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Sample records for cys618ser ret germline

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

    African Journals Online (AJOL)

    Makia Marafie

    2016-09-17

    Sep 17, 2016 ... multiple members of an Arab family with variable onset of MEN type ... fashion and caused by germline mutation in RET proto- oncogene. The main .... ing sudden severe high blood pressure crises that required immediate ...

  2. 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

    Context: The A883F germline mutation of the REarranged during Transfection 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...

  3. Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10

    NARCIS (Netherlands)

    Frank-Raue, Karin; Rybicki, Lisa A.; Erlic, Zoran; Schweizer, Heiko; Winter, Aurelia; Milos, Ioana; Toledo, Sergio P. A.; Toledo, Rodrigo A.; Tavares, Marcos R.; Alevizaki, Maria; Mian, Caterina; Siggelkow, Heide; Huefner, Michael; Wohllk, Nelson; Opocher, Giuseppe; Dvorakova, Sarka; Bendlova, Bela; Czetwertynska, Malgorzata; Skasko, Elzbieta; Barontini, Marta; Sanso, Gabriela; Vorlaender, Christian; Maia, Ana Luiza; Patocs, Attila; Links, Thera P.; de Groot, Jan Willem; Kerstens, Michiel N.; Valk, Gerlof D.; Miehle, Konstanze; Musholt, Thomas J.; Biarnes, Josefina; Damjanovic, Svetozar; Muresan, Mihaela; Wuester, Christian; Fassnacht, Martin; Peczkowska, Mariola; Fauth, Christine; Golcher, Henriette; Walter, Martin A.; Pichl, Josef; Raue, Friedhelm; Eng, Charis; Neumann, Hartmut P. H.

    2011-01-01

    Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for cl

  4. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Mehdi Hedayati

    2011-01-01

    Full Text Available Medullary thyroid carcinoma occurs in both sporadic (75% and hereditary (25% forms. The missense mutations of RET proto-oncogene in MTC development have been well demonstrated. To investigate the spectrum of predominant RET germline mutations in exons 10, 11, and 16 in hereditary MTC in Iranian population, 217 participants were included. Genomic DNAs were extracted from the leukocytes using the standard Salting Out/Proteinase K method. Mutation detection was performed through PCR-RFLP and DNA sequencing. In 217 participants, 43 missense mutations were identified in exons 10 (6%, 11 (13%, and 16 (0.9%. Moreover, a novel germline mutation was detected in exon 11 (S686N. Also four different polymorphisms were found in intron 16 in eight patients. The obtained data showed the frequency profile of RET mutations in Iranian individuals with MTC (19.8%. The most frequent mutation in our population was C634G whereas in most population it was C634R. Altogether, these results underline the importance of the genetic background of family members of any patient with MTC.

  5. Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes.

    Science.gov (United States)

    Ercolino, Tonino; Lai, Roberta; Giachè, Valentino; Melchionda, Salvatore; Carella, Massimo; Delitala, Alessandro; Mannelli, Massimo; Fanciulli, Giuseppe

    2014-02-25

    Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease with an estimated incidence of 1 in 3000/3500 live births. NF1 is caused by a mutation in a gene which encodes a protein known as neurofibromin. In up to 5% of cases, NF1 is associated with pheochromocytomas. RET proto-oncogene encodes a member of the receptor tyrosine kinase family involved in the normal development or the neoplastic growth of neural crest cell lineages. Germ-line RET mutations account for cases of Multiple Endocrine Neoplasia type 2 (MEN2), an autosomal dominant genetic syndrome where medullary thyroid carcinoma (MTC) is the major and more clinically severe feature, with nearly complete penetrance. C-cell hyperplasia (CCH) is described in MEN2 patients, and it has been implicated as the precursor of in situ MTC. Patients with RET mutations develop pheochromocytomas in 50% of cases. Rarely, patients with NF1 have been found to present, in addition to the NF1 clinical picture, other lesions, such as parathyroid hyperplasia/adenoma and/or medullary thyroid carcinoma. In spite of the presence of these MEN2 lesions, in none of these patients mutations of gene RET have been found so far. In this report, we describe the first case of a patient affected by a germ-line mutation in both NF1 and RET genes.

  6. Germline mutations of the RET proto-oncogene in pedigree with MEN type 2A: DNA analysis and its implications for pediatric surgery.

    Science.gov (United States)

    Shimotake, T; Iwai, N; Inoue, K; Inazawa, J; Nishisho, I

    1996-06-01

    To assess the feasibility of screening for multiple endocrine neoplasia type 2A (MEN 2A), the authors used DNA sequence analysis to evaluate the RET proto-oncogene in a kindred with MEN 2A. The kindred consisted of 95 members (1 to 79 years of age) and their spouses, and spanned five generations. Genomic DNA was extracted from peripheral blood lymphocytes or lymphoblastoid cell lines established from the family members, and the RET gene was amplified by polymerase chain reaction (PCR) using RET-specific primers (10q 11.2) and was sequenced. Periodic endocrine screening also was performed, by measuring the plasma calcitonin concentration after provocation with pentagastrin (0.5 microgram/kg intravenously) to assess its reliability for detecting the associated neoplasms. Nineteen patients were confirmed to have MEN 2A by medical records or the screening program. The DNA sequence of the PCR products from clinically established MEN 2A patients showed a mutation at codon 634 (TGC-->CGC) that resulted in an amino acid change from cysteine to arginine. Endocrine screening tests showed that six other family members had a mutated RET protooncogene. DNA sequencing can detect high-risk cases at a preclinical stage of the disease. The establishment of mutated MEN 2A gene carriers allows pediatric surgeons to consider total thyroidectomy at a very early stage of neoplasm development (C-cell hyperplasia) or even prophylactically.

  7. THE PHYSICAL MAP OF THE HUMAN RET PROTOONCOGENE

    NARCIS (Netherlands)

    PASINI, B; HOFSTRA, RMW; YIN, L; BOCCIARDI, R; SANTAMARIA, G; GROOTSCHOLTEN, PM; CECCHERINI, [No Value; PATRONE, G; PRIOLO, M; BUYS, CHCM; ROMEO, G

    1995-01-01

    The RET proto-oncogene, a transmembrane tyrosine kinase receptor, is involved in the development of at least five different disease phenotypes. RET is activated through somatic rearrangements in a number of cases of papillary thyroid carcinoma while germ-line point mutations are associated with thre

  8. RET Gene Abnormalities and Thyroid Disease: Who Should be Screened and When

    OpenAIRE

    Salehian, Behrouz; Samoa, Raynald

    2013-01-01

    Mutations in the RET proto-oncogene have been implicated in the pathogenesis of several forms of medullary thyroid cancer (MTC). Multiple endocrine neoplasia type 2 (MEN-2) is an autosomal dominant syndrome caused by germline activating mutations of the RET proto-oncogene and has been categorized into three distinct clinical forms. MEN-2A is associated with MTC, bilateral pheochromocytoma, and primary hyperparathyroidism. MEN-2B is associated with MTC, bilateral pheochromocytoma, and mucosal ...

  9. RET codon 609 mutations: a contribution for better clinical managing

    Directory of Open Access Journals (Sweden)

    Caterina Mian

    2012-01-01

    Full Text Available Medullary thyroid carcinoma currently accounts for 5-8% of all thyroid cancers. The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate. As many as 75% of all medullary thyroid carcinomas are sporadic, with an average age at presentation reported as 60 years, and the remaining 25% are hereditary with an earlier age of presentation, ranging from 20 to 40 years. Germline RET proto-oncogene mutations are the genetic causes of multiple endocrine neoplasia type 2 and a strong genotype-phenotype correlation exists, particularly between a specific RET codon mutation and the (a age-related onset and (b thyroid tumor progression, from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, to nodal metastases. RET mutations predispose an individual to the development of medullary thyroid carcinomas and can also influence the individual response to RET protein receptor-targeted therapies. RET codon 609point mutations are rare genetic events belonging to the intermediate risk category for the onset of medullary thyroid carcinoma. A large genealogy resulting in a less aggressive form of medullary thyroid carcinoma is associated with the high penetrance of pheochromocytoma and has been reported in the literature. In this short review article, we comment on our previous report of a large multiple endocrine neoplasia type 2A kindred with the same Cys609Ser germline RET mutation in which, conversely, the syndrome was characterized by a slightly aggressive, highly penetrant form of medullary thyroid carcinoma that was associated with low penetrance of pheochromocytoma and primary hyperparathyroidism.

  10. 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.

    Sediments of a coconut husk retting yard and a reference station in Cochin backwaters, Kerala, India were studied for 1 yr. Effects of monsoon were found significant Organic carbon and organic matter showed enrichment in the retting ground sediments...

  11. Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effecters to a multifunctional docking site

    NARCIS (Netherlands)

    Geneste, O; Bidaud, C; De Vita, G; Hofstra, RMW; Tartare-Deckert, S; Buys, CHCM; Lenoir, GM; Santoro, M; Billaud, M

    1999-01-01

    The RET gene codes for a transmembrane tyrosine kinase which is a subunit of a multimeric complex that acts as a receptor for four structurally related molecules: the glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin and persephin, Germline mutations of RET cause a dominantly in

  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

    883F carriers. Intervention: The intervention was thyroidectomy. Main Outcome Measures: 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. Results: One...

  13. Mutations in the RET proto-oncogene in sporadic pheochromocytomas

    Energy Technology Data Exchange (ETDEWEB)

    Thibodeau, S.N.; Lindor, N.M.; Honchel, R. [Mayo Clinic and Foundation, Rochester, MN (United States)] [and others

    1994-09-01

    Mutations in the RET proto-oncogene have recently been demonstrated in kindreds with Multiple Endocrine Neoplasia (MEN) types 2A and 2B. Both of these autosomal dominant disorders are characterized by the development of neoplasia in cell lines of neural crest origin, such as medullary throid carcinomas and pheochromocytomas. Individuals with MEN 2B have, in addition, ganglioneuromas of the lips, tongue and colon, a marfanoid habitus, and corneal nerve thickening. Approximately 90% of patients with MEN 2A have a germline mutation in exons 10 or 11, while 95% of patients with MEN 2B have a T{yields}C transition in codon 918 of exon 16. In this study, pheochromocytomas from 29 individuals who had no clinical evidence of MEN 2A or 2B (sporadic) were examined for the presence of either germline or somatic mutations in exons 10, 11, and 16 of the RET proto-oncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in one of the three exons. One tumor had a G{yields}A transition in codon 609 (exon 10), another had a 6 bp deletion encompassing codons 632 & 633 (exon 11), and the final tumor had a T{yields}C transition in codon 918 (exon 16). These mutations were not found in the corresponding normal DNA from these individuals, indicating that the mutation were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET proto-oncogene, our data suggests that: (1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN 2A or 2B; and (2) somatic mutations in the RET proto-oncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas.

  14. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines.

    Science.gov (United States)

    Chappuis-Flament, S; Pasini, A; De Vita, G; Ségouffin-Cariou, C; Fusco, A; Attié, T; Lenoir, G M; Santoro, M; Billaud, M

    1998-12-03

    The RET gene encodes a receptor tyrosine kinase whose function is essential during the development of kidney and the intestinal nervous system. Germline mutations affecting one of five cysteines (Cys609, 611, 618, 620 and 634) located in the juxtamembrane domain of the RET receptor are responsible for the vast majority of two cancer-prone disorders, multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC). These mutations lead to the replacement of a cysteine by an alternate amino acid. Mutations of the RET gene are also the underlying genetic cause of Hirschsprung disease (HSCR), a congenital aganglionosis of the hindgut. In a fraction of kindreds, MEN 2A cosegregate with HSCR and affected individuals carry a single mutation at codons 609, 618 or 620. To examine the consequences of cysteine substitution on RET function, we have introduced a Cys to Arg mutation into the wild-type RET at either codons 609, 618, 620, 630 or 634. We now report that each mutation induces a constitutive catalytic activity due to the aberrant disulfide homodimerization of RET. However, mutations 630 and 634 activate RET more strongly than mutations 609, 618 or 620 as demonstrated by quantitative assays in rodent fibroblasts and pheochromocytoma PC12 cells. Biochemical analysis revealed that mutations 618 and 620, and to a lesser extent mutation 609, result in a marked reduction of the level of RET at the cell surface and as a consequence decrease the amount of RET covalent dimer. These findings provide a molecular basis explaining the range of phenotype engendered by alterations of RET cysteines and suggest a novel mechanism whereby mutations of cysteines 609, 618 and 620 exert both activating and inactivating effects.

  15. RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling.

    Science.gov (United States)

    Widowati, Titis; Melhem, Shamiram; Patria, Suryono Y; de Graaf, Bianca M; Sinke, Richard J; Viel, Martijn; Dijkhuis, Jos; Sadewa, Ahmad H; Purwohardjono, Rochadi; Soenarto, Yati; Hofstra, Robert Mw; Sribudiani, Yunia

    2016-06-01

    Hirschsprung disease (HSCR) is a major cause of chronic constipation in children. HSCR can be caused by germline mutations in RET and EDNRB. Defining causality of the mutations identified is difficult and almost exclusively based on in silico predictions. Therefore, the reported frequency of pathogenic mutations might be overestimated. We combined mutation analysis with functional assays to determine the frequencies of proven pathogenic RET and EDNRB mutations in HSCR. We sequenced RET and EDNRB in 57 HSCR patients. The identified RET-coding variants were introduced into RET constructs and these were transfected into HEK293 cells to determine RET phosphorylation and activation via ERK. An exon trap experiment was performed to check a possible splice-site mutation. We identified eight rare RET-coding variants, one possible splice-site variant, but no rare EDNRB variants. Western blotting showed that three coding variants p.(Pr270Leu), p.(Ala756Val) and p.(Tyr1062Cys) resulted in lower activation of RET. Moreover, only two RET variants (p.(Ala756Val) and p.(Tyr1062Cys)) resulted in reduced ERK activation. Splice-site assays on c.1880-11A>G could not confirm its pathogenicity. Our data suggest that indeed almost half of the identified rare variants are proven pathogenic and that, hence, functional studies are essential for proper genetic counseling.

  16. 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.

  17. Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility.

    Science.gov (United States)

    Toledo, Rodrigo A; Hatakana, Roxanne; Lourenço, Delmar M; Lindsey, Susan C; Camacho, Cleber P; Almeida, Marcio; Lima, José V; Sekiya, Tomoko; Garralda, Elena; Naslavsky, Michel S; Yamamoto, Guilherme L; Lazar, Monize; Meirelles, Osorio; Sobreira, Tiago J P; Lebrao, Maria Lucia; Duarte, Yeda A O; Blangero, John; Zatz, Mayana; Cerutti, Janete M; Maciel, Rui M B; Toledo, Sergio P A

    2015-02-01

    Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility.

  18. Effect of retS gene on antibiotics production in Pseudomonas fluorescens FD6.

    Science.gov (United States)

    Zhang, Qingxia; Xiao, Qi; Xu, Jingyou; Tong, Yunhui; Wen, Jia; Chen, Xijun; Wei, Lihui

    2015-11-01

    A hybrid sensor kinase termed RetS (regulator of exopolysaccharide and Type III secretion) controls expression of numerous genes in Pseudomonas aeruginosa. To investigate the function of RetS in P. fluorescens FD6, the retS gene was disrupted. Genetic inactivation of retS resulted in enhanced production of 2, 4-diacetylphloroglucinol, pyrrolnitrin, and pyoluteorin. The retS mutant also exhibited significant increase in phlA-lacZ, prnA-lacZ, and pltA-lacZ transcription levels, influencing expression levels of the small regulatory RNAs RsmX and RsmZ. In the gacSretS double mutant, all the phenotypic changes caused by the retS deletion were reversed to the level of gacS single mutant. Furthermore, the retS mutation drastically elevated biofilm formation and improved the colonization ability of strain FD6 on wheat rhizospheres. Based on these results, we proposed that RetS negatively controlled the production of antibiotics through the Gac/Rsm pathway in P. fluorescens FD6.

  19. 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…

  20. Fuskeåret 2016

    DEFF Research Database (Denmark)

    Sodemann, Morten

    2017-01-01

    2016 var året, hvor vi lagde fakta på intensivafdelingen med svær åndenød utallige gange. For at give 2017 en bedre stafet end den, som 2016 er kommet i mål med, er der grund til at holde fast i, at fakta, tillid, evidens, ekspertise og viden er efterspurgte offentlige goder....

  1. ret en daarna

    NARCIS (Netherlands)

    E. Dommering

    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.

  2. Fantaasia killapeod : [rets.] / Ain Kaalep

    Index Scriptorium Estoniae

    Kaalep, Ain, 1926-

    1997-01-01

    Ilm.: Looming 1968, nr. 10, lk. 1592-1595 . Rets. rmt.: Alliksaar, Artur. Nimetu saar. Tallinn : Perioodika, 1966. 80 lk. (Loomingu Raamatukogu; 1966, 7); Alliksaar, Artur. Olematus võiks ju ka olemata olla. Tallinn ; Perioodika, 1968. 80 lk. (Loomingu Raamatukogu; 1968, 9/10).

  3. Fantaasia killapeod : [rets.] / Ain Kaalep

    Index Scriptorium Estoniae

    Kaalep, Ain, 1926-

    1997-01-01

    Ilm.: Looming 1968, nr. 10, lk. 1592-1595 . Rets. rmt.: Alliksaar, Artur. Nimetu saar. Tallinn : Perioodika, 1966. 80 lk. (Loomingu Raamatukogu; 1966, 7); Alliksaar, Artur. Olematus võiks ju ka olemata olla. Tallinn ; Perioodika, 1968. 80 lk. (Loomingu Raamatukogu; 1968, 9/10).

  4. 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...

  5. The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas.

    Science.gov (United States)

    Cetta, F; Chiappetta, G; Melillo, R M; Petracci, M; Montalto, G; Santoro, M; Fusco, A

    1998-03-01

    Familial adenomatous polyposis (FAP) is caused by germ-line mutations of the apc gene, and it is associated with an increased risk of developing papillary thyroid carcinomas. We have previously reported that a significant fraction of sporadic human papillary thyroid carcinomas is characterized by gene rearrangements affecting the ret protooncogene. These rearrangements generate chimeric transforming oncogenes designated ret/ptc. By a combined immunohistochemical and RT-PCR approach, we analyzed, for ret/ptc oncogene activation, papillary thyroid carcinomas occurred in two FAP kindreds, both showing typical apc gene mutations. Kindred 1 had seven members affected by FAP, and among these, three patients showed papillary thyroid carcinomas. Kindred 2 had two patients, mother and daughter, affected by colonic polyposis; the 20-yr-old daughter showed also a papillary carcinoma. Here we report that ret/ptc1 oncogene was activated in two of the three papillary carcinomas of FAP kindred 1 and in the papillary carcinoma of FAP kindred 2. These findings document that loss of function of apc coexists with gain of function of ret in some papillary thyroid carcinomas, suggesting that ret/ptc1 oncogene activation could be a progression step in the development of FAP-associated thyroid tumors.

  6. Retórica y derecho hoy

    OpenAIRE

    Francisco Javier Dorantes-Díaz

    2014-01-01

    Basándose en las propuestas de Perelman y su nueva retórica, el autor analiza la importancia de la retórica en la argumentación jurídica, particularmente en las repúblicas democráticas donde se han instituido los juicios orales, y argumenta a favor de que la retórica vuelva a ser un instrumento para la búsqueda de soluciones justas en el derecho.

  7. Retórica y derecho hoy

    OpenAIRE

    Francisco Javier Dorantes-Díaz

    2014-01-01

    Basándose en las propuestas de Perelman y su nueva retórica, el autor analiza la importancia de la retórica en la argumentación jurídica, particularmente en las repúblicas democráticas donde se han instituido los juicios orales, y argumenta a favor de que la retórica vuelva a ser un instrumento para la búsqueda de soluciones justas en el derecho.

  8. RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients

    Indian Academy of Sciences (India)

    B P Sharma; D Saranath

    2011-09-01

    Germline mutations of RET gene are pathognomonic of multiple endocrine neoplasia (MEN; MEN 2A/MEN 2B) and familial medullary thyroid carcinoma (FMTC), constituting 25% of medullary thyroid carcinomas (MTCs). We investigated RET gene mutations and polymorphisms at exons 10, 11, 13, 14, 15 and 16 in 140 samples, comprising 51 clinically diagnosed MTC patients, 39 family members of patients and 50 normal individuals. The method of choice was PCR and direct nucleotide sequencing of the PCR products. RET gene mutations were detected in 15 (29.4%) patients, with MEN 2A/FMTC in 13 patients and MEN 2B in 2 patients. Further, 39 family members of seven index cases were analysed, wherein four of the seven index cases showed identical mutations, in 13 of 25 family members. We also examined single nucleotide polymorphisms (SNPs) in RET gene exons in 101 unrelated samples. Significant differences in the allelic frequencies of SNPs at codons 691, 769, 836 and 904 between patient and control groups were not observed. However, SNP frequencies were significantly different in the Indian group as compared with other European groups. We identified two novel, rare and unique SNPs separately in single patients. Our study demonstrated presence of MEN 2A/MEN 2B/FMTC-associated mutations in accordance with the reported literature. Thus, RET gene mutations in exons 10, 11, 13, 14, 15 and 16 constitute a rapid test to confirm diagnosis and assess risk of the disease in familial MEN 2A/MEN 2B/FMTC.

  9. Retórica y derecho hoy

    Directory of Open Access Journals (Sweden)

    Francisco Javier Dorantes-Díaz

    2014-03-01

    Full Text Available Basándose en las propuestas de Perelman y su nueva retórica, el autor analiza la importancia de la retórica en la argumentación jurídica, particularmente en las repúblicas democráticas donde se han instituido los juicios orales, y argumenta a favor de que la retórica vuelva a ser un instrumento para la búsqueda de soluciones justas en el derecho.

  10. 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

  11. Mechanism of Kenaf Retting Using Aerobes

    Institute of Scientific and Technical Information of China (English)

    卢士森; 陈季华; 黄秀宝

    2001-01-01

    The experimental results showed that the duration of microbial retting processing of kenaf fibers by using aerobic microbe was four times shorter than that by using anaerobic microbe. The residual gum percentage,breaking strength, breaking elongation and linear density of aerobic retted kenaf bundle fibers did not show significantly difference with that of anaerobic retted kenaf bundle fibers by ANOVA-Tukey's studentized test at a = 5% except for the softness. The bioenergetic principle and the calculation of the amount of ATP produced during the decomposition processing of kenaf gums were used to explain why the retting duration in the case of using aerobic microbes was much shorter than that of using anaerobic microbes.

  12. 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...... was obtained using P. radiata Cel 26 compared to 248 MPa with field retting....

  13. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase

    OpenAIRE

    Marialuisa Moccia; Qingsong Liu; Teresa Guida; Giorgia Federico; Annalisa Brescia; Zheng Zhao; Hwan Geun Choi; Xianming Deng; Li Tan; Jinhua Wang; Marc Billaud; Gray, Nathanael S.; Francesca Carlomagno; Massimo Santoro

    2015-01-01

    Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-media...

  14. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.

    Science.gov (United States)

    Krampitz, Geoffrey W; Norton, Jeffrey A

    2014-07-01

    The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.

  15. Mutation of RET proto-oncogene in Hirschsprung's disease and intestinal neuronal dysplasia

    Institute of Scientific and Technical Information of China (English)

    Jin-Fa Tou; Min-Ju Li; Tao Guan; Ji-Cheng Li; Xiong-Kai Zhu; Zhi-Gang Feng

    2006-01-01

    AIM: To investigate the genetic relationship between Hirschsprung's disease (HD) and intestinal neuronal dysplasia (IND) in Chinese population.METHODS: Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control.Genomic DNA was extracted according to standard procedure. Exons 11,13,15,17 of RET proto-oncogene were amplified by polymerase chain reaction (PCR).The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism (SSCP)and sequencing of the positive amplified products was performed.RESULTS: Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11at nucleotide 15165 G→A (G667S), 2 frameshift mutations in exon 13 at nucleotide 18974 (18974insG), 1missense mutation in exon 13 at nucleotide 18919 A→G (K756E) and 1silent mutation in exon 15 at nucleotide 20692 G→A(Q916Q) were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G→A and 1 silent mutation in exon 13at nucleotide 18888 T→G (L745L) were detected. No mutation was found in IND patients and controls.CONCLUSION: Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of RET proto-oncogene mutation is quite different between IND and HD in Chinese population. IND is a distinct clinical entity genetically different from HD.

  16. 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.

  17. Sõna viidi, teine toodi : [rets.] / Ain Kaalep

    Index Scriptorium Estoniae

    Kaalep, Ain, 1926-

    1997-01-01

    Ilm.: Keel ja Kirjandus 1986, nr. 7, lk. 438-439. Rets. rmt.: Sõja laul. Das Estnische Kriegslied. Zusammengestellt und mit Hilfe von Bertolt Brecht und Margarete Steffin ins Deutsche übertragen vom Hella Wuolijoki, estnisch und deutsch herausgegeben und kommentiert von Hans Peter Neureuter, Ruth Mirov und Ülo Tedre. Helsinki : Otava, 1984. 181 lk.

  18. c-RET molecule in malignant melanoma from oncogenic RET-carrying transgenic mice and human cell lines.

    Directory of Open Access Journals (Sweden)

    Yuichiro Ohshima

    Full Text Available Malignant melanoma is one of the most aggressive cancers and its incidence worldwide has been increasing at a greater rate than that of any other cancer. We previously reported that constitutively activated RFP-RET-carrying transgenic mice (RET-mice spontaneously develop malignant melanoma. In this study, we showed that expression levels of intrinsic c-Ret, glial cell line-derived neurotrophic factor (Gdnf and Gdnf receptor alpha 1 (Gfra1 transcripts in malignant melanomas from RET-transgenic mice were significantly upregulated compared with those in benign melanocytic tumors. These results suggest that not only introduced oncogenic RET but also intrinsic c-Ret/Gdnf are involved in murine melanomagenesis in RET-mice. We then showed that c-RET and GDNF transcript expression levels in human malignant melanoma cell lines (HM3KO and MNT-1 were higher than those in primary cultured normal human epithelial melanocytes (NHEM, while GFRa1 transcript expression levels were comparable among NHEM, HM3KO and MNT-1. We next showed c-RET and GFRa1 protein expression in HM3KO cells and GDNF-mediated increased levels of their phosphorylated c-RET tyrosine kinase and signal transduction molecules (ERK and AKT sited potentially downstream of c-RET. Taken together with the finding of augmented proliferation of HM3KO cells after GDNF stimulation, our results suggest that GDNF-mediated c-RET kinase activation is associated with the pathogenesis of malignant melanoma.

  19. La pulsión retórica

    OpenAIRE

    2011-01-01

    El presente trabajo empieza refiriéndose a la relación gramática-retórica para situarse en esta última disciplina a la que, siguiendo a Quintiliano, describe en su aspecto restringido, como el arte del orador. Luego intenta mostrar la extensión del hacer retórico tanto en sentido horizontal como vertical. En el primero, alude a una retórica de uso y a una retórica de la necesidad. En el segundo, siguiendo a Alfonso Reyes, indaga en una cierta retórica infusa con la que cuenta cualquier habla...

  20. La pulsión retórica

    OpenAIRE

    Raúl Dorra

    2011-01-01

    El presente trabajo empieza refiriéndose a la relación gramática-retórica para situarse en esta última disciplina a la que, siguiendo a Quintiliano, describe en su aspecto restringido, como el arte del orador. Luego intenta mostrar la extensión del hacer retórico tanto en sentido horizontal como vertical. En el primero, alude a una retórica de uso y a una retórica de la necesidad. En el segundo, siguiendo a Alfonso Reyes, indaga en una cierta retórica infusa con la que cuenta cualquier habla...

  1. RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family

    Directory of Open Access Journals (Sweden)

    Elisangela P. S. Quedas

    2012-01-01

    Full Text Available Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.

  2. Lessons for Inductive Germline Determination

    Science.gov (United States)

    Seervai, Riyad N.H.; Wessel, Gary M.

    2015-01-01

    SUMMARY Formation of the germline in an embryo marks a fresh round of reproductive potential, yet the developmental stage and location within the embryo where the primordial germ cells (PGCs) form differs wildly among species. In most animals, the germline is formed either by an inherited mechanism, in which maternal provisions within the oocyte drive localized germ-cell fate once acquired in the embryo, or an inductive mechanism that involves signaling between cells that directs germ-cell fate. The inherited mechanism has been widely studied in model organisms such as Drosophila melanogaster, Caenorhabditis elegans, Xenopus laevis, and Danio rerio. Given the rapid generation time and the effective adaptation for laboratory research of these organisms, it is not coincidental that research on these organisms has led the field in elucidating mechanisms for germline specification. The inductive mechanism, however, is less well understood and is studied primarily in the mouse (Mus musculus). In this review, we compare and contrast these two fundamental mechanisms for germline determination, beginning with the key molecular determinants that play a role in the formation of germ cells across all animal taxa. We next explore the current understanding of the inductive mechanism of germ-cell determination in mice, and evaluate the hypotheses for selective pressures on these contrasting mechanisms. We then discuss the hypothesis that the transition between these determination mechanisms, which has happened many times in phylogeny, is more of a continuum than a binary change. Finally, we propose an analogy between germline determination and sex determination in vertebrates—two of the milestones of reproduction and development—in which animals use contrasting strategies to activate similar pathways. PMID:23450642

  3. Lessons for inductive germline determination.

    Science.gov (United States)

    Seervai, Riyad N H; Wessel, Gary M

    2013-08-01

    Formation of the germline in an embryo marks a fresh round of reproductive potential, yet the developmental stage and location within the embryo where the primordial germ cells (PGCs) form differs wildly among species. In most animals, the germline is formed either by an inherited mechanism, in which maternal provisions within the oocyte drive localized germ-cell fate once acquired in the embryo, or an inductive mechanism that involves signaling between cells that directs germ-cell fate. The inherited mechanism has been widely studied in model organisms such as Drosophila melanogaster, Caenorhabditis elegans, Xenopus laevis, and Danio rerio. Given the rapid generation time and the effective adaptation for laboratory research of these organisms, it is not coincidental that research on these organisms has led the field in elucidating mechanisms for germline specification. The inductive mechanism, however, is less well understood and is studied primarily in the mouse (Mus musculus). In this review, we compare and contrast these two fundamental mechanisms for germline determination, beginning with the key molecular determinants that play a role in the formation of germ cells across all animal taxa. We next explore the current understanding of the inductive mechanism of germ-cell determination in mice, and evaluate the hypotheses for selective pressures on these contrasting mechanisms. We then discuss the hypothesis that the transition between these determination mechanisms, which has happened many times in phylogeny, is more of a continuum than a binary change. Finally, we propose an analogy between germline determination and sex determination in vertebrates-two of the milestones of reproduction and development-in which animals use contrasting strategies to activate similar pathways.

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

    Science.gov (United States)

    Liu, Ming; Ale, Marcel T; Kołaczkowski, Bartłomiej; Fernando, Dinesh; Daniel, Geoffrey; Meyer, Anne S; Thygesen, Anders

    2017-12-01

    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 of the microbial evolution (by gene sequencing) and enzyme profiles were conducted. By phylogenetic frequency mapping, different types of fungi, many belonging to the Ascomycota phylum were found on the fibres during the first 2 weeks of field retting, and thereafter, different types of bacteria, notably Proteobacteria, also proliferated on the field retted fibres. Extracts from field retted fibres exhibited high glucanase activities, while extracts from P. radiata Cel 26 retted fibres showed high polygalacturonase and laccase activities. As a result, fungal retting gave a significantly higher glucan content in the fibres than field retting (77 vs. 67%) and caused a higher removal of pectin as indicated by lower galacturonan content of fibres (1.6%) after fibres were retted for 20 days with P. radiata Cel 26 compared to a galacturonan content of 3.6% for field retted fibres. Effective fibre stiffness increased slightly after retting with P. radiata Cel 26 from 65 to 67 GPa, while it decreased after field retting to 52 GPa. Effective fibre strength could not be determined similarly due to variations in fibre fracture strain and fibre-matrix adhesion. A maximum composite strength with 50 vol% fibres of 307 MPa was obtained using P. radiata Cel 26 compared to 248 MPa with field retting.

  5. Microbial diversity observed during hemp retting.

    Science.gov (United States)

    Ribeiro, Alexandra; Pochart, Philippe; Day, Arnaud; Mennuni, Sarah; Bono, Pierre; Baret, Jean-Luc; Spadoni, Jean-Louis; Mangin, Irène

    2015-05-01

    Historically used in textile and paper industry, hemp fibres have started to find new applications in composite materials with important economic and ecological advantages. However, their applications are limited since manufacturers have some difficulties to standardise fabrication processes. This study is a first step before selection and isolation of strains that could later be used to optimise microbial retting efficiency and hence fibre quality. We studied six samples harvested on different ground types, at different dates and with different retting durations on field to obtain an exhaustive representation of the process. After DNA extraction, total bacteria and fungi associated with stems during retting were specifically quantified using real-time PCR. Then, using sequence analysis of randomly cloned 16S and 18S ribosomal RNA (rRNA) genes, a phylogenetic characterisation of the dominant microorganisms was carried out. Quantitatively, we showed that there were 8.1-9.5 log₁₀ 16S rRNA gene copies per gram of hemp straw for bacteria and 8.6-9.6 log₁₀ 18S rRNA gene copies per gram for fungi. Qualitatively, we noticed a higher bacterial diversity in comparison to fungi. This work showed that in the different samples, the same species were present but in significantly different proportions according to ground type, harvest dates and retting durations on field. The most frequent bacterial sequences were affiliated to species Escherichia coli, Pantoea agglomerans, Pseudomonas rhizosphaerae, Rhodobacter sp., Pseudomonas fulva, Rhizobium huautlense and Massilia timonae, whereas fungal sequences were principally related to the genera Cladosporium and Cryptococcus.

  6. Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization

    Directory of Open Access Journals (Sweden)

    Meadows Rena M

    2011-03-01

    Full Text Available Abstract Background The GDNF family ligands (GFLs are regulators of neurogenic inflammation and pain. We have previously shown that GFLs increase the release of the sensory neuron neuropeptide, calcitonin gene-related peptide (CGRP from isolated mouse DRG. Results Inhibitors of the mitogen-activated protein kinase (MAPK pathway abolished the enhancement of CGRP release by GDNF. Neurturin-induced enhancement in the stimulated release of CGRP, used as an indication of sensory neuronal sensitization, was abolished by inhibition of the phosphatidylinositol-3 kinase (PI-3K pathway. Reduction in Ret expression abolished the GDNF-induced sensitization, but did not fully inhibit the increase in stimulus-evoked release of CGRP caused by neurturin or artemin, indicating the presence of Ret-independent GFL-induced signaling in sensory neurons. Integrin β-1 and NCAM are involved in a component of Ret-independent GFL signaling in sensory neurons. Conclusions These data demonstrate the distinct and variable Ret-dependent and Ret-independent signaling mechanisms by which GFLs induce sensitization of sensory neurons. Additionally, there is a clear disconnect between intracellular signaling pathway activation and changes in sensory neuronal function.

  7. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.

    Directory of Open Access Journals (Sweden)

    Marialuisa Moccia

    Full Text Available Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI, ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.

  8. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.

    Science.gov (United States)

    Moccia, Marialuisa; Liu, Qingsong; Guida, Teresa; Federico, Giorgia; Brescia, Annalisa; Zhao, Zheng; Choi, Hwan Geun; Deng, Xianming; Tan, Li; Wang, Jinhua; Billaud, Marc; Gray, Nathanael S; Carlomagno, Francesca; Santoro, Massimo

    2015-01-01

    Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.

  9. Identification and Retting Efficiencies of Fungi Isolated from Dew-Retted Flax in the United States and Europe

    OpenAIRE

    Henriksson, G.; Akin, D. E.; Hanlin, R. T.; Rodriguez, C.; Archibald, D. D.; Rigsby, L L; Eriksson, K. L.

    1997-01-01

    Seven strains of filamentous fungi and one yeast were isolated from flax that was dew retted in the United States. These filamentous fungi were subcultured to purity and identified, and six appear not to have been reported earlier as isolates from dew-retted flax. Five of the purified U.S. strains, two fungi isolated from flax that was dew retted in Europe, and a laboratory culture of Aspergillus sojae were tested for their ability to ret flax stems. The monocultures were evaluated for the de...

  10. DDR-økonomerne havde ret i noget

    DEFF Research Database (Denmark)

    Bryld, Claus

    2016-01-01

    Siden Murens fald har der været frit løb for milliardærer og markedsliberalisme. Resultatet peger på, at de kommunistiske økonomer havde ret, når de malede skræmmescenarier af Vestens uhæmmede kapitalisme....

  11. Cognición y Retórica

    Directory of Open Access Journals (Sweden)

    Coronel Ramos, Marco Antonio

    2004-01-01

    Full Text Available Pocos términos existen tan mudables en la cultura occidental como el de retórica. Se le define como arte de la persuasión, como teoría de la argumentación o incluso como ciencia literaria. Todas estas perspectivas tienen un denominador común: entienden los tropos y figuras retóricas como instrumentos comunicativos y literarios. Sin obviar estos desarrollos de la retórica, los autores de este trabajo tratan de discernir los aspectos cognitivos rastreables en la retórica clásica y, al tiempo, ofrecer un acercamiento a lo que sería una retórica cognitiva, basada en el presupuesto de que tropos y figuras son redes conceptuales que estructuran el pensamiento humano.…

  12. Overexpression of wild-type c-RET and zero prevalence of RET/PTC rearrangements are associated with papillary thyroid cancer (PTC) in Kuwait.

    Science.gov (United States)

    El-Abdallah, Abir A; Junaid, Thamradeen A

    2011-02-01

    Papillary thyroid carcinoma (PTC) is common in Kuwait. The activation of the RET oncogene by DNA rearrangement (RET/PTC) is known to have an important role in PTC carcinogenesis. However, the real frequency of the RET/PTC expression in PTC is variable between different studies. This study seeks to determine the prevalence of RET/PTC and to analyze the RET oncogene expression associated with PTC in Kuwait. RET expression and DNA rearrangements (RET/PTC 1, RET/PTC 2 and RET/PTC 3) were studied by RT-PCR in different thyroid diseases. Results were confirmed by the Southern blot and by immunohistochemistry. Quantitative real-time PCR was used to determine the level of RET mRNA expression in PTCs. Wild-type (nonrearranged) c-RET oncogene was overexpressed in 60% of PTC cases and absent in follicular thyroid carcinoma (FTC), anaplastic thyroid carcinoma (ATC), follicular adenomas (FA) or normal thyroid. No RET/PTC rearrangement was detected in any sample. The c-RET expression in Hashimoto's thyroiditis and multinodular goiter was limited to follicular cells with PTC-like nuclear changes. The overexpression of wild-type c-RET is a characteristic molecular event of PTCs in Kuwait. The prevalence of RET/PTC is zero and among the lowest recorded in the world. Copyright © 2010 Elsevier Inc. All rights reserved.

  13. Comparative study of RetCamRetCam II vs. binocular ophthalmoscopy in a screening program for retinopathy of prematurity.

    Science.gov (United States)

    Tejada-Palacios, P; Zarratea, L; Moral, M; de la Cruz-Bértolo, J

    2015-08-01

    To determine the performance of RetCam vs. binocular ophthalmoscopy (BIO) in a screening program for retinopathy of prematurity (ROP). Observational comparative study with prospective data collection. Examinations with RetCam (n=169) were performed on 83 infants included in a screening program for ROP and stored for analysis at a later stage. An experienced ophthalmologist examined the ocular fundus with binocular indirect ophthalmoscopy (BIO). The RetCam images were assessed for the presence of ROP, zone, grade, and presence of plus disease. RetCam and BIO data were compared by visually to estimate sensitivity, specificity, positive (VPP) and negative (VPN) predictive values. ROP disease was detected in 108 eyes with BIO, and in 74 with RetCam. Out of 306 eyes examined with RetCam, false negative results were found in 34 eyes, with no false positives. Sensitivity of RetCam exam vs. BIO was 0.68, and specificity was 0.99. Positive predictive value was 0.93 and negative predictive value was 0.85. All 34 ROP cases not detected with RetCam were in zone III or outer zone II. They were all mild and regressed spontaneously. No threshold ROP was missed with RetCam. Binocular indirect ophthalmoscopy is the reference method for the diagnosis of ROP. RetCam may be used as an alternative for ROP screening. Copyright © 2010 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  14. RET receptor in the gut of developing cat.

    Science.gov (United States)

    Lucini, C; D'angelo, L; de Girolamo, P; Castaldo, L

    2013-02-01

    RET receptor is a transmembrane protein which, together with the glial-cell-line derived neurotrophic factor family receptors alpha, forms a receptor complex upon activation by the glial-cell-line-derived neurotrophic ligands (GFLs). RET signaling is crucial for: (a) development of the enteric nervous system and kidney; (b) development of sympathetic, parasympathetic, motor, and sensory neurons; (c) postnatal maintenance of dopaminergic neurons; (d) spermatogenesis. In humans, RET mutations cause the Hirschsprung's disease, characterized by megacolon aganglionosis, and different types of cancer, the multiple endocrine neoplasia type 2A and type 2B and familial medullary thyroid. In the earliest aged cat embryos studied (stage 9 according to Knopse), RET immunoreactivity (IR) was observed in few cells detected in bilateral rows extending latero-ventrally to the neural tube and dorso-laterally to the foregut. In the successive aged group (stage 11), RET IR was observed in few single or grouped epithelial cells of the anterior gut and in small clustered cells scattered in the mesenchyme around the anterior gut. From stage 14-22 (the last stage 22 includes foetuses around the birth), RET IR was seen in neurons and fibers of the enteric nervous system. The appearance and intensification of RET-IR in the gut occurred with cranio/caudal and external/internal directions during the development. These results, thus, suggest the involvement of GFLs in the neuroblast migration, proliferation and differentiation. For a short period of development, these molecules might also act on some cells of the epithelium.

  15. Bacterial population structure of the jute-retting environment.

    Science.gov (United States)

    Munshi, Tulika K; Chattoo, Bharat B

    2008-08-01

    Jute is one of the most versatile bast fibers obtained through the process of retting, which is a result of decomposition of stalks by the indigenous microflora. However, bacterial communities associated with the retting of jute are not well characterized. To investigate the presence of microorganisms during the process of jute retting, full-cycle rRNA approach was followed, and two 16S rRNA gene libraries, from jute-retting locations of Krishnanagar and Barrackpore, were constructed. Phylotypes affiliating to seven bacterial divisions were identified in both libraries. The bulk of clones came from Proteobacteria ( approximately 37, 41%) and a comparatively smaller proportion of clones from the divisions-Firmicutes ( approximately 11, 12%), Cytophaga-Flexibacter-Bacteroidetes group (CFB; approximately 9, 7%), Verrucomicrobia ( approximately 6, 5%), Acidobacteria ( approximately 4, 5%), Chlorobiales ( approximately 5, 5%), and Actinobacteria ( approximately 4, 2%) were identified. Percent coverage value and diversity estimations of phylotype richness, Shannon-Weiner index, and evenness confirmed the diverse nature of both the libraries. Evaluation of the retting waters by whole cell rRNA-targeted flourescent in situ hybridization, as detected by domain- and group-specific probes, we observed a considerable dominance of the beta-Proteobacteria (25.9%) along with the CFB group (24.4%). In addition, 32 bacterial species were isolated on culture media from the two retting environments and identified by 16S rDNA analysis, confirming the presence of phyla, Proteobacteria ( approximately 47%), Firmicutes ( approximately 22%), CFB group ( approximately 19%), and Actinobacteria ( approximately 13%) in the retting niche. Thus, our study presents the first quantification of the dominant and diverse bacterial phylotypes in the retting ponds, which will further help in improving the retting efficiency, and hence the fiber quality.

  16. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

    Directory of Open Access Journals (Sweden)

    Soo-Kyung Choi

    Full Text Available Multiple endocrine neoplasia type 2B (MEN2B is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.

  17. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

    Science.gov (United States)

    Choi, Soo-Kyung; Yoon, Song-Ro; Calabrese, Peter; Arnheim, Norman

    2012-01-01

    Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.

  18. A newly identified missense mutation in RET codon 666 is associated with the development of medullary thyroid carcinoma.

    Science.gov (United States)

    Yamazaki, Masanori; Hanamura, Toru; Ito, Ken-ichi; Uchino, Shinya; Sakurai, Akihiro; Komatsu, Mitsuhisa

    2014-01-01

    A 38-year-old woman with a thyroid nodule measuring approximately 2 cm was suspected to have medullary thyroid carcinoma (MTC) because of markedly elevated serum calcitonin and carcinoembryonic antigen levels. There were no signs of pheochromocytoma, whereas primary hyperparathyroidism was suspected based on the findings of inappropriate hypersecretion of parathyroid hormone although no parathyroid tumor was detected with imaging studies. RET mutation analysis revealed a novel germline missense mutation in codon 666, c.1997A>G (p.K666R). She underwent total thyroidectomy with lymphadenectomy and simultaneous total parathyroidectomy with autotransplantation of parathyroid tissue. She was given calcium lactate and alfacalcidol to prevent postoperative hypocalcemia. Pathological findings of the thyroid tumor were compatible with MTC, but the resected parathyroid glands were intact. To our knowledge, c.1997A>G (p.K666R) is a new RET mutation. This is a minor variant, but it is significant because of the possible pathogenicity in tumor formation. It is often difficult to determine whether MTC is generated as part of MEN2-related disease or familial MTC when it is a unique manifestation. In addition, it is still unclear whether all missense mutations in this codon reported previously will lead to the same clinical course and prognosis. Further careful observations of clinical presentation are required to determine the clinical features associated with this variant.

  19. Distinct Temporal Regulation of RET Isoform Internalization: Roles of Clathrin and AP2.

    Science.gov (United States)

    Crupi, Mathieu J F; Yoganathan, Piriya; Bone, Leslie N; Lian, Eric; Fetz, Andrew; Antonescu, Costin N; Mulligan, Lois M

    2015-11-01

    The RET receptor tyrosine kinase (RTK) contributes to kidney and nervous system development, and is implicated in a number of human cancers. RET is expressed as two protein isoforms, RET9 and RET51, with distinct interactions and signaling properties that contribute to these processes. RET isoforms are internalized from the cell surface into endosomal compartments in response to glial cell line-derived neurotropic factor (GDNF) ligand stimulation but the specific mechanisms of RET trafficking remain to be elucidated. Here, we used total internal reflection fluorescence (TIRF) microscopy to demonstrate that RET internalization occurs primarily through clathrin coated pits (CCPs). Activated RET receptors colocalize with clathrin, but not caveolin. The RET51 isoform is rapidly and robustly recruited to CCPs upon GDNF stimulation, while RET9 recruitment occurs more slowly and is less pronounced. We showed that the clathrin-associated adaptor protein complex 2 (AP2) interacts directly with each RET isoform through its AP2 μ subunit, and is important for RET internalization. Our data establish that interactions with the AP2 complex promote RET receptor internalization via clathrin-mediated endocytosis but that RET9 and RET51 have distinct internalization kinetics that may contribute to differences in their biological functions.

