, Michael; O' Kelly, Michael; Tamayo, Pablo; Weir, Barbara A; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Jakkula, Lakshmi; Feiler, Heidi S; Hodgson, J Graeme; James, C David; Sarkaria, Jann N; Brennan, Cameron; Kahn, Ari; Spellman, Paul T; Wilson, Richard K; Speed, Terence P; Gray, Joe W; Meyerson, Matthew; Getz, Gad; Perou, Charles M; Hayes, D Neil; Network, The Cancer Genome Atlas Research

    2009-09-03

    The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

  5. Cyr61/CCN1 and CTGF/CCN2 mediate the pro-angiogenic activity of VHL mutant renal carcinoma cells

    Science.gov (United States)

    Chintalapudi, Mastan R.; Markiewicz, Margaret; Kose, Nurgun; Dammai, Vincent; Champion, Kristen J.; Hoda, Rana S.; Trojanowska, Maria; Hsu, Tien

    2008-01-01

    The von Hippel-Lindau (VHL) protein serves as a negative regulator of hypoxia inducible factor-alpha subunit (HIF-α). Since HIF regulates critical angiogenic factors such as vascular endothelial growth factor (VEGF) and lesions in VHL gene are present in a majority of the highly vascularized renal cell carcinoma (RCC), it is believed that deregulation of the VHL-HIF pathway is crucial for the pro-angiogenic activity of RCC. Although VEGF has been confirmed as a critical angiogenic factor up-regulated in VHL mutant cells, the efficacy of anti-angiogenic therapy specifically targeting VEGF signaling remains modest. In this study we developed a three-dimensional in vitro assay to evaluate the ability of RCC cells to promote cord formation by the primary human dermal microvascular endothelial cells (HDMECs). Compared to VHL wild-type cells, VHL mutant RCC cells demonstrated a significantly increased pro-angiogenic activity, which correlated with increased secretion of Cyr61/CCN1, CTGF/CCN2 and VEGF in conditioned culture medium. Both CCN proteins are required for HDMEC cord formation as shown by RNAi knock-down experiments. Importantly, the pro-angiogenic activities conferred by the CCN proteins and VEGF are additive, suggesting non-overlapping functions. Expression of the CCN proteins is at least partly dependent on the HIF-2α function, the dominant HIF-α isoform expressed in RCC. Finally, immunohistochemical staining of Cyr61/CCN1 and CTGF/CCN2 in renal cell carcinoma tissue samples showed that increased expression of these proteins correlates with loss of VHL protein expression. These findings strengthened the notion that the hypervascularized phenotype of RCC is afforded by multiple pro-angiogenic factors that function in parallel pathways. PMID:18212329

  6. Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL gene in an extended Hungarian von Hippel-Lindau family

    Directory of Open Access Journals (Sweden)

    Fazakas Ferenc

    2008-04-01

    Full Text Available Abstract Von Hippel-Lindau disease (VHL is a rare autosomal dominant disease characterized by development of cystic and tumorous lesions at multiple sites, including the brain, spinal cord, kidneys, adrenals, pancreas, epididymis and eyes. The clinical phenotype results from molecular abnormalities of the VHL tumor suppressor gene, mapped to human chromosome 3p25-26. The VHL gene encodes two functionally active VHL proteins due to the presence of two translational initiation sites separated by 53 codons. The majority of disease-causing mutations have been detected downstream of the second translational initiation site, but there are conflicting data as to whether few mutations located in the first 53 codons, such as the Pro25Leu could have a pathogenic role. In this paper we report a large Hungarian VHL type 2 family consisting of 32 members in whom a disease-causing AGT80AAT (Ser80Ile c.239G>A, p.Ser80Ile mutation, but not the concurrent CCT25CTT (Pro25Leu c.74C>T, p.Pro25Leu variant co-segregated with the disease. To our knowledge, the Ser80Ile mutation has not been previously described in VHL type 2 patients with high risk of pheochromocytoma and renal cell cancer. Therefore, this finding represents a novel genotype-phenotype association and VHL kindreds with Ser80Ile mutation will require careful surveillance for pheochromocytoma. We concluded that the Pro25Leu variant is a rare, neutral variant, but the presence such a rare gene variant may make genetic counseling difficult.

  7. Ret Finger Protein: An E3 Ubiquitin Ligase Juxtaposed to the XY Body in Meiosis

    Directory of Open Access Journals (Sweden)

    Isabelle Gillot

    2009-01-01

    Full Text Available During prophase I of male meiosis, the sex chromosomes form a compact structure called XY body that associates with the nuclear membrane of pachytene spermatocytes. Ret Finger Protein is a transcriptional repressor, able to interact with both nuclear matrix-associated proteins and double-stranded DNA. We report the precise and unique localization of Ret Finger Protein in pachytene spermatocytes, in which Ret Finger Protein takes place of lamin B1, between the XY body and the inner nuclear membrane. This localization of Ret Finger Protein does not seem to be associated with O-glycosylation or sumoylation. In addition, we demonstrate that Ret Finger Protein contains an E3 ubiquitin ligase activity. These observations lead to an attractive hypothesis in which Ret Finger Protein would be involved in the positioning and the attachment of XY body to the nuclear lamina of pachytene spermatocytes.

  8. HOXB5 cooperates with NKX2-1 in the transcription of human RET.

    Directory of Open Access Journals (Sweden)

    Jiang Zhu

    Full Text Available The enteric nervous system (ENS regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i HOXB5 transcription factor mediates RET expression, and (ii mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5' upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297, which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype.

  9. Enhanced sensitivity of the RET proto-oncogene to ionizing radiation in vitro.

    Science.gov (United States)

    Volpato, Claudia Béu; Martínez-Alfaro, Minerva; Corvi, Raffaella; Gabus, Coralie; Sauvaigo, Sylvie; Ferrari, Pietro; Bonora, Elena; De Grandi, Alessandro; Romeo, Giovanni

    2008-11-01

    Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia and thyroid cancer. It has been known for a long time that exposure of cells to radiation results in extensive DNA damage; however, a small number of studies have tried to explain the mechanisms of radiation-induced carcinogenesis. The high prevalence of RET/PTC rearrangements in patients who have received external radiation, and the evidence of in vitro induction of RET rearrangements in human cells, suggest an enhanced sensitivity of the RET genomic region to damage by ionizing radiation. To assess whether RET is indeed more sensitive to radiations than other genomic regions, we used a COMET assay coupled with fluorescence in situ hybridization, which allows the measurement of DNA fragmentation in defined genomic regions of single cells. We compared the initial DNA damage of the genomic regions of RET, CXCL12/SDF1, ABL, MYC, PLA2G2A, p53, and JAK2 induced by ionizing radiation in both a lymphoblastoid and a fetal thyroid cell line. In both cell lines, RET fragmentation was significantly higher than in other genomic regions. Moreover, a differential distribution of signals within the COMET was associated with a higher percentage of RET fragments in the tail. RET was more susceptible to fragmentation in the thyroid-derived cells than in lymphoblasts. This enhanced susceptibility of RET to ionizing radiation suggests the possibility of using it as a radiation exposure marker.

  10. Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein.

    Science.gov (United States)

    Liu, Sheng-Jie; Wang, Jiang-Yi; Peng, Shuang-He; Li, Teng; Ning, Xiang-Hui; Hong, Bao-An; Liu, Jia-Yuan; Wu, Peng-Jie; Zhou, Bo-Wen; Zhou, Jing-Cheng; Qi, Nie-Nie; Peng, Xiang; Zhang, Jiu-Feng; Ma, Kai-Fang; Cai, Lin; Gong, Kan

    2018-03-29

    PurposeVon Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL).MethodsVHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.ResultsMissense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p counseling and pathogenesis studies.Genetics in Medicine advance online publication, 29 March 2018; doi:10.1038/gim.2017.261.

  11. A estrutura retórica do verbete Spinoza

    Directory of Open Access Journals (Sweden)

    Marilena Chaui

    2009-12-01

    Full Text Available Propomos uma análise do verbete "Spinoza" do Dictionnaire Historique et Critique salientando a estrutura retórica do texto, em cujo centro se encontra a nova figura do ateu, construída por Bayle, o ateu especulativo ou "o ateu de sistema".The paper presents a study of the rhetorical framework of the article "Spinoza" in Bayle's Dictionnaire Historique et Critique and the new image of the atheist as athée de système.

  12. Sp1/3 and NF-1 mediate basal transcription of the human P2X1 gene in megakaryoblastic MEG-01 cells

    Directory of Open Access Journals (Sweden)

    Ennion Steven J

    2006-03-01

    Full Text Available Abstract Background P2X1 receptors play an important role in platelet function as they can induce shape change, granule centralization and are also involved in thrombus formation. As platelets have no nuclei, the level of P2X1 expression depends on transcriptional regulation in megakaryocytes, the platelet precursor cell. Since nothing is known about the molecular mechanisms regulating megakaryocytic P2X1 expression, this study aimed to identify and functionally characterize the P2X1 core promoter utilized in the human megakaryoblastic cell line MEG-01. Results In order to identify cis-acting elements involved in the transcriptional regulation of P2X1 expression, the ability of 4.7 kb P2X1 upstream sequence to drive luciferase reporter gene expression was tested. Low promoter activity was detected in proliferating MEG-01 cells. This activity increased 20-fold after phorbol-12-myristate-13-acetate (PMA induced differentiation. A transcription start site was detected 365 bp upstream of the start codon by primer extension. Deletion analysis of reporter constructs indicated a core promoter located within the region -68 to +149 bp that contained two Sp1 sites (named Sp1a and Sp1b and an NF-1 site. Individual mutations of Sp1b or NF-1 binding sites severely reduced promoter activity whereas triple mutation of Sp1a, Sp1b and NF-1 sites completely abolished promoter activity in both untreated and PMA treated cells. Sp1/3 and NF-1 proteins were shown to bind their respective sites by EMSA and interaction of Sp1/3, NF-1 and TFIIB with the endogenous P2X1 core promoter in MEG-01 cells was demonstrated by chromatin immunoprecipitation. Alignment of P2X1 genes from human, chimp, rat, mouse and dog revealed consensus Sp1a, Sp1b and NF-1 binding sites in equivalent positions thereby demonstrating evolutionary conservation of these functionally important sites. Conclusion This study has identified and characterized the P2X1 promoter utilized in MEG-01 cells and

  13. O cultivo retórico da escuta

    Directory of Open Access Journals (Sweden)

    Jorge Cardoso Filho

    2014-08-01

    Full Text Available Esse artigo discute o modo como, na cultura contemporânea, hábitos perceptivos podem ser cultivados de forma relacionada ao ambiente sociocultural e técnico, especificamente no campo da escuta musical. Delimita seu foco de investigação nas estratégias empregadas a fim de persuadir a escuta de algoe de determinado modo, demonstrando preocupação com a dimensão retórica atuante no campo da percepção musical. Aponta a necessidade de entendimento dos mecanismos pelos quais a escuta é formatada na relação com os gêneros musicais, com as estratégias de midiatização e com os padrões de sensibilidade. Por fim, toma as estratégias empregadas no processo produtivo de dois álbuns do gênero musical Rock como exemplos de atuação dessa retórica: o álbum The Joshua Tree (1987, da banda irlandesa U2, e Nevermind (1991, da banda estadunidense Nirvana.

  14. Acceptance and commitment therapy in youth with neurofibromatosis type 1 (NF1) and chronic pain and their parents: A pilot study of feasibility and preliminary efficacy.

    Science.gov (United States)

    Martin, Staci; Wolters, Pamela L; Toledo-Tamula, Mary Anne; Schmitt, Shawn Nelson; Baldwin, Andrea; Starosta, Amy; Gillespie, Andrea; Widemann, Brigitte

    2016-06-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting about 1 in 3,500 individuals. Chronic pain is commonly reported among individuals with NF1 and plexiform neurofibroma tumors (PNs). Acceptance and Commitment Therapy (ACT), an empirically supported method for addressing chronic pain, helps individuals re-focus on valued relationships and activities. This pilot study investigated the feasibility and preliminary efficacy of a brief ACT workshop in the NF1 population. Eligible participants included adolescents and young adults (AYA; 12-21 years) with NF1 and chronic pain that interfered with daily functioning and their parents. Patients and parents completed baseline measures of pain interference, pain intensity, functional disability, pain acceptance, depression, and anxiety. Then, AYA and parents participated separately in a 2-day small-group ACT workshop. A telephone booster session occurred 1 month post-intervention. Three-month post-treatment measures were completed by mail. Ten adolescents (4 males; M age = 16.9 years) and seven parents provided baseline and 3-month data. Mean satisfaction with the study was moderate to high (3.9 for patients and 4.6 for parents on a 1-5 scales). Patients and parents reported significant declines in patients' pain interference at 3 months post-treatment. Patient-reported pain intensity significantly declined from baseline to 3 months. Parents reported marginally greater acceptance of their child's pain. No changes emerged in functional ability or mood. Preliminary findings suggest that a brief ACT group intervention is feasible and may help AYA with NF1 and PNs cope with their chronic pain, although larger randomized studies are needed to confirm treatment efficacy. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Linen Most Useful: Perspectives on Structure, Chemistry, and Enzymes for Retting Flax

    Science.gov (United States)

    Akin, Danny E.

    2013-01-01

    The components of flax (Linum usitatissimum) stems are described and illustrated, with reference to the anatomy and chemical makeup and to applications in processing and products. Bast fiber, which is a major economic product of flax along with linseed and linseed oil, is described with particular reference to its application in textiles, composites, and specialty papers. A short history of retting methods, which is the separation of bast fiber from nonfiber components, is presented with emphasis on water retting, field retting (dew retting), and experimental methods. Past research on enzyme retting, particularly by the use of pectinases as a potential replacement for the current commercial practice of field retting, is reviewed. The importance and mechanism of Ca2+ chelators with pectinases in retting are described. Protocols are provided for retting of both fiber-type and linseed-type flax stems with different types of pectinases. Current and future applications are listed for use of a wide array of enzymes to improve processed fibers and blended yarns. Finally, potential lipid and aromatic coproducts derived from the dust and shive waste streams of fiber processing are indicated. PMID:25969769

  16. Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathways

    International Nuclear Information System (INIS)

    Tufro, Alda; Teichman, Jason; Banu, Nazifa; Villegas, Guillermo

    2007-01-01

    Vascular endothelial growth factor (VEGF-A) plays multiple roles in kidney development: stimulates cell proliferation, survival, tubulogenesis, and branching morphogenesis. However, the mechanism that mediates VEGF-A induced ureteric bud branching is unclear. Glial-derived neurotrophic factor (GDNF) signaling through tyrosine kinase c-RET is the major regulator of ureteric bud branching. Here we examined whether VEGF-A regulates RET signaling. We determined that ureteric bud-derived cells express the main VEGF-A signaling receptor, VEGFR2 and RET, by RT-PCR, immunoblotting, and immunocytochemistry. We show that the VEGF-A isoform VEGF 165 induces RET-tyr 1062 phosphorylation in addition to VEGFR2 autophosphorylation, that VEGF 165 and GDNF have additive effects on RET-tyr 1062 phosphorylation, and that VEGFR2 and RET co-immunoprecipitate. Functionally, VEGF 165 induces ureteric bud cell proliferation and branching morphogenesis. Similarly, in embryonic kidney explants VEGF 165 induces RET-tyr 1062 phosphorylation and upregulates GDNF. These findings provide evidence for a novel cooperative interaction between VEGFR2 and RET that mediates VEGF-A functions in ureteric bud cells

  17. No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma

    NARCIS (Netherlands)

    Hofstra, R. M.; Cheng, N. C.; Hansen, C.; Stulp, R. P.; Stelwagen, T.; Clausen, N.; Tommerup, N.; Caron, H.; Westerveld, A.; Versteeg, R.; Buys, C. H.

    1996-01-01

    Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogene RET plays a role in neurocrest differentiation. In humans expression of RET is limited to certain tumor

  18. Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Lyle J Burdine

    Full Text Available Constitutive activation of the Rearranged during Transfection (RET proto-oncogene leads to the development of MEN2A medullary thyroid cancer (MTC. The relatively clear genotype/phenotype relationship seen with RET mutations and the development of MEN2A is unusual in the fact that a single gene activity can drive the progression towards metastatic disease. Despite knowing the oncogene responsible for MEN2A, MTC, like most tumors of neural crest origin, remains largely resistant to chemotherapy. Constitutive activation of RET in a SK-N-MC cell line model reduces cell sensitivity to chemotherapy. In an attempt to identify components of the machinery responsible for the observed RET induced chemoresistance, we performed a proteomic screen of histones and associated proteins in cells with a constitutively active RET signaling pathway. The proteomic approach identified DNA-PKcs, a DNA damage response protein, as a target of the RET signaling pathway. Active DNA-PKcs, which is phosphorylated at site serine 2056 and localized to chromatin, was elevated within our model. Treatment with the RET inhibitor RPI-1 significantly reduced s2056 phosphorylation in RET cells as well as in a human medullary thyroid cancer cell line. Additionally, inhibition of DNA-PKcs activity diminished the chemoresistance observed in both cell lines. Importantly, we show that activated DNA-PKcs is elevated in medullary thyroid tumor samples and that expression correlates with expression of RET in thyroid tumors. These results highlight one mechanism by which RET signaling likely primes cells for rapid response to DNA damage and suggests DNA-PKcs as an additional target in MTC.

  19. Tipo/retórica. Una aproximación a la retórica tipográfica

    Directory of Open Access Journals (Sweden)

    Roberto Gamonal Arroyo

    2012-04-01

    Full Text Available A simple vista la Retórica y la Tipografía parecen dos disciplinas con poco en común, pero en este artículo veremos cómo estas dos materias, con muchos siglos de existencia, tienen nexos inquebrantables que abren nuevas vías de investigación. La letra es la representación verbal y visual de nuestro lenguaje y nuestro pensamiento. Su agrupación en palabras y oraciones conforman textos cuyo objetivo principal es persuadir al lector para ser leídas. Y esta persuasión la ejerce no sólo a través de su contenido, sino también de su forma.

  20. Comparative evaluation of RetCam vs. gonioscopy images in congenital glaucoma

    Directory of Open Access Journals (Sweden)

    Raj V Azad

    2014-01-01

    Full Text Available Purpose: To compare clarity, exposure and quality of anterior chamber angle visualization in congenital glaucoma patients, using RetCam and indirect gonioscopy images. Design: Cross-sectional study Participants. Congenital glaucoma patients over age of 5 years. Materials and Methods: A prospective consecutive pilot study was done in congenital glaucoma patients who were older than 5 years. Methods used are indirect gonioscopy and RetCam imaging. Clarity of the image, extent of angle visible and details of angle structures seen were graded for both methods, on digitally recorded images, in each eye, by two masked observers. Outcome Measures: Image clarity, interobserver agreement. Results: 40 eyes of 25 congenital glaucoma patients were studied. RetCam image had excellent clarity in 77.5% of patients versus 47.5% by gonioscopy. The extent of angle seen was similar by both methods. Agreement between RetCam and gonioscopy images regarding details of angle structures was 72.50% by observer 1 and 65.00% by observer 2. Conclusions: There was good agreement between RetCam and indirect gonioscopy images in detecting angle structures of congenital glaucoma patients. However, RetCam provided greater clarity, with better quality, and higher magnification images. RetCam can be a useful alternative to gonioscopy in infants and small children without the need for general anesthesia.

  1. Comparative evaluation of RetCam vs. gonioscopy images in congenital glaucoma.

    Science.gov (United States)

    Azad, Raj V; Chandra, Parijat; Chandra, Anuradha; Gupta, Aparna; Gupta, Viney; Sihota, Ramanjit

    2014-02-01

    To compare clarity, exposure and quality of anterior chamber angle visualization in congenital glaucoma patients, using RetCam and indirect gonioscopy images. Cross-sectional study Participants. Congenital glaucoma patients over age of 5 years. A prospective consecutive pilot study was done in congenital glaucoma patients who were older than 5 years. Methods used are indirect gonioscopy and RetCam imaging. Clarity of the image, extent of angle visible and details of angle structures seen were graded for both methods, on digitally recorded images, in each eye, by two masked observers. Image clarity, interobserver agreement. 40 eyes of 25 congenital glaucoma patients were studied. RetCam image had excellent clarity in 77.5% of patients versus 47.5% by gonioscopy. The extent of angle seen was similar by both methods. Agreement between RetCam and gonioscopy images regarding details of angle structures was 72.50% by observer 1 and 65.00% by observer 2. There was good agreement between RetCam and indirect gonioscopy images in detecting angle structures of congenital glaucoma patients. However, RetCam provided greater clarity, with better quality, and higher magnification images. RetCam can be a useful alternative to gonioscopy in infants and small children without the need for general anesthesia.

  2. RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

    Directory of Open Access Journals (Sweden)

    Man-Ting So

    Full Text Available Rare (RVs and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis. While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic, rare coding sequence (CDS variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial.Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel distributed among 100 patients (16.64%. Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5' untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR. Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.

  3. Nexos estratégicos entre la retórica y la publicidad

    Directory of Open Access Journals (Sweden)

    Luis Gallardo Vera

    2011-06-01

    Full Text Available El presente artículo contribuye a establecer nexos estratégicos entre la retórica y la publicidad. La adopción del prisma estratégico en los estudios retóricos de la publicidad no es común, sin embargo, la relación entre retórica y publicidad a un nivel estratégico es evidente, teniendo presente los estudios que han investigado la simbiosis entre las dos actividades.Del universo compuesto por las investigaciones sobre retórica y publicidad se seleccionó una muestra de las obras susceptibles de responder a la pregunta de cuáles son los nexos estratégicos entre la retórica y la publicidad. Con este criterio se conformó una muestra teóricamente conducida del universo. La hipótesis de partida ha sido que, si existen documentos que indaguen en la relación entre la retórica y la publicidad, es posible construir un documento que muestre de un modo amplio cuáles son los nexos estratégicos entre ambas actividades. Finalmente, se contrastó que, efectivamente, este documento es único al mostrar ampliamente cuáles son los nexos estratégicos existentes entre la retórica y la publicidad.

  4. Kinetics of Natural Detoxification of Hydrogen Cyanide Contained In Retted Cassava Roots

    Directory of Open Access Journals (Sweden)

    2016-11-01

    Full Text Available This work presents the kinetics of natural detoxification of hydrogen cyanide contained in retted cassava roots. Retting is traditional fermentation of cassava, performed to soften the roots. During retting, cyanide diffuses into water used for the retting. The fresh cassava roots (bitter and sweet varieties used for this experiment were separately retted at ambient 0 temperature of 30 C. The cyanide content and pH were monitored daily. From the analysis of the experimental results, a first order consecutive rate equation is an adequate tool for explaining the mechanism of HCN reduction (or decay in retted cassava roots. The detoxification constants for the bound cyanide in the bitter and sweet cassava roots were 0.378/day and 0.438/day respectively, while that of the free hydrogen cyanide were 0.63/day and 0.74/day for the bitter and sweet varieties respectively. Cassava tubers from different species cannot be fermented with the same retting condition unless they have same or close functional properties.

  5. CO2, GDP and RET: An aggregate economic equilibrium analysis for Turkey

    International Nuclear Information System (INIS)

    Kumbaroglu, Guerkan; Karali, Nihan; Arikan, Yildiz

    2008-01-01

    There is a worldwide interest in renewable electricity technologies (RETs) due to growing concerns about global warming and climate change. As an EU candidate country whose energy demand increases exponentially, Turkey inevitably shares this common interest on RET. This study, using an aggregate economic equilibrium model, explores the economic costs of different policy measures to mitigate CO 2 emissions in Turkey. The model combines energy demands, capital requirements and labor inputs at a constant elasticity of substitution under an economy-wide nested production function. Growing energy demand, triggered by economic growth, is met by increased supply and initiates new capacity additions. Investment into RET is encouraged via the incorporation of (a) endogenous technological learning through which the RET cost declines as a function of cumulative capacity, and (b) a willingness to pay (WTP) function which imposes the WTP of consumers as a lower bound on RET installation. The WTP equation is obtained as a function of consumer income categories, based on data gathered from a pilot survey in which the contingent valuation methodology was employed. The impacts of various emission reduction scenarios on GDP growth and RET diffusion are explored. As expected, RET penetration is accelerated under faster technological learning and higher WTP conditions. It is found that stabilizing CO 2 emissions to year 2005 levels causes economic losses amounting to 17% and 23% of GDP in the years 2020 and 2030, respectively

  6. Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Moyle, Louise A; Blanc, Eric; Jaka, Oihane; Prueller, Johanna; Banerji, Christopher Rs; Tedesco, Francesco Saverio; Harridge, Stephen Dr; Knight, Robert D; Zammit, Peter S

    2016-11-14

    Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, we over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD. RET is dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of either RET9 or RET51 increased myoblast proliferation, whereas siRNA-mediated knockdown of Ret induced myogenic differentiation. Suppressing RET activity using Sunitinib, a clinically-approved tyrosine kinase inhibitor, rescued differentiation in both DUX4-expressing murine myoblasts and in FSHD patient-derived myoblasts. Importantly, Sunitinib also increased engraftment and differentiation of FSHD myoblasts in regenerating mouse muscle. Thus, DUX4-mediated activation of Ret prevents myogenic differentiation and could contribute to FSHD pathology by preventing satellite cell-mediated repair. Rescue of DUX4-induced pathology by Sunitinib highlights the therapeutic potential of tyrosine kinase inhibitors for treatment of FSHD.

  7. Lack of a Functional VHL Gene Product Sensitizes Renal Cell Carcinoma Cells to the Apoptotic Effects of the Protein Synthesis Inhibitor Verrucarin A

    Directory of Open Access Journals (Sweden)

    Girma M. Woldemichael

    2012-08-01

    Full Text Available Verrucarin A (VA is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as a selective inhibitor of clear cell renal cell carcinoma (CCRCC cell proliferation in a high-throughput screen of a library of naturally occurring small molecules. CCRCC arises as a result of loss-of-function mutations in the von Hippel-Lindau (VHL gene. Here we show that VA inhibits protein translation initiation culminating in apoptosis through the extrinsic signaling pathway. Reintroduction of the VHL gene in CCRCC cells afforded resistance to VA's apoptotic effects. This resistance is mediated in part by the formation of stress granules that entrap signaling molecules that initiate the apoptotic signaling cascade. The VHL gene product was found to be a component of stress granules that develop as result of VA treatment. These findings reveal an important role for the VHL gene product in cytotoxic stress response and have important implications for the rational development of VA-related compounds in chemotherapeutic targeting of CCRCC.

  8. Lack of a functional VHL gene product sensitizes renal cell carcinoma cells to the apoptotic effects of the protein synthesis inhibitor verrucarin A.

    Science.gov (United States)

    Woldemichael, Girma M; Turbyville, Thomas J; Vasselli, James R; Linehan, W Marston; McMahon, James B

    2012-08-01

    Verrucarin A (VA) is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as a selective inhibitor of clear cell renal cell carcinoma (CCRCC) cell proliferation in a high-throughput screen of a library of naturally occurring small molecules. CCRCC arises as a result of loss-of-function mutations in the von Hippel-Lindau (VHL) gene. Here we show that VA inhibits protein translation initiation culminating in apoptosis through the extrinsic signaling pathway. Reintroduction of the VHL gene in CCRCC cells afforded resistance to VA's apoptotic effects. This resistance is mediated in part by the formation of stress granules that entrap signaling molecules that initiate the apoptotic signaling cascade. The VHL gene product was found to be a component of stress granules that develop as result of VA treatment. These findings reveal an important role for the VHL gene product in cytotoxic stress response and have important implications for the rational development of VA-related compounds in chemotherapeutic targeting of CCRCC.

  9. Lack of a Functional VHL Gene Product Sensitizes Renal Cell Carcinoma Cells to the Apoptotic Effects of the Protein Synthesis Inhibitor Verrucarin A12

    Science.gov (United States)

    Woldemichael, Girma M; Turbyville, Thomas J; Vasselli, James R; Linehan, W Marston; McMahon, James B

    2012-01-01

    Verrucarin A (VA) is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as a selective inhibitor of clear cell renal cell carcinoma (CCRCC) cell proliferation in a high-throughput screen of a library of naturally occurring small molecules. CCRCC arises as a result of loss-of-function mutations in the von Hippel-Lindau (VHL) gene. Here we show that VA inhibits protein translation initiation culminating in apoptosis through the extrinsic signaling pathway. Reintroduction of the VHL gene in CCRCC cells afforded resistance to VA's apoptotic effects. This resistance is mediated in part by the formation of stress granules that entrap signaling molecules that initiate the apoptotic signaling cascade. The VHL gene product was found to be a component of stress granules that develop as result of VA treatment. These findings reveal an important role for the VHL gene product in cytotoxic stress response and have important implications for the rational development of VA-related compounds in chemotherapeutic targeting of CCRCC. PMID:22952429

  10. Skeletal Complications in Neurofibromatosis Type 1: the Role of Neurofibromin Haploinsufficiency in Defective Skeletal Remodeling and Bone Healing in NF1

    Science.gov (United States)

    2009-01-01

    pathogenesis of pseudoarthrosis of the tibia (1). Health reports from the Vanderbilt mouse colony indicated exposure to mouse parvo virus (MPV) and...facility following the quarantine period and two, clean, consecutive monthly health reports, consistent with BIDMC Animal Research Facility animal...M.D., Sowa, H., Starbuck , M., Liu, X., Ron, D., Parada, L.F., and Karsenty, G. 2006. ATF4 mediation of NF1 functions in osteoblast reveals a

  11. Distributional effects of the Australian Renewable Energy Target (RET) through wholesale and retail electricity price impacts

    International Nuclear Information System (INIS)

    Cludius, Johanna; Forrest, Sam; MacGill, Iain

    2014-01-01

    The Australian Renewable Energy Target (RET) has spurred significant investment in renewable electricity generation, notably wind power, over the past decade. This paper considers distributional implications of the RET for different energy users. Using time-series regression, we show that the increasing amount of wind energy has placed considerable downward pressure on wholesale electricity prices through the so-called merit order effect. On the other hand, RET costs are passed on to consumers in the form of retail electricity price premiums. Our findings highlight likely significant redistributive transfers between different energy user classes under current RET arrangements. In particular, some energy-intensive industries are benefiting from lower wholesale electricity prices whilst being largely exempted from contributing to the costs of the scheme. By contrast, many households are paying significant RET pass through costs whilst not necessarily benefiting from lower wholesale prices. A more equitable distribution of RET costs and benefits could be achieved by reviewing the scope and extent of industry exemptions and ensuring that methodologies to estimate wholesale price components in regulated electricity tariffs reflect more closely actual market conditions. More generally, these findings support the growing international appreciation that policy makers need to integrate distributional assessments into policy design and implementation. - Highlights: • The Australian RET has complex yet important distributional impacts on different energy users. • Likely wealth transfers from residential and small business consumers to large energy-intensive industry. • Merit order effects of wind likely overcompensate exempt industry for contribution to RET costs. • RET costs for households could be reduced if merit order effects were adequately passed through. • Need for distributional impact assessments when designing and implementing clean energy policy

  12. RET fusions in a small subset of advanced colorectal cancers at risk of being neglected.

    Science.gov (United States)

    Pietrantonio, F; Di Nicolantonio, F; Schrock, A B; Lee, J; Morano, F; Fucà, G; Nikolinakos, P; Drilon, A; Hechtman, J F; Christiansen, J; Gowen, K; Frampton, G M; Gasparini, P; Rossini, D; Gigliotti, C; Kim, S T; Prisciandaro, M; Hodgson, J; Zaniboni, A; Chiu, V K; Milione, M; Patel, R; Miller, V; Bardelli, A; Novara, L; Wang, L; Pupa, S; Sozzi, G; Ross, J; Di Bartolomeo, M; Bertotti, A; Ali, S; Trusolino, L; Falcone, A; de Braud, F; Cremolini, C

    2018-03-10

    Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: 1) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811); 2) cohorts screened at two Italian and one South Korean Institutions; 3) Foundation Medicine Inc. database. Next generation sequencing data were analyzed for RET rearranged cases. RET fusions were more frequent in older patients (median age of 66 vs. 60 years, p = 0.052), with ECOG PS 1-2 (90% vs. 50%, p = 0.02), right-sided (55% vs. 32%, P=0.013), previously unresected primary tumors (58% vs. 21%, P<0.001), RAS and BRAF wild-type (100% vs. 40%, p < 0.001) and MSI-high (48% vs. 7%, P<0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 vs. 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P<0.001). In the multivariable model, RET rearrangements were still associated with shorter OS [HR: 2.97; 95% CI, 1.25-7.07; P=0.014], while primary tumor location, RAS and BRAF mutations and MSI status were not. Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

  13. Renal cell tumors with clear cell histology and intact VHL and chromosome 3p: a histological review of tumors from the Cancer Genome Atlas database.

    Science.gov (United States)

    Favazza, Laura; Chitale, Dhananjay A; Barod, Ravi; Rogers, Craig G; Kalyana-Sundaram, Shanker; Palanisamy, Nallasivam; Gupta, Nilesh S; Williamson, Sean R

    2017-11-01

    Clear cell renal cell carcinoma is by far the most common form of kidney cancer; however, a number of histologically similar tumors are now recognized and considered distinct entities. The Cancer Genome Atlas published data set was queried (http://cbioportal.org) for clear cell renal cell carcinoma tumors lacking VHL gene mutation and chromosome 3p loss, for which whole-slide images were reviewed. Of the 418 tumors in the published Cancer Genome Atlas clear cell renal cell carcinoma database, 387 had VHL mutation, copy number loss for chromosome 3p, or both (93%). Of the remaining, 27/31 had whole-slide images for review. One had 3p loss based on karyotype but not sequencing, and three demonstrated VHL promoter hypermethylation. Nine could be reclassified as distinct or emerging entities: translocation renal cell carcinoma (n=3), TCEB1 mutant renal cell carcinoma (n=3), papillary renal cell carcinoma (n=2), and clear cell papillary renal cell carcinoma (n=1). Of the remaining, 6 had other clear cell renal cell carcinoma-associated gene alterations (PBRM1, SMARCA4, BAP1, SETD2), leaving 11 specimens, including 2 high-grade or sarcomatoid renal cell carcinomas and 2 with prominent fibromuscular stroma (not TCEB1 mutant). One of the remaining tumors exhibited gain of chromosome 7 but lacked histological features of papillary renal cell carcinoma. Two tumors previously reported to harbor TFE3 gene fusions also exhibited VHL mutation, chromosome 3p loss, and morphology indistinguishable from clear cell renal cell carcinoma, the significance of which is uncertain. In summary, almost all clear cell renal cell carcinomas harbor VHL mutation, 3p copy number loss, or both. Of tumors with clear cell histology that lack these alterations, a subset can now be reclassified as other entities. Further study will determine whether additional entities exist, based on distinct genetic pathways that may have implications for treatment.

  14. Modifications Caused by Enzyme-Retting and Their Effect on Composite Performance

    Directory of Open Access Journals (Sweden)

    Jonn A. Foulk

    2011-01-01

    Full Text Available Bethune seed flax was collected from Canada with seed removed using a stripper header and straw pulled and left in field for several weeks. Unretted straw was decorticated providing a coarse fiber bundle feedstock for enzyme treatments. Enzyme treatments using a bacterial pectinolytic enzyme with lyase activity were conducted in lab-scale reactors. Four fiber specimens were created: no retting, minimal retting, moderate retting, and full retting. Fiber characterization tests: strength, elongation, diameter, metal content, wax content, and pH were conducted with significant differences between fibers. Thermosetting vinyl ester resin was used to produce composite panels via vacuum-assisted infusion. Composite performance was evaluated using fiber bundle pull-out, tensile, impact, and interlaminar shear tests. Composite tests indicate that composite panels are largely unchanged among fiber samples. Variation in composite performance might not be realized due to poor interfacial bonding being of larger impact than the more subtle changes incurred by the enzyme treatment.

  15. Developmental wiring of specific neurons is regulated by RET-1/Nogo-A in Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Torpe, Nanna; Nørgaard, Steffen; Høye, Anette M.

    2017-01-01

    Nogo-A is a membrane-bound protein that functions to inhibit neuronal migration, adhesion, and neurite outgrowth during development. In the mature nervous system, Nogo-A stabilizes neuronal wiring to inhibit neuronal plasticity and regeneration after injury. Here, we show that RET-1, the sole Nog...... present a previously unidentified function for RET-1 in the nervous system of C. elegans.......-A homolog in Caenorhabditis elegans, is required to control developmental wiring of a specific subset of neurons. In ret-1 deletion mutant animals, specific ventral nerve cord axons are misguided where they fail to respect the ventral midline boundary. We found that ret-1 is expressed in multiple neurons...

  16. A multinodular goiter as the initial presentation of a renal cell carcinoma harbouring a novel VHL mutation

    Directory of Open Access Journals (Sweden)

    Silva Eduardo

    2006-10-01

    Full Text Available Abstract Background Secondary involvement of the thyroid gland is rare. Often the origin of the tumor is difficult to identify from the material obtained by fine-needle aspiration cytology. Renal cell carcinoma of the clear-cell type is one of the more common carcinomas to metastasize to the thyroid gland. Somatic mutations of the von Hippel-Lindau tumor suppressor gene are associated with the sporadic form of this tumor. We aimed to illustrate the potential utility of DNA based technologies to search for specific molecular markers in order to establish the anatomic site of origin. Case Presentation A 54-yr-old Caucasian male complaining of a rapidly increasing neck tumor was diagnosed as having a clear-cell tumor by fine-needle aspiration cytology. A positive staining for cytokeratin as well as for vimentin and CD10 in the absence of staining for thyroglobulin, calcitonin and TTF1 suggested a renal origin confirmed by computed tomography. Using frozen RNA, obtained from cells left inside the needle used for fine needle aspiration cytology, it was possible to identify a somatic mutation (680 delA in the VHL gene. Conclusion In the presence of a clear-cell tumor of the thyroid gland, screening for somatic mutations in the VHL gene in material derived from thyroid aspirates might provide additional information to immunocytochemical studies and therefore plays a contributory role to establish the final diagnosis. Moreover, in a near future, this piece of information might be useful to define a targeted therapy.

  17. Controlled retting of hemp fibres: Effect of hydrothermal pre-treatmen tand enzymatic retting on the mechanical properties of unidirectiona lhemp/epoxy composites

    DEFF Research Database (Denmark)

    Liu, Ming; Silva, Diogo Alexandre Santos; Fernando, Dinesh

    2016-01-01

    The objective of this work was to investigate the use of hydrothermal pre-treatment and enzymatic retting to remove non-cellulosic compounds and thus improve the mechanical properties of hemp fibre/epoxy composites. Hydrothermal pre-treatment at 100 kPa and 121 °C combined with enzymatic retting...... produced fibres with the highest ultimate tensile strength (UTS) of 780 MPa. Compared to untreated fibres, this combined treatment exhibited a positive effect on the mechanical properties of hemp fibre/epoxy composites, resulting in high quality composites with low porosity factor (αpf) of 0.08.Traditional...

  18. Novel tumorigenic rearrangement, Δrfp/ret, in a papillary thyroid carcinoma from externally irradiated patient

    International Nuclear Information System (INIS)

    Saenko, Vladimir; Rogounovitch, Tatiana; Shimizu-Yoshida, Yuki; Abrosimov, Aleksandr; Lushnikov, Eugeny; Roumiantsev, Pavel; Matsumoto, Naomichi; Nakashima, Masahiro; Meirmanov, Serik; Ohtsuru, Akira; Namba, Hiroyuki; Tsyb, Anatoly; Yamashita, Shunichi

    2003-01-01

    Molecular analysis of cDNA derived from a papillary thyroid carcinoma (PTC) (follicular variant of papillary thyroid carcinoma on histology) which developed in an externally irradiated patient 4 years after exposure identified a portion of the 5' region, exons 1-3, of the rfp gene juxtaposed upstream of the fragment encoding the tyrosine kinase (TK) domain of the ret gene. The fusion gene, termed Δrfp/ret, was the result of a balanced chromosomal translocation t(6;10) (p21.3;q11.2) confirmed by interphase FISH painting, with breakpoints occurring in introns 3 and 11 of the rfp and ret genes, respectively. Both Δrfp/ret and reciprocal ret/rfp chimeric introns had small deletions around breakpoints consistent with presumed misrepair of a radiation-induced double-strand DNA break underlying the rearrangement. No extensive sequence homology was found between the fragments flanking the breakpoints. The fusion protein retained the propensity to form oligomers likely to be mediated by a coiled-coil of the RFP polypeptide as assessed by a yeast two-hybrid system. NIH 3T3 fibroblasts stably transfected with a mammalian expression vector encoding full-length ΔRFP/RET readily gave rise to the tumors in athymic mice suggestive of high transforming potential of the fusion protein. Thus, the Δrfp/ret rearrangement may be causatively involved in cancerogenesis and provides additional evidence of the role of activated ret oncogene in the development of a subset of papillary thyroid carcinoma

  19. Comparative evaluation of RetCam vs. gonioscopy images in congenital glaucoma

    OpenAIRE

    Azad, Raj V; Chandra, Parijat; Chandra, Anuradha; Gupta, Aparna; Gupta, Viney; Sihota, Ramanjit

    2014-01-01

    Purpose: To compare clarity, exposure and quality of anterior chamber angle visualization in congenital glaucoma patients, using RetCam and indirect gonioscopy images. Design: Cross-sectional study Participants. Congenital glaucoma patients over age of 5 years. Materials and Methods: A prospective consecutive pilot study was done in congenital glaucoma patients who were older than 5 years. Methods used are indirect gonioscopy and RetCam imaging. Clarity of the image, extent of angle visible a...

  20. Combined treatment of retting flax wastewater using Fenton oxidation and granular activated carbon

    OpenAIRE

    Abou-Elela, Sohair I.; Ali, Mohammed Eid M.; Ibrahim, Hanan S.

    2016-01-01

    The process of retting flax produces a huge amount of wastewater which is characterized with bad unpleasant smell and high concentration of organic materials. Treatment of such waste had always been difficult because of the presence of refractory organic pollutants such as lignin. In this study, treatment of retting wastewater was carried out using combined system of Fenton oxidation process followed by adsorption on granular activated carbon (GAC). The effects of operating condition on Fento...

  1. Novel tumorigenic rearrangement, {delta}rfp/ret, in a papillary thyroid carcinoma from externally irradiated patient

    Energy Technology Data Exchange (ETDEWEB)

    Saenko, Vladimir; Rogounovitch, Tatiana; Shimizu-Yoshida, Yuki; Abrosimov, Aleksandr; Lushnikov, Eugeny; Roumiantsev, Pavel; Matsumoto, Naomichi; Nakashima, Masahiro; Meirmanov, Serik; Ohtsuru, Akira; Namba, Hiroyuki; Tsyb, Anatoly; Yamashita, Shunichi

    2003-06-19

    Molecular analysis of cDNA derived from a papillary thyroid carcinoma (PTC) (follicular variant of papillary thyroid carcinoma on histology) which developed in an externally irradiated patient 4 years after exposure identified a portion of the 5' region, exons 1-3, of the rfp gene juxtaposed upstream of the fragment encoding the tyrosine kinase (TK) domain of the ret gene. The fusion gene, termed {delta}rfp/ret, was the result of a balanced chromosomal translocation t(6;10) (p21.3;q11.2) confirmed by interphase FISH painting, with breakpoints occurring in introns 3 and 11 of the rfp and ret genes, respectively. Both {delta}rfp/ret and reciprocal ret/rfp chimeric introns had small deletions around breakpoints consistent with presumed misrepair of a radiation-induced double-strand DNA break underlying the rearrangement. No extensive sequence homology was found between the fragments flanking the breakpoints. The fusion protein retained the propensity to form oligomers likely to be mediated by a coiled-coil of the RFP polypeptide as assessed by a yeast two-hybrid system. NIH 3T3 fibroblasts stably transfected with a mammalian expression vector encoding full-length {delta}RFP/RET readily gave rise to the tumors in athymic mice suggestive of high transforming potential of the fusion protein. Thus, the {delta}rfp/ret rearrangement may be causatively involved in cancerogenesis and provides additional evidence of the role of activated ret oncogene in the development of a subset of papillary thyroid carcinoma.

  2. Bacterial succession and metabolite changes during flax (Linum usitatissimum L.) retting with Bacillus cereus HDYM-02.

    Science.gov (United States)

    Zhao, Dan; Liu, Pengfei; Pan, Chao; Du, Renpeng; Ping, Wenxiang; Ge, Jingping

    2016-09-02

    High-throughput sequencing and GC-MS (gas chromatography-mass spectrometry) were jointly used to reveal the bacterial succession and metabolite changes during flax (Linum usitatissimum L.) retting. The inoculation of Bacillus cereus HDYM-02 decreased bacterial richness and diversity. This inoculum led to the replacement of Enterobacteriaceae by Bacillaceae. The level of aerobic Pseudomonadaceae (mainly Azotobacter) and anaerobic Clostridiaceae_1 gradually increased and decreased, respectively. Following the addition of B. cereus HDYM-02, the dominant groups were all degumming enzyme producers or have been proven to be involved in microbial retting throughout the entire retting period. These results could be verified by the metabolite changes, either degumming enzymes or their catalytic products galacturonic acid and reducing sugars. The GC-MS data showed a clear separation between flax retting with and without B. cereus HDYM-02, particularly within the first 72 h. These findings reveal the important bacterial groups that are involved in fiber retting and will facilitate improvements in the retting process.