  20. Germline modification of domestic animals.

    Science.gov (United States)

    Tang, L; González, R; Dobrinski, I

    2015-01-01

    Genetically-modified domestic animal models are of increasing significance in biomedical research and agriculture. As authentic ES cells derived from domestic animals are not yet available, the prevailing approaches for engineering genetic modifications in those animals are pronuclear microinjection and somatic cell nuclear transfer (SCNT, also known as cloning). Both pronuclear microinjection and SCNT are inefficient, costly, and time-consuming. In animals produced by pronuclear microinjection, the exogenous transgene is usually inserted randomly into the genome, which results in highly variable expression patterns and levels in different founders. Therefore, significant efforts are required to generate and screen multiple founders to obtain animals with optimal transgene expression. For SCNT, specific genetic modifications (both gain-of-function and loss-of-function) can be engineered and carefully selected in the somatic cell nucleus before nuclear transfer. SCNT has been used to generate a variety of genetically modified animals such as goats, pigs, sheep and cattle; however, animals resulting from SCNT frequently suffer from developmental abnormalities associated with incomplete nuclear reprogramming. Other strategies to generate genetically-modified animals rely on the use of the spermatozoon as a natural vector to introduce genetic material into the female gamete. This sperm mediated DNA transfer (SMGT) combined with intracytoplasmatic sperm injection (ICSI) has relatively high efficiency and allows the insertion of large DNA fragments, which, in turn, enhance proper gene expression. An approach currently being developed to complement SCNT for producing genetically modified animals is germ cell transplantation using genetically modified male germline stem cells (GSCs). This approach relies on the ability of GSCs that are genetically modified in vitro to colonize the recipient testis and produce donor derived sperm upon transplantation. As the genetic change

  1. Achieving immortality in the C. elegans germline.

    Science.gov (United States)

    Smelick, Chris; Ahmed, Shawn

    2005-01-01

    Germline immortality is a topic that has intrigued theoretical biologists interested in aging for over a century. The germ cell lineage can be passed from one generation to the next, indefinitely. In contrast, somatic cells are typically only needed for a single generation and are then discarded. Germ cells may, therefore, harbor rejuvenation mechanisms that enable them to proliferate for eons. Such processes are thought to be either absent from or down-regulated in somatic cells, although cell non-autonomous forms of rejuvenation are formally possible. A thorough description of mechanisms that foster eternal youth in germ cells is lacking. The mysteries of germline immortality are being addressed in the nematode Caenorhabditis elegans by studying mutants that reproduce normally for several generations but eventually become sterile. The mortal germline mutants probably become sterile as a consequence of accumulating various forms of heritable cellular damage. Such mutants are abundant, indicating that several different biochemical pathways are required to rejuvenate the germline. Thus, forward genetics should help to define mechanisms that enable the germline to achieve immortality.

  2. Mutation of RET gene in Chinese patients with Hirschsprung's disease

    Institute of Scientific and Technical Information of China (English)

    Ji-Cheng Li; Shi-Ping Ding; Ying Song; Min-Ju Li

    2002-01-01

    AIM: To investigate the pathogenic mechanism of Hirschsprung's disease (HD) at the molecular level and to elucidate the relationship between RET oncogene and Chinese patients with HD.METHODS: Exon 13 of RET oncogene from 20 unrelated HD patients was analyzed with polymerase chain reactionsingle strand conformation polymorphism (PCR-SSCP). The positive amplifying products were then sequenced. According to the results of SSCP and DNA sequence, SSCP was done as well for the samples from the family other members of some cases with mutated RET gene.RESULTS: SSCP analysis indicated that mobility abnormality existed in 4 unrelated HD patients. Direct DNA sequence analysis identified a missense mutation, T to G at the nucleotide 18 888 and a frameshift mutation at the nucleotide 18 926 insG. In a HD family, the sicked child and his father were the same heterozygous missense mutation (T to G at nucleotide 18 888).CONCLUSION: Among Chinese HD patients, RET gene mutations may exist in considerable proportion with different patterns. These new discoveries indicate that RET mutations may play an important role in the pathogenesis of unrelated HD in the Chinese population. PCR-SSCP combined with DNA sequence can be used as a tool in the genetic diagnosis of HD.

  3. Retórica y literatura: desde Homero, actividades gemelas

    Directory of Open Access Journals (Sweden)

    Luis Quintana-Tejera

    2014-03-01

    Full Text Available En este ensayo se argumenta que siglos antes de que se escribieran los más antiguos manuales de retórica conocidos hoy en día, diversas acciones elocutivas claramente enmarcables en la doctrina de esta disciplina aparecen referidas en La Iliada, lo cual demuestra que el uso de la retórica como método de análisis del discurso y cómo técnica de producción del discurso está inscrito en los orígenes mismos de los textos literarios.

  4. Assessment of RET/PTC1 and RET/PTC3 rearrangements in fine-needle aspiration biopsy specimens collected from patients with Hashimoto's thyroiditis

    Directory of Open Access Journals (Sweden)

    Cyniak-Magierska Anna

    2011-01-01

    Full Text Available Abstract Background RET/PTC rearrangements are the most frequent molecular changes in papillary thyroid carcinoma (PTC. So far, 15 main RET/PTC rearrangements have been described, among which RET/PTC1 and RET/PTC3 are the most common in PTC - especially in radiation-induced tumours. RET/PTC1 and RET/PTC3 are the result of intrachromosomal paracentric inversions in chromosome 10, where RET and the activating genes (H4 and ELE1, respectively are located. Recently, RET/PTC rearrangements have been shown not only in PTC but also in benign thyroid lesions, including Hashimoto's thyroiditis (HT. The aim of study was an assessment of RET/PTC1 and RET/PTC3 rearrangements in patients with Hashimoto's thyroiditis. Materials and methods Thyroid aspirates, eligible for the study, were obtained from 26 patients with Hashimoto's thyroiditis by fine-needle aspiration biopsy (FNAB. Each aspirate was smeared for conventional cytology, while its remaining part was immediately washed out of the needle. The cells, obtained from the needle, were used in further investigation. Total RNA from FNAB was extracted by use of an RNeasy Micro Kit, based on modified Chomczynski and Sacchi's method and reverse transcription (RT-PCR was done. Quantitative evaluation of RET/PTC1 and RET/PTC3 rearrangements by real-time PCR was performed by an ABI PRISM® 7500 Sequence Detection System. In the study, PTC tissues with known RET/PTC1 and RET/PTC3 rearrangements served as a reference standard (calibrator, while β-actin gene was used as endogenous control. Results Amplification reactions were done in triplicate for each examined sample. No RET/PTC1 and RET/PTC3 rearrangements were found in the examined samples. Conclusions Our results indicate that RET/PTC1 and RET/PTC3 rearrangements in Hashimoto's thyroiditis, if any, are rather rare events and further investigations should be conducted in order to determine molecular changes, connecting Hashimoto's thyroiditis with PTC.

  5. RET-targeting molecular stratified non-small-cell lung cancers

    OpenAIRE

    Tsuchihara, Katsuya

    2013-01-01

    Recent advances in lung cancer genomics have successfully characterized therapeutic targets of lung cancer. RET fusion gene products are among the newest target molecules for lung adenocarcinoma. Preclinical findings and preliminary reports regarding potential tumor control by RET-targeting multi-kinase inhibitors encourage further clinical trials. The infrequent prevalence of RET fusion gene-positive cases may be a major obstacle hindering the development of RET-targeted therapy. Thus, it is...

  6. Activated RET/PTC oncogene elicits immediate early and delayed response genes in PC12 cells.

    Science.gov (United States)

    Califano, D; Monaco, C; de Vita, G; D'Alessio, A; Dathan, N A; Possenti, R; Vecchio, G; Fusco, A; Santoro, M; de Franciscis, V

    1995-07-06

    The expression of the receptor-like tyrosine kinase RET is associated with tumors, tissues or cell lines of neural crest origin. In addition RET products (Ret) are involved in determining cell fate during the differentiation of the enteric nervous system and during renal organogenesis. However, as yet, no direct evidence exists to indicate that the Ret kinase activity might interfere in a specific way with cellular differentiation, or proliferation, of a neural crest derived cell line. By using two constitutively activated forms of RET (RET/PTC1 and RET/PTC3) in transient transfection experiments, we have obtained evidence that active RET could reprogramme the gene expression pattern in the rat pheochromocytoma PC12 cell line. Transcription driven by gene promoters, such as NGFI-A and vgf, which belong, respectively, to primary and delayed response genes to nerve growth factor (NGF), and by the neuron-specific enolase (NSE) promoter, is rapidly induced by the expression of activated RET oncogenes. This induction is not elicited in other non neural derived cell types tested. We also demonstrate that endogenous ras activity is required for RET induction of these neural markers. Finally, in the RET/PTC transfected PC12 cells, NGF is unable to induce further their transcription. This suggests that RET/PTC could share an intracellular signalling pathway with the NGF-receptor.

  7. [Oncogenes RET/PTC and mechanisms of their involvement in thyroid cancerogenesis].

    Science.gov (United States)

    Voskoboĭnyk, L H

    2009-01-01

    Papillary thyroid carcinomas are the most common type of thyroid oncopathology, and are rather often associated with the expression of RET/PTC oncogens. The first oncogen RET/PTC1 was isolated more than 20 years ago. Now 13 different forms of RET/PTC are known, and 12 different partner-genes are described, that could be involved in formation of RET/PTC oncogenes. The most common of them are RET/PTC1 and RET/PTC3 forms. The great majority of oncogens RET/PTC, except for two--ELKS-RET and HOOK3-RET, have been founded in radioaction-induced thyroid tumors. There is an opinion that the key role in development of papillary thyroid carcinomas belongs to RET/PTC oncogens. The data about different types of RET/PTC oncogens, factors, that lead to their formation have been described in the present review. Also different mechanisms of activation of transduction pathways and gene's expression in thyroid cells after RET/PTC induction have been presented.

  8. Epigenetic inheritance and plasticity: The responsive germline.

    Science.gov (United States)

    Jablonka, Eva

    2013-04-01

    Developmental plasticity, the capacity of a single genotype to give rise to different phenotypes, affects evolutionary dynamics by influencing the rate and direction of phenotypic change. It is based on regulatory changes in gene expression and gene products, which are partially controlled by epigenetic mechanisms. Plasticity involves not just epigenetic changes in somatic cells and tissues; it can also involve changes in germline cells. Germline epigenetic plasticity increases evolvability, the capacity to generate heritable, selectable, phenotypic variations, including variations that lead to novel functions. I discuss studies that show that some complex adaptive responses to new challenges are mediated by germline epigenetic processes, which can be transmitted over variable number of generations, and argue that the heritable variations that are generated epigenetically have an impact on both small-scale and large-scale aspects of evolution. First, I review some recent ecological studies and models that show that germline (gametic) epigenetic inheritance can lead to cumulative micro-evolutionary changes that are rapid and semi-directional. I suggest that "priming" and "epigenetic learning" may be of special importance in generating heritable, fine-tuned adaptive responses in populations. Second, I consider work showing how genomic and environmental stresses can also lead to epigenome repatterning, and produce changes that are saltational.

  9. Dancing Around My Technology Classroom Box (My Second RET Lab)

    Science.gov (United States)

    Carter, Terry

    2010-01-01

    The laboratory the author had been assigned for his RET (Research Experience for Teachers) at Vanderbilt University is new and different from the one he had previously experienced. This summer he was assigned to the Microfluidics and Lab-on-a-chip laboratory to help research dielectrophoresis. As this is an emerging technology, there was not a lot…

  10. Meie esimese luuletõlke-antoloogia puhul : [rets.] / Ain Kaalep

    Index Scriptorium Estoniae

    Kaalep, Ain, 1926-

    1997-01-01

    Ilm.: Kirjandus kriitiku pilguga : artikleid, arvustusi ja aastaülevaateid 1975-1976. Tallinn : Eesti Raamat, 1978, lk. 25-31 ; Keel ja Kirjandus 1975, nr. 5, lk. 309-311 . Rets. rmt.: Sang, August. Laenatud laulud I: luuletõlkeid. Tallinn : Eesti Raamat, 1973. 336 lk.; Sang, August. Laenatud laulud II: luuletõlkeid. Tallinn : Eesti Raamat, 1974. 392 lk.

  11. Incidence of RET mutations in patients with Hirschsprung's disease

    NARCIS (Netherlands)

    Sancandi, M; Ceccherini, [No Value; Costa, M; Fava, M; Chen, B; Wu, Y; Hofstra, R; Laurie, T; Griffths, M; Burge, D; Tam, PKH

    2000-01-01

    Background: RET mutations have been reported variously to affect 7% to 41% of Hirschsprung's disease (HSCR) patients depending on familial or sporadic occurrence of the disease, length of aganglionosis and possible association with other disease phenotypes. The authors report a study of the incidenc

  12. DNA topoisomerases participate in fragility of the oncogene RET.

    Directory of Open Access Journals (Sweden)

    Laura W Dillon

    Full Text Available Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH-induced DNA breakage within the RET oncogene, in which 144 APH-induced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication.

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

    National Research Council Canada - National Science Library

    Roberto Gamonal Arroyo

    2012-01-01

    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...

  14. 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.

  15. El Fedro y la Ret??rica de Arist??teles

    OpenAIRE

    Vallejo Campos, ??lvaro

    1994-01-01

    En este art??culo se analiza la relaci??n entre la ret??rica concebida como t??chne en el Fedro y la Ret??rica de Arist??teles, con referencias al Grilo y al Curso de Ret??rica impartido por Arist??teles en la Academia. El autor defiende la existencia de diferencias profundas entre el supuesto programa plat??nico para la conversi??n de la ret??rica en t??chne y la obra de Arist??teles. Por tanto la Ret??rica no se puede considerar la continuaci??n del proyecto plat??nico del Fedro. Para Plat?...

  16. 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

  17. The oogenic germline starvation response in C. elegans.

    Directory of Open Access Journals (Sweden)

    Hannah S Seidel

    Full Text Available Many animals alter their reproductive strategies in response to environmental stress. Here we have investigated how L4 hermaphrodites of Caenorhabditis elegans respond to starvation. To induce starvation, we removed food at 2 h intervals from very early- to very late-stage L4 animals. The starved L4s molted into adulthood, initiated oogenesis, and began producing embryos; however, all three processes were severely delayed, and embryo viability was reduced. Most animals died via 'bagging,' because egg-laying was inhibited, and embryos hatched in utero, consuming their parent hermaphrodites from within. Some animals, however, avoided bagging and survived long term. Long-term survival did not rely on embryonic arrest but instead upon the failure of some animals to produce viable progeny during starvation. Regardless of the bagging fate, starved animals showed two major changes in germline morphology: All oogenic germlines were dramatically reduced in size, and these germlines formed only a single oocyte at a time, separated from the remainder of the germline by a tight constriction. Both changes in germline morphology were reversible: Upon re-feeding, the shrunken germlines regenerated, and multiple oocytes formed concurrently. The capacity for germline regeneration upon re-feeding was not limited to the small subset of animals that normally survive starvation: When bagging was prevented ectopically by par-2 RNAi, virtually all germlines still regenerated. In addition, germline shrinkage strongly correlated with oogenesis, suggesting that during starvation, germline shrinkage may provide material for oocyte production. Finally, germline shrinkage and regeneration did not depend upon crowding. Our study confirms previous findings that starvation uncouples germ cell proliferation from germline stem cell maintenance. Our study also suggests that when nutrients are limited, hermaphrodites scavenge material from their germlines to reproduce. We discuss

  18. RET receptor expression in thyroid follicular epithelial cell-derived tumors.

    Science.gov (United States)

    Bunone, G; Uggeri, M; Mondellini, P; Pierotti, M A; Bongarzone, I

    2000-06-01

    The RET proto-oncogene encodes a receptor tyrosine kinase for transforming growth factor-beta-related neurotrophic factors, which include GDNF and neurturin. The expression of RET proto-oncogene was detected in several tissues, such as spleen, thymus, lymph nodes, salivary gland, and spinal cord, and in several neural crest-derived cell lines. RET expression in the thyroid gland was reported to be restricted to neural crest-derived C cells. The presence of RET mRNA or protein has not yet been reported in thyroid follicular cells. We previously demonstrated the expression of oncogenic rearranged versions of RET in papillary thyroid carcinomas: tumors derived from thyroid follicular cells. To assess the expression of the normal RET proto-oncogene in follicular cells, we analyzed its expression in a panel of neoplasias originating from thyroid follicular epithelial cells: papillary carcinomas and both follicular adenomas and carcinomas. We also demonstrated the presence of RET normal transcripts in two follicular thyroid carcinoma lymph node metastases. Moreover, we found the presence of the RET/ELE1 transcript, the reciprocal complementary form of the oncogenic fusion transcript ELE1/RET, in a papillary thyroid carcinoma specimen expressing the RET/PTC3 oncogene, thus demonstrating that the RET promoter is active in those cells after rearrangement. Finally, we show that in a papillary carcinoma-derived cell line expressing the proto-RET receptor and the related GFRalpha2 co-receptor, GDNF treatment induced RET tyrosine phosphorylation and subsequent signal transduction pathway, indicating that RET could be active in thyroid follicular cells.

  19. Ética, Retórica y democracia

    OpenAIRE

    Diego Bautista, Oscar

    2012-01-01

    “Ética, Retórica y Democracia” se orienta al análisis de la retórica en la vida política y su papel en el juego democrático. Esta obra muestra algunas características básicas de esta disciplina dedicada al estudio de la palabra así como las dos clases generales que existen de la misma, acompañadas de los elementos que las distinguen. También, retoma la cuestión que desde antaño se planteaban en la Grecia Clásica acerca de si el político debe o no hablar con la verdad en su discurso. Otro ...

  20. Germline genome-editing research and its socioethical implications.

    Science.gov (United States)

    Ishii, Tetsuya

    2015-08-01

    Genetically modifying eggs, sperm, and zygotes ('germline' modification) can impact on the entire body of the resulting individual and on subsequent generations. With the advent of genome-editing technology, human germline gene modification is no longer theoretical. Owing to increasing concerns about human germline gene modification, a voluntary moratorium on human genome-editing research and/or the clinical application of human germline genome editing has recently been called for. However, whether such research should be suspended or encouraged warrants careful consideration. The present article reviews recent research on mammalian germline genome editing, discusses the importance of public dialogue on the socioethical implications of human germline genome-editing research, and considers the relevant guidelines and legislation in different countries.

  1. RET/PTC Translocations and Clinico-Pathological Features in Human Papillary Thyroid Carcinoma.

    Science.gov (United States)

    Romei, Cristina; Elisei, Rossella

    2012-01-01

    Thyroid carcinoma is the most frequent endocrine cancer accounting for 5-10% of thyroid nodules. Papillary histotype (PTC) is the most prevalent form accounting for 80% of all thyroid carcinoma. Although much is known about its epidemiology, pathogenesis, clinical, and biological behavior, the only documented risk factor for PTC is the ionizing radiation exposure. Rearrangements of the Rearranged during Transfection (RET) proto-oncogene are found in PTC and have been shown to play a pathogenic role. The first RET rearrangement, named RET/PTC, was discovered in 1987. This rearrangement constitutively activates the transcription of the RET tyrosine-kinase domain in follicular cell, thus triggering the signaling along the MAPK pathway and an uncontrolled proliferation. Up to now, 13 different types of RET/PTC rearrangements have been reported but the two most common are RET/PTC1 and RET/PTC3. Ionizing radiations are responsible for the generation of RET/PTC rearrangements, as supported by in vitro studies and by the evidence that RET/PTC, and particularly RET/PTC3, are highly prevalent in radiation induced PTC. However, many thyroid tumors without any history of radiation exposure harbor similar RET rearrangements. The overall prevalence of RET/PTC rearrangements varies from 20 to 70% of PTCs and they are more frequent in childhood than in adulthood thyroid cancer. Controversial data have been reported on the relationship between RET/PTC rearrangements and the PTC prognosis. RET/PTC3 is usually associated with a more aggressive phenotype and in particular with a greater tumor size, the solid variant, and a more advanced stage at diagnosis which are all poor prognostic factors. In contrast, RET/PTC1 rearrangement does not correlate with any clinical-pathological characteristics of PTC. Moreover, the RET protein and mRNA expression level did not show any correlation with the outcome of patients with PTC and no correlation between RET/PTC rearrangements and the

  2. RET single nucleotide polymorphism in Indonesians with sporadic Hirschsprung’s disease

    Directory of Open Access Journals (Sweden)

    Saryono

    2010-08-01

    Full Text Available The tyrosine kinase receptor RET, which is the protein product of the RET gene, is involved in the development of the mammalian nervous system that causes Hirschsprung’s disease (HSCR. RETs are cell surface molecules that are expressed in cells derived from the neural crest. The purpose of this study was to investigate the polymorphism of the RET gene in HSCR in the Yogyakarta population. Genomic DNA was extracted from surgically removed bowel tissues of 54 unrelated HSCR patients. Exon 2 of the RET gene was amplified by polymerase chain reaction (PCR and analyzed by restriction fragment length polymorphism (RFLP. Molecular results were compared with clinical performance of Hirschsprung patients. RET polymorphism was detected in exon 2 in all of the 54 Indonesian HSCR patients. The allelic distribution of the c135GàA polymorphism in the RET exon 2 indicated that the A allele was more frequent in patients than in control individuals (chi-square test, p= 0.001. Thus the RET variant allele A is over-represented in patients affected with the HSCR phenotype. Polymorphism of exon 2 of the RET gene was found in sporadic Hirschsprung’s disease in the Yogyakarta population, which suggests that the RET gene plays important roles in the pathogenesis of HSCR.

  3. Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC.

    Science.gov (United States)

    Unger, K; Malisch, E; Thomas, G; Braselmann, H; Walch, A; Jackl, G; Lewis, P; Lengfelder, E; Bogdanova, T; Wienberg, J; Zitzelsberger, H

    2008-07-31

    The aim of this study is to investigate additional genetic alterations in papillary thyroid carcinomas (PTCs) with known RET/PTC rearrangements. We applied array-based comparative genomic hybridization (array CGH) to 33 PTC (20 PTC from adults, 13 post-Chernobyl PTC from children) with known RET/PTC status. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups were obtained by statistical testing (Fisher's exact test in combination with Benjamini-Hochberg FDR-controlling procedure). FISH analysis on FFPE sections was applied to validate the array CGH data. Deletions were found more frequently in RET/PTC-positive and RET/PTC-negative tumours than amplifications. Specific aberration signatures were identified that discriminated between RET/PTC-positive and RET/PTC-negative cases (aberrations on chromosomes 1p, 3q, 4p, 7p, 9p/q, 10q, 12q, 13q and 21q). In addition, childhood and adult RET/PTC-positive cases differ significantly for a deletion on the distal part of chromosome 1p. There are additional alterations in RET/PTC-positive tumours, which may act as modifiers of RET activation. In contrast, alterations in RET/PTC-negative tumours indicate alternative routes of tumour development. The data presented serve as a starting point for further studies on gene expression and function of genes identified in this study.

  4. RET single nucleotide polymorphism in Indonesians with sporadic Hirschsprung’s disease

    Directory of Open Access Journals (Sweden)

    Saryono Saryono

    2016-02-01

    Full Text Available The tyrosine kinase receptor RET, which is the protein product of the RET gene, is involved in the development of the mammalian nervous system that causes Hirschsprung’s disease (HSCR. RETs are cell surface molecules that are expressed in cells derived from the neural crest. The purpose of this study was to investigate the polymorphism of the RET gene in HSCR in the Yogyakarta population. Genomic DNA was extracted from surgically removed bowel tissues of 54 unrelated HSCR patients. Exon 2 of the RET gene was amplified by polymerase chain reaction (PCR and analyzed by restriction fragment length polymorphism (RFLP. Molecular results were compared with clinical performance of Hirschsprung patients. RET polymorphism was detected in exon 2 in all of the 54 Indonesian HSCR patients. The allelic distribution of the c135GàA polymorphism in the RET exon 2 indicated that the A allele was more frequent in patients than in control individuals (chi-square test, p= 0.001. Thus the RET variant allele A is over-represented in patients affected with the HSCR phenotype. Polymorphism of exon 2 of the RET gene was found in sporadic Hirschsprung’s disease in the Yogyakarta population, which suggests that the RET gene plays important roles in the pathogenesis of HSCR.

  5. High growth rate of benign thyroid nodules bearing RET/PTC rearrangements.

    Science.gov (United States)

    Sapio, Maria Rosaria; Guerra, Anna; Marotta, Vincenzo; Campanile, Elisabetta; Formisano, Raffaele; Deandrea, Maurilio; Motta, Manuela; Limone, Paolo Piero; Fenzi, Gianfranco; Rossi, Guido; Vitale, Mario

    2011-06-01

    Benign thyroid nodules display a broad range of behaviors from a stationary size to a progressive growth. The RET/PTC oncogene has been documented in a fraction of benign thyroid nodules, besides papillary thyroid carcinomas, and it might therefore influence their growth. The aim of the present work was to evaluate whether RET/PTC in benign thyroid nodules associates with a different nodular growth rate. In this prospective multicentric study, 125 subjects with benign nodules were included. RET rearrangements were analyzed in cytology samples; clinical and ultrasonographic nodule characteristics were assessed at the start and at the end of the study. RET/PTC was present in 19 nodules. The difference between the mean baseline nodular volume of the RET/PTC- and RET/PTC+ nodules was not significant. After 36 months of follow-up, the RET/PTC+ group (n = 16) reached a volume higher than the RET/PTC- group (n = 90) (5.04 ± 2.67 vs. 3.04 ± 2.26 ml; P = 0.0028). We calculated the monthly change of nodule volumes as a percentage of baseline. After a mean follow-up of 36.6 months, the monthly volume increase of nodules bearing a RET rearrangement was 4.3-fold that of nodules with wild-type RET (1.83 ± 1.2 vs. 0.43 ± 1.0% of baseline volume; P < 0.0001). Benign thyroid nodules bearing RET rearrangements grow more rapidly than those with wild-type RET. Searching for RET rearrangements in benign thyroid nodules might be useful to the clinician in choosing the more appropriate and timely therapeutic option.

  6. 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.

  7. 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.

  8. Translational control in germline stem cell development.

    Science.gov (United States)

    Slaidina, Maija; Lehmann, Ruth

    2014-10-13

    Stem cells give rise to tissues and organs during development and maintain their integrity during adulthood. They have the potential to self-renew or differentiate at each division. To ensure proper organ growth and homeostasis, self-renewal versus differentiation decisions need to be tightly controlled. Systematic genetic studies in Drosophila melanogaster are revealing extensive regulatory networks that control the switch between stem cell self-renewal and differentiation in the germline. These networks, which are based primarily on mutual translational repression, act via interlocked feedback loops to provide robustness to this important fate decision.

  9. Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors.

    Science.gov (United States)

    Fleming, Michael S; Vysochan, Anna; Paixão, Sόnia; Niu, Jingwen; Klein, Rüdiger; Savitt, Joseph M; Luo, Wenqin

    2015-04-02

    RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfrα2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfrα2 null mice display comparable early central projection deficits, but Gfrα2 null RA mechanoreceptors recover later. Loss of Gfrα1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfrα1;Gfrα2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRα1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling.

  10. 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.

  11. 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.

  12. Absence of mutations in the RET gene in acute myeloid leukemia

    NARCIS (Netherlands)

    Visser, M; Hofstra, RMW; Stulp, RP; Wu, Y; Buys, CHCM; Willemze, R; Landegent, JE

    1997-01-01

    Expression of the tyrosine kinase receptor RET has previously been detected in normal hematopoietic cells, and especially in cells of the myeloid lineage. Furthermore, RET was shown to be differentially expressed in acute myeloid leukemia (AML), a disease characterized by excessive cell growth and a

  13. 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

  14. RET and GDNF gene scanning in Hirschprung patients using two dual denaturing gel systems

    NARCIS (Netherlands)

    Hofstra, RMW; Wu, Y; Stulp, RP; Elfferich, P; Osinga, J; Maas, SM; Siderius, L; Brooks, AS; Von der Ende, JJ; Heydendael, VMR; Severijnen, RSVM; Bax, KMA; Meijers, C; Buys, CHCM

    2000-01-01

    Hirschsprung disease (HSCR) is a congenital disorder characterised by intestinal obstruction due to an absence of intramural ganglia along variable lengths of the intestine. RET is the major gene involved in HSCR. Mutations in the GDNF gene, and encoding one of the RET ligands, either alone or in co

  15. A temperature condensation trend in the debris-disk binary system Zet2 Ret

    CERN Document Server

    Saffe, C; Arancibia, M Jaque; Buccino, A; Jofre, E

    2016-01-01

    We explore condensation temperature Tc trends in the unique binary system Zet1 Ret - Zet2 Ret, to determine whether there is a depletion of refractories, which could be related to the planet formation process. The star Zet2 Ret hosts a debris disk which was detected by an IR excess and confirmed by direct imaging and numerical simulations, while Zet1 Ret does not present IR excess nor planets. We carried out a high-precision abundance determination in both components of the binary system via a line-by-line, strictly differential approach. The stellar parameters Teff , log g, [Fe/H] and vturb were determined by imposing differential ionization and excitation equilibrium of Fe I and Fe II lines, with an updated version of the program FUNDPAR. The star Zet1 Ret resulted slightly more metal rich than Zet2 Ret by 0.02 dex. In the differential calculation of Zet1 Ret using Zet2 Ret as reference, the abundances of the refractory elements resulted higher than the volatile elements, and the trend of the refractory ele...

  16. Methods in Molecular Biology: Germline Stem Cells | Center for Cancer Research

    Science.gov (United States)

    The protocols in Germline Stem Cells are intended to present selected genetic, molecular, and cellular techniques used in germline stem cell research. The book is divided into two parts. Part I covers germline stem cell identification and regulation in model organisms. Part II covers current techniques used in in vitro culture and applications of germline stem cells.

  17. RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer.

    Science.gov (United States)

    Lodish, Maya B; Stratakis, Constantine A

    2008-04-01

    Hereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of-function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, and will summarize the therapies designed to strategically interfere with the pathologic activation of the RET oncogene.

  18. Germline mosaicism at the fragile X locus

    Energy Technology Data Exchange (ETDEWEB)

    Papp, A.C.; Snyder, P.J.; Sedra, M.S. [Ohio State Univ., Columbus, OH (United States)] [and others

    1994-09-01

    The fragile X full mutation, which is associated with the phenotypic expression of the disorder, is characterized by an expansion of CGG repeat and hypermethylation of the CpG island adjacent to the FMR1 gene. New mutations leading to amplification of the CGG repeat have not been reported. We have identified a fragile X syndrome pedigree where the disorder is associated with a molecular deletion. The deletion was present in the DNA of two affected sons but was absent in the mother`s somatic cell (lymphocyte) DNA. This was confirmed by dosage analysis of the Southern blot using StB12-3 and an additional probe against the dystrophin gene and by PCR analysis of DXS548 alleles. The results are consistent with the deletion arising as a postzygotic event in the mother, who therefore is germinally mosaic. The case reported here clearly demonstrates that FMR1 deletions, unlike the expansions, are not always inherited and the finding of heterozygosity or normal dosage from lymphocyte DNA in the mother of a deletion case does not necessarily rule out the possibility of having a second affected child. The deletion of FMR1 gene may be responsible for a small but significant number of fragile X cases. Therefore, it is imperative that those involved in genetic counseling recognize this diagnostic pitfall. Since it depends upon the size of the mutant clone in the mosaic mother, the exact recurrence risk in germline carriers is unknown. However, prenatal and carrier testing should be performed independently of the outcome of the mother. Furthermore, it is possible that the deletion may not be restricted to the germline, and therefore the mother may actually be a somatic mosaic.

  19. RET(MEN 2B) is active in the endoplasmic reticulum before reaching the cell surface.

    Science.gov (United States)

    Runeberg-Roos, P; Virtanen, H; Saarma, M

    2007-12-13

    MEN 2B (multiple endocrine neoplasia type 2B) is an autosomal dominant cancer syndrome caused by an oncogenic form of the receptor tyrosine kinase REarranged during transfection (RET). The MEN 2B syndrome is associated with an abnormal autophosphorylation of the mutated receptor even without ligand-stimulation. Here, we characterize the activation of a RET(MEN 2B) variant carrying the point mutation Met918Thr, and show that the 150 kDa precursor of RET(MEN 2B) becomes phosphorylated already during synthesis in the endoplasmic reticulum (ER). At least three different tyrosine residues (Tyr905, Tyr1062, Tyr1096) of the RET(MEN 2B) precursor are phosphorylated before the oncogenic receptor reaches the cell surface. We also demonstrate that the precursor of RET(MEN 2B) interacts with both growth factor receptor-bound protein and Src homology 2 domain-containing already in the ER, and that this interaction is dependent on the kinase activity of RET. With the aid of two RET mutants (RET(MEN 2B/S32L) and RET(MEN 2B/F393L)), which accumulate in the ER, we show that the oncogenic precursor of the receptor has the capacity to activate AKT, extracellular signal-regulated kinase and signal transducer and activator of transcription 3 from the ER. Taken together, our data demonstrate that the oncogenic precursor of RET(MEN 2B) is phosphorylated, interacts with adapter proteins and induces downstream signalling from the ER.

  20. Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-1, in small cell lung carcinoma

    NARCIS (Netherlands)

    Mulligan, LM; Timmer, T; Ivanchuk, SM; Campling, BG; Young, LC; Rabbitts, PH; Sundaresan, [No Value; Hofstra, RMW; Eng, C

    1998-01-01

    RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors of these cell types. RET activation may be mediated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFR alpha-1). Activating RET mutations are found i

  1. A novel RET/PTC variant detected in a pediatric patient with papillary thyroid cancer without ionization history.

    Science.gov (United States)

    Halkova, Tereza; Dvorakova, Sarka; Vaclavikova, Eliska; Sykorova, Vlasta; Vcelak, Josef; Sykorova, Pavla; Vlcek, Petr; Reboun, Martin; Katra, Rami; Kodetova, Daniela; Schrumpf, Melanie; van Wezel, Tom; Morreau, Hans; Bendlova, Bela

    2015-12-01

    Papillary thyroid carcinoma (PTC) is the most frequent type of thyroid cancer. Its development is often caused by the formation of RET/PTC fused genes. RET/PTC1 is the most prevalent form, where exon 1 of CCDC6 gene is fused with the intracellular portion of RET protooncogene starting with exon 12. We have discovered a novel RET/PTC1 variant which we have named RET/PTC1ex9 in metastatic PTC of 8-year-old boy. RET/PTC1ex9 detection was performed by real-time polymerase chain reaction with melting curve analysis and subsequent Sanger and next-generation sequencing. A fusion of exon 1 of CCDC6 with exon 9 of extracellular domain of RET followed by exon 12 of RET was revealed. This is the first RET/PTC variant among PTC cases that contain the extracellular part of RET. This observation could be probably explained by incorrect splicing of RET due to the somatic 32-bp deletion in exon-intron 11 boundary of RET. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. An RET Experience with Geochemical Analysis of Azores Lavas

    Science.gov (United States)

    Carpenter, C.; D'Albany, D.; Humayun, M.; Dixon, P.

    2009-12-01

    Each summer, the Center for Integrating Research and Learning (CIRL) at the National High Magnetic Field Laboratory (NHMFL) operates a Research Experiences for Teachers (RET) program. This six-week program provides stipends for teachers to work in the laboratories of NHMFL scientists. Faculty members of the Geochemistry Program at the NHMFL frequently host RET teachers to facilitate the broader dissemination of Geoscience knowledge among K-12 educators. During the summer of 2009, David d’Albany and Charles Carpenter, participated in the RET program for K-12 teachers at the NHMFL in Tallahassee, Florida. Mr. d’Albany is a Biology teacher at King IB High School in Tampa, Florida. Mr. Carpenter is a Physics teacher at Lawton Chiles High School in Tallahassee, Florida. Both teachers had the opportunity to analyze the elemental composition of a volcanic rock from the Azores Islands, in the North Atlantic. The Azores Islands represent a set of nine volcanic islands, near the active Azores Triple Junction, on the mid-Atlantic Ridge around 38°N, generally conceived as the products of a deep mantle plume. The analytical method used was Laser Ablation Inductively Coupled Plasma Mass Spectrometry (ICP-MS) using a New Wave UP193FX excimer laser ablation system coupled to a Thermo Element XR magnetic sector ICP-MS. This method allowed solid sampling of a large area of the basaltic matrix, and separately of the olivine (peridot) crystals within the matrix, from a lava sample from the island of Faial. Elemental data were obtained on a broader spectrum of elements (65 elements) than currently available in the geochemical literature for these islands. Chondrite-normalized rare earth element abundances for the sample provided a precise match with data for other lavas from the island of Faial from the GEOROC database. It should be noted that all 14 lanthanides, excluding Pm, were measured with ICP-MS, compared with about 8 elements determined by previous bulk rock techniques

  3. RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients.

    Science.gov (United States)

    Kato, Shumei; Subbiah, Vivek; Marchlik, Erica; Elkin, Sheryl K; Carter, Jennifer L; Kurzrock, Razelle

    2017-04-15

    Purpose: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RETExperimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.Results: Among diverse cancers, RET aberrations were identified in 88 cases [1.8% (88/4, 871)], with mutations being the most common alteration [38.6% (34/88)], followed by fusions [30.7% (27/88), including a novel SQSTM1-RET] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to RET anomalies [81.8% (72/88)], with the most common being in TP53-associated genes [59.1% (52/88)], cell cycle-associated genes [39.8% (35/88)], the PI3K signaling pathway [30.7% (27/88)], MAPK effectors [22.7% (20/88)], or other tyrosine kinase families [21.6% (19/88)]. RET fusions were mutually exclusive with MAPK signaling pathway alterations. All 72 patients harboring coaberrations had distinct genomic portfolios, and most [98.6% (71/72)] had potentially targetable coaberrations with either an FDA-approved or an investigational agent. Two cases with lung (KIF5B-RET) and medullary thyroid carcinoma (RET M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown.Conclusions:RET aberrations were seen in 1.8% of diverse cancers, with most cases harboring actionable, albeit distinct, coexisting alterations. The current report suggests that optimal targeting of patients with RET anomalies will require customized combination strategies. Clin Cancer Res; 23(8); 1988-97. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. Identification of germline transcriptional regulatory elements in Aedes aegypti

    Science.gov (United States)

    Akbari, Omar S.; Papathanos, Philippos A.; Sandler, Jeremy E.; Kennedy, Katie; Hay, Bruce A.

    2014-02-01

    The mosquito Aedes aegypti is the principal vector for the yellow fever and dengue viruses, and is also responsible for recent outbreaks of the alphavirus chikungunya. Vector control strategies utilizing engineered gene drive systems are being developed as a means of replacing wild, pathogen transmitting mosquitoes with individuals refractory to disease transmission, or bringing about population suppression. Several of these systems, including Medea, UDMEL, and site-specific nucleases, which can be used to drive genes into populations or bring about population suppression, utilize transcriptional regulatory elements that drive germline-specific expression. Here we report the identification of multiple regulatory elements able to drive gene expression specifically in the female germline, or in the male and female germline, in the mosquito Aedes aegypti. These elements can also be used as tools with which to probe the roles of specific genes in germline function and in the early embryo, through overexpression or RNA interference.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Developmental Wiring of Specific Neurons Is Regulated by RET-1/Nogo-A in Caenorhabditis elegans.

    Science.gov (United States)

    Torpe, Nanna; Nørgaard, Steffen; Høye, Anette M; Pocock, Roger

    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 Nogo-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 during development, and, through mosaic analysis, showed that ret-1 controls axon guidance in a cell-autonomous manner. Finally, as in mammals, ret-1 regulates ephrin expression, and dysregulation of the ephrin ligand VAB-2 is partially responsible for the ret-1 mutant axonal defects. Together, our data present a previously unidentified function for RET-1 in the nervous system of C. elegans. Copyright © 2017 by the Genetics Society of America.

  10. Clinical Report: Germline Mosaicism in Cornelia de Lange Syndrome

    Science.gov (United States)

    Slavin, Thomas P.; Lazebnik, Noam; Clark, Dinah M.; Vengoechea, Jaime; Cohen, Leslie; Kaur, Maninder; Konczal, Laura; Crowe, Carol A.; Corteville, Jane E.; Nowaczyk, Malgorzata J.; Byrne, Janice L.; Jackson, Laird G.; Krantz, Ian D.

    2012-01-01

    Cornelia de Lange syndrome (CdLS) is a genetic disorder associated with delayed growth, intellectual disability, limb reduction defects and characteristic facial features. Germline mosaicism has been a described mechanism for CdLS when there are several affected offspring of apparently unaffected parents. Presently, the recurrence risk for CdLS has been estimated to be as high as 1.5%; however, this figure may be an underrepresentation. We report on the molecularly defined germline mosaicism cases from a large CdLS database, representing the first large case series on germline mosaicism in CdLS. Of the 12 families, eight have been previously described; however, four have not. No one specific gene mutation, either in the NIPBL or the SMC1A gene, was associated with an increased risk for germline mosaicism. Suspected or confirmed cases of germline mosaicism in our database range from a conservative 3.4% up to 5.4% of our total cohort. In conclusion, the potential reproductive recurrence risk due to germline mosiacism should be addressed in prenatal counseling for all families who have had a previously affected pregnancy or child with CdLS. PMID:22581668

  11. RET/PTC rearrangement in benign and malignant thyroid diseases: a clinical standpoint.

    Science.gov (United States)

    Marotta, Vincenzo; Guerra, Anna; Sapio, Maria Rosaria; Vitale, Mario

    2011-10-01

    Cytological examination of fine needle aspiration biopsy is the primary means for distinguishing benign from malignant nodules. However, as inconclusive cytology is very frequent, the introduction of molecular markers in the preoperative diagnosis of thyroid nodules has been proposed in recent years. In this article, we review the clinical implications of preoperative detection of rearrangements of the RET gene (RET/papillary thyroid carcinoma (PTC)) in thyroid nodules. The prevalence of RET/PTC in PTC depends on the histological subtypes, geographical factors, radiation exposure, and detection method. Initially, RET/PTC was considered an exclusive PTC hallmark and later it was also found sporadically in benign thyroid lesions. More recently, the very sensitive detection methods, interphase fluorescence in situ hybridization (FISH) and Southern blot on RT-PCR amplicons, demonstrated that the oligoclonal occurrence of RET rearrangement in benign thyroid lesions is not a rare event and suggested that it could be associated with a faster enlargement in benign nodules. For this reason, RET/PTC cannot be considered as an absolute marker of PTC, and its diagnostic application must be limited to assays able to distinguish between clonal and oligoclonal expression. Detection of RET/PTC by quantitative assays will be useful for diagnostic purposes in cytology specimens when a precise cutoff will be fixed in a clinical setting. Until that time, less sensitive RET/PTC detection methods and FISH analysis remain the most appropriate means to refine inconclusive cytology. Future studies with a long follow-up will further clarify the clinical significance of low level of RET rearrangements in benign nodules.

  12. [Pooled Analysis of RET/PTC Gene Rearrangement Rate in Sporadic and Radiogenic Thyroid Papillary Carcinoma].

    Science.gov (United States)

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

    2015-01-01

    The database of publications on molecular epidemiology of RET/PTC rearrangements in sporadic and radiogenic thyroid papillary carcinoma has been formed (197 sources at the end of 2014; coverage of 100%). Based on this database a pooled analysis of data on the rates of RET/PTC1, RET/PTC3 and RET/PTC in total was conducted. Statistical approach involves a simple pooling, as well as calculations on the models of random and fixed effects. Since almost all the strata were characterized by heterogeneity, simple pooling and random effect models were adequate. Calculations using both models led to almost identical results. For rates of RET/PTC1, RET/PTC3 and RET/PTC in total with respect to formed carcinoma striations the following values (pooling, in %) were obtained: sporadic, total--13.2; 8.9; 21.2; sporadic, adults--13.3; 9.9; 21.1; sporadic, children--22.4; 17.5; 44.5; radiogenic, total--20.9; 20.3; 40.4; radiotherapy (exposure in childhood)--31.1; 11.8; 42.5; children affected after the Chernobyl accident--19.9; 23.6; 46.1; radiological incidents (exposure in adulthood)--19.9; 7.7; 18.4. Statistically proven is the reliability of differences of carcinoma indicators for children compared with adults (both sporadic and radiogenic tumors) and for radiogenic cancer compared with sporadic. The greatest increase in rate after irradiation was found for RET/PTC1, previously characterized in vitro as one of radiogenic types of RET/PTC.

  13. [RET/PTC rearrangement affects multifocal formation of papillary thyroid carcinoma].

    Science.gov (United States)

    Zhang, X; Su, X; Chen, W C; Li, Y; Yang, Z Y; Deng, W Z; Deng, T C; Yang, A K

    2017-06-07

    Objective:RET/PTC gene rearrangement can lead to aberrant activation of tyrosine kinase receptors, which is a common mutation in papillary thyroid carcinoma (PTC). This study focuses on the association of RET/PTC rearrangements with PTC clinical factors. Methods: From January 2011 to December 2013, a total of 114 patients with PTC were enrolled in this study. Clinicopathological parameters, lifestyle, and thyroid hormone levels were collected. RET/PTC rearrangements were detected by TaqMan PCR and verified by Sanger sequencing.Data were analyzed with SPSS software, including chi-square test, Fisher's exact test, Mann-Whitney U test, Student's t-test, and Logistic regression. Results:RET/PTC rearrangements were not found in all paracancerous normal thyroid tissues, and were detected in 23.68% (27/114) of PTC. Further analysis revealed no correlation between RET/PTC rearrangement and thyroid function, clinicopathologic parameters, and lifestyle in the total PTC group or in the subgroup of patients with concomitant diseases (including Hashimoto's thyroiditis and nodular goiter). But in the subgroup of PTC without concomitant disease, RET/PTC rearrangement was associated with tumor multifocal (P=0.018), and RET/PTC-positive PTC patients had an increased risk of tumor multifocal (OR=5.57, 95% CI 1.39-22.33). It was also found that RET/PTC rearrangement was associated with an abnormal increase in TSH level of one month after surgery (P= 0.037). Conclusion: Nodular goiter and Hashimoto 's thyroiditis may be a confounding factor in PTC. RET/PTC rearrangement may play an important role in the occurrence of thyroid carcinoma multifocal after exclusion of this confounding factor.

  14. 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.

  15. Molecular identification of rapidly adapting mechanoreceptors and their developmental dependence on ret signaling.

    Science.gov (United States)

    Luo, Wenqin; Enomoto, Hideki; Rice, Frank L; Milbrandt, Jeffrey; Ginty, David D

    2009-12-24

    In mammals, the first step in the perception of form and texture is the activation of trigeminal or dorsal root ganglion (DRG) mechanosensory neurons, which are classified as either rapidly (RA) or slowly adapting (SA) according to their rates of adaptation to sustained stimuli. The molecular identities and mechanisms of development of RA and SA mechanoreceptors are largely unknown. We found that the "early Ret(+)" DRG neurons are RA mechanoreceptors, which form Meissner corpuscles, Pacinian corpuscles, and longitudinal lanceolate endings. The central projections of these RA mechanoreceptors innervate layers III through V of the spinal cord and terminate within discrete subdomains of the dorsal column nuclei. Moreover, mice lacking Ret signaling components are devoid of Pacinian corpuscles and exhibit a dramatic disruption of RA mechanoreceptor projections to both the spinal cord and medulla. Thus, the early Ret(+) neurons are RA mechanoreceptors and Ret signaling is required for the assembly of neural circuits underlying touch perception.

  16. 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...

  17. High rate of BRAF and RET/PTC dual mutations associated with recurrent papillary thyroid carcinoma.

    Science.gov (United States)

    Henderson, Ying C; Shellenberger, Thomas D; Williams, Michelle D; El-Naggar, Adel K; Fredrick, Mitchell J; Cieply, Kathleen M; Clayman, Gary L

    2009-01-15

    Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, usually possesses BRAF mutation or rearranged in translation (RET)/PTC rearrangements. PTC usually possesses BRAF mutation or RET/PTC rearrangements. The mutation status of patients with recurrent PTC has never been characterized in a large population. Mutation status was determined in a cohort of 54 patients with recurrent PTC and analyzed for clinicopathologic relationships. BRAF and ras mutations were determined by PCR and sequencing of genomic DNA. RET/PTC rearrangements were analyzed by reverse transcription-PCR. BRAF mutation in exon 15 (V600E) was found in 42/54 (77.8%) recurrent PTC patients. The RET/PTC rearrangements were detected in 9 of 54 (16.7%) patients. In addition, 5 of 54 (9.3%) recurrent PTC patients had both a BRAF mutation and a RET/PTC rearrangement. The prevalence of tumors with dual mutations found in the recurrent population far exceeds the frequency historically reported for patients with primary PTC. Patients with dual mutations were significantly older (80% older than 45 years) than patients with a BRAF mutation alone (38% older than 45 years). Recurrent PTC is significantly associated with a predominant BRAF mutation. RET/PTC rearrangements, although commonly associated with primary PTCs in younger patients, are uncommonly found in recurrent PTC patients. In addition, the incidence of dual mutations was higher in patients with recurrent PTC than in those primary PTC, as reported by others.

  18. Sunitinib inhibits papillary thyroid carcinoma with RET/PTC rearrangement but not BRAF mutation.

    Science.gov (United States)

    Jeong, Woo-Jin; Mo, Ji-Hun; Park, Min Woo; Choi, Ik Joon; An, Soo-Youn; Jeon, Eun-Hee; Ahn, Soon-Hyun

    2011-09-01

    Sunitinib, a multi-targeted tyrosine kinase inhibitor, is frequently incorporated into the management of papillary thyroid carcinoma refractory to standard therapies. Although clinical trials are in progress, the mechanism of action in papillary thyroid carcinomas is not clear, especially regarding the effect on BRAF mutation. We investigated the effect of sunitinib on papillary thyroid carcinoma cells harboring RET/PTC rearrangement and BRAF mutation using TPC-1M, SNU-790, and B-cPAP cell lines. Cell growth of papillary thyroid cancer cells with RET/PTC rearrangement was effectively inhibited at low doses of sunitinib (IC50=0.658 μM), whereas that of BRAF mutated cells required higher doses. Immunoblotting revealed effective blocking of MEK/ERK pathway in RET/PTC rearrangement cells, but not in BRAF mutated cells. Cell cycle analysis showed G1 arrest in RET/PTC rearrangement cells. In vivo orthotopic thyroid cancer mouse model demonstrated statistically significant tumor growth inhibition by sunitinib in RET/PTC rearrangement cancer cells. We conclude that sunitinib effectively inhibits RET/PTC rearrangement cells but not BRAF mutated cells. These data suggest that sunitinib exerts its effect by inhibiting the upstream MAPK signaling cascade. These findings support the unsatisfactory treatment outcomes of sunitinib in many already ongoing clinical trials compared to other tyrosine kinase inhibitors. Clinical application of sunitinib should be directed accordingly.

  19. 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

    2007-01-01

    Somatotrophs are the only pituitary cells that express Ret, GFRα1 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 PKCδ, JNK, c/EBPα and CREB induced by a complex of Ret, caspase 3 and PKCδ. 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. PMID:17380130

  20. 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.

  1. Retórica y Estado de Derecho

    Directory of Open Access Journals (Sweden)

    Maccormick, Neil

    1999-11-01

    Full Text Available Not available

    El lugar común de que las proposiciones jurídicas son intrínsecamente argumentabIes se opone al lugar común rival de que el Estado de Derecho (Rule of Law es valorado en consideración a la certeza jurídica. La reconciliación de esos aparentes contrarios toma en cuenta las aportaciones de las teorías de la retórica y de las teorías procedímentales de la razón práctica, situando así el problema de la indeterminación del Derecho en el contexto del carácter cuestionable de la acción estatal en los Estados libres. Esto no es incompatible con, sino exigido por, el Estado de Derecho, que es indebidamente considerada como asegurador de la certeza jurídica; la certeza derrotable es lo que resulta más deseable o alcanzable.

  2. Retórica como método no direito: o entimema e o paradigma como bases de uma retórica judicial analítica

    OpenAIRE

    LIMA, Pedro Parini de

    2007-01-01

    O presente trabalho funda-se na discussão sobre a possibilidade de se utilizar a retórica como método no processo de criação e aplicação do direito. Como base para a pesquisa, estabeleceu-se a retórica antiga de Aristóteles e a retórica analítica de Ottmar Ballweg. Da primeira, toma-se o modelo de uma lógica própria da retórica fundada no entimema e no paradigma a dedução e a indução retóricas. Da segunda, a tripartição em diferentes níveis da retórica como linguagem e...

  3. Key Signaling Events for Committing Mouse Pluripotent Stem Cells to the Germline Fate.

    Science.gov (United States)

    Wang, Jian-Qi; Cao, Wen-Guang

    2016-01-01

    The process of germline development carries genetic information and preparatory totipotency across generations. The last decade has witnessed remarkable successes in the generation of germline cells from mouse pluripotent stem cells, especially induced germline cells with the capacity for producing viable offspring, suggesting clinical applications of induced germline cells in humans. However, to date, the culture systems for germline induction with accurate sex-specific meiosis and epigenetic reprogramming have not been well-established. In this study, we primarily focus on the mouse model to discuss key signaling events for germline induction. We review mechanisms of competent regulators on primordial germ cell induction and discuss current achievements and difficulties in inducing sex-specific germline development. Furthermore, we review the developmental identities of mouse embryonic stem cells and epiblast stem cells under certain defined culture conditions as it relates to the differentiation process of becoming germline cells.

  4. CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth.

    Science.gov (United States)

    Strock, Christopher J; Park, Jong-In; Rosen, Mark; Dionne, Craig; Ruggeri, Bruce; Jones-Bolin, Susan; Denmeade, Samuel R; Ball, Douglas W; Nelkin, Barry D

    2003-09-01

    All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and approximately 40% of the sporadic cases of MTC, the RET kinase is constitutively activated by mutation. This suggests that RET may be an effective therapeutic target for treatment of MTC. We show that the indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET in MTC cells. These compounds effectively inhibit RET phosphorylation in a dose-dependent manner at concentrations <100 nM in 0.5% serum and at somewhat higher concentrations in the presence of 16% serum. They also blocked the growth of these MTC cells in culture. CEP-751 and its prodrug, CEP-2563, also inhibited tumor growth in MTC cell xenografts. These results show that inhibiting RET can block the growth of MTC cells and may have a therapeutic benefit in MTC.

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  6. File list: ALL.Gon.10.AllAg.Germline_stem_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Gon.10.AllAg.Germline_stem_cells mm9 All antigens Gonad Germline stem cells SRX...X1060554,SRX1060555 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Gon.10.AllAg.Germline_stem_cells.bed ...

  7. Genetic mosaicism of a frameshift mutation in the RET gene in a family with Hirschsprung disease.

    Science.gov (United States)

    Müller, Charlotte M; Haase, Michael G; Kemnitz, Ivonne; Fitze, Guido

    2014-05-10

    Mutations and polymorphisms in the RET gene are a major cause of Hirschsprung disease (HSCR). Theoretically, all true heterozygous patients with a new manifestation of a genetically determined disease must have parents with a genetic mosaicism of some extent. However, no genetic mosaicism has been described for the RET gene in HSCR yet. Therefore, we analyzed families with mutations in the RET gene for genetic mosaicism in the parents of the patients. Blood samples were taken from patients with HSCR and their families/parents to sequence the RET coding region. Among 125 families with HSCR, 33 families with RET mutations were analyzed. In one family, we detected a frameshift mutation due to a loss of one in a row of four cytosines in codon 117/118 of the RET gene (c.352delC) leading to a frameshift mutation in the protein (p.Leu118Cysfs*105) that affected two siblings. In the blood sample of the asymptomatic father we found a genetic mosaicism of this mutation which was confirmed in two independent samples of saliva and hair roots. Quantification of peak-heights and comparison with different mixtures of normal and mutated plasmid DNA suggested that the mutation occurred in the early morula stadium of the founder, between the 4- and 8-cell stages. We conclude that the presence of a RET mutation leading to loss of one functional allele in 20 to 25% of the cells is not sufficient to cause HSCR. The possibility of a mosaicism has to be kept in mind during genetic counseling for inherited diseases.

  8. Rap1GAP interacts with RET and suppresses GDNF-induced neurite outgrowth

    Institute of Scientific and Technical Information of China (English)

    Li Jiao; Yong Zhang; Chun Hu; Yong-Gang Wang; Aijun Huang; Cheng He

    2011-01-01

    Glial cell line-derived neurotrophic factor(GDNF)was originally recognized for its ability to promote survival of midbrain dopaminergic neurons,but it has since been demonstrated to be crucial for the survival and differentiation of many neuronal subpopulations,including motor neurons,sympathetic neurons,sensory neurons and enteric neurons.To identify possible effectors or regulators of GDNF signaling,we performed a yeast two-hybrid screen using the intracellular domain of RET,the common signaling receptor of the GDNF family,as bait.Using this approach,we identified RaplGAP,a GTPase-activating protein(GAP)for Rap1,as a novel RET-binding protein.Endogenous RaplGAP co-immunoprecipitated with RET in neural tissues,and RET and RaplGAP were co-expressed in dopaminergic neurons of the mesencephalon,in addition,overexpression of RaplGAP attenuated GDNF-induced neurite outgrowth,whereas suppressing the expression of endogenous RaplGAP by RNAi enhanced neurite outgrowth.Furthermore,using co-immunoprecipitation analyses,we found that the interaction between RET and RaplGAP was enhanced following GDNF treatment.Mutagenesis analysis revealed that Tyr981 in the intracellular domain of RET was crucial for the interaction with RapiGAP.Moreover,we found that RaplGAP negatively regulatedGNDFinduced ERK activation and neurite outgrowth.Taken together,our results suggest the involvement of a novel interaction of RET with Rap l GAP in the regulation of GDNF-mediated neurite outgrowth.

  9. Impact of RET proto-oncogene analysis on the clinical management of multiple endocrine neoplasia type 2

    Directory of Open Access Journals (Sweden)

    Toledo Sergio Pereira de Almeida

    2006-01-01

    Full Text Available Multiple endocrine neoplasia type 2 (MEN2 is an autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, primary hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia type 2 is still an underdiagnosed, or late-diagnosed condition in many areas of the world. Since 1993, when the first missense RET proto-oncogene (RET mutations were reported in MEN2, up to 46 different RET-causing disease mutations have been described. Since a strong genotype-phenotype correlation exists for MEN2, the detection of RET mutations has produced a major impact in early recognition and treatment of MTC and MEN2. Presently, RET mutation analysis should be performed for all MEN2 cases and their at-risk familial relatives. Further, prophylactic total thyroidectomy is indicated in all cases harboring activating gametic RET mutations. In most RET mutation carriers, prophylactic total thyroidectomy is indicated at ages as early as a few months to 4 years of age, promoting longer survival and improvement of quality of life or even definitive cure. We discuss the large impact of RET proto-oncogene analysis on the clinical management of MEN2 and the role of early RET molecular DNA diagnosis in providing clinicians and surgeons with valuable information that enables them to indicate early total thyroidectomy.

  10. Combined Effect of Water Retting and Sodium Hydroxide Concentration on Properties of Luffa Cylindrica Fibres

    Directory of Open Access Journals (Sweden)

    Charles Wetaka

    2016-11-01

    Full Text Available Luffa cylindrica is an annual climbing plant whose fruit has a vascular network of fibres. These fibres are held together by pectins which degrade during water retting to release the fibres. In this paper, the extraction of luffa cylindrica fibres together with the combined effect of water retting and alkali treatment on its tensile properties are reported. The fibres were extracted from mature fruits of Luffa cylindrica through aerobic water retting process over a duration of 2 weeks, 4 weeks and 8 weeks. The extracted fibres were oven dried to a moisture content of 9.74±1.1% and tested in tension at gauge lengths of 10 mm. The fibres were characterized in terms of moisture regain, lignin content, hemicellulose content, and cellulose content. The combined effect of water retting and sodium hydroxide (NaOH concentration on the fibre’s breaking load, elongation, tenacity and linear density was also investigated. The luffa cylindrica fibres had a moisture regain of 10.81%, lignin content of 12.03%, cellulose content of 65.69%, and hemicellulose content of 19%. The linear density of the fibres retted for 2-8 weeks was 572–470 dTex .The determined breaking load of the fibres retted for 2-8 weeks was 1444.19-417.04 cN and 997.81-298.05 cN after treatments with 0% -16% NaOH. The fibre elongation was 4.0-24% after 2-8 weeks of retting and 4.3-14.5 % after treatments with 0% -16% NaOH. Tenacity of luffa cylindrica fibres was 6.0-25.25 cN/Tex after 2-8 weeks of retting and 5.9-20.22 cN/Tex after treatments with 0% -16% NaOH. From the study, an increase in aerobic water retting and concentration of NaOH had a positive effect on the tensile properties of the luffa cylindrica fibres.

  11. 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

  12. Molecular Basis of Medullary Thyroid Carcinoma: The Role of RET Polymorphisms

    Directory of Open Access Journals (Sweden)

    Ana Luiza Maia

    2011-12-01

    Full Text Available Medullary thyroid carcinoma is a rare malignant tumor originating in parafollicular C cells. It accounts for 5 to 8% of all thyroid cancers. MTC develops in either sporadic (75% or hereditary form (25%. Genetic and molecular studies have demonstrated the involvement of the RET proto-oncogene in hereditary MTC and, less often, in its sporadic form. Although a strong genotype-phenotype correlation has been described, wide clinical heterogeneity is observed among families with the same RET mutation or even in carriers of the same kindred. In recent years, several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. Some studies have reported associations between the presence of polymorphisms and development or progression of MTC. Nonetheless, other studies failed to demonstrate any effect of the RET variants. Differences in the genetic background of distinct populations or methodological approaches have been suggested as potential reasons for the conflicting results. Here, we review current knowledge concerning the molecular pathogenesis of sporadic and hereditary MTC. In particular, we analyze the role of RET polymorphisms in the clinical presentation and prognosis of MTC based on the current literature.

  13. Ecotoxicological effects of jute retting on the survival of two freshwater fish and two invertebrates.

    Science.gov (United States)

    Mondal, Debjit Kumar; Kaviraj, Anilava

    2008-04-01

    Severe deterioration of water quality occurs during jute retting in ponds, canals, floodplain lakes, and other inland water bodies in the rural areas of West Bengal in India. Attempts were made to evaluate changes in the physicochemical parameters of water caused by jute retting, and their impact on the survival of two species of freshwater fish (Labeo rohita and Hypophthalmicthys molitrix) and two species of freshwater invertebrate (Daphnia magna, a Cladocera, and Branchiura sowerbyi, an Oligochaeta). Results showed that jute retting in a pond for 30 days resulted in a sharp increase in the BOD (>1,000 times) and COD (>25 times) of the water, along with a sharp decrease in dissolved oxygen (DO). Free CO(2), total ammonia, and nitrate nitrogen also increased (three to five times) in water as a result of jute retting. Ninety-six-hour static bioassays performed in the laboratory with different dilutions of jute-retting water (JRW) revealed that D. magna and B. sowerbyi were not susceptible to even the raw JRW whereas fingerlings of both species of fish were highly susceptible, L. rohita being more sensitive (96 h LC(50) 37.55% JRW) than H. molitrix (96 h LC(50) 57.54% JRW). Mortality of fish was significantly correlated with the percentage of JRW.

  14. Ret is essential to mediate GDNF's neuroprotective and neuroregenerative effect in a Parkinson disease mouse model

    Science.gov (United States)

    Drinkut, Anja; Tillack, Karsten; Meka, Durga P; Schulz, Jorg B; Kügler, Sebastian; Kramer, Edgar R

    2016-01-01

    Glial cell line-derived neurotrophic factor (GDNF) is a potent survival and regeneration-promoting factor for dopaminergic neurons in cell and animal models of Parkinson disease (PD). GDNF is currently tested in clinical trials on PD patients with so far inconclusive results. The receptor tyrosine kinase Ret is the canonical GDNF receptor, but several alternative GDNF receptors have been proposed, raising the question of which signaling receptor mediates here the beneficial GDNF effects. To address this question we overexpressed GDNF in the striatum of mice deficient for Ret in dopaminergic neurons and subsequently challenged these mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Strikingly, in this established PD mouse model, the absence of Ret completely abolished GDNF's neuroprotective and regenerative effect on the midbrain dopaminergic system. This establishes Ret signaling as absolutely required for GDNF's effects to prevent and compensate dopaminergic system degeneration and suggests Ret activation as the primary target of GDNF therapy in PD. PMID:27607574

  15. RET/PTC rearrangement is prevalent in follicular Hürthle cell carcinomas.

    Science.gov (United States)

    de Vries, Margriet M; Celestino, Ricardo; Castro, Patricia; Eloy, Catarina; Máximo, Valdemar; van der Wal, Jacqueline E; Plukker, John T M; Links, Thera P; Hofstra, Robert M W; Sobrinho-Simões, Manuel; Soares, Paula

    2012-11-01

    The molecular alterations underlying follicular Hürthle cell carcinomas (FHCCs) are largely unknown. In an attempt to clarify this issue, we analysed a series of Hürthle cell tumours for the presence of RET/PTC and PAX8/PPARG rearrangements and BRAF, HRAS and NRAS mutations. We investigated a series of 20 follicular Hürthle cell tumours [17 FHCCs and three follicular Hürthle cell adenomas (FHCAs)]. RET/PTC rearrangements were found in 33% of FHCAs and in 38% of FHCCs. All RET/PTC-positive FHCCs had a solid pattern of growth. PAX8/PPARG rearrangement was present in 27% of the FHCCs which displayed, in most cases, a follicular architecture. NRAS mutation was detected in one FHCC. An FHCC with a solid/microfollicular growth pattern scored positive for both RET/PTC and PAX8/PPARG rearrangement. Our study has shown a significant association between RET/PTC rearrangements and FHCCs with a solid growth pattern, thus raising the possibility of using tyrosine kinase inhibitors for the treatment of patients with FHCCs, which are often refractory to radioiodine treatment. © 2012 Blackwell Publishing Limited.

  16. Common germline polymorphisms associated with breast cancer-specific survival

    NARCIS (Netherlands)

    A. Pirie (Ailith); Q. Guo (Qi); P. Kraft (Peter); S. Canisius (Sander); D. Eccles (Diana); N. Rahman (Nazneen); H. Nevanlinna (Heli); C. Chen (Constance); S. Khan (Sofia); J.P. Tyrer (Jonathan); M.K. Bolla (Manjeet); Q. Wang (Qing); J. Dennis (Joe); K. Michailidou (Kyriaki); M. Lush (Michael); A.M. Dunning (Alison); M. Shah (Mitul); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mats); D. Lambrechts (Diether); C. Weltens (Caroline); K. Leunen; C. van Ongeval (Chantal); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); C. Blomqvist (Carl); K. Aittomäki (Kristiina); R. Fagerholm (Rainer); T.A. Muranen (Taru); J.E. Olsen (Janet E.); B. Hallberg (Boubou); C. Vachon (Celine); J.A. Knight (Julia); G. Glendon (Gord); A.M. Mulligan (Anna Marie); A. Broeks (Annegien); S. Cornelissen (Sten); C.A. Haiman (Christopher); B.E. Henderson (Brian); F. Schumacher (Frederick); L. Le Marchand (Loic); J.L. Hopper (John); H. Tsimiklis (Helen); C. Apicella (Carmel); M.C. Southey (Melissa); S.S. Cross (Simon); M.W.R. Reed (Malcolm); G.G. Giles (Graham); R.L. Milne (Roger); C.A. McLean (Catriona Ann); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); A.M.W. van den Ouweland (Ans); F. Marme (Federick); A. Schneeweiss (Andreas); R. Yang (Rongxi); B. Burwinkel (Barbara); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); H. Brenner (Hermann); K. Butterbach (Katja); B. Holleczek (B.); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); J. Li (Jingmei); J.S. Brand (Judith S.); M.K. Humphreys (Manjeet); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); F. Ficarazzi (Filomena); M.W. Beckmann (Matthias); R. Hein (Rebecca); A.B. Ekici (Arif); R. Balleine (Rosemary); K.-A. Phillips (Kelly-Anne); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); P. Menéndez (Primitiva); A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); K. Durda (Katarzyna); U. Hamann (Ute); M. Kabisch (Maria); H.U. Ulmer (Hans); T. Rud̈iger (Thomas); S. Margolin (Sara); V. Kristensen (Vessela); S. Nord (Siljie); D.G. Evans (Gareth); J. Abraham (Jean); H. Earl (Helena); C.J. Poole (Christopher J.); L. Hiller (Louise); J.A. Dunn (J.); S. Bowden (Sarah); R. Yang (Rose); D. Campa (Daniele); W.R. Diver (Ryan); S.M. Gapstur (Susan M.); M.M. Gaudet (Mia); S.E. Hankinson (Susan); R.N. Hoover (Robert); A. Hüsing (Anika); R. Kaaks (Rudolf); M.J. Machiela (Mitchell J.); W.C. Willett (Walter C.); M. Barrdahl (Myrto); F. Canzian (Federico); S.-F. Chin (Suet-Feung); C. Caldas (Carlos); D. Hunter (David); S. Lindstrom (Stephen); M. García-Closas (Montserrat); F.J. Couch (Fergus); G. Chenevix-Trench (Georgia); A. Mannermaa (Arto); I.L. Andrulis (Irene); P. Hall (Per); J. Chang-Claude (Jenny); D.F. Easton (Douglas); S.E. Bojesen (Stig); A. Cox (Angela); P.A. Fasching (Peter); P.D.P. Pharoah (Paul); M.K. Schmidt (Marjanka)

    2015-01-01

    textabstractIntroduction: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with brea

  17. Common germline polymorphisms associated with breast cancer-specific survival

    DEFF Research Database (Denmark)

    Pirie, Ailith; Guo, Qi; Kraft, Peter

    2015-01-01

    INTRODUCTION: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer...

  18. Common germline polymorphisms associated with breast cancer-specific survival

    NARCIS (Netherlands)

    A. Pirie (Ailith); Q. Guo (Qi); P. Kraft (Peter); S. Canisius (Sander); D. Eccles (Diana); N. Rahman (Nazneen); H. Nevanlinna (Heli); C. Chen (Constance); S. Khan (Sofia); J.P. Tyrer (Jonathan); M.K. Bolla (Manjeet); Q. Wang (Qing); J. Dennis (Joe); K. Michailidou (Kyriaki); M. Lush (Michael); A.M. Dunning (Alison); M. Shah (Mitul); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mats); D. Lambrechts (Diether); C. Weltens (Caroline); K. Leunen; C. van Ongeval (Chantal); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); C. Blomqvist (Carl); K. Aittomäki (Kristiina); R. Fagerholm (Rainer); T.A. Muranen (Taru); J.E. Olsen (Janet E.); B. Hallberg (Boubou); C. Vachon (Celine); J.A. Knight (Julia); G. Glendon (Gord); A.M. Mulligan (Anna Marie); A. Broeks (Annegien); S. Cornelissen (Sten); C.A. Haiman (Christopher); B.E. Henderson (Brian); F. Schumacher (Frederick); L. Le Marchand (Loic); J.L. Hopper (John); H. Tsimiklis (Helen); C. Apicella (Carmel); M.C. Southey (Melissa); S.S. Cross (Simon); M.W.R. Reed (Malcolm); G.G. Giles (Graham); R.L. Milne (Roger); C.A. McLean (Catriona Ann); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); A.M.W. van den Ouweland (Ans); F. Marme (Federick); A. Schneeweiss (Andreas); R. Yang (Rongxi); B. Burwinkel (Barbara); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); H. Brenner (Hermann); K. Butterbach (Katja); B. Holleczek (B.); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); J. Li (Jingmei); J.S. Brand (Judith S.); M.K. Humphreys (Manjeet); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); F. Ficarazzi (Filomena); M.W. Beckmann (Matthias); R. Hein (Rebecca); A.B. Ekici (Arif); R. Balleine (Rosemary); K.-A. Phillips (Kelly-Anne); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); P. Menéndez (Primitiva); A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); K. Durda (Katarzyna); U. Hamann (Ute); M. Kabisch (Maria); H.U. Ulmer (Hans); T. Rud̈iger (Thomas); S. Margolin (Sara); V. Kristensen (Vessela); S. Nord (Siljie); D.G. Evans (Gareth); J. Abraham (Jean); H. Earl (Helena); C.J. Poole (Christopher J.); L. Hiller (Louise); J.A. Dunn (J.); S. Bowden (Sarah); R. Yang (Rose); D. Campa (Daniele); W.R. Diver (Ryan); S.M. Gapstur (Susan M.); M.M. Gaudet (Mia); S.E. Hankinson (Susan); R.N. Hoover (Robert); A. Hüsing (Anika); R. Kaaks (Rudolf); M.J. Machiela (Mitchell J.); W.C. Willett (Walter C.); M. Barrdahl (Myrto); F. Canzian (Federico); S.-F. Chin (Suet-Feung); C. Caldas (Carlos); D. Hunter (David); S. Lindstrom (Stephen); M. García-Closas (Montserrat); F.J. Couch (Fergus); G. Chenevix-Trench (Georgia); A. Mannermaa (Arto); I.L. Andrulis (Irene); P. Hall (Per); J. Chang-Claude (Jenny); D.F. Easton (Douglas); S.E. Bojesen (Stig); A. Cox (Angela); P.A. Fasching (Peter); P.D.P. Pharoah (Paul); M.K. Schmidt (Marjanka)

    2015-01-01

    textabstractIntroduction: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with

  19. Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma

    DEFF Research Database (Denmark)

    Ylisaukko-oja, Sanna K.; Cybulski, Cezary; Lehtonen, Rainer;

    2006-01-01

    analyzed for somatic FH mutations. Two patients diagnosed with ovarian mucinous cystadenoma (two out of 33, 6%) were found to be FH germline mutation carriers. One of the changes was a novel mutation (Ala231Thr) and the other one (435insAAA) was previously described in FH deficiency families. These results...

  20. Germline promoter hypermethylation of tumor suppressor genes in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Pu-Yuan Wu; Zheng Zhang; Jing-Mei Wang; Wen-Wen Guo; Nong Xiao; Qiong He; Ya-Ping Wang; Yi-Mei Fan

    2012-01-01

    AIM: To explore germline hypermethylation of the tumor suppressor genes MLH1 , CDH1 and P16INK4a in suspected cases of hereditary gastric cancer (GC). METHODS: A group of 140 Chinese GC patients in whom the primary cancer had developed before the age of 60 or who had a familial history of cancer were screened for germline hypermethylation of the MLH1 , CDH1 and P16INK4a tumor suppressor genes. Genomic DNA was extracted from peripheral blood leukocytes and modified by sodium bisulfite. The treated DNA was then subjected to bisulfite DNA sequencing for a specific region of the MLH1 promoter. The methylation status of CDH1 or P16INK4a was assayed using methylation- specific PCR. Clonal bisulfite allelic sequencing in positive samples was performed to obtain a comprehensive analysis of the CpG island methylation status of these promoter regions. RESULTS: Methylation of the MLH1 gene promoter was detected in the peripheral blood DNA of only 1/140 (0.7%) of the GC patient group. However, this methylation pattern was mosaic rather than the allelic pattern which has previously been reported for MLH1 in hereditary non-polyposis colorectal cancer (HNPCC) patients. We found that 10% of the MLH1 alleles in the peripheral blood DNA of this patient were methylated, consistent with 20% of cells having one methylated allele. No germline promoter methylation of the CDH1 or P16INK4a genes was detected. CONCLUSION: Mosaic germline epimutation of the MLH1 gene is present in suspected hereditary GC patients in China but at a very low level. Germline epimutation of the CDH1 or P16INK4a gene is not a frequent event.

  1. Inhibition of RET Increases the Efficacy of Anti-Estrogen and is a Novel Treatment Strategy for Luminal Breast Cancer

    Science.gov (United States)

    Spanheimer, Philip M.; Park, Jung-Min; Askeland, Ryan W.; Kulak, Mikhail V.; Woodfield, George W.; De Andrade, James P.; Cyr, Anthony R.; Sugg, Sonia L.; Thomas, Alexandra; Weigel, Ronald J.

    2014-01-01

    Purpose Recent findings suggest that combination treatment with anti-estrogen and anti-RET may offer a novel treatment strategy in a subset of breast cancer patients. We investigated the role of RET in potentiating the effects of anti-estrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to affect ERK1/2 activation in primary breast cancer. Experimental Design Growth response, ERK1/2 activation, Ki-67 and TUNEL were assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment. Results Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (p=0.01) and hormone insensitive (p<0.001) ERα-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (p<0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared to single agent (p=0.003), with tamoxifen reducing proliferative index and vandetanib inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (p<0.001) in RET-positive tumors vs. 14% (p=ns) in RET-negative tumors. Conclusions Vandetanib potentiated the anti-growth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of anti-estrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer. PMID:24526731

  2. A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis.

    Science.gov (United States)

    Bagheri-Yarmand, Rozita; Sinha, Krishna M; Gururaj, Anupama E; Ahmed, Zamal; Rizvi, Yasmeen Q; Huang, Su-Chen; Ladbury, John E; Bogler, Oliver; Williams, Michelle D; Cote, Gilbert J; Gagel, Robert F

    2015-05-01

    The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. Moreover, chromatin immunoprecipitation assays revealed that ATF4 occupancy increased at the NOXA promoter in TT cells treated with tyrosine kinase inhibitors or the ATF4 inducer eeyarestatin as well as in RET-depleted TT cells. Together these findings reveal RET as a novel dual kinase with nuclear localization and provide mechanisms by which RET represses the proapoptotic genes through direct interaction with and phosphorylation-dependent inactivation of ATF4 during the pathogenesis of medullary thyroid cancer.

  3. RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case Series of 14 Patients.

    Science.gov (United States)

    Sarfaty, Michal; Moore, Assaf; Neiman, Victoria; Dudnik, Elizabeth; Ilouze, Maya; Gottfried, Maya; Katznelson, Rivka; Nechushtan, Hovav; Sorotsky, Hadas Gantz; Paz, Keren; Katz, Amanda; Saute, Milton; Wolner, Mira; Moskovitz, Mor; Miller, Vincent; Elvin, Julia; Lipson, Doron; Ali, Siraj; Gutman, Lior Soussan; Dvir, Addie; Gordon, Noa; Peled, Nir

    2017-07-01

    RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Distinct pathways regulated by RET and estrogen receptor in luminal breast cancer demonstrate the biological basis for combination therapy.

    Science.gov (United States)

    Spanheimer, Philip M; Cyr, Anthony R; Gillum, Matthew P; Woodfield, George W; Askeland, Ryan W; Weigel, Ronald J

    2014-04-01

    We investigated directed therapy based on TFAP2C-regulated pathways to inform new therapeutic approaches for treatment of luminal breast cancer. TFAP2C regulates the expression of genes characterizing the luminal phenotype including ESR1 and RET, but pathway cross talk and potential for distinct elements have not been characterized. Activation of extracellular signal-regulated kinases (ERK) and AKT was assessed using phosphorylation-specific Western blot. Cell proliferation was measured with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] after siRNA (small interfering RNA) gene knockdown or drug treatment. Cell cycle, Ki-67, and cleaved caspase 3 were measured by fluorescence-activated cell sorting. Tumorigenesis was assessed in mice xenografts. Knockdown of TFAP2C or RET inhibited GDNF (glial cell line-derived neurotrophic factor)-mediated activation of ERK and AKT in MCF-7 cells. Similarly, sunitinib, a small-molecule inhibitor of RET, blocked GDNF-mediated activation of ERK and AKT. Inhibition of RET either by gene knockdown or by treatment with sunitinib or vandetanib reduced RET-dependent growth of luminal breast cancer cells. Interestingly, knockdown of TFAP2C, which controls both ER (estrogen receptor) and RET, demonstrated a greater effect on cell growth than either RET or ER alone. Parallel experiments using treatment with tamoxifen and sunitinib confirmed the increased effectiveness of dual inhibition of the ER and RET pathways in regulating cell growth. Whereas targeting the ER pathway altered cell proliferation, as measured by Ki-67 and S-phase, anti-RET primarily increased apoptosis, as demonstrated by cleaved caspase 3 and increased TUNEL (terminal deoxyneucleotidyl transferase dUTP nick end labeling) expression in xenografts. ER and RET primarily function through distinct pathways regulating proliferation and cell survival, respectively. The findings inform a therapeutic approach based on combination therapy with antiestrogen and

  5. Inhibition of RET increases the efficacy of antiestrogen and is a novel treatment strategy for luminal breast cancer.

    Science.gov (United States)

    Spanheimer, Philip M; Park, Jung-Min; Askeland, Ryan W; Kulak, Mikhail V; Woodfield, George W; De Andrade, James P; Cyr, Anthony R; Sugg, Sonia L; Thomas, Alexandra; Weigel, Ronald J

    2014-04-15

    Recent findings suggest that combination treatment with antiestrogen and anti-RET may offer a novel treatment strategy in a subset of patients with breast cancer. We investigated the role of RET in potentiating the effects of antiestrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to affect extracellular signal-regulated kinase 1/2 (ERK1/2) activation in primary breast cancer. Growth response, ERK1/2 activation, Ki-67, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment. Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (P = 0.01) and hormone insensitive (P < 0.001) estrogen receptor α (ERα)-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (P < 0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared with single agent (P = 0.003), with tamoxifen-reducing proliferative index and vandetanib-inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (P < 0.001) in RET-positive tumors versus 14% (P = ns) in RET-negative tumors. Vandetanib potentiated the antigrowth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of antiestrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer. ©2014 AACR.

  6. Cellular localization of GDNF and its GFRalpha1/RET receptor complex in the developing pancreas of cat

    Science.gov (United States)

    Lucini, C; Maruccio, L; Facello, B; Cocchia, N; Tortora, G; Castaldo, L

    2008-01-01

    Glial cell line-derived neurotrophic factor (GDNF) acts through RET receptor tyrosine kinase and its co-receptor GFRalpha1. In an effort to better understand the possible biological contribution of the GDNF and GFRalpha1/RET complex in pancreatic development, in this study we report the cellular localization of these proteins in the pancreas of domestic cat embryos and fetuses by immunocytochemical methods. In early embryos, GDNF, GFRalpha and RET immunoreactivity (IR) was localized in closely intermingled cells. GDNF and RET immunoreactive cells displayed chromogranin (an endocrine marker) and PGP 9.5 (a neuronal marker) IR, respectively. GFRalpha IR was present in both a few GDNF/chromogranin and RET/PGP 9.5 immunoreactive cells. In elderly fetuses, GDNF and GFRalpha IR were co-localized in glucagon cells and RET IR was detected in few neurons and never co-localized with GFRalpha or GDNF IR. In early embryos, the presence of GDNF IR in chromogranin immunoreactive cells and GFRalpha1/RET complex IR in PGP9.5 immunoreactive cells seems to suggest a paracrine action of GDNF contained in endocrine cell precursors on neuronal cell precursors expressing its receptor complex. The presence in different cell populations of RET and its co-receptor GFRalpha1 IR could be due to independent signaling of GRFalpha1. Thus, the co-presence of GDNF and GFRalpha1 in chromogranin and glucagon cells could lead to the hypothesis that GDNF can act in an autocrinal manner. In fetuses, RET IR was detected only in intrapancreatic ganglia. Because of the lack of GFRalpha1 IR in pancreatic innervation, RET receptor could be activated by other GFR alphas and ligands of GDNF family. In conclusion, these findings suggest that in differently aged embryos and fetuses the GDNF signal is differently mediated by RET and GFRalpha1. PMID:19014364

  7. Differences in Strength and Timing of the mtDNA Bottleneck between Zebrafish Germline and Non-germline Cells

    Directory of Open Access Journals (Sweden)

    Auke B.C. Otten

    2016-07-01

    Full Text Available We studied the mtDNA bottleneck in zebrafish to elucidate size, timing, and variation in germline and non-germline cells. Mature zebrafish oocytes contain, on average, 19.0 × 106 mtDNA molecules with high variation between oocytes. During embryogenesis, the mtDNA copy number decreases to ∼170 mtDNA molecules per primordial germ cell (PGC, a number similar to that in mammals, and to ∼50 per non-PGC. These occur at the same developmental stage, implying considerable variation in mtDNA copy number in (non-PGCs of the same female, dictated by variation in the mature oocyte. The presence of oocytes with low mtDNA numbers, if similar in humans, could explain how (de novo mutations can reach high mutation loads within a single generation. High mtDNA copy numbers in mature oocytes are established by mtDNA replication during oocyte development. Bottleneck differences between germline and non-germline cells, due to early differentiation of PGCs, may account for different distribution patterns of familial mutations.

  8. 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.

  9. [Diagnostic value of BRAFV600E and RET/PTC oncogenes in thyroid nodule aspirates].

    Science.gov (United States)

    Guerra, Anna; Carrano, Mario; Angrisani, Elisabetta; Vitale, Mario

    2013-01-01

    Fine-needle aspiration cytology (FNC) is the primary means to distinguish benign form malignant nodules. Aim of this study is to evaluate the diagnostic value of BRAF(V600E) and RET/PTC oncogenes in a large cohort of thyroid nodules with inconclusive FNC. We searched for BRAF(V600E) and RET/PTC in 299 thyroid nodule aspirates then removed by surgery. RET/PTC demonstrated a poor specificity. The search for BRAF(V600E) demonstrated to be useful in 25 cases, identifying a PTC in 2 false negative, 2 inadequate, 11 indeterminate and 10 suspicious FNC. Detection of BRAF(V600E) revealed to be a useful tool to refine inconclusive cytology.

  10. La sûreté à l’aéroport de Zurich

    OpenAIRE

    Leese, Matthias; Wildi, Lisa

    2017-01-01

    Après les attentats de Bruxelles et d’Istanbul en 2016, les mesures de sûreté ont été temporairement renforcées dans les aéroports internationaux, y compris celui de Zurich. Les responsables se demandent aujourd’hui comment améliorer la protection des aéroports côté ville et si certains contrôles de sûreté ne devraient pas être placés en amont. Néanmoins, les événements n’ont pas entraîné de modification profonde du dispositif de sûreté. ISSN:2296-0228

  11. GDNF-Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease.

    Science.gov (United States)

    Kramer, Edgar R; Liss, Birgit

    2015-12-21

    Glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the midbrain dopaminergic (DA) system. While Ret signaling clearly impacts on the development, maintenance and regeneration of the mesostriatal DA system, the physiological functions of GDNF for the DA system are still unclear. Nevertheless, GDNF is still considered to be an excellent candidate to protect and/or regenerate the mesostriatal DA system in Parkinson disease (PD). Clinical trials with GDNF on PD patients are, however, so far inconclusive. Here, we review the current knowledge of GDNF and Ret signaling and function in the midbrain DA system, and their crosstalk with proteins and signaling pathways associated with PD. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  12. Retórica y hermenéutica en Aristóteles

    OpenAIRE

    2007-01-01

    En este artículo se intentan entresacar las principales ideas de Aristóteles sobre la hemenéutica. Es verdad que algunas de ellas pueden hallarse en el De interpretatione, pero otras se encuentran en la Retórica. Por eso se trata la hermenéutica aristotélica en conexión con su arte retórica. En ella se cumple la idea de que aquello que sirve para encodificar sirve también para decodificar; y, así como la retórica enseña a hablar y a escribir, también enseña a leer o a interpretar. De manera m...

  13. Assessing RET/PTC in thyroid nodule fine-needle aspirates: the FISH point of view.

    Science.gov (United States)

    Caria, Paola; Dettori, Tinuccia; Frau, Daniela V; Borghero, Angela; Cappai, Antonello; Riola, Alessia; Lai, Maria L; Boi, Francesco; Calò, Piergiorgio; Nicolosi, Angelo; Mariotti, Stefano; Vanni, Roberta

    2013-08-01

    RET/PTC rearrangement and BRAF(V600E) mutation are the two prevalent molecular alterations associated with papillary thyroid carcinoma (PTC), and their identification is increasingly being used as an adjunct to cytology in diagnosing PTC. However, there are caveats associated with the use of the molecular approach in fine-needle aspiration (FNA), particularly for RET/PTC, that should be taken into consideration. It has been claimed that a clonal or sporadic presence of this abnormality in follicular cells can distinguish between malignant and benign nodules. Nevertheless, the most commonly used PCR-based techniques lack the capacity to quantify the number of abnormal cells. Because fluorescence in situ hybridization (FISH) is the most sensitive method for detecting gene rearrangement in a single cell, we compared results from FISH and conventional RT-PCR obtained in FNA of a large cohort of consecutive patients with suspicious nodules and investigated the feasibility of setting a FISH-FNA threshold capable of distinguishing non-clonal from clonal molecular events. For this purpose, a home brew break-apart probe, able to recognize the physical breakage of RET, was designed. While a ≥3% FISH signal for broken RET was sufficient to distinguish nodules with abnormal follicular cells, only samples with a ≥6.8% break-apart FISH signal also exhibited positive RT-PCR results. On histological analysis, all nodules meeting the ≥6.8% threshold proved to be malignant. These data corroborate the power of FISH when compared with RT-PCR in quantifying the presence of RET/PTC in FNA and validate the RT-PCR efficiency in detecting clonal RET/PTC alterations.

  14. La construcción retórica de la crisis organizacional

    OpenAIRE

    2015-01-01

    En situaciones de crisis las organizaciones emplean retóricas a partir de las cuales intentan reparar su imagen hacia el exterior. Este artículo retoma presupuestos, categorías y metodologías propias de la retórica organizacional con el fin de analizar la manera como los miembros comunican los procesos de crisis que desde hace varios años ha afrontado una organización del Eje Cafetero Colombiano. El análisis cluster realizado a esta organización muestra seis pantallas terminológicas a part...

  15. La muerte como discurso retórico en algunos textos religiosos novohispanos

    OpenAIRE

    Rubial García, Antonio

    2012-01-01

    El estudio de la muerte como discurso retórico en algunos textos novohispanos diseña un escenario más para la investigación para mostrar cómo los autores religiosos novohispanos percibieron retóricamente la muerte en distintos tipos de narración. El tema se ha estudiado desde la antropología e investigadores como Claudio Lomnitz han encontrado contradicciones entre la visión cristiana y la imposición de una nueva concepción del estado a partir de la conquista.

  16. Technical evaluation of RETS-required reports for Fort Calhoun Station Unit 1

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-06-24

    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 Fort Calhoun Station Unit 1 were two Semiannual Reports for Technical Specification 5.9.4. 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. 4 refs.

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

    OpenAIRE

    Felicísimo Valbuena de la Fuente

    2007-01-01

    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 ...

  18. Avatares históricos de la retórica

    Directory of Open Access Journals (Sweden)

    Arantxa Capdevila Gómez

    2005-06-01

    Full Text Available La intención de este artículo es ofrecer una idea general de la historia de la retórica y repasar sus etapas principales, para así analizar mejor las tendencias actuales. Esta reseña histórica, además, permitirá ver la evolución y los cambios de la retórica y, sobre todo, las relaciones entre sus características en el pasado y las que tiene en el momento presente.

  19. História, retórica, poética, prova: a leitura de Carlo Ginzburg da Retórica de Aristóteles

    OpenAIRE

    Carlos Eduardo de Almeida Ogawa

    2010-01-01

    O historiador italiano Carlo Ginzburg envolveu-se ao longo das décadas de 1980 e 90 nas discussões norte-americanas sobre o pós-modernismo, investindo contra o que ele chamava de tendências céticas dos defensores do pós-modernismo. Sua caracterização da tendência intelectual assimila o que ele chama de tendência lingüística ao uso da palavra retórica. Sua proposta para refutar as teses dessas tendências passa pela recuperação da Retórica de Aristóteles e do caráter judiciário da prova. O pres...

  20. 荧光假单胞菌2P24中retS对抗生素2,4-二乙酰基间苯三酚合成的影响%Effect of retS gene on biosynthesis of 2, 4-diacetylphloroglucinol in Pseudomonas fluorescens 2P24

    Institute of Scientific and Technical Information of China (English)

    刘九成; 张伟; 吴小刚; 张力群

    2013-01-01

    Regulator of exopolysaccharide and type IE secretion ( RetS ) is a hybrid sensor kinase/response regulator protein located on bacterial membrane, and essential for expression of numerous genes.In Pseudomonas aeruginosa, RetS modulates the phosphorylation state of another kinase GacS via a direct interaction.[ Objective] The goal of this study is to study the effect of retS on the antibiotic 2, 4-diacetyl-phloroglucinol (2,4-DAPG) production in P.fluorescens 2P24.[Methods] Production of 2,4-DAPG in strain 2P24 and its mutants was quantified by HPLC.To determine the effect of RetS on the Gac/Rsm pathway, the promoters of the small RNA genes rsinX/rsmY/rsmZ and regulatory genes rsmA/rsmE in the Rsm pathway were fused with a promoterless lacZ, and the promoter activities were measured in 2P24 and the retS-deficient mutants.[ Results] Genetic inactivation of the retS in strain 2P24 increased the production of an uncharacterized red pigment and the antibiotic 2,4-DAPG.RetS negatively regulated the transcription of the small RNAs RsmX and RsmZ.In the retS and gacS double mutant or the retS and gacA double mutant, all the phenotypic changes caused by the retS deletion were reversed to the level of gacS or gacA single gene mutant.[Conclusion] In P.fluorescens 2P24, RetS negatively regulates the production of antibiotic 2,4-DAPG through the Gac/Rsm pathway.%假单胞菌中RetS是一个位于膜上的感应激酶,对多种基因的表达都有调控作用.在铜绿假单胞菌中,RetS可以与另一个感应激酶GacS直接互作,并抑制GacS的磷酸化.[目的]本文利用遗传学方法研究了荧光假单胞菌2P24中RetS对抗生素2,4-二乙酰基间苯三酚(2,4-DAPG)合成的影响,并对其可能的调控机制进行了初步探索.[方法]利用高压液相色谱法(HPLC)检测2P24及其衍生菌株中2,4-DAPG的产量.将Gac/Rsm 信号途径中小RNA及调控蛋白的转录报告质粒转入到菌株2P24及其retS突变菌株中,检查RetS对以上基因转录

  1. 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.

  2. Germline TERT promoter mutations are rare in familial melanoma

    DEFF Research Database (Denmark)

    Harland, Mark; Petljak, Mia; Robles-Espinoza, Carla Daniela;

    2016-01-01

    Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57...... T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers....... The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte...

  3. Prevalence of deleterious ATM germline mutations in gastric cancer patients.

    Science.gov (United States)

    Huang, Dong-Sheng; Tao, Hou-Quan; He, Xu-Jun; Long, Ming; Yu, Sheng; Xia, Ying-Jie; Wei, Zhang; Xiong, Zikai; Jones, Sian; He, Yiping; Yan, Hai; Wang, Xiaoyue

    2015-12-01

    Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment.