  3. Observation of aggregation triggered by Resonance Energy Transfer (RET) induced intermolecular pairing force.

    Science.gov (United States)

    Pan, Xiaoyong; Wang, Weizhi; Ke, Lin; Zhang, Nan

    2017-07-20

    In this report, we showed the existence of RET induced intermolecular pairing force by comparing their fluorescence behaviors under room illumination vs standing in dark area for either PFluAnt solution or PFluAnt&PFOBT mixture. Their prominent emission attenuation under room illumination brought out the critical role of photo, i.e. RET induced intermolecular pairing force in induction of polymer aggregation. Constant UV-Vis absorption and fluorescence spectra in terms of both peak shapes and maximum wavelengths implied no chemical decomposition was involved. Recoverable fluorescence intensity, fluorescence lifetime as well as NMR spectra further exclude photo induced decomposition. The controllable on/off state of RET induced intermolecular pairing force was verified by the masking effect of outside PFluAnt solution which function as filter to block the excitation of inside PFluAnt and thus off the RET induced intermolecular pairing force. Theoretical calculation suggest that magnitude of RET induced intermolecular pairing force is on the same scale as that of van der Waals interaction. Although the absolute magnitude of RET induced intermolecular pairing force was not tunable, its effect can be magnified by intentionally turn it "on", which was achieved by irradiance with 5 W desk lamp in this report.

  4. The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth.

    Science.gov (United States)

    Cañibano, Carmen; Rodriguez, Noela L; Saez, Carmen; Tovar, Sulay; Garcia-Lavandeira, Montse; Borrello, Maria Grazia; Vidal, Anxo; Costantini, Frank; Japon, Miguel; Dieguez, Carlos; Alvarez, Clara V

    2007-04-18

    Somatotrophs are the only pituitary cells that express Ret, GFRalpha1 and GDNF. This study investigated the effects of Ret in a somatotroph cell line, in primary pituitary cultures and in Ret KO mice. Ret regulates somatotroph numbers by inducing Pit-1 overexpression, leading to increased p53 expression and apoptosis, both of which can be prevented with Ret or Pit-1 siRNA. The Pit-1 overexpression is mediated by sustained activation of PKCdelta, JNK, c/EBPalpha and CREB induced by a complex of Ret, caspase 3 and PKCdelta. In the presence of GDNF, Akt is activated, and the Pit-1 overexpression and resulting apoptosis are blocked. The adenopituitary of Ret KO mice is larger than normal, showing Pit-1 and somatotroph hyperplasia. In normal animals, activation of the Ret/Pit-1/p53 pathway by retroviral introduction of Ret blocked tumor growth in vivo. Thus, somatotrophs have an intrinsic mechanism for controlling Pit-1/GH production through an apoptotic/survival pathway. Ret might be of value for treatment of pituitary adenomas.

  5. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto's thyroiditis

    DEFF Research Database (Denmark)

    Wirtschafter, A; Schmidt, R; Rosen, D

    1997-01-01

    specific genes in patients diagnosed with Hashimoto's disease. The newly identified oncogenes RET/PTC1 and RET/PTC3 provide useful and specific markers of the early stages of papillary carcinoma as they are highly specific for malignant cells. Using a sensitive and specific reverse transcriptase......-polymerase chain reaction (RT-PCR) assay, we found messenger RNA (mRNA) expression for the RET/PTC1 and RET/PTC3 oncogenes in 95% of the Hashimoto's patients studied. All Hashimoto's patients presenting without histopathologic evidence of papillary thyroid cancer showed molecular genetic evidence of cancer...

  6. New Insights into c-Ret Signalling Pathway in the Enteric Nervous System and Its Relationship with ALS

    Directory of Open Access Journals (Sweden)

    M. J. Luesma

    2014-01-01

    Full Text Available The receptor tyrosine kinase Ret (c-Ret transduces the glial cell line-derived neurotrophic factor (GDNF signal, one of the neurotrophic factors related to the degeneration process or the regeneration activity of motor neurons in amyotrophic lateral sclerosis (ALS. The phosphorylation of several tyrosine residues of c-Ret seems to be altered in ALS. c-Ret is expressed in motor neurons and in the enteric nervous system (ENS during the embryonic period. The characteristics of the ENS allow using it as model for central nervous system (CNS study and being potentially useful for the research of human neurological diseases such as ALS. The aim of the present study was to investigate the cellular localization and quantitative evaluation of marker c-Ret in the adult human gut. To assess the nature of c-Ret positive cells, we performed colocalization with specific markers of cells that typically are located in the enteric ganglia. The colocalization of PGP9.5 and c-Ret was preferentially intense in enteric neurons with oval morphology and mostly peripherally localized in the ganglion, so we concluded that the c-Ret receptor is expressed by a specific subtype of enteric neurons in the mature human ENS of the gut. The functional significance of these c-Ret positive neurons is discussed.

  7. New insights into c-Ret signalling pathway in the enteric nervous system and its relationship with ALS.

    Science.gov (United States)

    Luesma, M J; Cantarero, I; Álvarez-Dotu, J M; Santander, S; Junquera, C

    2014-01-01

    The receptor tyrosine kinase Ret (c-Ret) transduces the glial cell line-derived neurotrophic factor (GDNF) signal, one of the neurotrophic factors related to the degeneration process or the regeneration activity of motor neurons in amyotrophic lateral sclerosis (ALS). The phosphorylation of several tyrosine residues of c-Ret seems to be altered in ALS. c-Ret is expressed in motor neurons and in the enteric nervous system (ENS) during the embryonic period. The characteristics of the ENS allow using it as model for central nervous system (CNS) study and being potentially useful for the research of human neurological diseases such as ALS. The aim of the present study was to investigate the cellular localization and quantitative evaluation of marker c-Ret in the adult human gut. To assess the nature of c-Ret positive cells, we performed colocalization with specific markers of cells that typically are located in the enteric ganglia. The colocalization of PGP9.5 and c-Ret was preferentially intense in enteric neurons with oval morphology and mostly peripherally localized in the ganglion, so we concluded that the c-Ret receptor is expressed by a specific subtype of enteric neurons in the mature human ENS of the gut. The functional significance of these c-Ret positive neurons is discussed.

  8. VHL Frameshift Mutation as Target of Nonsense-Mediated mRNA Decay in Drosophila melanogaster and Human HEK293 Cell Line

    Directory of Open Access Journals (Sweden)

    Lucia Micale

    2009-01-01

    Full Text Available There are many well-studied examples of human phenotypes resulting from nonsense or frameshift mutations that are modulated by Nonsense-Mediated mRNA Decay (NMD, a process that typically degrades transcripts containing premature termination codons (PTCs in order to prevent translation of unnecessary or aberrant transcripts. Different types of germline mutations in the VHL gene cause the von Hippel-Lindau disease, a dominantly inherited familial cancer syndrome with a marked phenotypic variability and age-dependent penetrance. By generating the Drosophila UAS:Upf1D45B line we showed the possible involvement of NMD mechanism in the modulation of the c.172delG frameshift mutation located in the exon 1 of Vhl gene. Further, by Quantitative Real-time PCR (QPCR we demonstrated that the corresponding c.163delG human mutation is targeted by NMD in human HEK 293 cells. The UAS:Upf1D45B line represents a useful system to identify novel substrates of NMD pathway in Drosophila melanogaster. Finally, we suggest the possible role of NMD on the regulation of VHL mutations.

  9. Ret and Etv4 Promote Directed Movements of Progenitor Cells during Renal Branching Morphogenesis.

    Directory of Open Access Journals (Sweden)

    Paul Riccio

    2016-02-01

    Full Text Available Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM, combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret-/- or Etv4-/- sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret

  10. RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements

    Directory of Open Access Journals (Sweden)

    Iván Plaza-Menacho

    2016-12-01

    Full Text Available Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, αC helix, and an unconventional activation-loop serine phosphorylation site that engages the HRD motif and promotes phospho-tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with direct implications for drug discovery.

  11. Spatial Positioning of RET and H4 Following Radiation Exposure Leads to Tumor Development

    Directory of Open Access Journals (Sweden)

    Yuri E. Nikiforov

    2001-01-01

    Full Text Available Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia, thyroid cancer, soft tissue sarcomas, and many others. Although it has been known for a long time that radiation exposure to the cell results in extensive DNA damage, including double strand DNA breaks, the exact mechanisms of radiation-induced carcinogenesis remain unknown. Recently, a large increase in incidence of thyroid cancer was observed in children exposed to radiation after the Chernobyl nuclear accident [1]. A high prevalence of chromosomal rearrangements involving the RET gene was found among these radiation-induced thyroid tumors [2,3]. As a result of such rearrangement, a portion of the RET gene is fused with another gene, typically with the H4 or ELE1. However, since the DNA targets of ionizing radiation are randomly distributed throughout the cell nucleus, the reason for predilection for the RET rearrangements in thyroid cells was unclear.

  12. Technical evaluation of RETS-required reports for Turkey Point Units No. 3 and 4

    International Nuclear Information System (INIS)

    Magleby, E.H.; Young, T.E.; Henscheid, J.W.

    1985-01-01

    A review of the reports required by Federal regulations and the plant specific Radiological Effluent Technical Specifications (RETS) for operations conducted during 1983 was performed. The periodic reports reviewed were the Annual Radiological Environmental Operating Report for 1983 and Semiannual Radioactive Effluent Release Reports for 1983. The principal review guidelines were the plant's specific RETS, NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants'', and NRC Guidance on the Review of the Process Control Programs. The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines

  13. Technical evaluation of RETS-required reports for the La Crosse boiling water reactor

    International Nuclear Information System (INIS)

    Magleby, E.H.; Young, T.E.

    1985-01-01

    A review of the reports required by federal regulations and the plant-specific Radiological Effluent Technical Specifications (RETS) for operations conducted during 1983 was performed. The periodic reports reviewed were the Annual Radiological Environmental Operating Report for 1983 and the Semiannual Radioactive Effluent Release Reports for 1983. The principal review guidelines were the plant-specific RETS, NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants'', and NRC Guidance on the Review of the Process Control Programs. The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines. 5 refs

  14. Technical evaluation of RETS-required reports for Duane Arnold Energy Center Unit No. 1

    International Nuclear Information System (INIS)

    Young, T.E.; Magleby, E.H.; Henscheid, J.W.

    1985-01-01

    A review of the reports required by federal regulations and the plant-specific Radiological Effluent Technical Specifications (RETS) for operations conducted during 1983 was performed. The periodic reports reviewed were the Annual Radiological Environmental Operating Report for 1983 and the Semiannual Radioactive Effluent Release Reports for 1983. The principal review guidelines were the plant's specific RETS, NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants'', and NRC Guidance on the Review of the Process Control Programs. The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines. 8 refs

  15. Technical evaluation of RETS-required reports for Kewaunee Nuclear Power Plant for 1983

    International Nuclear Information System (INIS)

    Magleby, E.H.; Young, T.E.

    1985-01-01

    A review of the reports required by Federal regulations and the plant-specific Radiological Effluent Technical Specifications (RETS) for operations conducted at the Kewaunee Nuclear Power Plant during 1983 was performed. The periodic reports reviewed were the two Semiannual Effluent Release Reports for 1983 and the annual Kewaunee Environmental Radioactivity Survey. The principal review guidelines were the plant's specific RETS and NRC guidance given in NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants.'' The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines

  16. Characterization and vectorization of siRNA targeting RET/PTC1 in human papillary thyroid carcinoma cells

    Directory of Open Access Journals (Sweden)

    Massade L.

    2011-10-01

    Full Text Available RET/PTC1 fusion oncogene is the most common genetic alteration identified to date in thyroid papillary carcinomas (PTC and represents a good target for small interfering RNA (siRNA. Our aim was: i to target the RET/PTC1 oncogene by siRNAs, ii to assess the knockdown effects on cell growth and cell cycle regulation and iii to vectorize it in order to protect it from degradation. Methods. Human cell lines expressing RET/PTC1 were transfected by siRNA RET/PTC1, inhibition of the oncogene expression was assessed by qRT-PCR and by Western blot. Conjugation of siRNA RET/PTC1 to squalene was performed by coupling it to squalene. In vivo studies are performed in nude mice. Conclusion. In this short communication, we report the main published results obtained during last years.

  17. A germline RET proto-oncogene mutation in multiple members of an ...

    African Journals Online (AJOL)

    Makia Marafie

    2016-09-17

    Sep 17, 2016 ... The Egyptian Journal of Medical Human Genetics (2017) 18, 193–197. HOSTED BY ... been reported in 85% of tested individuals, nearly 50% of them are amino acid .... [1] Krampitz GW, Norton JA. RET gene mutations ...

  18. Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?

    DEFF Research Database (Denmark)

    Hansen, H S; Torring, H; Godballe, C

    2000-01-01

    BACKGROUND: The results and consequences of genetic testing in a family with familial medullary thyroid carcinoma (FMTC) are described. METHODS: In the screening of relatives, serum calcitonin is replaced by RET mutation analysis that was performed in families suspected of hereditary medullary th...

  19. A germline RET proto-oncogene mutation in multiple members of an ...

    African Journals Online (AJOL)

    Background: Multiple endocrine neoplasia type 2A (MEN2A) is a rare cancer associated-syndrome, inherited in an autosomal dominant fashion and caused by germline mutation in RET proto-oncogene. Clinical diagnosis depends on the manifestation of two or more certain endocrine tumors in an individual, such as ...

  20. Variants in RET Associated With Hirschsprung's Disease Affect Binding of Transcription Factors and Gene Expression

    NARCIS (Netherlands)

    Sribudiani, Yunia; Metzger, Marco; Osinga, Jan; Rey, Amanda; Burns, Alan J.; Thapar, Nikhil; Hofstra, Robert M. W.

    BACKGROUND & AIMS: Two noncoding variations in RET-the T allele of the single nucleotide polymorphism (SNP) rs2435357 (Enh1:C>T) and the A allele of the SNP rs2506004 (Enh2:C>A)-are associated with Hirschsprung's disease. These SNPs are in strong linkage disequilibrium and located in an enhancer

  1. Synergistic growth inhibition of cancer cells harboring the RET/PTC1 ...

    Indian Academy of Sciences (India)

    Synergistic growth inhibition of cancer cells harboring the RET/PTC1 oncogene by staurosporine and rotenone involves enhanced cell death. ANTÓNIO PEDRO GONÇALVES, ARNALDO VIDEIRA, VALDEMAR MÁXIMO and PAULA SOARES. J. Biosci. 36(4), September 2011, 639-648, © Indian Academy of Sciences.

  2. No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma

    NARCIS (Netherlands)

    Hofstra, RMW; Cheng, NC; Stulp, RP; Stelwagen, T; Clausen, N; Tommerup, N; Caron, H; Westerveld, A; Buys, CHCM

    Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogene RET plays a role in neurocrest differentiation. In humans expression of RT is limited to certain tumor

  3. Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

    DEFF Research Database (Denmark)

    Perea, Daniel; Guiu, Jordi; Hudry, Bruno

    2017-01-01

    Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant...

  4. The Establishment of a Formal Midwest Renewable Energy Tracking System (M-RETS) Organization

    Energy Technology Data Exchange (ETDEWEB)

    Maria Redmond; Chela Bordas O' Connor

    2010-06-30

    The objectives identified in requesting and utilizing this funding has been met. The goal was to establish a formal, multi-jurisdictional organization to: (1) ensure the policy objectives of the participating jurisdictions are addressed through increased tradability of the Renewable Energy Credits (RECs) from M-RETS and to eliminate the possibility that a single jurisdiction will be the sole arbiter of the operation of the system; (2) facilitate the establishment of REC standards including the attributes related to, the creation, trading, and interaction with other trading and tracking systems; and (3) have a centralized and established organization that will be responsible for the contracting and governance responsibilities of a multi-jurisdictional tracking system. The M-RETS Inc. Board ensures that the system remains policy neutral; that the attributes of generation are tracked in a way that allows the system users to easily identify and trade relevant RECs; that the system can add jurisdictions as needed or desired; and that the tracking system operate in such a way to allow for the greatest access possible for those participating in other tracking or trading systems by allowing those systems to negotiate with a single M-RETS entity for the import and export of RECs. M-RETS as an organizational body participates and often leads the discussions related to the standardization of RECs and increasing the tradability of M-RETS RECs. M-RETS is a founding member of the Environmental Trading Network of North America (ETNNA) and continues to take a leadership role in the development of processes to facilitate trading among tracking systems and to standardize REC definitions. The Board of Directors of M-RETS, Inc., the non-profit corporation, continues to hold telephone/internet Board meetings. Legal counsel continues working with the board and APX management on a new agreement with APX. The board expects to have an agreement and corresponding fee structure in place by

  5. Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice

    International Nuclear Information System (INIS)

    El Khoury, Diala; Courty, José; Hovanessian, Ara G; Prévost-Blondel, Armelle; Destouches, Damien; Lengagne, Renée; Krust, Bernard; Hamma-Kourbali, Yamina; Garcette, Marylène; Niro, Sandra; Kato, Masashi; Briand, Jean-Paul

    2010-01-01

    The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity. The in vivo antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model. Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days. In parallel, the molecular basis for the action of HB-19 was investigated on a melanoma cell line (called TIII) derived from a cutaneous nodule of a RET mouse. HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors, several-months delay in the incidence of large tumors, a lower frequency of cutaneous nodules, and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue. Moreover, microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls. Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition, impair anchorage-independent growth, and reduce their tumorigenic potential in mice. Moreover, HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9, and tumor necrosis factor-α in the TIII cells and in melanoma tumors of RET mice. Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice, it delayed for several months the onset and frequency of cutaneous tumors, and exerted a significant inhibitory effect on visceral metastasis. Consequently, HB-19 could provide a novel therapeutic agent by itself or

  6. The allele frequency of two single nucleotide polymorphisms in the von Hippel-Lindau (VHL) tumor suppressor gene in the Taiwanese population.

    Science.gov (United States)

    Wang, Wen-Chung; Chen, Hui-Ju; Shu, Wei-Pang; Tsai, Yi-Chang; Lai, Yen-Chein

    2011-10-01

    The von Hippel-Lindau (VHL) tumor suppressor gene located on chromosome 3p25-26 is implicated in VHL disease. Two informative single nucleotide polymorphisms are at positions 19 and 1149 on the nucleotide sequence from Gene Bank NM_000551. In this study we examined the allele frequencies at these two loci in the Taiwanese population and compared the results to those from European ethnic populations. The allele frequency was examined in 616 healthy individuals including 301 university students and 315 neonates. Both A/G polymorphisms were investigated using restriction fragment length polymorphism analysis created by restriction enzymes, BsaJ I and Acc I. Among these subjects, the allele frequencies at 19 SNP and 1149 SNP for variant G were 0.130 and 0.133, respectively. And these results were significant differences from those of the Caucasian populations. In addition, 90% of the tested subjects had identical genotypes at these two loci suggesting the existence of nonrandom association of alleles. We found that the G allele frequency at these two loci in the Taiwanese population is much lower than that in people from Western countries. This phenomenon may be attributed to ethnic effects. Copyright © 2011. Published by Elsevier B.V.

  7. Estudio retórico-comunicativo de los debates presidenciales mexicanos (2006

    Directory of Open Access Journals (Sweden)

    Felicísimo Valbuena de la Fuente

    2007-01-01

    Full Text Available En su Retórica, Aristóteles distinguió materiales de prueba personal (ethos,argumentales (logos y dramáticos, o de experiencia (pathos. También distinguió entre discursos judiciales, deliberativos y epidícticos o demostrativos. El autor de este trabajo quiere demostrar que la Retórica de Aristóteles sigue vigente analizando los debates presidenciales mexicanos en 2006. Se ocupa de cómo cada candidato se atuvo a las normas de los debates, su concepción del público y cómo emplearon los tres tipos de materiales. Asimismo, ilustra sus afirmaciones con numerosos ejemplos.

  8. La traducción como ejercicio retórico y gramatical

    OpenAIRE

    Chico Rico, Francisco

    2009-01-01

    Este trabajo de investigación se centra fundamentalmente en los debates disciplinares latinos en torno a la traducción y a su importancia para la formación del orador en particular y para la educación para la comunicación social en general. En este contexto se aborda el ejercicio de la traducción tanto en el marco de la teoría retórica como en el dominio de la teoría gramatical, así como en el seno de las relaciones entre aquél y éste, ya que si la teoría retórica consideró la traducción fund...

  9. Radiological Effluent Technical Specifications (RETS) implementation: Zion Generating Station Units 1 and 2

    International Nuclear Information System (INIS)

    Serrano, W.; Akers, D.W.; Duce, S.W.; Mandler, J.W.; Simpson, F.B.; Young, T.E.

    1985-06-01

    A review of the Radiological Effluent Technical Specifications (RETS) of the Zion Generating Station Units 1 and 2 was performed. The principal review guidelines used were NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants,'' and Draft 7 of NUREG-0472, Revision 3, ''Radiological Effluent Technical Specifications for Pressurized Water Reactors.'' Draft submittals were discussed with the Licensee by both EG and G and the NRC staff until all items requiring changes to the Technical Specifications were resolved. The Licensee then submitted final proposed RETS to the NRC which were evaluated and found to be in compliance with the NRC review guidelines. The proposed Offsite Dose Calculation Manual was reviewed and generally found to be consistent with the NRC review guidelines. 35 refs., 2 figs., 1 tab

  10. Key Roles for MYC, KIT and RET signaling in secondary angiosarcomas

    DEFF Research Database (Denmark)

    Styring, E; Seinen, J; Dominguez-Valentin, M

    2014-01-01

    of the gene signature to an external data set. RESULTS: In total, 103 genes were significantly deregulated between primary and secondary angiosarcomas. Secondary angiosarcomas showed upregulation of MYC, KIT and RET and downregulation of CDKN2C. Functional annotation analysis identified multiple target genes...... in the receptor protein tyrosine kinase pathway. The results were validated using RT-qPCR and immunohistochemistry. Further, the gene signature was applied to an external data set and, herein, distinguished primary from secondary angiosarcomas. CONCLUSIONS: Upregulation of MYC, KIT and RET and downregulation......BACKGROUND: Angiosarcomas may develop as primary tumours of unknown cause or as secondary tumours, most commonly following radiotherapy to the involved field. The different causative agents may be linked to alternate tumorigenesis, which led us to investigate the genetic profiles of morphologically...

  11. Retórica do consumo: o discurso em ação persuasiva

    OpenAIRE

    Pinheiro, Noslen Nascimento

    2016-01-01

    Diante das inúmeras possibilidades de estudo que o discurso publicitário proporciona, propomos, neste trabalho, uma análise retórica dos títulos de anúncios veiculados em revistas impressas de 1808 a 2015, no Brasil. Em alguns casos, a análise se estende aos textos adicionais para elucidar as intenções argumentativas do orador. Nossa proposta baseia-se essencialmente em uma fundamentação teórica sobre a retórica, exposta no capítulo 1, as quais são baseadas nas teorias de Aristóteles (1985...

  12. A cross-talk between TrkB and Ret tyrosine kinases receptors mediates neuroblastoma cells differentiation.

    Directory of Open Access Journals (Sweden)

    Carla Lucia Esposito

    Full Text Available Understanding the interplay between intracellular signals initiated by multiple receptor tyrosine kinases (RTKs to give the final cell phenotype is a major pharmacological challenge. Retinoic acid (RA-treatment of neuroblastoma (NB cells implicates activation of Ret and TrkB RTKs as critical step to induce cell differentiation. By studying the signaling interplay between TrkB and Ret as paradigmatic example, here we demonstrate the existence of a cross-talk mechanism between the two unrelated receptors that is needed to induce the cell differentiation. Indeed, we show that TrkB receptor promotes Ret phosphorylation by a mechanism that does not require GDNF. This reveals to be a key mechanism, since blocking either TrkB or Ret by small interfering RNA causes a failure in NB biochemical and morphological differentiation. Our results provide the first evidence that a functional transactivation between distinct tyrosine kinases receptors is required for an important physiological process.

  13. IMPACT OF JUTE RETTING ON PHYTOPLANKTON DIVERSITY AND AQUATIC HEALTH: BIOMONITORING IN A TROPICAL OXBOW LAKE

    Directory of Open Access Journals (Sweden)

    Dipankar Ghosh

    2015-11-01

    Full Text Available Phytoplankton acts as a primary producer and biological filter of aquatic ecosystem. Jute retting during monsoon is a common anthropological activity in the rural Bengal. Quantitative seasonal bio-monitoring of phytoplankton community composition with relative abundance and its diversity indices was carried out in this study from April 2013 to March 2014 to assess water quality and the impact of jute retting on phytoplankton diversity of a tropical fresh water oxbow lake in Nadia district of India. We recorded a total of 34 genera of 5 distinct classes, Chlorophyceae (15, Bacillariophyceae (13, Cyanophyceae (4, Dinophyceae (1 and Euglenophyceae (1. Members of Chlorophyceae dominated throughout the year. Unlike Cyanophyceae, Bacillariophyceae was found to be significantly increased during monsoon when compared to the rest of the year. Average phytoplankton density was highest in post-monsoon (8760/L followed by monsoon (4680/L and pre-monsoon (3650/L. Owing to the dominance of class Chlorophyceae and Bacillariophyceae we found this lake to be oligotrophic to mesotrophic. Indices values of genera richness, Shannon-Wiener, evenness and Simpson’s diversity reached their lowest 14, 1.61, 0.61 and 0.68 in monsoon and highest 23, 2.42, 0.77 and 0.86 in post monsoon respectively. The lowest diversity values during monsoon clearly suggested that the selected lake has highest anthropogenic pollution due to jute retting which impacted significantly on phytoplankton diversity. Therefore, the lake is not conducive for fish growth especially during monsoon and we opine that there is a need to regulate jute retting process, intensity and its density in the lake during the monsoon to ensure enhanced biodiversity for sustainable management and conservation of aquatic environment of this Oxbow lake.

  14. Prisen Årets studenter start-up går til Drop Bucket

    DEFF Research Database (Denmark)

    Lassen, Lisbeth

    2015-01-01

    DTU’s ny pris for årets mest innovative studerende blev ved universitetets årsfest givet til Heiða Gunnarsdóttir Nolsøe og Marie Stampe Berggreen, som står bag virksomheden Drop Bucket. Koncerndirektør for innovation og entreprenørskab, Marianne Thellersen, overakte prisen til de to innovatører s...

  15. Comparison of GFL–GFRα complexes: further evidence relating GFL bend angle to RET signalling

    International Nuclear Information System (INIS)

    Parkash, Vimal; Goldman, Adrian

    2009-01-01

    The second crystal structure of the GDNF-GFRα1 complex provides further evidence that GFL signalling through RET is determined by the bend angle in the GFL. Glial cell line-derived neurotrophic factor (GDNF) activates the receptor tyrosine kinase RET by binding to the GDNF-family receptor α1 (GFRα1) and forming the GDNF 2 –GFRα1 2 –RET 2 heterohexamer complex. A previous crystal structure of the GDNF 2 –GFRα1 2 complex suggested that differences in signalling in GDNF-family ligand (GFL) complexes might arise from differences in the bend angle between the two monomers in the GFL homodimer. Here, a 2.35 Å resolution structure of the GDNF 2 –GFRα1 2 complex crystallized with new cell dimensions is reported. The structure was refined to a final R factor of 22.5% (R free = 28%). The structures of both biological tetrameric complexes in the asymmetric unit are very similar to 2v5e and different from the artemin–GFRα3 structure, even though there is a small change in the structure of the GDNF. By comparison of all known GDNF and artemin structures, it is concluded that GDNF is more bent and more flexible than artemin and that this may be related to RET signalling. Comparisons also suggest that the differences between artemin and GDNF arise from the increased curvature of the artemin ‘fingers’, which both increases the buried surface area in the monomer–monomer interface and changes the intermonomer bend angle. From sequence comparison, it is suggested that neuturin (the second GFL) adopts an artemin-like conformation, while persephin has a different conformation to the other three

  16. Screening for retinopathy of prematurity-a comparison between binocular indirect ophthalmoscopy and RetCam 120

    Directory of Open Access Journals (Sweden)

    Shah Parag

    2006-01-01

    Full Text Available Aim: To compare the photographic screening for retinopathy of prematurity (ROP using RetCam 120 with binocular indirect ophthalmoscope (BIO, which is the current gold standard. Setting and Design: Prospective, comparative study. Materials and Methods: A total of 87 RetCam examinations were performed on 27 premature babies. They were stored in a separate file after deleting the identifying information. At the same visit using the BIO with scleral depression, an experienced vitreoretinal surgeon evaluated the fundus in detail. A masked examiner then evaluated the RetCam photographs for presence or absence of ROP, the stage and zone of the disease, and the presence or absence of plus disease. These data were then compared with the BIO findings to determine the sensitivity, specificity, and the positive and negative predictive values of the method. Results: ROP was detected in 63 of 87 examinations by BIO and in 56 of 87 RetCam examinations. Nine RetCam examinations were false-negative and two were false-positive. Sensitivity of RetCam was 85.71% (54/63 and specificity was 91.66% (22/24. The positive and negative predictive values were 96.43% and 70.97% respectively. Conclusion: Nine cases having ROP were missed by the RetCam. All these cases were either in zone 3 or the outer part of zone 2, which later regressed. These were missed mostly because of the restricted mobility of the camera head caused by its size and the barrier caused by the lid speculum arms. No case of threshold ROP was missed. RetCam may replace BIO for screening of ROP.

  17. Mitos no Desengajamento Moral: Retóricas da Samarco em um Crime Corporativo

    Directory of Open Access Journals (Sweden)

    Cintia Rodrigues de Oliveira Medeiros

    2017-12-01

    Full Text Available Nesta pesquisa, conduzimos uma análise retórica com o objetivo de explorar os mecanismos de desengajamento moral utilizados pela Samarco no caso do crime ocorrido com a quebra de uma barragem sob sua administração, em novembro de 2015, em Minas Gerais. O corpus de pesquisa submetido à análise retórica constitui-se de publicações contendo declarações da empresa e de seus representantes sobre o caso em questão. Como resultados, mostramos que a Samarco utiliza-se de três mitos na sua retórica: (a Nós estamos fazendo o que deve ser feito; (b Nós não colocamos a sociedade e o meio ambiente em risco; e (c A culpa não é nossa. Esses três mitos são recursos representativos do desengajamento moral (Bandura, 1999 da empresa para cometer um crime corporativo. Nossa análise identificou três mecanismos: deslocamento de culpa; minimização e distorção das consequências; e rotulagem eufemística.

  18. Combined treatment of retting flax wastewater using Fenton oxidation and granular activated carbon

    Directory of Open Access Journals (Sweden)

    Sohair I. Abou-Elela

    2016-07-01

    Full Text Available The process of retting flax produces a huge amount of wastewater which is characterized with bad unpleasant smell and high concentration of organic materials. Treatment of such waste had always been difficult because of the presence of refractory organic pollutants such as lignin. In this study, treatment of retting wastewater was carried out using combined system of Fenton oxidation process followed by adsorption on granular activated carbon (GAC. The effects of operating condition on Fenton oxidation process such as hydrogen peroxide and iron concentration were investigated. In addition, kinetic study of the adsorption process was elaborated. The obtained results indicated that degradation of organic matters follows a pseudo-first order reaction with regression coefficient of 0.98. The kinetic model suggested that the rate of reaction was highly affected by the concentration of hydrogen peroxide. Moreover, the results indicated that the treatment module was very efficient in removing the organic and inorganic pollutants. The average percentage removal of chemical oxygen demand (COD, total suspended solid (TSS, oil, and grease was 98.60%, 86.60%, and 94.22% with residual values of 44, 20, and 5 mg/L, respectively. The treated effluent was complying with the National Regulatory Standards for wastewater discharge into surface water or reuse in the retting process.

  19. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Abschuetz, Oliver [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Osen, Wolfram [Division of Translational Immunology, German Cancer Center, Heidelberg 69120 (Germany); Frank, Kathrin [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Kato, Masashi [Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi 487-8501 (Japan); Schadendorf, Dirk [Department of Dermatology, University Hospital Essen, Essen 45122 (Germany); Umansky, Viktor, E-mail: v.umansky@dkfz.de [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany)

    2012-04-26

    Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy.

  20. Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7.

    Science.gov (United States)

    Pandey, A; Liu, X; Dixon, J E; Di Fiore, P P; Dixit, V M

    1996-05-03

    Adapter proteins containing Src homology 2 (SH2) domains link transmembrane receptor protein-tyrosine kinases to downstream signal transducing molecules. A family of SH2 containing adapter proteins including Grb7 and Grb10 has been recently identified. We had previously shown that Grb10 associates with Ret via its SH2 domain in an activation-dependent manner (Pandey, A., Duan, H., Di Fiore, P.P., and Dixit, V.M. (1995) J. Biol, Chem. 270, 21461-21463). We now demonstrate that the related adapter molecule Grb7 also associates with Ret in vitro and in vivo, and that the binding of the SH2 domain of Grb7 to Ret is direct. This binding is dependent upon Ret autophosphorylation since Grb7 is incapable of binding a kinase-defective mutant of Ret. Thus two members of the Grb family, Grb7 and Grb10, likely relay signals emanating from Ret to other, as yet, unidentified targets within the cell.

  1. Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Amanda J. Watson

    2016-05-01

    Full Text Available RET (REarranged during Transfection is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent.   At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR, lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments.   In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series.  Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.

  2. A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies.

    Science.gov (United States)

    Platt, Adam; Morten, John; Ji, Qunsheng; Elvin, Paul; Womack, Chris; Su, Xinying; Donald, Emma; Gray, Neil; Read, Jessica; Bigley, Graham; Blockley, Laura; Cresswell, Carl; Dale, Angela; Davies, Amanda; Zhang, Tianwei; Fan, Shuqiong; Fu, Haihua; Gladwin, Amanda; Harrod, Grace; Stevens, James; Williams, Victoria; Ye, Qingqing; Zheng, Li; de Boer, Richard; Herbst, Roy S; Lee, Jin-Soo; Vasselli, James

    2015-03-23

    To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3-1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4-6 copies in ≥40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with

  3. Bap1 and Pbrm1: Determinants of Tumor Grade and mTOR Activation in VHL-Deficient Mouse Models of Renal Cell Carcinoma.

    Science.gov (United States)

    Leung, Janet Y; Kim, William Y

    2017-08-01

    Large genome sequencing efforts have identified frequent mutations in the histone-modifying and chromatin-remodeling genes BAP1 and PBRM1 in clear cell renal cell carcinoma (ccRCC). In this issue of Cancer Discovery , Gu and colleagues model these genetic events in mice and report that dual inactivation of Vhl with either Bap1 or Pbrm1 results in faithful genetically engineered murine models of ccRCC. Moreover, their work establishes that Bap1 and Pbrm1 are determinants of tumor grade and mTORC1 activation and provocatively suggests that the cell of origin of ccRCC may lie in PAX8-expressing Bowman capsule cells. Cancer Discov; 7(8); 802-4. ©2017 AACR See related article by Gu et al., p. 900 . ©2017 American Association for Cancer Research.

  4. Ny EU-dom om afgifter på motorkøretøjer - en bombe under de nationale registreringsafgifter

    DEFF Research Database (Denmark)

    Thygesen, Jette

    2013-01-01

    Gennem tiden har EU-Domstolen, i en mængde sager, taget stilling til medlemsstaternes ret til at opkræve afgift af motorkøretøjer. EU-Domstolen har således taget stilling til, om afgift på motorkøretøjer er forenelig med EU-retten i forbindelse med arbejdskraftens frie bevægelighed, etableringsre...

  5. Mecanismos argumentativos en las cartas al director: La interrogación retórica

    Directory of Open Access Journals (Sweden)

    Joan Gabriel Burguera Serra

    2010-11-01

    Full Text Available Normal 0 21 false false false ES X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabla normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} El objetivo de este artículo se centra en la descripción de la funcionalidad pragmática de la interrogación retórica en las cartas al director. El punto de partida radica en entender las cartas al director como textos con finalidades comunicativas relacionadas con el asentamiento de actos de habla de queja o desaprobación y aceptar, en consecuencia, que el potencial argumentativo que subyace a las interrogaciones retóricas comporta la idoneidad de las mismas en el marco textual indicado. En último término, se proponen unos mecanismos descriptivos básicos para evidenciar las correspondencias entre estructura formal e interpretación retórica de enunciados interrogativos.

  6. Improving retting of fibre through genetic modification of flax to express pectinases.

    Science.gov (United States)

    Musialak, Magdalena; Wróbel-Kwiatkowska, Magdalena; Kulma, Anna; Starzycka, Eligia; Szopa, Jan

    2008-02-01

    Flax (Linum usitatissimum L.) is a raw material used for important industrial products. Linen has very high quality textile properties, such as its strength, water absorption, comfort and feel. However, it occupies less than 1% of the total textile market. The major reason for this is the long and difficult retting process by which linen fibres are obtained. In retting, bast fibre bundles are separated from the core, the epidermis and the cuticle. This is accomplished by the cleavage of pectins and hemicellulose in the flax cell wall, a process mainly carried out by plant pathogens like filamentous fungi. The remaining bast fibres are mainly composed of cellulose and lignin. The aim of this study was to generate plants that could be retted more efficiently. To accomplish this, we employed the novel approach of transgenic flax plant generation with increased polygalacturonase (PGI ) and rhamnogalacturonase (RHA) activities. The constitutive expression of Aspergillus aculeatus genes resulted in a significant reduction in the pectin content in tissue-cultured and field-grown plants. This pectin content reduction was accompanied by a significantly higher (more than 2-fold) retting efficiency of the transgenic plant fibres as measured by a modified Fried's test. No alteration in the lignin or cellulose content was observed in the transgenic plants relative to the control. This indicates that the over-expression of the two enzymes does not affect flax fibre composition. The growth rate and soluble sugar and starch contents were in the range of the control levels. It is interesting to note that the RHA and PGI plants showed higher resistance to Fusarium culmorum and F. oxysporum attack, which correlates with the increased phenolic acid level. In this report, we demonstrate for the first time that over-expression of the A. aculeatus genes results in flax plants more readily usable for fibre production. The biochemical parameters of the cell wall components indicated that

  7. Cidadania: ret?rica e realidade nas pol?ticas sociais de Manaus

    OpenAIRE

    Pereira, Raimundo Emerson Dourado

    2004-01-01

    Este trabalho discute os aspectos que norteiam a quest?o da cidadania, verificando o distanciamento que a ret?rica governamental adquire ao ser confrontada ? reprodu??o da pobreza e da exclus?o social no espa?o urbano de Manaus. Partimos do entendimento de que os programas assistenciais implantados nesta cidade podem se constituir em espa?o onde ? poss?vel observar, dentre outras quest?es que podem ser suscitadas no contexto das pol?ticas sociais no capitalismo perif?rico, as contradi??es que...

  8. Improvement of Haramay Fiber by Pre-treatment of Retting Process withPhosphoric Acid

    International Nuclear Information System (INIS)

    Kuntari-Sasas; Neni-Rustini Eriawati

    2000-01-01

    Haramay as bast fiber contains of cellulose fiber as the main part, mixedwith hemi cellulose, pectin, and lignin as binding material for cellulosefiber to keep it together in the bundle form. For textile material, this bastfiber has to be freed from its binding material, called as retting process,before subjecting to scouring, dyeing and finishing process in textileindustry. In the retting process the dissolve of binding material can be doneeither by using enzyme in bio technology or extraction with strong alkalinecondition in common technology. Using sodium hydroxide for dissolving thebinding material can be carried out easily with good dissolving ability, butcan render the strength retention of the cellulose fiber. Pre-treatment ofthe bast fiber with phosphoric acid (H 3 PO 4 ), is expected to hydrolyze someof the binding materials that can not be dissolved in alkaline condition,including natural pigment that colored the fiber with creamy white. In thisstudy, the pre-treatment process before retting with phosphoric acid wascarried out in various condition, such as concentration of phosphoric acid (5ml/l- 25 ml/l), time and temperature of pre-treatment (1-3 hours at 50 o C or12-24 hours at room temperature), followed by neutralization in dilutealkaline. The retting process was carried out by means of scouring in variousconcentration of sodium hydroxide (NaOH 38 o Be, 10 ml/l-30 m/l), and then wascontinued with bleaching process in hydrogen peroxide solution. Aftercarrying out those experiment, the bast fiber that called haramay wassubjected to testing for weight reduction, strength retention and degree ofwhiteness. From the testing results it is concluded that pre-treatment withphosphoric acid can increase the weight reduction, strength retention ortenacity and degree of whiteness of haramay fiber compared to the oneswithout pre-treatment with phosphoric acid. The best result was obtained bypre-treatment with 5 ml/l H 3 PO 4 at 50 o C for 2 hours, continued by

  9. Le facteur humain et la sûreté de fonctionnement dans le ...

    African Journals Online (AJOL)

    Notre contribution porte sur le rôle fondamental du facteur humain dans le management intégré des risques d'une part et du rôle déterminant qu'il peut avoir à jouer pour que la sûreté de fonctionnement réponde à sa propriété d'autre part. Un rôle illustré à travers une analyse de risque dans un complexe de Gaz Naturel ...

  10. Análisis retórico del esténcil o estarcido

    Directory of Open Access Journals (Sweden)

    Heiner Mercado-Percia

    2012-01-01

    Full Text Available En esta exposición intentaré dar respuesta a las siguientes preguntas: ¿Puede expresarse un discurso retórico por medio de una imagen? Y si esto es posible ¿cómo esta imagen puede persuadir a un auditorio? Estas preguntas surgen a partir de una imagen de esténcil o estarcido llamada Disney War,apareció en los muros de muchas ciudades del mundo, incluida Medellín, y que es promocionada o expuesta a través de la Internet.

  11. Book Review: Zarzo, E. (2016), Memoria Retórica y Experiencia Estética. Retórica, Estética y Educación. Madrid: Dykinson

    OpenAIRE

    Davide Mombelli

    2016-01-01

    Memoria retórica y experiencia estética. Retórica, Estética y Educación, recently published by Dykinson, is a fundamental body of research on rhetoric memory and aesthetic experience, two objects of study which, although having generated much literature separately, have not been considered in their reciprocity until now. The author, Esther Zarzo, who earned her Ph.D. in Philosophy, has published several investigations of both a theoretical and practical nature concerning the treatment and...

  12. RET/PTC1-Driven Neoplastic Transformation and Proinvasive Phenotype of Human Thyrocytes Involve Met Induction and β-Catenin Nuclear Translocation

    Directory of Open Access Journals (Sweden)

    Giuliana Cassinelli

    2009-01-01

    Full Text Available Activation of the RET gene by chromosomal rearrangements generating RET/PTC oncogenes is a frequent, early, and causative event in papillary thyroid carcinoma (PTC. We have previously shown that, in human primary thyrocytes, RET/PTC1 induces a transcriptional program including the MET proto-oncogene. In PTCs, β-catenin is frequently mislocated to the cytoplasm nucleus. We investigated the interplay between Ret/ptc1 signaling and Met in regulating the proinvasive phenotype and β-catenin localization in cellular models of human PTC. Here, we show that Met protein is expressed and is constitutively active in human thyrocytes exogenously expressing RET/PTC1 as well as a mutant (Y451F devoid of the main Ret/ptc1 multidocking site. Both in transformed thyrocytes and in the human PTC cell line TPC-1, Ret/ptc1-Y451-dependent signaling and Met cooperated to promote a proinvasive phenotype. Accordingly, gene/functional silencing of either RET/PTC1 or MET abrogated early branching morphogenesis in TPC-1 cells. The same effect was obtained by blocking the common downstream effector Akt. Y451 of Ret/ptc1 was required to promote proliferation and nuclear translocation of β-catenin, suggesting that these oncogene-driven effects are Met-independent. Pharmacologic inhibition of Ret/ptc1 and Met tyrosine kinases by the multitarget small molecule RPI-1 blocked cell proliferation and invasive ability and dislocated β-catenin from the nucleus. Altogether, these results support that Ret/ptc1 cross talks with Met at transcriptional and signaling levels and promotes β-catenin transcriptional activity to drive thyrocyte neoplastic transformation. Such molecular network, promoting disease initiation and acquisition of a proinvasive phenotype, highlights new options to design multitarget therapeutic strategies for PTCs.