  4. Human germline antibody gene segments encode polyspecific antibodies.

    Science.gov (United States)

    Willis, Jordan R; Briney, Bryan S; DeLuca, Samuel L; Crowe, James E; Meiler, Jens

    2013-04-01

    Structural flexibility in germline gene-encoded antibodies allows promiscuous binding to diverse antigens. The binding affinity and specificity for a particular epitope typically increase as antibody genes acquire somatic mutations in antigen-stimulated B cells. In this work, we investigated whether germline gene-encoded antibodies are optimal for polyspecificity by determining the basis for recognition of diverse antigens by antibodies encoded by three VH gene segments. Panels of somatically mutated antibodies encoded by a common VH gene, but each binding to a different antigen, were computationally redesigned to predict antibodies that could engage multiple antigens at once. The Rosetta multi-state design process predicted antibody sequences for the entire heavy chain variable region, including framework, CDR1, and CDR2 mutations. The predicted sequences matched the germline gene sequences to a remarkable degree, revealing by computational design the residues that are predicted to enable polyspecificity, i.e., binding of many unrelated antigens with a common sequence. The process thereby reverses antibody maturation in silico. In contrast, when designing antibodies to bind a single antigen, a sequence similar to that of the mature antibody sequence was returned, mimicking natural antibody maturation in silico. We demonstrated that the Rosetta computational design algorithm captures important aspects of antibody/antigen recognition. While the hypervariable region CDR3 often mediates much of the specificity of mature antibodies, we identified key positions in the VH gene encoding CDR1, CDR2, and the immunoglobulin framework that are critical contributors for polyspecificity in germline antibodies. Computational design of antibodies capable of binding multiple antigens may allow the rational design of antibodies that retain polyspecificity for diverse epitope binding.

  5. Federal Regulation of Gene Therapy: Who Will Save our Germline?

    OpenAIRE

    2003-01-01

    This paper will attempt to address some of these more complex issues involving human gene therapy and the encompassing regulations. The first section will deal with the science of gene therapy and will briefly touch upon the scientific hurdles that remain for scientists in this field, as this is important to understanding many of the ethical issues. This section will be divided into a basic genetic overview, a description of somatic gene therapy, and a summary of germline gene therapy. The se...

  6. Germline HABP2 Mutation Causing Familial Nonmedullary Thyroid Cancer

    OpenAIRE

    Gara, Sudheer Kumar; Jia, Li; Merino, Maria J.; Agarwal, Sunita K.; Zhang, Lisa; Cam, Maggie; Patel, Dhaval; Kebebew, Electron

    2015-01-01

    Familial nonmedullary thyroid cancer accounts for 3 to 9% of all cases of thyroid cancer, but the susceptibility genes are not known. Here, we report a germline variant of HABP2 in seven affected members of a kindred with familial nonmedullary thyroid cancer and in 4.7% of 423 patients with thyroid cancer. This variant was associated with increased HABP2 protein expression in tumor samples from affected family members, as compared with normal adjacent thyroid tissue and samples from sporadic ...

  7. 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...

  8. Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system.

    Directory of Open Access Journals (Sweden)

    Edgar R Kramer

    2007-03-01

    Full Text Available Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF and brain-derived neurotrophic factor (BDNF may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD, a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret and BDNF (TrkB. We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.

  9. RET/PTC rearrangement is prevalent in follicular Hurthle cell carcinomas

    NARCIS (Netherlands)

    de Vries, Margriet M.; Celestino, Ricardo; Castro, Patricia; Eloy, Catarina; Maximo, Valdemar; van der Wal, Jacqueline E.; Plukker, John T. M.; Links, Thera P.; Hofstra, Robert M. W.; Sobrinho-Simoes, Manuel; Soares, Paula

    2012-01-01

    Aims: The molecular alterations underlying follicular Hurthle cell carcinomas (FHCCs) are largely unknown. In an attempt to clarify this issue, we analysed a series of Hurthle cell tumours for the presence of RET/PTC and PAX8/PPARG rearrangements and BRAF, HRAS and NRAS mutations. Methods and result

  10. Differential Contributions of Rare and Common, Coding and Noncoding Ret Mutations to Multifactorial Hirschsprung Disease Liability

    NARCIS (Netherlands)

    Emison, Eileen Sproat; Garcia-Barcelo, Merce; Grice, Elizabeth A.; Lantieri, Francesca; Amiel, Jeanne; Burzynski, Grzegorz; Fernandez, Raquel M.; Hao, Li; Kashuk, Carl; West, Kristen; Miao, Xiaoping; Tam, Paul K. H.; Griseri, Paola; Ceccherini, Isabella; Pelet, Anna; Jannot, Anne-Sophie; de Pontual, Loic; Henrion-Caude, Alexandra; Lyonnet, Stanislas; Verheij, Joke B. G. M.; Hofstra, Robert M. W.; Antinolo, Guillermo; Borrego, Salud; McCallion, Andrew S.; Chakravarti, Aravinda

    2010-01-01

    The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C -> T allele (rs2435357: p = 3.9 x 10(-43) in European

  11. Alegoría de la retórica en un biombo de Juan Correa

    Directory of Open Access Journals (Sweden)

    Arnulfo Herrera

    2014-03-01

    Full Text Available A partir de un análisis iconográfico se decodifica una alegoría de la retórica incluida en el Biombo de los cuatro elementos y las artes liberales, pintado en México hacia el año 1700 por Juan Correa.

  12. DNA POLYMORPHISMS AND CONDITIONS FOR SSCP ANALYSIS OF THE 20 EXONS OF THE RET PROTOONCOGENE

    NARCIS (Netherlands)

    CECCHERINI, [No Value; HOFSTRA, RMW; LUO, Y; STULP, RP; BARONE, [No Value; STELWAGEN, T; BOCCIARDI, R; NIJVEEN, H; BOLINO, A; SERI, M; RONCHETTO, P; PASINI, B; BOZZANO, M; BUYS, CHCM; ROMEO, G

    1994-01-01

    Recently identified mutations affecting different domains of the RET proto-oncogene are associated with Multiple Endocrine Neoplasia type 2A (MEN 2A) and type 2B (MEN 2B), familial and sporadic Medullary Thyroid Carcinomas (MTC) and Hirschsprung disease (HSCR). In order to facilitate the screening f

  13. Estructura retórica del monólogo televisivo

    Directory of Open Access Journals (Sweden)

    Pedro J. Gómez

    2012-04-01

    Full Text Available En el presente artículo demostraremos que los monólogos televisivos de mayor éxito funcionan con una estructura bastante similar e inspirada en la del discurso retórico clásico. Esta característica permite situar a las denominadas stand-up comedies entre los discursos de ficción con una mayor carga retórica en el plano del contenido, hecho que contrasta con la menor presencia de elementos retóricos típicamente visuales. No han sido objeto de este estudio las figuras retóricas literarias, muy abundantes, utilizadas en cada monólogo, aunque en algún momento se pueda hacer referencia a alguna de ellas. El estudio concluye con algunas reglas generales, de uso común en la mayor parte de los monólogos televisivos o al menos, en los de mayor éxito.

  14. Cell lineage analysis of the mammalian female germline.

    Directory of Open Access Journals (Sweden)

    Yitzhak Reizel

    Full Text Available Fundamental aspects of embryonic and post-natal development, including maintenance of the mammalian female germline, are largely unknown. Here we employ a retrospective, phylogenetic-based method for reconstructing cell lineage trees utilizing somatic mutations accumulated in microsatellites, to study female germline dynamics in mice. Reconstructed cell lineage trees can be used to estimate lineage relationships between different cell types, as well as cell depth (number of cell divisions since the zygote. We show that, in the reconstructed mouse cell lineage trees, oocytes form clusters that are separate from hematopoietic and mesenchymal stem cells, both in young and old mice, indicating that these populations belong to distinct lineages. Furthermore, while cumulus cells sampled from different ovarian follicles are distinctly clustered on the reconstructed trees, oocytes from the left and right ovaries are not, suggesting a mixing of their progenitor pools. We also observed an increase in oocyte depth with mouse age, which can be explained either by depth-guided selection of oocytes for ovulation or by post-natal renewal. Overall, our study sheds light on substantial novel aspects of female germline preservation and development.

  15. Cell lineage analysis of the mammalian female germline.

    Science.gov (United States)

    Reizel, Yitzhak; Itzkovitz, Shalev; Adar, Rivka; Elbaz, Judith; Jinich, Adrian; Chapal-Ilani, Noa; Maruvka, Yosef E; Nevo, Nava; Marx, Zipora; Horovitz, Inna; Wasserstrom, Adam; Mayo, Avi; Shur, Irena; Benayahu, Dafna; Skorecki, Karl; Segal, Eran; Dekel, Nava; Shapiro, Ehud

    2012-01-01

    Fundamental aspects of embryonic and post-natal development, including maintenance of the mammalian female germline, are largely unknown. Here we employ a retrospective, phylogenetic-based method for reconstructing cell lineage trees utilizing somatic mutations accumulated in microsatellites, to study female germline dynamics in mice. Reconstructed cell lineage trees can be used to estimate lineage relationships between different cell types, as well as cell depth (number of cell divisions since the zygote). We show that, in the reconstructed mouse cell lineage trees, oocytes form clusters that are separate from hematopoietic and mesenchymal stem cells, both in young and old mice, indicating that these populations belong to distinct lineages. Furthermore, while cumulus cells sampled from different ovarian follicles are distinctly clustered on the reconstructed trees, oocytes from the left and right ovaries are not, suggesting a mixing of their progenitor pools. We also observed an increase in oocyte depth with mouse age, which can be explained either by depth-guided selection of oocytes for ovulation or by post-natal renewal. Overall, our study sheds light on substantial novel aspects of female germline preservation and development.

  16. Mutation rates and the evolution of germline structure

    Science.gov (United States)

    2016-01-01

    Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates. This article is part of the themed issue ‘Dating species divergences using rocks and clocks'. PMID:27325834

  17. 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

  18. A novel RET rearrangement (ACBD5/RET) by pericentric inversion, inv(10)(p12.1;q11.2), in papillary thyroid cancer from an atomic bomb survivor exposed to high-dose radiation.

    Science.gov (United States)

    Hamatani, Kiyohiro; Eguchi, Hidetaka; Koyama, Kazuaki; Mukai, Mayumi; Nakachi, Kei; Kusunoki, Yoichiro

    2014-11-01

    During analysis of RET/PTC rearrangements in papillary thyroid cancer (PTC) among atomic bomb survivors, a cDNA fragment of a novel type of RET rearrangement was identified in a PTC patient exposed to a high radiation dose using the improved 5' RACE method. This gene resulted from the fusion of the 3' portion of RET containing tyrosine kinase domain to the 5' portion of the acyl-coenzyme A binding domain containing 5 (ACBD5) gene, by pericentric inversion inv(10)(p12.1;q11.2); expression of the fusion gene was confirmed by RT-PCR. ACBD5 gene is ubiquitously expressed in various human normal tissues including thyroid. Full-length cDNA of the ACBD5-RET gene was constructed and then examined for tumorigenicity. Enhanced phosphorylation of ERK proteins in the MAPK pathway was observed in NIH3T3 cells transfected with expression vector encoding the full-length ACBD5/RET cDNA, while this was not observed in the cells transfected with empty expression vector. Stable NIH3T3 transfectants with ACBD5-RET cDNA induced tumor formation after their injection into nude mice. These findings suggest that the ACBD5-RET rearrangement is causatively involved in the development of PTC.

  19. Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma.

    Science.gov (United States)

    Zou, Minjing; Baitei, Essa Y; Alzahrani, Ali S; BinHumaid, Faisal S; Alkhafaji, Dania; Al-Rijjal, Roua A; Meyer, Brian F; Shi, Yufei

    2014-08-01

    RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC. We investigated 88 PTC for concomitant mutations. Mutation in BRAF exon 15, KRAS, NRAS, and HRAS were studied by polymerase chain reaction (PCR)-sequencing of tumor DNA; RET/PTC rearrangement was determined by reverse transcription (RT)-PCR-sequencing of tumor cDNA. BRAF(V600E) was detected in 39 of 82 classic PTC (CPTC) and in all three tall-cell variants (49%, 42/85). KRAS mutation (p.Q61R and p.S65N) was detected in two CPTC (2%, 2/88) and NRAS(Q61R) in one CPTC and two follicular variant PTC (FVPTC; 3%, 3/88). KRAS(S65N) was identified for the first time in thyroid cancer and could activate mitogen-associated protein kinase (MAPK). RET/PTC-1 was detected in nine CPTC, one tall-cell variant, and two FVPTC. Concomitant BRAF(V600E) and KRAS, or BRAF(V600E) and RET/PTC-1 mutations were found in two CPTC, and six CPTC and one tall-cell variant, respectively. In total, 11 concomitant mutations were found in 88 PTC samples (13%), and most of them were in the advanced stage of disease (8/11, 73%; pPTC and are associated with poor prognosis. The concomitant mutations may represent intratumor heterogeneity and could exert a gene dosage effect to promote disease progression. KRAS(S65N) can constitutively activate the MAPK pathway.

  20. Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease.

    Science.gov (United States)

    Di Zanni, Eleonora; Adamo, Annalisa; Belligni, Elga; Lerone, Margherita; Martucciello, Giuseppe; Mattioli, Girolamo; Pini Prato, Alessio; Ravazzolo, Roberto; Silengo, Margherita; Bachetti, Tiziana; Ceccherini, Isabella

    2017-07-01

    HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Estudio del protooncogen Ret en neoplasia endocrina multiple 2A y en carcinoma medular en tiroides familiar: Hallazgos clínico-patológicos en portadores asintomáticos Analysis of the RET protooncogene in multiple endocrine neoplasia 2A and in familial medullary thyroid carcinoma: Clinical-pathological findings in asymptomatic carriers

    Directory of Open Access Journals (Sweden)

    S. Belli

    2003-01-01

    carriers, including 5 children aged 11±3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germline novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed.

  2. Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection.

    Science.gov (United States)

    Yoon, Song-Ro; Choi, Soo-Kung; Eboreime, Jordan; Gelb, Bruce D; Calabrese, Peter; Arnheim, Norman

    2013-06-06

    Noonan syndrome (NS) is among the most common Mendelian genetic diseases (∼1/2,000 live births). Most cases (50%-84%) are sporadic, and new mutations are virtually always paternally derived. More than 47 different sites of NS de novo missense mutations are known in the PTPN11 gene that codes for the protein tyrosine phosphatase SHP-2. Surprisingly, many of these mutations are recurrent with nucleotide substitution rates substantially greater than the genome average; the most common mutation, c.922A>G, is at least 2,400 times greater. We examined the spatial distribution of the c.922A>G mutation in testes from 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2 interacts with the transcriptional activator STAT3. Given STAT3's function in mouse spermatogonial stem cells, we suggest that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 might also play a previously unrecognized role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome and MEN2B. Looking at recurrent mutations driven by germline selection in different gene families can help highlight common causal signaling pathways.

  3. Spectroscopic characterization of enzymatic flax retting: Factor analysis of FT-IR and FT-Raman data

    Science.gov (United States)

    Archibald, D. D.; Henrikssen, G.; Akin, D. E.; Barton, F. E.

    1998-06-01

    Flax retting is a chemical, microbial or enzymatic process which releases the bast fibers from the stem matrix so they can be suitable for mechanical processing before spinning into linen yarn. This study aims to determine the vibrational spectral features and sampling methods which can be used to evaluate the retting process. Flax stems were retted on a small scale using an enzyme mixture known to yield good retted flax. Processed stems were harvested at various time points in the process and the retting was evaluated by conventional methods including weight loss, color difference and Fried's test, a visual ranking of how the stems disintegrate in hot water. Spectroscopic measurements were performed on either whole stems or powders of the fibers that were mechanically extracted from the stems. Selected regions of spectra were baseline and amplitude corrected using a variant of the multiplicative signal correction method. Principal component regression and partial least-squares regression with full cross-validation were used to determine the spectral features and rate of spectral transformation by regressing the spectra against the retting time in hours. FT-Raman of fiber powders and FT-IR reflectance of whole stems were the simplest and most precise methods for monitoring the retting transformation. Raman tracks the retting by measuring the decrease in aromatic signal and subtle changes in the C-H stretching vibrations. The IR method uses complex spectral features in the fingerprint and carbonyl region, many of which are due to polysaccharide components. Both spectral techniques monitor the retting process with greater precision than the reference method.

  4. [RET/PTC Gene Rearrangements in the Sporadic and Radiogenic Thyroid Tumors: Molecular Genetics, Radiobiology and Molecular Epidemiology].

    Science.gov (United States)

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

    2015-01-01

    A review of molecular genetic, radiobiological and molecular epidemiological studies of gene (chromosome) rearrangements RET/PTC in the cells of the thyroid gland as well as the laws in relation to radiation exposure in vitro, in vivo and human populations identified with them are submitted. The data on the c-RET gene and its chimeric constructs with the gene-donors (RET/PTC rearrangements) are considered. The information about the history of the RET/PTC discovery, their types, carcinogenic potential and specificity both to tumor and non-tumor thyroid disease especially for papillary thyroid carcinoma are provided. The data (seven studies) on the induction of RET/PTC after irradiation of tumor and normal thyroid cells in vitro and mice are reviewed. The mechanisms of RET/PTC induction may be associated with DNA double strand breaks and oxidative stress. Some information (three publications) about the possibility of RET/PTC induction by low doses of radiation with low LET (to 0.1 Gy) is given and it is concluded that their potential evidentiary is generally weak. The achievements in the molecular epidemiology of RET/PTC frequency for exposed and unexposed cohorts are stated. At the same time it is noted that, despite the vast array. of data accumulated from 30 countries of the world and more than 20 years of research, the formed provisions are weakly confirmed statistically and have no base corresponding to the canons of evidence-based medicine. The possibility of use of the RET/PTC presence or their frequencies as markers of the papillary thyroid carcinomas and, specifically, their radiogenic forms, is considered. In the first case the answer may be positive, while in the second, the situation is characterized by uncertainty. Based to the above mentioned we came to a conclusion about the need of a pooled or meta-analysis of the totality of the published data.

  5. Induction of RET dependent and independent pro-inflammatory programs in human peripheral blood mononuclear cells from Hirschsprung patients.

    Directory of Open Access Journals (Sweden)

    Marta Rusmini

    Full Text Available Hirschsprung disease (HSCR is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes and adaptive (B and T lymphocytes human peripheral blood mononuclear cells (PBMCs and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF and glycosyl-phosphatidylinositol membrane anchored co-receptor α1 (GFRα1 trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1 and cytokines (IL-1β, IL-6 and IL-8 and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-Rα. Although at different levels, the modulation of these "RET-dependent genes" occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these "RET-independent genes", there are CSF-1R, IL1-R1, IL1-R2 and TGFβ-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of

  6. 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

  7. Building block style recipes for productivity improvement in OPC, RET and ILT flows

    Science.gov (United States)

    Wu, Linghui; Kwa, Denny; Wan, Jinyin; Wang, Tom; St. John, Matt; Deeth, Steven; Chen, Xiaohui; Cecil, Tom; Meng, Xiaodong; Lucas, Kevin

    2016-03-01

    Traditional model-based Optical Proximity Correction (OPC) and rule-based Resolution Enhancement Technology (RET) methods have been the workhorse mask synthesis methods in volume production for logic and memory devices for more than 15 years. Rule-based OPC methods have been in standard use for over 20 years now. With continuous technical enhancements, these methods have proven themselves robust, flexible and fast enough to meet many of the technical needs of even the most advanced nodes. Inverse Lithography Technology (ILT) methods are well known to have strong benefits in finding flexible mask pattern solutions to improve process window for the most advanced design locations where traditional methods are not sufficient. However, OPC/RET requirements at each node have changed radically in the last 20 years beyond just technical requirements. The volume of engineering work to be done has also skyrocketed. The number of device layers which need OPC/RET can be 10X higher than in earlier nodes. Additionally, the number of mask layers per device layer is often 2X or more times higher with multiple patterning. Finally, the number of features to correct per mask increases ~2X with each node. These factors led to a large increase in the number of OPC engineers needed to develop the complex new OPC/RET recipes for advanced nodes. In this paper, we describe new developments which significantly improve the productivity of OPC engineers to deploy Rule Based OPC (RBOPC), Model Based OPC (MBOPC), AF, and ILT recipes in modern manufacturing flows. In addition to technical improvements such as novel multiple segment hotspot fixing solvers and ILT hot-spot fixing necessary to support correction needs, we have re-architected the entire flow based on how OPC engineers now develop and maintain OPC/RET recipes. The re-architecture of the flow takes advantages of more recent developments in modular and structured programming methods which are known to benefit ease engineering software

  8. ret/PTC-1 expression alters the immunoprofile of thyroid follicular cells

    Directory of Open Access Journals (Sweden)

    Aherne Sinead

    2008-05-01

    Full Text Available Abstract Background Hashimoto Thyroiditis (H.T. is a destructive autoimmune thyroid condition whose precise molecular pathogenesis remains unclear. ret/PTC-1 is a chimeric transcript which has been described in autoimmune thyroid disease (AITD and thyroid neoplasia. The purpose of this study was to observe the immunogenic effect exposure to H.T. and control lymphocyte supernatant would have on normal (Nthy-ori and ret/PTC-1 (TPC-1 expressing thyroid cell line models. Results A 2 × 2 matrix comprising Nthy-ori and TPC-1 cell lines and H.T. and control lymphocyte supernatant was designed and utilised as follows; activated lymphocytic supernatant from a H.T. and normal control were co-cultured with a cell line derived from normal thyroid (Nthy-ori and also a cell line derived from a papillary thyroid carcinoma that endogenously expresses ret/PTC-1 (TPC-1. The co-cultures were harvested at 0, 6 and 18 hour time points. Gene expression analysis was performed on RNA extracted from thyrocytes using TaqMan® Immune profiling Low-Density Arrays (Applied Biosystems, CA, USA comprising gene expression markers for 93 immune related targets plus 3 endogenous controls. Stimulation of the normal thyroid cell line model with activated T cell supernatant from the H.T. donor yielded global up-regulation of immune targets when compared with control supernatant stimulation. In particular, a cohort of targets (granzyme B, CD3, CD25, CD152, CD45 associated with cytotoxic cell death; T cell receptor (TCR and T cell signaling were up-regulated in the normal cell line model. When the ret/PTC-1 expressing thyroid cell line was co-cultured with H.T. lymphocyte supernatant, in comparison to control supernatant stimulation, down-regulation of the same subset of immune targets was seen. Conclusion Co-culturing H.T. lymphocyte supernatant with a normal thyroid cell line model leads to over-expression of a subset of targets which could contribute to the pathogenesis of H

  9. Caenorhabditis elegans MES-3 is a target of GLD-1 and functions epigenetically in germline development.

    Science.gov (United States)

    Xu, L; Paulsen, J; Yoo, Y; Goodwin, E B; Strome, S

    2001-11-01

    The maternal-effect sterile (MES) proteins are maternally supplied regulators of germline development in Caenorhabditis elegans. In the hermaphrodite progeny from mes mutant mothers, the germline dies during larval development. On the basis of the similarities of MES-2 and MES-6 to known transcriptional regulators and on the basis of the effects of mes mutations on transgene expression in the germline, the MES proteins are predicted to be transcriptional repressors. One of the MES proteins, MES-3, is a novel protein with no recognizable motifs. In this article we show that MES-3 is localized in the nuclei of embryos and germ cells, consistent with its predicted role in transcriptional regulation. Its distribution in the germline and in early embryos does not depend on the wild-type functions of the other MES proteins. However, its nuclear localization in midstage embryos and its persistence in the primordial germ cells depend on wild-type MES-2 and MES-6. These results are consistent with biochemical data showing that MES-2, MES-3, and MES-6 associate in a complex in embryos. The distribution of MES-3 in the adult germline is regulated by the translational repressor GLD-1: MES-3 is absent from the region of the germline where GLD-1 is known to be present, MES-3 is overexpressed in the germline of gld-1 mutants, and GLD-1 specifically binds the mes-3 3' untranslated region (3' UTR). Analysis of temperature-shifted mes-3(bn21ts) worms and embryos indicates that MES-3 function is required in the mother's germline and during embryogenesis to ensure subsequent normal germline development. We propose that MES-3 acts epigenetically to induce a germline state that is inherited through both meiosis and mitosis and that is essential for survival of the germline.

  10. Common germline polymorphisms associated with breast cancer-specific survival.

    Science.gov (United States)

    Pirie, Ailith; Guo, Qi; Kraft, Peter; Canisius, Sander; Eccles, Diana M; Rahman, Nazneen; Nevanlinna, Heli; Chen, Constance; Khan, Sofia; Tyrer, Jonathan; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Lush, Michael; Dunning, Alison M; Shah, Mitul; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Lambrechts, Dieter; Weltens, Caroline; Leunen, Karin; van Ongeval, Chantal; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Blomqvist, Carl; Aittomäki, Kristiina; Fagerholm, Rainer; Muranen, Taru A; Olsen, Janet E; Hallberg, Emily; Vachon, Celine; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Broeks, Annegien; Cornelissen, Sten; Haiman, Christopher A; Henderson, Brian E; Schumacher, Frederick; Le Marchand, Loic; Hopper, John L; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C; Cross, Simon S; Reed, Malcolm Wr; Giles, Graham G; Milne, Roger L; McLean, Catriona; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John Wm; van den Ouweland, Ans Mw; Marme, Federick; Schneeweiss, Andreas; Yang, Rongxi; Burwinkel, Barbara; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Brenner, Hermann; Butterbach, Katja; Holleczek, Bernd; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Devilee, Peter; Tollenaar, Robert Aem; Seynaeve, Caroline; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Ficarazzi, Filomena; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Balleine, Rosemary; Phillips, Kelly-Anne; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Durda, Katarzyna; Hamann, Ute; Kabisch, Maria; Ulmer, Hans Ulrich; Rüdiger, Thomas; Margolin, Sara; Kristensen, Vessela; Nord, Siljie; Evans, D Gareth; Abraham, Jean; Earl, Helena; Poole, Christopher J; Hiller, Louise; Dunn, Janet A; Bowden, Sarah; Yang, Rose; Campa, Daniele; Diver, W Ryan; Gapstur, Susan M; Gaudet, Mia M; Hankinson, Susan; Hoover, Robert N; Hüsing, Anika; Kaaks, Rudolf; Machiela, Mitchell J; Willett, Walter; Barrdahl, Myrto; Canzian, Federico; Chin, Suet-Feung; Caldas, Carlos; Hunter, David J; Lindstrom, Sara; Garcia-Closas, Montserrat; Couch, Fergus J; Chenevix-Trench, Georgia; Mannermaa, Arto; Andrulis, Irene L; Hall, Per; Chang-Claude, Jenny; Easton, Douglas F; Bojesen, Stig E; Cox, Angela; Fasching, Peter A; Pharoah, Paul Dp; Schmidt, Marjanka K

    2015-04-22

    Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.

  11. Parallel germline infiltration of a lentivirus in two Malagasy lemurs.

    Directory of Open Access Journals (Sweden)

    Clément Gilbert

    2009-03-01

    Full Text Available Retroviruses normally infect the somatic cells of their host and are transmitted horizontally, i.e., in an exogenous way. Occasionally, however, some retroviruses can also infect and integrate into the genome of germ cells, which may allow for their vertical inheritance and fixation in a given species; a process known as endogenization. Lentiviruses, a group of mammalian retroviruses that includes HIV, are known to infect primates, ruminants, horses, and cats. Unlike many other retroviruses, these viruses have not been demonstrably successful at germline infiltration. Here, we report on the discovery of endogenous lentiviral insertions in seven species of Malagasy lemurs from two different genera -- Cheirogaleus and Microcebus. Combining molecular clock analyses and cross-species screening of orthologous insertions, we show that the presence of this endogenous lentivirus in six species of Microcebus is the result of one endogenization event that occurred about 4.2 million years ago. In addition, we demonstrate that this lentivirus independently infiltrated the germline of Cheirogaleus and that the two endogenization events occurred quasi-simultaneously. Using multiple proviral copies, we derive and characterize an apparently full length and intact consensus for this lentivirus. These results provide evidence that lentiviruses have repeatedly infiltrated the germline of prosimian species and that primates have been exposed to lentiviruses for a much longer time than what can be inferred based on sequence comparison of circulating lentiviruses. The study sets the stage for an unprecedented opportunity to reconstruct an ancestral primate lentivirus and thereby advance our knowledge of host-virus interactions.

  12. 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

    -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......Hashimoto's thyroiditis is an inflammatory disease of the thyroid gland with autoimmune etiology. Patients afflicted with Hashimoto's have a higher risk of thyroid malignancies such as papillary thyroid carcinoma. In the present study, we investigated the frequency of papillary thyroid carcinoma...... 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...

  13. Germ-line gene therapy and the medical imperative.

    Science.gov (United States)

    Munson, Ronald; Davis, Lawrence H

    1992-06-01

    Somatic cell gene therapy has yielded promising results. If germ cell gene therapy can be developed, the promise is even greater: hundreds of genetic diseases might be virtually eliminated. But some claim the procedure is morally unacceptable. We thoroughly and sympathetically examine several possible reasons for this claim but find them inadequate. There is no moral reason, then, not to develop and employ germ-line gene therapy. Taking the offensive, we argue next that medicine has a prima facie moral obligation to do so.

  14. CDH1 germline mutations and hereditary lobular breast cancer.

    Science.gov (United States)

    Corso, Giovanni; Intra, Mattia; Trentin, Chiara; Veronesi, Paolo; Galimberti, Viviana

    2016-04-01

    Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 germline mutations (that encodes for the E-cadherin protein), and lobular breast cancer is the second most frequent type of neoplasia. Recently, novel E-cadherin constitutional alterations have been identified in pedigree clustering only for lobular breast carcinoma without evidence of diffuse gastric tumors and in absence of BRCA1/2 mutations. This first evidence opens novel questions about the inherited correlation between diffuse gastric and lobular breast cancers. In this brief review we revise the literature data about the CDH1 mutation frequency affecting exclusively lobular breast cancer, providing clinical recommendation for asymptomatic mutation carriers.

  15. Human Germline Mutation and the Erratic Evolutionary Clock

    Science.gov (United States)

    Przeworski, Molly

    2016-01-01

    Our understanding of the chronology of human evolution relies on the “molecular clock” provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not “a mutation rate” but a precise characterization of how mutations accumulate in development in males and females—knowledge that remains elusive. PMID:27760127

  16. Germline HABP2 Mutation Causing Familial Nonmedullary Thyroid Cancer.

    Science.gov (United States)

    Gara, Sudheer Kumar; Jia, Li; Merino, Maria J; Agarwal, Sunita K; Zhang, Lisa; Cam, Maggie; Patel, Dhaval; Kebebew, Electron

    2015-07-30

    Familial nonmedullary thyroid cancer accounts for 3 to 9% of all cases of thyroid cancer, but the susceptibility genes are not known. Here, we report a germline variant of HABP2 in seven affected members of a kindred with familial nonmedullary thyroid cancer and in 4.7% of 423 patients with thyroid cancer. This variant was associated with increased HABP2 protein expression in tumor samples from affected family members, as compared with normal adjacent thyroid tissue and samples from sporadic cancers. Functional studies showed that HABP2 has a tumor-suppressive effect, whereas the G534E variant results in loss of function.

  17. 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...

  18. 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.

  19. Petrus Ramus y el ocaso de la retórica cívica

    Directory of Open Access Journals (Sweden)

    Laura ADRIÁN LARA

    2008-01-01

    Full Text Available Petrus Ramus (Pierre de la Ramée, 1515-1572 fue profesor Real de Elocuencia y Filosofía en el Collège Royal (París. Movido por su vocación pedagógica redefinió el ámbito de las artes liberales, despojando a la retórica de su contenido tradicional. Para Ramus la retórica consiste solo en la elocutio, no es un saber cívico tal y como lo entendieron los humanistas italianos que entroncan con la tradición greco-romana. Continuando el espíritu escolástico del norte de Europa, Ramus subraya la preeminencia de la dialéctica y consolida la noción de méthode que tanta importancia cobrará a partir del siglo XVII.

  20. Análise do discurso e estudos retóricos

    OpenAIRE

    2015-01-01

    Rhetoric in Detail reúne 12 estudos escritos por pesquisadores que se definem, principalmente, como retóricos que empregam teoria e/ou método da Análise do Discurso linguística. Esses estudos fazem uso de uma variedade de recursos de análise analítica, incluindo os da Análise Crítica do Discurso, da Sociolinguística Interacional, da Análise Narrativa e da análise de corpus informatizado. Eles ilustram a utilidade da Análise do Discurso em uma variedade de sites retóricos, incluindo os discurs...

  1. Petrus Ramus y el ocaso de la retórica cívica

    OpenAIRE

    Adrián Lara, Laura

    2008-01-01

    Petrus Ramus (Pierre de la Ramée, 1515-1572) fue profesor Real de Elocuencia y Filosofía en el Collège Royal (París). Movido por su vocación pedagógica redefinió el ámbito de las artes liberales, despojando a la retórica de su contenido tradicional. Para Ramus la retórica consiste solo en la elocutio, no es un saber cívico tal y como lo entendieron los humanistas italianos que entroncan con la tradición greco-romana. Continuando el espíritu escolástico del norte de Europa, Ramus subraya la pr...

  2. RET mutations in a large indian family with medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    D M Mahesh

    2014-01-01

    Full Text Available Background: Medullary thyroid carcinoma (MTC is a tumor arising from the para follicular (C cells of the thyroid gland and can occur either sporadically or as part of an inherited syndrome. A proportion of these cases carry an autosomal dominant mutation in the RET (REarranged during Transfection proto-oncogene. Screening for these mutations in the affected patients and the carriers ′′at risk′′ which includes the first-degree relatives is of utmost importance for early detection and prompt treatment including prophylactic thyroidectomy in cases that harbor these mutations. Results: This report presents details of screening and subsequent follow-up of a large Indian family, where the index case was found to carry p.Cys634Ser mutation involving exon 11 of the RET gene. These data are of value considering the paucity of information within the region in context of screening large families affected by these mutations.

  3. Retórica del videoarte. Estudio aplicado a la videopoesía

    Directory of Open Access Journals (Sweden)

    Giorgio De Marchis

    2012-04-01

    Full Text Available No hay estudios académicos de tipo cuantitativo sobre el videoarte. Las posibilidades expresivas son tan amplias que la aproximación de este tipo resulta harto difícil. Este artículo está basado en un estudio cuantitativo de una rama del videoarte, la videopoesía. El corpus de análisis está formado por 28 trabajos en los que se estudia la frecuencia, las relaciones entre diferentes tipos de figuras, además de la densidad retórica. Se logran conclusiones sobre un posible estilo de la videopoesía, relaciones significativas entre grupos de figuras, aunque puedan ser circunstanciales, y sobre la alta densidad retórica de los textos.

  4. 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.

  5. La retórica como doctrina de la comunicación eficaz

    Directory of Open Access Journals (Sweden)

    Gerardo Ramírez-Vidal

    2014-03-01

    Full Text Available En este ensayo se explican conceptos básicos para el conocimiento y la práctica de la retórica, así como sus usos y aplicaciones en ámbitos como la política, la cultura, la enseñanza, la prédica religiosa, el análisis literario, la comunicación de masas y la comunicación interpersonal.

  6. 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.

  7. Prefacio de "Retórica, Política e Ideología"

    OpenAIRE

    López Eire, Antonio

    2000-01-01

    The preface of these congressional proceedings explains the relationship between Rhetoric, Politics and Ideology from Ancient Greece to the present times, the main focus of the second Logo Meeting held in Salamanca in 1997. En este prefacio se expone la relación entre retórica, política e ideología desde la Antigua Grecia hasta nuestros días.

  8. Open-ended question: is immortality exclusively inherent to the germline?--A mini-review.

    Science.gov (United States)

    Lepperdinger, Günter

    2009-01-01

    All somatic cells are subject to aging. Germline links generations, and thus, pluripotent germ cells are considered potentially immortal. The current understanding how the germline escapes this otherwise inevitable phenomenon is outlined in this article. (c) 2008 S. Karger AG, Basel.

  9. Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients.

    Science.gov (United States)

    Yamaguchi, Ken; Urakami, Kenichi; Nagashima, Takeshi; Shimoda, Yuji; Ohnami, Shumpei; Ohnami, Sumiko; Ohshima, Keiichi; Mochizuki, Tohru; Hatakeyama, Keiichi; Serizawa, Masakuni; Akiyama, Yasuto; Maruyama, Kouji; Katagiri, Hirohisa; Ishida, Yuji; Takahashi, Kaoru; Nishimura, Seiichiro; Terashima, Masanori; Kawamura, Taiichi; Kinugasa, Yusuke; Yamakawa, Yushi; Onitsuka, Tetsuro; Ohde, Yasuhisa; Sugino, Takashi; Ito, Ichiro; Matsubayashi, Hiroyuki; Horiuchi, Yasue; Mizuguchi, Maki; Yamazaki, Mutsumi; Inoue, Kengo; Wakamatsu, Kimiko; Sugiyama, Misato; Uesaka, Katsuhiko; Kusuhara, Masatoshi

    2016-01-01

    Using whole exome sequencing data obtained from 1,685 Japanese cancer patients, we examined genetic variations of germline TP53 and found 10 types of non-synonymous single nucleotide variants. In the present study, we focused on 6 patients with germline D49H mutation located in the transactivation domain 2 of p53 protein, since the mutation seemed to be prevalent in cancer patients and to be pathogenic. According to the initial survey for family history of the proband with the germline TP53 D49H mutation, one osteosarcoma patient and his pedigree fulfill the criteria for Li-Fraumeni-like syndrome and the 2009 Chompret criteria for germline TP53 mutation screening. Since this patient possesses double germline mutations of TP53 D49H and A159D, further studies are required to evaluate contribution of the D49H mutation in this morbidity. The remaining 5 patients had family histories of cancer, but none fulfills the criteria either for the Li-Fraumeni/Li-Fraumeni-like syndromes or the 2009 Chompret criteria for germline TP53 mutation screening. It is possible to postulate that the germline TP53 D49H mutation is likely to be low-penetrant in some pedigrees. The present study also indicates that the survey for the germline TP53 mutation plays an important role in clinical practice as it will prevent mistaking cancer patients with unusual heredities for sporadic cases.

  10. 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.

  11. The histone code reader SPIN1 controls RET signaling in liposarcoma.

    Science.gov (United States)

    Franz, Henriette; Greschik, Holger; Willmann, Dominica; Ozretić, Luka; Jilg, Cordula Annette; Wardelmann, Eva; Jung, Manfred; Buettner, Reinhard; Schüle, Roland

    2015-03-10

    The histone code reader Spindlin1 (SPIN1) has been implicated in tumorigenesis and tumor growth, but the underlying molecular mechanisms remain poorly understood. Here, we show that reducing SPIN1 levels strongly impairs proliferation and increases apoptosis of liposarcoma cells in vitro and in xenograft mouse models. Combining signaling pathway, genome-wide chromatin binding, and transcriptome analyses, we found that SPIN1 directly enhances expression of GDNF, an activator of the RET signaling pathway, in cooperation with the transcription factor MAZ. Accordingly, knockdown of SPIN1 or MAZ results in reduced levels of GDNF and activated RET explaining diminished liposarcoma cell proliferation and survival. In line with these observations, levels of SPIN1, GDNF, activated RET, and MAZ are increased in human liposarcoma compared to normal adipose tissue or lipoma. Importantly, a mutation of SPIN1 within the reader domain interfering with chromatin binding reduces liposarcoma cell proliferation and survival. Together, our data describe a molecular mechanism for SPIN1 function in liposarcoma and suggest that targeting SPIN1 chromatin association with small molecule inhibitors may represent a novel therapeutic strategy.

  12. Characterization of Bacterial Strains Isolated from a Novel Seawater-based Retting Treatment of Hemp

    Institute of Scientific and Technical Information of China (English)

    ZHU Run-ye; CHEN Jian-yong; FENG Xin-xing; ZHANG Jian-chun

    2008-01-01

    Cultivable bacteria were isolated from seawater-based retting treatment of hemp, in which three of purified strains (SW - 1, SW - 2, and S - SW1) produced relatively high levels of pectinase activities, and also produced mannanases and xylanases.PCR - based entebacterial repetitive intergenic consensus primers (ERIC- PCR) were employed for fingerprinting DNA of the bacterial strains.The ERIC - PCR fingerprints of stains SW- 1, SW -1, and S -SW1 were found to be different, and should be further identified for each isolate.Strains SW - 1 and SW - 2 were identified as Stenotrophomnas maltophilia, while strain S - SW1 was assigned to Ochrobactrum anthropi by BIOLOG system.These two species represented rhizosphere bacterial genera, and possibly were introduced by the hemp plants.These organisms seemed potentially capable of producing pectinase and hemicellulase, and thus effectively degrading the gum substances in the seawater retting.This research could be helpful for improving a novel seawater-based retting treatment of hemp.

  13. 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.

  14. Marco Fabio Quintiliano y la retórica democrática

    Directory of Open Access Journals (Sweden)

    Víctor ALONSO ROCAFORT

    2008-01-01

    Full Text Available Desde finales del siglo veinte estamos asistiendo a un resurgir de la retórica en diversos campos académicos, algo a lo que no resulta ajena la teoría política. Se debe precisar que se habla de diversas retóricas, ya se reivindiquen unos u otros autores, o se haga hincapié en determinados aspectos de la misma. Este trabajo se enmarca en una línea comprometida en revisar fundamentos sustanciales del conocimiento, la filosofía, la ética y la praxis política, en lo que algunos califican ya de retórica democrática. Desde ahí recuperamos a uno de sus grandes autores clásicos, Marco Fabio Quintiliano. Sus propuestas enriquecerán aquellas otras que han ido a contracorriente de las visiones triunfales de la ciencia política moderna, y que desde los años cincuenta ha tenido en autores como Hannah Arendt, Sheldon Wolin, Hans G. Gadamer, Eric Voegelin o Leo Strauss a sus mayores adalides.

  15. Pensamiento retórico y masculinidades: de la dicotomía al continuum

    Directory of Open Access Journals (Sweden)

    Fernando FERNÁNDEZ-LLÉBREZ

    2008-01-01

    Full Text Available El presente artículo versa sobre la escisión que se ha producido dentro de la teoría política moderna entre dialéctica y retórica. Esta escisión abarca diferentes aspectos de razonar teórico y de la vida; uno de estos es el que remite a la consideración de las identidades y, en concreto, las referidas al género y al sexo. En ese sentido, tomaremos como hilo conductor dicha cuestión referida para explorar las pertinentes escisiones. Para ello, se ahondará en los aspectos que definen al sexo y al género en nuestras sociedades, haciendo especial hincapié en el estereotipo masculino moderno y planteando que es preciso desarrollar una teoría sobre los sexos y los géneros que vaya más allá de las dicotomías dialécticas existentes en la que el pensamiento humanista retórico tiene mucho que aportar. Así se pretende, de la mano de las identidades y subjetividades de género, desarrollar la dimensión retórica de la vida, algo que fue abandonado por ciertas consideraciones teórico políticas y que es preciso reabrir.

  16. Discurso e retórica: sobre o procedimento reductio ad Hitlerum

    Directory of Open Access Journals (Sweden)

    João Kogawa

    2017-01-01

    Full Text Available Este trabalho objetiva compreender o funcionamento retórico-discursivo da estratégia argumentativa reductio ad Hitlerum, empregada por Frei Betto para comparar o regime nazista constituído na Alemanha dos anos 1920 e a Bancada Evangélica que compõe uma parte do Congresso Nacional brasileiro atualmente. Este trabalho se debruça sobre a expressão “ovo da serpente”, empregada na comparação construída por meio da metáfora e da metonímia. O arcabouço teórico é constituído pela Retórica clássica (Aristóteles, pela Retórica contemporânea (Angenot, por reflexões derivadas de Jakobson e pela Análise do Discurso de linha francesa (Pêcheux. O sofisma reductio ad Hitlerum se caracteriza por despertar a cólera dos interlocutores, pois não há motivos racionais ou lógicos para se concordar com esse argumento emocional.

  17. La teoría del estilo en la retórica grecorromana

    Directory of Open Access Journals (Sweden)

    Esther Paglialunga

    2009-10-01

    Full Text Available Este artículo se propone una revisión de los principios sostenidos por los más importantes retóricos de la Antigüedad grecorromana en torno a la teoría del estilo del discurso en prosa. A través de la exposición de los conceptos de los principales autores, desde Aristóteles en el libro III de la Retórica hasta el tratado Sobre las formas del estilo de Hermógenes, se intentará demostrar la permanencia de ciertos criterios relativos al estilo. Entre ellos, destacaremos la división en tres o más categorías; los elementos que las distinguen, y la progresiva asimilación de toda la literatura (incluida la poesía en la sistematización teórica ofrecida en los tratados retóricos.

  18. Assessment of changes in community level physiological profile and molecular diversity of bacterial communities in different stages of jute retting.

    Science.gov (United States)

    Das, Biswapriya; Chakrabarti, Kalyan; Ghosh, Sagarmoy; Chakraborty, Ashis; Saha, Manabendra Nath

    2013-12-01

    Retting of jute is essentially microbiological and biochemical in nature. Community Level Physiological Profiles (CLPP) as well as genomic diversity of bacterial communities were assessed in water samples collected during pre-retting, after 1st and 2nd charges of retting. The water samples were collected from two widely cultivated jute growing locations, Sonatikari (22 degrees 41'27"N; 88 degrees 35'44"E) and Baduria (22 degrees 44'24"N; 88 degrees 47'24"E), West Bengal, India. The CLPP, expressed as net area under substrate utilization curve, was studied by carbon source utilization patterns in BIOLOG Ecoplates. Molecular diversity was studied by polymerase chain reaction followed by denaturing gradient gel electrophoresis (PCR-DGGE) of total DNA from water samples. Both between locations and stages of retting, substrate utilizations pattern were carbohydrates > carboxylic acids > polymers > amino acids > amines/amides > phenolic compounds. Differential substrate utilization pattern as well as variation in banding pattern in DGGE profiles was observed between the two locations and at different stages of retting. The variations in CLPP in different stages of retting were due to the change in bacterial communities.

  19. RET Recognition of GDNF-GFRα1 Ligand by a Composite Binding Site Promotes Membrane-Proximal Self-Association

    Directory of Open Access Journals (Sweden)

    Kerry M. Goodman

    2014-09-01

    Full Text Available The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM and low-angle X-ray scattering (SAXS data, of the RET extracellular domain (RETECD, GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RETECD envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RETECD cysteine-rich domain (CRD contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation.

  20. Concomitant BRAF(V600E) mutation and RET/PTC rearrangement is a frequent occurrence in papillary thyroid carcinoma.

    Science.gov (United States)

    Guerra, Anna; Zeppa, Pio; Bifulco, Maurizio; Vitale, Mario

    2014-02-01

    The tyrosine kinase receptors/RAS/RAF/MAPK cascade is a site of mutational events associated with thyroid carcinogenesis. Some studies suggest the reciprocal exclusion of different oncogenes in the mitogen-activated protein kinase cascade, whereas others suggest that BRAF mutations and RET rearrangements can simultaneously occur in sporadic cases. The aim of this study was to determine the prevalence of concomitant BRAF(V600E) mutation and RET/PTC rearrangements in the same tumor and its association with some clinicopathological features. The percentage of mutant BRAF alleles and the presence of RET/PTC rearrangements were determined by means of pyrosequencing and Southern blot analysis of reverse transcription polymerase chain reaction products in a series of 72 conventional papillary thyroid carcinomas (PTCs). Then, the associations between clinicopathological characteristics and mutation status were assessed. BRAF(V600E) alleles were present in 32 out of 72 PTCs (44.4%) in the range of 5.1-44.7% of total BRAF alleles. RET/PTC was present in 26 tumors (36.1%). Concomitant subclonal BRAF and RET/PTC were demonstrated in 14 PTCs (19.4%), and none of the oncogenes was detected in 22 tumors (30.5%). Only BRAF(V600E) was associated with a more advanced tumor staging. The present study demonstrates that concomitant BRAF mutation and RET/PTC rearrangement is a frequent event in PTC.

  1. Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology.

    Science.gov (United States)

    Frett, Brendan; Carlomagno, Francesca; Moccia, Maria Luisa; Brescia, Annalisa; Federico, Giorgia; De Falco, Valentina; Admire, Brittany; Chen, Zhongzhu; Qi, Wenqing; Santoro, Massimo; Li, Hong-yu

    2015-07-20

    Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen led to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a type II tyrosine kinase inhibitor that is able to bind the "DFG-out" conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown to be active on VEGFR2, which can block the blood supply required for RET-stimulated growth. In cell-based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg(-1)  day(-1) per os, Pz-1 abrogated the formation of tumors induced by RET-mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity at concentrations of up to 100.0 mg kg(-1), which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways.

  2. How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer

    Science.gov (United States)

    Prazeres, Hugo; Torres, Joana; Rodrigues, Fernando; Couto, Joana P.; Vinagre, João; Sobrinho-Simões, Manuel; Soares, Paula

    2011-01-01

    The significance of RET in thyroid cancer comes from solid evidence that, when inherited, an RET activating mutation primes C-cells to transform into medullary carcinomas. Moreover, environmental exposure to radiation also induces rearranged transforming RET “isoforms” that are found in papillary thyroid cancer. The RET gene codes for a tyrosine kinase receptor that targets a diverse set of intracellular signaling pathways. The nature of RET point mutations predicts differences in the mechanisms by which the receptor becomes activated and correlates with different forms of clinical presentation, age of onset, and biological aggressiveness. A number of RET-targeting Tyrosine Kinase Inhibitors (TKIs) are currently undergoing clinical trials to evaluate their effectiveness in the treatment of thyroid cancer, and it is conceivable that the RET genotype may also influence response to these compounds. The question that now emerges is whether, in the future, the rational for treatment of refractory thyroid cancer will be based on the management of an abnormal RET signal. In this paper we address the RET-targeting TKIs and review studies about the signaling properties of distinct RET mutants as a means to predict response and design combinatorial therapies for the soon to be available TKIs. PMID:21765992

  3. The fate of BRCA1-related germline mutations in triple-negative breast tumors

    Science.gov (United States)

    Kotoula, Vassiliki; Fostira, Florentia; Papadopoulou, Kyriaki; Apostolou, Paraskevi; Tsolaki, Eleftheria; Lazaridis, Georgios; Manoussou, Kyriaki; Zagouri, Flora; Pectasides, Dimitrios; Vlachos, Ioannis; Tikas, Ioannis; Lakis, Sotiris; Konstantopoulou, Irene; Pentheroudakis, George; Gogas, Helen; Papakostas, Pavlos; Christodoulou, Christos; Bafaloukos, Dimitrios; Razis, Evangelia; Karavasilis, Vasilios; Bamias, Christina; Yannoukakos, Drakoulis; Fountzilas, George

    2017-01-01

    The preservation of pathogenic BRCA1/2 germline mutations in tumor tissues is usually not questioned, while it remains unknown whether these interact with somatic genotypes for patient outcome. Herein we compared germline and tumor genotypes in operable triple-negative breast cancer (TNBC) and evaluated their combined effects on prognosis. We analyzed baseline germline and primary tumor genotype data obtained by Sanger and Next Generation Sequencing in 194 TNBC patients. We also performed multiple tests interrogating the preservation of germline mutations in matched tumors and breast tissue from carriers with available material. Patients had been treated within clinical trials with adjuvant anthracyclines-taxanes based chemotherapy. We identified 50 (26%) germline mutation carriers (78% in BRCA1) and 136 (71%) tumors with somatic mutations (83% in TP53). Tumor mutation patterns differed between carriers and non-carriers (P<0.001); PIK3CA mutations were exclusively present in non-carriers (P=0.007). Germline BRCA1/2 mutations were not detected in matched tumors and breast tissues from 14 out of 33 (42%) evaluable carriers. Microsatellite markers revealed tumor loss of the germline mutant allele in one case only. Tumors that had lost the germline mutation demonstrated a higher incidence of somatic TP53 mutations as compared to tumors with preserved germline mutations (P=0.036). Germline mutation status significantly interacted with tumor TP53 mutations for patient disease-free survival (interaction P=0.026): In non-carriers, tumor TP53 mutations did not affect outcome; In carriers, those with mutated TP53 tumors experienced more relapses compared to those with wild-type TP53 tumors (36% vs. 9% relapse rate, respectively). In conclusion, we show that loss of germline BRCA1/2 mutations is not a rare event in TNBC. This finding, the observed differences in tumor genotypes with respect to germline status and the prognostic interaction between germline BRCA1-related and

  4. Recombination, transcription, and diversity of a partially germline-joined VH in a mammal.

    Science.gov (United States)

    Wang, Xinxin; Miller, Robert D

    2012-09-01

    Full or partially germline-joined V genes have been described in a number of different vertebrate lineages where they can contribute to the expressed antibody repertoire through different mechanisms. Here we demonstrate that VH3.1, a partially germline-joined VH gene in the opossum Monodelphis domestica, can undergo V(D)J recombination to generate productive IgH transcripts. VH3.1 is fused to a DH gene segment in the germline DNA and is the only known example of a germline-joined VH in a mammal. B cells that have recombined VH3.1 were not detected until nearly 2 months of age, around the time of weaning, and much later than B cells using the conventional VH. Compared to opossum IgH transcripts using the conventional VH genes, those with VH3.1 have unusually long CDR3 due to the length of the germline-joined DH.

  5. C. elegans germline-deficient mutants respond to pathogen infection using shared and distinct mechanisms.

    Directory of Open Access Journals (Sweden)

    Michael TeKippe

    Full Text Available Reproduction extracts a cost in resources that organisms are then unable to utilize to deal with a multitude of environmental stressors. In the nematode C. elegans, development of the germline shortens the lifespan of the animal and increases its susceptibility to microbial pathogens. Prior studies have demonstrated germline-deficient nematodes to have increased resistance to gram negative bacteria. We show that germline-deficient strains display increased resistance across a broad range of pathogens including gram positive and gram negative bacteria, and the fungal pathogen Cryptococcus neoformans. Furthermore, we show that the FOXO transcription factor DAF-16, which regulates longevity and immunity in C. elegans, appears to be crucial for maintaining longevity in both wild-type and germline-deficient backgrounds. Our studies indicate that germline-deficient mutants glp-1 and glp-4 respond to pathogen infection using common and different mechanisms that involve the activation of DAF-16.

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  1. File list: InP.Gon.50.AllAg.Germline_stem_cells [Chip-atlas[Archive

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  2. Epigenetic inheritance systems contribute to the evolution of a germline.

    Science.gov (United States)

    Lachmann, Michael; Libby, Eric

    2016-08-19

    Differentiation within multicellular organisms is controlled by epigenetic markers transmitted across cell division. The process of differentiation will modify these epigenetic markers so that information that one cell type possesses can be lost in the transition to another. Many of the systems that encode these markers also exist in unicellular organisms but do not control differentiation. Thus, during the evolution of multicellularity, epigenetic inheritance systems were probably exapted for their current use in differentiation. We show that the simultaneous use of an information carrier for differentiation and transmission across generations can lead to the evolution of cell types that do not directly contribute to the progeny of the organism and ergo a germ-soma distinction. This shows that an intrinsic instability during a transition from unicellularity to multicellularity may contribute to widespread evolution of a germline and its maintenance, a phenomenon also relevant to the evolution of eusociality. The difference in epigenetic information contents between different cell lines in a multicellular organism is also relevant for the full-success cloning of higher animals, as well as for the maintenance of single germlines over evolutionary timescales.This article is part of the themed issue 'The major synthetic evolutionary transitions'.

  3. Sequences sufficient for programming imprinted germline DNA methylation defined.

    Directory of Open Access Journals (Sweden)

    Yoon Jung Park

    Full Text Available Epigenetic marks are fundamental to normal development, but little is known about signals that dictate their placement. Insights have been provided by studies of imprinted loci in mammals, where monoallelic expression is epigenetically controlled. Imprinted expression is regulated by DNA methylation programmed during gametogenesis in a sex-specific manner and maintained after fertilization. At Rasgrf1 in mouse, paternal-specific DNA methylation on a differential methylation domain (DMD requires downstream tandem repeats. The DMD and repeats constitute a binary switch regulating paternal-specific expression. Here, we define sequences sufficient for imprinted methylation using two transgenic mouse lines: One carries the entire Rasgrf1 cluster (RC; the second carries only the DMD and repeats (DR from Rasgrf1. The RC transgene recapitulated all aspects of imprinting seen at the endogenous locus. DR underwent proper DNA methylation establishment in sperm and erasure in oocytes, indicating the DMD and repeats are sufficient to program imprinted DNA methylation in germlines. Both transgenes produce a DMD-spanning pit-RNA, previously shown to be necessary for imprinted DNA methylation at the endogenous locus. We show that when pit-RNA expression is controlled by the repeats, it regulates DNA methylation in cis only and not in trans. Interestingly, pedigree history dictated whether established DR methylation patterns were maintained after fertilization. When DR was paternally transmitted followed by maternal transmission, the unmethylated state that was properly established in the female germlines could not be maintained. This provides a model for transgenerational epigenetic inheritance in mice.

  4. CDH1 germline mutation in hereditary gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Hai-Dan Wang; Jun Ren; Lian Zhang

    2004-01-01

    This paper provides a bird's-eye view both in preclinical and clinical aspects of E-cadherin germline gene (CDH1)in gastric cancer patients and their families. E-cadherin,a product of CDH1 gene, belonging to the functionally related trans-membrane glycoprotein family, is responsible for the Ca2+-dependent cell-cell adhesion mechanism and contributes to dissociation followed by acquisition of cell motility, which usually occurs in the first step of cancer invasion and metastasis. CDH1 gene germline mutation is common in many types of carcinoma,and occurs very frequent in hereditary gastric carcinoma (HGC) patients and their families. Recently, more and more researches support that E-cadherin plays an important role in the differentiation, growth and invasion of HGC. So it is of great value to clarify its mechanisms both for understanding HGC pathogenesis and for clinical therapy, especially in China, where there are a high risk population of gastric cancer and a high HGC incidence rate. In this paper, recent researches on CDH1 gene mutation, especially its role in tumor genesis and progress of HGC, are reviewed, and advances in evaluation of its mutation status for HGC diagnosis, therapy and prognosis,are also discussed briefly.

  5. Autologous Germline Mitochondrial Energy Transfer (AUGMENT) in Human Assisted Reproduction.

    Science.gov (United States)

    Woods, Dori C; Tilly, Jonathan L

    2015-11-01

    Ovarian aging is characterized by a decline in both the total number and overall quality of oocytes, the latter of which has been experimentally tied to mitochondrial dysfunction. Clinical studies in the late 1990s demonstrated that transfer of cytoplasm aspirated from eggs of young female donors into eggs of infertile women at the time of intracytoplasmic sperm injection improved pregnancy success rates. However, donor mitochondria were identified in offspring, and the United States Food and Drug Administration raised questions about delivery of foreign genetic material into human eggs at the time of fertilization. Accordingly, heterologous cytoplasmic transfer, while promising, was in effect shut down as a clinical protocol. The recent discovery of adult oogonial (oocyte-generating) stem cells in mice, and subsequently in women, has since re-opened the prospects of delivering a rich source of pristine and patient-matched germline mitochondria to boost egg health and embryonic developmental potential without the need for young donor eggs to obtain cytoplasm. Herein we overview the science behind this new protocol, which has been patented and termed autologous germline mitochondrial energy transfer, and its use to date in clinical studies for improving pregnancy success in women with a prior history of assisted reproduction failure.

  6. Epigenetic inheritance systems contribute to the evolution of a germline

    Science.gov (United States)

    Libby, Eric

    2016-01-01

    Differentiation within multicellular organisms is controlled by epigenetic markers transmitted across cell division. The process of differentiation will modify these epigenetic markers so that information that one cell type possesses can be lost in the transition to another. Many of the systems that encode these markers also exist in unicellular organisms but do not control differentiation. Thus, during the evolution of multicellularity, epigenetic inheritance systems were probably exapted for their current use in differentiation. We show that the simultaneous use of an information carrier for differentiation and transmission across generations can lead to the evolution of cell types that do not directly contribute to the progeny of the organism and ergo a germ–soma distinction. This shows that an intrinsic instability during a transition from unicellularity to multicellularity may contribute to widespread evolution of a germline and its maintenance, a phenomenon also relevant to the evolution of eusociality. The difference in epigenetic information contents between different cell lines in a multicellular organism is also relevant for the full-success cloning of higher animals, as well as for the maintenance of single germlines over evolutionary timescales. This article is part of the themed issue ‘The major synthetic evolutionary transitions’. PMID:27431523

  7. RBC-Y和RET-Y在肾性贫血患者铁缺乏监测中的应用%Application of RBC-Y and RET-Y in monitoring renal anemia patients with iron deficiency

    Institute of Scientific and Technical Information of China (English)

    黄福达; 杨山虹

    2014-01-01

    目的:探讨RBC-Y和RET-Y在肾性贫血患者铁缺乏监测中的应用价值。方法收集慢性肾衰竭(CRF)引起的肾性贫血组和健康对照组血液标本,分别检测 RBC-Y、RET-Y、铁蛋白(SF)、可溶性转铁蛋白受体(sTfR)等指标,以sTfR>2.25 mg/L作为铁缺乏的“金标准”,利用 ROC曲线分析RBC-Y、RET-Y和SF等参数在诊断肾性贫血患者铁缺乏的性能。结果肾性贫血组与健康对照组间RBC-Y和RET-Y两参数结果差异有统计学意义(P<0.001),经ROC曲线分析RBC-Y、RET-Y和SF在诊断肾性贫血患者铁缺乏时曲线下面积分别为0.811、0.780、0.530,当临界值为151.6时,RBC-Y诊断铁缺乏的灵敏度为81.0%,特异性为75.0%;当临界值为1580.5时,RET-Y诊断铁缺乏的灵敏度为74.6%,特异性为75.0%;当临界值为96μg/L时,SF诊断铁缺乏的灵敏度为61.9%,特异性为58.3%。结论 RBC-Y和RET-Y可作为CRF引起的肾性贫血患者铁缺乏的诊断指标。%Objective To explore the clinical value of RBC-Y and RET-Y in monitoring the iron deficiency of the patients who suffer with renal anemia .Methods Blood samples were collected from patients with renal anemia of CRF and normal control individuals ,then RBC-Y ,RET-Y ,SF and sTfR were detected respectively and sTfR >2 .25 mg/L was regarded as "gold standard"of the iron deficiency ,using ROC curve to analyze RBC-Y ,RET-Y and SF for the diagnosis of the iron deficiency of the patients who suffer with renal anemia was studied .Results There are sig-nificant differences in RBC-Y and RET-Y between renal anemia group and control group .The RBC-Y ,RET-Y and SF area under the ROC curve are 0 .811 ,0 .780 ,0 .530 ,the sensitivity of RBC-Y in diagnosing iron deficiency is 81 .0%and specificity is 75 .0% when the critical value is 151 .6 ;sensitivity of RET-Y is 74 .6% and specificity is 75 .0%when the critical value is 1 580 .5;sensitivity of

  8. The molecular anatomy of spontaneous germline mutations in human testes.

    Science.gov (United States)

    Qin, Jian; Calabrese, Peter; Tiemann-Boege, Irene; Shinde, Deepali Narendra; Yoon, Song-Ro; Gelfand, David; Bauer, Keith; Arnheim, Norman

    2007-09-01

    The frequency of the most common sporadic Apert syndrome mutation (C755G) in the human fibroblast growth factor receptor 2 gene (FGFR2) is 100-1,000 times higher than expected from average nucleotide substitution rates based on evolutionary studies and the incidence of human genetic diseases. To determine if this increased frequency was due to the nucleotide site having the properties of a mutation hot spot, or some other explanation, we developed a new experimental approach. We examined the spatial distribution of the frequency of the C755G mutation in the germline by dividing four testes from two normal individuals each into several hundred pieces, and, using a highly sensitive PCR assay, we measured the mutation frequency of each piece. We discovered that each testis was characterized by rare foci with mutation frequencies 10(3) to >10(4) times higher than the rest of the testis regions. Using a model based on what is known about human germline development forced us to reject (p < 10(-6)) the idea that the C755G mutation arises more frequently because this nucleotide simply has a higher than average mutation rate (hot spot model). This is true regardless of whether mutation is dependent or independent of cell division. An alternate model was examined where positive selection acts on adult self-renewing Ap spermatogonial cells (SrAp) carrying this mutation such that, instead of only replacing themselves, they occasionally produce two SrAp cells. This model could not be rejected given our observed data. Unlike the disease site, similar analysis of C-to-G mutations at a control nucleotide site in one testis pair failed to find any foci with high mutation frequencies. The rejection of the hot spot model and lack of rejection of a selection model for the C755G mutation, along with other data, provides strong support for the proposal that positive selection in the testis can act to increase the frequency of premeiotic germ cells carrying a mutation deleterious to an

  9. The molecular anatomy of spontaneous germline mutations in human testes.

    Directory of Open Access Journals (Sweden)

    Jian Qin

    2007-09-01

    Full Text Available The frequency of the most common sporadic Apert syndrome mutation (C755G in the human fibroblast growth factor receptor 2 gene (FGFR2 is 100-1,000 times higher than expected from average nucleotide substitution rates based on evolutionary studies and the incidence of human genetic diseases. To determine if this increased frequency was due to the nucleotide site having the properties of a mutation hot spot, or some other explanation, we developed a new experimental approach. We examined the spatial distribution of the frequency of the C755G mutation in the germline by dividing four testes from two normal individuals each into several hundred pieces, and, using a highly sensitive PCR assay, we measured the mutation frequency of each piece. We discovered that each testis was characterized by rare foci with mutation frequencies 10(3 to >10(4 times higher than the rest of the testis regions. Using a model based on what is known about human germline development forced us to reject (p < 10(-6 the idea that the C755G mutation arises more frequently because this nucleotide simply has a higher than average mutation rate (hot spot model. This is true regardless of whether mutation is dependent or independent of cell division. An alternate model was examined where positive selection acts on adult self-renewing Ap spermatogonial cells (SrAp carrying this mutation such that, instead of only replacing themselves, they occasionally produce two SrAp cells. This model could not be rejected given our observed data. Unlike the disease site, similar analysis of C-to-G mutations at a control nucleotide site in one testis pair failed to find any foci with high mutation frequencies. The rejection of the hot spot model and lack of rejection of a selection model for the C755G mutation, along with other data, provides strong support for the proposal that positive selection in the testis can act to increase the frequency of premeiotic germ cells carrying a mutation

  10. RET/PTC Rearrangements Are Associated with Elevated Postoperative TSH Levels and Multifocal Lesions in Papillary Thyroid Cancer without Concomitant Thyroid Benign Disease.

    Science.gov (United States)

    Su, Xuan; He, Caiyun; Ma, Jiangjun; Tang, Tao; Zhang, Xiao; Ye, Zulu; Long, Yakang; Shao, Qiong; Shao, Jianyong; Yang, Ankui

    2016-01-01

    RET/PTC rearrangements, resulting in aberrant activity of the RET protein tyrosine kinase receptor, occur exclusively in papillary thyroid cancer (PTC). In this study, we examined the association between RET/PTC rearrangements and thyroid hormone homeostasis, and explored whether concomitant diseases such as nodular goiter and Hashimoto's thyroiditis influenced this association. A total of 114 patients diagnosed with PTC were enrolled in this study. Thyroid hormone levels, clinicopathological parameters and lifestyle were obtained through medical records and surgical pathology reports. RET/PTC rearrangements were detected using TaqMan RT-PCR and validated by direct sequencing. No RET/PTC rearrangements were detected in benign thyroid tissues. RET/PTC rearrangements were detected in 23.68% (27/114) of PTC tissues. No association between thyroid function, clinicopathological parameters and lifestyle was observed either in total thyroid cancer patients or the subgroup of patients with concomitant disease. In the subgroup of PTC patients without concomitant disease, RET/PTC rearrangement was associated with multifocal cancer (P = 0.018). RET/PTC rearrangement was also correlated with higher TSH levels at one month post-surgery (P = 0.037). Based on likelihood-ratio regression analysis, the RET/PTC-positive PTC cases showed an increased risk of multifocal cancers in the thyroid gland (OR = 5.57, 95% CI, 1.39-22.33). Our findings suggest that concomitant diseases such as nodular goiter and Hashimoto's thyroiditis in PTC may be a confounding factor when examining the effects of RET/PTC rearrangements. Excluding the potential effect of this confounding factor showed that RET/PTC may confer an increased risk for the development of multifocal cancers in the thyroid gland. Aberrantly increased post-operative levels of TSH were also associated with RET/PTC rearrangement. Together, our data provides useful information for the treatment of papillary thyroid cancer.

  11. [The correlation between BRAF mutations, RET/PTC rearrangements and platelet-derived growth factor B expression in papillary thyroid carcinomas].

    Science.gov (United States)

    Wang, Ping; Wang, Yan-gang; Zhao, Wen-juan; Fu, Yu-dong; Wang, Luan; Wang, Fang; Zhao, Shi-hua

    2012-12-01

    To investigate the prevalence of BRAF T1799A mutation and RET/PTC rearrangement in Qingdao and detect the expression of platelet-derived growth factor B (PDGF-B) in order to investigate the correlation between gene mutation and PDGF-B. Fresh tissue from 48 papillary thyroid carcinomas (PTC) patients was examined for BRAF mutation RET rearrangements (RET/PTC1 and RET/PTC3) by PCR, followed by direct-sequence analysis. The expression of PDGF was analyzed by immunohistochemistry. Among the 48 patients, 14 (29.2%) were micro PTC; 18 (37.5%) had BRAF T1799A mutations and 23(47.9%) had RET/PTC rearrangement. There were 17 (35.4%) cases of RET/PTC1 and 6 (12.5%) of RET/PTC3, with no multiple rearrangements. Both BRAF T1799A mutation and RET/PTC rearrangement were present in 6 (12.5%) cases of non-micro PTC. The level of PDGF-B expression in BRAF T1799A positive was higher than that in the negative, and the level of PDGF-B expression in RET/PTC3 was higher than that in RET/PTC1 (P PTC rearrangement is higher in Qingdao. BRAF T1799A mutation and RET/PTC3 rearrangement in patients suggests a poorer prognosis than the negative one. The BRAF T1799A mutation and RET/PTC3 rearrangement may strengthen the expression of PDGF-B. Both variations suggest a poor prognosis.

  12. El olvido de la retórica en el posthumanismo heideggeriano El olvido de la retórica en el posthumanismo heideggeriano

    Directory of Open Access Journals (Sweden)

    Víctor Alonso-rocafort

    2009-04-01

    Full Text Available El posthumanismo parte de la premisa de estar superando un humanismo obsoleto en diversos puntos fundamentales. Autores como Peter Sloterdijk retoman así la crítica que, en su momento, Martin Heidegger realizara al humanismo en su ya célebre Carta a Jean Beaufret. Pero el pensador del olvido del ser había olvidado en este caso el humanismo, o al menos a su corriente no platónica y meridional: la retórica humanista y democrática. De este modo el posthumanismo, en sus interesantes propuestas, parte con el déficit no sólo de este olvido poco inocente, sino de lo que implica: la asunción de ciertos rasgos del pensamiento gótico. Frente a ello y a la idea de tabula rasa, invitamos en este trabajo a rescatar la retórica como un modo democrático de enfrentarse a los problemas actuales de la política.Posthumanism is based on the premise that there are several key points at which obsolete humanism must be superseded. Authors such as Peter Sloterdijk have updated the critique that Martin Heidegger levelled at humanism in his well-known Letter to Jean Beaufret. But the thinker who dealt with the forgetting of being forgot to consider the non-platonic and Southern current of humanism: the idea of humanist and democratic rhetoric. In this fashion posthumanism could offer interesting proposals, while starting from a rather less-than-innocent conceptual deficit, and forgetting the implications of its assumption of certain aspects of Gothic thought. In contrast, and against the idea of the tabula rasa, in this study we invite the reader to join us in re-examining Rhetoric as a democratic means of facing current problems in politics.

  13. Elicitation of broadly neutralizing antibodies against HIV-1 – the germline/maturation hypothesis

    Directory of Open Access Journals (Sweden)

    Prabakaran ePonraj

    2014-08-01

    Full Text Available We have previously observed that all known broadly neutralizing antibodies (bnAbs against HIV-1 are highly divergent from their putative germline predecessors in contrast to bnAbs against henipaviruses and SARS coronavirus, which are much less divergent from their germline counterparts. We have hypothesized that because the germline antibodies are so different compared to the highly somatically mutated HIV-1 bnAbs they may not bind to the Env. This led us to the hypothesis that the immunogenicity of the highly conserved epitopes on the HIV-1 envelope glycoproteins (Envs is reduced or eliminated by their very weak or absent interactions with germline antibodies. Thus immune responses leading to elicitation of bnAbs may not be initiated and/or sustained; even if they are, the maturation pathways are so complex that prolonged periods of time may be required for elicitation of such bnAbs. In support of the hypothesis, our initial experiments showed that germline-like precursors of several bnAbs do not bind to their epitopes. Recently, a number of research groups working in the HIV vaccine field have obtained data supporting and further expanding the germline/maturation hypothesis. Vaccine immunogens that could bind putative germline antibody predecessors of known bnAbs were successfully generated. However, guiding the immune system through the exceptionally complex antibody maturation pathways in order to elicit those bnAbs remains a major challenge. Here, we summarize developments in the HIV-1 vaccine field based on the germline/maturation hypothesis including our recent data demonstrating germline-like VRC01 antibodies in a human cord blood IgM library.

  14. Lynch Syndrome Caused by Germline PMS2 Mutations

    DEFF Research Database (Denmark)

    Ten Broeke, Sanne W; Brohet, Richard M; Tops, Carli M

    2015-01-01

    . Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers. RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52......PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98...... years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P

  15. Germline transcription: a key regulator of accessibility and recombination.

    Science.gov (United States)

    Abarrategui, Iratxe; Krangel, Michael S

    2009-01-01

    The developmental control of V(D)J recombination is imposed at the level of chromatin accessibility of recombination signal sequences (RSSs) to the recombinase machinery. Cis-acting transcriptional regulatory elements such as promoters and enhancers play a central role in the control of accessibility in vivo. However, the molecular mechanisms by which these elements influence accessibility are still under investigation. Although accessibility for V(D)J recombination is usually accompanied by germline transcription at antigen receptor loci, the functional significance of this transcription in directing RSS accessibility has been elusive. In this chapter, we review past studies outlining the complex relationship between V(D)J recombination and transcription as well as our current understanding on how chromatin structure is regulated during gene expression. We then summarize recent work that directly addresses the functional role of transcription in V(D)J recombination.

  16. Understanding what determines the frequency and pattern of human germline mutations.

    Science.gov (United States)

    Arnheim, Norman; Calabrese, Peter

    2009-07-01

    Surprising findings about human germline mutation have come from applying new technologies to detect rare mutations in germline DNA, from analysing DNA sequence divergence between humans and closely related species, and from investigating human polymorphic variation. In this Review we discuss how these approaches affect our current understanding of the roles of sex, age, mutation hot spots, germline selection and genomic factors in determining human nucleotide substitution mutation patterns and frequencies. To enhance our understanding of mutation and disease, more extensive molecular data on the human germ line with regard to mutation origin, DNA repair, epigenetic status and the effect of newly arisen mutations on gamete development are needed.

  17. RET and PHOX2B genetic polymorphisms and Hirschsprung's disease susceptibility: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Chun-mei Liang

    Full Text Available BACKGROUND: Many publications have evaluated the correlation between RET, PHOX2B polymorphisms and Hirschsprung's disease with conflicting results. We performed this meta-analysis to clarify the association of RET, PHOX2B polymorphisms with HSCR. METHODS: We searched Pubmed, Elsevier Science Direct, China National Knowledge Infrastructure database, Chinese Biomedical database, Google scholar. The combined odds ratio (OR with 95% CI was calculated to estimate the strength of the association. Heterogeneity and publication bias were also assessed. RESULTS: In total, 16 studies concerning RET and 4 studies concerning PHOX2B were included in the meta-analysis. The effects of five polymorphisms of RET (rs1800858, rs1800860, rs1800861, rs10900297, rs2435357 and one polymorphism (rs28647582 of PHOX2B were evaluated. We found a significant correlation between RET polymorphisms and HSCR. For rs1800858, the overall ORs (95% CI of the A versus G, AA versus GG, AA/AG versus GG and AA versus GG/AG were 3.81 (2.28-6.35; 8.36 (3.45-20.25; 3.59 (1.83-7.02; and 6.60 (3.66-11.89. For rs1800861, the comparison of subjects in the G versus T, GG versus TT, GG/TG versus TT and GG versus TT/TG were 2.85(1.81-4.47; 5.38(2.68-10.80; 3.07(2.17-4.34 and 4.14(1.84-9.30 respectively. For rs10900297, the comparison results showed statistically significant. (OR(C versus A = 5.05,95%CI = 4.16-6.13; OR(CC versus AA = 9.73, 95%CI = 5.94-15.94; OR(CC/AC versus AA = 5.31, 95%CI = 3.27-6.82; OR(CC versus AC/AA = 7.06,95%CI = 5.60-8.91. But, for rs1800860, the GG/GA versus AA did not reach statistical association (OR = 3.77, 95% CI = 0.94-15.07 and the G versus A, GG versus AA, GG versus GA/AA were 2.23 (1.60-3.11;4.56 (1.14-18.27; 2.38 (1.66-3.43 respectively. For rs2435357, the T versus C, TT versus CC, TT/TC versus CC and TT versus CC/TC were 4.53 (3.27-6.27; 11.44 (5.67-23.10; 4.04 (2.92-5.57, and 9.01(5.25-15.46.The single polymorphism of PHOX2B gene wasn't related to the risk

  18. Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

    Science.gov (United States)

    Jiao, Yuchen; Sausen, Mark; Leary, Rebecca; Bettegowda, Chetan; Roberts, Nicholas J.; Bhan, Sheetal; Ho, Allen S.; Khan, Zubair; Bishop, Justin; Westra, William H.; Wood, Laura D.; Hruban, Ralph H.; Tufano, Ralph P.; Robinson, Bruce; Dralle, Henning; Toledo, Sergio P. A.; Toledo, Rodrigo A.; Morris, Luc G. T.; Ghossein, Ronald A.; Fagin, James A.; Chan, Timothy A.; Velculescu, Victor E.; Vogelstein, Bert; Kinzler, Kenneth W.; Papadopoulos, Nickolas; Nelkin, Barry D.; Ball, Douglas W.

    2013-01-01

    Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome. PMID:23264394

  19. 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.

  20. Já estais saciados! A figura retórico-argumentativa da ironia no corpus paulinum

    Directory of Open Access Journals (Sweden)

    Moisés Olímpio Ferreira

    2014-04-01

    Full Text Available O presente trabalho visa a refletir sobre a força enunciativa da figura retórica da ironia, que se constitui de um raciocínio argumentativo indireto, mas não menos persuasivo. Ao afirmar o contrário do que realmente se deseja enunciar, ao pôr em destaque uma conclusão diferente daquela que se pretende e suas consequências, ao apontar a absurdidade, a falta de lógica, a contrariedade aos princípios admitidos, estabelece-se uma distância, pelo menos parcial, entre orador e auditório. Partindo de conhecimentos em comum acerca de fatos, normas ou opiniões, e mesmo a respeito das posições pessoais do orador, a ironia expõe aquele a quem é dirigida a uma argumentação de forte impacto. Nesse processo, o lógos revela as diferenças, os níveis de tensões entre os interlocutores, podendo, como resultado, reforçar as identidades fracas, reduzir as diferenças fortes, ou mesmo, estabelecer o distanciamento definitivo. A presente análise será realizada a partir do ferramental da Nova Retórica perelmaniana, observando o papel persuasivo dessa figura retórica nas manobras de influência daquele que a enuncia. Tendo em vista que partimos dos textos escritos em língua grega, a gramática do Prof. Henrique Murachco será o nosso aparato teórico para as traduções em língua portuguesa.

  1. Nuevas estrategias retóricas en la sociedad de la neopublicidad

    Directory of Open Access Journals (Sweden)

    Jesus Bermejo Berros

    2013-01-01

    Full Text Available El artículo presenta un nuevo tipo de estrategia retórica utilizada por la publicidad en la actualidad que está dando lugar a diferentes manifestaciones publicitarias, entre ellas la aparición de un nuevo tipo de publicidad, que hemos denominado neopublicidad. Esta nueva estrategia, que modifica los procedimientos retóricos seguidos hasta ahora por la publicidad clásica del siglo XX, se caracteriza por el enmascaramiento, que se sirve de recursos como el borrado de los marcadores de género, la hibridación y la fusión informativa. Este procedimiento tiene consecuencias sobre la manera en que el receptor responde al proceso persuasivo. Se ilustra la manifestación y finalidad de este fenómeno de transformación publicitaria en uno de los formatos publicitarios más clásico, el gráfico, donde hemos podido identificar tres tipos de neopublicidad: la publicidad integrada, el neopublireportaje y la publicidad autoreferencial. Estas nuevas estrategias son distintas a aquellas impulsadas en la sociedad de la postpublicidad, favorecidas éstas por las nuevas formas de comunicación resultantes de las nuevas tecnologías de la información y la comunicación, pero convergen con ellas en un marco social común donde la retórica publicitaria está evolucionando hacia nuevas formas de persuasión.

  2. Retting of jute grown in arsenic contaminated area and consequent arsenic pollution in surface water bodies.

    Science.gov (United States)

    Majumder, Aparajita; Bairagya, M D; Basu, B; Gupta, P C; Sarkar, S

    2013-01-01

    Arsenic (As) toxicity of ground water in Bengal delta is a major environmental catastrophe. Cultivation of jute, a non edible crop after summer rice usually reduces arsenic load of the soil. However, during retting of jute As is present in the crop and thus increase its amount in surface water bodies. To test this hypothesis, a study was carried out in ten farmers' field located in As affected areas of West Bengal, India. As content of soil and variou the jute plant were recorded on 35 and 70 days after sowing (DAS) as well as on harvest date (110 DAS). During the study period, due to the influence of rainfall, As content of surface (0-150 mm) soil fluctuates in a narrow range. As content of jute root was in the range of 1.13 to 9.36 mg kg(-1). As content of both root and leaf attained highest concentration on 35 DAS and continuously decreased with the increase in crop age. However, in case of shoot, the As content initially decreased by 16 to 50% during 35 to 70 DAS and on 110 DAS the value slightly increased over 70 DAS. Retting of jute in pond water increased the water As content by 0.2 to 2.0 mg L(-1). The increment was 1.1 to 4 times higher over the WHO safe limit (0.05 mg L(-1)) for India and Bangladesh. Microbiological assessment in this study reveals the total bacterial population of pre and post retting pond water. Bacterial strains capable in transforming more toxic As-III to less toxic AS-V were screened and six of them were selected based on their As tolerance capacity. Importantly, identified bacterial strain Bacterium C-TJ19 (HQ834294) has As transforming ability as well as pectinolytic activity, which improves fibre quality of jute. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. 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

  4. A Retórica do silêncio The rhetoric of silence

    Directory of Open Access Journals (Sweden)

    Cesar Marino Villavicencio

    2011-12-01

    Full Text Available A teoria da retórica na música barroca revela-se, de modo geral, interpretativa e heterogênea, não havendo uma linha de pensamento fixa. Essa heterogeneidade torna-se evidente quando se analisa a utilização dos silêncios como figuras retóricas. Para definir as intencionalidades dos silêncios é necessário considerar os afetos que os cercam. Assim, por haver diversos afetos inerentes, há ainda mais deliberações subjetivas na análise dos silêncios. Sugerindo uma visão retórica plural, propõe-se diversos tipos de categorização bem como a coexistência de interpretações. Para apresentar os desdobramentos dos objetivos estéticos da meraviglia, que focam o escopo pragmático de deslumbrar inesperadamente criando percepções chocantes de admiração, busca-se um equilíbrio entre a teoria e a prática através de exemplificações musicais. A retórica é vista como a energia inerente na emoção e no pensamento, transmitida por meio de um sistema de signos, entre os quais a música, com o objetivo de influenciar terceiros em suas decisões e ações.There is a lack of a single doctrine for the use of rhetoric in baroque music. The rhetorical theory has interpretative and heterogeneous qualities. Musical silences are among the rhetorical figures of the baroque. To frame the intentionalities of silences it is necessary to consider the affects that surround them. This means that to describe silences we are even more subjected to a variety of interpretations. In favor of a pluralistic view of rhetoric, embracing a diversity of categorizations is suggested. In order to reveal some of the aesthetic objectives of the meraviglia, which are focused on provoking a shocking sense of wonderment through creating experiences that astonish with delight, musical examples of the pathetic use of silences are presented. Rhetoric is viewed as the energy inherent in emotion and thought, transmitted through a system of signs, including music, to

  5. El pan del misterio: interpretación socio-retórica de Juan 6

    Directory of Open Access Journals (Sweden)

    Juan Esteban Londoño

    2017-01-01

    Full Text Available Este artículo estudia el capítulo 6 del Evangelio de Juan desde una perspectiva socio-retórica. Enfatiza las estrategias de persuasión que aparecen en el texto para convencer a la audiencia de una alta cristología, y destaca los sentidos profundos de las palabras simbólicas, como también los valores y significados de un mundo social y cultural en conflicto con la sinagoga y las iglesias judeo-cristianas.

  6. Acerca del retículo de las pretopologías sobre un conjunto X

    Directory of Open Access Journals (Sweden)

    Félix A. Páez Díaz

    2011-12-01

    Full Text Available Mostramos que (Pretop(X, ≤, el retículo de las pretopologías sobre un conjunto arbitrario X, siempre tiene un esqueleto, y presentamos una caracterización de los coátomos en Pretop(X en términos de ultratopologías sobre X. Abstract. We show that (Pretop(X, ≤, the lattice of pretopologies on an arbitrary set X, always has a framework; we present a characterization of the co-atoms in Pretop(X in terms of ultratopologies on X.

  7. The GTPase-activating protein Rap1GAP: A new player to modulate Ret signaling

    Institute of Scientific and Technical Information of China (English)

    Gustavo Paratcha; Fernanda Ledda

    2011-01-01

    @@ Glial cell line-derived neurotrophic factor (GDNF) plays a critical role in orchestrating the development and maintenance of different populations of central and peripheral neurons. GDNF was initially discovered by its abil-ity to promote the survival of ventral midbrain dopaminergic neurons [1]. In addition, GDNF promotes the survival and control the differentiation of motor neurons and many peripheral neurons, including sensory and sympathetic neu- rons. Moreover, it is required to induce proliferation, migration and survival of enteric neurons. GDNF promotes these trophic effects through the activation of the receptor tyrosine kinase (RTK) Ret.

  8. La retórica política del presidente Clinton

    Directory of Open Access Journals (Sweden)

    José J. SANMARTÍN

    2008-01-01

    Full Text Available El estudio de la retórica política empleada por Clinton durante sus dos mandatos en la Casa Blanca, ofrece un panorama plural y sugerente de las expectativas que genera entre sus ciudadanos el sistema político de Estados Unidos, así como de las funciones simbólicas e institucionales que debe asumir el Presidente. Patriotismo, democracia, prosperidad, son valores arraigados en la psicología popular que Clinton utilizó para desarrollar su propio mensaje político.

  9. Escapes da retórica da objetividade nas fotografias do jornal Zero Hora

    OpenAIRE

    Renata Lohmann; Ana Taís Martins Portanova Barros

    2016-01-01

    O presente artigo tem como objetivo estudar a questão da objetividade no fotojornalismo. Para tal, faz um estudo de como se dão os escapes da retórica da objetividade nas fotografias publicadas no jornal Zero Hora, de Porto Alegre, apresentando uma série de imagens veiculadas pelo periódico no ano de 2011. Apresenta conceitos de diversos autores como Roland Barthes, Arlindo Machado, Jacques Aumont e Philippe Dubois para averiguar o que seriam possíveis indicadores de conotação na fotografia. ...

  10. Escapes da retórica da objetividade nas fotografias do jornal Zero Hora

    Directory of Open Access Journals (Sweden)

    Renata Lohmann

    2016-08-01

    Full Text Available O presente artigo tem como objetivo estudar a questão da objetividade no fotojornalismo. Para tal, faz um estudo de como se dão os escapes da retórica da objetividade nas fotografias publicadas no jornal Zero Hora, de Porto Alegre, apresentando uma série de imagens publicadas pelo jornal no ano de 2011. Apresenta conceitos de diversos autores como Roland Barthes, Arlindo Machado, Jacques Aumont e Philippe Dubois para averiguar o que seriam possíveis indicadores de conotação na fotografia.

  11. 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.

  12. The Neuron-Specific Rai (ShcC) Adaptor Protein Inhibits Apoptosis by Coupling Ret to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway

    Science.gov (United States)

    Pelicci, Giuliana; Troglio, Flavia; Bodini, Alessandra; Melillo, Rosa Marina; Pettirossi, Valentina; Coda, Laura; De Giuseppe, Antonio; Santoro, Massimo; Pelicci, Pier Giuseppe

    2002-01-01

    Rai is a recently identified member of the family of Shc-like proteins, which are cytoplasmic signal transducers characterized by the unique PTB-CH1-SH2 modular organization. Rai expression is restricted to neuronal cells and regulates in vivo the number of postmitotic sympathetic neurons. We report here that Rai is not a common substrate of receptor tyrosine kinases under physiological conditions and that among the analyzed receptors (Ret, epidermal growth factor receptor, and TrkA) it is activated specifically by Ret. Overexpression of Rai in neuronal cell lines promoted survival by reducing apoptosis both under conditions of limited availability of the Ret ligand glial cell line-derived neurotrophic factor (GDNF) and in the absence of Ret activation. Overexpressed Rai resulted in the potentiation of the Ret-dependent activation of phosphatidylinositol 3-kinase (PI3K) and Akt. Notably, increased Akt phosphorylation and PI3K activity were also found under basal conditions, e.g., in serum-starved neuronal cells. Phosphorylated and hypophosphorylated Rai proteins form a constitutive complex with the p85 subunit of PI3K: upon Ret triggering, the Rai-PI3K complex is recruited to the tyrosine-phosphorylated Ret receptor through the binding of the Rai PTB domain to tyrosine 1062 of Ret. In neurons treated with low concentrations of GDNF, the prosurvival effect of Rai depends on Rai phosphorylation and Ret activation. In the absence of Ret activation, the prosurvival effect of Rai is, instead, phosphorylation independent. Finally, we showed that overexpression of Rai, at variance with Shc, had no effects on the early peak of mitogen-activated protein kinase (MAPK) activation, whereas it increased its activation at later time points. Phosphorylated Rai, however, was not found in complexes with Grb2. We propose that Rai potentiates the MAPK and PI3K signaling pathways and regulates Ret-dependent and -independent survival signals. PMID:12242309

  13. 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.

  14. Temporal and spatial localization of three germline-specific proteins in medaka.

    Science.gov (United States)

    Aoki, Yumiko; Nagao, Issei; Saito, Daisuke; Ebe, Youko; Kinjo, Masataka; Tanaka, Minoru

    2008-03-01

    We show that germline-specific proteins, olvas (vasa), nanos, and tdrd1 (tudor), alter their localization in the cytoplasm during germline development in the medaka (Oryzias latipes). By immunohistochemical analysis, these three germline-specific proteins were detectable on granule-like structures in the cytoplasm of migrating primordial germ cells. In the germ cells of the gonadal primordia, these granules formed a hollow area lacking these three protein components. During the sexual differentiation of the female gonads, the granules were found to be reduced in size in the germ cells undergoing cystic division and they showed a perinuclear localization in the oocytes. However, the germ cells in the male gonads retained their hollow granules during this early sex differentiation stage. We further demonstrate the differential localization of olvas, nanos, and tdrd1 on these granules during medaka germline development.

  15. Structure of the germline genome of Tetrahymena thermophila and relationship to the massively rearranged somatic genome.

    Science.gov (United States)

    Hamilton, Eileen P; Kapusta, Aurélie; Huvos, Piroska E; Bidwell, Shelby L; Zafar, Nikhat; Tang, Haibao; Hadjithomas, Michalis; Krishnakumar, Vivek; Badger, Jonathan H; Caler, Elisabet V; Russ, Carsten; Zeng, Qiandong; Fan, Lin; Levin, Joshua Z; Shea, Terrance; Young, Sarah K; Hegarty, Ryan; Daza, Riza; Gujja, Sharvari; Wortman, Jennifer R; Birren, Bruce W; Nusbaum, Chad; Thomas, Jainy; Carey, Clayton M; Pritham, Ellen J; Feschotte, Cédric; Noto, Tomoko; Mochizuki, Kazufumi; Papazyan, Romeo; Taverna, Sean D; Dear, Paul H; Cassidy-Hanley, Donna M; Xiong, Jie; Miao, Wei; Orias, Eduardo; Coyne, Robert S

    2016-11-28

    The germline genome of the binucleated ciliate Tetrahymena thermophila undergoes programmed chromosome breakage and massive DNA elimination to generate the somatic genome. Here, we present a complete sequence assembly of the germline genome and analyze multiple features of its structure and its relationship to the somatic genome, shedding light on the mechanisms of genome rearrangement as well as the evolutionary history of this remarkable germline/soma differentiation. Our results strengthen the notion that a complex, dynamic, and ongoing interplay between mobile DNA elements and the host genome have shaped Tetrahymena chromosome structure, locally and globally. Non-standard outcomes of rearrangement events, including the generation of short-lived somatic chromosomes and excision of DNA interrupting protein-coding regions, may represent novel forms of developmental gene regulation. We also compare Tetrahymena's germline/soma differentiation to that of other characterized ciliates, illustrating the wide diversity of adaptations that have occurred within this phylum.

  16. Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients

    DEFF Research Database (Denmark)

    Bennedbæk, Marc; Rossing, Maria; Rasmussen, Åse K

    2016-01-01

    BACKGROUND: Germline mutations in the succinate dehydrogenase complex genes SDHB, SDHC, and SDHD predispose to pheochromocytomas and paragangliomas. Here, we examine the SDHB, SDHC, and SDHD mutation spectrum in the Danish population by screening of 143 Danish pheochromocytoma and paraganglioma...

  17. Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline.

    Science.gov (United States)

    Crichton, James H; Dunican, Donncha S; Maclennan, Marie; Meehan, Richard R; Adams, Ian R

    2014-05-01

    The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline.

  18. Targeted Germline Modifications in Rats Using CRISPR/Cas9 and Spermatogonial Stem Cells

    Directory of Open Access Journals (Sweden)

    Karen M. Chapman

    2015-03-01

    Full Text Available Organisms with targeted genomic modifications are efficiently produced by gene editing in embryos using CRISPR/Cas9 RNA-guided DNA endonuclease. Here, to facilitate germline editing in rats, we used CRISPR/Cas9 to catalyze targeted genomic mutations in rat spermatogonial stem cell cultures. CRISPR/Cas9-modified spermatogonia regenerated spermatogenesis and displayed long-term sperm-forming potential following transplantation into rat testes. Targeted germline mutations in Epsti1 and Erbb3 were vertically transmitted from recipients to exclusively generate “pure,” non-mosaic mutant progeny. Epsti1 mutant rats were produced with or without genetic selection of donor spermatogonia. Monoclonal enrichment of Erbb3 null germlines unmasked recessive spermatogenesis defects in culture that were buffered in recipients, yielding mutant progeny isogenic at targeted alleles. Thus, spermatogonial gene editing with CRISPR/Cas9 provided a platform for generating targeted germline mutations in rats and for studying spermatogenesis.