  13. RET/PTC1-Driven Neoplastic Transformation and Proinvasive Phenotype of Human Thyrocytes Involve Met Induction and β-Catenin Nuclear Translocation1

    Science.gov (United States)

    Cassinelli, Giuliana; Favini, Enrica; Degl'Innocenti, Debora; Salvi, Alessandro; De Petro, Giuseppina; Pierotti, Marco A; Zunino, Franco; Borrello, Maria Grazia; Lanzi, Cinzia

    2009-01-01

    Activation of the RET gene by chromosomal rearrangements generating RET/PTC oncogenes is a frequent, early, and causative event in papillary thyroid carcinoma (PTC). We have previously shown that, in human primary thyrocytes, RET/PTC1 induces a transcriptional program including the MET proto-oncogene. In PTCs, β-catenin is frequently mislocated to the cytoplasm nucleus. We investigated the interplay between Ret/ptc1 signaling and Met in regulating the proinvasive phenotype and β-catenin localization in cellular models of human PTC. Here, we show that Met protein is expressed and is constitutively active in human thyrocytes exogenously expressing RET/PTC1 as well as a mutant (Y451F) devoid of the main Ret/ptc1 multidocking site. Both in transformed thyrocytes and in the human PTC cell line TPC-1, Ret/ptc1-Y451-dependent signaling and Met cooperated to promote a proinvasive phenotype. Accordingly, gene/functional silencing of either RET/PTC1 or MET abrogated early branching morphogenesis in TPC-1 cells. The same effect was obtained by blocking the common downstream effector Akt. Y451 of Ret/ptc1 was required to promote proliferation and nuclear translocation of β-catenin, suggesting that these oncogene-driven effects are Met-independent. Pharmacologic inhibition of Ret/ptc1 and Met tyrosine kinases by the multitarget small molecule RPI-1 blocked cell proliferation and invasive ability and dislocated β-catenin from the nucleus. Altogether, these results support that Ret/ptc1 cross talks with Met at transcriptional and signaling levels and promotes β-catenin transcriptional activity to drive thyrocyte neoplastic transformation. Such molecular network, promoting disease initiation and acquisition of a proinvasive phenotype, highlights new options to design multitarget therapeutic strategies for PTCs. PMID:19107227

  14. La red de técnicos en salud (rets: logros y desafíos The network of health technicians (rets: achievements and challenges

    Directory of Open Access Journals (Sweden)

    Alcira Castillo Martínez

    2005-03-01

    Full Text Available Se presenta una experiencia de cooperación en red de instituciones de formación de técnicos en salud y la facilitación de la Organización Panamericana de la Salud (OPS, incluyendo el contexto de cambio y las nuevas políticas de recursos humanos con sus implicaciones en el mundo del trabajo y la educación. Constituye una síntesis integradora de los procesos socio-afectivos y técnicos que le dan fuerza y dinámica a la Red de Técnicos en Salud (Rets. Se considera su creación, objetivos, estructura y organización, así como la gestión de la OPS y de los actores institucionales denominados Núcleos de Desarrollo (Nudes con sus proyectos dinamizadores. Por último, se señalan las valoraciones y avances de lo realizado por los actores de los distintos países de América Latina y el Caribe Hispano. Se destaca la utilización de novedosos mecanismos de gestión en la cooperación técnica al reflexionar sobre los factores que influyen en la sostenibilidad y el éxito de experiencias en red con potencial movilizador y articulador para la cooperación horizontal en un mundo globalizado.This article relates an experience of cooperation through a network of institutions oriented to the training of health technicians, under the guidance of the Pan-American Health Organization (OPS. It also deals with present changes in the field and with the new human resources policies, with their respective implications in the world of work and of education. The experience may be regarded as an attempt to integrate the social-affective and technical processes that give strength and dynamism to the Network of Health Technicians (Rets. We examine its creation, objectives, structure and organization, as well as the OPS' management and the role of the institutional actors called Development Nuclei (Nudes and their stimulating projects. Finally, we point to the advantages and progressive characteristics of the work done by professionals in the various Latin

  15. Application of RetCamⅡ in the screening of neonatal fundus disease

    Directory of Open Access Journals (Sweden)

    Zhi-Gang Xiao

    2013-08-01

    Full Text Available AIM: To investigate the safe and reliable examination method for neonatal fundus screening.METHODS: Fundus information of 2 836 neonates performed by RetCamⅡ in our hospital from January 1, 2012 to December 31, 2012 were retrospectively analyzed, including 1 625 cases(57.30%of premature infants which were first examined 1-4 weeks after birth and 1 211 cases(42.70%of term infants which were first examined within 4 weeks after birth.RESULTS: Totally 454 cases of abnormalfundus were found, including 207 cases(12.74%of retinopathy of prematurity(ROP, ROPⅠ in 118 cases(57%, ROPⅡ in 58 cases(28.02%, ROPⅢ in 23 cases(11.11%, ROPⅣ in 8 cases(3.86%, no case of ROPV. A total of 247(20.40%term infants had abnormal fundus, of which 68 cases(27.53%were developmental or hereditary disease, retinoblastoma in 1 case(0.40%, retinal hemorrhage in 102 cases(41.30%, retinal exudative changes in 68 cases(27.53%, optic atrophy in 5 cases(2.02%and optic disc edema in 3 cases(1.21%.CONCLUSION: Neonatal fundus diseases were so various and harmful that early screening should be attended to. Premature infants and term infants with high risk are treated as focus group of fundus screening and RetCamII examination is safe and effective.

  16. miR-449 overexpression inhibits papillary thyroid carcinoma cell growth by targeting RET kinase-β-catenin signaling pathway.

    Science.gov (United States)

    Li, Zongyu; Huang, Xin; Xu, Jinkai; Su, Qinghua; Zhao, Jun; Ma, Jiancang

    2016-10-01

    Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and represent approximately 80% of all thyroid cancers. The present study is aimed to investigate the role of microRNA (miR)-449 in the progression of PTC. Our results revealed that miR-449 was underexpressed in the collected PTC specimens compared with non-cancerous PTC tissues. Overexpression of miR-449 induced a cell cycle arrest at G0/G1 phase and inhibited PTC cell growth in vitro. Further studies revealed that RET proto-oncogene (RET) is a novel miR-449 target, due to miR-449 bound directly to its 3'-untranslated region and miR-449 mimic reduced the protein expression of RET. Similar to the effects of miR-449 overexpression, RET downregulation inhibited cell growth, whereas RET overexpression reversed the inhibitive effect of miR-449 mimic. Furthermore, miR-449 overexpression inhibited the nuclear translocation of β-catenin and reduced the expression of several downstream genes, including c-Myc, cyclin D1, T cell-specific transcription factor (TCF) and lymphoid enhancer-binding factor 1 (LEF-1), and inactivated the β-catenin pathway in TPC-1 cells. Moreover, overexpression of β-catenin prevented miR-449-reduced cell cycle arrest and cell viability. In xenograft animal experiments, miR-449 overexpression effectively suppressed the tumor growth of PTC. Taken together, our research indicated that miR-449 functions as an anti-oncogene by targeting RET, and that miR-449 overexpression inhibited the growth of PTC by inactivating the β-catenin pathway. Thus, miR-449 may serve as a potential therapeutic strategy for the treatment of PTC.

  17. Technical evaluation of RETS-required reports for Browns Ferry Nuclear Power Station, Units 1, 2, and 3, for 1983

    International Nuclear Information System (INIS)

    Young, T.E.; Magleby, E.H.

    1985-01-01

    A review was performed of reports required by federal regulations and the plant-specific radiological effluent technical specifications (RETS) for operations conducted at Tennessee Valley Authority's Browns Ferry Nuclear Station, Units 1, 2, and 3, during 1983. The two periodic reports reviewed were (a) the Effluents and Waste Disposal Semiannual Report, First Half 1983 and (b) the Effluents and Waste Disposal Semiannual Report, Second Half 1983. The principal review guidelines were the plant's specific RETs and NRC guidance given in NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants.'' The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines

  18. Technical evaluation of RETS-required reports for Zion Nuclear Power Station, Units 1 and 2 for 1983

    International Nuclear Information System (INIS)

    Young, T.E.; Magleby, E.H.

    1985-01-01

    A review was performed on the reports required by Federal regulations and the plant-specific Radiological Effluent Technical Specifications (RETS) for operations conducted at Commonwealth Edison's Zion Nuclear Power Station during 1983. The two periodic reports reviewed: (1) were the Effluent and Waste Disposal Semiannual Report, July-December 1983, and (2) the Radioactive Waste and Environmental Monitoring Annual Report - 1983. The principal review guidelines were the plant's specific RETS and NRC guidance given in NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants.'' The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines

  19. Technical evaluation of RETS-required reports for the Edwin I. Hatch Nuclear Plant, Units 1 and 2

    International Nuclear Information System (INIS)

    Young, T.E.; Magleby, E.H.

    1985-01-01

    A review of the reports required by federal regulations and the plant-specific Radiological Effluent Technical Specifications (RETS) for operations conducted during 1983 was performed. The periodic reports reviewed for the Edwin I. Hatch Nuclear Plant were the Annual Radiological Environmental Operating Report for 1983 and the Semiannual Radioactive Effluent Release Reports for 1983. The principal review guidelines were the plant's specific RETS, NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants'', and NRC Guidance on the Review of the Process Control Programs. The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines. 7 refs

  20. Technical evaluation of RETS-required reports for Rancho Seco Nuclear Generating Station, Unit 1 for 1983

    International Nuclear Information System (INIS)

    Magleby, E.H.; Young, T.E.

    1985-01-01

    A review of the reports required by Federal regulations and the plant-specific Radiological Effluent Technical Specifications (RETS) for operations conducted during 1983 was performed. The periodic reports reviewed for the Rancho Seco Nuclear Generating Station, Unit 1 were the Semiannual Effluent Release Report, January 1, 1983 to June 30, 1983 and the Radiation Exposure, Environmental Protection, Effluent and Waste Disposal Report. The principal review guidelines were the plant's specific RETS which were based on NRC guidance given in NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants.'' The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines

  1. Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events

    Directory of Open Access Journals (Sweden)

    Castaño Luis

    2011-10-01

    Full Text Available Abstract Background RET is the major gene associated to Hirschsprung disease (HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In the present study, we have performed a comprehensive study of our HSCR series evaluating the involvement of both RET rare variants (RVs and common variants (CVs in the context of the disease. Methods RET mutational screening was performed by dHPLC and direct sequencing for the identification of RVs. In addition Taqman technology was applied for the genotyping of 3 RET CVs previously associated to HSCR, including a variant lying in an enhancer domain within RET intron 1 (rs2435357. Statistical analyses were performed using the SPSS v.17.0 to analyze the distribution of the variants. Results Our results confirm the strongest association to HSCR for the "enhancer" variant, and demonstrate a significantly higher impact of it in male versus female patients. Integration of the RET RVs and CVs analysis showed that in 91.66% of cases with both kinds of mutational events, the enhancer allele is in trans with the allele bearing the RET RV. Conclusions A gender effect exists on both the transmission and distribution of rare coding and common HSCR causing mutations. In addition, these RET CVs and RVs seem to act in a synergistic way leading to HSCR phenotype.

  2. The value of Ret-Hb and sTfR in the diagnosis of iron depletion in healthy, young children

    NARCIS (Netherlands)

    Uijterschout, L.; Domellöf, M.; Vloemans, J.; Vos, R.; Hudig, C.; Bubbers, S.; Verbruggen, S.; Veldhorst, M.; de Leeuw, T.; Teunisse, P. P.; van Goudoever, J. B.; Brus, F.

    2014-01-01

    Reticulocyte hemoglobin (Ret-Hb) content and soluble transferrin receptor (sTfR) are described as promising biomarkers in the analysis of iron status. However, the value of Ret-Hb and sTfR in the early detection of iron depletion, as frequently observed in children in high-income countries, is

  3. Zebrafish GDNF and its co-receptor GFRα1 activate the human RET receptor and promote the survival of dopaminergic neurons in vitro.

    Directory of Open Access Journals (Sweden)

    Tuulia Saarenpää

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF is a ligand that activates, through co-receptor GDNF family receptor alpha-1 (GFRα1 and receptor tyrosine kinase "RET", several signaling pathways crucial in the development and sustainment of multiple neuronal populations. We decided to study whether non-mammalian orthologs of these three proteins have conserved their function: can they activate the human counterparts? Using the baculovirus expression system, we expressed and purified Danio rerio RET, and its binding partners GFRα1 and GDNF, and Drosophila melanogaster RET and two isoforms of co-receptor GDNF receptor-like. Our results report high-level insect cell expression of post-translationally modified and dimerized zebrafish RET and its binding partners. We also found that zebrafish GFRα1 and GDNF are comparably active as mammalian cell-produced ones. We also report the first measurements of the affinity of the complex to RET in solution: at least for zebrafish, the Kd for GFRα1-GDNF binding RET is 5.9 μM. Surprisingly, we also found that zebrafish GDNF as well as zebrafish GFRα1 robustly activated human RET signaling and promoted the survival of cultured mouse dopaminergic neurons with comparable efficiency to mammalian GDNF, unlike E. coli-produced human proteins. These results contradict previous studies suggesting that mammalian GFRα1 and GDNF cannot bind and activate non-mammalian RET and vice versa.

  4. Investigation of the bacterial retting community of kenaf (Hibiscus cannabinus) under different conditions using next-generation semiconductor sequencing

    Science.gov (United States)

    The use of the natural fibers requires the development of cost-efficient processing of fibers with consistent, uniform properties. The microbial communities associated with kenaf (Hibiscus cannabinus) plant fibers during retting were determined in an effort to identify possible means of accelerating...

  5. Risøs virksomhedsregnskab 1999. Opfølgning på planerne for året 1999

    DEFF Research Database (Denmark)

    Forskningscenter Risø, Roskilde

    2000-01-01

    Risøs Virksomhedsregnskab 1999 er en opfølgning på planerne for Risøs virksomhed i 1999. Risøs bestyrelse skal som led i resultatkontrakten med Forskningsministeriet aflægge årlige rapporter om opfyldelsen af de fastlagte resultatkrav. Derudover gives engenerel overordnet rapportering af årets re...

  6. Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas.

    Science.gov (United States)

    La Perle, K M; Jhiang, S M; Capen, C C

    2000-08-01

    Papillary thyroid carcinomas in humans are associated with the ret/PTC oncogene and, following loss of p53 function, may progress to anaplastic carcinomas. Mice with thyroid-targeted expression of ret/PTC1 developed papillary thyroid carcinomas that were minimally invasive and did not metastasize. These mice were crossed with p53-/- mice to investigate whether loss of p53 would promote anaplasia and metastasis of ret/PTC1-induced thyroid tumors. The majority of p53-/- mice died or were euthanized by 17 weeks of age due to the development of thymic lymphomas, soft tissue sarcomas, and testicular teratomas. All ret/PTC1 mice developed thyroid carcinomas, but tumors in p53-/- mice were more anaplastic, larger in diameter, more invasive, and had a higher mitotic index than tumors in p53+/+ and p53+/- mice. Thyroid tumors did not metastasize in any of the experimental p53+/+ and p53+/- mice anaplasia and invasiveness of thyroid carcinomas.

  7. SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET

    DEFF Research Database (Denmark)

    Glerup, Simon; Lume, Maria; Olsen, Ditte

    2013-01-01

    is targeted to lysosomes and degraded while GFRα1 recycles, creating an efficient GDNF clearance pathway. The SorLA/GFRα1 complex further targets RET for endocytosis but not for degradation, affecting GDNF-induced neurotrophic activities. SorLA-deficient mice display elevated GDNF levels, altered dopaminergic...

  8. Phylogenetic analysis of the kenaf fiber microbial retting community by semiconductor sequencing of 16S rDNA amplicons

    Science.gov (United States)

    Kenaf, hemp, and jute have been used for cordage and fiber production since prehistory. To obtain the fibers, harvested plants are soaked in ponds where indigenous microflora digests pectins and other heteropolysaccharides, releasing fibers in a process called retting. Renewed interest in “green” ...

  9. Vindicación y elogio de la retórica deliberativa: glosas de Aristóteles

    Directory of Open Access Journals (Sweden)

    Vega Reñón, Luis

    2013-06-01

    Full Text Available Today we are witnessing the increasing interest in the argumentative rhetoric because of its close relationship with the public discourse. Two points have been highlighted in this regard: 1, the contribution of rhetoric to the critical revision of the ongoing programs of the so-called “deliberative democracy”; 2, the reading of Aristotle’s Rhetoric in line with these critical purposes. The aim of my paper is to develop this second point through an examination of the Aristotelian conception of rhetoric and his vindication of public deliberation.Hoy estamos asistiendo a un creciente interés por la retórica argumentativa debido a su estrecha relación con el discurso público. Tienen especial relieve dos puntos a este respecto: 1, la contribución de la retórica a la revisión crítica de los programas en curso de la llamada “democracia deliberativa”; 2, la lectura de la Retórica de Aristóteles en la línea de estos propósitos críticos. Mi artículo se propone desarrollar este segundo punto a través de un examen de la concepción aristotélica de la retórica y de su vindicación de la deliberación pública.

  10. Retórica fotográfica. Ingenio y provocación

    Directory of Open Access Journals (Sweden)

    Rafael Gómez Alonso

    2012-04-01

    Full Text Available La fotografía es uno de los medios visuales que más ha evolucionado, desde sus orígenes a mediados del siglo XIX hasta la actualidad, en sus formas de representación visual. La articulación de su lenguaje como medio de comunicación se vale de distintos modos de expresión, y en este sentido, la retórica juega un papel importante a la hora de ofrecer varias posibilidades de aplicación, en donde el ingenio y la utilización de sus capacidades estéticas (diseño, técnicas (instrumentos tecnológicos, culturales (reflejo de las prácticas sociales y argumentativas (cualidades narrativas son las claves de su sentido creativo.

  11. La retórica de lo extremo en la ultraderecha chilena

    Directory of Open Access Journals (Sweden)

    Juan Antonio González de Requena Farré

    2017-01-01

    Full Text Available Este artículo pretende caracterizar la ideología de la extrema de - recha chilena a través de su historia. Se realizó un análisis del discurso de los manifiestos y declaraciones de principios de cua - tro formaciones de ultraderecha de distintos momentos de la his- toria de Chile: el Movimiento Nacional Socialista, el Movimien - to Revolucionario Nacional Sindicalista, el Frente Nacionalista Patria y Libertad, así como Patria Nueva Sociedad. El enfoque retórico de la ideología ultraderechista permite reconstruir las autodescripciones ideológicas, las articulaciones del autoritaris- mo, los marcos figurativos y las principales construcciones argu - mentativas de la extrema derecha chilena.

  12. Relações retóricas estabelecidas por orações gerundiais adverbiais

    Directory of Open Access Journals (Sweden)

    Juliano Desiderato Antonio

    2012-01-01

    Full Text Available O objetivo deste trabalho é propor critérios para identificação das relações implícitas estabelecidas por orações gerundiais adverbiais em um corpus formado por elocuções formais (aulas e entrevistas. Para isso, tomam-se como fundamento teórico da pesquisa duas teorias funcionalistas, a Teoria da Estrutura Retórica do Texto (RST e a Gramática Discursivo-Funcional (GDF. Na visão da RST, além do conteúdo explícito veiculado pelas orações de um texto, há proposições implícitas que surgem das relações que se estabelecem entre partes do texto. Foram utilizados os parâmetros da GDF, factualidade, pressuposição, e as camadas dos níveis representacional e interpessoal em que ocorrem as orações para a identificação das relações retóricas estabelecidas pelas orações gerundiais adverbiais. Foram encontradas relações de meio, de resultado, de condição e de propósito, o que não significa que não se reconheça, neste trabalho, que outras relações como tempo (anterioridade, posterioridade, simultaneidade, concessão, causa, dentre outras, podem ser estabelecidas por orações gerundiais adverbiais. Os parâmetros da GDF demonstraram ser eficientes na identificação das relações.

  13. Bioelectricity generation from coconut husk retting wastewater in fed batch operating microbial fuel cell by phenol degrading microorganism

    International Nuclear Information System (INIS)

    Jayashree, C.; Arulazhagan, P.; Adish Kumar, S.; Kaliappan, S.; Yeom, Ick Tae; Rajesh Banu, J.

    2014-01-01

    Dual chamber microbial fuel cell (MFC) operated at fed batch mode for the treatment of retting wastewater has potently achieved both current generation and phenol removal. Hydraulic retention time (HRT) of the reactor was varied from 40 days to 10 days. COD (chemical oxygen demand) removal was 91% at 40 days HRT, with an initial COD concentration of 530 ± 50 g m −3 . Retting wastewater with an initial phenol concentration of 320 ± 60 g m −3 procured a highest phenol removal of 93% at 40 days HRT of the microbial fuel cell. Maximum power density of 362 mW m −2 was achieved using retting wastewater at HRT of 20 days with an internal resistance of 150 Ω in a dual chambered MFC. The bacterial strains in anode region, reported to be responsible for potential phenol removal, were identified as Ochrobactrum sp. RA1 (KJ408266), Ochrobactrum sp. RA2 (KJ408267) and Pesudomonas aeruginosa RA3 (KJ408268) using phylogenetic analysis. The study reveals that, dual chambered MFC effectively removed the phenol from retting wastewater along with power generation. - Highlights: • Maximum power density of 362 mW m −2 (150 Ω) was achieved at HRT of 20 days. • 91% COD removal and 93% phenol removal was observed at HRT of 40 days. • 25% coulombic efficiency was achieved in treatment of retting wastewater with MFC. • Phylogenetic analysis detect phenol degrading Ochrobactrum sp.RA1 in anode biofilm. • In addition, Ochrobactrum sp.RA2 and Pseudomonas aeruginosa RA3 were also isolated

  14. Retórica aplicada a la Enseñanza del Diseño Gráfico

    Directory of Open Access Journals (Sweden)

    Roberto Gamonal Arroyo

    2011-11-01

    Full Text Available Los conceptos fundamentales de la Retórica para la creación del discurso se pueden trasladar al Diseño Gráfico con la finalidad de construir piezas gráficas que son consideradas, a su vez, discursos visuales. En este sentido, tanto las operaciones retóricas como las figuras derivadas de ellas tienen un papel fundamental como elementos detonantes de la creatividad. Para evitar el uso de las figuras como un mero recurso estilístico, un error histórico cometido por la propia Retórica, éstas se convierten en la expresión figurada de un argumento en el que se modifica su grado cero para que resulte más llamativo e impactante a la audiencia a la que va dirigida el mensaje gráfico. A través de unas simples operaciones de adición, supresión, sustitución y permutación se producen variaciones de los elementos gráficos y de su grado cero de expresión (concepto del Grupo m que se cristalizan en figuras retóricas que generan nuevas composiciones con mayor potencia expresiva y creativa. En este artículo veremos cómo los estudiantes aplican estos conceptos retóricos para la conceptualización, creación y diseño de cubiertas para libros.

  15. Low dose irradiation of thyroid cells reveals a unique transcriptomic and epigenetic signature in RET/PTC-positive cells

    Energy Technology Data Exchange (ETDEWEB)

    Abou-El-Ardat, Khalil, E-mail: kabouela@sckcen.be [Radiobiology Unit, Molecular and Cellular Biology, GKD Building, Studiecentrum voor Kernenergie - Centre d' Etude de l' Energie Nucleaire (SCK-CEN), Boeretang 200, 2400 Mol (Belgium); Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Universiteit Gent, 9000 Ghent (Belgium); Monsieurs, Pieter [Radiobiology Unit, Molecular and Cellular Biology, GKD Building, Studiecentrum voor Kernenergie - Centre d' Etude de l' Energie Nucleaire (SCK-CEN), Boeretang 200, 2400 Mol (Belgium); Anastasov, Natasa; Atkinson, Mike [Department of Radiation Sciences, Helmholtz Zentrum Muenchen, Munich (Germany); Derradji, Hanane [Radiobiology Unit, Molecular and Cellular Biology, GKD Building, Studiecentrum voor Kernenergie - Centre d' Etude de l' Energie Nucleaire (SCK-CEN), Boeretang 200, 2400 Mol (Belgium); De Meyer, Tim [Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Universiteit Gent, 9000 Ghent (Belgium); Department of Applied Mathematics, Biometrics and Process Control, Faculty of Bioscience Engineering, Universiteit Gent, 9000 Ghent (Belgium); Bekaert, Sofie [Clinical Research Center, Faculty for Medicine and Health Sciences, Universiteit Gent, 185 De Pintelaan, 9000 Ghent (Belgium); Van Criekinge, Wim [Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Universiteit Gent, 9000 Ghent (Belgium); and others

    2012-03-01

    The high doses of radiation received in the wake of the Chernobyl incident and the atomic bombing of Hiroshima and Nagasaki have been linked to the increased appearance of thyroid cancer in the children living in the vicinity of the site. However, the data gathered on the effect of low doses of radiation on the thyroid remain limited. We have examined the genome wide transcriptional response of a culture of TPC-1 human cell line of papillary thyroid carcinoma origin with a RET/PTC1 translocation to various doses (0.0625, 0.5, and 4 Gy) of X-rays and compared it to response of thyroids with a RET/PTC3 translocation and against wild-type mouse thyroids irradiated with the same doses using Affymetrix microarrays. We have found considerable overlap at a high dose of 4 Gy in both RET/PTC-positive systems but no common genes at 62.5 mGy. In addition, the response of RET/PTC-positive system at all doses was distinct from the response of wild-type thyroids with both systems signaling down different pathways. Analysis of the response of microRNAs in TPC-1 cells revealed a radiation-responsive signature of microRNAs in addition to dose-responsive microRNAs. Our results point to the fact that a low dose of X-rays seems to have a significant proliferative effect on normal thyroids. This observation should be studied further as opposed to its effect on RET/PTC-positive thyroids which was subtle, anti-proliferative and system-dependent.

  16. Characterization of Bacterial and Fungal Community Dynamics by High-Throughput Sequencing (HTS Metabarcoding during Flax Dew-Retting

    Directory of Open Access Journals (Sweden)

    Christophe Djemiel

    2017-10-01

    Full Text Available Flax dew-retting is a key step in the industrial extraction of fibers from flax stems and is dependent upon the production of a battery of hydrolytic enzymes produced by micro-organisms during this process. To explore the diversity and dynamics of bacterial and fungal communities involved in this process we applied a high-throughput sequencing (HTS DNA metabarcoding approach (16S rRNA/ITS region, Illumina Miseq on plant and soil samples obtained over a period of 7 weeks in July and August 2014. Twenty-three bacterial and six fungal phyla were identified in soil samples and 11 bacterial and four fungal phyla in plant samples. Dominant phyla were Proteobacteria, Bacteroidetes, Actinobacteria, and Firmicutes (bacteria and Ascomycota, Basidiomycota, and Zygomycota (fungi all of which have been previously associated with flax dew-retting except for Bacteroidetes and Basidiomycota that were identified for the first time. Rare phyla also identified for the first time in this process included Acidobacteria, CKC4, Chlorobi, Fibrobacteres, Gemmatimonadetes, Nitrospirae and TM6 (bacteria, and Chytridiomycota (fungi. No differences in microbial communities and colonization dynamics were observed between early and standard flax harvests. In contrast, the common agricultural practice of swath turning affects both bacterial and fungal community membership and structure in straw samples and may contribute to a more uniform retting. Prediction of community function using PICRUSt indicated the presence of a large collection of potential bacterial enzymes capable of hydrolyzing backbones and side-chains of cell wall polysaccharides. Assignment of functional guild (functional group using FUNGuild software highlighted a change from parasitic to saprophytic trophic modes in fungi during retting. This work provides the first exhaustive description of the microbial communities involved in flax dew-retting and will provide a valuable benchmark in future studies aiming

  17. [The theme of disaster in health care: profile of technical and scientific production in the specialized database on disasters of the Virtual Health Library - VHL].

    Science.gov (United States)

    Rocha, Vania; Ximenes, Elisa Francioli; Carvalho, Mauren Lopes de; Alpino, Tais de Moura Ariza; Freitas, Carlos Machado de

    2014-09-01

    In the specialized database of the Virtual Health Library (VHL), the DISASTER database highlights the importance of the theme for the health sector. The scope of this article is to identify the profiles of technical and scientific publications in the specialized database. Based on systematic searches and the analysis of results it is possible to determine: the type of publication; the main topics addressed; the most common type of disasters mentioned in published materials, countries and regions as subjects, historic periods with the most publications and the current trend of publications. When examining the specialized data in detail, it soon becomes clear that the number of major topics is very high, making a specific search process in this database a challenging exercise. On the other hand, it is encouraging that the disaster topic is discussed and assessed in a broad and diversified manner, associated with different aspects of the natural and social sciences. The disaster issue requires the production of interdisciplinary knowledge development to reduce the impacts of disasters and for risk management. In this way, since the health sector is a interdisciplinary area, it can contribute to knowledge production.

  18. A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma

    OpenAIRE

    Silva, Adriana Madeira Alvares da [UNIFESP; Maciel, Rui Monteiro de Barros [UNIFESP; Dias-da-Silva, Magnus Régios [UNIFESP; Toledo, Silvia Regina Caminada de [UNIFESP; De Carvalho, Marcos B.; Cerutti, Janete Maria [UNIFESP

    2003-01-01

    Familial medullary thyroid carcinoma is related to germ-line mutations in the RET oncogene, mainly in cysteine codon 10 or 11, whereas noncysteine mutations in codons 13 - 15 are rare. We now report a new missense point mutation in exon 8 of the RET gene (1597G-->T) corresponding to a Gly(533)Cys substitution in the cystein-rich domain of RET protein in 76 patients from a 6-generation Brazilian family with 229 subjects, with ascendants from Spain. It is likely that the mutation causes familia...

  19. Functioning Mediastinal Paraganglioma Associated with a Germline Mutation of von Hippel-Lindau Gene

    Directory of Open Access Journals (Sweden)

    Thibault Bahougne

    2018-05-01

    Full Text Available We report the case of a 21-year old woman presenting with high blood pressure and raised normetanephrine levels. Indium-111-pentetreotide single photon-emission computed tomography with computed tomography (SPECT/CT and 2-deoxy-2-[fluorine-18]fluoro-d-glucose (FDG positron emission tomography/computed tomography (PET/CT imaging showing isolated tracer-uptake by a 2 cm tumor close to the costovertebral angle of the third thoracic vertebra. Thoracic surgery led to normalization of normetanephrine levels. Histological findings were consistent with the presence of a paraganglioma. Mutations in SDHA, SDHB, SDHC, SDHD, RET, SDHAF2, TMEM127, MAX, NF1, FH, MDH2, and EPAS1 were absent, but a heterozygous missense mutation, c.311G > T, was found in exon 1 of the von Hippel-Lindau gene, VHL, resulting in a glycine to valine substitution in the VHL protein at position 104, p.Gly104Val. This same mutation was found in both the mother and the 17-year old sister in whom a small retinal hemangioblastoma was also found. We diagnose an unusual functional mediastinal paraganglioma in this young patient with a germline VHL gene mutation, a mutation previously described as inducing polycythemia and/or pheochromocytoma but not paraganglioma or retinal hemangioblastoma.

  20. Establishment of a non-tumorigenic papillary thyroid cell line (FB-2) carrying the RET/PTC1 rearrangement.

    Science.gov (United States)

    Basolo, Fulvio; Giannini, Riccardo; Toniolo, Antonio; Casalone, Rosario; Nikiforova, Marina; Pacini, Furio; Elisei, Rossella; Miccoli, Paolo; Berti, Piero; Faviana, Pinuccia; Fiore, Lisa; Monaco, Carmen; Pierantoni, Giovanna Maria; Fedele, Monica; Nikiforov, Yuri E; Santoro, Massimo; Fusco, Alfredo

    2002-02-10

    A novel human thyroid papillary carcinoma cell line (FB-2) has been established and characterized. FB-2 cells harbor the RET/PTC1 chimeric oncogene in which the RET kinase domain is fused to the H4 gene. FB-2 cells neither formed colonies in semisolid media nor induced tumors after heterotransplant into severe combined immunodeficient mice. However, HMGI(Y), HMGI-C and c-myc genes, which are associated to thyroid cell transformation, were abundantly expressed in FB-2 cells but not in normal thyroid cells. FB-2 cells only partially retained the differentiated thyroid phenotype. In fact, the PAX-8 gene, which codes for a transcriptional factor required for thyroid cell differentiation, was expressed, while thyroglobulin, TSH-receptor and thyroperoxidase genes were not. Moreover, FB-2 cells produced high levels of interleukin (IL)-6 and IL-8. Copyright 2001 Wiley-Liss, Inc.

  1. Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease.

    Science.gov (United States)

    Sribudiani, Y; Chauhan, R K; Alves, M M; Petrova, L; Brosens, E; Harrison, C; Wabbersen, T; de Graaf, B M; Rügenbrink, T; Burzynski, G; Brouwer, R W W; IJcken, W F J van; Maas, S M; de Klein, A; Osinga, J; Eggen, B J L; Burns, A J; Brooks, A S; Shepherd, I T; Hofstra, R M W

    2018-03-27

    Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by absence of enteric ganglia in the distal part of the gut. Variants in ret proto-oncogene (RET) have been associated with up to 50% of familial and 35% of sporadic cases. We searched for variants that affect disease risk in a large, multi-generational family with history of HSCR in a linkage region previously associated with the disease (4q31.3-q32.3) and exome wide. We performed exome sequencing analyses of a family in the Netherlands with 5 members diagnosed with HSCR and 2 members diagnosed with functional constipation. We initially focused on variants in genes located in 4q31.3-q32.3. However, we also performed an exome-wide analysis in which known HSCR or HSCR-associated gene variants predicted to be deleterious were prioritized for further analysis. Candidate genes were expressed in HEK293, COS-7, and Neuro-2a cells and analyzed by luciferase and immunoblot assays. Morpholinos were designed to target exons of candidate genes and injected into 1-cell stage zebrafish embryos. Embryos were allowed to develop and stained for enteric neurons. Within the linkage region, we identified 1 putative splice variant in the LPS responsive beige-like anchor protein gene (LRBA). Functional assays could not confirm its predicted effect on mRNA splicing or on expression of the mab-21 like 2 gene (MAB21L2), which is embedded in LRBA. Zebrafish that developed following injection of the lrba morpholino had a shortened body axis and subtle gut morphological defects, but no significant reduction in number of enteric neurons compared with controls. Outside the linkage region, members of 1 branch of the family carried a previously unidentified RET variant or an in-frame deletion in the glial cell line derived neurotrophic factor gene (GDNF), which encodes a ligand of RET. This deletion was located 6 base pairs before the last codon. We also found variants in the indian hedgehog gene (IHH) and its mediator

  2. VizieR Online Data Catalog: The 4 brightest red giants in the UFD galaxy Ret 2 (Roederer+, 2016)

    Science.gov (United States)

    Roederer, I. U.; Mateo, M.; Bailey, J. I., III; Song, Y.; Bell, E. F.; Crane, J. D.; Loebman, S.; Nidever, D. L.; Olszewski, E. W.; Shectman, S. A.; Thompson, I. B.; Valluri, M.; Walker, M. G.

    2018-03-01

    There are only four stars brighter than the horizontal branch that are confirmed members of Ret 2 (Simon et al. 2015, J/ApJ/808/95; Walker et al. 2015, J/ApJ/808/108). We observed these four stars using one arm of the Michigan/Magellan Fiber System (M2FS) and MSpec double spectrograph (Bailey et al. 2012SPIE.8446E..5GB; Mateo et al. 2012SPIE.8446E..4YM) mounted on the Nasmyth platform at the 6.5 m Landon Clay Telescope (Magellan II) at Las Campanas Observatory, Chile. We observed four high-probability members of Ret 2 and one blank sky position simultaneously on 2015 November 14 and 16, with a total integration time of 6.67 hr. Both observations were taken in dark time. (4 data files).

  3. Aproximaciones retóricas al conflicto armado colombiano: una revisión bibliográfica

    Directory of Open Access Journals (Sweden)

    Giohanny Olave

    2014-01-01

    Full Text Available Este artículo relaciona investigaciones interesadas en la retórica del conflicto armado colombiano. Tales indagaciones plantean problemas de investigación alrededor del carácter persuasivo de los discursos del conflicto, desde disciplinas diversas. La consulta bibliográfica de base se complementó con una encuesta electrónica autoadministrada, dirigida a investigadores colombianos del discurso. En los resultados, se explican las principales problematizaciones que emergen de la revisión, presentándolas como aproximaciones retóricas que los autores trabajan con una mayor orientación hacia el ethos , el pathos o el logos . Una mirada relacional entre estos trabajos esclarece las tendencias investigativas sobre la violencia en clave discursiva y apunta el valor de esas contribuciones para los estudios sobre el conflicto armado.

  4. Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark

    DEFF Research Database (Denmark)

    Mathiesen, Jes Sloth; Kroustrup, Jens Peter; Vestergaard, Peter

    2017-01-01

    BACKGROUND: Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study we reported of an unusually high prevalence (33%) of families with the C611Y mutation and hypothesized that this might be due to a founder...... effect. We conducted the first nationwide study of haplotypes in MEN2A families aiming to investigate the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations. METHODS: The study included 21 apparently unrelated MEN2A families identified from a nationwide...... Danish RET cohort from 1994 to 2014. Twelve, two, two, three and two families carried the C611Y, C618F, C618Y, C620R and C634R mutation, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness. RESULTS: A common founder mutation was found...

  5. Technical evaluation of RETS-required reports for Crystal River Nuclear Generating Plant, Unit 3, for 1983

    International Nuclear Information System (INIS)

    Magleby, E.H.; Young, T.E.

    1985-01-01

    A review was performed on the reports required by Federal regulations and the plant-specific Radiological Effluent Technical Specifications (RETS) for operations conducted at Florida Power Corporation's Crystal River Nuclear Plant, Unit 3, during 1983. The three periodic reports reviewed were (1) the Effluent and Waste Disposal Semiannual Report, January 1-June 30, 1983, (2) the Effluent and Waste Disposal Semiannual Report, July 1-December 31, 1983, and (3) the Annual Environmental Operating Report, Radiological, 1983. The principal review guidelines were the plant's specific RETS and NRC guidance given in NUREG-0133, ''Preparation of Radiological Effluent Technical Specifications for Nuclear Power Plants.'' The Licensee's submitted reports were found to be reasonably complete and consistent with the review guidelines

  6. Formas retóricas de dizer: o jornalista Celso Ming e seus artigos de opinião

    OpenAIRE

    Santana, Maiara Pereira de

    2015-01-01

    Esta dissertação, produzida na linha Texto e discurso nas modalidades oral e escrita, do Programa de Estudos em Língua Portuguesa da Pontifícia Universidade Católica de São Paulo (PUC-SP), tem por objetivo realizar uma leitura retórica de artigo opinativo, especificamente, o de domínio econômico, escrito pelo jornalista Celso Ming para o jornal O Estado de São Paulo. Para análise, adota-se a perspectiva da retórica, arte e técnica grega, que se atém aos discursos que são passíveis de persuasã...

  7. [Dose-Response Dependences for Frequency of RET/PTC Gene Rearrangements in Papillary Thyroid Carcinoma after Irradiation. Simple Pooling Analysis of Molecular Epidemiological Data].

    Science.gov (United States)

    Koterov, A N; Ushenkova, L N; Biryukov, A P

    2016-01-01

    On the basis of all possible publications on the theme included in the previously formed base of sources on molecular epidemiology of RET/PTC rearrangements in thyroid papillary carcinoma a pooled analysis ("simple pooling data") on determination of the dose-effect dependences for RET/PTC frequency in radiogenic carcinomas of various irradiated groups was performed. (They are groups subjected to radiotherapeutic exposure, residents near the Chernobyl nuclear power plant (CNPP) and victims of nuclear bombing). The tendency to Pearson linear correlation (r = 0.746; p = 0.148) between the frequency of RET/PTC and the estimated dose on thyroid in the regions affected by the CNPP accident was revealed. But this tendency was recognized to be random owing to abnormally low values of the indicator for the most contaminated Gomel region. The method tentatively called "case-control" showed reliable differences in thyroid dose values for carcinomas with RET/PTC and without those. The versatility of changes was found: the lack of RET/PTC for radiotherapeutic impacts was associated with higher doses, whereas in case of the CNPP accident and for nuclear bombing victims it was the opposite. Probably, in the first case the "cellular cleaning" phenomenon after exposure to very high doses took place. Search of direct Pearson correlations between average/median thyroid doses on groups and RET/PTC frequency in carcinomas of these groups showed a high reliability for the dose-effect dependences- at the continuous dose scale (for RET/PTC in total and RET/PTC1 respectively: r = 0.830; p = 0.002 and r = 0.906; p = 0.0003); while there was no significant correlation received for RET/PTC3. When using the weighting least square regression analysis (proceeding from the number of carcinomas in samples), the specified regularities remained. Attempts to influence the strength of correlation by exception ofthe data of all the samples connected with the accident on the CNPP did not significantly

  8. Somatotropinomas, but not nonfunctioning pituitary adenomas, maintain a functional apoptotic RET/Pit1/ARF/p53 pathway that is blocked by excess GDNF.

    Science.gov (United States)

    Diaz-Rodriguez, Esther; Garcia-Rendueles, Angela R; Ibáñez-Costa, Alejandro; Gutierrez-Pascual, Ester; Garcia-Lavandeira, Montserrat; Leal, Alfonso; Japon, Miguel A; Soto, Alfonso; Venegas, Eva; Tinahones, Francisco J; Garcia-Arnes, Juan A; Benito, Pedro; Angeles Galvez, Maria; Jimenez-Reina, Luis; Bernabeu, Ignacio; Dieguez, Carlos; Luque, Raul M; Castaño, Justo P; Alvarez, Clara V

    2014-11-01

    Acromegaly is caused by somatotroph cell adenomas (somatotropinomas [ACROs]), which secrete GH. Human and rodent somatotroph cells express the RET receptor. In rodents, when normal somatotrophs are deprived of the RET ligand, GDNF (Glial Cell Derived Neurotrophic Factor), RET is processed intracellularly to induce overexpression of Pit1 [Transcription factor (gene : POUF1) essential for transcription of Pituitary hormones GH, PRL and TSHb], which in turn leads to p19Arf/p53-dependent apoptosis. Our purpose was to ascertain whether human ACROs maintain the RET/Pit1/p14ARF/p53/apoptosis pathway, relative to nonfunctioning pituitary adenomas (NFPAs). Apoptosis in the absence and presence of GDNF was studied in primary cultures of 8 ACROs and 3 NFPAs. Parallel protein extracts were analyzed for expression of RET, Pit1, p19Arf, p53, and phospho-Akt. When GDNF deprived, ACRO cells, but not NFPAs, presented marked level of apoptosis that was prevented in the presence of GDNF. Apoptosis was accompanied by RET processing, Pit1 accumulation, and p14ARF and p53 induction. GDNF prevented all these effects via activation of phospho-AKT. Overexpression of human Pit1 (hPit1) directly induced p19Arf/p53 and apoptosis in a pituitary cell line. Using in silico studies, 2 CCAAT/enhancer binding protein alpha (cEBPα) consensus-binding sites were found to be 100% conserved in mouse, rat, and hPit1 promoters. Deletion of 1 cEBPα site prevented the RET-induced increase in hPit1 promoter expression. TaqMan qRT-PCR (real time RT-PCR) for RET, Pit1, Arf, TP53, GDNF, steroidogenic factor 1, and GH was performed in RNA from whole ACRO and NFPA tumors. ACRO but not NFPA adenomas express RET and Pit1. GDNF expression in the tumors was positively correlated with RET and negatively correlated with p53. In conclusion, ACROs maintain an active RET/Pit1/p14Arf/p53/apoptosis pathway that is inhibited by GDNF. Disruption of GDNF's survival function might constitute a new therapeutic route in

  9. EGFR, ALK, RET, KRAS and BRAF alterations in never-smokers with non-small cell lung cancer.

    Science.gov (United States)

    Dong, Y U; Ren, Weihong; Qi, Jun; Jin, B O; Li, Ying; Tao, Huiqing; Xu, Ren; Li, Yanqing; Zhang, Qinxian; Han, Baohui

    2016-04-01

    Non-small cell lung cancer (NSCLC), caused by various mutations in a spectrum of cancer driver genes, may have distinct pathological characteristics and drug responses. Extensive genetic screening and pathological characterization is required for the design of customized therapies to improve patient outcomes. Notably, NSCLC in never-smokers exhibits distinctive clinicopathological features, which are frequently associated with tumorigenic mutations, and thus may be treated as a unique disease entity. However, to the best of our knowledge, these mutations have not been extensively and accurately characterized in an NSCLC study with a large sample size. Therefore, the present study enrolled a large cohort of NSCLC patients, which consisted of 358 never-smokers, for the screening of genetic alterations in the epidermal growth factor receptor (EGFR), ret proto-oncogene (RET), anaplastic lymphoma kinase (ALK), Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene serine/threonine kinase (BRAF) tumorigenic genes. It was identified that the mutation rate was 47.8, 7.5, 3.6, 1.4 and 0.3% for EGFR, ALK, KRAS, RET and BRAF, respectively. In addition, clinicopathological features associated with these mutations were characterized. EGFR mutations were more frequently observed in female and older patients. By contrast, KRAS mutations were more frequently detected in male patients, and ALK and RET translocations in younger patients. The cancer cells were frequently well-differentiated in carcinoma cases exhibiting EGFR mutations, however, were less differentiated in those with ALK translocations. In conclusion, the present study determined the frequency of oncogenic alterations and associated clinicopathological features in NSCLC exhibited by never-smokers using a large sample size. The results of the present study may enrich our knowledge of NSCLC in never-smokers and provide useful insights for improvement of the outcome of molecularly targeted therapies

  10. Microbiological and Biochemical Characterization of Cassava Retting, a Traditional Lactic Acid Fermentation for Foo-Foo (Cassava Flour) Production

    OpenAIRE

    Brauman, A.; Keleke, S.; Malonga, M.; Miambi, E.; Ampe, F.

    1996-01-01

    The overall kinetics of retting, a spontaneous fermentation of cassava roots performed in central Africa, was investigated in terms of microbial-population evolution and biochemical and physicochemical parameters. During the traditional process, endogenous cyanogens were almost totally degraded, plant cell walls were lysed by the simultaneous action of pectin methylesterase and pectate lysate, and organic acids (C2 to C4) were produced. Most microorganisms identified were found to be facultat...

  11. Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase*

    Science.gov (United States)

    Perrinjaquet, Maurice; Vilar, Marçal; Ibáñez, Carlos F.

    2010-01-01

    The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr687 in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr687 and association with components of the Tyr1062 signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser696, a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr687 as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions. PMID:20682772

  12. Protein-tyrosine phosphatase SHP2 contributes to GDNF neurotrophic activity through direct binding to phospho-Tyr687 in the RET receptor tyrosine kinase.