  19. 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

    Glial cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor that has reached clinical trials for Parkinson's disease. GDNF binds to its coreceptor GFRα1 and signals through the transmembrane receptor tyrosine kinase RET, or RET independently through NCAM or syndecan-3....... Whereas the GDNF signaling cascades are well described, cellular turnover and trafficking of GDNF and its receptors remain poorly characterized. Here, we find that SorLA acts as sorting receptor for the GDNF/GFRα1 complex, directing it from the cell surface to endosomes. Through this mechanism, GDNF...... 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...

  20. PAX8/PPARG and RET/PTC rearrangement detection is feasible in routine air dried fine needle aspiration (FNA) 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 carcinomas (FTC) and papillary carcinomas (PTC), their detection...... 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 RT-PCR. Methods: A new method for RNA extraction......). Similarly, RET/PTC was found in 3 of 96 FFPEs and in 4 of 96 FNAs. Two of 21 PTC samples and 3 of 42 FA samples carried this rearrangement. Conclusion: These data are the first to show the feasibility of extracting RNA from routine air dried FNA smears for the detection of PAX8/PPARG and RET...

  1. Familial Myelodysplastic/Acute Leukemia Syndromes—Myeloid Neoplasms with Germline Predisposition

    Science.gov (United States)

    Baptista, Renata Lyrio Rafael; dos Santos, Anna Cláudia Evangelista; Gutiyama, Luciana Mayumi; Solza, Cristiana; Zalcberg, Ilana Renault

    2017-01-01

    Although most cases of myeloid neoplasms are sporadic, a small subset has been associated with germline mutations. The 2016 revision of the World Health Organization classification included these cases in a myeloid neoplasm group with a predisposing germline mutational background. These patients must have a different management and their families should get genetic counseling. Cases identification and outline of the major known syndromes characteristics will be discussed in this text. PMID:28955657

  2. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

    Science.gov (United States)

    Flanagan, Sarah E; Haapaniemi, Emma; Russell, Mark A; Caswell, Richard; Lango Allen, Hana; De Franco, Elisa; McDonald, Timothy J; Rajala, Hanna; Ramelius, Anita; Barton, John; Heiskanen, Kaarina; Heiskanen-Kosma, Tarja; Kajosaari, Merja; Murphy, Nuala P; Milenkovic, Tatjana; Seppänen, Mikko; Lernmark, Åke; Mustjoki, Satu; Otonkoski, Timo; Kere, Juha; Morgan, Noel G; Ellard, Sian; Hattersley, Andrew T

    2014-08-01

    Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

  3. Årets gang i ord og sang, med Axel, Anna og lille Camilla

    DEFF Research Database (Denmark)

    Olesen, Lise Charlotte Sanders; Lefmann, Else

    rets gang i ord og sang med Axel, Anna og lille Camilla" henvender sig til de 5-8 årige i skole, hjem eller daginstitution - og består af: En illustreret bog med: 14 historier, der følger en familie, bestående af far, mor og tre børn. Gennem et helt år, måned for måned, hører vi om deres liv......, deres oplevelser, glæder og skuffelser. 14 sange, der ligeledes følger familiens liv gennem årstidernes skiften. Til sangene er der såvel noder som becifringer En CD Her er sangene først fuldt arrangeret med musik, børne- og voksenstemmer. Dernæst kommer musikken alene, således at Cd'en også kan bruges...... som akkompagnement, når man synger sangene. Materialet kan bruges på mange måder: Rent pædagogisk kan det bruges til at lære om årets gang og månedernes navne og rækkefølge Som en oplagt mulighed for at lære nye børnevenlige årstids sange i forskellige genre Som samtalestof med gode...

  4. Multiplexed transcriptome analysis to detect ALK, ROS1 and RET rearrangements in lung cancer

    Science.gov (United States)

    Rogers, Toni-Maree; Arnau, Gisela Mir; Ryland, Georgina L.; Huang, Stephen; Lira, Maruja E.; Emmanuel, Yvette; Perez, Omar D.; Irwin, Darryl; Fellowes, Andrew P.; Wong, Stephen Q.; Fox, Stephen B.

    2017-01-01

    ALK, ROS1 and RET gene fusions are important predictive biomarkers for tyrosine kinase inhibitors in lung cancer. Currently, the gold standard method for gene fusion detection is Fluorescence In Situ Hybridization (FISH) and while highly sensitive and specific, it is also labour intensive, subjective in analysis, and unable to screen a large numbers of gene fusions. Recent developments in high-throughput transcriptome-based methods may provide a suitable alternative to FISH as they are compatible with multiplexing and diagnostic workflows. However, the concordance between these different methods compared with FISH has not been evaluated. In this study we compared the results from three transcriptome-based platforms (Nanostring Elements, Agena LungFusion panel and ThermoFisher NGS fusion panel) to those obtained from ALK, ROS1 and RET FISH on 51 clinical specimens. Overall agreement of results ranged from 86–96% depending on the platform used. While all platforms were highly sensitive, both the Agena panel and Thermo Fisher NGS fusion panel reported minor fusions that were not detectable by FISH. Our proof–of–principle study illustrates that transcriptome-based analyses are sensitive and robust methods for detecting actionable gene fusions in lung cancer and could provide a robust alternative to FISH testing in the diagnostic setting. PMID:28181564

  5. Las discrepancias oficiales: la independencia de Kosovo y la retórica en Europa Occidental

    Directory of Open Access Journals (Sweden)

    Branislav Radeljić

    2014-10-01

    Full Text Available Este artículo examina los enfoques y las discrepancias oficiales que caracterizan la retórica de Europa occidental con respecto a la cuestión del estatuto de Kosovo. Desde los principios de la década de 1980, Kosovo ha sido cada vez más presente en los debates europeos, la tendencia que culminó con la intervención internacional de 1999 en la región y las negociaciones posteriores sobre su estatuto definitivo. Aunque los albaneses de Kosovo proclamaron su independencia en febrero 2008 y la mayoría de los Estados miembros de la UE decidieron reconocer Kosovo como un Estado independiente, la retórica de Europa occidental ha Estado bastante dividida. Este artículo muestra que, además de cinco miembros de la UE que han decidido no reconocer Kosovo desde el principio, y por lo tanto son suficientemente potentes para afectar a su progreso, tanto a nivel local como a nivel internacional, algunos de los Estados que lo han reconocido, a pesar de haber abandonado la política de “normas antes del estatuto”, también se han esforzado por desarrollar su pleno apoyo a la provincia – una discrepancia que seguramente cuestiona el apoyo de Occidente en general por la independencia de Kosovo.

  6. 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

  7. CSR-1 and P granules suppress sperm-specific transcription in the C. elegans germline.

    Science.gov (United States)

    Campbell, Anne C; Updike, Dustin L

    2015-05-15

    Germ granules (P granules) in C. elegans are required for fertility and function to maintain germ cell identity and pluripotency. Sterility in the absence of P granules is often accompanied by the misexpression of soma-specific proteins and the initiation of somatic differentiation in germ cells. To investigate whether this is caused by the accumulation of somatic transcripts, we performed mRNA-seq on dissected germlines with and without P granules. Strikingly, we found that somatic transcripts do not increase in the young adult germline when P granules are impaired. Instead, we found that impairing P granules causes sperm-specific mRNAs to become highly overexpressed. This includes the accumulation of major sperm protein (MSP) transcripts in germ cells, a phenotype that is suppressed by feminization of the germline. A core component of P granules, the endo-siRNA-binding Argonaute protein CSR-1, has recently been ascribed with the ability to license transcripts for germline expression. However, impairing CSR-1 has very little effect on the accumulation of its mRNA targets. Instead, we found that CSR-1 functions with P granules to prevent MSP and sperm-specific mRNAs from being transcribed in the hermaphrodite germline. These findings suggest that P granules protect germline integrity through two different mechanisms, by (1) preventing the inappropriate expression of somatic proteins at the level of translational regulation, and by (2) functioning with CSR-1 to limit the domain of sperm-specific expression at the level of transcription.

  8. Germline progenitors escape the widespread phenomenon of homolog pairing during Drosophila development.

    Directory of Open Access Journals (Sweden)

    Eric F Joyce

    Full Text Available Homolog pairing, which plays a critical role in meiosis, poses a potential risk if it occurs in inappropriate tissues or between nonallelic sites, as it can lead to changes in gene expression, chromosome entanglements, and loss-of-heterozygosity due to mitotic recombination. This is particularly true in Drosophila, which supports organismal-wide pairing throughout development. Discovered over a century ago, such extensive pairing has led to the perception that germline pairing in the adult gonad is an extension of the pairing established during embryogenesis and, therefore, differs from the mechanism utilized in most species to initiate pairing specifically in the germline. Here, we show that, contrary to long-standing assumptions, Drosophila meiotic pairing in the gonad is not an extension of pairing established during embryogenesis. Instead, we find that homologous chromosomes are unpaired in primordial germ cells from the moment the germline can be distinguished from the soma in the embryo and remain unpaired even in the germline stem cells of the adult gonad. We further establish that pairing originates immediately after the stem cell stage. This pairing occurs well before the initiation of meiosis and, strikingly, continues through the several mitotic divisions preceding meiosis. These discoveries indicate that the spatial organization of the Drosophila genome differs between the germline and the soma from the earliest moments of development and thus argue that homolog pairing in the germline is an active process as versus a passive continuation of pairing established during embryogenesis.

  9. Breast cancer risk and clinical implications for germline PTEN mutation carriers.

    Science.gov (United States)

    Ngeow, Joanne; Sesock, Kaitlin; Eng, Charis

    2017-08-01

    PTEN Hamartoma Tumor syndrome (PHTS) encompasses a clinical spectrum of heritable disorders including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and Proteus and Proteus-like syndrome that are associated with germline mutations in the PTEN tumor suppressor gene. Breast cancer risk estimates (67-85 %) for women with germline PTEN mutations are similar to those quoted for patients with germline mutations in the BRCA1/2 genes. With PTEN on several germline gene testing panels, finding PTEN mutations and variants have increased exponentially. PHTS can be differentiated from other hereditary cancer syndromes including Hereditary Breast Ovarian Cancer syndrome, Lynch syndrome, and hamartomatous polyposis syndromes based on personal as well as family history. However, many of the benign features of CS are common in the general population, making the diagnosis of CS challenging. Breast cancer patients with an identified germline PTEN mutation are at increased risk of endometrial, thyroid, renal, and colorectal cancers as well as a second breast cancer. Increased screening for the various component cancers as well as predictive testing in first-degree relatives is recommended. Prophylactic mastectomy may be considered especially if breast tissue is dense or if repeated breast biopsies have been necessary. Management of women with breast cancer suspected of CS who test negative for germline PTEN mutations should be managed as per a mutation carrier if she meets CS diagnostic criteria, and should be offered enrollment in research to identify other predisposition genes.

  10. Retóricas del cine de no ficción en la era de la post verdad

    OpenAIRE

    Cock Peláez., Alejandro

    2012-01-01

    En esta investigación doctoral analizo los principales cambios en las retóricas del cine de no ficción en la era de la post verdad, como una forma de intentar cartografiar las borrosas fronteras discursivas de esta forma cinematográfica, la cual al responder a nuevas maneras de entender la verdad y la realidad en la contemporaneidad, está explorando territorios retóricos que van más allá de los paradigmas clásicos y modernos, tan insertados en la centralidad de la institución documental. Así ...

  11. Mitate 見立: a retórica japonesa da repetição renovada

    Directory of Open Access Journals (Sweden)

    Madalena Hashimoto Cordaro

    Full Text Available A retórica do mitate tem sido discutida nas últimas décadas como central na produção do período Edo, não só no campo da poesia como no da pintura. Almeja-se aqui fazer um estudo monográfico sobre o termo, destacando exemplos literários e pictóricos, bem como uma interpretação sobre os modos pelos quais este artifício retórico permeia a cultura japonesa de vários períodos.

  12. Somatic mutations of the RET proto-oncogene are not required for tumor development in multiple endocrine neoplasia type 2 (MEN 2) gene carriers

    NARCIS (Netherlands)

    Landsvater, RM; deWit, MJ; Zewald, RA; Hofstra, RMW; Buys, CHCM; vanAmstel, HKP; Hoppener, JWM; Lips, CJM

    1996-01-01

    Germ line mutations in one allele of the RET proto-oncogene predispose to the multiple endocrine neoplasia type 2 (MEN 2) syndromes, To investigate whether these inherited mutations alone can cause the development of tumors in vivo (oncogene model) or whether somatic mutations in the homologous RET

  13. The Actin Cytoskeleton Is Involved in Glial Cell Line-Derived Neurotrophic Factor (GDNF-Induced Ret Translocation into Lipid Rafts in Dopaminergic Neuronal Cells

    Directory of Open Access Journals (Sweden)

    Li Li

    2017-09-01

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF, a potential therapeutic factor for Parkinson’s disease (PD, exerts its biological effects through the Ret receptor tyrosine kinase. The redistribution of Ret into lipid rafts substantially influences Ret signaling, but the mechanisms underlying Ret translocation remain unclear. The purpose of our study was to further explore the signaling mechanisms of GDNF and to determine whether the actin cytoskeleton is involved in the GDNF-induced Ret translocation into lipid rafts. In MN9D dopaminergic neuronal cells, we used density gradient centrifugation and immunofluorescence confocal microscopy to separate and visualize lipid rafts, co-immunoprecipitation to analyze protein-protein interactions, and latrunculin B (Lat B and jasplakinolide (Jas to disrupt and enhance the polymerization of the actin cytoskeleton, respectively. The results showed that Ret translocated into lipid rafts and coimmunoprecipitated with actin in response to GDNF treatment. After Lat B or Jas treatment, the Ret–F-actin association induced by GDNF was impaired or enhanced respectively and then the levels of Ret translocated into lipid rafts were correspondingly inhibited or promoted. These data indicate that actin polymerization and cytoskeletal remodeling are integral to GDNF-induced cell signaling in dopaminergic cells and define a new role of the actin cytoskeleton in promoting Ret redistribution into lipid rafts.

  14. Frequency of transferrin receptor positive reticulocytes (TF-Ret) in blood as an indicator of total-body radiation exposure: a pilot study in nuclear medicine patients.

    Science.gov (United States)

    Hempel, Klaus; Haenscheid, Heribert; Biko, Johannes; Hategan, Maria; Kaiser, Franz; Kreissl, Michael; Lorenz, Reinhard; Samnick, Samuel; Schirbel, Andreas; Varazashvili, Lali; Verchenya, Stanislav; Reiners, Christoph

    2012-11-01

    Approximately 3-20% of all reticulocytes in blood of healthy persons are immature and transferrin receptor positive (Tf-Ret). Tf-Ret were measured by flow cytometry in 27 patients treated with three different radiopharmaceuticals labeled with (131)I and in 25 healthy controls. Patients were chronically exposed within 6 days to blood doses from 0.18-1.89 Gy (D6). Typically, two-thirds of D6 was administered within the first day (D1). The study had to be confined to intra-subject investigations due to high biological variability of Tf-Ret counts. A significant radiation-induced decline was found in patients D1 doses that were ≥0.5 Gy. Tf-Ret frequency declined during the first 4 to 5 days of nuclear therapy to about 30-60% of its initial value, and increased in the following 3 days without reaching the initial value. At the time of nadir, the relative frequency of Tf-Ret was more depressed than that of reticulocytes and lymphocytes. The relative Tf-Ret frequency at nadir could be fitted to the equation: %-Tf-Ret=exp-(D1/D(o)). D(o) was found to be 1.0 ± 0.4 Gy (Mean ± SEM). The study shows that Tf-Ret frequency in blood might be a good parameter for estimation of the radiation dose to red marrow.

  15. Germline Mutations in Predisposition Genes in Pediatric Cancer

    Science.gov (United States)

    Edmonson, Michael N.; Gruber, Tanja A.; Easton, John; Hedges, Dale; Ma, Xiaotu; Zhou, Xin; Yergeau, Donald A.; Wilkinson, Mark R.; Vadodaria, Bhavin; Chen, Xiang; McGee, Rose B.; Hines-Dowell, Stacy; Nuccio, Regina; Quinn, Emily; Shurtleff, Sheila A.; Rusch, Michael; Patel, Aman; Becksfort, Jared B.; Wang, Shuoguo; Weaver, Meaghann S.; Ding, Li; Mardis, Elaine R.; Wilson, Richard K.; Gajjar, Amar; Ellison, David W.; Pappo, Alberto S.; Pui, Ching-Hon; Downing, James R.

    2016-01-01

    BACKGROUND The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. CONCLUSIONS Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American

  16. Dimerization Domain of Retinal Membrane Guanylyl Cyclase 1 (RetGC1) Is an Essential Part of Guanylyl Cyclase-activating Protein (GCAP) Binding Interface.

    Science.gov (United States)

    Peshenko, Igor V; Olshevskaya, Elena V; Dizhoor, Alexander M

    2015-08-01

    The photoreceptor-specific proteins guanylyl cyclase-activating proteins (GCAPs) bind and regulate retinal membrane guanylyl cyclase 1 (RetGC1) but not natriuretic peptide receptor A (NPRA). Study of RetGC1 regulation in vitro and its association with fluorescently tagged GCAP in transfected cells showed that R822P substitution in the cyclase dimerization domain causing congenital early onset blindness disrupted RetGC1 ability to bind GCAP but did not eliminate its affinity for another photoreceptor-specific protein, retinal degeneration 3 (RD3). Likewise, the presence of the NPRA dimerization domain in RetGC1/NPRA chimera specifically disabled binding of GCAPs but not of RD3. In subsequent mapping using hybrid dimerization domains in RetGC1/NPRA chimera, multiple RetGC1-specific residues contributed to GCAP binding by the cyclase, but the region around Met(823) was the most crucial. Either positively or negatively charged residues in that position completely blocked GCAP1 and GCAP2 but not RD3 binding similarly to the disease-causing mutation in the neighboring Arg(822). The specificity of GCAP binding imparted by RetGC1 dimerization domain was not directly related to promoting dimerization of the cyclase. The probability of coiled coil dimer formation computed for RetGC1/NPRA chimeras, even those incapable of binding GCAP, remained high, and functional complementation tests showed that the RetGC1 active site, which requires dimerization of the cyclase, was formed even when Met(823) or Arg(822) was mutated. These results directly demonstrate that the interface for GCAP binding on RetGC1 requires not only the kinase homology region but also directly involves the dimerization domain and especially its portion containing Arg(822) and Met(823).

  17. Germline Chd8 haploinsufficiency alters brain development in mouse.

    Science.gov (United States)

    Gompers, Andrea L; Su-Feher, Linda; Ellegood, Jacob; Copping, Nycole A; Riyadh, M Asrafuzzaman; Stradleigh, Tyler W; Pride, Michael C; Schaffler, Melanie D; Wade, A Ayanna; Catta-Preta, Rinaldo; Zdilar, Iva; Louis, Shreya; Kaushik, Gaurav; Mannion, Brandon J; Plajzer-Frick, Ingrid; Afzal, Veena; Visel, Axel; Pennacchio, Len A; Dickel, Diane E; Lerch, Jason P; Crawley, Jacqueline N; Zarbalis, Konstantinos S; Silverman, Jill L; Nord, Alex S

    2017-08-01

    The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8(+/del5) mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8(+/del5) mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8(+/del5) mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8(+/del5) mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.

  18. Interspecific germline transmission of cultured primordial germ cells.

    Directory of Open Access Journals (Sweden)

    Marie-Cecile van de Lavoir

    Full Text Available In birds, the primordial germ cell (PGC lineage separates from the soma within 24 h following fertilization. Here we show that the endogenous population of about 200 PGCs from a single chicken embryo can be expanded one million fold in culture. When cultured PGCs are injected into a xenogeneic embryo at an equivalent stage of development, they colonize the testis. At sexual maturity, these donor PGCs undergo spermatogenesis in the xenogeneic host and become functional sperm. Insemination of semen from the xenogeneic host into females from the donor species produces normal offspring from the donor species. In our model system, the donor species is chicken (Gallus domesticus and the recipient species is guinea fowl (Numida meleagris, a member of a different avian family, suggesting that the mechanisms controlling proliferation of the germline are highly conserved within birds. From a pragmatic perspective, these data are the basis of a novel strategy to produce endangered species of birds using domesticated hosts that are both tractable and fecund.

  19. Germline transmission of exogenous genes in the chicken.

    Science.gov (United States)

    Bosselman, R A; Hsu, R Y; Boggs, T; Hu, S; Bruszewski, J; Ou, S; Kozar, L; Martin, F; Green, C; Jacobsen, F

    1989-01-27

    Difficulties associated with in vitro manipulation and culture of the early chicken embryo have restricted generation of transgenic chickens to approaches that use replication-competent retroviruses. The need to produce transgenic chickens in the absence of replicating virus prompted development of a new method of gene transfer into the chicken. Microinjection of the replication-defective reticuloendotheliosis virus (REV) vector ME111 beneath unincubated chicken embryo blastoderms results in infection of germline stem cells. This vector contains genetic information exogenous to the chicken genome, including both the herpes simplex virus type 1 thymidine kinase gene and the Tn5 neomycin phosphotransferase gene. About 8 percent of male birds hatched from injected embryos contained vector DNA in their semen. All four positive males tested passed vector sequences onto their progeny. Analysis of G1 offspring showed that gonads of G0 male birds were mosaic with respect to insertion of vector provirus. Thus, primordial germ cells present in the unincubated chicken embryo blastoderm are susceptible to infection by defective REV vectors.

  20. Translational activation maintains germline tissue homeostasis during adulthood.

    Science.gov (United States)

    Nousch, Marco; Eckmann, Christian R

    2015-01-01

    Adult tissue maintenance is achieved through a tightly controlled equilibrium of 2 opposing cell fates: stem cell proliferation and differentiation. In recent years, the germ line emerged as a powerful in vivo model tissue to investigate the underlying gene expression mechanisms regulating this balance. Studies in numerous organisms highlighted the prevalence of post-transcriptional mRNA regulation, which relies on RNA-targeting factors that influence mRNA fates (e.g. decay or translational efficiency). Conserved translational repressors were identified that build negative feedback loops to ensure one or the other cell fate. However, to facilitate a fast and efficient transition between 2 opposing cell fates, translational repression per se appears not to be sufficient, suggesting the involvement of additional modes of gene expression regulation. Cytoplasmic poly(A) polymerases (cytoPAPs) represent a unique class of post-transcriptional mRNA regulators that modify mRNA 3' ends and positively influence cytoplasmic mRNA fates. We recently discovered that the 2 main cytoPAPs, GLD-2 and GLD-4, use distinct mechanisms to promote gene expression and that cytoPAP-mediated mRNA activation is important for regulating the size of the proliferative germ cell pool in the adult Caenorhabditis elegans gonad. Here, we comment on the different mechanisms of the 2 cytoPAPs as translational activators in germ cell development and focus on their biological roles in maintaining the balance between germline stem cell proliferation and differentiation in the Caenorhabditis elegans gonad.

  1. [Genetic tests in oncology practice with emphasis on the RET oncogene and VHL tumor suppressor gene].

    Science.gov (United States)

    Nesković, Gorana; Stanojević, Boban; Palmar, Ivan; Dimitrijević, Bogomir

    2002-07-01

    Molecular oncogenetics is the study of two distinct gene classes participating in the pathogenesis of malignant diseases: proto-oncogenes and tumour suppressors genes. Stepwise alterations in their structure are the basis of malignancy. Structural abnormalities range widely: gross genetic rearrangements including insertions, deletions, gene amplifications and single nucleotide deleotide deletions and substitutions. These gene alterations are determined by gene testing that increasingly are part of clinical diagnosis. Among many applications of oncogene testing is detection of hereditary forms of malignant disease with outstanding prophylactic and therapeutic importance. Along this line, gene testing provided for effective prevention of specific hereditary tumour types. Analysis of hereditary pheochromocytoma two gene tests are established: detection of multiple endocrine neoplasia type 2 (MEN 2) using mutational analysis of RET gene and detection of von Hippel-Lindau syndrome using mutational analysis of VHL gene. These genes were characterized about a decade ago and their structure determined in detail. Numerous studies focus on expression of these genes in different tissues and the function of respective proteins. In extensive epidemiology the following facts are established: hereditary mutations in the RET gene in > 92% of cases with MEN 2 syndrome while in patients with von Hippel-Lindau syndrome hereditary mutations were detected in VHL gene in > 95% of cases. Such a high genotype--phenotype correlation forms the basis for clinical applications. Gene testing in oncology offers numerous advantages. If a patient with pheochromocytoma presents with hereditary mutation in the RET or VHL gene, family gene testing is recommended. Family member with hereditary gene mutation is indicative of the risk level of nearly 100% for MEN 2 or von Hippel-Lindau syndrome. In such cases surgery is warranted (e.g. in MEN 2 total thyroidectomy by the age of (6). Negative findings

  2. 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...

  3. 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...

  4. Dialéctica y Retórica en los "Topica" de Cicerón

    OpenAIRE

    Guzmán Brito,Alejandro

    2010-01-01

    La obra que Cicerón editó el 44 a. C. bajo el título de "tópica" ha tenido una infuencia mayor en la Historia del Derecho, de la Lógica y de la Retórica. El presente trabajo explica los conceptos fundamentales que aparecen en aquel libro.

  5. A rare haplotype of the RET proto-oncogene is a risk-modifying allele in Hirschsprung disease

    NARCIS (Netherlands)

    Griseri, P; Pesce, B; Patrone, G; Osinga, J; Puppo, F; Sancandi, M; Hofstra, R; Romeo, G; Ravazzolo, R; Devoto, M; Ceccherini, [No Value

    2002-01-01

    Hirschsprung disease (HSCR) is a common genetic disorder characterized by intestinal obstruction secondary to enteric aganglionosis. HSCR demonstrates a complex pattern of inheritance, with the RET proto-oncogene acting as a major gene and with several additional susceptibility loci related to the R

  6. Dialéctica y Retórica en los "Topica" de Cicerón

    OpenAIRE

    Guzmán Brito,Alejandro

    2010-01-01

    La obra que Cicerón editó el 44 a. C. bajo el título de "tópica" ha tenido una infuencia mayor en la Historia del Derecho, de la Lógica y de la Retórica. El presente trabajo explica los conceptos fundamentales que aparecen en aquel libro.

  7. 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.

  8. Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

    Science.gov (United States)

    Schilling, T; Bürck, J; Sinn, H P; Clemens, A; Otto, H F; Höppner, W; Herfarth, C; Ziegler, R; Schwab, M; Raue, F

    2001-01-20

    We have determined the frequency of 918 RET proto-oncogene mutations (ATG-->ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG-->ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild-type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow-up time. However, 918mt patients showed more aggressive development of distant metastases during follow-up (p = 0.032, Fisher's exact test) with decreased metastases-free survival (p rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log-rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow-up treatment.

  9. Macumba surrealista: observações de Benjamin Péret em terreiros cariocas nos anos 1930

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    Emerson Giumbelli

    2015-06-01

    Full Text Available ResumoBenjamin Péret, poeta surrealista francês, viveu no Brasil entre 1929 e 1931, período no qual observou rituais em terreiros afro-brasileiros e compôs relatos registrados em uma série de artigos (“Candomblé e macumba” publicados em um jornal paulistano. O texto oferece uma análise desse conjunto de artigos, recorrendo a outras referências de e sobre Péret. Privilegia dois conjuntos de questões. Primeiro, como as observações do poeta francês dialogam com as etnografias contemporâneas sobre grupos e rituais de origem africana. Segundo, os diálogos que se estabelecem entre o olhar de Péret e preocupações de parcela do modernismo brasileiro. As transformações pelas quais passam as religiões afro-brasileiras podem ser vistas como processos que colocam em jogo questões semelhantes ao projeto modernista de “descoberta do Brasil”. O relato de Péret, com suas marcas surrealistas, é ao mesmo tempo testemunha e produto dessa busca.

  10. HO-1, RET and PML as possible markers for risk stratification of acute myelocytic leukemia and prognostic evaluation.

    Science.gov (United States)

    Yu, Meisheng; Wang, Jishi; Ma, Dan; Chen, Shuya; Lin, Xiaojing; Fang, Qin; Zhe, Nana

    2015-11-01

    Heme oxygenase-1 (HO-1) is an inducible isoform of HO that is activated in response to oxidative stress and has anti-apoptotic and pro-proliferative effects on leukemia cells. RET, a tyrosine kinase receptor; its expression levels are associated with the differentiation degree of acute myelocytic leukemia (AML) cells. The promyelocytic leukemia (PML) gene inhibits cell proliferation and tumor growth, participates in the differentiation of hematopoietic progenitor cells and induces cell apoptosis. However, the association between the expression levels of HO-1, RET and PML genes and the risk stratification of AML and prognosis have not previously been reported. In the present study, HO-1 was expressed in the human AML Kasumi-1, HL-60 and THP-1 cell lines, and HO-1 expression was regulated by Hemin (20 µmol/l) and ZnPPIX (10 µmol/l). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis demonstrated that expression of RET and PML were positively and negatively correlated with HO-1 expression, respectively. Bone marrow samples (18 favorable, 55 intermediate, 15 adverse and 2 unknown karyotype AML cases and 20 healthy donors) were collected from 90 randomly selected AML patients upon their first visit. The mRNA and protein expression of HO-1, RET and PML in samples was detected by RT-qPCR and western blot analysis. At the mRNA level, the adverse group expressed significantly higher levels of HO-1 and RET compared with the levels in the favorable and normal groups. The PML mRNA expression levels in adverse patient samples was lower compared with those of the intermediate group and favorable group. Western blot analysis demonstrated that the expression levels of HO-1, RET and PML proteins in all risk groups exhibited the same pattern of expression as was observed for the mRNA levels. The overall survival and relapse-free survival rates were shortest in AML patients with high HO-1 expression (Kaplan-Meier; log-rank, P<0.01). The results of the

  11. El humor gráfico desde una perspectiva retórica

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    Martha C. Chamorro Díaz

    2012-04-01

    Full Text Available Normalmente los géneros de opinión devienen en textos argumentativos, puesto que el objetivo del autor es convencer al público sobre su modo de percibir la realidad, exponiendo sus puntos de vista. En este sentido, los chistes gráficos pueden ser herramientas de opinión, y por ello se basan tanto en el análisis gráfico como en el discursivo utilizando básicamente herramientas provenientes de la retórica, dado que las mismas están presentes en la instancia verbal y en la gráfica conformándose como elementos constructivos de la transmisión de pensamientos, puntos de vista y análisis de los acontecimientos.

  12. Jean Calvin (1509-1564) - i 500-året for hans fødsel

    DEFF Research Database (Denmark)

    Jørgensen, Ninna

    2010-01-01

    Artiklen er en introduktion til Calvins liv og tankeverden i anledning af 500-året for hans fødsel. Udgangspunkt er hans selvforståelse, som den kommer til udtryk i hans Salmekommentar og den forståelse af Salmerne som en sjælens "anatomi" og en vejledning til bøn, som står ved roden af hans...... teologi. Calvins humanistiske baggrund, engagement i reformationen, eksil, og ydre og indre modstandere beskrives sammen med et overblik over hans teologi, som den fremstår i Institutio. Denne inkluderer den dobbelte erkendelse af Gud som Skaber og som Frelser, hvori forsynet er en væsentlig del af første...

  13. THE USE OF MICROORGANISMS OF CASSAVA RETTING FOR THE PRODUCTION OF PECTINOLYTIC ENZYMES

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    Sonagnon H. S. Kouhoundé

    2014-12-01

    Full Text Available Pectinolytic enzymes are used in the food industry for the extraction, clarification and filtration of fruit juice and wine. Depending on their mode of action, these enzymes are classified into two major groups, namely: esterases (methylesterase and depolymerases (polygalacturonase and lyase. Among the methods for their preparation, fermentation is the most used, and its application depends upon knowledge of the strain’s requirements; many parameters are taken into consideration most of which relate to the strain used. Knowledge and control of these parameters are required for optimal production of these enzymes. Many microorganisms (Aspergillus niger; Kluyveromyces marxianus; Trichoderma viride BITRS-1001; Bacillus licheniformis; Saccharomyces pastorianus etc. have already been studied and we suggested that there is a possibility of producing these enzymes using the microorganisms employed for the retting of cassava. This review provides a wealth of knowledge on the production of pectinolytic enzymes, using different substrates and microorganisms.

  14. Dialética e retórica em Pedro Abelardo

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    João Carlos Salles Pires da Silva

    1996-12-01

    Full Text Available Abelardo é reconhecido como um argumentador temível. Neste texto, procuramos mostrar como o uso de expedientes retóricos e o refinamento de sua técnica argumentativa associam-se intimamente e encontram em sua obra uma justificação teórica. Assim, recursos (como a redução ao absurdo, que parecem apenas garantir.o sucesso e sobrevivência do mestre itinerante, apontam para a defesa filosófica da independência da linguagem; deste modo, ao tempo em que denunciam a extrema inserção do filósofo em seu contexto histórico e sua preocupação com seu específico público, condensam elementos de sua autonomia intelectual e pioneirismo.

  15. GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

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    Hidekazu Ishida

    2016-07-01

    Full Text Available A surface marker that distinctly identifies cardiac progenitors (CPs is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2, specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

  16. Retórica fotográfica. Ingenio y provocación

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    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.

  17. 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.

  18. Retórica aplicada a la Enseñanza del Diseño Gráfico

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    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.

  19. Relações retóricas estabelecidas por orações gerundiais adverbiais

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    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.

  20. La determinación retórica del ser

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    Álvaro Vallejo Campos

    2014-05-01

    Full Text Available En el presente trabajo se pretende reflexionar sobre la ontología del discurso utópico platónico en la República. Platón opone la figura del filósofo gobernante, que es de quien depende que el proyecto sea realizable, a «los amantes de los espectáculos» y a «los hombres de acción». Todas estas figuras, que pertenecen a la sofística y la retórica, son en realidad «amantes de la opinión», de manera que la demarcación del verdadero filósofo supone defender contra estos una idea del arte de gobernar basada en la epistḗmē y en una concepción normativa del ser. De los diversos sentidos que tiene el ser en la ontología platónica, existencial, predicativo y veritativo, el proyecto platónico del arte de gobernar se fundamenta en una concepción normativa del ser, cuya perfección esencial no viene determinada por la nuda existencia, sino por la identidad y la unidad de la forma. La ontología platónica así definida, en unos términos que vienen determinados en gran medida por su discusión con la retórica, se convierte en el fundamento del paradigma para la construcción de la ciudad ideal, cuya validez no está condicionada por la existencia empírica de las cosas.

  1. New methodologies for lower-K1 EUV OPC and RET optimization

    Science.gov (United States)

    Hooker, Kevin; Kazarian, Aram; Zhou, Xibin; Tuttle, Josh; Xiao, Guangming; Zhang, Yunqiang; Lucas, Kevin

    2017-03-01

    EUV lithography is viewed as a highly desirable technology for 5nm and 7nm node patterning cost reduction and process simplicity. However, for the 5nm and 7nm nodes EUV not only needs to function in a low-K1 resolution environment but has several new and complex patterning issues which will need accurate compensation by mask synthesis tools and flows. The main new issues are: long-range flare variation across the chip, feature dependent focus offsets due to high mask topography, asymmetry inducing shadowing effects which vary across the lens slit, significantly higher lens aberrations, illumination source changes (across the lens and with time) and new resist exposure mechanisms. These solutions must be successfully deployed at low K1 values and must be integrated together to create OPC/RET flows which have high resolution, high accuracy, and are fast to deploy. Therefore, the combined requirements of low-K1 resolution, full reticle correction accuracy and process window can be even more challenging than in current optical lithography mask synthesis flows. Advanced computational methods such as ILT and model-based SRAF optimization are well known to have considerable benefits in process window and resolution for low-K1 193 lithography. However, these methods have not been well studied to understand their benefits for lower-K1 EUV lithography where fabs must push EUV resolution, 2D accuracy and process window to their limits. In this paper, we investigate where inverse lithography methods can improve EUV patterning weaknesses vs. traditional OPC/RET. We first show how ILT can be used to guide a better understanding of optimal solutions for EUV mask synthesis. We then provide detailed comparisons of ILT and traditional methods on a wide range of mask synthesis applications.

  2. A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality.

    Science.gov (United States)

    Buckley, Bethany A; Burkhart, Kirk B; Gu, Sam Guoping; Spracklin, George; Kershner, Aaron; Fritz, Heidi; Kimble, Judith; Fire, Andrew; Kennedy, Scott

    2012-09-20

    Epigenetic information is frequently erased near the start of each new generation. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance). A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.

  3. Characterisation and germline transmission of cultured avian primordial germ cells.

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    Joni Macdonald

    Full Text Available BACKGROUND: Avian primordial germ cells (PGCs have significant potential to be used as a cell-based system for the study and preservation of avian germplasm, and the genetic modification of the avian genome. It was previously reported that PGCs from chicken embryos can be propagated in culture and contribute to the germ cell lineage of host birds. PRINCIPAL FINDINGS: We confirm these results by demonstrating that PGCs from a different layer breed of chickens can be propagated for extended periods in vitro. We demonstrate that intracellular signalling through PI3K and MEK is necessary for PGC growth. We carried out an initial characterisation of these cells. We find that cultured PGCs contain large lipid vacuoles, are glycogen rich, and express the stem cell marker, SSEA-1. These cells also express the germ cell-specific proteins CVH and CDH. Unexpectedly, using RT-PCR we show that cultured PGCs express the pluripotency genes c-Myc, cKlf4, cPouV, cSox2, and cNanog. Finally, we demonstrate that the cultured PGCs will migrate to and colonise the forming gonad of host embryos. Male PGCs will colonise the female gonad and enter meiosis, but are lost from the gonad during sexual development. In male hosts, cultured PGCs form functional gametes as demonstrated by the generation of viable offspring. CONCLUSIONS: The establishment of in vitro cultures of germline competent avian PGCs offers a unique system for the study of early germ cell differentiation and also a comparative system for mammalian germ cell development. Primary PGC lines will form the basis of an alternative technique for the preservation of avian germplasm and will be a valuable tool for transgenic technology, with both research and industrial applications.

  4. Germline copy number variation and ovarian cancer survival

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    Brooke L Fridley

    2012-08-01

    Full Text Available Copy number variants (CNVs have been implicated in many complex diseases. We examined whether inherited CNVs were associated with overall survival among women with invasive epithelial ovarian cancer. Germline DNA from 1,056 cases (494 deceased, average of 3.7 years follow-up was interrogated with the Illumina 610quad genome-wide array containing, after quality control exclusions, 581,903 single nucleotide polymorphisms (SNPs and 17,917 CNV probes. Comprehensive analysis capitalized upon the strengths of three complementary approaches to CNV classification. First, to identify small CNVs, single markers were evaluated and, where associated with survival, consecutive markers were combined. Two chromosomal regions were associated with survival using this approach (14q31.3 rs2274736 p=1.59x10-6, p=0.001; 22q13.31 rs2285164 p=4.01x10-5, p=0.009, but were not significant after multiple testing correction. Second, to identify large CNVs, genome-wide segmentation was conducted to characterize chromosomal gains and losses, and association with survival was evaluated by segment. Four regions were associated with survival (1q21.3 loss p=0.005, 5p14.1 loss p=0.004, 9p23 loss p=0.002, and 15q22.31 gain p=0.002; however, again, after correcting for multiple testing, no regions were statistically significant, and none were in common with the single-marker approach. Finally, to evaluate associations with general amounts of copy number changes across the genome, we estimated CNV burden based on genome-wide numbers of gains and losses; no associations with survival were observed (p>0.40. Although CNVs that were not well-covered by the Illumina 610quad array merit investigation, these data suggest no association between inherited CNVs and survival after ovarian cancer.

  5. HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen.

    Science.gov (United States)

    Jardine, Joseph G; Kulp, Daniel W; Havenar-Daughton, Colin; Sarkar, Anita; Briney, Bryan; Sok, Devin; Sesterhenn, Fabian; Ereño-Orbea, June; Kalyuzhniy, Oleksandr; Deresa, Isaiah; Hu, Xiaozhen; Spencer, Skye; Jones, Meaghan; Georgeson, Erik; Adachi, Yumiko; Kubitz, Michael; deCamp, Allan C; Julien, Jean-Philippe; Wilson, Ian A; Burton, Dennis R; Crotty, Shane; Schief, William R

    2016-03-25

    Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. Using deep mutational scanning and multitarget optimization, we developed a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. These methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.

  6. Transgenerational epigenetic imprinting of the male germline by endocrine disruptor exposure during gonadal sex determination.

    Science.gov (United States)

    Chang, Hung-Shu; Anway, Matthew D; Rekow, Stephen S; Skinner, Michael K

    2006-12-01

    Embryonic exposure to the endocrine disruptor vinclozolin at the time of gonadal sex determination was previously found to promote transgenerational disease states. The actions of vinclozolin appear to be due to epigenetic alterations in the male germline that are transmitted to subsequent generations. Analysis of the transgenerational epigenetic effects on the male germline (i.e. sperm) identified 25 candidate DNA sequences with altered methylation patterns in the vinclozolin generation sperm. These sequences were identified and mapped to specific genes and noncoding DNA regions. Bisulfite sequencing was used to confirm the altered methylation pattern of 15 of the candidate DNA sequences. Alterations in the epigenetic pattern (i.e. methylation) of these genes/DNA sequences were found in the F2 and F3 generation germline. Therefore, the reprogramming of the male germline involves the induction of new imprinted-like genes/DNA sequences that acquire an apparent permanent DNA methylation pattern that is passed at least through the paternal allele. The expression pattern of several of the genes during embryonic development were found to be altered in the vinclozolin F1 and F2 generation testis. A number of the imprinted-like genes/DNA sequences identified are associated with epigenetic linked diseases. In summary, an endocrine disruptor exposure during embryonic gonadal sex determination was found to promote an alteration in the epigenetic (i.e. induction of imprinted-like genes/DNA sequences) programming of the male germline, and this is associated with the development of transgenerational disease states.

  7. Pan-cancer analysis reveals technical artifacts in TCGA germline variant calls.

    Science.gov (United States)

    Buckley, Alexandra R; Standish, Kristopher A; Bhutani, Kunal; Ideker, Trey; Lasken, Roger S; Carter, Hannah; Harismendy, Olivier; Schork, Nicholas J

    2017-06-12

    Cancer research to date has largely focused on somatically acquired genetic aberrations. In contrast, the degree to which germline, or inherited, variation contributes to tumorigenesis remains unclear, possibly due to a lack of accessible germline variant data. Here we called germline variants on 9618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types. We identified batch effects affecting loss of function (LOF) variant calls that can be traced back to differences in the way the sequence data were generated both within and across cancer types. Overall, LOF indel calls were more sensitive to technical artifacts than LOF Single Nucleotide Variant (SNV) calls. In particular, whole genome amplification of DNA prior to sequencing led to an artificially increased burden of LOF indel calls, which confounded association analyses relating germline variants to tumor type despite stringent indel filtering strategies. The samples affected by these technical artifacts include all acute myeloid leukemia and practically all ovarian cancer samples. We demonstrate how technical artifacts induced by whole genome amplification of DNA can lead to false positive germline-tumor type associations and suggest TCGA whole genome amplified samples be used with caution. This study draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.

  8. Retinal degeneration 3 (RD3) protein inhibits catalytic activity of retinal membrane guanylyl cyclase (RetGC) and its stimulation by activating proteins.

    Science.gov (United States)

    Peshenko, Igor V; Olshevskaya, Elena V; Azadi, Seifollah; Molday, Laurie L; Molday, Robert S; Dizhoor, Alexander M

    2011-11-08

    Retinal membrane guanylyl cyclase (RetGC) in the outer segments of vertebrate photoreceptors is controlled by guanylyl cyclase activating proteins (GCAPs), responding to light-dependent changes of the intracellular Ca(2+) concentrations. We present evidence that a different RetGC binding protein, retinal degeneration 3 protein (RD3), is a high-affinity allosteric modulator of the cyclase which inhibits RetGC activity at submicromolar concentrations. It suppresses the basal activity of RetGC in the absence of GCAPs in a noncompetitive manner, and it inhibits the GCAP-stimulated RetGC at low intracellular Ca(2+) levels. RD3 opposes the allosteric activation of the cyclase by GCAP but does not significantly change Ca(2+) sensitivity of the GCAP-dependent regulation. We have tested a number of mutations in RD3 implicated in human retinal degenerative disorders and have found that several mutations prevent the stable expression of RD3 in HEK293 cells and decrease the affinity of RD3 for RetGC1. The RD3 mutant lacking the carboxy-terminal half of the protein and associated with Leber congenital amaurosis type 12 (LCA12) is unable to suppress the activity of the RetGC1/GCAP complex. Furthermore, the inhibitory activity of the G57V mutant implicated in cone-rod degeneration is strongly reduced. Our results suggest that inhibition of RetGC by RD3 may be utilized by photoreceptors to block RetGC activity during its maturation and/or incorporation into the photoreceptor outer segment rather than participate in dynamic regulation of the cyclase by Ca(2+) and GCAPs.

  9. La retórica del texto argumentativo en la columna de opinión "Escenas Políticas" de Jaime Campmay (1983)

    OpenAIRE

    Román Portas, Lourdes

    2016-01-01

    La tesis aborda la columna “Escenas Políticas” de Jaime Campmany durante el año 1983 con el objetivo de determinar las propiedades argumentativas y estilísticas más sobresalientes del autor. Para ello analiza, desde la perspectiva de la retórica, los 265 artículos publicados por Jaime Campmany durante ese año en ABC. El análisis efectuado contempla las operaciones retóricas de la intellectio, inventio, dispositio y elocutio. De todo ello se deduce la riqueza retórico-argumentativa de la pr...

  10. Fragment-based discovery of a dual pan-RET/VEGFR2 kinase inhibitor optimized for single-agent polypharmacology1

    OpenAIRE

    Frett, Brendan; Carlomagno, Francesca; Moccia, Maria Luisa; Brescia, Annalisa; Federico, Giorgia; De Falco, Valentina; Admire, Brittany; Chen, Zhongzhu; Qi, Wenqing; Santoro, Massimo; Li, Hong-yu

    2015-01-01

    Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen lead to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a Type-II tyrosine kinase inhibitor, able to bind the DFG-out conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown active on VEGFR2, which can block blood supply required for RET-stimulat...

  11. Argumentación o retórica, una de las piezas claves para la construcción de la realidad social

    OpenAIRE

    Díaz Arenas, Pedro Felipe; Posada Ramírez, Jorge Gregorio

    2012-01-01

    Este artículo busca mostrar que es la retórica, y no la argumentación, la prácticahumana decisiva en la construcción y sostenimiento de la realidad social. Es lacapacidad de persuadir a auditorios lo que constituye los principios rectores de lasinstituciones sociales, y no el debate crítico y argumentado de ideas. Para esto, enla primera parte se distinguirá entre argumentación y retórica. Se mostrará que enla argumentación prima la demostración de verdades, mientras que en la retórica,el con...