    Science.gov (United States)

    Perrinjaquet, Maurice; Vilar, Marçal; Ibáñez, Carlos F

    2010-10-08

    The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr(687) in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr(687) and association with components of the Tyr(1062) signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser(696), a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr(687) as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions.

  13. Break-apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements.

    Science.gov (United States)

    Colato, Chiara; Vicentini, Caterina; Cantara, Silvia; Pedron, Serena; Brazzarola, Paolo; Marchetti, Ivo; Di Coscio, Giancarlo; Chilosi, Marco; Brunelli, Matteo; Pacini, Furio; Ferdeghini, Marco

    2015-05-01

    Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes. Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed. We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR. Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off. FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy. © 2015 European Society of Endocrinology.

  14. Retórica contrastiva y enseñanza del discurso formal en lenguas afines

    Directory of Open Access Journals (Sweden)

    Pilar Robles Garrote

    2014-08-01

    Full Text Available Normal 0 21 false false false ES X-NONE X-NONE El presente artículo trata de evidenciar la utilidad de la retórica contrastiva en la enseñanza del discurso formal en lenguas afines, aportando algunos datos empíricos obtenidos en un análisis lingüístico cuyo objetivo principal es determinar los puntos en común y divergencias encontradas en algunos recursos estilísticos propios del lenguaje formal en lengua española e italiana. Es un estudio de carácter exploratorio realizado a partir de un corpus oral de conferencias dictadas en lengua española e italiana por oradores nativos. Tras analizar y comparar los recursos estilísticos utilizados por los informantes (preguntas, ejemplos, citas y reiteraciones, los resultados revelan que, si bien los recursos del discurso oral formal encontrados en las conferencias analizadas poseen características análogas, existen divergencias entre estas dos lenguas afines que pueden confluir en una percepción distinta del aspecto pragmático.

  15. Application of 119Sn Moessbauer spectroscopy to investigations of RET2-X2-type phases

    International Nuclear Information System (INIS)

    Goerlich, E.

    1991-01-01

    Moessbauer spectroscopy of 119 Sn is an effective tool to study nuclear hyperfine interactions which in turn are important as a source of information complementary to that supplied by ''classical'' methods. However, particularly when the effects are subtle, experimental conditions as well as data analysis should be handled with care. The attention is devoted primarily to the finite absorber thickness effects. As examples serve our recent results obtained from investigations of ternary tetragonal phases of RET 2 X 2 -type. In EuPd 2 Si 2 mixed valent system 119 Sn was used as probe which detects the influence of Eu-valency change at a distant site of Si. Electrical resistivity measurements in CeNi 2 Sn 2 may indicate a Kondo-type behaviour while Moessbauer effect leads to the conclusion in favour of a magnetically ordered state. The analysis of resonance absorption spectra of CeAg 2 Sn 2 using a full transmission integral indicates the presence of a metallic β-tin in the sample, while data fitting within the thin absorber approximation has lead to the opposite conclusion. Neither in CeNi 2 Sn 2 nor in ErNi 2 Sn 2 the temperature dependence of the recoil free factors alone cannot explain the observed broadening of spectra at low temperatures. (author). 14 refs, 13 figs

  16. Analysis of action of device with spring pins for picking up of retted flax straw

    Directory of Open Access Journals (Sweden)

    V. G. Chernikov

    2016-01-01

    Full Text Available Weather conditions in flax cultivation areas during harvesting time can be characterized with high rainfalls, relative humidity and, in some areas, extremely low temperature. Clogging of fields with stones, grass germination through flax swaths, often an absence of homogeneity on length and thickness of straw in swaths require working out new devices for straw lifting. Existing devices for picking up do not provide a high-quality lifting of flax swaths and have a low coefficient of reliability of the process. Researches and experimental-design works were carried out to create a constructive-technological scheme of the picking up device of cylindrical type with spring-loaded rigid pins. The mathematical model of the device operation when a pin touching an obstacle. The condition of balance of the mechanism under which the pin of a cilinder will operate technological process of picking up of retted flax straw without action of the safety device (spring was described. The offered method of calculation of operation of this device was introduced in a common flax swath lifter-turners

  17. Sermão I de Santa Catarina: Latim e Retórica

    Directory of Open Access Journals (Sweden)

    João Bortolanza

    2007-07-01

    Full Text Available Este artigo mostra um pequeno resultado do projeto de pesquisa Ánálise do Latim empregado por Vieira em seus Sermões’. O latim é a própria retórica de Vieira e o levantamento das citações latinas permite reconstruir todo seu labor intelectual. É o que me proponho demonstrar no Sermão I de Santa Catarina, que tem como epígrafe e mote apenas a expressão latina ne forte. A expressão é extraída da frase das virgens prudentes ne forte sufficiat nobis et vobis. Esse “para que não por acaso” passa a ser explorado a partir da etimologia forte > Fortuna, esta, por sua vez, representada pela roda, a roda da Fortuna, sempre instável. E a roda, com a palma e a espada, é um dos troféus da vitória da virgem mártir Catarina em sua imagem. Desfilam frases dos textos sagrados e de clássicos, como Sêneca, Plínio e Plutarco.

  18. Resonance energy transfer (RET)-Induced intermolecular pairing force: a tunable weak interaction and its application in SWNT separation.

    Science.gov (United States)

    Pan, Xiaoyong; Chen, Hui; Wang, Wei Zhi; Ng, Siu Choon; Chan-Park, Mary B

    2011-07-21

    This paper explores evidence of an optically mediated interaction that is active in the separation mechanism of certain selective agents through consideration of the contrasting selective behaviors of two conjugated polymers with distinct optical properties. The involvement of a RET-induced intermolecular pairing force is implied by the different illumination response behaviors. The magnitude of this interaction scales with the external stimulus parameter, the illumination irradiance (I), and thus is tunable. This suggests a facile technique to modify the selectivity of polymers toward specific SWNT species by altering the polymer structure to adjust the corresponding intermolecular interaction. This is the first experimental verification and application of a RET-induced intermolecular pairing force to SWNT separation. With this kind of interaction taken into account, reasonable interpretation of some conflicting data, especially PLE maps, can be easily made. The above conclusion can be applied to other substances as long as they are electrically neutral and there is photon-induced RET between them. The significant magnitude of this interaction makes direct manipulation of molecules/particles possible and is expected to have applications in molecular engineering. © 2011 American Chemical Society

  19. EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53.

    Science.gov (United States)

    Bogusz, Agata M

    2017-01-01

    Posttransplant lymphoproliferative disorders (PTLDs) are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV). EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL) 13 years after heart-lung transplant. Histological examination revealed marked pleomorphism of the malignant cells including nodular areas reminiscent of classical Hodgkin lymphoma (cHL) with abundant large, bizarre Hodgkin-like cells. By immunostaining, the malignant cells were immunoreactive for CD45, CD20, CD79a, PAX5, BCL6, MUM1, and p53 and negative for CD15, CD30, latent membrane protein 1 (LMP1), and EBV-encoded RNA (EBER). Flow cytometry demonstrated lambda light chain restricted CD5 and CD10 negative B-cells. Fluorescence in situ hybridization studies (FISH) were negative for cMYC , BCL2, and BCL6 rearrangements but showed deletion of TP53 and monosomy of chromosome 17. Next-generation sequencing studies (NGS) revealed numerous genetic alterations including 6 pathogenic mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53 (x2) genes and 30 variants of unknown significance (VOUS) in ABL1, ASXL1, ATM, BCOR, BCORL1, BRNIP3, CDH2, CDKN2A, DNMT3A, ETV6, EZH2, FBXW7, KIT, NF1, RUNX1, SETPB1, SF1, SMC1A, STAG2, TET2, TP53, and U2AF2.

  20. EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53

    Directory of Open Access Journals (Sweden)

    Agata M. Bogusz

    2017-01-01

    Full Text Available Posttransplant lymphoproliferative disorders (PTLDs are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV. EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL 13 years after heart-lung transplant. Histological examination revealed marked pleomorphism of the malignant cells including nodular areas reminiscent of classical Hodgkin lymphoma (cHL with abundant large, bizarre Hodgkin-like cells. By immunostaining, the malignant cells were immunoreactive for CD45, CD20, CD79a, PAX5, BCL6, MUM1, and p53 and negative for CD15, CD30, latent membrane protein 1 (LMP1, and EBV-encoded RNA (EBER. Flow cytometry demonstrated lambda light chain restricted CD5 and CD10 negative B-cells. Fluorescence in situ hybridization studies (FISH were negative for cMYC, BCL2, and BCL6 rearrangements but showed deletion of TP53 and monosomy of chromosome 17. Next-generation sequencing studies (NGS revealed numerous genetic alterations including 6 pathogenic mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53(x2 genes and 30 variants of unknown significance (VOUS in ABL1, ASXL1, ATM, BCOR, BCORL1, BRNIP3, CDH2, CDKN2A, DNMT3A, ETV6, EZH2, FBXW7, KIT, NF1, RUNX1, SETPB1, SF1, SMC1A, STAG2, TET2, TP53, and U2AF2.

  1. Germline mutation of RET proto-oncogene’s exons 17 and 18 in Iranian medullary thyroid carcinoma patients

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    Marjan Zarif Yeganeh

    2017-03-01

    Full Text Available Background: Thyroid carcinoma is the most common endocrine malignancy. Medullary thyroid carcinoma (MTC approximately accounts for 5-10% of all thyroid carcinoma. Nowadays, it is obviously, the mutations in REarranged during transfection (RET proto-oncogene, especially, mutations in exons 10, 11 and 16 are associated with MTC pathogenesis and occurrence. Thus, early diagnosis of MTC by mutation detection in RET proto-oncogene allows to identify patients who do not have any developed symptoms. The aim of this study was to screening of germline mutations in RET proto-oncogene exons 17 and 18 in MTC patients and their first degree relatives in Iranian population. Methods: In this cross-sectional study, three hundred eleven participates (190 patients, 121 their relatives were referred to endocrine research center, Shahid Beheshti University of Medical Science during September 2013 until September 2015. The inclusion criteria were pathological and clinical diagnosis. After whole blood sampling, genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection in exons 17 and 18 was performed using PCR and direct DNA sequencing methods. Results: In this study, twenty missense mutations [CGC>TGC, c.2944C>T, p.Arg982Cys (rs17158558] which included 16 heterozygote and 4 homozygote mutations were found in codon 982 (exon 18. In the present study, 154 G>A (rs2742236 and 4 C>T (rs370072408 nucleotide changes were detected in exons 18 and intron 17 respectively. There was no mutation in exon 17. Conclusion: It seems that because of arginine to cysteine substitutions in RET tyrosine kinase protein structure and its polyphen score (0.955 and SIFT score (0.01 the mutation in codon 982 (exon 18 could be have pathogenic effects. On the other hands, the mentioned mutation frequency was 6.4% among MTC patients, so this mutation of exon 18 could be checked in genetic screening tests of RET

  2. Modulatory role of phospholipase D in the activation of signal transducer and activator of transcription (STAT-3 by thyroid oncogenic kinase RET/PTC

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    Kim Dong Wook

    2008-05-01

    Full Text Available Abstract Background RET/PTC (rearranged in transformation/papillary thyroid carcinomas gene rearrangements are the most frequent genetic alterations identified in papillary thyroid carcinoma. Although it has been established that RET/PTC kinase plays a crucial role in intracellular signaling pathways that regulate cellular transformation, growth, and proliferation in thyroid epithelial cells, the upstream signaling that leads to the activation of RET/PTC is largely unknown. Based on the observation of high levels of PLD expression in human papillary thyroid cancer tissues, we investigated whether PLD plays a role in the regulating the RET/PTC-induced STAT3 activation. Methods Cancer tissue samples were obtained from papillary thyroid cancer patients (n = 6. The expression level of PLD was examined using immunohistochemistry and western blotting. Direct interaction between RET/PTC and PLD was analyzed by co-immunoprecipitation assay. PLD activity was assessed by measuring the formation of [3H]phosphatidylbutanol, the product of PLD-mediated transphosphatidylation, in the presence of n-butanol. The transcriptional activity of STAT3 was assessed by m67 luciferase reporter assay. Results In human papillary thyroid cancer, the expression levels of PLD2 protein were higher than those in the corresponding paired normal tissues. PLD and RET/PTC could be co-immunoprecipitated from cells where each protein was over-expressed. In addition, the activation of PLD by pervanadate triggered phosphorylation of tyrosine 705 residue on STAT-3, and its phosphorylation was dramatically higher in TPC-1 cells (from papillary carcinoma that have an endogenous RET/PTC1 than in ARO cells (from anaplastic carcinoma without alteration of total STAT-3 expression. Moreover, the RET/PTC-mediated transcriptional activation of STAT-3 was synergistically increased by over-expression of PLD, whereas the PLD activity as a lipid hydrolyzing enzyme was not affected by RET

  3. Risk Profile of the RET A883F Germline Mutation: An International Collaborative Study.

    Science.gov (United States)

    Mathiesen, Jes Sloth; Habra, Mouhammed Amir; Bassett, John Howard Duncan; Choudhury, Sirazum Mubin; Balasubramanian, Sabapathy Prakash; Howlett, Trevor A; Robinson, Bruce G; Gimenez-Roqueplo, Anne-Paule; Castinetti, Frederic; Vestergaard, Peter; Frank-Raue, Karin

    2017-06-01

    The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists. To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels. Retrospective analysis. International collaboration. Included were 13 A883F carriers. The intervention was thyroidectomy. Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate. One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data. MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level. Copyright © 2017 Endocrine Society

  4. La retórica y el análisis de la tecnología y de la sociedad actuales. Presentación.

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    Giorgio De Marchis

    2013-02-01

    Full Text Available Es un honor para mí presentar el segundo monográfico dedicado a la retórica de la revista académica Icono 14. El anterior fue el primer número del volumen 3, en 2005. Pasa el tiempo, y queda claro que la retórica no muere, sino que se transforma. Esto es así porque la retórica es el estudio de la comunicación eficaz. Todo emisor desea que su comunicación sea lo más efectiva posible, esto es, que la comunicación logre los objetivos del comunicador. Creo que una de las fortalezas de la retórica clásica es que ha construido un andamiaje muy sólido, ordenado, que permite un análisis estructurado, y sin embargo flexible, que le facilita adaptarse a los cambios tecnológicos y sociales. Algunos artículos publicados en este monográfico sirven de ejemplo de dicha estructura trabada, pero también maleable del análisis retórico. El presente monográfico pretende integrar la retórica clásica con la tecnología actual, y ambas con las formas de comunicación social que los cambios tecnológicos han propiciado. En este número se publican nueve artículos que se ocupan de muy distintos temas, y que demuestran fehacientemente qué es la aproximación retórica actual. A continuación anotaré algunos breves comentarios sobre los artículos publicados para que el lector dirija su atención hacia aquellos textos que más le pudieran interesar.

  5. Lentiviral expression of retinal guanylate cyclase-1 (RetGC1 restores vision in an avian model of childhood blindness.

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    Melissa L Williams

    2006-06-01

    Full Text Available Leber congenital amaurosis (LCA is a genetically heterogeneous group of retinal diseases that cause congenital blindness in infants and children. Mutations in the GUCY2D gene that encodes retinal guanylate cyclase-1 (retGC1 were the first to be linked to this disease group (LCA type 1 [LCA1] and account for 10%-20% of LCA cases. These mutations disrupt synthesis of cGMP in photoreceptor cells, a key second messenger required for function of these cells. The GUCY1*B chicken, which carries a null mutation in the retGC1 gene, is blind at hatching and serves as an animal model for the study of LCA1 pathology and potential treatments in humans.A lentivirus-based gene transfer vector carrying the GUCY2D gene was developed and injected into early-stage GUCY1*B embryos to determine if photoreceptor function and sight could be restored to these animals. Like human LCA1, the avian disease shows early-onset blindness, but there is a window of opportunity for intervention. In both diseases there is a period of photoreceptor cell dysfunction that precedes retinal degeneration. Of seven treated animals, six exhibited sight as evidenced by robust optokinetic and volitional visual behaviors. Electroretinographic responses, absent in untreated animals, were partially restored in treated animals. Morphological analyses indicated there was slowing of the retinal degeneration.Blindness associated with loss of function of retGC1 in the GUCY1*B avian model of LCA1 can be reversed using viral vector-mediated gene transfer. Furthermore, this reversal can be achieved by restoring function to a relatively low percentage of retinal photoreceptors. These results represent a first step toward development of gene therapies for one of the more common forms of childhood blindness.

  6. Association of RET Genetic Polymorphisms and Haplotypes with Papillary Thyroid Carcinoma in the Portuguese Population: A Case-Control Study

    Science.gov (United States)

    Santos, Marina; Azevedo, Teresa; Martins, Teresa; Rodrigues, Fernando J.; Lemos, Manuel C.

    2014-01-01

    Thyroid cancer has a multifactorial aetiology resulting from the interaction of genetic and environmental factors. Several low penetrance susceptibility genes have been identified but their effects often vary between different populations. Somatic point mutations and translocations of the REarranged during Transfection (RET) proto-oncogene are frequently found in thyroid cancer. The aim of this case-control study was to determine the effect of four well known RET single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma. A total of 545 Portuguese patients and 543 controls were genotyped by PCR and restriction enzyme analysis, for the following SNPs: G691S (exon 11, rs1799939 G/A), L769L (exon 13, rs1800861 T/G), S836S (exon 14, rs1800862 C/T), and S904S (exon 15, rs1800863 C/G). The minor allele of S836S was overrepresented in patients with papillary thyroid carcinoma (PTC) when compared to controls (OR 1.57; 95% CI 1.05–2.35; p = 0.026). The GGTC haplotype was also overrepresented in PTC (OR 2.51; 95% CI 1.07–5.91; p = 0.029). No associations were found in follicular thyroid carcinoma (FTC). Multivariate logistic regression analysis showed no differences regarding gender, age at diagnosis, lymph node or distant metastasis. However, a near significant overrepresentation of the minor alleles of G691S and S904S was found in patients with tumours greater than 10 mm of diameter at diagnosis. These data suggest that the RET S836S polymorphism in exon 14 and the GGTC haplotype are risk factors for PTC, but not FTC, and that the G691S/S904S polymorphisms might be associated with tumour behaviour. PMID:25330015

  7. A prova retórica do logos no filme narrativo de ficção

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    Carolina Assunção e ALVES

    2016-08-01

    Full Text Available RESUMO O logos consiste na prova retórica técnica/artística, segundo (Aristóteles, 2000, em que o orador demonstra ou tenta demonstrar a verdade pelo discurso; ou seja, trata-se do uso do raciocínio lógico com o objetivo de fundar uma proposição persuasiva. Para autores como (Amossy, 2006 e (Olbrechts-Tyteca e Perelman, 2008, os gêneros discursivos, uma vez que sempre visam a algum tipo de impacto sobre o público, são providos de argumentatividade em diferentes graus e intenções. Neste artigo, pretendemos discutir possibilidades de emprego da prova retórica do logos no filme narrativo de ficção, sob a perspectiva da análise argumentativa do discurso e da teoria semiolinguística (Charaudeau, 2001. O método utilizado consiste na aplicação de algumas categorias do logos à análise argumentativo-discursiva de algumas sequências do filme O Poderoso Chefão II (The Godfather Part II, 1974, de Francis Ford Coppola, levando em consideração os elementos da linguagem cinematográfica envolvidos. Esta pesquisa permitiu verificar a proficuidade da abordagem do filme de ficção como objeto de estudo nessa área, bem como a relação intrínseca entre as provas retóricas do ethos, do pathos e do logos.

  8. IMPACT OF JUTE RETTING ON NATIVE FISH DIVERSITY AND AQUATIC HEALTH OF ROADSIDE TRANSITORY WATER BODIES: AN ASSESSMENT IN EASTERN INDIA

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    Dipankar Ghosh

    2015-09-01

    Full Text Available Roadside transitory water bodies being manmade depressions have a great ecological and socio-economic importance from years. The effects of agricultural runoffs, jute retting, macro-phytes infestations and inadequate rainfall in changed climate often degrade transitory water bodies’ environment while the biodiversity have impacted severely because of population pressure, over exploitation and indiscriminate use of fine meshed fishing gears as a whole. Physico-chemical and biological analysis with fish species composition, relative abundance, diversity indices like species richness, evenness and Shannon-Wiener index were carried out for pre-, during and post-jute retting season and for year mean as a whole to assess impact of jute retting on the roadside transitory water body’s environmental health and indigenous fish diversity at Sahebnagar village in Nadia District, India. All the physico-chemical parameters barring biochemical oxygen demand and water transparency remained more or less same or marginally got little changed during those three seasons. As much as 19 native fish species with varied relative abundances and dominances were identified. Jute retting impacted lower native fish diversity indices like Shannon-Wiener index values (1.94 to 2.68 clearly indicated poor to moderate pollution status of the transitory water body in that area during monsoon in particular and throughout the year in general. So we opined there should be some control over the intense jute retting in the road side transitory water bodies for sustainable management of these manmade resources.

  9. Cálculo vectorial discreto para problemas elípticos sobre retículas uniformes

    OpenAIRE

    Santos Gutiérrez, Roberto

    2004-01-01

    Esta tesina se enmarca dentro de los trabajos en el campo del análisis numérico denominados genéricamente como "discretizaciones miméticas de la mecánica del medio continuo". La idea consiste en establecer un cálculo vectorial sobre retículas uniformes siguiendo el modelo del caso continuo, de forma que se plantean los problemas elípticos directamente en medios discretos. Esto conduce a obtener operadores discretos análogos al gradiente, divergencia y laplaciano, y se demuestra que estos oper...

  10. Carlos Germán Belli y Jorge Eduardo Eielson. Un ensayo de retórica comparada

    OpenAIRE

    Fernández-Cozman, Camilo

    2016-01-01

    Carlos Germán Belli y Jorge Eduardo Eielson son dos poetas peruanos. El autor intenta comparar la obra de ambos poetas sobre la base del análisis de las figuras literarias y de las técnicas argumentativas. Se trata de una óptica de Retórica Comparada. Los dos poetas realizan una crítica de las estructuras de poder hegemónico y ello se evidencia en dos poemas representativos: "La ración" y "Cappella Sistina".

  11. The increased incidence of the RET p.Gly691Ser variant in French-Canadian vesicoureteric reflux patients is not replicated by a larger study in Ireland.

    LENUS (Irish Health Repository)

    Darlow, John M

    2012-02-01

    The p.Gly691Ser variant of the RET protein, resulting from the \\'A\\' allele of the SNP rs1799939 in exon 11 of the RET gene, was recently found to be present in a high proportion of primary vesicoureteric reflux (pVUR) patients in Quebec. We have determined the genotype of this SNP in 221 unrelated index cases of pVUR from the Irish population, in 190 full siblings of 160 of the index cases, and in 592 healthy controls. We found no significant difference in genotype or allele frequencies in patients and controls, and no tendency of affected siblings to share the same genotype. We also found no difference in the presence of additional phenotypic features such as duplex kidneys, between patients with and without the \\'A\\' allele, and no difference in grade of reflux. We find no evidence of any influence of RET SNP rs1799939 on pVUR phenotype.

  12. Imperfect conformation of experimental and epidemiological data for frequency of RET/РТС gene rearrangements in papillary thyroid carcinoma for the Chernobyl accident

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    Ushenkova L.N.

    2013-12-01

    Full Text Available In an overview and analytical study of the epidemiological data on the frequency of RET/РТС gene rearrangements in sporadic and radiogenic (patients after radiotherapy, residents of contaminated after the Chernobyl disaster areas, victims after the atomic bombings, etc. carcinomas of the thyroid gland were examined. In general, the observed epidemiological laws were confirmed in radiobiology experiments by irradiation of different cultures of thyroid cells and ex vivo with the exception of Chernobyl cohorts. Induction of RET/РТС gene rearrangements by 131l exposure in children carcinomas of Chernobyl residents in mice did not observe too. It is concluded that the situation with the frequency of RET/РТС rearrangements in thyroid carcinoma in Chernobyl cohorts once again confirms the multifactorial nature of the induction and development of these tumors with a contribution of radiation and non-radiation factors (iodine deficiency and different stresses.

  13. A interação retórico-discursiva e suas múltiplas variáveis

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    Melliandro Mendes Galinari

    2012-11-01

    Full Text Available O presente artigo procura construir uma visão de conjunto acercados elementos envolvidos numa interação retórico-discursiva e suasrespectivas designações teórico-conceituais. A enunciação, vista sobuma ótica argumentativa e entendida como um processo comunicativoestabelecido entre uma instância de produção e outra de recepção dodiscurso, institui-se pela atuação de inúmeras variáveis. Comoexemplo, pode-se citar os próprios argumentos veiculados pelodiscurso (logos, ethos e pathos, as modalidades possíveis de adesão(teses, ações e emoções, o gênero discursivo/textual e uma série defatores situacionais (orador, auditório, elementos dóxicos,características sócio-históricas, etc.. O artigo, enfim, salienta aimportância de se levar em consideração, conjuntamente, taiselementos durante uma análise discursiva e procura aproximar aAnálise do Discurso da Retórica e da Sofística.

  14. El argumento de probabilidad (τὸ εἰκός en la retórica griega

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    Heiner Mercado Percia

    2015-01-01

    Full Text Available Los discursos de oradores como Isócrates, Gorgias, Antifonte, Lisias, entre otros, e igualmente, los dos tratados de retórica que conservamos de la segunda mitad del siglo IV a. C no sólo pueden considerarse como piezas literarias construidas con gran habilidad o como manuales con recetas para aplicar, sino como fuente de conceptos de interés para la filosofía. En este artículo se analiza uno de esos conceptos, τὸ εἰκός. Traducido normalmente como “probable” o “verosímil”, los eikóta son recursos argumentativos utilizados desde los orígenes de la práctica de arte retórico, sobre todo en espacios judiciales y, particularmente, fueron usados en aquellos litigios en los que la falta de testigos o testimonios hacía difícil inclinar favorablemente al juez. Pero también los eikóta ocuparon el centro de la crítica platónica por ser definidos como opuestos a la verdad (ἀλήθεια.

  15. Retóricas sobre el fraccionamiento del Partido Liberal en Medellín: 1958-1986

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    Juan Carlos Arenas Gómez

    2006-01-01

    Full Text Available Este artículo pretende poner en evidencia los motivos y analizar las razones esgrimidas por los miembros de los partidos cuando protagonizan un proceso de fragmentación. Aborda las retóricas o conjunto de argumentos utilizados, de manera individual o colectiva, por los miembros del partido liberal en Medellín para justificar los procesos de fragmentación y su desmonte durante el Frente Nacional. El examen se estructura a partir del vínculo entre dichas retóricas y las problemáticas que afrontan las organizaciones partidistas y los individuos que actúan dentro de ellas para mantenerse vigentes: en primer lugar, la aplicación de reglas del juego impuestas tanto por el sistema político como por las autoridades del partido; en segundo lugar, las tensiones surgidas tanto alrededor de la selección de candidatos a cargos públicos como del reparto burocrático; en tercer lugar, las elecciones y los resultados que los partidos obtienen en ellas.

  16. Craniopharyngiomas express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors.

    Science.gov (United States)

    Garcia-Lavandeira, Montserrat; Saez, Carmen; Diaz-Rodriguez, Esther; Perez-Romero, Sihara; Senra, Ana; Dieguez, Carlos; Japon, Miguel A; Alvarez, Clara V

    2012-01-01

    Adult stem cells maintain some markers expressed by embryonic stem cells and express other specific markers depending on the organ where they reside. Recently, stem/progenitor cells in the rodent and human pituitary have been characterized as expressing GFRA2/RET, PROP1, and stem cell markers such as SOX2 and OCT4 (GPS cells). Our objective was to detect other specific markers of the pituitary stem cells and to investigate whether craniopharyngiomas (CRF), a tumor potentially derived from Rathke's pouch remnants, express similar markers as normal pituitary stem cells. We conducted mRNA and Western blot studies in pituitary extracts, and immunohistochemistry and immunofluorescence on sections from normal rat and human pituitaries and 20 CRF (18 adamantinomatous and two papillary). Normal pituitary GPS stem cells localized in the marginal zone (MZ) express three key embryonic stem cell markers, SOX2, OCT4, and KLF4, in addition to SOX9 and PROP1 and β-catenin overexpression. They express the RET receptor and its GFRA2 coreceptor but also express the coreceptor GFRA3 that could be detected in the MZ of paraffin pituitary sections. CRF maintain the expression of SOX2, OCT4, KLF4, SOX9, and β-catenin. However, RET and GFRA3 expression was altered in CRF. In 25% (five of 20), both RET and GFRA3 were detected but not colocalized in the same cells. The other 75% (15 of 20) lose the expression of RET, GFRA3, or both proteins simultaneously. Human pituitary adult stem/progenitor cells (GPS) located in the MZ are characterized by expression of embryonic stem cell markers SOX2, OCT4, and KLF4 plus the specific pituitary embryonic factor PROP1 and the RET system. Redundancy in RET coreceptor expression (GFRA2 and GFRA3) suggest an important systematic function in their physiological behavior. CRF share the stem cell markers suggesting a common origin with GPS. However, the lack of expression of the RET/GFRA system could be related to the cell mislocation and deregulated

  17. Egr-1 and serum response factor are involved in growth factors- and serum-mediated induction of E2-EPF UCP expression that regulates the VHL-HIF pathway.

    Science.gov (United States)

    Lim, Jung Hwa; Jung, Cho-Rok; Lee, Chan-Hee; Im, Dong-Soo

    2008-11-01

    E2-EPF ubiquitin carrier protein (UCP) has been shown to be highly expressed in common human cancers and target von Hippel-Lindau (VHL) for proteosomal degradation in cells, thereby stabilizing hypoxia-inducible factor (HIF)-1alpha. Here, we investigated cellular factors that regulate the expression of UCP gene. Promoter deletion assay identified binding sites for early growth response-1 (Egr-1) and serum response factor (SRF) in the UCP promoter. Hepatocyte or epidermal growth factor (EGF), or phorbol 12-myristate 13-acetate induced UCP expression following early induction of Egr-1 expression in HeLa cells. Serum increased mRNA and protein levels of SRF and UCP in the cell. By electrophoretic mobility shift and chromatin immunoprecipitation assays, sequence-specific DNA-binding of Egr-1 and SRF to the UCP promoter was detected in nuclear extracts from HeLa cells treated with EGF and serum, respectively. Overexpression of Egr-1 or SRF increased UCP expression. RNA interference-mediated depletion of endogenous Egr-1 or SRF impaired EGF- or serum-mediated induction of UCP expression, which was required for cancer cell proliferation. Systemic delivery of EGF into mice also increased UCP expression following early induction of Egr-1 expression in mouse liver. The induced UCP expression by the growth factors or serum increased HIF-1alpha protein level under non-hypoxic conditions, suggesting that the Egr-1/SRF-UCP-VHL pathway is in part responsible for the increased HIF-1alpha protein level in vitro and in vivo. Thus, growth factors and serum induce expression of Egr-1 and SRF, respectively, which in turn induces UCP expression that positively regulates cancer cell growth.

  18. Changes in Teachers' Beliefs and Classroom Practices Concerning Inquiry-Based Instruction Following a Year-Long RET-PLC Program

    Science.gov (United States)

    Miranda, Rommel J.; Damico, Julie B.

    2015-01-01

    This mixed-methods study examines how engaging science teachers in a summer Research Experiences for Teachers (RET) followed by an academic-year Professional Learning Community (PLC) focused on translating teacher research experiences to inquiry-based classroom lessons might facilitate changes in their beliefs and classroom practices regarding…

  19. Plasma levels of calcitonin in medullary thyroid carcinoma patients with and without the RET proto-oncogene mutations in exons 10 and 11

    Directory of Open Access Journals (Sweden)

    Samira Ehyayi

    2017-09-01

    Conclusion: Routine measurement of calcitonin has been investigated as a screening method for the diagnosis of medullary thyroid carcinoma patients. Nevertheless, additional data are required to definitely support routine measurement of calcitonin due to the role of RET proto-oncogene.

  20. Retórica de la historia. Un desafío al exceso de las nuevas tecnologías.

    Directory of Open Access Journals (Sweden)

    Pedro Javier Gómez Martínez

    2013-01-01

    Full Text Available El presente artículo se propone analizar un cierto tipo de figuras retóricas que se da en la obra audiovisual en el nivel de la propia historia, afectando al plano del contenido antes que al de la expresión. Hemos utilizado como caso de estudio la serie televisiva Pulseres vermelles ("Pulseras rojas", 2011, creada por Albert Espinosa y dirigida por Pau Freixas. El formato ha sido exportado más allá de nuestras fronteras. Steven Spielberg ha adquirido los derechos. Con un apreciable éxito de público y crítica, esta serie ha conquistado el corazón de numerosos espectadores a partir de temáticas emocionales de enorme compromiso, valiéndose además de un aparato retórico muy eficaz, parte del cual analizaremos aquí. Dichas circunstancias inducen a reflexionar sobre la importancia de la historia frente al discurso. Defendemos que la serie da prioridad a una retórica del contenido sobre la retórica de la expresión.

  1. Regulation of the Na,K-ATPase gamma-subunit FXYD2 by Runx1 and Ret signaling in normal and injured non-peptidergic nociceptive sensory neurons.

    Directory of Open Access Journals (Sweden)

    Stéphanie Ventéo

    Full Text Available Dorsal root ganglia (DRGs contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury.

  2. Cold DUst around NEarby Stars (DUNES). First results. A resolved exo-Kuiper belt around the solar-like star ζ2 Ret

    NARCIS (Netherlands)

    Eiroa, C.; Fedele, D.; Maldonado, J.; Gonzalez-Garcia, B. M.; Rodmann, J.; Heras, A. M.; Pilbratt, G. L.; Augereau, J. -Ch.; Mora, A.; Montesinos, B.; Ardila, D.; Bryden, G.; Liseau, R.; Stapelfeldt, K.; Launhardt, R.; Solano, E.; Bayo, A.; Absil, O.; Arevalo, M.; Barrado, D.; Beichmann, C.; Danchi, W.; del Burgo, C.; Ertel, S.; Fridlund, M.; Fukagawa, M.; Gutierrez, R.; Gruen, E.; Kamp, I.; Krivov, A.; Lebreton, J.; Loehne, T.; Lorente, R.; Marshall, J.; Martinez-Arnaiz, R.; Meeus, G.; Montes, D.; Morbidelli, A.; Mueller, S.; Mutschke, H.; Nakagawa, T.; Olofsson, G.; Ribas, I.; Roberge, A.; Sanz-Forcada, J.; Thebault, P.; White, G. J.; Wolf, S.; Walker, H.

    We present the first far-IR observations of the solar-type stars δ Pav, HR 8501, 51 Peg and ζ2 Ret, taken within the context of the DUNES Herschel open time key programme (OTKP). This project uses the PACS and SPIRE instruments with the objective of studying infrared excesses due to exo-Kuiper belts

  3. Who Are the Science Teachers That Seek Professional Development in Research Experience for Teachers (RET's)? Implications for Teacher Professional Development

    Science.gov (United States)

    Saka, Yavuz

    2013-01-01

    To address the need to better prepare teachers to enact science education reforms, the National Science Foundation has supported a Research Experience for Teachers (RET's) format for teacher professional development. In these experiences, teachers work closely with practicing scientists to engage in authentic scientific inquiry. Although…

  4. Influencia de la retórica musical de Los Beatles en los “jingles” y en la publicidad

    Directory of Open Access Journals (Sweden)

    Anton Alvarez Ruiz

    2013-01-01

    Full Text Available Este artículo explora de qué manera los jingles publicitarios se han visto influidos por la música de The Beatles. Para ello, utiliza una metodología descriptiva, comparativa y diacrónica. Tras estudiar brevemente la historia e importancia de los jingles, analizando algunas características de las canciones de The Beatles y su semejanza con los jingles publicitarios. En las canciones mencionadas se detallan las principales figuras retóricas encontradas, tanto en los textos como en las frases musicales y su influencia en la música publicitaria. También se estudia la única pieza publicitaria conocida realizada por The Beatles en su carrera. Por último, se analiza la posterior utilización de sus canciones y su imagen en varias campañas muy significadas, realizadas por la publicidad comercial en las últimas décadas.

  5. Effect of harvest time and field retting duration on the chemical composition, morphology and mechanical properties of hemp fibers

    DEFF Research Database (Denmark)

    Liu, Ming; Fernando, Dinesh; Daniel, Geoffrey

    2015-01-01

    tThe large variability in the mechanical properties of hemp fibers is an issue in relation to their use inhigh-grade composites. The objective of the present study was to determine the optimal growth stage forharvesting hemp fibers for use in composites and to evaluate the effect of field retting......% at seed maturity.A highly significant reduction in cellulose deposition in fiber cell walls was reflected by reduced fiberwall thickness with plant maturity and was related to the development and ripening of hemp seeds.A statistically significant increase in lignin deposition and a slight decrease...... in pectins in hemp fibercell walls were also noted with stem maturity. Microscopy observations and histochemical analyzescorroborated the results from the chemical analyzes and revealed variations in morphological aspectsand spatial micro-distributions of carbohydrates and lignin within the cell structure...

  6. Apelo ao consenso e impossibilidades da retórica: o caso do XI governo constitucional português

    OpenAIRE

    Lopo, Teresa Teixeira

    2016-01-01

    Resumo Neste artigo analisa-se como se formulou o apelo ao consenso no discurso pedagógico oficial do XI governo constitucional português, considerando os valores orientadores do processo de decisão e as crenças associadas ao impacto da política educativa e os seus resultados, em termos dos consensos alcançados na relação com os partidos políticos com representação parlamentar. Verificou-se ter sido uma construção retórica feliz do discurso, a desencadear, para além da concordância naturalmen...

  7. ExRET-Opt: An automated exergy/exergoeconomic simulation framework for building energy retrofit analysis and design optimisation

    International Nuclear Information System (INIS)

    García Kerdan, Iván; Raslan, Rokia; Ruyssevelt, Paul; Morillón Gálvez, David

    2017-01-01

    Highlights: • Development of a building retrofit-oriented exergoeconomic-based optimisation tool. • A new exergoeconomic cost-benefit indicator is developed for design comparison. • Thermodynamic and thermal comfort variables used as constraints and/or objectives. • Irreversibilities and exergetic cost for end-use processes are substantially reduced. • Robust methodology that should be pursued in everyday building retrofit practice. - Abstract: Energy simulation tools have a major role in the assessment of building energy retrofit (BER) measures. Exergoeconomic analysis and optimisation is a common practice in sectors such as the power generation and chemical processes, aiding engineers to obtain more energy-efficient and cost-effective energy systems designs. ExRET-Opt, a retrofit-oriented modular-based dynamic simulation framework has been developed by embedding a comprehensive exergy/exergoeconomic calculation method into a typical open-source building energy simulation tool (EnergyPlus). The aim of this paper is to show the decomposition of ExRET-Opt by presenting modules, submodules and subroutines used for the framework’s development as well as verify the outputs with existing research data. In addition, the possibility to perform multi-objective optimisation analysis based on genetic-algorithms combined with multi-criteria decision making methods was included within the simulation framework. This addition could potentiate BER design teams to perform quick exergy/exergoeconomic optimisation, in order to find opportunities for thermodynamic improvements along the building’s active and passive energy systems. The enhanced simulation framework is tested using a primary school building as a case study. Results demonstrate that the proposed simulation framework provide users with thermodynamic efficient and cost-effective designs, even under tight thermodynamic and economic constraints, suggesting its use in everyday BER practice.

  8. Leerse a sí mismo: hermenéutica, política y retórica en Thomas Hobbes

    Directory of Open Access Journals (Sweden)

    María José Rossi

    2014-11-01

    Full Text Available El reconocimiento del conflicto como realidad constitutiva de lo humano y la necesidad de un cierre que pasa por la fijación de la palabra justa encuentran en Hobbes su primera formulación. El pasaje de la instancia retórico-interpretativa a la axiomático-científica se da en Leviatan a través de tres momentos: introspectivo, contractual, estadual; su despliegue permite reconocer a la hermenéutica como resorte imprescindible para la implantación de un orden político fundado en la articulación entre ser (una antropología, decir (una retórica y actuar (una praxis. El intérprete resulta así un operador clave en el ajuste de las instancias natural y político-social

  9. O enigma do espelho. A retórica do silêncio nas Confissões de Agostinho de Hipona

    OpenAIRE

    Ricardo Reali Taurisano

    2014-01-01

    Três eram as principais tarefas da retórica clássica: instruir, deleitar e mover as almas à ação. Nas Confissões, contudo, percebe-se que elas são excedidas por um emprego nada convencional dos recursos da ars, de que rhetor Agostinho era mestre, a fim de perse-guir finalidade filosófica ulterior: dizer o indizível. Trata-se do uso duma palavra retórica que se quer circular, tautócrona, oblíqua, poética, oracular e paradoxal, em sua eloquência silenciosa. Numa primeira parte, pretende-se ress...

  10. ADOPTION OF RENEWABLE ENERGY TECHNOLOGIES (RET) IN TOURISM INDUSTRY- (A CASE OF OSOGBO AND OLORUNDA LOCAL GOVERNMENT AREAS IN OSUN STATE, NIGERIA)

    OpenAIRE

    Sonubi, O.K.; Ogunjimi, A. A.; Adeyemo, A. I.

    2017-01-01

    Hotel accommodation in Nigeria is comparatively more expensive than its neighbours in the sub region of West Africa. It is one of the most expensive globally. This is attributable to its operating environment. Any sustainable means of reducing running costs would be most welcome. A study on adoption of renewable energy technologies (RET) was conducted in Osogbo and Olorunda Local Government Areas of Osun State, Nigeria. Data were obtained from registered hotels in the two local government are...

  11. Retórica de influência social e negociação, segundo poder/reconhecimento na sociedade

    Directory of Open Access Journals (Sweden)

    Edson Alves de Souza Filho

    2014-04-01

    Full Text Available Estudamos o modo de negociar a pressão provocada por personagens considerados mais ou menos poderosos/reconhecidos na sociedade perante a identificação étnica do participante. Tratamos os fenômenos segundo as teorias de influência social ou retóricas de ação social. Trabalhamos com situações simuladas de pressão para recriar experiências possíveis de interação. Participaram 207 estudantes de ensino médio de escolas públicas estaduais, identificados como negros, brancos e morenos. Os resultados indicaram retóricas/ações como recusas, aceitação e não decisão às pressões. As retóricas/ações antecipadas foram de cordialidade, interesse próprio, hostilidade, interesse do outro. Os brancos tenderam a aceitar mais a pressão de personagens poderosos e os negros, em menor proporção, a recusar. Quanto aos personagens minoritários, houve aceitação da pressão nos grupos, indicando menor controvérsia. Discutimos os resultados nos marcos da dinâmica de relações entre grupos na sociedade.

  12. Associations between RET tagSNPs and their haplotypes and susceptibility, clinical severity, and thyroid function in patients with differentiated thyroid cancer.

    Directory of Open Access Journals (Sweden)

    Caiyun He

    Full Text Available It is unclear whether common genetic variants of the RET proto-oncogene contribute to disease susceptibility, clinical severity, and thyroid function in differentiated thyroid cancer (DTC.A total of 300 DTC patients and 252 healthy controls were enrolled in this study. Seven RET tagging single nucleotide polymorphisms were genotyped using the KASPar platform.Subgroup analysis showed that concomitant thyroid benign diseases were less likely to occur in DTC subjects with the rs1799939 AG or AG plus AA genotypes (odds ratio (OR = 1.93 and 1.88, P = 0.009 and 0.011, respectively. A rare haplotype, CGGATAA, was associated statistically with a reduced risk of DTC (OR = 0.18, P = 0.001. Concerning the aggressive features of DTC, higher level of N stage was more likely to occur in subjects carrying the wild-type genotypes at rs1800860 site (for dominant model: OR = 0.48, P = 0.008. Another rare haplotype, CAAGCGT, conferred increased risk for the occurrence of distant metastasis (OR = 7.57, P = 0.009. Notably, higher thyroid stimulating hormone levels and lower parathyroid hormone levels were found in patients with rs2075912, rs2565200, and rs2742240 heterozygotes and rare homozygotes; similar results were observed between PTH levels and rs1800858.This study provided useful information on RET variants that should be subjected to further study.

  13. Delta-He, Ret-He and a New Diagnostic Plot for Differential Diagnosis and Therapy Monitoring of Patients Suffering from Various Disease-Specific Types of Anemia.

    Science.gov (United States)

    Weimann, Andreas; Cremer, Malte; Hernáiz-Driever, Pablo; Zimmermann, Mathias

    2016-01-01

    The present study was aimed to prove the usefulness of a new diagnostic plot (Hema-Plot), illustrating the relationship between the hemoglobin content of reticulocytes (Ret-He) as a marker of functional iron deficiency and the difference between the reticulocyte and erythrocyte hemoglobin content (Delta-He) as a marker of an impaired hemoglobinization of newly formed reticulocytes occurring during inflammatory processes, to differentiate between various disease-specific types of anemia. A complete blood and reticulocyte count was performed on routine EDTA blood samples from 345 patients with and without various disease-specific types of anemia using the Sysmex XN-9000 hematology analyzer: blood healthy newborns (n = 23), blood healthy adults (n = 31), patients suffering from anemia of chronic disease (ACD) due to diverse oncological, chronic inflammatory, or autoimmune diseases (total n = 138) with (n = 65) and without therapy (n = 73), patients with thalassemia and/or hemoglobinopathy (n = 18), patients with iron deficiency anemia (IDA) (n = 35), patients with a combination of ACD and IDA (n = 17), as well as patients suffering from sepsis (total n = 83) with (n = 32) and without therapy (n = 51). The results for Ret-He, Delta-He, and C-reactive protein (CRP) were statistically compared (Mann-Whitney U Test) between the particular patient groups and the diagnostic plots were drawn. Delta-Hemoglobin showed a statistically significant difference between blood healthy newborns and blood healthy adults (p ≤ 0.05), while Ret-He and C-reactive protein did not. In addition, of all three biomarkers only Delta-He showed a statistically significant difference (p ≤ 0.05) between the ACD/IDA and IDA cohort. Delta-He, Ret-He, and CRP showed a statistically significant difference between patient cohorts with and without therapy suffering from ACD, ACD/IDA, and sepsis before and after medical therapy (p ≤ 0.05). The Hema-Plot illustrated the dynamic character of Ret-He and

  14. Ciberlenguaje y principios de retórica clásica. Redes sociales: el caso Facebook

    Directory of Open Access Journals (Sweden)

    Inmaculada Berlanga

    2010-05-01

    Full Text Available Las Tecnologías de la Información y la Comunicación (TICs han propiciado cambios en las formas de comunicarnosy relacionarnos en la sociedad. Como concreción de esta nueva realidad destaca el espectacular auge alcanzadopor las redes sociales on line. El discurso oral se ve enriquecido con el lenguaje icónico y el audiovisual, privilegiadosen la cultura de hoy, por ello, esta investigación se pregunta si el discurso empleado en las redes sociales favorece elobjetivo planteado por estas plataformas tecnológicas al ayudar a compartir información. Se trata de un trabajo decampo que analiza el lenguaje, tanto de la interfaz de la red como el de los usuarios que participan en una de las redessociales más populares de hoy: Facebook. El estudio recorre las tres dimensiones del proceso comunicativo: sintáctica,semántica y pragmática y a través de pantallas se capturan otros elementos que configuran el contexto de este procesoque le confieren dinamismo y creatividad a la interacción. Se plantea la conveniencia de mirar a los personajes que alo largo de la historia han brillado en el arte de comunicar y recuperar algunos parámetros de la retórica clásica en loque atañe a la correcta construcción del discurso y a su veracidad. Finalmente, reclama planteamos algunos elementosteórico del ciberlenguaje y la necesidad de aprovechar la potencialidad que brindan las redes sociales en cuanto asu capacidad de inmediatez, intuitividad e interactividad, para humanizar la conversación con lenguajes atractivos,eficaces, cercanos y correctos.

  15. Nuclear molecular imaging of paragangliomas; Imagerie moleculaire nucleaire des paragangliomes

    Energy Technology Data Exchange (ETDEWEB)

    Taieb, D.; Tessonnier, L.; Mundler, O. [Service central de biophysique et de medecine nucleaire, CHU de la Timone, 13 - Marseille (France)

    2010-08-15

    Paragangliomas (PGL) are relatively rare neural crest tumors originating in the adrenal medulla (usually called pheochromocytoma), chemoreceptors (i.e., carotid and aortic bodies) or autonomic ganglia. These tumors are highly vascular, usually benign and slow-growing. PGL may occur as sporadic or familial entities, the latter mostly in association with germline mutations of the succinate dehydrogenase (SDH) B, SDHC, SDHD, SDH5, von Hippel-Lindau (VHL), ret proto-oncogene (RET), neurofibromatosis 1 (NF1) (von Recklinghausen's disease), prolyl hydroxylase domain protein 2 (PHD2) genes and TMEM127. Molecular nuclear imaging has a central role in characterization of PGL and include: somatostatin receptor imaging ({sup 111}In, {sup 68}Ga), MIBG scintigraphy ({sup 131}I, {sup 123}I), {sup 18}F-dihydroxy-phenylalanine ({sup 18}F-DOPA) positron emission tomography (PET), and {sup 18}F-deoxyglucose ({sup 18}F-FDG) PET. The choice of the tracer is not yet fully established but the work-up of familial forms often require the combination of multiple approaches. (authors)

  16. Análisis retórico-pragmático de la publicidad de cosméticos y productos de belleza en revistas femeninas

    OpenAIRE

    Jesús Alonso, Beatriz de

    2015-01-01

    Se trata de un análisis retórico-pragmático de gráficas publicitarias en revistas de moda conocidas como Vogue, Elle, Cosmopolitan, Telva y Glamour. Además, se hace un estudio de estereotipos y prototipos de la mujer en la actual sociedad y recoge una bibliografía relevante en torno a la materia. En el análisis se reflejan dos partes: una teórica y otra de imagen que explican los conceptos más relevantes del trabajo. Grado en Publicidad y Relaciones Públicas

  17. Sobre el sentimiento de vergüenza en la Ética Nicomaquea y la Retórica de Aristóteles

    OpenAIRE

    Gil Blasco, Marta

    2013-01-01

    En el siguiente estudio examinaremos el sentimiento de vergüenza desde dos planteamientos distintos formulados por Aristóteles: el de la Retórica, por una parte, y el de la Ética Nicomaquea, por otra, con la finalidad de dar cuenta de las diferencias, así como de los puntos de confluencia que existen entre ambos. Asimismo, consideraremos la intrincada conexión que existe entre la agencia humana y cuestiones tales como la voluntariedad, la responsabilidad y la culpa, así como el papel fundamen...

  18. Retórica vs. Comportamiento en las relaciones comerciales. Un análisis de las relaciones de Venezuela hacia Estados Unidos. Periodo 2007-2012

    OpenAIRE

    Osorio Quevedo, Alejandra

    2015-01-01

    El objetivo de esta monografía es analizar la incongruencia entre la retórica antiestadounidense empleada por Hugo Chávez durante su segundo mandato presidencial y las relaciones comerciales entre Venezuela y Estados Unidos, caracterizadas por la continua y considerable exportación de crudo venezolano. Por consiguiente, tras una descripción del discurso y de la política exterior del entonces mandatario, aunada a la exposición de estadísticas del comercio bilateral de crudo venezolano; se estu...

  19. Didáctica de la Literatura Comparada: Las figuras retóricas en la literatura y en otras semióticas

    Directory of Open Access Journals (Sweden)

    José Enrique Peláez Malagón

    2011-01-01

    Full Text Available Dentro del campo de la teoría literaria nos encontramos con las llamadas figuras retóricas, elemento imprescindible a la hora de abordar cualquier comentario de texto que quiera centrarse en lo estrictamente literario. Una forma de abordar este problema es utilizar la literatura comparada, esto es, buscar en la pintura, la música, el cine o la publicidad, referentes de los mismos recursos estilísticos que ayuden a comprender mejor y a asimilar toda una serie de conceptos, muchas de las veces un tanto oscuros para un alumno cuya lengua materna no es el español.

  20. Tópica de la responsabilidad. Reivindicación de la retórica para la ciudadanía moderna

    OpenAIRE

    José Luis Ramírez

    2003-01-01

    En este ensayo se parte del pensamiento de Aristóteles, para formular una tópica de la responsabilidad basada en la retórica, la lógica y la política. Tres espacios de vida en los cuales se debe desarrollar la personalidad del buen ciudadano, ése que practica el arte del correcto pensar, del bien hablar y del justo obrar. Una nueva ciudadanía social es impensable sin esos elementos que ya suponía el estagirista como necesarios e insustituibles para la concreción del...

  1. Ecletismo e retórica na filosofia brasileira: de Silvestre Pinheiro Ferreira (1769-1846) ao frei Francisco do Monte Alverne (1784-1858)

    OpenAIRE

    Duran, Maria Renata da Cruz

    2015-01-01

    Resumo Este artigo trata da filosofia eclética de Victor Cousin conforme seus repetidores brasileiros do início do século XIX: Silvestre Pinheiro Pereira e frei Francisco do Monte Alverne. O objetivo principal é estudar as relações entre o ecletismo e a retórica em prol da justificação dos limites, da dispersão e da superficialidade do debate filosófico local. Revisando as obras de Antônio Paim, Laerte Ramos de Carvalho e Maria Beatriz Nizza da Silva, destacou-se, especialmente, alguns pressu...

  2. Havde Friedman alligevel ret?

    DEFF Research Database (Denmark)

    Koch, Carsten Allan

    2005-01-01

    Den amerikanske økonom Milton Friedmans artikel om virksomheders sociale ansvar, The Social Responsibility of Business is to Increase Its Profit, er en af de mest kontroversielle bidrag til litteraturen om virksomheders ledelse og sociale ansvar. Men Friedmans artikel er, omend nok undervurderet,...... profit er til gavn for det økonomiske systems funktionsmåde, og at en uddeling af en ikketriviel andel af den vil svække denne rolle. Dette er analysens hovedresultat. Derudover præsenteres en række modifikationer til det ovenstående hovedresultat....

  3. Universelle rettigheder - oplysningstidens ret?

    DEFF Research Database (Denmark)

    Schaumburg-Müller, Sten

    2007-01-01

    Ideen om universelle rettigheder er ældre end Oplysningstiden, men i perioden blev universelle rettigheder gennemført i USA og Frankrig, ligesom perioden indeholdt kritik af forestillingen om universelle rettigheder.......Ideen om universelle rettigheder er ældre end Oplysningstiden, men i perioden blev universelle rettigheder gennemført i USA og Frankrig, ligesom perioden indeholdt kritik af forestillingen om universelle rettigheder....

  4. Caminhos retóricos e sorrisos incômodos : argumentação e humor em "A encalhada", de Ingrid Guimarães e Aloísio Abre

    OpenAIRE

    Ferraz, Luana

    2015-01-01

    Esta dissertação aborda a construção retórica da comicidade em peças teatrais. Para tanto, propõe a investigação das estratégias retóricas que enfatizam o efeito cômico no esquete “A encalhada”, de Ingrid Guimarães e Aloísio de Abreu – uma das nove cenas que compõem o espetáculo Cócegas (EMI, 2004), interpretado pelas atrizes brasileiras Heloísa Périssé e Ingrid Guimarães. O embasamento teórico para este trabalho é fornecido, principalmente, pelos tratados da Retórica Antiga...

  5. Tendencias de la Comunicación del Tercer Sector en la web 2.0: Análisis retórico de los tropos

    Directory of Open Access Journals (Sweden)

    Isidoro Arroyo Almaraz

    2013-08-01

    Full Text Available Los grandes éxitos de determinados mensajes a través de las redes sociales han hecho que este nuevo “medio” se vea como un modelo muy interesante para el Tercer Sector. En este artículo llevamos a cabo el análisis de aspectos formales y de contenido de las comunicaciones del Tercer Sector en las redes sociales y se determinan las tendencias que se repiten  destacando, entre otros,  el uso retórico de los tropos. Se percibe una tendencia hacia la similitud de los mensajes estudiados en sus aspectos narrativos, expresivos, persuasivos y retóricos. Los mensajes de carácter social distribuidos a través de las redes sociales muestran, en su construcción, perfiles uniformes y homogéneos en sus aspectos formales. Se concluye que utilizan las mismas piezas ya usadas en otros medios por lo que se infiere que no piensan en las bondades de las redes sociales para aprovechar los recursos específicos de éstas.  

  6. Analysis of RET promoter CpG island methylation using methylation-specific PCR (MSP), pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM): impact on stage II colon cancer patient outcome.

    Science.gov (United States)

    Draht, Muriel X G; Smits, Kim M; Jooste, Valérie; Tournier, Benjamin; Vervoort, Martijn; Ramaekers, Chantal; Chapusot, Caroline; Weijenberg, Matty P; van Engeland, Manon; Melotte, Veerle

    2016-01-01

    Already since the 1990s, promoter CpG island methylation markers have been considered promising diagnostic, prognostic, and predictive cancer biomarkers. However, so far, only a limited number of DNA methylation markers have been introduced into clinical practice. One reason why the vast majority of methylation markers do not translate into clinical applications is lack of independent validation of methylation markers, often caused by differences in methylation analysis techniques. We recently described RET promoter CpG island methylation as a potential prognostic marker in stage II colorectal cancer (CRC) patients of two independent series. In the current study, we analyzed the RET promoter CpG island methylation of 241 stage II colon cancer patients by direct methylation-specific PCR (MSP), nested-MSP, pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM). All primers were designed as close as possible to the same genomic region. In order to investigate the effect of different DNA methylation assays on patient outcome, we assessed the clinical sensitivity and specificity as well as the association of RET methylation with overall survival for three and five years of follow-up. Using direct-MSP and nested-MSP, 12.0 % (25/209) and 29.6 % (71/240) of the patients showed RET promoter CpG island methylation. Methylation frequencies detected by pyrosequencing were related to the threshold for positivity that defined RET methylation. Methylation frequencies obtained by pyrosequencing (threshold for positivity at 20 %) and MS-HRM were 13.3 % (32/240) and 13.8 % (33/239), respectively. The pyrosequencing threshold for positivity of 20 % showed the best correlation with MS-HRM and direct-MSP results. Nested-MSP detected RET promoter CpG island methylation in deceased patients with a higher sensitivity (33.1 %) compared to direct-MSP (10.7 %), pyrosequencing (14.4 %), and MS-HRM (15.4 %). While RET methylation frequencies detected by nested

  7. A nova retórica do grande capital: a publicidade brasileira entre o neoliberalismo e a democratização

    Directory of Open Access Journals (Sweden)

    Maria Eduarda da Mota Rocha

    2008-09-01

    Full Text Available Resumo: O artigo analisa a emergência de uma nova retórica do grande capital, na publicidade brasileira contemporânea, a partir das relações entre três níveis: o do contexto político e econômico, o do campo publicitário e o dos anúncios. Estas relações permitem explicar as transformações dos valores fundamentais que informam o discurso publicitário, entendido como a retórica do capital, a quem cabe construir a boa vontade da “opinião pública” e converter parte desta em consumidores efetivos dos produtos e serviços. Por isso, os valores em torno dos quais se organizam os anúncios revelam as estratégias de legitimação do capital, no conteúdo que atribuem à imagem de uma “vida plena”. A nova retórica do grande capital é marcada por estratégias narrativas que têm como centro os “conceitos” de “qualidade de vida” e de “responsabilidade social”, em detrimento dos “conceitos” de “status” e “tecnologia” que marcaram a publicidade do período anterior. Abstract: The article analyzes the emergence of big capital new rhetoric in the contemporary Brazilian advertisements, based on the relationships among three levels: the economical and political context, the advertising field, and the advertisements themselves. These relationships allow us to explain the transformations of the basic values that inform the advertisement discourse, understood here as the rhetoric of the capital, that has the task of constructing the good will of public opinion and convert part of them into effective products and services consumers. Therefore, the values around which the ads organize reveal the legitimating strategies of the capital in the contents that attribute to the image of a full life. The new rhetoric of the big capital is marked by narrative strategies that have at the center the concepts of quality of life and social responsibility, in detriment of the concepts of status and technology that have marked the

  8. Differential expression of galectin-3, CK19, HBME1, and Ret oncoprotein in the diagnosis of thyroid neoplasms by fine needle aspiration biopsy

    Directory of Open Access Journals (Sweden)

    Saleh Husain

    2009-01-01

    Full Text Available Background: Fine needle aspiration biopsy (FNAB is a common and excellent procedure for the evaluation of thyroid lesions that require surgical resection. At times, the FNAB diagnosis can be difficult, particularly of follicular-patterned lesions. Previous studies have shown that some immunohistochemical (IHC markers may be helpful in establishing more accurate diagnosis. In this study, our goal was to evaluate four of the recently investigated markers in differentiating benign from malignant thyroid nodules on FNABs. Materials and Methods: We performed IHC staining of galectin-3, Ret oncoprotein (Ret, HBME-1, and cytokeratin 19 (CK19, on cell block sections of thyroid FNAB cases that had corresponding surgical resections. They included 44 benign lesions (37 hyperplastic or cellular nodules, HN; and 7 follicular adenomas, FA and 27 malignant tumors (6 follicular carcinoma, FC; 19 classic papillary carcinoma, PTC; and 2 follicular variant of papillary carcinoma, FVPC. The stains were done according to the standard avidin-biotin-peroxidase method. Results: Statistical analysis showed that immunoexpression was significantly higher in the malignant group for all four markers. The sensitivity for positive expression for all benign lesions versus malignant tumors was as follows: 10/44 (22.7% versus 25/27 (92.6% for galectin-3; 14/44 (31.8% versus 23/27 (85% for Ret; 12/44 (27.3% versus 24/27 (88.8% for HBME-1; and 13/44 (29.5% versus 23/27 (85% for CK19. The sensitivity and specificity was highest for galectin-3 (92.6% and 77.3%, respectively followed by HMBE-1 (88.9% and 72.7%, respectively. When combining the markers′ expressions, the panel of galectin-3 + HBME-1 showed the highest sensitivity and specificity (90.7% and 75%, respectively, but this was, however, lower than galectin-3 alone (92.3% and 77.3%, respectively. Conclusion: We conclude that galectin-3 is the best single marker in differentiating benign from malignant thyroid lesions with

  9. Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A, MEN 2B and FMTC : Two novel mutations and one de novo mutation for MEN 2A

    NARCIS (Netherlands)

    Landsvater, RM; Jansen, RPM; Hofstra, RMW; Buys, CHCM; Lips, CJM; vanAmstel, HKP

    Hereditary C-cell carcinoma is encountered in multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and familial medullary thyroid carcinoma (FMTC). Mutations of the RET proto-oncogene are associated with all three diseases. To obtain an insight into the molecular heterogeneity of MEN 2 syndromes

  10. Risøs årsrapport 2005. Opfølgning på planerne for året 2005

    DEFF Research Database (Denmark)

    2006-01-01

    Risøs årsrapport 2005 er en opfølgning på planerne for Risøs virksomhed i 2005. Risøs bestyrelse skal som led i resultatkontrakten med Ministeriet for Videnskab, Teknologi og Udvikling aflægge årlige rapporter om opfyldelsen af de fastlagte resultatkrav.Nærværende rapport indeholder data til brug...... for denne vurdering. Derudover gives et billede af Risøs økonomi og faglige aktiviteter, der relateres til Risøs mission, vision og strategi. Rapportering af årets resultater er baseret på det interneplanlægnings- og opfølgningssystem, og rapporten er opbygget efter Økonomistyrelsens nye koncept...... for årsrapporter....

  11. Le système de sûreté lyonnais selon les arrêtés du 6 décembre 1833

    Directory of Open Access Journals (Sweden)

    Amos Frappa

    2010-01-01

    Full Text Available Le 6 décembre 1833, le maire de Lyon Gabriel Prunelle adopte trois arrêtés instaurant un service de sûreté. Il s’agit de la seconde ville française à se doter d’un groupe de policiers spécialisé dans la recherche et l’arrestation des malfaiteurs. Un an plus tôt, le préfet de police Gisquet met à profit l’expérience de «  la Rousse », surnom donné à la brigade de l’ancien bagnard Vidocq, pour équiper la capitale d’une telle structure. Le premier des textes du 6 décembre 1833 fixe les attributi...

  12. RET/PTC and PAX8/PPARγ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with I-131 radiation dose and other characteristics

    Science.gov (United States)

    Leeman-Neill, Rebecca J.; Brenner, Alina V.; Little, Mark P.; Bogdanova, Tetiana I.; Hatch, Maureen; Zurnadzy, Liudmyla Y.; Mabuchi, Kiyohiko; Tronko, Mykola D.; Nikiforov, Yuri E.

    2012-01-01

    Background Childhood exposure to I-131 from the 1986 Chernobyl accident led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited. Methods We performed mutational analysis of 62 PTCs diagnosed in a Ukrainian cohort of patients who were Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with I-131 dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and I-131 exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients. PMID:23436219

  13. Detection of PAX8/PPARG and RET/PTC Rearrangements Is Feasible in Routine Air-Dried Fine Needle Aspiration Smears

    DEFF Research Database (Denmark)

    Ferraz, Carolina; Rehfeld, Christian; Krogdahl, Annelise

    2012-01-01

    Background: The diagnostic limitations of fine needle aspiration (FNA), like the indeterminate category, can be partially overcome by molecular analysis. As PAX8/PPARG and RET/PTC rearrangements have been detected in follicular thyroid carcinomas (FTCs) and papillary thyroid carcinomas (PTCs......), their detection in FNA smears could improve the FNA diagnosis. To date, these rearrangements have never been analyzed in routine air-dried FNA smears, but only in frozen tissue, formalin-fixed paraffin-embedded (FFPE) tissue, and in fresh FNA material. Fixed routine air-dried FNA samples have hitherto been judged...... as generally not suitable for testing these rearrangements in a clinical setting. Therefore, the objective of the present study was to investigate the feasibility of extracting RNA from routine air-dried FNA smears for the detection of these rearrangements with real-time polymerase chain reaction (RT...

  14. The history of NATO TNF policy: The role of studies, analysis and exercises conference proceedings. Volume 3: Papers by Gen. Robert C. Richardson III (Ret.)

    Energy Technology Data Exchange (ETDEWEB)

    Rinne, R.L. [ed.

    1994-02-01

    This conference was organized to study and analyze the role of simulation, analysis, modeling, and exercises in the history of NATO policy. The premise was not that the results of past studies will apply to future policy, but rather that understanding what influenced the decision process-and how-would be of value. The structure of the conference was built around discussion panels. The panels were augmented by a series of papers and presentations focusing on particular TNF events, issues, studies, or exercises. The conference proceedings consist of three volumes. Volume 1 contains the conference introduction, agenda, biographical sketches of principal participants, and analytical summary of the presentations and discussion panels. Volume 2 contains a short introduction and the papers and presentations from the conference. This volume contains selected papers by Brig. Gen. Robert C. Richardson III (Ret.).

  15. La articulación retórico-estilística de las perífrasis verbales de infinitivo y gerundio en "Pedro Páramo"

    Directory of Open Access Journals (Sweden)

    Adriana Ávila-Figueroa

    2012-07-01

    Full Text Available ResumenEl tema de las perífrasis verbales es uno de los más complejos y debatidos en la tradición gramatical. Las descripciones propuestas en las gramáticas y estudios dedicados al tema de las perífrasis verbales explican principalmente tres valores: temporal, aspectual y modal. Gómez Torregop señala que entre estos valores es posible añadir el estilístico. El propósito de este trabajo es describir el uso de las perífrasis verbales de infinitivo y gerundio en la novela mexicana "Pedro Páramo" de Juan Rulfo y su articulación retórico-estilística.Palabras clave: figuras retóricas, perífrasis verbales, estilística, infinitivo y gerundio.AbstractThe verbal periphrasis is one of the more complex and debated topics in the grammatical tradition. The current descriptions proposed by the main reference grammars as well as by most of the works dedicated to the verbal periphrasis explain three main values: temporal, aspectual and modal. Gómez Torrego points that between these values is possible to add the stylistic one. The purpose of this article is to describe the use of the infinite and gerundive verbal periphrasis in the mexican novel "Pedro Páramo" by Juan Rulfo and its rhetorical and stylistic articulation.Keywords: rhetorical figures, verbal periphrasis, stylistics, infinitive and gerundive.

  16. Book Review: Zarzo, E. (2016, Memoria Retórica y Experiencia Estética. Retórica, Estética y Educación. Madrid: Dykinson

    Directory of Open Access Journals (Sweden)

    Davide Mombelli

    2016-10-01

    Full Text Available Memoria retórica y experiencia estética. Retórica, Estética y Educación, recently published by Dykinson, is a fundamental body of research on rhetoric memory and aesthetic experience, two objects of study which, although having generated much literature separately, have not been considered in their reciprocity until now. The author, Esther Zarzo, who earned her Ph.D. in Philosophy, has published several investigations of both a theoretical and practical nature concerning the treatment and development of the faculty of memory. From among her theoretical works, standouts include “Historia, memoria y tiempo” (2015a, which addresses the relationship between memory and history from a metaphysical approach in order to explain some of the mnemonic aporiae underlying historical knowledge; and from among her work of a practical nature standouts include, “La mirada topológica” (2013, focused on the media of today's exploitation of the image, and, "The art of memory in the Digital Age"(2015b, in which different implementation strategies of the classical rhetorical techniques found in Virtual Learning Environments are considered. Regarding the investigation’s second object, the aesthetic experience, it is important to highlight the author’s editing work carried out in collaboration with Prof. Pedro Aullón de Haro of the fundamental work by Alfonso Reyes, El Deslinde(2014, whose concept of literary experience is crucial to understanding the text at hand. As Esther Zarzo explains in the introduction, the choice of such objects of study is justified by the need to analyse the epistemological consequences of the revolution produced by electronic media that enable the external storage and transmission of information, since any modifications to the way of organising and accessing content substantially affects the individual and collective experience, both in regard to knowledge and to self-knowledge, along with the experience of time. According

  17. A rare mutation in the RET-protooncogen associated with mixed medullary-follicular micro-carcinoma of the thyroid gland

    Energy Technology Data Exchange (ETDEWEB)

    Richter, K.; Huwe, A.; Boldt, H.; Dresel, S. [Nuklearmedizinische Klinik, HELIOS-Klinikum Berlin-Buch (Germany); Geipel, D. [St.-Hedwig-Krankenhaus, Bereich Endokrine Chirurgie (Germany); Mairinger, T. [Inst. fuer Pathologie, HELIOS-Klinikum Emil von Behring (Germany); Schwabe, M. [Inst. fuer Pathologie, Charite Berlin Campus Mitte (Germany)

    2008-07-01

    Medullary thyroid carcinoma (MTC) arises from parafollicular C-cells of the thyroid and accounts for 1% to 10% of all thyroid cancers (1). MTC can be sporadic or hereditary. Hereditary MTC represents 20% to 30% of all MTC with an autosomal dominant pattern of transmission and a high degree of penetrance (>90%). It can be transmitted as a single entity (sporadic), familial MTC (FMTC), or it can arise as part of a multiple endocrine neoplasia (MEN) syndrome type 2A or 2B. Both genders are equally affected. (1, 9) The identification of hereditary MTC has been facilitated in recent years by the direct analysis of germline point mutations of the RET(rearranged during transfection)-protooncogene, a 21 exon gene that encodes a plasma membrane-bound tyrosine kinase receptor, localised on chromosome 10q11.2, which is expressed in tissues derived from the neural crest. To date codon mutations in nine different exons were identified (7, 8, 16, 22, 29) causing MEN 2A (MTC in combination with pheochromocytoma and hyperparathyroidism, including rare variants with Hirschsprung's disease and cutaneous lichen amyloidosis), FMTC (MTC as a sole disease phenotype) and MEN 2B (MTC in combination with pheochromocytoma, multiple mucosa neuromas, and marfanoid habitus). The most common mutation, accounting for over 80% of all mutations associated with MEN 2A (or Sipple's) syndrome affects codon 634 in exon 11 of the RET-protooncogene. Other mutations affect codon 630 in exon 11, and codons 609, 611, 618, 620 in exon 10 - they also cause FMTC, although some have a classic MEN 2A syndrome. 5% to 10% of families with FMTC have mutations that affect codons 768, 790, 791 in exon 13: codons 804, 844 in exon 14, and codon 891 in exon 15 (3, 4, 10). The much more aggressive MEN 2B is caused by a single mutation converting a methionine into a threonine at codon 918 in exon 16, and has been identified in approximately 95% of patients with MEN 2B. Other rare mutations associated with MEN 2

  18. A retórica da reeleição: mapeando os discursos dos Programas Eleitorais (HGPE em 1998 e 2006

    Directory of Open Access Journals (Sweden)

    Mônica Machado

    2009-06-01

    Full Text Available O artigo avalia a produção dos discursos do HGPE na TV dos partidos de dois candidatos à reeleição para a Presidência da República: Fernando Henrique (PSDB em 1998 e Luiz Inácio Lula da Silva (PT em 2006. É objeto de reflexão indagar até que ponto as campanhas orientadas para reconduzir o mandatário ao poder têm estruturas estratégicas discursivas similares nos dois contextos, apesar de inscrições partidárias e orientações políticas distintas. Como metodologia, utiliza procedimentos para entender os elementos retóricos de cada campanha e apreender as estratégias de persuasão. Nota-se que o estímulo ao voto retrospectivo, o discurso a favor da continuidade da gestão administrativa, o lugar de autoridade do candidato-Presidente e a ênfase em discurso programático de cunho econômico são enunciados proferidos pelos mandatários nos dois contextos. É lícito supor, então, que a retórica da reeleição favorece posições privilegiadas na disputa.The article evaluates the production of the speeches of electoral advertising in TV of the two presidential candidates: Fernando Henrique (PSDB in 1998 and Luis Inácio Lula of Silva (PT in 2006. Therefore, the point is to investigate to what extent the campaigns show discursive strategic structures - similar in the two contexts - in spite of supporting registrations and different political orientations. The methodology uses procedures to understand the rhetorical elements of each campaign and persuasion strategies. In both campaigns one observes the incentive to the retrospective vote, the speech in favor of the continuity of the administration, the place of the candidate-president's authority, the emphasis in speech of economical issues. One can suggest that the rhetoric of the reelection favors positions in the electoral dispute.

  19. Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan

    Science.gov (United States)

    Sigurdson, Alice J.; Land, Charles E.; Bhatti, Parveen; Pineda, Marbin; Brenner, Alina; Carr, Zhanat; Gusev, Boris I.; Zhumadilov, Zhaxibay; Simon, Steven L.; Bouville, Andre; Rutter, Joni L.; Ron, Elaine; Struewing, Jeffery P.

    2010-01-01

    Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-62). Cases with thyroid nodules (n=907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender, and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history, and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, p = 0.03) and GFRA1 -193C>G (rs not assigned, p = 0.05) and decreased risk with XRCC1 R194W (rs1799782, p-trend = 0.03) and TGFB1 T263I (rs1800472, p = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n=25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% confidence interval 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT p value = 0.02). Polymorphisms in RET signaling, DNA repair, and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways, such as genes in double strand break repair, apoptosis, and

  20. Las retóricas del público. El espacio de consumo del arte como institución política

    Directory of Open Access Journals (Sweden)

    Bayón, Fernando

    2012-04-01

    Full Text Available This article aims to show how the space for leisure practices in the art sector is a political construction. To do this, the essay focuses on public (art audience as key concept. It argues that art audiences are critically engaged and politically significant communities, through which each society gives an institutional dimension to cultural practices. In dialogue with modern thinkers such as Adorno, Baudrillard, Warburg and Benjamin, or architects like Rem Koolhaas, the article presents audiences and publics from both a social and institutional points of view, understanding that the temporal and spatial dynamics behind their community boundaries are worth exploring. We think that there are at least two dominant forms of an emerging social rhetoric that are producing innovative ways of building the spaces for consuming cultural offer in the late modern society: we call them rhetorics of convergence and rhetorics of persuation.

    Este artículo pretende poner de manifiesto cómo el espacio de las prácticas de ocio cultural es una construcción política. Para ello, escoge como categoría central al público, en tanto formación comunitaria por medio de la cual cada sociedad institucionaliza de forma dinámica las prácticas de ocio asociadas a la oferta artística. En diálogo con pensadores como Adorno, Baudrillard, Warburg o Benjamin, se describen las dimensiones espaciales y temporales en que se desarrollan los vínculos comunitarios, específicos de la institución del “público” en el sector cultural. Para ello, el ensayo intenta identificar cuáles son las estrategias comunicativas que están produciendo esos espacios de presencia y esos tiempos de experiencia para las prácticas del ocio cultural en las sociedades del consumismo avanzado. Las he llamado retóricas de la convergencia y retóricas de la persuasión.

  1. Retórica clásica y redes on line: dos realidades convergentes y análogas. Perspectivas y prospectivas de 9 expertos en Comunicación

    Directory of Open Access Journals (Sweden)

    Inma Berlanga

    2013-01-01

    Full Text Available El presente trabajo pretende probar la relación entre la retórica clásica y las redes sociales on line como realidades convergentes y análogas, así como las sinergias que entre ellas se establecen en aras de una comunicación más persuasiva y eficaz. Para este objetivo se sirve de la técnica cualitativa de la entrevista en profundidad a expertos en el tema, que resellen nuestra hipótesis sobre estas mutuas transferencias. En un momento de éxtasis de la comunicación, mediado por el boom de las redes on line, redescubrir los principios retóricos originales puede ser de alta pertinencia a fin de devolver a la comunicación su faceta más humana y creativa.

  2. Traducción y educación para la comunicación social: el ejercicio de la traducción en la instrucción retórica

    OpenAIRE

    Chico Rico, Francisco

    2008-01-01

    Este trabajo de investigación se centra fundamentalmente en los debates disciplinares latinos en torno a la traducción y a su importancia para la formación del orador en particular y para la educación para la comunicación social en general. En este contexto se aborda el ejercicio de la traducción tanto en el marco de la teoría retórica como en el dominio de la teoría gramatical, así como en el seno de las relaciones entre aquél y éste, ya que si la teoría retórica consideró la traducción fund...

  3. Drug Response and Resistance in Advanced NF1-Associated Cancers

    Science.gov (United States)

    2014-05-01

    2003;13(1):20-7. 3. Maris JM, Wiersma SR, Mahgoub N, Thompson P, Geyer RJ, Lange BJ, Shannon KM. Monosomy 7 myelodysplastic syndrome and other second...myeloid disorders. N Engl J Med. 1994;330:597-601. 13. Side L, Taylor B, Cayouette M, Conner E, Thompson P, Luce M, Shannon K. Homozygous inactivation of...47. Bollag G, Adler F, elMasry N, McCabe PC, Conner E, Thompson P, McCormick F, Shannon K. Biochemical characterization of a novel KRAS insertional

  4. Characterizing Myeloid Cell Activation in NF1 Vasculopathy

    Science.gov (United States)

    2017-07-01

    in Obesity Related Metabolic Disease, American Diabetes Association, Boston, MA 3. *Bessler,WK, Hudson FZ, Fulton DJ, Ingram DA, Stansfield BK...Weintraub NL. Duffy Antigen Receptor for Chemokines Modulates Adipose Inflammation in Obesity Related Metabolic Disease, American Diabetes Association...Childhood Obesity : One Variable at a Time, American Academy of Pediatrics National Conference & Exhibition, San Francisco, CA 2016 Masoumy E

  5. A Functional Genomic Analysis of NF1-Associated Learning Disabilities

    National Research Council Canada - National Science Library

    Tang, Shao-Jun

    2006-01-01

    Learning disabilities severely deteriorate the life of many NFI patients. However, the pathogenic process for NFI-associated learning disabilities has not been fully understood and an effective therapy is not available...

  6. Natural History of Plexiform Neurofibromas in NF1. Addendum

    Science.gov (United States)

    2008-10-01

    findings, or for lesions that are rapidly enlarging . It was not a goal of this study to diagnose plexiform neurofibromas on the basis of MRI but rather...spinae, and gluteus. Genitourinary organs including the kidneys and ureter, the penis and scrotum in males, and the uterus in females were evaluated...intensity soft-tissue lesions causing mass effect on the surrounding abdominal structures, iliac vessels, sacrum, and iliac bones. Enlargement of sacral

  7. Estratégias Retóricas de Legitimação nos Relatórios da Administração: Respostas ao Movimento Antitabagista

    Directory of Open Access Journals (Sweden)

    Susana Cipriano Dias Raffaelli

    2017-05-01

    Full Text Available O movimento antitabagista brasileiro impulsionou o desenvolvimento de peças regulatórias que desafiaram a legitimidade das empresas do setor. As organizações podem adotar ações estratégicas retóricas, visando ganhar, manter ou recuperar legitimidade. Tais ações são evidenciadas em Relatórios da Administração (RA por se caracterizarem como instrumentos de comunicação social. Desse modo, o presente artigo almeja identificar como a empresa líder do setor tabagista, a Souza Cruz S/A, utilizou os conteúdos dos RAs como instrumento de estratégia retórica de legitimação, no período de 1986 a 2012. O Institucionalismo Organizacional foi utilizado como referencial teórico, e a metodologia para tratamento dos dados foi a análise de conteúdo. Evidenciou-se que a Souza Cruz S/A empreendeu esforços para manter sua legitimidade no período analisado, intensificando o uso de apelos retóricos (ethos, pathos e logos em defesa dos argumentos: (a fumar é uma escolha racional adulta; (b a legislação favorece o comércio ilegal de cigarros; e (c as atividades da empresa beneficiam a sociedade. Assim, este trabalho destaca os RAs como fonte de análise em estudos organizacionais, evidencia a retórica como possibilidade estratégica e propícia aos gestores reflexões acerca da influência do ambiente nas estratégias organizacionais.

  8. As necessidades e os desejos na formação discursiva do marketing: base consistente ou retórica legitimadora?

    Directory of Open Access Journals (Sweden)

    Vinícius Andrade Brei

    Full Text Available Neste artigo realizamos uma análise crítica da gênese histórica da área de marketing até sua constituição atual, com um foco principal: verificar se as necessidades e os desejos dos clientes são base consistente da formação histórica, discursiva, do marketing ou, apenas, retórica legitimadora para a atuação da área. Adotamos uma orientação filosófico-epistemológica baseada na teoria do discurso proposta por Michel Foucault, que nos permitiu constatar que a centralidade das necessidades e dos desejos dos clientes no discurso contemporâneo do marketing é resultado de uma série de transformações e disputas históricas pela hegemonia de uma determinada idéia ou ponto de vista, mas sempre ancorada em condições socioeconômicas, ambientais, favoráveis às transformações ocorridas. Em outras palavras, concluímos que as transformações discursivas, constituintes da área, foram o resultado de um processo produzido social e historicamente, tendo ocorrido muito mais como um resultado de mudanças na economia e no mundo empresarial do que como uma espécie de "vocação" natural do marketing.

  9. Entre la retórica legal y eclesiástica:una misión antiesclavista en el siglo XVII

    Directory of Open Access Journals (Sweden)

    Rebeca Moreno Orama

    2015-06-01

    Full Text Available En 1537 la Iglesia prohibió la esclavitud de los amerindios, y no sería sino hasta 1839 que hiciera lo mismo con la esclavitud africana. Entre los siglos entre una postura a la otra, la impugnación religiosa de la esclavitud africana estuvo en manos de unos cuantos misioneros. Este trabajo discute cómo a través del empleo de la retórica legal y eclesiástica, el capuchino Francisco José de Jaca construye en su Resolución (La Habana, 1681un proyecto misionero alterno, centrado en la denuncia del cuerpo católico envuelto en la esclavitud y no en la evangelización de los africanos. In 1537 the Catholic Church prohibited Amerindian slavery, but not until 1839 would they do the same with African slavery. Between the centuries that span from one position to the other, religious condemnation of African slavery was in the hands of but a few missionaries. This work discusses how, through the employment of legal and ecclesiastic rhetoric, the Capuchin monk Francisco José de Jaca constructs in his Resolución (Havana, 1681 an alternative missionary project, focused on the denunciation of the Catholic body involved in the slavery institution and not on the evangelization of Africans.

  10. ¿Qué significa estar bien informado? Retóricas, percepciones y actitudes ante el problema del etiquetado de los alimentos transgénicos

    Directory of Open Access Journals (Sweden)

    JÓSEAN LARRIÓN

    2016-01-01

    Full Text Available En este trabajo realizo un estudio de caso de la controversia sobre el etiquetado de los alimentos transgénicos, centrándome en España y la Unión Europea. Inicialmente, comparo los discursos sociales que conciben el etiquetado fundamentalmente como un problema o como una solución. Después, analizo las principales respuestas legislativas y los aspectos concretos que en este ámbito siguen siendo polémicos. A continuación, expongo los límites del modelo del déficit cognitivo y el problema de establecer qué información es relevante o irrelevante. El trabajo concluye mostrando la presencia de las retóricas de la seguridad y el riesgo, y proponiendo un esquema de posiciones sociales ante el consumo de transgénicos, su etiquetado diferencial y el quehacer científico en nuestras sociedades.

  11. A trapaça e os trapaceiros: algumas sugestões para uma abordagem retórica dos gêneros do discurso

    Directory of Open Access Journals (Sweden)

    Marco Antônio Gutierrez

    2010-07-01

    Full Text Available http://dx.doi.org/10.5007/1807-9288.2008v4n2p33 A correspondência indesejada (spam representa na melhor hipótese um incômodo e, na pior, um risco à segurança e à privacidade dos usuários. No entanto, trata-se de fenômeno típico do uso massivo da Internet e só isso parece-nos suficiente para indicar a necessidade de sua compreensão. O presente artigo aborda uma das categorias mais insidiosas desse tipo de correspondência – as mensagens de Cavalo de Tróia, elaboradas por criminosos com o objetivo de instalar programas maliciosos nos computadores de usuários incautos. Nossa abordagem, porém, será eminentemente retórica, buscando compreender o fenômeno como um jogo argumentativo, como parte de um contexto mais amplo destinado a situar e categorizar gêneros emergentes do discurso em meio digital.

  12. Las jerarquías étnicas y la retórica del multiculturalismo estatal en San José del Guaviare

    Directory of Open Access Journals (Sweden)

    Carlos del Cairo

    2011-01-01

    Full Text Available Este artículo analiza las tensiones entre las jerarquías étnicas en San José del Guaviare y la valoración positiva de la diversidad cultural que introdujo la retórica del multiculturalismo estatal. En particular, describe la posición diferencial que ocupa la gente jiw, tucano y nukak de acuerdo con las jerarquías elaboradas por los "blancos" del pueblo, los tucanos y los funcionarios estatales. Las características de estas jerarquías permiten cuestionar tres reduccionismos constitutivos del multiculturalismo estatal colombiano, a saber, la presunción de la unidad en la diversidad étnica, la esencialización de la diferencia cultural y la reificación de la comunidad. El artículo destaca la importancia de analizar las percepciones sobre la diferencia cultural en procesos que van más allá de la formalidad multicultural que exaltan las instituciones estatales.

  13. Retórica y divulgación científica. Una propuesta para la web de empresas biotecnológicas

    Directory of Open Access Journals (Sweden)

    María Luisa García Hernández

    2017-03-01

    Full Text Available La retórica como teoría de la argumentación y de la persuasión se relaciona con un modo específico de enfocar la divulgación científica, que ya no se concibe como mera alfabetización, sino como un diálogo. Tal cambio implica la participación activa de la sociedad en la toma de decisiones sobre la orientación de la ciencia. Con ese marco, entendemos que empresas como las biotecnológicas, cuya actividad despierta entre la ciudadanía filias y fobias que pueden marcar su devenir, deben tomar un papel activo en esas conversaciones. Sobre ese planteamiento hemos seleccionado una muestra constituida por pymes biotecnológicas asentadas en cuatro parques tecnológicos de Andalucía. Hemos analizado los textos de las páginas de inicio de 29 pymes; porque entendemos que esos relatos, propios y no intermediados, nos permiten conocer si consideran a la ciudadanía como auditorio de interés al que dirigirse, primer paso para hacer de la divulgación el eje de su comunicación corporativa. La respuesta es negativa.

  14. Análisis de retóricas políticas y periodísticas a raíz de las elecciones presidenciales colombianas de 2006

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    Adriana María Ángel Botero

    2008-01-01

    Full Text Available Se analizan las retóricas empleadas por los candidatos a la Presidencia de la República de Colombia en la campaña electoral de 2006 y las de los periodistas que los entrevistaron a través de las cadenas radiales con mayor audiencia nacional. Para dar cuenta de las retóricas se recurre a los planteamientos de Bourdieu y a las categorías de análisis de conversación propuestas por Potter y Verón. Una vez realizados los análisis intra y extradiscursivo a las entrevistas radiales, se explican los mecanismos a partir de los cuales los periodistas construyen su discurso basándose en retóricas como las de la objetividad, y el maniqueísmo; y se exponen las características a través de las cuales los políticos configuran un discurso basado en la estructura del relato.

  15. Metáfora: a funcionalidade do tropo na articulação da retórica e da filosofia na mundividência renascentista

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    Ana C. Martins

    2009-12-01

    Full Text Available Desde os fundamentos aristotélicos que o processo de metapherein, assente na similitudo e transferência semântica, concilia, de forma promissora, a argumentação retórica e a problematização filosófica, forma e conteúdo, res et uerba. Os humanistas quinhentistas, fiéis a esta indissociabilidade e na esteira do ideal de imitativo e aemulatio do legado da Antiguidade Clássica, rentabilizaram as virtualidades e potencialidades da metáfora, convertendo o tropo num instrumento de pedagogia, de génese e criação literárias. A historiografia renascentista é pejada, por isso, de tratados e colectâneas, repositórios enciclopédicos de sentenças morais, que estão a serviço da formação integral e que espelham um escrupuloso e afincado trabalho filológico. O homem renascentista é, assim, instigado a reflectir sobre a sua natura, diante da sua condição dual, dos seus vícios e virtudes, das suas forças e fragilidades, e a leitura metafórica ajuda-o, neste sentido, a redimensionar o mundo e a projectarse nele, a representar, a conhecer e a descobrir(-se na sua condição polimórfica, nas suas misérias e nos seus sonhos.