  12. Transposition and gene disruption in the male germline of the mouse.

    Science.gov (United States)

    Dupuy, A J; Fritz, S; Largaespada, D A

    2001-06-01

    We have tested a synthetic, functional, transposon called Sleeping Beauty for use in mice as a germline insertional mutagen. We describe experiments in which mutagenic, polyadenylation-site trapping, transposon vectors were introduced into the germline of mice. When doubly transgenic males, expressing the Sleeping Beauty transposase gene (SB10) and harboring poly(A)-trap transposon vectors, were outcrossed to wild-type females, offspring were generated with new transposon insertions. The frequency of new transposon insertion is roughly two per male gamete. These new insertions can be passed through the germline to the next generation and can insert into or near genes. We have generated a preliminary library of 24 mice harboring 56 novel insertion sites, including one insertion into a gene represented in the EST database and one in the promoter of the galactokinase (Gck) gene. This technique has promise as a new strategy for forward genetic screens in the mouse or functional genomics.

  13. Transgenerational effects of proton beam irradiation on Caenorhabditis elegans germline apoptosis.

    Science.gov (United States)

    Min, Hyemin; Sung, Minhee; Son, Miseol; Kawasaki, Ichiro; Shim, Yhong-Hee

    2017-08-26

    When treating cancer using radiation therapy, it is critical to increase patient survival rates and to reduce side effects. In this respect, proton beam radiation treatment performs better than other radiation treatments because of its high target specificity. However, complications still remain after proton beam radiation treatment. Among them, the risk to progeny after irradiation of their parents is a major concern. In this study, we analyzed the transgenerational effects of proton beam irradiation using the model organism Caenorhabditis. elegans. We found that germline apoptosis increased after proton beam irradiation and its effects were sustained transgenerationally. Moreover, we identified that a germline-specific histone methyltransferase component, SET-2, has a critical role in transmitting the transgenerational effect on germline apoptosis to the next generation after proton beam irradiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Germline mosaicism in osteopathia striata with cranial sclerosis--recurrence in siblings.

    Science.gov (United States)

    O'Byrne, James J; Phelan, Ethna; Steenackers, Ellen; van Hul, Wim; Reardon, William

    2016-04-01

    We report recurrence of osteopathia striata with cranial sclerosis (OSCS) in two full siblings conceived by unaffected parents. Molecular confirmation of OSCS in both siblings was achieved by identification of a novel heterozygous mutation in the WTX gene. Neither parent had clinical features of OSCS nor was the pathogenic mutation demonstrable in DNA extracted from both peripheral blood leucocytes and buccal cells. This case demonstrates germline mosaicism in OSCS and represents the third report of mosaicism affecting the germline in families with OSCS. Previous reports were of parental gonadosomal mosaicism, with one showing recurrence in multiple children. Our observation adds to a body of evidence that suggests that germline mosaicism in OSCS may occur more frequently than believed previously and may have implications for counselling families with OSCS.

  15. PUF-8, a Pumilio homolog, inhibits the proliferative fate in the Caenorhabditis elegans germline.

    Science.gov (United States)

    Racher, Hilary; Hansen, Dave

    2012-10-01

    Stem cell populations are maintained by keeping a balance between self-renewal (proliferation) and differentiation of dividing stem cells. Within the Caenorhabditis elegans germline, the key regulator maintaining this balance is the canonical Notch signaling pathway, with GLP-1/Notch activity promoting the proliferative fate. We identified the Pumilio homolog, PUF-8, as an inhibitor of the proliferative fate of stem cells in the C. elegans germline. puf-8(0) strongly enhances overproliferation of glp-1(gf) mutants and partially suppresses underproliferation of a weak glp-1(lf) mutant. The germline tumor that is formed in a puf-8(0); glp-1(gf) double mutant is due to a failure of germ cells to enter meiotic prophase. puf-8 likely inhibits the proliferative fate through negatively regulating GLP-1/Notch signaling or by functioning parallel to it.

  16. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1.

    Science.gov (United States)

    Toonen, Joseph A; Anastasaki, Corina; Smithson, Laura J; Gianino, Scott M; Li, Kairong; Kesterson, Robert A; Gutmann, David H

    2016-05-01

    Neurofibromatosis type 1 (NF1) is a common neurogenetic condition characterized by significant clinical heterogeneity. A major barrier to developing precision medicine approaches for NF1 is an incomplete understanding of the factors that underlie its inherent variability. To determine the impact of the germline NF1 gene mutation on the optic gliomas frequently encountered in children with NF1, we developed genetically engineered mice harboring two representative NF1-patient-derived Nf1 gene mutations (c.2542G>C;p.G848R and c.2041C>T;p.R681X). We found that each germline Nf1 gene mutation resulted in different levels of neurofibromin expression. Importantly, only R681X(CKO) but not G848R(CKO), mice develop optic gliomas with increased optic nerve volumes, glial fibrillary acid protein immunoreactivity, proliferation and retinal ganglion cell death, similar to Nf1 conditional knockout mice harboring a neomycin insertion (neo) as the germline Nf1 gene mutation. These differences in optic glioma phenotypes reflect both cell-autonomous and stromal effects of the germline Nf1 gene mutation. In this regard, primary astrocytes harboring the R681X germline Nf1 gene mutation exhibit increased basal astrocyte proliferation (BrdU incorporation) indistinguishable from neo(CKO) astrocytes, whereas astrocytes with the G848R mutation have lower levels of proliferation. Evidence for paracrine effects from the tumor microenvironment were revealed when R681X(CKO) mice were compared with conventional neo(CKO) mice. Relative to neo(CKO) mice, the optic gliomas from R681X(CKO) mice had more microglia infiltration and JNK(Thr183/Tyr185) activation, microglia-produced Ccl5, and glial AKT(Thr308) activation. Collectively, these studies establish that the germline Nf1 gene mutation is a major determinant of optic glioma development and growth through by both tumor cell-intrinsic and stromal effects.

  17. Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients

    Institute of Scientific and Technical Information of China (English)

    Mohd Nizam Zahary; Gurjeet Kaur; Muhammad Radzi Abu Hassan; Harjinder Singh; Venkatesh R Naik; Ravindran Ankathil

    2012-01-01

    AIM:To investigate the protein expression profile of mismatch repair (MMR) genes in suspected cases of Lynch syndrome and to characterize the associated germline mutations.METHODS:Immunohistochemical analysis of tumor samples was performed to determine the protein expression profile of MMR protein.Germline mutation screening was carried out on peripheral blood samples.The entire exon regions of MLH1 and MSH2 genes were amplified by polymerase chain reaction,screened by denaturing high performance liquid chromatography (dHPLC) and analyzed by DNA sequencing to characterize the germline mutations.RESULTS:Three out of 34 tissue samples (8.8%) and four out of 34 tissue samples (11.8%) showed loss of nuclear staining by immunohistochemistry,indicating the absence of MLH1 and MSH2 protein expression in carcinoma cells,respectively.dHPLC analysis followed by DNA sequencing showed these samples to have germline mutations of MSH2 gene.However,no deleterious mutations were identified in any of the 19 exons or coding regions of MLH1 gene,but we were able to identify MLH1 promoter polymorphism,-93G >A (rs1800734),in 21 out of 34 patients (61.8%).We identified one novel mutation,transversion mutation c.2005G > C,which resulted in a missense mutation (Gly669Arg),a transversion mutation in exon 1,c.142G > T,which resulted in a nonsense mutation (Glu48Stop)and splice-site mutation,c.2006-6T > C,which was adjacent to exon 13 of MSH2 gene.CONCLUSION:Germline mutations were identified in four Malaysian Lynch syndrome patients.Immunohistochemical analysis of tumor tissue proved to be a good pre-screening test before proceeding to germline mutation analysis of DNA MMR genes.

  18. Germline mutation rates in mice following in utero exposure to diesel exhaust particles by maternal inhalation

    DEFF Research Database (Denmark)

    Ritz, Caitlin; Ruminski, Wojciech; Hougaard, Karin S.

    2011-01-01

    (PAPs) from industrial environments cause DNA damage and mutations in the sperm of adult male mice. Effects on the female and male germline during critical stages of development (in utero) are unknown. In mice, previous studies have shown that expanded simple tandem repeat (ESTR) loci exhibit high rates...... and mated with control CBA mice. The F2 descendents were collected and ESTR germline mutation rates were derived from full pedigrees (mother, father, offspring) of F1 male and female mice. We found no evidence for increased ESTR mutation rates in females exposed in utero to DEP relative to control females...

  19. Simultaneous Analysis of Germline Crips and Snips in High Risk Prostate Cancer Families

    Science.gov (United States)

    2007-10-01

    AUTHOR(S) Jianfeng Xu, M.D., Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: jxu@wfubmc.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION...support that we can use the panel to accurately identify germline CNPs. Identifying germline CNPs among 48 HapMap subjects using Affymetrix 500K...dataset, which contains allele intensity data for 48 individuals (including 5 HapMap CEPH trios, 5 Yoruban trios, three other non- HapMap trios, and 9

  20. Identification of Germline Genetic Mutations in Pancreatic Cancer Patients

    Science.gov (United States)

    Salo-Mullen, Erin E.; O’Reilly, Eileen; Kelsen, David; Ashraf, Asad M.; Lowery, Maeve; Yu, Kenneth; Reidy, Diane; Epstein, Andrew S.; Lincoln, Anne; Saldia, Amethyst; Jacobs, Lauren M.; Rau-Murthy, Rohini; Zhang, Liying; Kurtz, Robert; Saltz, Leonard; Offit, Kenneth; Robson, Mark; Stadler, Zsofia K.

    2016-01-01

    Background Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. We sought to determine mutation prevalence and characteristics that predict for inherited predisposition to PAC. Methods We identified 175 consecutive PAC patients who underwent clinical genetics assessment at Memorial Sloan Kettering between 2011–2014. Clinical data, family history, and germline results were evaluated. Results Among 159 PAC patients who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95%CI, 9.5%–20.7%), including BRCA2(n=13), BRCA1(n=4), p16(n=2), PALB2(n=1), and Lynch syndrome(n=4). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish(AJ) (n=95) and 7.1% in non-AJ(n=56) patients. In AJ patients with strong, weak, or absent family history of BRCA-associated cancers, mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. Mean age at diagnosis in all mutation carriers was 58.5y(range 45–75y) compared to 64y(range 27–87y) in non-mutation carriers(P=0.02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC(≤50y) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to non-mutation carriers(P=0.34). Mutation prevalence in early-onset patients(n=21) was 28.6%, including BRCA1(n=2), p16(n=2), MSH2(n=1) and MLH1(n=1). Conclusion Mutations in BRCA2 account for over 50% of PAC patients with an identified susceptibility syndrome. AJ patients had high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, inherited predisposition to PAC is associated with earlier age at PAC diagnosis suggesting that this subset of patients may also represent a population warranting further evaluation. PMID:26440929

  1. αβ T cell receptor germline CDR regions moderate contact with MHC ligands and regulate peptide cross-reactivity.

    Science.gov (United States)

    Attaf, Meriem; Holland, Stephan J; Bartok, Istvan; Dyson, Julian

    2016-10-24

    αβ T cells respond to peptide epitopes presented by major histocompatibility complex (MHC) molecules. The role of T cell receptor (TCR) germline complementarity determining regions (CDR1 and 2) in MHC restriction is not well understood. Here, we examine T cell development, MHC restriction and antigen recognition where germline CDR loop structure has been modified by multiple glycine/alanine substitutions. Surprisingly, loss of germline structure increases TCR engagement with MHC ligands leading to excessive loss of immature thymocytes. MHC restriction is, however, strictly maintained. The peripheral T cell repertoire is affected similarly, exhibiting elevated cross-reactivity to foreign peptides. Our findings are consistent with germline TCR structure optimising T cell cross-reactivity and immunity by moderating engagement with MHC ligands. This strategy may operate alongside co-receptor imposed MHC restriction, freeing germline TCR structure to adopt this novel role in the TCR-MHC interface.

  2. Small RNA in situ hybridization in Caenorhabditis elegans, combined with RNA-seq, identifies germline-enriched microRNAs.

    Science.gov (United States)

    McEwen, Tamara J; Yao, Qiuming; Yun, Sijung; Lee, Chin-Yung; Bennett, Karen L

    2016-10-15

    Over four hundred different microRNAs (miRNAs) have been identified in the genome of the model organism the nematode Caenorhabditis elegans. As the germline is dedicated to the preservation of each species, and almost half of all the cells in an adult nematode are germline, it is likely that regulatory miRNAs are important for germline development and maintenance. In C. elegans the miR35 family has strong maternal effects, contributing to normal embryogenesis and to adult fecundity. To determine whether any particular miRNAs are greatly enriched in the C. elegans germline we used RNA-seq to compare the miRNA populations in several germline-defective strains of adult C. elegans worms, including glp-4(germline proliferation-4), glh-1(germline helicase-1) and dcr-1(dicer-1). Statistical analyses of RNA-seq comparisons identified 13 miRNAs that are germline-enriched, including seven members of the well-studied miR35 family that were reduced as much as 1000-fold in TaqMan qRT PCR miRNA assays. Along with the miR35s, six others: miR-56 (a member of the miR51 family),-70, -244, -260 , -788 and -4813, none of which previously considered as such, were also identified by RNA-seq as germline-enriched candidates. We went on to develop a successful miRNA in situ hybridization protocol for C. elegans, revealing miR35s specifically concentrate during oogenesis in the pachytene region of the gonad, and persist throughout early embryogenesis, while in adult animals neither let-7 nor miR-228 has a germline-bias.

  3. The correlation between BRAF mutations, RET/PTC rearrangements and platelet-derived growth factor B expression in papillary thyroid carcinomas

    Institute of Scientific and Technical Information of China (English)

    王萍

    2013-01-01

    Objective To investigate the prevalence of BRAF T1799A mutation and RET/PTC rearrangement in Qingdao and detect the expression of platelet-derived growth factor B(PDGF-B) in order to investigate the correlation

  4. Discovery of 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides as novel RET kinase inhibitors.

    Science.gov (United States)

    Han, Mei; Li, Shan; Ai, Jing; Sheng, Rong; Hu, Yongzhou; Hu, Youhong; Geng, Meiyu

    2016-12-01

    A series of novel 4-chloro-benzamides derivatives containing substituted five-membered heteroaryl ring were designed, synthesized and evaluated as RET kinase inhibitors for cancer therapy. Most of compounds exhibited moderate to high potency in ELISA-based kinase assay. In particular, compound I-8 containing 1,2,4-oxadiazole strongly inhibited RET kinase activity both in molecular and cellular level. In turn, I-8 inhibited cell proliferation driven by RET wildtype and gatekeeper mutation. The results implied that 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides are promising lead compounds as novel RET kinase inhibitor for further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Comparative role of phosphotyrosine kinase domains of c-ros and c-ret protooncogenes in metanephric development with respect to growth factors and matrix morphogens.

    Science.gov (United States)

    Liu, Z Z; Wada, J; Kumar, A; Carone, F A; Takahashi, M; Kanwar, Y S

    1996-08-25

    Receptor-like protooncogenes, with tyrosine kinase catalytic domains, are expressed in neoplastic and fetal tissues and potentially have a role in embryonic development. Which protooncogene may have the dominant role in embryonic renal development during the "postinductive" period, i.e., Day 10 onward, was addressed in this study by utilizing an in vitro organ culture system. The role of various receptor-like protooncogenes, with the emphasis on c-ros and c-ret, was investigated by antisense-oligodeoxynucleotide (ODN) gene-targeting strategies at a point in metanephric development when reciprocal-inductive interactions between the epithelium and mesenchyme have already been initiated and are rampant. Also, their relationship with other morphogens, like extracellular matrix (ECM) proteins and growth factors, was studied. Initial in situ hybridization and RT-PCR analyses revealed a similar spatiotemporal expression for both c-ros and c-ret in the embryonic kidneys. At Day 13, they were mainly expressed in the developing nephrons in the nephrogenic zone and ureteric bud branches, where the signals from the mesenchymal ligands are transduced to the epithelial cell surface receptors. Minimal expression was observed in the newborn kidneys. Inclusion of antisense ODNs, derived from the phosphotyrosine kinase domains, inhibited metanephric growth in the organ culture; the most dramatic effects were observed with the c-ret antisense ODN. The c-ret-induced dysmorphogenetic effects were characterized as a decrease in the population of nephrons, atrophy of the mesenchymal cells, and loss of acuteness of the tips of ureteric bud branches. Interestingly, the ureteric bud branches continue to grow in the atrophic mesenchyme. Both c-ros and c-ret antisense ODNs reduced the gene expression and biosynthesis of various ECM proteins. The proteoglycans, expressed at the epithelial:mesenchymal interface, were most adversely affected, especially by the c-ret antisense. The treatment of

  6. Rational-Emotive Therapy: Research Data That Supports the Clinical and Personality Hypotheses of Ret and Other Modes of Cognitive-Behavior Therapy

    Science.gov (United States)

    Ellis, Albert

    1977-01-01

    This article examines 32 important clinical and personality hypotheses of rational-emotive therapy (RET) and other modes of cognitive-behavior therapy and lists a large number of research studies that provide empirical confirmation of these hypotheses. (Author)

  7. 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

  8. 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.

  9. La Retórica del mito en el Carmen 64 de Catulo: Una propuesta de interpretación

    Directory of Open Access Journals (Sweden)

    Emilio Pascual Barciela

    2013-06-01

    Full Text Available El objetivo ha consistido en realizar una aproximación crítica, desde el marco de la Retórica, al Carmen 64 de Catulo para exponer una hipótesis en torno a la función que desempeña el episodio mítico de Ariadna en la globalidad del poema. Por un lado, se trataría de comprobar la idoneidad del sistema retórico en su aplicación a la exégesis de textos literarios latinos. Por otro, mostrar que dicho episodio no sólo desempeña el cometido de ornatus y eruditio, sino que su presencia supone un enriquecimiento en sus niveles semióticos de significación.

  10. La retórica de los vendedores y limosneros en el transporte público de Bogotá

    OpenAIRE

    Bernal Chávez, Julio Alexander; Vega Ortiz, Mabel Gineth

    2016-01-01

    Este artículo presenta el análisis de las estructuras argumentativas emergentes en los discursos de vendedores ambulantes y limosneros que, a diario, tienen lugar en los buses del transporte público en la ciudad de Bogotá (Colombia), desde las categorías propuestas por la retórica aristotélica (inventio y dispositio, particularmente). Para ello, se inicia con la contextualización histórica del fenómeno, atendiendo a las causas sociales y económicas que lo provocan; el estudio de la retórica, ...

  11. Response of Cultural Lake Eutrophication to Hemp-retting in Quidenham Mere of England in Post-Medieval

    Institute of Scientific and Technical Information of China (English)

    CHENG Xiaoying; LI Shijie; SHEN Qing; XUE Jing

    2007-01-01

    To study the influence of human activity on natural lake, chironomid fauna change in the 700 560cm lake sediment in Quidenham Mere of England associated with chironomid inferred TP presented that the lake experienced a whole eutrophication process due to human hemp-retting in Post-Medieval based on the history record and pollen analysis, which was confirmed by mollusc and ostracod analysis. However, the response of chironomid and mollusc to retting was the strongest with ostracod a little behind. It proved that cultural eutrophication existed in history and could be recovered by itself despite of some long-term unachievable destroy. And it was most important for external nutrient to be cut off during lake restoration even in ancient times.

  12. La retórica de los vendedores y limosneros en el transporte público de Bogotá

    OpenAIRE

    Bernal Chávez, Julio Alexander; Vega Ortiz, Mabel Gineth

    2016-01-01

    Este artículo presenta el análisis de las estructuras argumentativas emergentes en los discursos de vendedores ambulantes y limosneros que, a diario, tienen lugar en los buses del transporte público en la ciudad de Bogotá (Colombia), desde las categorías propuestas por la retórica aristotélica (inventio y dispositio, particularmente). Para ello, se inicia con la contextualización histórica del fenómeno, atendiendo a las causas sociales y económicas que lo provocan; el estudio de la retórica, ...

  13. La palabra persuasiva: centros de interés de la Retórica de Aristóteles

    OpenAIRE

    Racionero, Quintín

    2006-01-01

    El autor hace un balance de las novedades incorporadas, en el ámbito de las investigaciones aristotélicas, por su traducción al español de la Retórica de ARISTÓTELES. Para el autor, la suya no fue sólo una traducción sino, sobre todo, un comentario sistemático que intenta en primer lugar en la Introducción del libro evaluar el estado de la investigación contemporánea en torno a la Retórica, proponiendo una interpretación sintética de alcance general; y en segundo lugar, en las notas a p...

  14. Disease-modifying polymorphisms and C609Y mutation of RET associated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A

    Directory of Open Access Journals (Sweden)

    Rowena Speak

    2016-11-01

    Full Text Available Mutations of the rearranged during transfection (RET proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A. Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC, but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S, but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon–intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification.

  15. Ud af røret? Planer, processer og paradokser omkring det Københavnske kloaksystem 1840-2001

    DEFF Research Database (Denmark)

    Lindegaard, Hanne

    Afhandlingen handler om Københavns mere en 100 år gamle kloakteknologi, der i mange år har været en usynlig, stabil og taken for granted hverdagsinstallation, som ikke i særlig høj grad er blevet diskuteret eller problematiseret, men opfattet som en fuldstændig løsning på en række af byens proble...

  16. Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features.

    Science.gov (United States)

    Durand, Stéphanie; Ferraro-Peyret, Carole; Joufre, Mireille; Chave, Annie; Borson-Chazot, Françoise; Selmi-Ruby, Samia; Rousset, Bernard

    2009-06-01

    About 60-70% of papillary thyroid carcinomas (PTC) present a BRAF(T1799A) gene mutation or a rearrangement of RET gene (RET/PTC). In this study, we examined whether PTC without BRAF(T1799A) mutation and without RET/PTC rearrangement named PTC-ga(-) were distinguishable from PTC-ga(+) (with one or the other gene alteration) on the basis of gene expression characteristics. We analyzed the mutational state of 116 PTC and we compared gene expression profiles of PTC-ga(+) and PTC-ga(-) from data of a 200 gene macroarray and quantitative PCR. Seventy five PTC were PTC-ga(+) and 41 were PTC-ga(-). Unsupervised analyses of macroarray data by hierarchical clustering led to a complete segregation of PTC-ga(+) and PTC-ga(-). In a series of 42 genes previously recognized as PTC 'marker' genes, 22 were found to be expressed at a comparable level in PTC-ga(-) and normal tissue. Thyroid-specific genes, TPO, TG, DIO1, and DIO2 were under-expressed in PTC-ga(+) but expressed at a normal level in PTC-ga(-). A few genes including DUOX1 and DUOX2 were selectively dys-regulated in PTC-ga(-). Tumor grade of PTC-ga(-) was lower than that of PTC-ga(+). There was a strong association between the mutational state and histiotype of PTC; 81% of PTC follicular variants were corresponded to PTC-ga(-), whereas 84% of PTC of classical form were PTC-ga(+). In conclusion, we show that PTC without BRAF(T1799A) mutation or RET/PTC rearrangement, mainly corresponding to follicular variants, maintain a thyroid differentiation expression level close to that of normal tissue and should be of better prognosis than PTC with one or the other gene alteration.

  17. Aspectos linguísticos e retóricos no plenário jurídico

    OpenAIRE

    Torquato Feba, Lucilene Favareto

    2012-01-01

    O presente trabalho visa a uma análise dos articuladores textuais, enquanto recursos retóricos e persuasivos presentes no discurso jurídico, sendo que, o corpus abarca recortes de discursos judiciários colhidos durante a sessão de júri na cidade de PE-São Paulo. Os dados evidenciaram que, a presença dos articuladores argumentativos influenciou na decisão final do referido julgamento.

  18. Testing for Depéret's Rule (Body Size Increase) in Mammals using Combined Extinct and Extant Data.

    Science.gov (United States)

    Bokma, Folmer; Godinot, Marc; Maridet, Olivier; Ladevèze, Sandrine; Costeur, Loïc; Solé, Floréal; Gheerbrant, Emmanuel; Peigné, Stéphane; Jacques, Florian; Laurin, Michel

    2016-01-01

    Whether or not evolutionary lineages in general show a tendency to increase in body size has often been discussed. This tendency has been dubbed "Cope's rule" but because Cope never hypothesized it, we suggest renaming it after Depéret, who formulated it clearly in 1907. Depéret's rule has traditionally been studied using fossil data, but more recently a number of studies have used present-day species. While several paleontological studies of Cenozoic placental mammals have found support for increasing body size, most studies of extant placentals have failed to detect such a trend. Here, we present a method to combine information from present-day species with fossil data in a Bayesian phylogenetic framework. We apply the method to body mass estimates of a large number of extant and extinct mammal species, and find strong support for Depéret's rule. The tendency for size increase appears to be driven not by evolution toward larger size in established species, but by processes related to the emergence of new species. Our analysis shows that complementary data from extant and extinct species can greatly improve inference of macroevolutionary processes.

  19. SorLA Controls Neurotrophic Activity by Sorting of GDNF and Its Receptors GFRα1 and RET

    Directory of Open Access Journals (Sweden)

    Simon Glerup

    2013-01-01

    Full Text Available Glial cell-line-derived neurotrophic factor (GDNF is a potent neurotrophic factor that has reached clinical trials for Parkinson’s disease. GDNF binds to its coreceptor GFRα1 and signals through the transmembrane receptor tyrosine kinase RET, or RET independently through NCAM or syndecan-3. Whereas the GDNF signaling cascades are well described, cellular turnover and trafficking of GDNF and its receptors remain poorly characterized. Here, we find that SorLA acts as sorting receptor for the GDNF/GFRα1 complex, directing it from the cell surface to endosomes. Through this mechanism, GDNF 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 function, marked hyperactivity, and reduced anxiety, all of which are phenotypes related to abnormal GDNF activity. Taken together, these findings establish SorLA as a critical regulator of GDNF activity in the CNS.

  20. 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.

  1. Por uma retórica do discurso: argumentação técnica, emotiva e representacional

    Directory of Open Access Journals (Sweden)

    Ivo José Dittrich

    2008-01-01

    Full Text Available

    O ponto de partida do presente artigo é o de que a retórica do discurso resulta da ação integrada e complementar entre argumentos de ordem técnica, emotiva e representacional. Dependendo do interlocutor e dos objetivos do discurso, predomina um ou outro. A partir desses princípios, pode-se dizer que, dependendo da argumentação predominante, tem-se discursos com uma retórica mais técnica, mais emotiva ou mais representacional. Enquanto a argumentação técnica racionaliza o discurso, a emotiva lhe confere sensibilização e a representacional, credibilidade. Uma Teoria da Argumentação deveria situar, portanto, seus fundamentos teóricos e metodológicos na correlação entre esses diferentes aspectos da argumentação, principalmente quando se trata de analisar discursos do ponto de vista retórico.

  2. Fragment-based discovery of a dual pan-RET/VEGFR2 kinase inhibitor optimized for single-agent polypharmacology1

    Science.gov (United States)

    Frett, Brendan; Carlomagno, Francesca; Moccia, Maria Luisa; Brescia, Annalisa; Federico, Giorgia; De Falco, Valentina; Admire, Brittany; Chen, Zhongzhu; Qi, Wenqing; Santoro, Massimo; Li, Hong-yu

    2015-01-01

    Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen lead to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a Type-II tyrosine kinase inhibitor, able to bind the DFG-out conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown active on VEGFR2, which can block blood supply required for RET-stimulated growth. In cell based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg/kg/day per os, Pz-1 abrogated formation of tumors induced by RET-mutant fibroblasts and blocked phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity up to 100.0 mg/kg, which indicated a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways PMID:26126987

  3. Más allá de la retórica: la sociedad vigilante

    Directory of Open Access Journals (Sweden)

    Javier Roiz

    2013-01-01

    Full Text Available Una lectura política de la sociedad moderna, coloca en disputatio la Vigilia y la Letargia. El poder impera por la vigilancia, el estar alerta, sobre todo para el control y para la guerra. A su vez, busca la supresión de la letargia, el descanso y la pacificación. Las sociedades del yo gobiernan dominando el foro interno de los ciudadanos, pues en éste es donde la creación y la libertad tienen su pleno desarrollo crítico, pues no puede ser normado. Preferiblemente el principio de gobernabilidad pública debiera situarse en el self y no en el yo. Desde el espacio del sí mismo, es donde se debiera legislar el orden de todos para una mejor convivencia. Pero eso haría posible una sociedad de retóricos que se deslindan del mundo regido por la dialéctica, que impone sus lógicas deductivas. El mundo de vida de los ciudadanos se ve reducido a normas impuestas por un poder externo que los esclaviza: el de la sociedad que no duerme, vigilante a través de sus fuerzas coactivas para que el control social se cumpla con el consentimiento de los gobernados.

  4. 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.

  5. Protection of germline gene expression by the C. elegans Argonaute CSR-1.

    Science.gov (United States)

    Wedeles, Christopher J; Wu, Monica Z; Claycomb, Julie M

    2013-12-23

    In Caenorhabditis elegans, the Piwi-interacting small RNA (piRNA)-mediated germline surveillance system encodes more than 30,000 unique 21-nucleotide piRNAs, which silence a variety of foreign nucleic acids. What mechanisms allow endogenous germline-expressed transcripts to evade silencing by the piRNA pathway? One likely candidate in a protective mechanism is the Argonaute CSR-1, which interacts with 22G-small RNAs that are antisense to nearly all germline-expressed genes. Here, we use an in vivo RNA tethering assay to demonstrate that the recruitment of CSR-1 to a transcript licenses expression of the transcript, protecting it from piRNA-mediated silencing. Licensing occurs mainly at the level of transcription, as we observe changes in pre-mRNA levels consistent with transcriptional activation when CSR-1 is tethered. Furthermore, the recruitment of CSR-1 to a previously silenced locus transcriptionally activates its expression. Together, these results demonstrate a rare positive role for an endogenous Argonaute pathway in heritably licensing and protecting germline transcripts.

  6. A conserved upstream motif orchestrates autonomous, germline-enriched expression of Caenorhabditis elegans piRNAs.

    Directory of Open Access Journals (Sweden)

    Allison C Billi

    Full Text Available Piwi-interacting RNAs (piRNAs fulfill a critical, conserved role in defending the genome against foreign genetic elements. In many organisms, piRNAs appear to be derived from processing of a long, polycistronic RNA precursor. Here, we establish that each Caenorhabditis elegans piRNA represents a tiny, autonomous transcriptional unit. Remarkably, the minimal C. elegans piRNA cassette requires only a 21 nucleotide (nt piRNA sequence and an ∼50 nt upstream motif with limited genomic context for expression. Combining computational analyses with a novel, in vivo transgenic system, we demonstrate that this upstream motif is necessary for independent expression of a germline-enriched, Piwi-dependent piRNA. We further show that a single nucleotide position within this motif directs differential germline enrichment. Accordingly, over 70% of C. elegans piRNAs are selectively expressed in male or female germline, and comparison of the genes they target suggests that these two populations have evolved independently. Together, our results indicate that C. elegans piRNA upstream motifs act as independent promoters to specify which sequences are expressed as piRNAs, how abundantly they are expressed, and in what germline. As the genome encodes well over 15,000 unique piRNA sequences, our study reveals that the number of transcriptional units encoding piRNAs rivals the number of mRNA coding genes in the C. elegans genome.

  7. Functional analysis of Tudor-domain-containing proteins in the zebrafish germline

    NARCIS (Netherlands)

    Huang, H.Y.

    2012-01-01

    The Argonaute protein family consists of two distinct sub-clades: AGO and PIWI proteins. AGO proteins can form RNA induced silencing complex (RISC) and are responsible for RNAi and miRNA pathways. PIWI proteins are mostly expressed in the germline and together with specific small RNA groups, named

  8. Prophylactic Laparoscopic Total Gastrectomy with Jejunal Pouch Reconstruction in Patients Carrying a CDH1 Germline Mutation

    NARCIS (Netherlands)

    Haverkamp, L.; Sluis, P.C. van der; Ausems, M.G.; Horst, S. van der; Siersema, P.D.; Ruurda, J.P.; Offerhaus, G.J.; Hillegersberg, R. van

    2015-01-01

    BACKGROUND: For patients with an identified germline E-cadherin-1 (CDH1) mutation, prophylactic gastrectomy is the treatment of choice to eliminate the high risk of developing diffuse gastric cancer. Laparoscopic total gastrectomy with jejunal pouch reconstruction is a novel approach that may be esp

  9. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

    NARCIS (Netherlands)

    Post, R.S. van der; Vogelaar, I.P.; Carneiro, F.; Guilford, P.; Huntsman, D.; Hoogerbrugge, N.; Caldas, C.; Schreiber, K.E.; Hardwick, R.H.; Ausems, M.G.; Bardram, L.; Benusiglio, P.R.; Bisseling, T.M.; Blair, V.; Bleiker, E.; Boussioutas, A.; Cats, A.; Coit, D.; DeGregorio, L.; Figueiredo, J.; Ford, J.M.; Heijkoop, E.; Hermens, R.; Humar, B.; Kaurah, P.; Keller, G.; Lai, J.; Ligtenberg, M.J.; O'Donovan, M.; Oliveira, C.; Pinheiro, H.; Ragunath, K.; Rasenberg, E.; Richardson, S.; Roviello, F.; Schackert, H.; Seruca, R.; Taylor, A.; Huurne, A. Ter; Tischkowitz, M.; Joe, S.T.; Dijck, B. van; Grieken, N.C. van; Hillegersberg, R. van; Sandick, J.W. van; Vehof, R.; Krieken, J.H.J.M. van; Fitzgerald, R.C.

    2015-01-01

    Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, inc

  10. Morphological predictors of BRCA1 germline mutations in young women with breast cancer

    NARCIS (Netherlands)

    Southey, M. C.; Ramus, S. J.; Dowty, J. G.; Smith, L. D.; Tesoriero, A. A.; Wong, E. E. M.; Dite, G. S.; Jenkins, M. A.; Byrnes, G. B.; Winship, I.; Phillips, K-A; Giles, G. G.; Hopper, J. L.

    2011-01-01

    BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data. METHOD

  11. Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism.

    Science.gov (United States)

    Trevisson, E; Forzan, M; Salviati, L; Clementi, M

    2014-04-01

    Neurofibromatosis type 1 (NF1) is caused by loss of function mutations of the NF1 gene, which are de novo in 50% of cases. Although this gene shows one of the highest mutation rates in the human genome, germline mosaicism is very rare in this condition. We describe the molecular analysis of a family in which neurofibromatosis type 1 occurred in two out of four siblings born to unaffected parents. Molecular analysis of the NF1 gene identified in both patients the same splicing mutation c.1392+1G>A, which was absent in parental lymphocytes. Microsatellite analysis showed that the two affected siblings shared the same maternal allele, however a specific PCR-RFLP assay excluded the presence of the NF1 splicing mutation in multiple maternal tissues. Our molecular and clinical findings are consistent with a germline mosaicism for the NF1 splicing mutation. This is the first case of maternal germline mosaicism for a NF1 mutation characterized so far at the molecular level. Our data confirm that germline mosaicism is rare in neurofibromatosis 1, but it has important implications for genetic counseling.

  12. Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning.

    Science.gov (United States)

    Anastasaki, Corina; Woo, Albert S; Messiaen, Ludwine M; Gutmann, David H

    2015-06-15

    Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype-phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cyclic AMP generation, there was a neurofibromin dose-dependent reduction in dopamine (DA) levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse strains in which hippocampal-based learning and memory is DA-dependent to establish that neuronal DA levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset

    NARCIS (Netherlands)

    Pinto, Carla; Veiga, Isabel; Pinheiro, Manuela; Peixoto, Ana; Pinto, Armando; Lopes, Jose M.; Reis, Rui M.; Oliveira, Carla; Baptista, Manuela; Roque, Lucia; Regateiro, Fernando; Cirnes, Luis; Hofstra, Robert M. W.; Seruca, Raquel; Castedo, Sergio; Teixeira, Manuel R.

    2009-01-01

    The Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant disease caused by TP53 germline mutations. This study aimed to characterize the TP53 mutational spectrum in patients suspected to have LFS in Portugal and to evaluate the influence of the MDM2-SNP309 and TP53-72Arg variants and of telomere

  14. First report of a de novo germline mutation in the MLH1 gene

    NARCIS (Netherlands)

    Stulp, Rein P; Vos, Yvonne J; Mol, Bart; Karrenbeld, Arend; de Raad, Monique; van der Mijle, Huub J C; Sijmons, Rolf H

    2006-01-01

    Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of other tumor types. Germline mutations in the DNA mismatch repair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. The vast m

  15. PARENTAL ORIGIN AND GERMLINE MOSAICISM OF DELETIONS AND DUPLICATIONS OF THE DYSTROPHIN GENE - A EUROPEAN STUDY

    NARCIS (Netherlands)

    VANESSEN, AJ; ABBS, S; BAIGET, M; BAKKER, E; BOILEAU, C; VANBROECKHOVEN, C; BUSHBY, K; CLARKE, A; CLAUSTRES, M; COVONE, AE; FERRARI, M; FERLINI, A; GALLUZZI, G; GRIMM, T; GRUBBEN, C; JEANPIERRE, M; KAARIAINEN, H; LIECHTIGALLATI, S; MELIS, MA; VANOMMEN, GJB; PONCIN, JE; SCHEFFER, H; SCHWARTZ, M; SPEER, A; STUHRMANN, M; VERELLENDUMOULIN, C; WILCOX, DE; TENKATE, LP

    1992-01-01

    Knowledge about the parental origin of new mutations and the occurrence of germline mosaicism is important for estimating recurrence risks in Duchenne (DMD) and Becker muscular dystrophy (BMD). However, there are problems in resolving these issues partly because not all mutations can as yet be direc

  16. Hereditary diffuse gastric cancer : updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

    NARCIS (Netherlands)

    van der Post, Rachel S.; Vogelaar, Ingrid P.; Carneiro, Fatima; Guilford, Parry; Huntsman, David; Hoogerbrugge, Nicoline; Caldas, Carlos; Schreiber, Karen E. Chelcun; Hardwick, Richard H.; Ausems, Margreet G. E. M.; Bardram, Linda; Benusiglio, Patrick R.; Bisseling, Tanya M.; Blair, Vanessa; Bleiker, Eveline; Boussioutas, Alex; Cats, Annemieke; Coit, Daniel; DeGregorio, Lynn; Figueiredo, Joana; Ford, James M.; Heijkoop, Esther; Hermens, Rosella; Humar, Bostjan; Kaurah, Pardeep; Keller, Gisella; Lai, Jennifer; Ligtenberg, Marjolijn J. L.; O'Donovan, Maria; Oliveira, Carla; Pinheiro, Hugo; Ragunath, Krish; Rasenberg, Esther; Richardson, Susan; Roviello, Franco; Schackert, Hans; Seruca, Raquel; Taylor, Amy; ter Huurne, Anouk; Tischkowitz, Marc; Joe, Sheena Tjon A.; van Dijck, Benjamin; van Grieken, Nicole C. T.; van Hillegersberg, Richard; van Sandick, Johanna W.; Vehof, Rianne; van Krieken, J. Han; Fitzgerald, Rebecca C.

    2015-01-01

    Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, inc

  17. Dorsomorphin promotes survival and germline competence of zebrafish spermatogonial stem cells in culture.

    Directory of Open Access Journals (Sweden)

    Ten-Tsao Wong

    Full Text Available Zebrafish spermatogonial cell cultures were established from Tg(piwil1:neo;Tg(piwil1:DsRed transgenic fish using a zebrafish ovarian feeder cell line (OFC3 that was engineered to express zebrafish Lif, Fgf2 and Gdnf. Primary cultures, initiated from testes, were treated with G418 to eliminate the somatic cells and select for the piwil1:neo expressing spermatogonia. Addition of dorsomorphin, a Bmp type I receptor inhibitor, prolonged spermatogonial stem cell (SSC survival in culture and enhanced germline transmission of the SSCs following transplantation into recipient larvae. In contrast, dorsomorphin inhibited the growth and survival of zebrafish female germline stem cells (FGSCs in culture. In the presence of dorsomorphin, the spermatogonia continued to express the germ-cell markers dazl, dnd, nanos3, vasa and piwil1 and the spermatogonial markers plzf and sox17 for at least six weeks in culture. Transplantation experiments revealed that 6 week-old spermatogonial cell cultures maintained in the presence of dorsomorphin were able to successfully colonize the gonad in 18% of recipient larvae and produce functional gametes in the resulting adult chimeric fish. Germline transmission was not successful when the spermatogonia were cultured 6 weeks in the absence of dorsomorphin before transplantation. The results indicate that Bmp signaling is detrimental to SSCs but required for the survival of zebrafish FGSCs in culture. Manipulation of Bmp signaling could provide a strategy to optimize culture conditions of germline stem cells from other species.

  18. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Shah, S.; Schrader, K.A.; Waanders, E.; Timms, A.E.; Vijai, J.; Miething, C.; Wechsler, J.; Yang, J.; Hayes, J.; Klein, R.J.; Zhang, Jinghui; Wei, L.; Wu, G.; Rusch, M.; Nagahawatte, P.; Ma, J; Chen, S.C.; Song, G.; Cheng, J.; Meyers, P.; Bhojwani, D.; Jhanwar, S.; Maslak, P.; Fleisher, M.; Littman, J.; Offit, L.; Rau-Murthy, R.; Fleischut, M.H.; Corines, M.; Murali, R.; Gao, X.; Manschreck, C.; Kitzing, T.; Murty, V.V.; Raimondi, S.C.; Kuiper, R.P.; Simons, A.; Schiffman, J.D.; Onel, K.; Plon, S.E.; Wheeler, D.A.; Ritter, D.; Ziegler, D.S.; Tucker, K.; Sutton, R.; Chenevix-Trench, G.; Li, J.; Huntsman, D.G.; Hansford, S.; Senz, J.; Walsh, T.; Lee, M. van der; Hahn, C.N.; Roberts, K.G.; King, M.C.; Lo, S.M.; Levine, R.L.; Viale, A.; Socci, N.D.; Nathanson, K.L.; Scott, H.S.; Daly, M.; Lipkin, S.M.; Lowe, S.W.; Downing, J.R.; Altshuler, D.; Sandlund, J.T.; Horwitz, M.S.; Mullighan, C.G.; Offit, K.

    2013-01-01

    Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly1

  19. Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma

    NARCIS (Netherlands)

    van den Berg, Anke; Maggio, Ewerton; Diepstra, A; de Jong, Doetje; van Krieken, J; Poppema, S

    2002-01-01

    FAS germline mutations have been associated with the development of autoimmune lymphoproliferative syndrome (ALPS). Occurrence of Hodgkin lymphoma (HL) has been reported in 2 families with ALPS. In both families an uncle of the index patient developed HL. A 15-year-old boy with autoommune thrombopen

  20. No recombination of mtDNA after heteroplasmy for 50 generations in the mouse maternal germline

    Science.gov (United States)

    Hagström, Erik; Freyer, Christoph; Battersby, Brendan J.; Stewart, James B.; Larsson, Nils-Göran

    2014-01-01

    Variants of mitochondrial DNA (mtDNA) are commonly used as markers to track human evolution because of the high sequence divergence and exclusive maternal inheritance. It is assumed that the inheritance is clonal, i.e. that mtDNA is transmitted between generations without germline recombination. In contrast to this assumption, a number of studies have reported the presence of recombinant mtDNA molecules in cell lines and animal tissues, including humans. If germline recombination of mtDNA is frequent, it would strongly impact phylogenetic and population studies by altering estimates of coalescent time and branch lengths in phylogenetic trees. Unfortunately, this whole area is controversial and the experimental approaches have been widely criticized as they often depend on polymerase chain reaction (PCR) amplification of mtDNA and/or involve studies of transformed cell lines. In this study, we used an in vivo mouse model that has had germline heteroplasmy for a defined set of mtDNA mutations for more than 50 generations. To assess recombination, we adapted and validated a method based on cloning of single mtDNA molecules in the λ phage, without prior PCR amplification, followed by subsequent mutation analysis. We screened 2922 mtDNA molecules and found no germline recombination after transmission of mtDNA under genetically and evolutionary relevant conditions in mammals. PMID:24163253

  1. In Genes We Trust: Germline Engineering, Eugenics, and the Future of the Human Genome.

    Science.gov (United States)

    Powell, Russell

    2015-12-01

    Liberal proponents of genetic engineering maintain that developing human germline modification technologies is morally desirable because it will result in a net improvement in human health and well-being. Skeptics of germline modification, in contrast, fear evolutionary harms that could flow from intervening in the human germline, and worry that such programs, even if well intentioned, could lead to a recapitulation of the scientifically and morally discredited projects of the old eugenics. Some bioconservatives have appealed as well to the value of retaining our "given" human biological nature as a reason for restraining the development and use of human genetic modification technologies even where they would tend to increase well-being. In this article, I argue that germline intervention will be necessary merely to sustain the levels of genetic health that we presently enjoy for future generations-a goal that should appeal to bioliberals and bioconservatives alike. This is due to the population-genetic consequences of relaxed selection pressures in human populations caused by the increasing efficacy and availability of conventional medicine. This heterodox conclusion, which I present as a problem of intergenerational justice, has been overlooked in medicine and bioethics due to certain misconceptions about human evolution, which I attempt to rectify, as well as the sordid history of Darwinian approaches to medicine and social policy, which I distinguish from the present argument.

  2. Meiotic double-strand breaks uncover and protect against mitotic errors in the C. elegans germline.

    Science.gov (United States)

    Stevens, Deanna; Oegema, Karen; Desai, Arshad

    2013-12-01

    In sexually reproducing multicellular organisms, genetic information is propagated via the germline, the specialized tissue that generates haploid gametes. The C. elegans germline generates gametes in an assembly line-like process-mitotic divisions under the control of the stem cell niche produce nuclei that, upon leaving the niche, enter into meiosis and progress through meiotic prophase [1]. Here, we characterize the effects of perturbing cell division in the mitotic region of the C. elegans germline. We show that mitotic errors result in a spindle checkpoint-dependent cell-cycle delay, but defective nuclei are eventually formed and enter meiosis. These defective nuclei are eliminated by programmed cell death during meiotic prophase. The cell death-based removal of defective nuclei does not require the spindle checkpoint but instead depends on the DNA damage checkpoint. Removal of nuclei resulting from errors in mitosis also requires Spo11, the enzyme that creates double-strand breaks to initiate meiotic recombination. Consistent with this, double-strand breaks are increased in number and persist longer in germlines with mitotic defects. These findings reveal that the process of initiating meiotic recombination inherently selects against nuclei with abnormal chromosomal content generated by mitotic errors, thereby ensuring the genomic integrity of gametes.

  3. Plant germline formation: common concepts and developmental flexibility in sexual and asexual reproduction

    OpenAIRE

    Schmidt, Anja; Schmid, Marc W.; Grossniklaus, Ueli

    2015-01-01

    The life cycle of flowering plants alternates between two heteromorphic generations: a diploid sporophytic generation and a haploid gametophytic generation. During the development of the plant reproductive lineages - the germlines - typically, single sporophytic (somatic) cells in the flower become committed to undergo meiosis. The resulting spores subsequently develop into highly polarized and differentiated haploid gametophytes that harbour the gametes. Recent studies have provided insights...