  16. La (reconstrucció visual i retòrica de Jaume I a la Festa de l’Estendard de Mallorca durant l’època foral

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    Francesc Granell Sales

    2017-06-01

    Full Text Available Resum: L’article pretén adverar de quina manera es configurava i s’identificava la figura del rei en Jaume a la Festa de l’Estendard, la commemoració anual de la conquesta cristiana de la ciutat de Mallorca, mitjançant l’anàlisi dels elements visuals i retòrics planificats per al desenvolupament d’aquella. Cal parar atenció, concretament, a dos d’aquests elements: el portaestandard que anava a cavall ben abillat amb armadura i altres objectes i l’eloqüent prèdica –coneguda com el Sermó de la Conquesta– que pronunciava un clergue acreditat per a tal funció.   Paraules clau: Jaume I, imatge règia, festes de la Baixa Edat Mitjana, iconografia del poder, Regne de Mallorca Abstract: This paper attempts to discuss the manner in which the image of king James I was customized and established in the Festa de l’Estendard, the annual commemoration ceremony of the christian conquest of the city of Mallorca. We will do so through an analysis of the visual and rhetorical elements planned for the unfolding of the ritual. One should focus particular attention on two of these elements: the standard bearer on horseback well attired in armour and other objects and the speech known as the «Sermó de la Conquesta» delivered by a cleric. Keywords: James I of Aragon, Royal Image, Late Medieval Ceremonies, Iconography of Power, Kingdom of Mallorca

  17. Argumentos Comestibles. La construcción retórica de la percepción pública de los alimentos transgénicos

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    Herrera Racionero, Paloma

    2005-04-01

    Full Text Available The main goal of this paper is to analyze how the difíerent types of reasons are constructed in order to créate one public perception or another about genetically modified food. Despite the apparent newness of this kind of foods, these reasons can be assimilated to two fiindamental discourse formations with ampie presence in all the scientific discoveríes. When modelling our analysis on these two rhetorical strategies —that we called 'illustrate' and 'romantic'— the latent presuppositions of the social agents considered and the preconceptions that these agents try to induce in the public opinión are shown. It is also shown a series of important shades and directions that usually escape to the more common analysis in terms of 'pros' and 'cons' genetically modified food.

    El objetivo de este trabajo es analizar cómo se construyen los diferentes tipos de argumentos orientados a crear una u otra percepción pública de los alimentos transgénicos. No obstante la aparente novedad de este tipo de alimentos, dichos argumentos pueden asimilarse a dos tipos fundamentales de formaciones discursdivas de amplia tradición ante las diferentes aportaciones de la ciencia. Al modelar nuestro análisis sobre estas dos estrategias retóricas —que llamamos ilustrada y romántica—se ponen de manifiesto los presupuestos latentes de los agentes sociales y las preconcepciones que estos agentes tratan de inducir en la opinión pública, así como una serie de importantes matices y orientaciones que suelen escapar a un análisis en términos de 'pros* y 'contras' de los alimentos transgénicos.

  18. Modèle conceptuel commun pour la supervision des systèmes de sûreté du CERN

    CERN Document Server

    Hammouti, L

    2000-01-01

    La supervision des systèmes de sûreté des accélérateurs et des zones expérimentales du CERN est gérée spécifiquement d'une machine à l'autre. Chaque programme a été conçu et réalisé au moyen de la technologie de l'époque et sans suivre un modèle conceptuel commun. La situation actuelle risque de poser des problèmes importants pour l'avenir. En effet la disparité des systèmes de supervision et la nécessité de les faire évoluer ou de les renouveler alourdissent sensiblement la charge de travail ainsi que le coût de la maintenance. D'autre part, il est difficile, voire impossible, de les faire communiquer entre eux, or cela constitue une des requêtes principales de l'opération pour une meilleure coordination de l'exploitation. Le but de ce document consiste à présenter les bases d'un modèle conceptuel unique, en cours d'élaboration dans le cadre du LHC, afin de répondre aux problèmes et aux requêtes posés. Ce modèle servira de référence pour le renouvellement et l'évolution ...

  19. COMPREENDER OS DIREITOS HUMANOS EM CABO VERDE: da retórica político-filosófica à praxis jurídica

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    Nataniel Andrade Monteiro

    2016-07-01

    Full Text Available O artigo procura analisar a coerência entre a retórica político-filosófica e a praxis jurídica, tendo como locus de análise os direitos humanos em Cabo Verde. Numa perspectiva histórica, a afirmação dos direitos humanos aconteceu de forma paulatina num processo de sucessivas lutas e revindicações que culminaram em 1948 com a Declaração Universal dos Direitos Humanos. A Declaração é protegida pelo ordenamento jurídico de diferentes Estados e é um dos temas mais debatidos a nível mundial. O caso de Cabo Verde não constitui excepção a este fenómeno, apesar de ser um Estado modelo em África em matéria de direitos humanos. Porém, existem preocupações no que se refere às denúncias de violações constantes como sejam: a morosidade da justiça, as condições precárias das instalações prisionais, os abusos por parte de agentes policiais, a hostilidade contras as mulheres e os abusos contra as crianças. Deste modo, procuramos compreender esta problemática à luz da filosofia política contemporânea, analisando para o efeito um conjunto de perspectivas que configuram a retórica político-filosófica e a práxis jurídica. Palavras-chave: Democracia; Direitos Humanos; Retórica Político-filosófica; Praxis Jurídica. UNDERSTANDING HUMAN RIGHTS IN CAPE VERDE: Political-philosophical rhetoric to legal praxis ABSTRACT The article seeks to analyses the coherence between the political-philosophical rhetoric and legal praxis, with the locus of human rights analysis in Cape Verde. In a historical perspective, the affirmation of human rights happened so gradual a process of successive fights and claims that culminated in 1948 with the Universal Declaration of Human Rights. The statement is protected by the legislation of different States and is one of the most discussed themes worldwide. The case of Cape Verde is no exception to this phenomenon, despite being a model State in Africa in the field of human rights. However

  20. La dynamique des régimes de régulation de la sûreté nucléaire française à la lumière de ses instruments

    OpenAIRE

    Chanton , Olivier; Mangeon , Michael; Pallez , Frédérique; Rolina , Grégory

    2016-01-01

    International audience; L’accident de Fukushima a provoqué une prise de conscience sans précédent concernant l’importance des risques naturels à l’échelle internationale. En mettant en cause plusieurs aspects institutionnels, et notamment les liens de dépendance entre l’autorité de sûreté nucléaire et le ministère de l’industrie japonais, les analyses de l’accident posent également la question de la gouvernance et de la régulation des risques nucléaires avec une acuité nouvelle (Delamotte 201...

  1. Cidadania, educação e responsabilidade social: falácias gastas em um discurso retórico?

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    Mark Sandro Sorprezo de Almeida

    2002-12-01

    Full Text Available The pressing questioning in the present work is established in the proposal of use of the words as instruments of changes, as foundations of the yearnings of a society in transition. The proposal of an educational work that unites the social responsibility to the citizenship demands clarity regarding the social political objectives that guides it, of the vision of world and the concepts of education, citizenship, man, world, knowledge, culture, among others. As to form this professional it consists of one of the educational quandaries and more, it is questioned existence of professionals of the education enabled to exert this formation. The proposal here in conjugating, citizenship, education and social responsibility, of a first analysis consists of the questioning of the rhetorical speech through the presentation of the concepts for then considering the use of such justinian codes as transforming instruments and proportioners. To educate, to form the responsible citizen I obtain and with the society, critic and asset, whichever the society of the future.O questionamento premente no presente trabalho funda-se na proposta de utilização dos vocábulos como instrumentos de mudanças, como alicerces dos anseios de uma sociedade em transição. A proposta de um trabalho educacional que alie a responsabilidade social à cidadania exige clareza a respeito dos objetivos sócio-políticos que a norteiam, da visão de mundo e dos conceitos de educação, cidadania, homem, mundo, conhecimento, cultura, entre outros. Como formar este profissional consiste em um dos dilemas educacionais e mais, questiona-se a existência de profissionais da educação capacitados para exercer esta formação. A proposta aqui em conjugar, cidadania, educação e responsabilidade social, em uma primeira análise consiste no questionamento do discurso retórico através da apresentação dos conceitos para então propor a utilização de tais institutos como instrumentos

  2. Tensiones retóricas y semánticas en ética de la investigación Rhetorical and semantic tensions in research ethics

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    Miguel Kottow

    2007-10-01

    Full Text Available Comienza en recientes años un movimiento de revisión que utiliza la retórica y las desarticulaciones semánticas para legitimar prácticas que tradicionalmente se rechazarían como transgresiones éticas. En la ética de investigación se valida el reclutamiento de personas incapaces de ejercer su autonomía y se propone la incorporación de individuos vulnerados en la investigación para satisfacer el bien común. Esta propuesta atenta contra normativas establecidas que prohíben preferir intereses sociales o científicos por encima de los individuales, utilizando arbitrariamente la idea del bien público, puesto que la mayoría de las investigaciones sirven a intereses particulares de orden corporativo. Se debilita las definiciones de coerción y explotación, justificando la inclusión de probandos carentes de competencia mental y legitimando prácticas que en el entendido usual de estos conceptos son francas transgresiones a la ética de investigación con seres humanos. Cada vez más proyectos de investigación son trasladados a Latinoamérica, haciendo necesario que nuestra bioética se mantenga alerta frente a los intentos de debilitar la protección de individuos y comunidades que participan en estudios patrocinados desde instituciones comerciales del Primer Mundo.In recent years, rhetorical and semantic disjunctions have been used to validate practices traditionally rejected as ethical transgressions. According to such research ethics, subjects unable to exercise their autonomy are freely recruited, and vulnerable individuals are incorporated into research that purportedly serves the common good. The suggestions violate established rules that prohibit placing social or scientific interests above individual needs. The common good is invoked arbitrarily, since most such research serves private corporate interests. The definitions of coercion and exploitation are weakened, thus allowing the inclusion of mentally compromised research

  3. Tecnología y marketing: el papel de la retórica comercial en el desarrollo de dispositivos de navegación

    Directory of Open Access Journals (Sweden)

    Mendonça, Pedro

    2012-02-01

    Full Text Available The present article aims to link technology and marketing in the process of imagination and concretization of functions for mobile navigation devices. It focuses on the performance of marketing and sales, as rhetorical agents, in the technical path of building the product. Empirically, it is a case study of a Portuguese company, NDrive, whose main innovation is the introduction of photographic images in these devices replacing traditional maps. Since we identify in the field of innovation a platform of relation between the two spheres of inquiry (technology and marketing, it is in the theoretical studies of innovation that we produce much of the analysis of the different emerging questions, many connected to the central issues of contemporary technological transformation.

    Este artículo pretende relacionar tecnología y marketing en los procesos de imaginación y desarrollo de funcionalidades en dispositivos de navegación móvil. Se centra en la actuación de los departamentos empresariales de marketing, y de los trabajadores comerciales en general, como agentes retóricos que tienen un papel clave en los caminos técnicos de construcción del producto. En términos empíricos, se trata de un estudio de caso a una empresa portuguesa, Ndrive, que tiene como innovación principal la introducción de imagen fotográfica en los dispositivos de navegación, en vez de los tradicionales mapas. El campo de la innovación que se identifica es una plataforma donde se relacionan los dos ámbitos en cuestión (tecnología y marketing. Por ello, se utiliza la esfera teórica de los estudios de innovación para abordar el análisis de las diferentes problemáticas que van surgiendo en el desarrollo final del producto, muchas de ellas ligadas a las cuestiones centrales de la transformación tecnológica contemporánea.

  4. Os regimentos das corporações dos ofícios mecânicos: O caso do Retábulo-mor da Sé de Lamego (1506-1511 do pintor português Vasco Fernandes

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    Joana Salgueiro

    2010-08-01

    Full Text Available O núcleo em estudo: Retábulo-mor da Sé de Lamego (1506-1511, obra de incontestável importância histórico-artística do pintor quinhentista Vasco Fernandes, “Grão Vasco”, é um conjunto valiosamente documentado pelo seu contrato de obra, que subsistiu até à actualidade. No entanto, sabe-se que muitas vezes os dados empiricamente percepcionados ou mesmo presentes nos actos notariais relativos à feitura do retábulo, por inúmeras razões, nem sempre correspondem na íntegra à realidade. O trabalho que se segue, tem como objectivo, cruzar o conhecimento técnico e material dos suportes destas pinturas, com os dados analisados nos regimentos das corporações dos ofícios mecânicos do trabalho das madeiras: carpinteiros, carpinteiros de marcenaria, marceneiros, entalhadores (e por comparação pintores; de modo a determinar, através das metodologias de examinação dos aprendizes dos ofícios, e restantes normativas, as técnicas e materiais de execução exigidas, no contexto histórico do período Renascentista português.

  5. Recursos pragmático-retóricos de las narrativas de queja para la construcción social de la identidad de mujeres desplazadas por la violencia política en Colombia

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    Yudi Herrera Núñez

    2015-12-01

    Full Text Available Las mujeres desplazadas por la violencia política en Colombia, no solo se enfrentan a este flagelo sino que además son expuestas a condiciones de precariedad y al estigma por las comunidades de ‘acogida’. Esta investigación pretendeidentificar los correlatos retórico-pragmáticos de los procesos narrativos de construcciónidentitaria, y del enfoque de posicionamiento interaccional de Bamberg (1997 en el contexto de la entrevista de investigación. La muestra está conformada por 17 entrevistas semi-estructuradas conformadas como relatos de experiencias personales vividas a luego del proceso de desplazamiento forzado. Los principales resultados, extraídos de nuestro estudio, destacan el uso de ‘narrativas de queja’ (Günthner (2007 como uno de los recursos preferidos que las narradoras emplean para construir su identidad. En estos relatos, el amplio despliegue de recursos narrativos, pragmáticos, retóricos y evaluativos pareciesen estar en función del objetivo interaccional de producir el alineamiento del interlocutor. En las narrativas de queja los recursosmás frecuentes son el discurso directo, el uso de presente histórico y diversos recursos evaluativos. Las narrativas se constituyen en los principales territorios donde los co-conversadores buscan y encuentran formas para mitigar el ‘problema interactivo’ y conforman una imagen de sí mismos de formas que sean interactivamente útiles.

  6. Detección de una mutación no estándar en el Proto-oncogen RET por mutagénesis dirigida Detection of a non-standard mutation in the ret protoncogene by site directed mutagenesis

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    Sebastián Real

    2005-03-01

    Full Text Available El síndrome de MEN2A es una enfermedad autosómica dominante que se caracteriza por el desarrollo de cáncer medular de tiroides, feocromocitoma e hiperplasia de paratiroides. Mutaciones en el ret proto-oncogén se asocian con MEN2A, con una penetrancia cercana al 100%. El gen se encuentra en el cromosoma 10q11.2 y codifica para una proteína transmembrana con función de receptor del tipo tirosina quinasa. Mutaciones que afectan el dominio extracelular de la proteína estimulan la dimerización espontánea del receptor y un aumento de la actividad de tirosina quinasa basal. El codón 634 codifica para una cisteína, y es considerado un sitio hot-spot por encontrarse mutado en el 85% de las familias con MEN2A. Para este sitio, nuestro grupo desarrolló en 2002 una metodología de detección indirecta y económica. Ante una familia sospechada de MEN2A, se aplicó esta estrategia, que reveló un codón 634 sano. Por posterior secuenciación se confirmó que el paciente índice portaba una mutación en el codón 611. Se desarrolló una nueva estrategia familia-específica por PCR mutagénica, que permitió diagnosticar en nuestro país a todos los integrantes de la familia con costos accesibles. Un niño en el cual se halló la mutación, fue tiroidectomizado preventivamente, y a la fecha goza de buena salud. De esta manera, combinando la estrategia de detección de mutaciones en el sitio hot-spot y un posterior diseño de otra metodología familia-específica se pudo diagnosticar e intervenir preventivamente a la familia, sin enviar todas las muestras al extranjero.MEN2A is an autosomic dominant disease, characterized by medullary thyroid cancer, pheochromocytoma and parathyroid hyperplasia. Mutations in the ret proto-oncogene are associated with this disease, with almost 100% of pennetrance. The gene, situated on chromosome 10q11.2, codes for a transmembrane protein with a tirosinkinase-like receptor function. Mutations that affect its

  7. La e-migración: un nuevo espacio para pensar la retórica de la integración en las políticas migratorias

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    Mauricio Nihil Olivera Cajiga

    2013-01-01

    Full Text Available Este artículo, basado en un estudio comparativo de migrantes franceses y ecuatorianos en Barcelona, discute la retórica de la integración en las políticas migratorias dentro del contexto de las tecnologías de la información y la comunica­ción (TIC. Los resultados que se presentan permiten problematizar las relaciones de los migrantes en Barcelona a partir de sus prácticas sociales en las TICs, así como también plantear la existencia de unas características tecnológicas, geográficas y sociales (TGS que crean un nuevo espacio que llamamos e-migración. Se argumenta en este artículo que el discurso de la integración y las TICs, que forma parte de la retórica de las administraciones de gobierno catalana, ocultan desigualdades estructurales entre los migrantes comunitarios y no comunitarios. El estudio de caso de franceses y ecuatorianos migrantes en Cataluña es una muestra de cómo se gestiona la diversidad en clave cultura para categorizar a determinadas poblaciones y no para integrarlas. Palabras clave: integración, política, e-migración, ecuatorianos, franceses, TIC, Barcelona, retórica.   E-migration: a new space to think the rhetoric of integration in migration policies  Abstract This article, based on a comparative study of French and Ecuadorian migrants in Barcelona, discusses the rhetoric of integration in migration policies within the context of information and communication technologies (ICT. The results presented allow to question the relationship of migrants in Barcelona taking into account their ICT social practices, as well as propose the existence of technological, geographical and social (TGS characteristics to create a new space we call e-migration. It is argued in this article that the discourse of integration and ICT, which is part of the rhetoric of the Catalan government administrations, hides structural inequalities between migrants from EU and outside of the EU. The case study of French and Ecuadorian

  8. Retórica e poder: o paratexto prefacial de autoria feminina no Brasil do século XIX = Rhetoric and power: the feminine prefacial paratext in Brazil in the nineteen century

    Directory of Open Access Journals (Sweden)

    Tabak, Fani Miranda

    2014-01-01

    Full Text Available Neste trabalho, voltamos nosso olhar para paratextos prefaciais produzidos por autoras oitocentistas, considerando a importância dos mesmos para o estudo e o resgate de obras praticamente esquecidas dentro da tradição historiográfica. Ao ampliarmos o conceito de transtextualidade, desenvolvido por Gérard Genette, tornamos evidente a paratextualidade como fenômeno de provocação frente a uma situação periférica no discurso produzido por escritoras. A quebra dos padrões retóricos da captatio benevolentiae, bem como a tentativa de readequação do prefácio a um possível público habituado às normas vigentes, torna o paratexto um elemento importante a ser considerado na própria compreensão do posicionamento autoral feminino

  9. Configuraciones retórico-lingüísticas del resumen en artículos científicos de economía: Contrastes en el interior de la disciplina

    OpenAIRE

    Stagnaro, Daniela

    2015-01-01

    En las últimas décadas, la lingüística especializada ha contribuido al conocimiento del discurso académico-científico, especialmente, de las características lingüístico- retóricas de géneros centrales de la comunicación científica. Entre ellos, el artículo científico y su resumen han recibido amplia atención por su centralidad en el proceso de investigación. Sin embargo, la bibliografía tiende a tratar el discurso de cada disciplina de manera homogénea sin considerar las ramas o los posiciona...

  10. La resurrección retórica de la República en 1890: Un análisis sobre las relaciones entre elocuencia, oratoria y política en la Argentina a fines del siglo XIX

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    Leonardo D. Hirsch

    Full Text Available El trabajo tiene como objetivo hacer un análisis de las relaciones entre retórica, oratoria y política en la Argentina, a lo largo del siglo XIX, en general, y durante la crisis de 1890, en particular. En este sentido creemos que en la particular coyuntura de 1890 se temió sobre todo por la desintegración del cuerpo político de la República como consecuencia de la creciente indiferencia de los ciudadanos por la cosa pública. Los Cívicos, en consecuencia, decidieron emprender una "campaña de regeneración", fundada sobre la creencia en el "poder soberano de la palabra", y en la legitimidad que otorgaba la elocuencia de sus oradores, para transformar los hábitos políticos.

  11. Nuevos mecanismos de regulación del balance energético. Papel de AMPK y del estrés del retículo endoplasmático hipotalámico

    OpenAIRE

    Seoane Collazo, Patricia

    2018-01-01

    AMPK es un sensor celular que se activa en estado de baja energía. Las evidencias actuales vinculan la AMPK hipotalámica con la regulación central del balance energético. Sin embargo, cual es la isoforma de AMPK y el tipo neuronal que está mediando estos efectos todavía no se ha dilucidado. En esta Tesis, demostramos que la inhibición de AMPKα1 en las neuronas SF1 del núcleo ventromedial del hipotálamo protege contra la obesidad inducida por dieta al disminuir el estrés del retículo endoplasm...

  12. Detection of Gene Rearrangements in Circulating Tumor Cells: Examples of ALK-, ROS1-, RET-Rearrangements in Non-Small-Cell Lung Cancer and ERG-Rearrangements in Prostate Cancer.

    Science.gov (United States)

    Catelain, Cyril; Pailler, Emma; Oulhen, Marianne; Faugeroux, Vincent; Pommier, Anne-Laure; Farace, Françoise

    2017-01-01

    Circulating tumor cells (CTCs) hold promise as biomarkers to aid in patient treatment stratification and disease monitoring. Because the number of cells is a critical parameter for exploiting CTCs for predictive biomarker's detection, we developed a FISH (fluorescent in situ hybridization) method for CTCs enriched on filters (filter-adapted FISH [FA-FISH]) that was optimized for high cell recovery. To increase the feasibility and reliability of the analyses, we combined fluorescent staining and FA-FISH and developed a semi-automated microscopy method for optimal FISH signal identification in filtration-enriched CTCs . Here we present these methods and their use for the detection and characterization of ALK-, ROS1-, RET-rearrangement in CTCs from non-small-cell lung cancer and ERG-rearrangements in CTCs from prostate cancer patients.

  13. Teoría retórica como teoría del texto y narración digital como narración hipertextual: perspectivas de estudio entre la tradición y la modernidad

    OpenAIRE

    Chico Rico, Francisco

    2007-01-01

    El principal objetivo de este estudio es el de cubrir un capítulo que cada vez se hace más necesario en cualquier foro de debate sobre las tecnologías de la creación en la era digital: el relativo a la consideración de la llamada "hiperficción" o, para hablar con propiedad, "narración hipertextual" —como narración literaria de linealidad no fijada y comunicada a través de la pantalla de un ordenador— desde la perspectiva teórico-metodológica del sistema retórico, entendido como teoría del tex...

  14. Dano moral: análise de argumentos decisórios em acórdão trabalhista sob a ótica da Nova Retórica

    Directory of Open Access Journals (Sweden)

    Barbara Bedin

    2013-05-01

    Full Text Available Neste trabalho objetivou-se analisar os argumentos valorados por desembargadores para formar o entendimento do significado de dano moral – que equivale a um fenômeno jurídico passível de ser indenizado. Para alcançar tal objetivo, examinou-se, em um estudo exploratório, o acórdão n. 0000192-11.2011.5.04.0001, proferido pela Quarta Turma do Tribunal Regional do Trabalho da Quarta Região (Rio Grande do Sul, Brasil, que trata de uma indenização por dano moral. Os argumentos foram levantados e analisados sob a ótica da Nova Retórica de Perelman e Olbrecht-Tyteca.

  15. A ironia na literatura canadense: uma estratégia retórica e estrutural exibindo dissonâncias e diferenças = The irony in Canadian literature: a rhetorical and structural strategy displaying differences and dissonance

    Directory of Open Access Journals (Sweden)

    Klondy Lúcia de Oliveira Agra

    2012-01-01

    Full Text Available Neste artigo, observo, com base na literatura canadense, os sentidos dados à ironia utilizada como estratégia retórica e estrutural. A partir da pesquisa bibliográfica, procuro por esclarecimentos sobre a característica da ironia canadense, sua forma e seu foco específico com apoio das teorias crítica, pós-moderna e pós-colonial.In this article, the result of study about Canadian literature, I observe the use of the irony as a rhetorical and structural strategic. From the bibliographical research, I look for clarification on the characteristic of Canadian irony, its form and its specific focus with support from critical theory, postmodern and post-colonial.

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    Full Text Available |pid:none) Rickettsia massiliae MTU5, compl... 226 2e-57 CP001635_813( CP001635 |pid:none) Variovorax parad...Value CP000087_1092( CP000087 |pid:none) Rickettsia bellii RML369-C, com... 229 2e-58 CP000683_198( CP000683

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    Lifescience Database Archive (English)

    Full Text Available eading fra... 75 2e-12 AF134593_1( AF134593 |pid:none) Homo sapiens L-pipecolic acid oxid... 75 2e-12 AX8822...k... 108 1e-22 (Q29RU9) RecName: Full=Peroxisomal sarcosine oxidase; S... 75 1e-12 BC114006_1( BC114006 |pid...:none) Bos taurus L-pipecolic acid oxidas... 75 1e-12 AY892312_1( AY892312 |pid:n

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    Full Text Available anslated Amino Acid sequence n*iahvq*kigalsgpflvsrtgdvg*tkywdktsnih**ipqkvlvh*dsrtvamevgi r*gvcnnspakwtspeng...plnss ivddyqxtrccklpssvqlrgvrlfh Frame B: n*iahvq*kigalsgpflvsrtgdvg*tkywdktsnih**ipqkvlvh*dsrtvamevgi r*gvcnns

  6. Técnica dramática y retórica de las pasiones en el Tratado completo del arte del canto de Manuel García

    Directory of Open Access Journals (Sweden)

    Díaz Marroquín, Lucía

    2007-12-01

    Full Text Available The history of European singing technique, from the Italian origins of the stile rappresentativo and the early Seicento musical drama to the heights of bel canto, seems inextricably related to the classical rhetorical and philosophical theories, later re-interpreted by the humanist and rationalist authors. Manuel García’s Tratado completo del arte del canto inherits this tradition and contributes to it with every single observation or musical example included in this eminently practical work.

    Desde los orígenes italianos del stile rappresentativo y del drama musical, en los últimos años del siglo XVI y primeros del XVII, hasta el esplendor del bel canto, la historia de los tratados de canto europeos se encuentra inseparablemente asociada a las teorías retóricas y filosóficas clásicas, más tarde reinterpretadas por los autores humanistas y preenciclopedistas. Al escribir su Tratado completo del arte del canto, una obra eminentemente práctica, Manuel García hereda esta tradición y contribuye a ella con cada una de las observaciones y ejemplos musicales que propone.

  7. Tradição e retórica imagética: a construção da propaganda visual oposicionista no levante de 1932 em São Paulo

    Directory of Open Access Journals (Sweden)

    João Paulo Rodrigues

    2011-06-01

    Full Text Available Esgotando-se o tempo de vida das testemunhas do levante de 1932 o dever de memória respeitante a ele segue candente. Com efeito, a intensidade deste movimento perpassa, também, a historiografia, que aparece cindida em posições mais críticas ou aclamativas, reproduzindo, de certo modo, as polêmicas nascidas no próprio confronto. Em boa medida, por conseguinte, conhecer melhor a "Revolução Constitucionalista" implica exumar as leituras que os insurrectos faziam da realidade vivida e as representações de que lançavam mão, com vistas a vencer as correlações de forças que os acometiam. Essas preocupações são abordadas neste artigo, que o faz, no entanto, sob o prisma alvissareiro das imagens e da produção cultural vinculada à propaganda proselitista. São elas que trazem à tona a retórica constitucionalista, eivada por teores regionalistas, sustentada por redes de relações sociais e, dadas às sutilezas, imiscuídas profundamente na memória histórica.

  8. ¿Obedecer las leyes?: utilitarismo, retórica forense y autoridad en el Critón de Platón (50a6-50b5

    Directory of Open Access Journals (Sweden)

    Eduardo Esteban Magoja

    2017-07-01

    Full Text Available En el Critón de Platón se instala un interesante argumento utilitarista para justificar la obligación política de los ciudadanos. El argumento sostiene que la violación de las leyes lleva a la destrucción de cualquier sistema jurídico y acarrea resultados perjudiciales para los miembros de la comunidad (50a6-50c. En este trabajo realizaremos un análisis crítico del argumento bajo los postulados de tres corrientes utilitaristas: el utilitarismo de acto, la generalización utilitarista y el utilitarismo de regla. Veremos cómo esta clase de argumentación presenta algunos inconvenientes a la hora de justificar la obediencia al derecho. Una vez realizado este estudio se propondrá otra interpretación complementaria sobre el significado del pasaje, en la que se destacará su costado retórico forense y la idea de la autoridad del derecho.

  9. Sobre a retórica da exclusão: a incidência do discurso ideológico em serviços substitutivos de cuidado a psicóticos

    Directory of Open Access Journals (Sweden)

    Christian Ingo Lenz Dunker

    Full Text Available O Brasil atravessa um vigoroso processo de reforma psiquiátrica. Pressionado pelo Movimento dos Trabalhadores de Saúde Mental, o Ministério da Saúde adotou como uma de suas diretrizes de ação favorecer a inclusão social dos portadores de transtornos mentais no Brasil. Nos moldes propostos pelos partidários da reforma psiquiátrica, o tratamento da psicose deve enfatizar a negação da lógica manicomial através de uma política compensatória de benefícios e da participação em movimentos sociais. Neste artigo, examinamos alguns aspectos ideológicos dessa proposta e algumas de suas inflexões clínicas. Procuramos mostrar como o efeito de circulação de discursos pode abrir campos de significação onde certos modos de compreensão e socialização são estimulados em detrimento de outros. Argumentamos que a retórica baseada na oposição entre inclusão e exclusão pode ser pensada em sua dupla incidência, clínica e ideológica.

  10. Identification of sumoylation sites in CCDC6, the first identified RET partner gene in papillary thyroid carcinoma, uncovers a mode of regulating CCDC6 function on CREB1 transcriptional activity.

    Directory of Open Access Journals (Sweden)

    Chiara Luise

    Full Text Available CCDC6 was originally identified in chimeric genes as caused by chromosomal translocation involving the RET protooncogene in some thyroid tumors. Recognised as a 65 kDa pro-apoptotic phosphoprotein, CCDC6 has been enrolled as an ATM substrate that contribute to protect genome integrity by modulating PP4c activity in response to genotoxic stress. Recently, CCDC6 has been identified as a repressor of CREB1-dependent transcription. Sumoylation has emerged as an important mechanism in transcriptional control. Here, we report the identification and characterization of three sites of sumoylation in CCDC6 (K74, K266 and K424 which are highly conserved in vertebrates. We demonstrate that the post-translational modifications by SUMO2 constrain most of the CCDC6 protein in the cytosol and affect its functional interaction with CREB1 with a decrease of CCDC6 repressive function on CREB1 transcriptional activity. Indeed, the impairment of functional outcome of sumoylated CCDC6 is obtained knocking down all three the sumoylation sites. Interestingly, in thyroid cells the SUMO2-mediated CCDC6 post-translational modifications are induced by Forskolin, a cAMP analog. Signal transduction via the cAMP pathway is known to be ubiquitous and represents a major line of communication between many organisms and their environment. We believe that CCDC6 could be an important player in the dynamics of cAMP signaling by fine regulating CREB1 transcriptional activity in normal and transformed thyroid cells.

  11. As estratégias de retórica na disputa pela Prefeitura de São Paulo em 2004: PT, mandatário, versus PSDB, desafiante

    Directory of Open Access Journals (Sweden)

    Luciana Fernandes Veiga

    2007-06-01

    Full Text Available A experiência do PT no governo (nos âmbitos nacional e local suscitou a curiosidade sobre possíveis alterações no seu discurso eleitoral na disputa pela Prefeitura de São Paulo. O foco desta análise está nas continuidades e rupturas das estratégias retóricas elaboradas a partir dos eixos ideológico (esquerda e direita e pragmático (mandatário e desafiante. A preocupação central é o discurso do PT, e a análise da comunicação apresentada pelo PSDB tem um caráter complementar. Todos os programas e spots veiculados pelas campanhas do PT e do PSDB em São Paulo foram analisados a partir de métodos qualitativos e quantitativos.The experience of the Worker's Party at the Brazilian national and local governments has estimuladted the curiosity about changings in its electoral discourse at the elections for the São Paulo Mayor. This article focuses on the changes and continuities of rethorical strategieand the analysis is based on campaign 'spots' veiculated by the Worker's Party and the Brazilian Social Democratic Party.

  12. Argumentos retóricos sobre Interrupción Voluntaria del Embarazo en Colombia. Análisis jurisprudencial desde la teoría de la argumentación jurídica de Perelman

    Directory of Open Access Journals (Sweden)

    Karolina Naranjo Velasco

    2011-06-01

    Full Text Available RESUMEN El presente trabajo aborda los conceptos planteados por Chaïm Perelman en su teoría de la argumentación, con el fin de lograr una comprensión del razonamiento en las decisiones judiciales tomadas por la Corte Constitucional de Colombia, en relación a tres casos sobre interrupción voluntaria del embarazo (IVE. En primer lugar, se aborda la teoría de la  “Nueva Retórica” de Chaïm Perelman, y en especial su aplicación en el campo del Derecho. A continuación se hace un breve repaso de las premisas de la argumentación y las técnicas argumentativas manteniendo un enfoque de carácter jurídico. Para finalizar, se analiza la motivación de las sentencias de la Corte Constitucional colombiana en materia de IVE, aplicando la descripción e interpretación propuestas por Perelman.   ABSTRACT This paper uses the concepts developed by Chaïm Perelman in his theory of argumentation, in order to understand the argument of the Constitutional Court of Colombia on three cases of voluntary interruption of pregnancy (VIP. First, it addresses the theory of “New Rhetoric” of Chaïm Perelman, and especially its application in law. Secondly, there is a brief approach to the premises and techniques of argument within a legal approach. Finally, we analyze the argumentation of the sentences of the Colombian Constitutional Court on VIP, using the description and interpretation proposed by Perelman

  13. Retóricas de la droga

    OpenAIRE

    Derrida, Jacques

    2010-01-01

    Entrevista a Jacques Derrida.Autrement. No es Ud. un especialista en toxicomanía, sin embargo pensamos -y es un poco lo que presupone esta entrega- que, como filósofo, tenga algo que decir de interés para el campo propio, específico, de la toxicomanía. Así fuese a través de conceptos comunes, tales como dependencia", "libertad", "placer", "goce".

  14. Zebrafish as a Model to Study NF1-Associated Learning Deficits

    Science.gov (United States)

    2016-07-01

    and Spencer, 1966). The duration of habituated behavior provides a metric for nonassociative learning ( short - term habituation) and memory formation...ing memory . We evaluated learning by exposing larvae to dark- flash stimuli delivered at 3 s interstimulus intervals (ISIs) and measuring short - term ...behavioral outcomes. The fact that we observed robust improve- ments in learning and memory in our experiments even though we used only short - term

  15. Identifying Neurofibromin-Specific Regulatory Nodes for Therapeutic Targeting in NF1

    Science.gov (United States)

    2016-10-01

    Neurofibromin, Spred1, Spred2, neurofibromatosis, therapeutic targeting 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a...PKC iota , NLK, CHK1, CHK2, RSK1, RSK2, RSK3, RSK4, ICK, PCTK1, CAMKK2, SRPK2, COT, DYRK2, GRK1, PKC mu, PKC nu, PKC theta, PKC zeta, IKK alpha, IKK

  16. Health-Related Quality of Life for Pediatric NF1 Patients

    National Research Council Canada - National Science Library

    Bradlyn, Andrew S; Harris, Carole V

    2006-01-01

    .... Following this initial field trial, the second generation instrument will be tested administered in a battery of measures to furthers assess its reliability and validity as well as its applicability...

  17. Receptor Tyrosine Kinases as Targets for Treatment of Peripheral Nerve Sheath Tumors in NF 1 Patients

    Science.gov (United States)

    2010-03-01

    expression analysis after laser-assisted microdissection. Int. J. Mol. Med., 11, 449–453. 22.Plaat,B.E., Molenaar ,W.M., Mastik,M.F., Hoekstra,H.J., te...and erbB2 in MPNST Neuro-oNcology • D E C E M B E R 2 0 0 8 957 20. Plaat BE, Molenaar WM, Mastik MF, Hoekstra HJ, te Meerman GJ, van den Berg E

  18. Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

    Science.gov (United States)

    2015-06-01

    in the general population. Specific learning disabilities in reading, spelling and math occur in 20% of children without overt central nervous...Fusion of a kinase gene , ALK, to a nucleolar protein gene , NPM, in non-Hodgkin’s lymphoma. Science 263, 1281-1284 (1994). 12 Mossâe, Y. P. et al...Identification of ALK as a major familial neuroblastoma predisposition gene . Nature 455, 930-935 (2008). 13 Janoueix-Lerosey, I. et al. Somatic and

  19. Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

    Science.gov (United States)

    2016-08-01

    Rogers funded training. Charity Miltenberger, 2015: Role mentor undergraduate student of Concordia University for research as part of Murdock Trust...Cincinnati Children’s Hospital . The complicated breeding scheme combined with the delayed shipment of the mice has prolonged this project and as a result

  20. Neurofibromatosis Type 1 (Nf1) and Pregnancy - Case With Positive Outcomes

    OpenAIRE

    Astrit M. Gashi; Curr Gjocaj; Jakup Ismajli; Xhevdet Gojnovci

    2018-01-01

    Apregnancy is categorized as with high-risk when the life of the mother or the fetus becomes fragile due to various diseases. Many health problems can be manifested in women before pregnancy, during and after pregnancy. Some health problems can also begin in early adolescence with very light clinical signs, but during pregnancy because of the hormonal changes that may occur, lead to intensification of the disease. We report the management of a 26-year-old woman patient diagnosed with neurofib...

  1. Social and Emotional Functioning of Children with NF-1 and Their Families: A Case Controlled Study

    National Research Council Canada - National Science Library

    Noll, Robert

    2000-01-01

    ...) of children with NF and explore potential linkages between NF and QOL in these 3 domains. The second objective of this work is to evaluate parental distress, family functioning, and child rearing practices...

  2. Social and Emotional Functioning of Children With NF-1 and Their Families; A Case Controlled Study

    National Research Council Canada - National Science Library

    Noll, Robert

    2001-01-01

    ...) of children with NF and explore potential linkages between NF and QOL in these 3 domains. The second objective of this work is to evaluate parental distress, family functioning, and child rearing practices...

  3. Novel Therapeutic Development of NF1-Associated Malignant Peripheral Nerve Sheath Tumor (MPNST)

    Science.gov (United States)

    2016-08-01

    generations of clinical investigations for MPNST. Impact on technology transfer: Nothing to report. Impact on society beyond science and technology ...dilution; Cell Signaling Technology , Danvers, MA). All immunostaining studies were performed on a Leica Bond-RX and Bond-3 automated stainer platform (Leica...monophasic, biphasic, and poorly differentiated examples, retained expression of this marker. A recent study showed that neurofibromin C-terminus ( NFC

  4. Quantitative {sup 18}F-DOPA PET/CT in pheochromocytoma. The relationship between tumor secretion and its biochemical phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Amodru, Vincent; Brue, Thierry; Castinetti, Frederic [Aix-Marseille University, Department of Endocrinology, Conception University Hospital, Marseille (France); Guerin, Carole; Sebag, Frederic [Aix-Marseille University, Department of Endocrine Surgery, Conception University Hospital, Marseille (France); Delcourt, Sarkis; Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, European Center for Research in Medical Imaging, Marseille (France); Romanet, Pauline [Aix-Marseille University, Laboratory of Molecular Biology, Conception Hospital and CNRS, CRN2M UMR 7286, Marseille (France); Loundou, Anderson [Aix-Marseille University, Department of Public Health, EA3279 Self-perceived Health Assessment Research Unit, La Timone University, Marseille (France); Viana, Bruna; Pacak, Karel [National Institutes of Health, Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD (United States)

    2018-02-15

    {sup 18}F-FDOPA illustrates the properties of uptake and storage of catecholamines in pheochromocytomas (PHEOs). Until now, the relationship between {sup 18}F-FDOPA quantitative parameters and a PHEO secretory profile has not been specifically evaluated. Fifty-six patients (56% females, median age: 47.5 yrs) with non-metastatic PHEO, evaluated by {sup 18}F-FDOPA PET/CT, were included in this retrospective study. Forty-five patients had negative genetic testing (80.4%); five patients (8.9%) had RET, two patients (3.6%) had SDHB, two had SDHD (3.6%), one patient (1.8%) had NF1, and one patient had a VHL (1.8%) mutation. Correlation between {sup 18}F-FDOPA metabolic parameters (tumor SUVmax, tumor SUVmean, tumor SUVmax/liver SUVmax, MTV 42%, total lesion uptake), urinary metanephrines (MNs), and plasma chromogranin A (CgA) were evaluated. All patients had positive {sup 18}F-FDOPA PET/CT. On univariate analysis, there was a strong correlation between all metabolic parameters and urinary MNs and plasma chromogranin A (CgA). The highest correlations were observed between total lesion (TL) uptake and the value of urinary MNs regardless of their nature (p = 8.10{sup -15} and r = 0.80) and between MTV 42% and plasma CgA levels (p = 2.10{sup -9}, r = 0.74). On multivariate analysis, the correlation of uptake parameters and CgA levels did not persist further due to the relation of CgA and tumor diameter. A correlation between TL uptake and the normetanephrine/metanephrine ratio (NMN/MN) was also found, a finding that was in accordance with in vitro studies, which were found to have a higher catecholamine content in epinephrine producing PHEOs. This retrospective study shows a correlation between {sup 18}F-FDOPA uptake, especially using TL uptake, urinary MNs, and a PHEO biochemical phenotype. This illustrates that beyond its localization value, {sup 18}F-FDOPA PET further enables PHEO characterization at a specific metabolic level. (orig.)

  5. Malignant peripheral nerve sheath tumours in inherited disease

    Directory of Open Access Journals (Sweden)

    Evans D

    2012-10-01

    Full Text Available Abstract Background Malignant peripheral nerve sheath tumours (MPNST are rare tumours known to occur at high frequency in neurofibromatosis 1 (NF1, but may also occur in other cancer prone syndromes. Methods The North West Regional Genetic Register covers a population of 4.1 million and was interrogated for incidence of MPNST in 12 cancer prone syndromes. Age, incidence and survival curves were generated for NF1. Results Fifty two of 1254 NF1 patients developed MPNST, with MPNST also occurring in 2/181 cases of schwannomatosis and 2/895 NF2 patients. Three cases were also noted in TP53 mutation carriers. However, there were no cases amongst 5727BRCA1/2 carriers and first degree relatives, 2029 members from Lynch syndrome families, nor amongst 447 Familial Adenomatous Polyposis, 202 Gorlin syndrome, nor 87 vHL cases. Conclusion MPNST is associated with schwannomatosis and TP53 mutations and is confirmed at high frequency in NF1. It appears to be only increased in NF2 amongst those that have been irradiated. The lifetime risk of MPNST in NF1 is between 9–13%.

  6. Controvérsias, conveniências e críticas na implantação da TV digital no Brasil: as negociações e os estratagemas retóricos empregados pelos agentes fomentadores [doi: 10.5329/RECADM.20090801004

    Directory of Open Access Journals (Sweden)

    Roberto Bazanini

    2009-05-01

    Full Text Available Normal 0 21 false false false PT-BR X-NONE X-NONE MicrosoftInternetExplorer4 RESUMO Controvérsias, conveniências e críticas constituem a essência das discussões e disputas presentes nos atos humanos, se observados pela ótica da ciência social. Partindo-se do conceito da atividade do administrador como ciência social aplicada, o objetivo do trabalho está em investigar as polêmicas envolvidas nos estratagemas retóricos empregados pelos seis principais agentes envolvidos no processo de implantação da TV digital no Brasil e, concomitantemente, analisar e discutir os interesses de cada um desses agentes como participativos da decisão técnica/política da escolha do padrão de TV digital. Por intermédio de pesquisa exploratória de natureza qualitativa, análise pós-factum, com emprego da técnica de entrevista em profundidade embasada na metodologia proposta pela Análise Retórica, buscou-se delinear na concepção das estratégias decididas continuamente, as diferentes etapas do processo que culminaram na outorga do padrão digital da TV brasileira em 02 de dezembro de 2007. Os resultados da pesquisa apontam para a adoção do padrão japonês em perfeita consonância com os interesses dos Radiodifusores e do Governo Federal, em detrimento dos interesses do Coletivo Intervozes, da Indústria de Telecoms e da Academia, sendo que, para a Indústria de Eletro-eletrônicos não houve interferências significativas no seu modelo de negócio. Esse caso constitui um instrutivo exemplo do surgimento das controvérsias, conveniências e críticas no emprego das estratégias por parte dos executivos atuando como agentes retóricos na defesa dos interesses de suas respectivas organizações.   Palavras-Chave Estratégia, Análise Retórica; TV Digital     ABSTRACT Controversies, conveniences and critiques constitute the essence of the quarrels and disputes gifts in the acts human, if observed for the optics of social science. Breaking

  7. Exploração mineira, memória e resistência: as retóricas ecológicas populares no conflito entre pequenos proprietários rurais e indústria mineira no centro de Portugal Mining, memory and resistance: popular ecological rhetoric in the conflict between small rural landowners and the mining industry in the Portuguese inland

    Directory of Open Access Journals (Sweden)

    Pedro Gabriel Silva

    2010-06-01

    Full Text Available Aborda-se um conflito entre pequenos proprietários rurais e uma empresa mineira durante a década de 1970 numa aldeia do interior, região ao centro de Portugal. Analisa-se a oposição popular à extração mineira a partir da memória social da destruição dos recursos agrários e da paisagem. A par da conjuntura política dos anos de 1970, explora-se o papel dos elementos ecológicos na estruturação da retórica e ação resistente. O artigo resulta de uma investigação que combina os marcos antropológico e histórico, onde a abordagem etnográfica enlaça a pesquisa documental em arquivos de empresas, estatais e locais.A conflict between small rural landowners and a mining company during the 1970's in a Portuguese inland hamlet is to be analyzed. Local opposition to mining is to be comprehended in the scope of social memory building after the perception of landscape destruction in the past. Besides the political background of the 1970's, ecological elements are explored to understand resistant rhetoric and action. This paper results from an investigation that combines anthropological and historical theories, where the ethnographic approach embraces the documentary research in companies, state and local archives.

  8. Estrategias institucionales y retórica de la ciencia en un Grupo de Investigación Arqueológica Español: una contribución a la sociología de la ciencia [retractado

    Directory of Open Access Journals (Sweden)

    Bermejo Barrera, José Carlos

    2008-06-01

    Full Text Available This article has been retracted. Please read the Spanish version of the Abstract or the Editorial Note included in the PDF version.RETRACTACIÓN La dirección de Arbor hace constar a sus lectores el siguiente comunicado: Se ha recibido en la dirección de Arbor y en la Comisión de Publicaciones del CSIC una reclamación formal que alega falta de objetividad y presencia de juicios de valor sin evidencia empírica en el artículo "Estrategias institucionales y retórica de la Ciencia en un grupo de investigación arqueológica español: una contribución a la sociología de la Ciencia" de José Carlos Bermejo Barrera, vol. 184, No. 731 (2008, págs. 497-506 de Arbor, por lo que solicita la revisión del procedimiento editorial seguido en su publicación. Recibida esta denuncia se constituyó una comisión de investigación independiente y se acordó la retirada cautelar del artículo hasta la finalización de dicha investigación. La revisión realizada por la Comisión del proceso editorial que concluyó con la publicación del citado trabajo, ha puesto de manifiesto que dicho artículo incumple el requisito de originalidad exigido por la revista en su normativa, un hecho cuya responsabilidad recae en el editor científico de este número monográfico al no someter dicho trabajo a una preceptiva y correcta evaluación. La falta de originalidad del artículo se ha comprobado en el proceso de revisión al detectar que existen dos publicaciones previas con similitud casi completa, hecho que nunca se informó al lector. Estas publicaciones son: •Bermejo Barrera, J.C. (2007 “Evidencia e interpretación no estudo da arte rupestre galega: estratexias institucionais e retórica da ciencia nun grupo de investigación arqueolóxia”. En : J.C. Bermejo Barrera, ¿Para que serve a Historia de Galicia?. Santiago de Compostela, Editorial Lóstrego, ISBN: 978-84-935696-5-5, 190 pp. •Bermejo Barrera, J.C. (2007 “Evidencia e interpretación en el

  9. TGF- β /NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence

    Czech Academy of Sciences Publication Activity Database

    Kretová, M.; Sabová, L.; Hodný, Zdeněk; Bartek, Jiří; Kollárovič, G.; Nelson, B. D.; Hubáčková, Soňa; Luciaková, K.

    2014-01-01

    Roč. 26, č. 12 (2014), s. 2903-2911 ISSN 0898-6568 R&D Projects: GA ČR GA13-17658S; GA ČR GA13-17555S Grant - others:Slovak Grant Agency VEGA(SK) [2/0107/11; Academy of Sciences of the Czech Republic(CZ) L200521301 Institutional support: RVO:68378050 Keywords : Smad * Nuclear factor 1 * Senescence * Adenine nucleotide translocase-2 * Transforming growth factor- β * Oxidative stress Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.315, year: 2014

  10. TGF-β/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence

    Czech Academy of Sciences Publication Activity Database

    Kretová, M.; Šabová, L.; Hodný, Zdeněk; Bartek, Jiří; Kollárovič, G.; Nelson, B. D.; Hubáčková, Soňa; Luciaková, K.

    2014-01-01

    Roč. 26, č. 12 (2014), s. 2903-2911 ISSN 0898-6568 R&D Projects: GA ČR GA13-17658S; GA ČR GA13-17555S Grant - others:Slovak Grant Agency(SK) VEGA [2/0107/11] Institutional support: RVO:68378050 Keywords : Smad * Nuclear factor 1 * Senescence * Adenine nucleotide translocase-2 * Transforming growth factor-β * Oxidative stress Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.315, year: 2014

  11. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL

    DEFF Research Database (Denmark)

    Staller, Peter; Sulitkova, Jitka; Lisztwan, Joanna

    2003-01-01

    Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source of t...

  12. Risk profile of the RET A883F germline mutation

    DEFF Research Database (Denmark)

    Mathiesen, Jes Sloth; Habra, Mouhammed Amir; Bassett, John Howard Duncan

    2017-01-01

    the highest to high risk level, although no well-defined risk profile for this mutation exists. Objective: To create a risk profile for the A883F mutation for appropriate classification in the ATA risk levels. Design: Retrospective analysis. Setting: International collaboration. Patients: Included were 13 A...... seems to have a more indolent natural course compared to that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high risk level....

  13. RET gene mutations and polymorphisms in medullary thyroid ...

    Indian Academy of Sciences (India)

    51 clinically diagnosed MTC patients, 39 family members of patients and 50 normal individuals. The method of .... Documentation system (Amersham Pharmacia Biotech,. Uppsala ... direct nucleotide sequencing to identify the mutations, using.

  14. Esencia retórica del mensaje publicitario

    Directory of Open Access Journals (Sweden)

    Antonio López Eire

    2013-11-01

    Full Text Available Taking into account the points of view of ancient Rhetoric and modem Pragmatics, the author demonstrates and explains the rhetorical character of the "language-acts" nowadays used in advertising. They have all the features of rhetorical "language acts" but are adapted to the peculiar conditions and purposes of advertising as a deep-rooted social fact.

  15. Medullary thyroid cancer: RET testing of an archival material

    DEFF Research Database (Denmark)

    Godballe, Christian; Jørgensen, Gita; Gerdes, Anne-Marie Axø

    2010-01-01

    Medullary thyroid carcinoma (MTC) might be sporadic (75%) or hereditary (25%). Until the mid nineties the diagnosis of hereditary MTC was based on family history, clinical evaluation, histological detection of C-cell hyperplasia and tumor multifocality. Patients and families with hereditary MTC...

  16. Medullary thyroid cancer: RET testing of an archival material

    DEFF Research Database (Denmark)

    Godballe, Christian; Jørgensen, Gita; Gerdes, Anne-Marie

    2009-01-01

    Medullary thyroid carcinoma (MTC) might be sporadic (75%) or hereditary (25%). Until the mid nineties the diagnosis of hereditary MTC was based on family history, clinical evaluation, histological detection of C-cell hyperplasia and tumor multifocality. Patients and families with hereditary MTC...

  17. Una retórica de la influencia

    Directory of Open Access Journals (Sweden)

    Cecilia González

    2008-07-01

    Full Text Available Entre las últimas décadas del siglo XIX y las primeras del XX se publica en el Río de la Plata un número considerable de relatos anclados en los debates que recorren la cultura europea del momento y que giran en torno a fenómenos de influencia. Este denominador común se declina, según los textos, en una serie de temas privilegiados : hipnosis, sugestión, herencia, mimetismo, vampirismo, parasitismo, emanación de todo tipo de rayos, ondas y fluidos capaces de modificar el comportamiento de un ...

  18. ANATOMÍA PATOLÓGICA Y TUMORES HEREDITARIOS

    Directory of Open Access Journals (Sweden)

    Dra. M. Teresa Vial

    2017-07-01

    Nos referiremos desde el punto de vista patológico a algunas de las neoplasias malignas incluidas en síndromes de cáncer hereditario causados por los principales y más frecuentes genes de predisposición genética. Cáncer de Mama (BRCA1/2, Cáncer Colorectal no Polipósico/Síndrome de Lynch (MMR, Cáncer Gástrico Hereditario, Poliposis adenomatosa familiar (PAF, Cáncer Renal y Síndrome de von Hippel Lindau (VHL y Cáncer Medular de Tiroides (RET.

  19. Developing, testing, and implementing a survey of scientist mentoring teachers as part of an RET: The GABI RET mentor survey.

    Science.gov (United States)

    Davey, B.

    2017-12-01

    The impacts of mentoring in education have been well established. Mentors have a large impact on their mentees and have been show to affect mentee attitudes towards learning, interest in subjects, future success, and more. While mentoring has a well-documented impact on the mentees, mentoring also has an impact on the mentors themselves. However, little has been studied empirically about these impacts. When we looked for a validated instrument that measured the impact of mentoring on the scientists working with the teachers, we found many anecdotal reports but no instruments that meet our specific needs. To this end, we developed, tested, and implemented our own instrument for measuring the impacts of mentoring on our scientist mentors. Our instrument contained both quantitative and qualitative items designed to reveal the effects of mentoring in two areas: 1) cognitive domain (mentoring, teaching, understanding K-12) and 2) affective domain (professional, personal, participation). We first shared our survey with experts in survey development and mentoring, gathered their feedback, and incorporated their suggestions into our instrument. We then had a subsection of our mentors complete the survey and then complete it again three to four days later (test-retest). Our survey has a high correlation for the test-retest quantitative items (0.93) and a high correlation (0.90) between the three reviewers of the qualitative items. From our findings, we feel we have a validated instrument (face, content, and contruct validity) that answers our research questions reliably. Our contribution to the study of mentoring of science teachers reveals a broad range of impacts on the mentors themselves including an improved understanding of the challenges of classroom teaching, a recognition of the importance of scientists working with science teachers, an enhanced ability to communicate their research and findings, and an increased interest and excitement for their own work.

  20. Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing.

    Science.gov (United States)

    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Shokeen, Yogender; Minhas, Sachin; Aggarwal, Shyam

    2016-10-01

    Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients.

  1. Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus

    DEFF Research Database (Denmark)

    Pooley, John R.; Flynn, Ben P.; Grøntved, Lars

    2017-01-01

    linked to structural and organizational roles, an absence of major tethering partners for GRs, and little or no evidence for binding at negative glucocorticoid response elements. A basic helix-loop-helix motif closely resembling a NeuroD1 or Olig2 binding site was found underlying a subset of GR binding......Glucocorticoids regulate hippocampal function in part by modulating gene expression through the glucocorticoid receptor (GR). GR binding is highly cell type specific, directed to accessible chromatin regions established during tissue differentiation. Distinct classes of GR binding sites...

  2. A Phase II Trial on the Effect of Low Dose versus High Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1)

    Science.gov (United States)

    2016-10-01

    Hamburg. We are working with EurodratCT to finalize our protocol, especially as it relates to the manufacture and transportation of study drug ...custodianship of study drug , cholecalciferol, from the manufacturer in Canada directly to Germany. Reviews from the IRBs and EurodratCT have led to revision of...a quality of life questionnaire (SF-36), fracture history survey, and activity survey. 2. KEYWORDS: 25(OH)D = 25-hydroxy vitamin D BMD = bone

  3. A Phase II Trial on the Effect of Low-Dose versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1)

    Science.gov (United States)

    2017-10-01

    to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data ...Cincinnati enrollment center CGRP = Clinical Genetics Research Program DEXA = dual energy x-ray absorptiometry Ddrops = formulation of...HAM. Task I.2 (mo 2): conduct an organizational face-to-face meeting between 4 PIs and data monitor A face-to-face meeting will not occur. All study

  4. A Phase II Trial on the Effect of Low-Dose versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1)

    Science.gov (United States)

    2013-10-01

    Zyban (Bupropion Hydrochloride Sustained Release Tablets ) Versus Placebo...Fixed Price. Role: Principal Investigator Kanner (PI) 04/01/1999 - 04...IMAGING Brain: CT or MRI : Nl Abnl T2HI Unknown Age of Imaging ____ Comments:________________ Spine: CT or MRI ...vitamin D? Why more people who choose a vitamin D supplement are choosing DdropsTM Other Vitamin D products (chewable tablets , liquid, etc.) Contain

  5. Carpet Layer (ret. tr.) 7-59.220; Linoleum Layer (const.; ret. tr.) 5-32.732--Technical Report on Standardization of the General Aptitude Test Battery.

    Science.gov (United States)

    Manpower Administration (DOL), Washington, DC. U.S. Training and Employment Service.

    The United States Training and Employment Service General Aptitude Test Battery (GATB), first published in 1947, has been included in a continuing program of research to validate the tests against success in many different occupations. The GATB consists of 12 tests which measure nine aptitudes: General Learning Ability; Verbal Aptitude; Numerical…

  6. Collected Papers. 1970-1980. M. D. Parrish, M. D., Colonel Medical Corps US Army (RET)

    Science.gov (United States)

    1981-01-01

    lie may believe that U. S. culture and comerce should dominate the vorld or that killing human embryos is a proper way to manage genetic and economic...regulation when it bring,; the embryo to develop according tc ILL - Resume of General Systems Theory - 3 - 7/6/73 a particular pattern or code...further the idea of Will and’Thotight which parallel destiny _ The Nature of’New Modern Mind: The Extinction of Causation and causality. He says that

  7. Palabras y silencios: la retórica del poder en los Andes

    Directory of Open Access Journals (Sweden)

    1997-01-01

    Full Text Available PAROLES ET SILENCES : LA RETHORIQUE DU POUVOIR DANS LES ANDES. La parole condense différents arguments et formes de pouvoir dans les sociétés andines. Le domaine social et le cadre cérémoniel appartiennent à ceux qui articulent bien les mots. La différenciation entre la valeur octroyée à la parole et celle correspondant aux silences implique diverses modalités de prestige de reconnaissance sociale et de pouvoir rituel dans les Andes. Les personnes, les vivants et les savants exercent une maîtrise subtile de la parole face aux étrangers, aux défunts et aux sots, qui demeurent socialement “muets”, silencieux. La palabra condensa diferentes argumentos y formas de poder en las sociedades andinas. El dominio social y el ámbito ceremonial pertenecen a los buenos articuladores de palabras. La diferenciación entre el valor otorgado a la palabra y el que corresponde a los silencios implica diferentes modalidades de prestigio, reconocimiento social y poder ritual en los Andes. Las personas, los vivos y los sabios ejercen un dominio exquisito de la palabra frente a los extraños, los difuntos y los “necios” que permanecen socialmente “mudos”, callados. WORDS AND SILENCES: THE RHETORIC OF POWER IN THE ANDES. Words have different meanings and means to exercise power in Andean societies. Social power and ceremonial environments belong people who are fluent in language. The difference between the value ascribed to the spoken word and that ascribed to silence implies several kinds of prestige, social recognition and ritual power in the Andes. “Ordinary”, alive and wise people exert an exquisite authority with words as compared with strange, dead and “stupid people” who remain socially 'dumb', silent.

  8. Teoretiske og eksperimentelle dynamiske undersøgelser af jernbanekøretøjer

    DEFF Research Database (Denmark)

    Jensen, Jens Christian

    1995-01-01

    by the theory of Shen, Hedrick and Elkins. The derivation of the dynamical equations is described, and special focus is placed on the contact between wheel and rail. This contact is treated locally elastic which means that the wheel is allowed to penetrate the rail. This method is capable of taking into account...... multiple coexisting contact areas between the wheel and rail. Various examples of the geometrical contact between wheel and rail are given and the influence of track gauge and rail inclination on the contact is outlined. The contact-geometry for a worn wheel-profile on new rails is determined and used...... in the simulations of the dynamics of the IC3 train. In the thesis the dynamics are numerically investigated for the IC3 running on three different track configurations: 1) A perfectly straight track 2) A measured track with irregularities 3) A curve When running on a straight track, we follow the linear...

  9. Argumentación retórica y controversias: un estudio de caso

    Directory of Open Access Journals (Sweden)

    Regner, Anna Carolina

    2011-02-01

    Full Text Available Charles Darwin and George Mivart once engaged in a famous polemic concerning the origin of species. I will analyze this polemic in the light of the conceptual framework and argumentative strategies of Darwin’s Origin of Species (1872 and Mivart’s On the Genesis of Species (1871. In order to understand the nature of their polemic, I will compare the problems they intended to deal with, their answers as well as their motivations, presuppositions, arguments, and argumentative strategies. In particular, I will focus on Mivart’s objections and Darwin’s responses as part of their argumentative strategies. I will treat refutation in its widest sense (without reducing it to merely proving falsehood as a collection of procedures to challenge an opponent’s position or proposition.

    Charles Darwin y George Mivart se envolvieron una vez en una famosa polémica en relación al origen de las especies. Analizaré esta polémica bajo el marco conceptual y las estrategias argumentativas de Darwin en Origin of Species (1872 y de Mivart en On the Genesis of Species (1871. Para entender la naturaleza de su polémica, compararé los problemas que se propusieron tratar, sus respuestas, así como también sus motivaciones, presuposiciones, argumentos y estrategias argumentativas. En detalle, me centraré en las objeciones de Mivart y en las respuestas de Darwin como parte de sus estrategias argumentativas. Trataré la refutación en su más amplio sentido (sin reducirlo a la mera prueba de su falsedad como una colección de procedimientos para desafiar una posición o propuesta del oponente.

  10. Reklamen som pastiche. Om Dansk Sygeplejeråds annoncekampagne efteråret 1986

    Directory of Open Access Journals (Sweden)

    Gunhild Agger

    1989-08-01

    Full Text Available Der er flere og flere medieproducenter, der anser modtagerne for at besidde en vis tekstuel intelligens. Fra detektivpasticher som Dick Spanner og Batman over den konstant genreparodierende "Moon- lighting" (De heldige helte til Poul og Nulles respektløse faktion "I sandhedens Tjeneste" leges der med betydningsdannelsen. Seerne/læserne indbydes til selv at spille ping-pong med billeder og tekst. Gunhild Agger analyserer her denne tendens, sådan som den kom- mer til udtryk inden for reklamen: Anker Jørgensen som James Bond, og kondomer til Prinsessen på Ærten! Mest indgående beskæftiger hun sig med Dansk Sygeplejeråds brug af myten om sygeplejersken i en annoncekampagne op mod overenskomstforhandlingerne i 1987. Gunhild Agger nøjes ikke med en indholdsanalyse af annoncerne, men beskriver hele kampagnen: Dansk Sygeplejeråds hensigter med frem- stødet, kampagnens lancering over for den tre-dobbelte målgruppe, læsernes formodede reception, og kampagnens politiske og holdnings- mæssige effekter.

  11. El asterisco barroco: urbanismo y retórica (poética)

    OpenAIRE

    Ruiz, Facundo

    2009-01-01

    De carácter ensayístico, el siguiente trabajo busca pensar cierta lógica de construcción estética que aparece, nítidamente, en el siglo XVII y bajo el diseño (dinámico) del plano en asterisco. Cierta configuración política del Estado-nación, así como la creciente extensión de un dominio imperialcolonial de la economía, ponen en primer plano el problema del espacio (y del control de su infinitud). Este fenómeno, entre otros, lleva a retrazar la antigua ciudad medieval y a reconfigu...

  12. [Rets. rmt. : Eliot A. Cohen. Supreme Command - Soldiers, Statesmen and Leadership in Wartime. 2003] / Margus Kolga

    Index Scriptorium Estoniae

    Kolga, Margus

    2004-01-01

    Raamat analüüsib tsiviil-militaarsuhteid ning sõjaväe tsiviiljuhtimist, kui palju peab tsiviilvõim sekkuma sõjapidamisse ja kaitseväe arendamisse, et strateegilised eesmärgid oleksid saavutatavad

  13. Turismo comunitario en Colombia: ¿retórica de Estado?

    Directory of Open Access Journals (Sweden)

    Sonia Emilse Rodríguez Rodríguez

    2018-05-01

    Full Text Available El presente artículo propone un análisis de la política pública sobre turismo comunitario en Colombia. Para ello, se elaboró un inventario de las políticas públicas colombianas en esta materia. De este inventario se percibió que la política pública de orden nacional sobre turismo comunitario no incluye elementos como financiación, seguimiento y planes de acción concretos para las estrategias propuestas, por lo que en la práctica son inoperantes. Esta constatación exige el análisis de las razones que sustentan tal fenómeno, como también obliga a una actitud propositiva que permita evitar la continuidad de este hecho. Se propone que las comunidades prestadoras de servicios de turismo comunitario se conviertan en gestoras de políticas públicas territoriales que garanticen el respeto por la identidad cultural y la preservación del medio natural, y que sean ellas mismas las que ejerzan el control en todos los momentos de esta actividad económica y cultural.

  14. Gruusia uus liider kardab riigipööret / Heiki Suurkask

    Index Scriptorium Estoniae

    Suurkask, Heiki, 1972-

    2003-01-01

    Gruusia sisepoliitilisest olukorrast. Autori sõnul ei tunnista Mikheil Saakashvili liidrirolli ei E. Shevardnadze pooldajad ega ka tema vastased. E. Shevardnadze süüdistab enda kukutamises USA-d. Vt. samas: Võimuvahetuse juhtkolmik

  15. Hemângio-retículo-endotelioma do pericárdio

    Directory of Open Access Journals (Sweden)

    Jônio F. de Salles

    1944-02-01

    Full Text Available The author presents a case of primitive hemangio-reticulo-endothelioma of the pericardium. The structure of the tumor is identical to that of cases reported as primitive of the heart, and similar to that of the hemorrhagic sarcoma of KAPOSI, without, however, the typical cutaneous lesion of the disease.

  16. Symptomatisk zinkmangel hos et brysternæret spædbarn

    DEFF Research Database (Denmark)

    Hvid, Lone; Zachariassen, Gitte; Honoré, Karina Dyrvig

    2018-01-01

    Nutrition containing zinc is of special practical importance in infants and children. Perinatal zinc deficiency manifestations include erosive dermatitis, alopecia, diarrhoea, central nervous system dysfunction and immune system deficiency. We present a case story of an ex-preterm, exclusively br...... breast-fed infant who presented with irritability, clinical signs of infection, an atypical rash and signs of oral candidiasis. Blood tests showed low plasma levels of zinc and subsequent analysis showed reduced zinc levels in the breast milk....

  17. Máquinas retóricas livres do documentário ciberativista

    Directory of Open Access Journals (Sweden)

    Bráulio de Britto Neves

    2010-08-01

    Full Text Available It’s been a decade since the publishing of pioneer documentaries ofthe cyberactivist movement. These documentaries represent a new turning point in documentary, because they prefigure new forms of documentary utterances, which aim the creation of horizontal relationships between enunciators, social actors andenunciatees. The poiesis of counterpublics that began in a fragmentary way, is now a deliberate purpose to the documentary-cyberactivist network.

  18. The rare intracellular RET mutation p.S891A in a Chinese Han ...

    Indian Academy of Sciences (India)

    2014-05-01

    May 1, 2014 ... Cancer (7th edition) TNM classification system (Edge and Compton 2010). Lymph-node status was defined according to the criteria of the American Thyroid Asso- ... age of five MTC patients was 41.2 years (range: 24–62.

  19. [Rets. rmt. : Glucksmann, Andre. Ouest contre Ouest. Pariis, 2003] / Malle Talvet

    Index Scriptorium Estoniae

    Talvet, Malle

    2004-01-01

    Prantsuse filosoofi Andre Glucksmanni raamat "Ouest contre Ouest" ehk "Lääs Lääne vastu" käsitleb rahvusvahelisi sündmusi 2002/2003, eelkõige Iraaki, terrorismi, Ameerika Ühendriike ja Prantsusmaad

  20. reté de fonctionnement d'architectures informatiques embarquées sur automobile

    OpenAIRE

    Ziegler , Christian

    1996-01-01

    The aim of the work presented in this dissertation is to guarantee that the increasing complexity of automotive embedded computer architectures does not degrade the dependability of the vehicle with respect to that of the vehicle containing classical mechanical equipment. The current tendency towards integration of the different embedded computer systems leads us to develop a spectrum of architectures allowing us to illustrate, classify and compare several possibilities between an entirely-fe...

  1. Når sex er en ret, hvem har så pligt?

    DEFF Research Database (Denmark)

    Munk-Madsen, Eva

    2007-01-01

    Socialministeriet har fastslået i en vejledning, at samfundet har omsorgspligt for funktionshæmmedes borgeres  seksuelle udfoldelsesmulighder. Tre grupper er udpeget som dem der skal varetage denne omsorgspligt på samfundets vegne: ansatte hjælpepersoner, seksualvejledere og prostituerede. I modt...

  2. Retórica como metódica para estudo do direito

    Directory of Open Access Journals (Sweden)

    João Maurício Adeodato

    2008-06-01

    Full Text Available Para as filosofias ontológicas,essencialistas, claramente dominantes na tradiçãoocidental e na filosofia do direito atual, a linguagemé mero instrumento, um meio para a descobertada verdade, que pode ser aparente, para umas,ou se esconder por trás das aparências, para outras,com todas as combinações e ecletismos. Ocomum é a idéia de que, com método, lógica, intuição,emoção e todo seu aparato cognoscitivo competentementeaplicado, é possível aos seres humanoschegar à verdade, assertiva que coagiriatodos a aceitá-la (“racionalidade”. No campo ético,a verdade equivale a correto, justo e outrosadjetivos laudat��rios. Este artigo defende a tesede que isso é uma ilusão altamente funcional e queos precários acordos da linguagem não são apenaso máximo de garantia possível, são a única. E aindaque seja temporária, autopoiética, circunstanciale freqüentemente rompida em suas promessas,é só o que se pode chamar de “racionalidade”.According to ontological, essentialistphilosophies, clearly prevailing in Westerntradition and in contemporary philosophy oflaw, language is a mere instrument to the discoveryof truth, which can be apparent to some, or tohide behind appearances, to others, with allcombinations and eclecticisms. The common ideais that with method, logic, intuition, emotion andall their knowledge apparatus, it is possible forhuman beings to find truth, statements whichwould compel everyone to acceptance(“rationality”. In what ethics is concerned, truthequals correctness, justice and other laudatoryadjectives. This paper defends the thesis thatthis is a highly functional illusion and that theprecarious agreements of language not onlyconstitute the maximum possible guarantees, theyare the only ones. Moreover, despite beingtemporary, autopoietic, circumstantial andfrequently disrespected, this is all that can becalled rationality.

  3. La retòrica i la lingüística, 1775-1900

    Directory of Open Access Journals (Sweden)

    Joan Solà

    2015-10-01

    Full Text Available It is a well known fact that school manuals' of the 18th and 19th centuries centred on the teaching of Rhetoric are closely linked with those geared towards the study of language in general and of Grammar in particular. The article, based on the work by Marcet-Solà, shows the relevance of this especial relationship and offers illustrative material from these manuals, restricted, like the work referred to, to the Catalan speaking area.

  4. Kairos. Træk af humanisme og posthumanisme i italiensk kultur (Politik, ret & samfund)

    DEFF Research Database (Denmark)

    Sørensen, Gert

    Humanisme, Posthumanisme, Italiensk kultur, Kairos, Dante, Machiavelli, Perniola (Mario), Agamben (Giorgio), Dobbeltstat......Humanisme, Posthumanisme, Italiensk kultur, Kairos, Dante, Machiavelli, Perniola (Mario), Agamben (Giorgio), Dobbeltstat...

  5. Sensor retínico espacio variante basado en tecnología CMOS

    OpenAIRE

    Pardo Carpio, Fernando

    1997-01-01

    La utilización de imágenes como entrada a un sistema de procesamiento es un tema de investigación que, desde hace tiempo, ha demostrado ser muy útil en múltiples aplicaciones que van desde la monitorización y control, a su utilización en sistemas de visión para robots. En la mayoría de las ocasiones se ha empleado una cámara convencional, de las utilizadas en consumo doméstico, para resolver los diferentes problemas de visión que se han ido planteando. Con la ampliación del mercado del pro...

  6. Le facteur humain et la sûreté de fonctionnement dans le ...

    African Journals Online (AJOL)

    Elle permettait d'optimiser le couple « performance-coût », en identifiant, évaluant et maîtrisant les pannes qu'il ... gestion des risques deviennent une ...... Etre en mesure de détecter les .... variés qui s'y déroulent, avoir le contrôle du.

  7. Retóricas del viaje a España, 1800-1900

    Directory of Open Access Journals (Sweden)

    Beatriz Colombi

    2014-06-01

    Full Text Available Partiendo de una reflexión crítica en torno a la literatura de viajes, se analizan los textos de Fray Servando, Sarmiento, Rubén Darío y Alfonso Reyes, para observar en ellos las relaciones que se establecen entre el viajero y, en este caso, España (expectativas, representaciones, descubrimientos.

  8. Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease.

    NARCIS (Netherlands)

    Frantzen, C.; Kruizinga, R.C.; Asselt, S.J. van; Zonnenberg, B.A.; Lenders, J.W.M.; Herder, W.W. de; Walenkamp, A.M.; Giles, R.H.; Hes, F.J.; Sluiter, W.J.; Pampus, M.G. van; Links, T.P.

    2012-01-01

    OBJECTIVE: We studied the reciprocal effect of pregnancy and von Hippel-Lindau (VHL) disease by analyzing the influence of pregnancy on VHL disease-related lesions and VHL disease on pregnancy outcome. METHODS: Medical charts and imaging reports from the VHL disease expertise centers in the

  9. Von Hippel-Lindau Disease

    Directory of Open Access Journals (Sweden)

    Hes Frederik J

    2005-11-01

    Full Text Available Abstract A germline mutation in the Von-Hippel Lindau (VHL gene predisposes carriers to development of abundantly vascularised tumours in the retina, cerebellum, spine, kidney, adrenal gland and pancreas. Most VHL patients die from the consequences of cerebellar haemangioblastoma or renal cell carcinoma. The VHL gene is a tumour suppressor gene and is involved in angiogenesis by regulation of the activity of hypoxia-inducible factor 1-α (HIF1-α. Clinical diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene, which is informative in virtually all VHL families. A patient with (suspicion for VHL is an indication for genetic counselling and periodical examination.

  10. A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in Renal Cell Carcinoma

    OpenAIRE

    Suwaki, Natsuko; Vanhecke, Elsa; Atkins, Katelyn M.; Graf, Manuela; Swabey, Katherine; Huang, Paul; Schraml, Peter; Moch, Holger; Cassidy, Amy; Brewer, Daniel; Al-Lazikani, Bissan; Workman, Paul; De-Bono, Johann; Kaye, Stan B.; Larkin, James

    2011-01-01

    Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. While VEGF and mTOR targeted therapies have shown clinical activity, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens to determine that Src kinase signaling is elevated in RCC cells that retain ...

  11. The allele frequency of two single nucleotide polymorphisms in the von Hippel-Lindau (VHL tumor suppressor gene in the Taiwanese population

    Directory of Open Access Journals (Sweden)

    Wen-Chung Wang

    2011-10-01

    Conclusion: We found that the G allele frequency at these two loci in the Taiwanese population is much lower than that in people from Western countries. This phenomenon may be attributed to ethnic effects.

  12. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

    Science.gov (United States)

    Dénes, Judit; Swords, Francesca; Rattenberry, Eleanor; Stals, Karen; Owens, Martina; Cranston, Treena; Xekouki, Paraskevi; Moran, Linda; Kumar, Ajith; Wassif, Christopher; Fersht, Naomi; Baldeweg, Stephanie E; Morris, Damian; Lightman, Stafford; Agha, Amar; Rees, Aled; Grieve, Joan; Powell, Michael; Boguszewski, Cesar Luiz; Dutta, Pinaki; Thakker, Rajesh V; Srirangalingam, Umasuthan; Thompson, Chris J; Druce, Maralyn; Higham, Claire; Davis, Julian; Eeles, Rosalind; Stevenson, Mark; O'Sullivan, Brendan; Taniere, Phillipe; Skordilis, Kassiani; Gabrovska, Plamena; Barlier, Anne; Webb, Susan M; Aulinas, Anna; Drake, William M; Bevan, John S; Preda, Cristina; Dalantaeva, Nadezhda; Ribeiro-Oliveira, Antônio; Garcia, Isabel Tena; Yordanova, Galina; Iotova, Violeta; Evanson, Jane; Grossman, Ashley B; Trouillas, Jacqueline; Ellard, Sian; Stratakis, Constantine A; Maher, Eamonn R; Roncaroli, Federico; Korbonits, Márta

    2015-03-01

    Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. The study was conducted at university hospitals. Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. Outcomes included genetic screening and clinical characteristics. Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

  13. Heterogeneous Genetic Background of the Association of Pheochromocytoma/Paraganglioma and Pituitary Adenoma: Results From a Large Patient Cohort

    Science.gov (United States)

    Dénes, Judit; Swords, Francesca; Rattenberry, Eleanor; Stals, Karen; Owens, Martina; Cranston, Treena; Xekouki, Paraskevi; Moran, Linda; Kumar, Ajith; Wassif, Christopher; Fersht, Naomi; Baldeweg, Stephanie E.; Morris, Damian; Lightman, Stafford; Agha, Amar; Rees, Aled; Grieve, Joan; Powell, Michael; Boguszewski, Cesar Luiz; Dutta, Pinaki; Thakker, Rajesh V.; Srirangalingam, Umasuthan; Thompson, Chris J.; Druce, Maralyn; Higham, Claire; Davis, Julian; Eeles, Rosalind; Stevenson, Mark; O'Sullivan, Brendan; Taniere, Phillipe; Skordilis, Kassiani; Gabrovska, Plamena; Barlier, Anne; Webb, Susan M.; Aulinas, Anna; Drake, William M.; Bevan, John S.; Preda, Cristina; Dalantaeva, Nadezhda; Ribeiro-Oliveira, Antônio; Garcia, Isabel Tena; Yordanova, Galina; Iotova, Violeta; Evanson, Jane; Grossman, Ashley B.; Trouillas, Jacqueline; Ellard, Sian; Stratakis, Constantine A.; Maher, Eamonn R.; Roncaroli, Federico

    2015-01-01

    Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. Setting: The study was conducted at university hospitals. Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. Outcome: Outcomes included genetic screening and clinical characteristics. Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma. PMID:25494863

  14. Bliv klogere på Mycoplasma bovis - Beslægtethed blandt de danske stammer: Afsløret

    DEFF Research Database (Denmark)

    Kokotovic, Branko

    Baggrund Bakterier tilhørende slægten Mycoplasma er årsag til forskellige sygdomme hos husdyr. De påvirker dyrenes velfærd samt fører til øgede produktionsomkostninger og betydelige økonomiske tab. I kvægbruget er en af de mest betydningsfulde mykoplasma på verdensplan Mycoplasma bovis, (M...

  15. Contradicciones del testimonio. Políticas de memoria y retóricas de la violencia en Chile postdictatorial

    OpenAIRE

    Peris Blanes, Jaume

    2008-01-01

    El artículo analiza la evolución de la función política y social de los testimonios y las intervenciones de los supervivientes, desde las primeras manifestaciones de denuncia de la dictadura de Pinochet hasta las políticas de memoria de la dictadura. Desde los primeros testimonios del exilio hasta la publicación del Informe sobre Torturas (2004) durante el gobierno de Ricardo Lagos, los testimonios de los supervivientes han cumplido funciones muy diferentes en la construcción de un sentido y ...

  16. Analysis of the RET, GDNF, EDN3, and EDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease

    NARCIS (Netherlands)

    Gath, R; Goessling, A; Keller, KM; Koletzko, S; Coerdt, W; Muntefering, H; Wirth, S; Hofstra, RMW; Mulligan, L; Eng, C; von Deimling, A

    Background-Hirschsprung disease (HSCR) is a frequent congenital disorder with an incidence of 1 in 5000 live births, characterised by the absence of parasympathetic intramural ganglion cells in the hindgut resulting in intestinal obstruction in neonates and severe constipation in infants and adults.

  17. Opfyldelsesværnetinget for løsørekøb i europæisk ret

    DEFF Research Database (Denmark)

    Steensgaard, Kasper

    2012-01-01

    Med indførelsen af Bruxelles I-forordningen skete der et afgørende skift i reguleringen og fortolkningen af opfyldelsesværneting i europæisk procesret. I køb af løsøre og tjenesteydelser skal stedet for opfyldelse i procesretlig henseende nu fastlægges efter en autonom EU-retlig regel. Efter en...... årrække med usikkerhed om, hvilken retsstilling den nye regel medførte, har EU-domstolen med afgørelsen i Car Trim v KeySafety Systems forsøgt at komme med en afklaring - det er imidlertid kun lykkedes delvist....

  18. Ciberlenguaje y principios de retórica clásica. Redes sociales: el caso Facebook

    OpenAIRE

    Inmaculada Berlanga; Estrella Martínez

    2010-01-01

    Las Tecnologías de la Información y la Comunicación (TICs) han propiciado cambios en las formas de comunicarnosy relacionarnos en la sociedad. Como concreción de esta nueva realidad destaca el espectacular auge alcanzadopor las redes sociales on line. El discurso oral se ve enriquecido con el lenguaje icónico y el audiovisual, privilegiadosen la cultura de hoy, por ello, esta investigación se pregunta si el discurso empleado en las redes sociales favorece elobjetivo planteado por estas plataf...

  19. Der er faresignaler her - om ret og heuristik i det almindelige, kommunale tilsyn med børn og unge

    DEFF Research Database (Denmark)

    Svendsen, Idamarie Leth

    2014-01-01

    KORT RESUME Kommunerne underlægges i stigende grad krav om at føre et aktivt og opsøgende tilsyn med børn og unge. Kravene fremgår af serviceloven med tilhørende forskrifter. Disse regler har sammenhæng med en række andre regler på det sociale og velfærdsretlige område i øvrigt, men også med forv...

  20. Fem sociale medier har »uindskrænket ret« til at misbruge alt dit indhold

    DEFF Research Database (Denmark)

    Nielsen, Jøren Ullits Olai

    2016-01-01

    Ved du, hvor meget kontrol du har over dit indhold på Facebook, YouTube, Snapchat, Instagram og Twitter? Her giver en juraforsker dig det forkromede overblik.......Ved du, hvor meget kontrol du har over dit indhold på Facebook, YouTube, Snapchat, Instagram og Twitter? Her giver en juraforsker dig det forkromede overblik....

  1. De la retórica a la realidad: la educación inclusiva en Sudáfrica

    Directory of Open Access Journals (Sweden)

    S. M. NAICKER

    1998-04-01

    Full Text Available Inclusion has different meanings in every context, because it depends on ideological, political social and economic circumstances where it develops.The South African context offers a singular case of inclusion because it is linked to tha challenge of education for all that means overcoming years of apartheid. After a short description of the past and the present of education in South Africa, this issue analyses the way in which it is possible to translate the rethoric of inclusion into reality, pointing out seven main considerations: 1 definition of inclusive education; 2 legitimacy of inclusive education; 3 possible implications for teaching practices: 4 possible implications for special schools; 5 teacher training; 6 pedagogical practices and 7 legislation

  2. Militærets betydning for demokratisering under det arabiske forar-tilfældene Tunesien, Egypten og Syrien

    DEFF Research Database (Denmark)

    Schmidt, Søren

    2013-01-01

    Popular uprising against authoritarian regimes is not enough to allow transition towards democracy to begin. The military has the final word on whether such an uprising will be successful or the uprising will be repressed in order to preserve the incumbent dictatorship. The military supported...

  3. Kommentarer til udvalgte skatteafgørelser - Rangfølgen mellem selskabsret, skatteret og EU-ret

    DEFF Research Database (Denmark)

    Werlauff, Erik

    2016-01-01

    for filialsammenlægningens skatteretlige virkningstidspunkt i Danmark. (6) Det gør ingen forskel for dette facit, om fusionsregnskabet følger årsregnskabsloven, IAS eller IFRS. Mellem årsregnskabsloven og selskabslovgivningen har sidstnævnte forrang. Mellem IAS/IFRS og selskabslovgivningen har førstnævnte forrang, men kun...

  4. Retórica Das Imagens Na Construção Do Discurso Anti-homofóbico

    Directory of Open Access Journals (Sweden)

    Daniel Mazzaro Vilar de Almeida

    2016-07-01

    Full Text Available Este trabalho consiste em analisar como o imaginário da tolerância é construído em imagens contidas em propagandas de prevenção à homofobia no Brasil e em outros países latino-americanos na contemporaneidade. O corpus é formado por propagandas veiculadas em redes sociais e o foco de nossa análise é o papel dos efeitos patêmicos na construção dos ethé de vítima. Para tanto, nos valemos das contribuições de Mendes (2010, 2012, 2013 sobre a análise integrada de imagens e de Wieviorka (2005 sobre a compreensão moderna da "vítima". Recorremos também a Butler (2010, segundo a qual a linguagem projeta feixes de realidade sobre o corpo social, marcando-o e moldando-o violentamente com base em um esquema heterossexual. Observamos, no corpus, a ocorrência de efeitos patêmicos ligados à empatia e ao medo [da violência], em uma escala que vai da repugnância ao terror. A finalidade de tais efeitos visados é justamente tentar sensibilizar os cidadãos para a causa do combate à homofobia. No que tange ao ethos, percebemos a projeção de uma imagem de si, inicialmente, como vítima, mas que se transforma em uma imagem de ator social capaz de lutar pelos seus direitos pelo fato de estar em uma propaganda de combate à homofobia.

  5. A Crítica ao Cinema Brasileiro Atual: a retórica das revistas Veja e Bravo!

    Directory of Open Access Journals (Sweden)

    GOMES, Regina

    2010-07-01

    Full Text Available The article presents the results of a rhetorical-comparative study of film reviews about Brazilian movies, published in magazines Veja and Bravo!, between the years 1997 and 2004. Although different institutions, the magazines used similar argumentative resources to convince the reader with aesthetic judgments predominantly positive of recent Brazilian cinema. However, Bravo! presented persuasive rhetoric more stronger that Veja magazine. The dialogue between rhetoric and journalistic criticism demarcated the discussion relating to the methods of interpretation and meaning construction in film reviews.

  6. Retórica hipertextual : para un modelo de análisis de la ficción interactiva

    OpenAIRE

    Mestre Pérez, Rosanna

    2007-01-01

    El artículo propone una metodología de análisis textual para las hiperficciones explorativas que sirva de instrumento didáctico de la literatura hipertextual en los niveles medio y superior. La propuesta contiene diez apartados (con descriptores, justificación y ejemplos en cada uno de ellos) y se fundamenta en dos premisas conceptuales: es imprescindible disponer de modelos de análisis que respondan a las características propias de la textualidad interactiva y trabajar con un modelo de enseñ...

  7. BEGJÆRET ETTER BERGETS DYP OG FJELLETS TINDER: OM SIDER VED DET DIKTERISKE FUNDAMENT HOS IBSEN OG HAMSUN

    Directory of Open Access Journals (Sweden)

    Even Arntzen

    2016-04-01

    Full Text Available Even though Knut Hamsun stubbornly denied it, all his life he had a strong and ambivalent interest for Henrik Ibsen. Quite well known are Hamsun's many attacks on Ibsen in articles and lectures, letters and novels. Less known is that there are several coinciding (intertextual motifs between Ibsen and Hamsun. In several of Ibsen's plays and poems the mountain motif is associated with poetic vocation and a descent and entry into an enclosed world of fantasy and imagination. The mountain motif is for sure attached to a form of penetration into a supernatural and demonic underworld, but also related to an upward and vertical movement, towards light, air and literary clarity. One finds strong traces of this double Ibsenian movement also in Hamsun's authorship, for example in the novels Pan and In Wonderland. But Hamsun seems to exceed Ibsen: in Hamsun's literary universe, the mountain motif is also linked to a revitalized dream of happiness, joy and an existential demand of exceeding oneself in the direction of a more authentic way of being human in the modern world.

  8. 17 børns syn på skolen i skoleåret 2016-2017

    DEFF Research Database (Denmark)

    Broström, Stig

    , at pigerne er målrettede og opgaveorienterede, mens drengene er larmende og vil være hurtigt færdige. Men når de har givet det generaliserende svar, tager de sig selv i det og reflekterer over, at det faktisk kommer an på personen. De hæver sig altså op over det stereotype billede af drenge og piger«. »Jeg...... konflikter. Pigerne går mere i detaljer og diskuterer for eksempel farven på opgavens omslag. Det, synes drengene, er latterligt«. Det ligner, at de fleste elever giver udtryk for en meget traditionel opfattelse af, at drengene larmer, og pigerne arbejder hårdere? »Ja, det kan man godt sige. Men drengene er...... har brug for mere kropslig aktivitet. Det siger noget om, at reformen kalder på mere bevægelse. Men det er ikke rigtig lykkedes«. Hvad er status på reformen blandt eleverne? »Generelt er alle glade for at gå i skole. De synes, det er dejligt at lære noget. Men det bliver rigtig spændende at gå i skole...

  9. Risøs virksomhedsregnskab 2001. Opfølgning på planerne for året 2001

    DEFF Research Database (Denmark)

    2002-01-01

    Risøs Virksomhedsregnskab 2001 er en opfølgning på planerne for Risøs virksomhed i 2001. Risøs bestyrelse skal som led i resultatkontrakten med Ministeriet for Videnskab, Teknologi og Udvikling aflægge årlige rapporter om opfyldelsen af de fastlagteresultatkrav. Nærværende rapport indeholder data...

  10. Risøs virksomhedsregnskab 2000. Opfølgning på planerne for året 2000

    DEFF Research Database (Denmark)

    Rosendahl, L.; Aabling-Thomsen, E.; Kjems, J.K.(eds.)

    2001-01-01

    Risøs Virksomhedsregnskab 2000 er en opfølgning på planerne for Risøs virksomhed i 2000. Risøs bestyrelse skal som led i resultatkontrakten med IT- og Forskningsministeriet aflægge årlige rapporter om opfyldelsen af de fastlagte resultatkrav. Nærværenderapport indeholder data til brug for denne v...

  11. El control social del gasto público en Brasil : Eficacia o retórica Mere?

    Directory of Open Access Journals (Sweden)

    Ana Paula Parra Leite

    2016-05-01

    Full Text Available El sistema de control del gasto público y la vigilancia moderna también comprende el control social. Por lo tanto, este estudio versa sobre el control social de Brasil, para en- tender si es un simple programa de acción o ya se muestra como una herramienta impor- tante de eficiencia, moralidad y coherencia en la aplicación de los fondos públicos. Por lo tanto, se utilizó como marco teórico la Teoría de “Los Costes de los Derechos” y el enfo- que fue adoptado el método deductivo, buscando a través de la investigación (teorética, identificar el aparato legal nacional sobre el tema (la ley y la doctrina, principalmente y diferenciar los tres tipos de control del Estado, a saber, el control interno, control externo y el control social. Al final, señala las principales conclusiones sobre el estado actual de la técnica de esta última modalidad en Brasil y si ya tiene algún resultado que implica cam- bios positivos en el comportamiento administrador nacional hacia la eficiencia esperada.

  12. Collected Papers 1955-1970, M. D. Parrish, M.D. Colonel Medical Corps US Army (RET),

    Science.gov (United States)

    1981-01-01

    hemseyves units are divided among the social worker, the psychol- than the game of extruding patients from the roup ogist and the technicians, each mental...they return for a midnight snack with their wives on Guam. Now aircrews function more expertly if the crew is ktept intact when it’s moved to new

  13. Pheochromocytoma-paraganglioma: Biochemical and genetic diagnosis.

    Science.gov (United States)

    Cano Megías, Marta; Rodriguez Puyol, Diego; Fernández Rodríguez, Loreto; Sención Martinez, Gloria Lisette; Martínez Miguel, Patricia

    Pheochromocytomas and paragangliomas are tumours derived from neural crest cells, which can be diagnosed by biochemical measurement of metanephrine and methoxytyramine. Advances in genetic research have identified many genes involved in the pathogenesis of these tumours, suggesting that up to 35-45% may have an underlying germline mutation. These genes have a singular transcriptional signature and can be grouped into 2 clusters (or groups): cluster 1 (VHL and SHDx), involved in angiogenesis and hypoxia pathways; and cluster 2 (MEN2 and NF1), linked to the kinase signalling pathway. In turn, these genes are associated with a characteristic biochemical phenotype (noradrenergic and adrenergic), and clinical features (location, biological behaviour, age of presentation, etc.) in a large number of cases. Early diagnosis of these tumours, accompanied by a correct genetic diagnosis, should eventually become a priority to enable better treatment, early detection of complications, proper screening of family members and related tumours, as well as an improvement in the overall prognosis of these patients. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  14. Clinical and Genetic Aspects of Sporadic Non-Medullar Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    U Rumjanzeva

    2006-03-01

    Full Text Available The role of somatic mutations in sporadic thyroid cancer is unclear today. Probably they coming out as aetiological factors in carcinogenesis as well as, respectfully to many authors, can to participate in TC pathogenesis and to determine the clinical course and prognosis of the disease. For today as main oncogenes taking part in initiation of thyroid malignant tumors are considered: RET/PTC, TRK, PTEN, P53, RAS, MET, PPARγ. By means of genetic investigations scientists are trying to solve problems with thyroid cancer differentiated diagnostics (cytokeratin-19, cytokeratin-20, mesothelial cells antigen (Hector Battifora MEsotelial (cell or HBME-1, loss of heterozigitoty (LOH in short arm of 3 chromosome (gene VHL -von Hippel Lindau, 3р26. Recently in foreign literature appeared reports of activated mutations in gene BRAF which most frequently are occurred in melanoma and papillary TC. Prognosis of thyroid cancer may reflected by the LOH as a biological breakage as well as changes of tumor suppressive gene P53 which fraught with decrease of disease prognosis. Thus, both researchers and clinicians have many questions concerning the role of genome, particularly in order to precise of genetic abnormality influence on tumor growth and therefore for assessment of clinical prognosis and with aim to chose adequate treatment tactic in each case.

  15. Isoform-specific interactions of the von Hippel-Lindau tumor suppressor protein

    OpenAIRE

    Minervini, Giovanni; Mazzotta, Gabriella M.; Masiero, Alessandro; Sartori, Elena; Corr?, Samantha; Potenza, Emilio; Costa, Rodolfo; Tosatto, Silvio C. E.

    2015-01-01

    Deregulation of the von Hippel-Lindau tumor suppressor protein (pVHL) is considered one of the main causes for malignant renal clear-cell carcinoma (ccRCC) insurgence. In human, pVHL exists in two isoforms, pVHL19 and pVHL30 respectively, displaying comparable tumor suppressor abilities. Mutations of the p53 tumor suppressor gene have been also correlated with ccRCC insurgence and ineffectiveness of treatment. A recent proteomic analysis linked full length pVHL30 with p53 pathway regulation t...

  16. [Genetic analysis of a family with Von Hippel-Lindau syndrome].

    Science.gov (United States)

    Lafuente-Sanchis, Aránzazu; Cuevas, José M; Alemany, Pilar; Cremades, Antonio; Zúñiga, Ángel

    Von Hippel-Lindau syndrome (VHL) is an autosomal dominant inherited disease associated with mutations in the VHL tumour suppressor gene located on chromosome 3p25. VHL is characterized by the development of multiple malignant and benign tumours in the central nervous system and internal organs, including liver, pancreas and the adrenal gland. More than 823 different mutations of the VHL gene have currently been identified. In the present study we describe the case of a family affected by VHL treated at the University Hospital of La Ribera and the results of the genetic analysis of three relatives, identifying the mutation R167G in exon 3 of VHL gene as the cause of VHL syndrome in this family. Copyright © 2016 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. The in vitro and in vivo effects of re-expressing methylated von Hippel-Lindau tumor suppressor gene in clear cell renal carcinoma with 5-aza-2'-deoxycytidine.

    Science.gov (United States)

    Alleman, Wade G; Tabios, Ray L; Chandramouli, Gadisetti V R; Aprelikova, Olga N; Torres-Cabala, Carlos; Mendoza, Arnulfo; Rogers, Craig; Rodgers, Craig; Sopko, Nikolai A; Linehan, W Marston; Vasselli, James R

    2004-10-15

    Clear cell renal carcinoma (ccRCC) is strongly associated with loss of the von Hippel-Lindau (VHL) tumor suppressor gene. The VHL gene is functionally lost through hypermethylation in up to 19% of sporadic ccRCC cases. We theorized that re-expressing VHL silenced by methylation in ccRCC cells, using a hypo-methylating agent, may be an approach to treatment in patients with this type of cancer. We test the ability of two hypo-methylating agents to re-express VHL in cell culture and in mice bearing human ccRCC and evaluate the effects of re-expressed VHL in these models. Real-time reverse transcription-PCR was used to evaluate the ability of zebularine and 5-aza-2'-deoxycytidine (5-aza-dCyd) to re-express VHL in four ccRCC cell lines with documented VHL gene silencing through hypermethylation. We evaluated if the VHL re-expressed after hypo-methylating agent treatment could recreate similar phenotypic changes in ccRCC cells observed when the VHL gene is re-expressed via transfection in cell culture and in a xenograft mouse model. Finally we evaluate global gene expression changes occurring in our cells, using microarray analysis. 5-Aza-dCyd was able to re-express VHL in our cell lines both in culture and in xenografted murine tumors. Well described phenotypic changes of VHL expression including decreased invasiveness into Matrigel, and decreased vascular endothelial growth factor and glucose transporter-1 expression were observed in the treated lines. VHL methylated ccRCC xenografted tumors were significantly reduced in size in mice treated with 5-aza-dCyd. Mice bearing nonmethylated but VHL-mutated tumors showed no tumor shrinkage with 5-aza-dCyd treatment. Hypo-methylating agents may be useful in the treatment of patients having ccRCC tumors consisting of cells with methylated VHL.

  18. Feocromocitoma-paraganglioma: del diagnóstico bioquímico al genético

    Directory of Open Access Journals (Sweden)

    Marta Cano Megías

    2016-09-01

    Full Text Available Los feocromocitomas y paragangliomas son tumores derivados de células de la cresta neural, que pueden ser diagnosticados mediante la determinación bioquímica de metanefrinas y metoxitiramina. Los avances en la investigación genética han permitido identificar múltiples genes implicados en la fisiopatogenia de estos tumores, de forma que hasta el 35-45% podrían tener una mutación germinal subyacente. Estos genes tienen una firma biológica de transcripción característica y se pueden agrupar en 2 grandes grupos (o clusters, el grupo 1 (VHL y SHDx, con implicación de la vía de la angiogénesis e hipoxia; y el grupo 2 (MEN2 y NF1, implicados en la vía de señalización de la cinasa. A su vez estos genes se asocian a un fenotipo bioquímico (adrenérgicos y noradrenérgicos, y presentación clínica (localización, comportamiento biológico, edad de presentación… característicos en un número elevado de casos. Un diagnóstico precoz de estos tumores, acompañado de un correcto diagnóstico genético, debe ser una prioridad que permita un mejor tratamiento, la detección precoz de complicaciones, un correcto screening de familiares y de otros tumores relacionados, así como una mejoría en el pronóstico global de estos pacientes.

  19. [Rets. rmt. : Stefan Halper, Jonathan Clarke. America Alone : The Neo-Conservatives and the Global Order. Cambridge 2004] / Maria Mälksoo

    Index Scriptorium Estoniae

    Mälksoo, Maria, 1979-

    2005-01-01

    Traditsiooniliste konservatiivide S. Halperi ja J. Clarki raamat harutab lahti neokonservatiivse ilmavaate, selle liikumise kujunemise ja mõjuvõimu laienemise ning näitavad, kuidas uuskonservatiivid võtsid võimu USA Riigidepartemangus ja Pentagonis

  20. Da ordet blev til handling. Maj 1968-Maj 2018 - 50 år med kritik. Refleksioner i anledning af 50- året for 1968

    DEFF Research Database (Denmark)

    Duelund, Peter

    Hvis vi definerer kulturpolitik bredt, som de idehistoriske, værdipolitiske og institutionelle kampe om produktion og distribution af symbolsk mening i samfundet et det muligt at anskue de mange forskellige, men sammenhængende kulturelle, politiske og kunstneriske begivenheder og initiativer i 19...

  1. Expresión de oncogén RET/PTC en tiroiditis de hashimoto y microcarcinomas papilares tiroideos mediante estudio inmunohistoquímico

    OpenAIRE

    Pareja Megía, María Jesús

    2001-01-01

    El desarrollo de neoplasias malignas en pacientes afectados por tiroiditis de Hashimoto es un importante problema clínico-terapéutico del que todavía se desconocen algunos aspectos etiopatogénicos. Los enfermos generalmente tienen un buen pronóstico, pero en ocasiones pueden desarrollar hipotiroidismo. Además, estos pacientes tienen un mayor riesgo para desarrollar neoplasias malignas como linfomas y carcinomas. La alta incidencia de carcinoma papilar en la tiroiditis de Hashimoto hace consid...

  2. Metáfora, sinestesia y otras figuras retóricas en El perfume. Historia de un asesino, de P. Süskind

    OpenAIRE

    Gaspar Verdú, Victoria

    2007-01-01

    This article questions the author’s intention in the so frequent use of metaphors and other rhetorical figures in Perfume. History of a Murderer. This novel is a landmark in the German narrative of the XXth Century, due to the originality in the plot and to the great load of poetic images. Along with hyperbole, litotes, parallelism, personification, metonymy, comparison, polysindeton, and other figures, we will observe that it emphasizes metaphor, particularly literary synaesth...

  3. Utforming og gjennomføring av norsk humanitær hjelp etter opprøret i Ungarn, 1956-1957

    OpenAIRE

    Olsen, Heidi Cecilie Vekony

    2016-01-01

    Denne masteroppgaven tar for seg Norges humanitære hjelp under Ungarnkrisen fra 1956 til 1957. Revolusjonen og den påfølgende flyktningkrisen ga opphav til en akutt nødsituasjon sentralt i Europa. Oppgaven beskriver hvordan norske myndigheter og norske hjelpeorganisasjoner, med fokus på Norges Røde Kors, planla og organiserte hjelpearbeidet, både i nærområdene og etter hvert også i Norge. Oppgaven argumenterer for at norske myndigheters reaksjon på Ungarnkrisen var et tidlig uttrykk for den f...

  4. Respostas a uma crítica marxista às perspectivas retórica e pragmática em economia

    Directory of Open Access Journals (Sweden)

    Danilo Araújo Fernandes

    2008-03-01

    Full Text Available Answers to a marxist critic of the rhetorical and pragmatic perspectives in economics. Based on recent discussions regarding the rhetorical perspective in economics, this paper presents an interpretation of the philosophical approach of Habermas which attempts to rescue the so called 'modern spirit', forgotten in the annals of the 19th century, similar to that presented by Marshall Berman in 1982. Following the reconstructive approach of Habermas's project of modernity, we attempt to show how a 'rhetorical approach' could be applied in the field of economics, and yet still be clearly modern by taking into account intersubjectivities, given the expanded sphere of human communication (as defended in the theory of communicative action of Habermas. In this sense, we will seek to demonstrate the philosophical limits of the anti-rhetorical critiques of, for example, Paulani (1996, 2003, 2005, 2006, which seem to underestimate the linguistic and intersubjective aspect of Habermas's philosophical project that can also be found in McCloskey’s methodological approach.

  5. Ecoturismo en la reserva Cuyabeno : realidad y retórica en la relación de los Siona con el turismo ecológico 1994

    OpenAIRE

    Arrueta, José Antonio

    1996-01-01

    El Turismo es una actividad que consiste básicamente en visitar lugares en donde buscamos satisfacer demandas relacionadas a información, diversión, conocimiento y placer. El turismo ecológico implica reglamentos de conducta de los visitantes, en relación a la preservación y conservación de los sitios naturales a silvestres que se visita. Incluye la participación de las poblaciones locales de los sitos de reserva como “beneficiarias” del ecoturismo. Estos "principios generales" del turismo ec...

  6. Risøs årsrapport 2004. Opfølgning på planerne for året 2004

    DEFF Research Database (Denmark)

    2005-01-01

    Risøs årsrapport 2004 er en opfølgning på planerne for Risøs virksomhed i 2003. Risøs bestyrelse skal som led i resultatkontrakten med Ministeriet for Videnskab, Teknologi og Udvikling aflægge årlige rapporter om opfyldelsen af de fastlagte resultatkrav.Nærværende rapport indeholder data til brug...

  7. Tecnología y marketing: el papel de la retórica comercial en el desarrollo de dispositivos de navegación

    OpenAIRE

    Mendonça, Pedro

    2012-01-01

    The present article aims to link technology and marketing in the process of imagination and concretization of functions for mobile navigation devices. It focuses on the performance of marketing and sales, as rhetorical agents, in the technical path of building the product. Empirically, it is a case study of a Portuguese company, NDrive, whose main innovation is the introduction of photographic images in these devices replacing traditional maps. Since we identify in the field of innovation a p...

  8. Sistemas de retículas: un método para diseñar nuevos conceptos de producto hacia el usuario

    Directory of Open Access Journals (Sweden)

    Eduardo Manchado-Pérez

    2013-01-01

    al diseño de producto puede resultar útil porque se orienta más a la generación de conceptos que al análisis de información, y es de aplicación más sencilla que la IK, aunque menos precisa. Mediante esta técnica se han definido las características estéticas y técnicas de un concepto innovador de motocicleta ecológica tipo Harley-Davidson.

  9. As mensagens estratégicas das "melhores e maiores" : a retórica das organizações na WEB

    OpenAIRE

    Borges, Jacquelaine Florindo

    2005-01-01

    O uso da Internet é crescente, desde os anos 90, como meio pelo qual empresas, governos e instituições diversas vêm se comunicando. A comunicação, também, tornou-se elemento estratégico para as organizações que, num contexto globalizado e interconectado, têm mais visibilidade perante diferentes públicos e sua legitimidade passa a ser avaliada pela capacidade de responder às necessidades, interesses, valores, desejos e sonhos desses públicos. As mudanças no contexto dos negócios decorrentes...

  10. La retórica bajo el barniz de la lógica : Samuel Ramos y su discurso sobre la inferioridad mexicana

    NARCIS (Netherlands)

    Houvenaghel, E.M.H.

    2014-01-01

    Samuel Ramos reflects on the essence of the Mexican people in the philosophical essay El perfil del hombre y la cultura en M´exico (1934). He emphasizes the sentiment of inferiority and the desire to hide this inferiority by camouflage strategies as a distinctive characteristic of the Mexican. This

  11. La prosa de Cervantes y el modo retórico: un caso práctico en El Quijote (I, L-LI)

    OpenAIRE

    Ramón Palerm, Vicente

    2011-01-01

    7 p. En el artículo se analiza el sabroso episodio que corona la discusión entre el canónigo y Don Quijote, donde el caballero defiende la lectura de los libros de caballeria. Así las cosas, irrumpe en la trama la presencia de un cabrero quien introduce el tópico de la misoginia, que sirve de inventio a la acción y va a justificar la atractiva historia que el cabrero referirá ante sus oyentes

  12. O uso de técnicas vocais como recursos retóricos na construção do discurso

    Directory of Open Access Journals (Sweden)

    Maria Ignez de Lima PEDROSO

    2008-12-01

    Full Text Available As técnicas vocais são um conjunto de procedimentos facilitadores da voz que podem interferir na qualidade vocal dos sujeitos. O conhecimento atualizado, desses procedimentos, por meio de um estudo linguístico-discursivo é imprescindível para a atuação em Fonoaudiologia Estética, que pode abranger em seus trabalhos a oratória. Esses fatores motivaram-me, primeiramente, a fazer um levantamento bibliográfico sobre as técnicas vocais para os diversos profissionais da voz falada e cantada, estudo que possibilitou a organização de uma coletânea das principais técnicas pesquisadas. Tomando essa pesquisa como ponto de partida, neste trabalho, minha proposta é apresentar uma reflexão e discussão focadas no uso das técnicas relacionadas, principalmente, à ação harmônica da conduta fonatória, que estão fundamentadas nos seguintes aspectos: relaxamento, respiração, articulação, projeção, flexibilidade vocal. Nessa discussão, saliento a importância da voz e de vários componentes linguísticos da dinâmica vocal (frequência, intensidade, entonação, ritmo e velocidade de fala, entre outros elementos prosódicos que, nos processos dialógico-argumentativos da oratória, funcionam como recursos persuasivos e de veridicção na construção do discurso de diversos profissionais da voz falada, tais como advogados, professores, pastores, vendedores, locutores e repórteres, dentre outros.

  13. O uso de técnicas vocais como recursos retóricos na construção do discurso

    Directory of Open Access Journals (Sweden)

    Maria Ignez de Lima PEDROSO

    2013-10-01

    Full Text Available As técnicas vocais são um conjunto de procedimentos facilitadores da voz que podem interferir na qualidade vocal dos sujeitos. O conhecimento atualizado, desses procedimentos, por meio de um estudo linguístico-discursivo é imprescindível para a atuação em Fonoaudiologia Estética, que pode abranger em seus trabalhos a oratória. Esses fatores motivaram-me, primeiramente, a fazer um levantamento bibliográfico sobre as técnicas vocais para os diversos profissionais da voz falada e cantada, estudo que possibilitou a organização de uma coletânea das principais técnicas pesquisadas. Tomando essa pesquisa como ponto de partida, neste trabalho, minha proposta é apresentar uma reflexão e discussão focadas no uso das técnicas relacionadas, principalmente, à ação harmônica da conduta fonatória, que estão fundamentadas nos seguintes aspectos: relaxamento, respiração, articulação, projeção, flexibilidade vocal. Nessa discussão, saliento a importância da voz e de vários componentes linguísticos da dinâmica vocal (frequência, intensidade, entonação, ritmo e velocidade de fala, entre outros elementos prosódicos que, nos processos dialógico-argumentativos da oratória, funcionam como recursos persuasivos e de veridicção na construção do discurso de diversos profissionais da voz falada, tais como advogados, professores, pastores, vendedores, locutores e repórteres, dentre outros.

  14. Retóricas de la pandemia. Derivas y resistencias en torno al arte argentino frente a la crisis del sida

    Directory of Open Access Journals (Sweden)

    Francisco Lemus

    2015-06-01

    Full Text Available This paper investigates the political-discourse relations between Grupo de Acción Gay (1984-1985 and the aesthetic and curatorial model devised by Jorge Gumier Maier in the Gallery of Visual Arts of Centro Cultural Rojas (1989-1997 in order to reflect on gay subjectivity processes generated from the impact of AIDS in Buenos Aires and resistance strategies into the art scene of the nineties. From these ideas, this work analyzes a group of images produced by Marcelo Pombo between 1982 and 1989 that introduce some questions about the troubled socio-sexual identity of homosexuality and the rhetoric of elimination on the AIDS pandemic.

  15. Viragem Retórica, Viragem Pragmática E Superação Da Metafísica

    Directory of Open Access Journals (Sweden)

    Narbal Marsillac Fontes

    2014-10-01

    Full Text Available É bem conhecida a expressão contemporânea rhetorical turn de autoria de Richard Rorty. Tal viragem não poderia ser pensada sem a reviravolta pragmática que a precede. Da mesma forma que também não se poderia pensar a valorização da linguagem ordinária e efetivamente usada sem o primeiro giro linguístico. O resultado, em última instância, dessas abordagens, é que se deve privilegiar, segundo Carrilho, a elocução em detrimento da proposição. A proposta é acompanhar estas reflexões e como elas auxiliaram alguns pensadores contemporâneos no esforço de superar a metafísica.

  16. A human model for multigenic inheritance : Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus

    NARCIS (Netherlands)

    Bolk, S; Pelet, A; Hofstra, RMW; Angrist, M; Salomon, R; Croaker, D; Buys, CHCM; Lyonnet, S; Chakravarti, A

    2000-01-01

    Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with approximate to 50% of familial cases being heterozygous for mutations in the receptor tyrosine

  17. El Retículo Endoplasmático Liso en Hepatocitos Estimulados con Distintas Dosis de Láser Infrarrojo

    OpenAIRE

    Cornejo, R; Garrido, O; Bustamante, C; Muñoz, M

    2014-01-01

    Veinticuatro ratas hembras Sprague Dawley de 4 meses de vida con peso aproximado de 250 g, fueron divididas en cuatro grupos (A, B, C y D), donde el grupo A (control) no recibió estimulación infrarroja, B se irradió con láser infrarrojo 4 J/cm², C con dosis de 8 J/cm² y D con 16 J/cm². La estimulación infrarroja se realizó diariamente, por 15 días ininterrumpidos. Las ratas fueron sacrificadas y se extrajeron muestras tanto de hígado normal (control) como estimulado con las distintas dosis in...

  18. La igualdad: entre la retórica republicana y la distinción racial. Cartagena de Indias 1810-1830

    Directory of Open Access Journals (Sweden)

    Edwin Monsalvo Mendoza

    2010-01-01

    Full Text Available Este artículo muestra la manera como la sociedad cartagenera aceptó y adecuó la idea de igualdad a su contexto local. Las condiciones demográficas de esta ciudad en donde predominaban las “castas de color” (negros, mulatos, zambos y pardos y la importancia política-militar que estos habían cobrado desde finales del siglo XVIII con su incorporación en las milicias, y especialmente con los sucesos de la independencia, trazaron el derrotero que desarrolló la igualdad política y socio-racial en esta ciudad colombiana.

  19. Retórica de la memoria, embotamiento de la atención, lejanía de la persuasión

    Directory of Open Access Journals (Sweden)

    Claudio Martyniuk

    2012-07-01

    Full Text Available This essay ―that form and also methodology definition― part of the problem of indifference and their tissue of senses, referring to the dis-appearance of people in Argentina. After submitting to the culture of human rights, the prosecution and concentration of efforts in the pun-ishment of those responsible for massacres, and the phenomena of crystallization of the memory of a past of extermination, the essay focuses on the problems of the attention and persuasion, in the critique of reification and dullness, bureaucratization of memory and the impoverishment of experience and theory, the soil acts of cruelty and continuity of exclusions and annihilations. The culture of memory, whose prism is the past, can stay away from extermination and impositions of this humiliation, new victims and the persistent indifference. Attention and persuasion, then, what can nominate and exceed beyond rhetoric manifested in ethics and politics of memory.

  20. Juristas y Teólogos en el Siglo XIV Ibérico: La retórica del antisemitismo

    Directory of Open Access Journals (Sweden)

    Andrea Gayoso

    2014-02-01

    Full Text Available Este artículo trata de la introducción de las distintas teorías filosóficas y teológicas producidas en las universidades europeas de los siglos XIII y XIV en la Península Ibérica, y de cómo ellas afectaron y contribuyeron a transformar las relaciones multiculturales que caracterizaban la vida social, intelectual y legal hispánica hasta mediados del siglo XIV. Más específicamente, mi propósito es tratar aquí la influencia de la introducción del escotismo en este contexto, el cual los historiadores han denominado Convivencia.

  1. La inserción del discurso nacionalista en la retórica del gobierno mexicano (1939-1948 y 1983-2002)

    OpenAIRE

    Gómez Villanueva, Beatriz

    2017-01-01

    La construcción de las representaciones que se han desarrollado en México para asumir una identidad nacional ha referido el concurso de factores diversos. En los albores del siglo XX, tras la Revolución Mexicana que inició en 1910, los grupos políticos beneficiados por el movimiento armado asumieron el poder gubernamental, y su discurso se convirtió en uno de los principales referentes que caracterizaron un concepto de nacionalismo que intentó integrar a una sociedad heterogénea y desarticula...

  2. La preceptiva historiográfica renacentista y la retórica de los discursos: antología de textos

    Directory of Open Access Journals (Sweden)

    Pineda, Victoria

    2007-10-01

    Full Text Available The debate over historians’ use of speeches in their narratives engagednumerous scholars and historiographers during the Early Modern period all across Europe.Some of them viewed the inclusion of speeches as a sign of the greatness of historyinsomuch as the speeches linked historical writing to oratory and rhetoric. On the otherhand, there were others who mistrusted the speeches for they revealed how apart history andtruth were. In this anthology I include chapters or passages of almost thirty artes historicaedealing with the subject. Brief commentaries on the texts are added. Texts range from thelate Cinquecento to the first waves of the Enlightenment.

  3. Alvorlige personskader ved færdselsuheld med indregistrerede motorkøretøjer blandt indbyggere i Odense Kommune 1990-1999

    DEFF Research Database (Denmark)

    Faergemann, Christian; Larsen, Lars Binderup

    2002-01-01

    INTRODUCTION: Since 1990, the number of persons treated at the Odense University Hospital for injuries following road traffic with registered motor vehicles has increased. In this study we wanted to examine if the increase included an increase in more severe injuries. MATERIAL AND METHODS...... of accidents (55 per ent). 66 per cent of the persons were hospitalised and 24 per cent died as a result of their injuries. Injuries localised at the head and neck were most frequent (29 per cent) followed by injuries localised at legs and arms (18 per cent and 23 per cent). DISCUSSION: The incidence of more...

  4. Ação afirmativa na Índia e no Brasil: um estudo sobre a retórica acadêmica

    OpenAIRE

    Feres Jr., João; Daflon, Verônica Toste

    2015-01-01

    Políticas de ação afirmativa têm sido aplicadas para resolver problemas sociais e políticos derivados da persistência de padrões sociais de desigualdade e discriminação em diversos países. Embora sejam comumente associadas aos Estados Unidos, as ações afirmativas foram aplicadas pioneiramente pela Índia, durante a década de 1950, quando a Constituição estabeleceu cotas nas legislaturas, no emprego público e no ensino superior para as Scheduled Castes eScheduled Tribes. O Brasil, por sua vez, ...

  5. Medarbejderes integritetsbeskyttelse i dansk ret - med særlig fokus på databeskyttelse, kontrol og overvågning i den private sektor

    DEFF Research Database (Denmark)

    Lind, Martin Gräs

    Bogen beskriver de juridiske regler for arbejdslivets møde med den privates sfære, herunder reglerne for databeskyttelse, kontrol og overvågning, integritetsbeskyttelse, e-mail og internet på arbejdspladsen, straffeattester, referencecheck, Privatansattes ytringsfrihed, alkohol og rygning...

  6. De la conception à la sûreté des barrages de correction torrentielle From design to safety and reliability assessment of torrent control dams

    Directory of Open Access Journals (Sweden)

    Jean-Marc Tacnet et Didier Richard

    2010-09-01

    Full Text Available Dans les bassins versants de montagne, les phénomènes torrentiels, de par leur caractère brutal et très rapide, présentent des risques importants pour les biens, les personnes et l'environnement. Afin de réduire ces risques, des mesures structurelles ont été mises en place, comme la construction de barrages de correction torrentielle. Mais comment caractériser l'état et l'efficacité de ces ouvrages ? Assurent-ils un niveau de sécurité suffisant ? Les auteurs s'intéressent ici aux principes de conception et à l'analyse des pathologies et défaillances de ce type d'ouvrages.To reduce risk level in mountain rivers floods prone areas, structural defence works are still mandatory. The global efficiency of those protection strategies depends on both functional and structural approaches. This article first presents main types and functions of torrent control dams. Afterwards, it describes the design and building requirements with references to the main failure situations that could be encountered. This technical background is finally identified as a basis for danger and risk analysis that are going to become mandatory for some categories of torrent control dams.

  7. La argumentación retórica como base interpretativa de la inducción aristotélica

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    Juan Andrés Mercado

    2013-11-01

    Full Text Available The passages in Aristotle's Rhetoric where induction (epagogé is discussed show it as a very useful kind of argumentation, somehow related to example (paradeígma. This latter is based on the perception of some kind of similarities among the things compared. The characteristics attributed by Aristotle to these forms of argument allow us to propose a framework in which the notion of epagogé can be unified, despite the fact that some parts of Aristotle's works may suggest to understand its different meanings in terms of opposition.

  8. La defensa de las emociones: Gorgias y la producción retórica de páthe en el Encomio de Helena

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    Emiliano J. Buis

    2016-10-01

    Full Text Available On the basis of a comparison with the rhetorical presentation of pathe as means of persuasion in Aristotle’s Rhetoric, this paper intends to shed light on the importance of the construction of emotional effects in the Encomium of Helen. The purpose is to show the way in which Gorgias manages to resort to an efficient argumentative use of affections (and their manipulation in the judicial arena even before the theoretical attempt by Aristotle.

  9. De la palabra-acción a la palabra-imitación: itinerario retórico de Cicerón

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    Carlos Lévy

    2012-12-01

    Full Text Available This paper aims to show how Cicero's consideration of eloquence as imitation was a late decision in his life caused by the circumstances. The expression "Ciceronian challenge" refers here to the conversion from a rhetoric based on the concept of force to a rhetoric where the concept of imitation has gained greater importance. Although during the early years of his career as orator, Cicero favored the representation of the spoken word as illocutionary and perlocutionary force -as in Austin's terms -, towards the end of his life he took a more abstract position in which the concept of imitation finally prevailed as a key word in his rhetoric.

  10. La retórica aristotélica y la oratoria de su tiempo (sobre el ejemplo de Lisias III

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    Francisco Cortés Gabaudan

    1998-12-01

    Full Text Available Aristotle's Rhetoric is a descriptive text to a greater extent than normally recognised and so our understanding of Aristotle can be improved with the analysis of speeches previous to him; as a case study, the third speech of Lysias has been chosen. The argumentation of judicial speeches previous to Aristotle was built with enthymemes whose first premises are based on emotions and characters explaining human behaviour; therefore the first purpose of Rhetoric 11.2-11 (about emotions and 11.2-17 (about characters was to supply the orators with first premises. In those speeches the emotions of the audience were stirred up by enthymemes; therefore Aristotle accepted that the orator could use emotions in this rational and logic way. Nevertheless he condemned the arousing of emotions by direct and irrational requests, a procedure found in the judicial speeches. This way the apparent contradictory treatment of emotions in Aristotle's Rhetoric can be solved.

  11. Retórica de la cuantificación: tuberculosis, estadística y mundo laboral en Colombia, 1916-1946

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    Victoria Estrada Orrego

    Full Text Available Resumen Este artículo examina los usos de estadísticas de tuberculosis en discursos médicos colombianos, la distancia entre éstos y las cifras publicadas oficialmente, así como la relación de la dinámica de lo cuantitativo con la campaña antituberculosa y con la objetivación de la tuberculosis en el mundo laboral en Colombia, en el periodo que va desde el inicio de la campaña (1916 al momento en que la tuberculosis entra en la lista de las enfermedades profesionales (1946. Analiza también la función crítica que las estadísticas laborales tuvieron en las primeras formulaciones del sistema de seguridad social colombiano y en la delimitación de las enfermedades profesionales. Estos procesos históricos se estudiaron según su inserción en el contexto internacional.

  12. Koncernbegreber i regnskabs- og selskabsretten - et studium i koncernbegrebers tilblivelse og indhold med baggrund i samspillet mellem internationale regnskabsstandarder, EU-retten og national ret

    DEFF Research Database (Denmark)

    Sørensen, Anne Birgitte Søgaard

    Siden 2005 har europæiske børsnoterede selskaber skullet aflægge koncernregnskaber efter IASB-organisationens regnskabsstandarder, og siden 2009-reformerne af henholdsvis årsregnskabsloven og selskabsloven har disse loves koncernbegreber skullet fortolkes i overensstemmelse hermed. Dette rejser en...

  13. Pathology of the Nervous System in Von Hippel-Lindau Disease

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    Alexander O. Vortmeyer

    2015-06-01

    Full Text Available Von Hippel-Lindau (VHL disease is a tumor syndrome that frequently involves the central nervous system (CNS. It is caused by germline mutation of the VHL gene. Subsequent VHL inactivation in selected cells is followed by numerous well-characterized molecular consequences, in particular, activation and stabilization of hypoxia-inducible factors HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis remains poorly understood. Hemangioblastomas are the most common manifestation in the CNS; however, CNS invasion by VHL disease-associated endolymphatic sac tumors or metastatic renal cancer also occur, and their differentiation from primary hemangioblastoma may be challenging. Finally, in this review, we present recent morphologic insights on the developmental concept of VHL tumorigenesis which is best explained by pathologic persistence of temporary embryonic progenitor cells. 

  14. Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials.

    Science.gov (United States)

    Suh, James H; Johnson, Adrienne; Albacker, Lee; Wang, Kai; Chmielecki, Juliann; Frampton, Garrett; Gay, Laurie; Elvin, Julia A; Vergilio, Jo-Anne; Ali, Siraj; Miller, Vincent A; Stephens, Philip J; Ross, Jeffrey S

    2016-06-01

    The National Comprehensive Cancer Network (NCCN) guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for EGFR, BRAF, ERBB2, and MET mutations; ALK, ROS1, and RET rearrangements; and MET amplification. We investigated the feasibility and utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) test, in clinical practice. CGP was performed to a mean coverage depth of 576× on 6,832 consecutive cases of NSCLC (2012-2015). Genomic alterations (GAs) (point mutations, small indels, copy number changes, and rearrangements) involving EGFR, ALK, BRAF, ERBB2, MET, ROS1, RET, and KRAS were recorded. We also evaluated lung adenocarcinoma (AD) cases without GAs, involving these eight genes. The median age of the patients was 64 years (range: 13-88 years) and 53% were female. Among the patients studied, 4,876 (71%) harbored at least one GA involving EGFR (20%), ALK (4.1%), BRAF (5.7%), ERBB2 (6.0%), MET (5.6%), ROS1 (1.5%), RET (2.4%), or KRAS (32%). In the remaining cohort of lung AD without these known drivers, 273 cancer-related genes were altered in at least 0.1% of cases, including STK11 (21%), NF1 (13%), MYC (9.8%), RICTOR (6.4%), PIK3CA (5.4%), CDK4 (4.3%), CCND1 (4.0%), BRCA2 (2.5%), NRAS (2.3%), BRCA1 (1.7%), MAP2K1 (1.2%), HRAS (0.7%), NTRK1 (0.7%), and NTRK3 (0.2%). CGP is practical and facilitates implementation of the NCCN guidelines for NSCLC by enabling simultaneous detection of GAs involving all seven driver oncogenes and KRAS. Furthermore, without additional tissue use or cost, CGP identifies patients with "pan-negative" lung AD who may benefit from enrollment in mechanism-driven clinical trials. National Comprehensive Cancer Network guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for several genomic alterations (GAs). The feasibility and utility of comprehensive genomic profiling were studied in NSCLC and in lung adenocarcinoma

  15. Metastatic Renal Cell Carcinoma versus Pancreatic Neuroendocrine Tumor in von Hippel-Lindau Disease: Treatment with Interleukin-2

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    Christopher Williams

    2005-01-01

    Full Text Available Differentiating between clear cell neuroendocrine tumor (NET of the pancreas and renal cell carcinoma (RCC metastatic to the pancreas can be challenging in patients with von Hippel-Lindau disease (VHL. The clear cell features of both NET and RCC in VHL patients may lead to misdiagnosis, inaccurate staging, and alternative treatment. We present a patient in which this occurred. As clear cell NETs closely resembling metastatic RCC are distinctive neoplasms of VHL and metastatic RCC to the pancreas in the VHL population is rare, careful pathologic examination should be performed prior to subjecting patients to definitive surgical or medical therapies.

  16. Management of Gene Variants of Unknown Significance

    DEFF Research Database (Denmark)

    Alosi, Daniela; Bisgaard, Marie Luise; Hemmingsen, Sophie Nowak

    2017-01-01

    by germline mutations in the VHL gene, which predispose to the development of multiple tumors such as central nervous system hemangioblastomas and renal cell carcinoma (RCC). Objective: We propose a method for the evaluation of VUS pathogenicity through our experience with the VHL missense mutation c.241C...... (IHC); 3) Assessment of the variant’s impact on protein structure and function, using multiple databases, in silico algorithms, and reports of functional studies. Results: Only one family member had clinical signs of vHL with early-onset RCC. IHC analysis showed no VHL protein expressed in the tumor...

  17. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells.

    Science.gov (United States)

    Koochekpour, S; Jeffers, M; Wang, P H; Gong, C; Taylor, G A; Roessler, L M; Stearman, R; Vasselli, J R; Stetler-Stevenson, W G; Kaelin, W G; Linehan, W M; Klausner, R D; Gnarra, J R; Vande Woude, G F

    1999-09-01

    Loss of function in the von Hippel-Lindau (VHL) tumor suppressor gene occurs in familial and most sporadic renal cell carcinomas (RCCs). VHL has been linked to the regulation of cell cycle cessation (G(0)) and to control of expression of various mRNAs such as for vascular endothelial growth factor. RCC cells express the Met receptor tyrosine kinase, and Met mediates invasion and branching morphogenesis in many cell types in response to hepatocyte growth factor/scatter factor (HGF/SF). We examined the HGF/SF responsiveness of RCC cells containing endogenous mutated (mut) forms of the VHL protein (VHL-negative RCC) with that of isogenic cells expressing exogenous wild-type (wt) VHL (VHL-positive RCC). We found that VHL-negative 786-0 and UOK-101 RCC cells were highly invasive through growth factor-reduced (GFR) Matrigel-coated filters and exhibited an extensive branching morphogenesis phenotype in response to HGF/SF in the three-dimensional (3D) GFR Matrigel cultures. In contrast, the phenotypes of A498 VHL-negative RCC cells were weaker, and isogenic RCC cells ectopically expressing wt VHL did not respond at all. We found that all VHL-negative RCC cells expressed reduced levels of tissue inhibitor of metalloproteinase 2 (TIMP-2) relative to the wt VHL-positive cells, implicating VHL in the regulation of this molecule. However, consistent with the more invasive phenotype of the 786-0 and UOK-101 VHL-negative RCC cells, the levels of TIMP-1 and TIMP-2 were reduced and levels of the matrix metalloproteinases 2 and 9 were elevated compared to the noninvasive VHL-positive RCC cells. Moreover, recombinant TIMPs completely blocked HGF/SF-mediated branching morphogenesis, while neutralizing antibodies to the TIMPs stimulated HGF/SF-mediated invasion in vitro. Thus, the loss of the VHL tumor suppressor gene is central to changes that control tissue invasiveness, and a more invasive phenotype requires additional genetic changes seen in some but not all RCC lines. These

  18. Pancreatic cyst development: insights from von Hippel-Lindau disease

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    van Asselt Sophie J

    2013-02-01

    Full Text Available Abstract Pancreatic cysts are a heterogeneous group of lesions, which can be benign or malignant. Due to improved imaging techniques, physicians are more often confronted with pancreatic cysts. Little is known about the origin of pancreatic cysts in general. Von Hippel-Lindau (VHL disease is an atypical ciliopathy and inherited tumor syndrome, caused by a mutation in the VHL tumor suppressor gene encoding the VHL protein (pVHL. VHL patients are prone to develop cysts and neuroendocrine tumors in the pancreas in addition to several other benign and malignant neoplasms. Remarkably, pancreatic cysts occur in approximately 70% of VHL patients, making it the only hereditary tumor syndrome with such a discernible expression of pancreatic cysts. Cellular loss of pVHL due to biallelic mutation can model pancreatic cystogenesis in other organisms, suggesting a causal relationship. Here, we give a comprehensive overview of various pVHL functions, focusing on those that can potentially explain pancreatic cyst development in VHL disease. Based on preclinical studies, cilia loss in ductal cells is probably an important early event in pancreatic cyst development.

  19. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development

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    Jimann Shin

    2012-11-01

    Neurofibromatosis type 1 (NF1 is a common, dominantly inherited genetic disorder that results from mutations in the neurofibromin 1 (NF1 gene. Affected individuals demonstrate abnormalities in neural-crest-derived tissues that include hyperpigmented skin lesions and benign peripheral nerve sheath tumors. NF1 patients also have a predisposition to malignancies including juvenile myelomonocytic leukemia (JMML, optic glioma, glioblastoma, schwannoma and malignant peripheral nerve sheath tumors (MPNSTs. In an effort to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, we employed targeted mutagenesis strategies to generate zebrafish harboring stable germline mutations in nf1a and nf1b, orthologues of NF1. Animals homozygous for loss-of-function alleles of nf1a or nf1b alone are phenotypically normal and viable. Homozygous loss of both alleles in combination generates larval phenotypes that resemble aspects of the human disease and results in larval lethality between 7 and 10 days post fertilization. nf1-null larvae demonstrate significant central and peripheral nervous system defects. These include aberrant proliferation and differentiation of oligodendrocyte progenitor cells (OPCs, dysmorphic myelin sheaths and hyperplasia of Schwann cells. Loss of nf1 contributes to tumorigenesis as demonstrated by an accelerated onset and increased penetrance of high-grade gliomas and MPNSTs in adult nf1a+/−; nf1b−/−; p53e7/e7 animals. nf1-null larvae also demonstrate significant motor and learning defects. Importantly, we identify and quantitatively analyze a novel melanophore phenotype in nf1-null larvae, providing the first animal model of the pathognomonic pigmentation lesions of NF1. Together, these findings support a role for nf1a and nf1b as potent tumor suppressor genes that also function in the development of both central and peripheral glial cells as well as melanophores in zebrafish.

  20. Nuevas retóricas para viejas prácticas. Repensando la idea de diversidad y su uso en la comprensión y abordaje de la discapacidad Nuevas retóricas para viejas prácticas. Repensando la idea de diversidad y su uso en la comprensión y abordaje de la discapacidad

    Directory of Open Access Journals (Sweden)

    M.E. Almeida

    2010-03-01

    Full Text Available El presente ensayo recupera las reflexiones y producciones del equipo interdisciplinario de investigadores y docentes de la Facultad de Trabajo Social (FTS de la Universidad Nacional de Entre Ríos (UNER, Argentina1. Nos proponemos por un lado revisar críticamente la noción de diversidad y las prácticas que en ella se fundan y por otra abordar la perspectiva de la producción social de la discapacidad desde el paradigma de la complejidad. Intentaremos deconstruir el concepto de diversidad, no para cambiarlo simplemente por otro que nos incomode menos, sino para sumergirnos en la maraña de sentidos en que la diversidad se inscribe como descriptor de un cierto orden de cosas. Entendemos que la noción de diversidad, en tanto descriptiva de un cierto cúmulo de tipos posibles es muy útil en el campo de lo biológico, pero sin duda es necesario discutir algunas implicancias de su traslado lineal al campo de lo social. Finalmente, proponemos pensar y pasar de la perspectiva de atención a/en la diversidad al abordaje en la complejidad recuperando la idea de experiencias de complejidad, en referencia a experiencias que ya no se organizan y legitiman en torno al señalamiento e identificación de tal o cual complejo (como un otro específico y/o su complejidad, sino experiencias capaces de reconocerla como condición intrínseca a toda experiencia pedagógica, social, política, cultural.This essay recovers ideas and productions of the interdisciplinary team of researchers and professors from the Faculty of Social Work at the National University of Entre Rios, Argentine. We propose a critical review of the practices and the notion of diversity are based from, by means of using the perspective of the social production of disability and the paradigm of complexity. We try to deconstruct the concept of diversity, not just to change it for more comfortable ideas, but to dive into the confusion of meanings that diversity is as a descriptor of a certain order of things. The notion of diversity can be useful in the biological field while describing a host of possible types, but it is certainly necessary to be discussed in the implications of his translation to the social field. Finally, we propose to move from the perspective of attention to and in diversity to approach the complexity of experience recovering the idea of complexity, referring to experiences that are not organized and legitimized around the signage and identification of a particular complex (as a specific one and his complexity, but experience can recognize it as an intrinsic condition of every educational, social, political, cultural experience.