  4. [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

  5. Chk2 and p53 regulate the transmission of healed chromosomes in the Drosophila male germline.

    Science.gov (United States)

    Titen, Simon W A; Lin, Ho-Chen; Bhandari, Jayaram; Golic, Kent G

    2014-02-01

    When a dicentric chromosome breaks in mitosis, the broken ends cannot be repaired by normal mechanisms that join two broken ends since each end is in a separate daughter cell. However, in the male germline of Drosophila melanogaster, a broken end may be healed by de novo telomere addition. We find that Chk2 (encoded by lok) and P53, major mediators of the DNA damage response, have strong and opposite influences on the transmission of broken-and-healed chromosomes: lok mutants exhibit a large increase in the recovery of healed chromosomes relative to wildtype control males, but p53 mutants show a strong reduction. This contrasts with the soma, where mutations in lok and p53 have the nearly identical effect of allowing survival and proliferation of cells with irreparable DNA damage. Examination of testes revealed a transient depletion of germline cells after dicentric chromosome induction in the wildtype controls, and further showed that P53 is required for the germline to recover. Although lok mutant males transmit healed chromosomes at a high rate, broken chromosome ends can also persist through spermatogonial divisions without healing in lok mutants, giving rise to frequent dicentric bridges in Meiosis II. Cytological and genetic analyses show that spermatid nuclei derived from such meiotic divisions are eliminated during spermiogenesis, resulting in strong meiotic drive. We conclude that the primary responsibility for maintaining genome integrity in the male germline lies with Chk2, and that P53 is required to reconstitute the germline when cells are eliminated owing to unrepaired DNA damage.

  6. Chk2 and p53 regulate the transmission of healed chromosomes in the Drosophila male germline.

    Directory of Open Access Journals (Sweden)

    Simon W A Titen

    2014-02-01

    Full Text Available When a dicentric chromosome breaks in mitosis, the broken ends cannot be repaired by normal mechanisms that join two broken ends since each end is in a separate daughter cell. However, in the male germline of Drosophila melanogaster, a broken end may be healed by de novo telomere addition. We find that Chk2 (encoded by lok and P53, major mediators of the DNA damage response, have strong and opposite influences on the transmission of broken-and-healed chromosomes: lok mutants exhibit a large increase in the recovery of healed chromosomes relative to wildtype control males, but p53 mutants show a strong reduction. This contrasts with the soma, where mutations in lok and p53 have the nearly identical effect of allowing survival and proliferation of cells with irreparable DNA damage. Examination of testes revealed a transient depletion of germline cells after dicentric chromosome induction in the wildtype controls, and further showed that P53 is required for the germline to recover. Although lok mutant males transmit healed chromosomes at a high rate, broken chromosome ends can also persist through spermatogonial divisions without healing in lok mutants, giving rise to frequent dicentric bridges in Meiosis II. Cytological and genetic analyses show that spermatid nuclei derived from such meiotic divisions are eliminated during spermiogenesis, resulting in strong meiotic drive. We conclude that the primary responsibility for maintaining genome integrity in the male germline lies with Chk2, and that P53 is required to reconstitute the germline when cells are eliminated owing to unrepaired DNA damage.

  7. First report of a de novo germline mutation in the MLH1 gene

    Institute of Scientific and Technical Information of China (English)

    Rein P Stulp; Yvonne J Vos; Bart Mol; Arend Karrenbeld; Monique de Raad; Huub JC van der Mijle; Rolf H Sijmons

    2006-01-01

    Hereditary non-polyposis colorectal carcinoma (HNPCC)is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of other tumor types. Germline mutations in the DNA mismatch repair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. The vast majority of these HNPCC-associated mutations have been proven,or assumed, given the family history of cancer, to be transmitted through several generations. To the best of our knowledge, only a single case of a de novo germline MMR gene mutation (in MSH2) has been reported till now. Here, we report a patient with a de novo mutation in MLH1. We identified a MLH1 Q701X truncating mutation in the blood lymphocytes of a male who had been diagnosed with rectal cancer at the age of 35. His family history of cancer was negative for the first- and second-degree relatives. The mutation could not be detected in the patient's parents and sibling and paternity was confirmed with a set of highly polymorphic markers. Non-penetrance and small family size is the common explanation of verified negative family histories of cancer in patients with a germline MMR gene mutation. However, in addition to some cases explained by non-paternity, de novo germline mutations should be considered as a possible explanation as well. As guidelines that stress not to restrict MMR gene mutation testing to patients with a positive family history are more widely introduced, more cases of de novo MMR gene germline mutations may be revealed.

  8. A population-based analysis of germline BAP1 mutations in melanoma

    Science.gov (United States)

    O’Shea, Sally J.; Robles-Espinoza, Carla Daniela; Harrigan, Jeanine; Jacq, Xavier; Hewinson, James; Iyer, Vivek; Merchant, Will; Elliott, Faye; Harland, Mark; Bishop, D. Timothy; Newton-Bishop, Julia A.

    2017-01-01

    Abstract Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma. PMID:28062663

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

    Directory of Open Access Journals (Sweden)

    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

  10. Prevalence of RET/PTC expression in papillary thyroid carcinoma and its correlation with prognostic factors in a north Indian population.

    Science.gov (United States)

    Mishra, A; Agrawal, V; Krishnani, N; Mishra, S K

    2009-01-01

    The prevalence of Rearranged during Transfection/Papillary Thyroid Carcinoma (RET/PTC) rearrangement in papillary thyroid carcinoma (PTC) varies in different geographic regions and its prognostic significance remains unclear. The aim of this study was to recognize the prevalence of RET/PTC expression in PTC from the endemically iodine-deficient region in Northern India and to correlate the expression with the clinicopathologic prognostic factors. Retrospective. Archival tissue used. Immunohistochemistry was performed to look for activated RET protein expression in 50 cases of PTC. No patient had any history of prior irradiation. Chi-square method, Student t test, and binary regression method. A P value of PTC (47.5%), followed by tumors with poorly differentiated areas (25%) and follicular variant (16.7%). RET expression was more prevalent in young patients (45.5 vs. 35.3%), females (43.3 vs. 40.0%), small tumors (33.3 vs. 26.7%), multicentric tumors (36.8 vs. 33.3%), tumors with extrathyroidal invasion (38.9 vs. 32.4%), and regional lymphadenopathy (55.2 vs. 22.2%), while it was less in cases with distant metastases (20 vs. 43.9%). There was no significant correlation of immunoreactivity with any prognostic factor. However, when the cases having immunoreactivity within histiocytes (n=26) and histiocytes + tumor tissue (n=28) were considered, then the expression was significantly more in cases with lymphadenopathy (P values=.009, in both instances). However, the exact clinical significance of RET/PTC positive histiocytes remained unexplained. Prevalence of RET/PTC in our study was consistent with the reported prevalence from other geographic areas. There was no significant correlation with the clinicopathologic factors. However, uniform techniques of detection and large international collaborative studies could clear the uncertainties regarding the prognostic importance of RET/PTC.

  11. Otra retórica del relato lírico

    Directory of Open Access Journals (Sweden)

    Marta Espinosa Berrocal

    2011-02-01

    Full Text Available Analyser le fantastique non seulement comme une “isotopie de la transgression” mais aussi comme un système rhétorique adopté par certains récits lyrico-poétiques, peut nous aider, d’une part, à comprendre comment les structures du fantastique s’articulent ; d’autre part, à établir une corrélation entre la fonction poétique inscrite dans l’enchaînement évènementiel propre à la narration et une symbolisation qui efface toute possibilité de référence unique. C’est dans cette conjonction que le fantastique fait son jeu, en apportant les mécanismes nécessaires qui permettent au récit poétique de s’approcher des territoires du mythique.Analizar lo fantástico no sólo como una “isotopía de la transgresión” sino como un sistema retórico adoptado por determinados relatos lírico-poéticos, puede ayudarnos por un lado a entender cómo se articulan las estructuras de lo fantástico, y por otro, a establecer una correlación entre la función poética diluida en la concatenación evenemencial propia de lo narrativo y una simbolización que desdibuja toda posibilidad de una referencialidad única. Es en esta coyuntura en la que lo fantástico entra en juego, aportando los mecanismos necesarios que posibilitan al relato poético acercarse a los territorios de lo mítico.

  12. Analysis of the Eye Diseases Screening Results of 933 Newborns by Ret Cam III%Ret CamⅢ筛查新生儿眼底病933例结果分析

    Institute of Scientific and Technical Information of China (English)

    陈刚; 杜梅; 李一青; 李梅君; 刘丽清

    2016-01-01

    Objective:To explore the application value of Ret Cam III in eye diseases screening in newborns, and to understand the oncome situation of fundus diseases for providing basis for the prevention and treatment of eye diseases in newborns. Methods: Ret Cam III was used to screen eye diseases in 933 newborns in this hospital from March 2015 to August 2015 and the discussion and analysis were carried out for the results. Results:87 cases of fundus diseases were detected among 933 newborns(9.32%), including 64 cases of fundus hemorrhage(6.86%);18 cases of retinopathy in premature infants(1.93%);5 cases of other eye diseases(0.54%);2 cases of optic atrophy(0.21%);2 cases of familial exudative vitreoretinopathy(0.21%);1 case of permanent hyaloid artery stump (0.11%). Conclusion:Because fundus diseases in newborns are not easy to be noticed at early stage, so it's necessary to pay attention to the screening, especially for the premature infants, and full term infants with high risk factors. Ret Cam III is easy to operate with wide range of observation, which is beneficial for promoting the diagnosis rate of fundus diseases in newborns, and for noticing and treating the diseases at early stage effectively.%目的:探讨Ret CamⅢ在新生儿眼底病筛查中的应用价值,了解新生儿眼底病发病情况,为新生儿眼病防治提供依据。方法:使用Ret CamⅢ对2015年3月至2015年8月生产及住院的933例新生儿进行眼病筛查,并对结果进行讨论分析。结果:933例新生儿中共检出眼底病变87例(占9.32%),其中眼底出血64例(占6.86%);早产儿视网膜病变18例(占1.93%);其他眼底病5例(占筛查总人数0.54%),其中视神经萎缩2例(占0.21%),家族渗出性玻璃体视网膜病变2例(占0.21%),永存性玻璃体动脉残留1例(占0.11%)。结论:新生儿眼底病早期可无明显症状,不易被发现,应重视早期筛查。早产儿及伴有高危因素的

  13. Diagnosis of retinoblastoma in early stage with RetCam Ⅱ: report of two cases%RetCamⅡ早期诊断视网膜母细胞瘤二例

    Institute of Scientific and Technical Information of China (English)

    王培锋; 李战; 殷纳新

    2011-01-01

    @@ 视网膜母细胞瘤(retinoblastoma,RB)是婴幼儿眼病中性质最严重、危害性最大的一种恶性肿瘤,其早期症状常易被忽视,大多数是在出现白瞳症等并发症时才发现.本院在使用RetCam Ⅱ进行新生儿眼底筛查时发现了2例RB,现报告如下.

  14. Una mirada desde la retórica aristotélica y la nueva retórica sobre el debate por la venta del reactor nuclear a Australia por parte de la empresa argentina INVAP

    OpenAIRE

    Fazio,María Eugenia

    2008-01-01

    En el presente trabajo se analizan dos discursos publicados en la Redes (Revista de estudios sobre ciencia y tecnología), con ocasión de la organización de un dossier dedicado al debate sobre la venta de un reactor nuclear a Australia por parte de la empresa argentina INVAP. Tomando como marco teórico la teoría clásica de la argumentación y la nueva retórica, se realiza una indagación en los textos centrada en la organización de las partes del discurso (dispositio), los hechos y las ver...

  15. Binding of inferred germline precursors of broadly neutralizing HIV-1 antibodies to native-like envelope trimers.

    Science.gov (United States)

    Sliepen, Kwinten; Medina-Ramírez, Max; Yasmeen, Anila; Moore, John P; Klasse, Per Johan; Sanders, Rogier W

    2015-12-01

    HIV-1 envelope glycoproteins (Env) and Env-based immunogens usually do not interact efficiently with the inferred germline precursors of known broadly neutralizing antibodies (bNAbs). This deficiency may be one reason why Env and Env-based immunogens are not efficient at inducing bNAbs. We evaluated the binding of 15 inferred germline precursors of bNAbs directed to different epitope clusters to three soluble native-like SOSIP.664 Env trimers. We found that native-like SOSIP.664 trimers bind to some inferred germline precursors of bNAbs, particularly ones involving the V1/V2 loops at the apex of the trimer. The data imply that native-like SOSIP.664 trimers will be an appropriate platform for structure-guided design improvements intended to create immunogens able to target the germline precursors of bNAbs.

  16. Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline

    DEFF Research Database (Denmark)

    Giannoulatou, Eleni; Maher, Geoffrey J; Ding, Zhihao

    2017-01-01

    Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover...

  17. Structural characterization and primary in vitro cell culture of locust male germline stem cells and their niche.

    Science.gov (United States)

    Dorn, David C; Dorn, August

    2011-03-01

    The establishment of in vitro culture systems to expand stem cells and to elucidate the niche/stem cell interaction is among the most sought-after culture systems of our time. To further investigate niche/stem cell interactions, we evaluated in vitro cultures of isolated intact male germline-niche complexes (i.e., apical complexes), complexes with empty niche spaces, and completely empty niches (i.e., isolated apical cells) from the testes of Locusta migratoria and the interaction of these complexes with isolated germline stem cells, spermatogonia (of transit-amplifying stages), cyst progenitor cells, cyst progenitor cell-like cells, cyst cells, and follicle envelope cells. The structural characteristics of these cell types allow the identification of the different cell types in primary cultures, which we studied in detail by light and electron microscopy. In intact testes germline stem cells strongly adhere to their niche (the apical cell), but emigrate from their niche and form filopodia if the apical complex is put into culture with "standard media." The lively movements of the long filopodia of isolated germline stem cells and spermatogonia may be indicative of their search for specific signals to home to their niche. All other incubated cell types (except for follicle envelope cells) expressed rhizopodia and lobopodia. Nevertheless isolated germline stem cells in culture do not migrate to empty niche spaces of nearby apical cells. This could indicate that apical cells lose their germline stem cell attracting ability in vitro, although apical cells devoid of germline stem cells either by emigration of germline stem cells or by mechanical removal of germline stem cells are capable of surviving in vitro up to 56 days, forming many small lobopodia and performing amoeboid movements. We hypothesize that the breakdown of the apical complex in vitro with standard media interrupts the signaling between the germline stem cells and the niche (and conceivably the cyst

  18. Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host.

    LENUS (Irish Health Repository)

    Gallagher, D J

    2013-09-01

    Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity.

  19. 甲状腺乳头状癌BRAF基因突变及RET/PTC基因重排与血小板源性生长因子B表达的相关性研究%The correlation between BRAF mutations, RET/PTC rearrangements and platelet-derived growth factor B expression in papillary thyroid carcinomas

    Institute of Scientific and Technical Information of China (English)

    王萍; 王颜刚; 赵文娟; 付浴东; 王娈; 王芳; 赵世华

    2012-01-01

    Objective To investigate the prevalence of BRAF T1799A mutation and RET/PTC rearrangement in Qingdao and detect the expression of platelet-derived growth factor B (PDGF-B) in order to investigate the correlation between gene mutation and PDGF-B.Methods Fresh tissue from 48 papillary thyroid carcinomas (PTC) patients was examined for BRAF mutation RET rearrangements (RET/PTC1 and RET/PTC3) by PCR,followed by direct-sequence analysis.The expression of PDGF was analyzed by immunohistochemistry.Results Among the 48 patients,14 (29.2%) were micro PTC; 18 (37.5%) had BRAF T1799A mutations and 23(47.9%) had RET/PTC rearrangement.There were 17 (35.4%) cases of RET/PTC1 and 6 (12.5%) of RET/PTC3,with no multiple rearrangements.Both BRAF T1799A mutation and RET/PTC rearrangement were present in 6 (12.5%) cases of non-micro PTC.The level of PDGF-B expression in BRAF T1799A positive was higher than that in the negative,and the level of PDGF-B expression in RET/PTC3 was higher than that in RET/PTC1 (P < 0.05).The more advanced neoplasm stage was,the stranger PDGF-B expression was.Conclusions The incidence of BRAF T1799A mutation and RET/PTC rearrangement is higher in Qingdao.BRAF T1799A mutation and RET/PTC3 rearrangement in patients suggests a poorer prognosis than the negative one.The BRAF T1799A mutation and RET/PTC3 rearrangement may strengthen the expression of PDGF-B.Both variations suggest a poor prognosis.%目的 观察青岛地区甲状腺乳头状癌(PTC) BRAF T1799A基因突变及RET/PTC基因重排的发生情况;检测癌组织中血小板源性生长因子B (PDGF-B)的表达,研究基因突变与PDGF-B的关系.方法 收集48例PTC患者新鲜PTC组织,采用PCR分别扩增BRAF、RET/PTC1、RET/PTC3基因,产物经测序证实.采用免疫组化方法检测肿瘤组织中PDGF-B的表达.结果 48例PTC中微小癌14例(29.2%);18例发生BRAF T1799A基因突变,突变率为37.5%;23例发生RET/PTC重排,重排率为47.9%,其中RET/PTC1

  20. An association of multiple endocrine neoplasia 2B, a RET mutation; constipation; and low substance P-nerve fiber density in colonic circular muscle.

    Science.gov (United States)

    King, Sebastian K; Southwell, Bridget R; Hutson, John M

    2006-02-01

    Multiple endocrine neoplasia (MEN) 2B is a rare hereditary syndrome that results from an activating mutation of the RET proto-oncogene. The RET gene is involved in the development of the enteric nervous system. Patients with MEN 2B have enlarged enteric ganglia and may be affected by gastrointestinal dysmotility. A deficiency of the neurotransmitter substance P (SP) has been identified in both pediatric and adult patients with chronic constipation. Three patients, in whom constipation was the presenting symptom and MEN 2B had been provisionally diagnosed, underwent genetic analysis. Seromuscular colonic biopsies were taken for immunofluorescence imaging in all 3 patients. A retrospective review of the patient notes was undertaken. All 3 patients had constipation refractory to conservative treatment. Genetic analyses in the 3 patients confirmed an identical RET mutation (Met918Thr). Immunofluorescence imaging in all 3 patients identified grossly enlarged myenteric plexus ganglia but surprisingly a low density of SP-labeled nerve fibers in the colonic circular muscle. Nitric oxide synthase and vasoactive intestinal peptide labeling were not reduced. The results show an association between MEN 2B and its most common RET mutation, colonic dysmotility, and low density of SP in the colonic circular muscle. Larger numbers of patients need to be studied to investigate whether low SP is primarily associated with the constipation or RET mutation and if it is a common feature of MEN 2B.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. GDNF selectively induces microglial activation and neuronal survival in CA1/CA3 hippocampal regions exposed to NMDA insult through Ret/ERK signalling.

    Directory of Open Access Journals (Sweden)

    Francesca Boscia

    Full Text Available The glial cell line-derived neurotrophic factor (GDNF is a potent survival factor for several neuronal populations in different brain regions, including the hippocampus. However, no information is available on the: (1 hippocampal subregions involved in the GDNF-neuroprotective actions upon excitotoxicity, (2 identity of GDNF-responsive hippocampal cells, (3 transduction pathways involved in the GDNF-mediated neuroprotection in the hippocampus. We addressed these questions in organotypic hippocampal slices exposed to GDNF in presence of N-methyl-D-aspartate (NMDA by immunoblotting, immunohistochemistry, and confocal analysis. In hippocampal slices GDNF acts through the activation of the tyrosine kinase receptor, Ret, without involving the NCAM-mediated pathway. Both Ret and ERK phosphorylation mainly occurred in the CA3 region where the two activated proteins co-localized. GDNF protected in a greater extent CA3 rather than CA1 following NMDA exposure. This neuroprotective effect targeted preferentially neurons, as assessed by NeuN staining. GDNF neuroprotection was associated with a significant increase of Ret phosphorylation in both CA3 and CA1. Interestingly, confocal images revealed that upon NMDA exposure, Ret activation occurred in microglial cells in the CA3 and CA1 following GDNF exposure. Collectively, this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF-induced Ret activation and neuroprotection, and suggest that, upon excitotoxicity, such neuroprotection involves a GDNF modulation of microglial cell activity.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma

    Indian Academy of Sciences (India)

    Xiao-Ping Qi; Rong-Xin Zhang; Jin-Lin Cao; Zhen-Guang Chen; Hang-Yang Jin; Ren-Rong Yang

    2014-06-01

    We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T > G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A > G (p.A45A), IVS4+48A >G, c. 1296A > G (p.A432A), c. 2071G > A (p.G691S), c. 2307T > G (p.L769L) and a variant c. 833C > A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.

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

    Directory of Open Access Journals (Sweden)

    Melissa L Williams

    2006-06-01

    Full Text Available BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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. Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma.

    Science.gov (United States)

    Sneddon, Sophie; Leon, Justine S; Dick, Ian M; Cadby, Gemma; Olsen, Nola; Brims, Fraser; Allcock, Richard J N; Moses, Eric K; Melton, Phillip E; de Klerk, Nicholas; Musk, A W Bill; Robinson, Bruce W S; Creaney, Jenette

    2015-05-25

    Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected individuals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.

  8. A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory.

    Science.gov (United States)

    Katz, David J; Edwards, T Matthew; Reinke, Valerie; Kelly, William G

    2009-04-17

    Epigenetic information undergoes extensive reprogramming in the germline between generations. This reprogramming may be essential to establish a developmental ground state in the zygote. We show that mutants in spr-5, the Caenorhabditis elegans ortholog of the H3K4me2 demethylase LSD1/KDM1, exhibit progressive sterility over many generations. This sterility correlates with the misregulation of spermatogenesis-expressed genes and transgenerational accumulation of the histone modification dimethylation of histone H3 on lysine 4 (H3K4me2). This suggests that H3K4me2 can serve as a stable epigenetic memory, and that erasure of H3K4me2 by LSD/KDM1 in the germline prevents the inappropriate transmission of this epigenetic memory from one generation to the next. Thus, our results provide direct mechanistic insights into the processes that are required for epigenetic reprogramming between generations.

  9. Cell-cycle quiescence maintains Caenorhabditis elegans germline stem cells independent of GLP-1/Notch.

    Science.gov (United States)

    Seidel, Hannah S; Kimble, Judith

    2015-11-09

    Many types of adult stem cells exist in a state of cell-cycle quiescence, yet it has remained unclear whether quiescence plays a role in maintaining the stem cell fate. Here we establish the adult germline of Caenorhabditis elegans as a model for facultative stem cell quiescence. We find that mitotically dividing germ cells--including germline stem cells--become quiescent in the absence of food. This quiescence is characterized by a slowing of S phase, a block to M-phase entry, and the ability to re-enter M phase rapidly in response to re-feeding. Further, we demonstrate that cell-cycle quiescence alters the genetic requirements for stem cell maintenance: The signaling pathway required for stem cell maintenance under fed conditions--GLP-1/Notch signaling--becomes dispensable under conditions of quiescence. Thus, cell-cycle quiescence can itself maintain stem cells, independent of the signaling pathway otherwise essential for such maintenance.

  10. Transcriptional signatures of somatic neoblasts and germline cells in Macrostomum lignano.

    Science.gov (United States)

    Grudniewska, Magda; Mouton, Stijn; Simanov, Daniil; Beltman, Frank; Grelling, Margriet; de Mulder, Katrien; Arindrarto, Wibowo; Weissert, Philipp M; van der Elst, Stefan; Berezikov, Eugene

    2016-12-20

    The regeneration-capable flatworm Macrostomum lignano is a powerful model organism to study the biology of stem cells in vivo. As a flatworm amenable to transgenesis, it complements the historically used planarian flatworm models, such as Schmidtea mediterranea. However, information on the transcriptome and markers of stem cells in M. lignano is limited. We generated a de novo transcriptome assembly and performed the first comprehensive characterization of gene expression in the proliferating cells of M. lignano, represented by somatic stem cells, called neoblasts, and germline cells. Knockdown of a selected set of neoblast genes, including Mlig-ddx39, Mlig-rrm1, Mlig-rpa3, Mlig-cdk1, and Mlig-h2a, confirmed their crucial role for the functionality of somatic neoblasts during homeostasis and regeneration. The generated M. lignano transcriptome assembly and gene expression signatures of somatic neoblasts and germline cells will be a valuable resource for future molecular studies in M. lignano.

  11. Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals

    Science.gov (United States)

    Bourassa, Cynthia V.; Lemieux Perreault, Louis-Philippe; Legault, Marc-André; Barhdadi, Amina; Ambalavanan, Amirthagowri; Brendgen, Mara; Vitaro, Frank; Noreau, Anne; Dionne, Ginette; Tremblay, Richard E.; Dion, Patrick A.; Boivin, Michel; Dubé, Marie-Pierre; Rouleau, Guy A.

    2016-01-01

    De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots. PMID:27723766

  12. Germline Transgenic Methods for Tracking Cells and Testing Gene Function during Regeneration in the Axolotl

    Science.gov (United States)

    Khattak, Shahryar; Schuez, Maritta; Richter, Tobias; Knapp, Dunja; Haigo, Saori L.; Sandoval-Guzmán, Tatiana; Hradlikova, Kristyna; Duemmler, Annett; Kerney, Ryan; Tanaka, Elly M.

    2013-01-01

    The salamander is the only tetrapod that regenerates complex body structures throughout life. Deciphering the underlying molecular processes of regeneration is fundamental for regenerative medicine and developmental biology, but the model organism had limited tools for molecular analysis. We describe a comprehensive set of germline transgenic strains in the laboratory-bred salamander Ambystoma mexicanum (axolotl) that open up the cellular and molecular genetic dissection of regeneration. We demonstrate tissue-dependent control of gene expression in nerve, Schwann cells, oligodendrocytes, muscle, epidermis, and cartilage. Furthermore, we demonstrate the use of tamoxifen-induced Cre/loxP-mediated recombination to indelibly mark different cell types. Finally, we inducibly overexpress the cell-cycle inhibitor p16INK4a, which negatively regulates spinal cord regeneration. These tissue-specific germline axolotl lines and tightly inducible Cre drivers and LoxP reporter lines render this classical regeneration model molecularly accessible. PMID:24052945

  13. Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function.

    Science.gov (United States)

    Chen, Yichang; Shu, Le; Qiu, Zhiqun; Lee, Dong Yeon; Settle, Sara J; Que Hee, Shane; Telesca, Donatello; Yang, Xia; Allard, Patrick

    2016-07-01

    Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures.

  14. Production of fat-1 transgenic rats using a post-natal female germline stem cell line.

    Science.gov (United States)

    Zhou, Li; Wang, Lei; Kang, Jing X; Xie, Wenhai; Li, Xiaoyong; Wu, Changqing; Xu, Bo; Wu, Ji

    2014-03-01

    Germline stem cell lines possess the abilities of self-renewal and differentiation, and have been established from both mouse and human ovaries. Here, we established a new female germline stem cell (FGSC) line from post-natal rats by immunomagnetic sorting for Fragilis, which showed a normal karyotype, high telomerase activity, and a consistent gene expression pattern of primordial germ cells after 1 year of culture. Using an in vitro differentiation system, the FGSC line could differentiate into oocytes. After liposome-based transfection with green fluorescent protein (GFP) or fat-1 vectors, the FGSCs were transplanted into the ovaries of infertile rats. The transplanted FGSCs underwent oogenesis, and the rats produced offspring carrying the GFP or fat-1 transgene after mating with wild-type male rats. The efficiency of gene transfer was 27.86-28.00%, and 2 months was needed to produce transgenic rats. These findings have implications in biomedical research and potential applications in biotechnology.

  15. Germline-transmitted genome editing in Arabidopsis thaliana Using TAL-effector-nucleases.

    Directory of Open Access Journals (Sweden)

    Joachim Forner

    Full Text Available Transcription activator-like effector nucleases (TALENs are custom-made bi-partite endonucleases that have recently been developed and applied for genome engineering in a wide variety of organisms. However, they have been only scarcely used in plants, especially for germline-modification. Here we report the efficient creation of small, germline-transmitted deletions in Arabidopsis thaliana via TALENs that were delivered by stably integrated transgenes. Using meristem specific promoters to drive expression of two TALEN arms directed at the CLV3 coding sequence, we observed very high phenotype frequencies in the T2 generation. In some instances, full CLV3 loss-of-function was already observed in the T1 generation, suggesting that transgenic delivery of TALENs can cause highly efficient genome modification. In contrast, constitutive TALEN expression in the shoot apical meristem (SAM did not cause additional phenotypes and genome re-sequencing confirmed little off-target effects, demonstrating exquisite target specificity.

  16. Germline-transmitted genome editing in Arabidopsis thaliana Using TAL-effector-nucleases.

    Science.gov (United States)

    Forner, Joachim; Pfeiffer, Anne; Langenecker, Tobias; Manavella, Pablo A; Manavella, Pablo; Lohmann, Jan U

    2015-01-01

    Transcription activator-like effector nucleases (TALENs) are custom-made bi-partite endonucleases that have recently been developed and applied for genome engineering in a wide variety of organisms. However, they have been only scarcely used in plants, especially for germline-modification. Here we report the efficient creation of small, germline-transmitted deletions in Arabidopsis thaliana via TALENs that were delivered by stably integrated transgenes. Using meristem specific promoters to drive expression of two TALEN arms directed at the CLV3 coding sequence, we observed very high phenotype frequencies in the T2 generation. In some instances, full CLV3 loss-of-function was already observed in the T1 generation, suggesting that transgenic delivery of TALENs can cause highly efficient genome modification. In contrast, constitutive TALEN expression in the shoot apical meristem (SAM) did not cause additional phenotypes and genome re-sequencing confirmed little off-target effects, demonstrating exquisite target specificity.

  17. Induction of Atherosclerosis in Mice and Hamsters Without Germline Genetic Engineering

    DEFF Research Database (Denmark)

    Bjørklund, Martin Mæng; Hollensen, Anne K; Hagensen, Mette K

    2014-01-01

    RATIONALE: Atherosclerosis can be achieved in animals by germline genetic engineering, leading to hypercholesterolemia, but such models are constrained to few species and strains, and they are difficult to combine with other powerful techniques involving genetic manipulation or variation. OBJECTIVE......: To develop a method for induction of atherosclerosis without germline genetic engineering. METHODS AND RESULTS: Recombinant adeno-associated viral vectors were engineered to encode gain-of-function proprotein convertase subtilisin/kexin type 9 mutants, and mice were given a single intravenous vector...... are a rapid and versatile method to induce atherosclerosis in animals. This method should prove useful for experiments that are high-throughput or involve genetic techniques, strains, or species that do not combine well with current genetically engineered models....

  18. Effective gene silencing in Drosophila ovarian germline by artificial microRNAs

    Institute of Scientific and Technical Information of China (English)

    Hailong Wang; YanJun Mu; Dahua Chen

    2011-01-01

    @@ Dear Editor, Drosophila oogenesis is of great interest because it represents an excellent model system to study a number of fascinating biological processes, such as stem cell regulation, germ cell meiosis and oocyte determination, as well as signal interactions between germline and soma.A typical Drosophila ovary is composed of 16-20 ovarioles, each consisting of an anterior functional unit called a germarium and a linear string of differentiated egg chambers posterior to the germarium [1] (Figure 1A and 1B).Drosophila oogenesis initiates at the tip of the germarium, when a germline stem cell (GSC) divides asymmetrically to generate a daughter GSC and a cystoblast that eventually develops into a mature egg [2] (Figure 1C and 1E).

  19. Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Generations.

    Science.gov (United States)

    Saben, Jessica L; Boudoures, Anna L; Asghar, Zeenat; Thompson, Alysha; Drury, Andrea; Zhang, Wendy; Chi, Maggie; Cusumano, Andrew; Scheaffer, Suzanne; Moley, Kelle H

    2016-06-28

    Maternal obesity impairs offspring health, but the responsible mechanisms are not fully established. To address this question, we fed female mice a high-fat/high-sugar diet from before conception until weaning and then followed the outcomes in the next three generations of offspring, all fed a control diet. We observed that female offspring born to obese mothers had impaired peripheral insulin signaling that was associated with mitochondrial dysfunction and altered mitochondrial dynamic and complex proteins in skeletal muscle. This mitochondrial phenotype persisted through the female germline and was passed down to the second and third generations. Our results indicate that maternal programming of metabolic disease can be passed through the female germline and that the transfer of aberrant oocyte mitochondria to subsequent generations may contribute to the increased risk for developing insulin resistance.

  20. Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Generations

    Directory of Open Access Journals (Sweden)

    Jessica L. Saben

    2016-06-01

    Full Text Available Maternal obesity impairs offspring health, but the responsible mechanisms are not fully established. To address this question, we fed female mice a high-fat/high-sugar diet from before conception until weaning and then followed the outcomes in the next three generations of offspring, all fed a control diet. We observed that female offspring born to obese mothers had impaired peripheral insulin signaling that was associated with mitochondrial dysfunction and altered mitochondrial dynamic and complex proteins in skeletal muscle. This mitochondrial phenotype persisted through the female germline and was passed down to the second and third generations. Our results indicate that maternal programming of metabolic disease can be passed through the female germline and that the transfer of aberrant oocyte mitochondria to subsequent generations may contribute to the increased risk for developing insulin resistance.

  1. Synchronous Onset of Breast and Pancreatic Cancers: Results of Germline and Somatic Genetic Analysis

    Directory of Open Access Journals (Sweden)

    Michael Castro

    2016-07-01

    Full Text Available Background: Synchronous cancers have occasionally been detected at initial diagnosis among patients with breast and ovarian cancer. However, simultaneous coexistence and diagnosis of breast and pancreas cancer has not previously been reported. Case Report: Paternal transmission of a germline BRCA2 mutation to a patient who was diagnosed at age 40 with locally advanced breast and pancreas cancer is presented. Somatic genomic analysis of both cancers with next-generation DNA sequencing confirmed the germline result and reported a variety of variants of unknown significance alterations, of which two were present in both the breast and pancreas cancers. Discussion: The possibility that genomic alterations could have been responsible for modulating the phenotypic or clinical expression of this rare presentation is considered. The authors call attention to the practice of privatizing the clinicogenetic information gained from genetic testing and call for health policy that will facilitate sharing in order to advance the outcomes of patients diagnosed with hereditary cancers.

  2. High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells

    Science.gov (United States)

    Pech, Matthew F.; Garbuzov, Alina; Hasegawa, Kazuteru; Sukhwani, Meena; Zhang, Ruixuan J.; Benayoun, Bérénice A.; Brockman, Stephanie A.; Lin, Shengda; Brunet, Anne; Orwig, Kyle E.; Artandi, Steven E.

    2015-01-01

    Telomerase inactivation causes loss of the male germline in worms, fish, and mice, indicating a conserved dependence on telomere maintenance in this cell lineage. Here, using telomerase reverse transcriptase (Tert) reporter mice, we found that very high telomerase expression is a hallmark of undifferentiated spermatogonia, the mitotic population where germline stem cells reside. We exploited these high telomerase levels as a basis for purifying undifferentiated spermatogonia using fluorescence-activated cell sorting. Telomerase levels in undifferentiated spermatogonia and embryonic stem cells are comparable and much greater than in somatic progenitor compartments. Within the germline, we uncovered an unanticipated gradient of telomerase activity that also enables isolation of more mature populations. Transcriptomic comparisons of TertHigh undifferentiated spermatogonia and TertLow differentiated spermatogonia by RNA sequencing reveals marked differences in cell cycle and key molecular features of each compartment. Transplantation studies show that germline stem cell activity is confined to the TertHigh cKit− population. Telomere shortening in telomerase knockout strains causes depletion of undifferentiated spermatogonia and eventual loss of all germ cells after undifferentiated spermatogonia drop below a critical threshold. These data reveal that high telomerase expression is a fundamental characteristic of germline stem cells, thus explaining the broad dependence on telomerase for germline immortality in metazoans. PMID:26584619

  3. ELLI-1, a novel germline protein, modulates RNAi activity and P-granule accumulation in Caenorhabditis elegans.

    Science.gov (United States)

    Andralojc, Karolina M; Campbell, Anne C; Kelly, Ashley L; Terrey, Markus; Tanner, Paige C; Gans, Ian M; Senter-Zapata, Michael J; Khokhar, Eraj S; Updike, Dustin L

    2017-02-01

    Germ cells contain non-membrane bound cytoplasmic organelles that help maintain germline integrity. In C. elegans they are called P granules; without them, the germline undergoes partial masculinization and aberrant differentiation. One key P-granule component is the Argonaute CSR-1, a small-RNA binding protein that antagonizes accumulation of sperm-specific transcripts in developing oocytes and fine-tunes expression of proteins critical to early embryogenesis. Loss of CSR-1 complex components results in a very specific, enlarged P-granule phenotype. In a forward screen to identify mutants with abnormal P granules, ten alleles were recovered with a csr-1 P-granule phenotype, eight of which contain mutations in known components of the CSR-1 complex (csr-1, ego-1, ekl-1, and drh-3). The remaining two alleles are in a novel gene now called elli-1 (enlarged germline granules). ELLI-1 is first expressed in primordial germ cells during mid-embryogenesis, and continues to be expressed in the adult germline. While ELLI-1 forms cytoplasmic aggregates, they occasionally dock, but do not co-localize with P granules. Instead, the majority of ELLI-1 aggregates accumulate in the shared germline cytoplasm. In elli-1 mutants, several genes that promote RNAi and P-granule accumulation are upregulated, and embryonic lethality, sterility, and RNAi resistance in a hypomorphic drh-3 allele is enhanced, suggesting that ELLI-1 functions with CSR-1 to modulate RNAi activity, P-granule accumulation, and post-transcriptional expression in the germline.

  4. Creatividad publicitaria y retórica. De la metáfora a los efectos especiales

    Directory of Open Access Journals (Sweden)

    Isidoro Arroyo Almaraz

    2012-04-01

    Full Text Available La Creatividad Publicitaria y la Retórica comparten elementos comunes. En este artículo, veremos cómo estas dos materias, con muchos siglos de existencia, abren nuevas vías de investigación. Las ideas se representan verbal y visualmente a través de los distintos lenguajes. Su agrupación en palabras y oraciones, imágenes y planos , efectos especiales conforman mensajes publicitarios cuyo objetivo principal es persuadir al consumidor para ser leídas, oídas, vistas y recordadas en imágenes mentales.

  5. A retórica do oprórbiu ou sobre as sentenças de Ccantemir

    Directory of Open Access Journals (Sweden)

    Laura Bădescu

    2009-11-01

    Full Text Available Dimitrie Cantemir foi o primeiro grande vulto da cultura romena. Extraordinário poliglota (falava turco, russo, latim, grego, francês, etc., o Príncipe Dimitrie Cantemir conseguiu obter o título de membro da Academia de Berlim, demonstrando assim as suas excepcionais qualidades científica.A História dos hieróglifos aparece como um precioso documento para conhecer a evolução da retórica aplicada à literatura romena. O uso das cartas e dos provérbios indica a dimensão perene do facto literário e, simultaneamente, confirma o estatuto de “obra aberta” atribuído à História dos hieróglifos. Ainda mais, a retórica das sentenças é utilizada como uma estratégia necessária numa certa idade do épico. È uma lição apreendida com Quintilianus, que afirmava que as obras históricas, através do que dizem, fazem parte da retórica.Tentamos comprovar a existência de uma retórica da culpa, expressa através das sentenças inseridas. Do ponto de vista das inserções, a conexão por concatenação torna-se, deste modo, válida. Huizinga falava da visão unitária que existia na época medieval no que respeita os provérbios, salientando os sobre a ironia, a resignação, a passividade, etc. Sem impor essas atitudes, o discurso sentencial de Cantemir as subsome, privilegiando assim a autoridade do historiador. A batalha do Unicórnio tem desta forma possibilidade de êxito no plano da verdade inexpugnável, porque o discurso, uma vez fixado pela sentença, se fecha sobre si mesmo, formulando a demonstração em termos éticos.

  6. El juego del Apocalipsis. Un viaje a Patmos, de Jorge Volpi. Una lectura desde la retórica

    Directory of Open Access Journals (Sweden)

    Luis Quintana-Tejera

    2014-01-01

    Full Text Available En esta novela de Jorge Volpi descubrimos la gran capacidad del narrador para usar distintos recursos estilísticos, entre los que encontramos la presencia de una historia omnisciente, el juego de espejos y los constantes giros retóricos. Los elementos intertextuales también son importantes, desta - ca sobre todo la isla de Patmos como trasfondo de la narración del Apocalip - sis en el Nuevo Testamento, y que también será el sitio donde se lleven a cabo las acciones de la novela analizada.

  7. 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...

  8. Germ-line Gene Editing: What are the Social and Moral Risks?

    OpenAIRE

    Sutton, Agneta

    2016-01-01

    Should we welcome all developments in gene editing? Somatic cell gene editing would be on a par with conventional therapies aimed at treating particular conditions or alleviating symptoms. It would solely affect the individual patient treated. It could thus serve as a welcome new kind of treatment for cancers and blood diseases such as ß-thalassaemia. Germ-line gene editing, on the other hand, would have hereditary effects. This raises special concerns about medical mishaps. Medical risks are...

  9. Male and female Drosophila germline stem cells: two versions of immortality.

    Science.gov (United States)

    Fuller, Margaret T; Spradling, Allan C

    2007-04-20

    Drosophila male and female germline stem cells (GSCs) are sustained by niches and regulatory pathways whose common principles serve as models for understanding mammalian stem cells. Despite striking cellular and genetic similarities that suggest a common evolutionary origin, however, male and female GSCs also display important differences. Comparing these two stem cells and their niches in detail is likely to reveal how a common heritage has been adapted to the differing requirements of male and female gamete production.

  10. A germline-centric view of cell fate commitment, reprogramming and immortality.

    Science.gov (United States)

    Torres-Padilla, Maria-Elena; Ciosk, Rafal

    2013-02-01

    To ensure species continuity, the tantalising developmental plasticity of early embryonic cells, also called totipotency, must be transmitted to the offspring. This responsibility rests within the reproductive cell lineage: the germ line. At the recent EMBO/EMBL symposium 'Germline - Immortality through Totipotency', researchers discussed the mechanisms that establish and control totipotency, with an eye towards the mechanisms that may endow germ cells with the ability to propagate totipotency across generations.

  11. Report of 16 kindreds and one kindred with hMLH1 germline mutation

    Institute of Scientific and Technical Information of China (English)

    Bo Zhao; Zhen-Jun Wang; Yu-Feng Xu; Yuan-Lian Wan; Peng Li; Yan-Ting Huang

    2002-01-01

    AIM: To analyze the diagnosis and treatment of 16 hereditarynonpolyposis colorectal cancer (HNPCC) kindreds, and toreport the first kindred with hMLH1 germline mutation inMainland China.METHODS: The diagnosis, treatment and follow-up study of16 HNPCC kindreds were retrospectively reviewed. Dataconceming site of the malignant tumor, age st the diagnosis,history of synchronous and/ or metachronous cancer, andhistopathology of tumors were recorded. All treatments hadwon formal consent. PCR and SSCP were used to screen thecoding region of hMLH1 and hMSH2 genes. Variant bandswere sequenced by a 377 DNA sequencer.RESULTS: Among sixteen kindreds, sixty-eight patients hada mean age of 50.8 years, including twenty-one multiplecancer patients and forty-six colorectal cancer patients(metachronous colorectal cancers in sixteen). A total of onehundred and one malignant neoplasms were found in thesesixty-eight patients, including 50 colonic, 17 rectal, 11gastric, 7 endometrial, and 4 esophageal cancers. 39.5%colorectal patients had metachronous cancers within tenyears who needed reopeertions. A germline G265T nonsensemutation was found in the third exon of hMLH1, resulting in astop codon and truncated protein. Three phenotypically normalfamily members were also found to carry the mutated gene.ONCLUSION: HNPCC is a typical auto-dominant hereditaryisease, the main characteristics include early onset andfrequency of cancers; predominance of colorectal,especially right-sided colon cancers; frequency of multipleprimary cancers (especially colorectal cancers). Segmentalresection for colorectal cancers is not eligible for colorectalcancer patient in HNPCC kindreds. Intensive follow-up isessential for all patients and possible gene carriers. The firstHNPCC kindred with hMUH1 gene germline mutation wasidentified in Mainland China, and three phenotypicallynormal family members were found to be carriers of themutated gene. The G265T germline (nonsense) mutation inthe third exon of hMLH1

  12. Meiotic silencing and fragmentation of the male germline restricted chromosome in zebra finch.

    Science.gov (United States)

    Schoenmakers, Sam; Wassenaar, Evelyne; Laven, Joop S E; Grootegoed, J Anton; Baarends, Willy M

    2010-06-01

    During male meiotic prophase in mammals, X and Y are in a largely unsynapsed configuration, which is thought to trigger meiotic sex chromosome inactivation (MSCI). In avian species, females are ZW, and males ZZ. Although Z and W in chicken oocytes show complete, largely heterologous synapsis, they too undergo MSCI, albeit only transiently. The W chromosome is already inactive in early meiotic prophase, and inactive chromatin marks may spread on to the Z upon synapsis. Mammalian MSCI is considered as a specialised form of the general meiotic silencing mechanism, named meiotic silencing of unsynapsed chromatin (MSUC). Herein, we studied the avian form of MSUC, by analysing the behaviour of the peculiar germline restricted chromosome (GRC) that is present as a single copy in zebra finch spermatocytes. In the female germline, this chromosome is present in two copies, which normally synapse and recombine. In contrast, during male meiosis, the single GRC is always eliminated. We found that the GRC in the male germline is silenced from early leptotene onwards, similar to the W chromosome in avian oocytes. The GRC remains largely unsynapsed throughout meiotic prophase I, although patches of SYCP1 staining indicate that part of the GRC may self-synapse. In addition, the GRC is largely devoid of meiotic double strand breaks. We observed a lack of the inner centromere protein INCENP on the GRC and elimination of the GRC following metaphase I. Subsequently, the GRC forms a micronucleus in which the DNA is fragmented. We conclude that in contrast to MSUC in mammals, meiotic silencing of this single chromosome in the avian germline occurs prior to, and independent of DNA double strand breaks and chromosome pairing, hence we have named this phenomenon meiotic silencing prior to synapsis (MSPS).

  13. Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

    OpenAIRE

    Rodríguez-Soler, María; Pérez-Carbonell, Lucía; Guarinos, Carla; Zapater, Pedro; Castillejo, Adela; Barberá, Víctor Manuel; Juárez, Miriam; Bessa, Xavier; Xicola, Rosa M; Clofent, Juan; Bujanda, Luis; Balaguer, Francesc; Reñé, Josep-Maria; de Castro, Luisa; Marín-Gabriel, José C.

    2013-01-01

    Background & Aims: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. Methods: We studied a population...

  14. High Throughput Sequencing of Germline and Tumor from Men With Early-Onset Metastatic Prostate Cancer

    Science.gov (United States)

    2014-10-01

    challenge, Dr. Tomlins has continued to develop state of the art technologies to use formalin-fixed paraffin-embedded (FFPE) prostate cancer specimens...men with early-onset, metastatic prostate cancer PRINCIPAL INVESTIGATOR: Kathleen A. Cooney, M.D. CONTRACTING ORGANIZATION...High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-13-1-0371 5c

  15. HABP2 germline variants are uncommon in familial nonmedullary thyroid cancer

    OpenAIRE

    Weeks, Alexia L.; Scott G Wilson; Ward, Lynley; Goldblatt, Jack; Hui, Jennie; Walsh, John P.

    2016-01-01

    Background The genetic basis of nonsyndromic familial nonmedullary thyroid cancer (FNMTC) is poorly understood. A recent study identified HABP2 as a tumor suppressor gene and identified a germline variant (G534E) in an extended FNMTC kindred. The relevance of this to other FNMTC kindreds is uncertain. Methods Sanger sequencing was performed on peripheral blood DNA from probands from 37 Australian FNMTC kindreds to detect the G534E variant. Whole exome data from 59 participants from 20 kindred...

  16. Protein phosphatase 1ß limits ring canal constriction during Drosophila germline cyst formation.

    Science.gov (United States)

    Yamamoto, Shinya; Bayat, Vafa; Bellen, Hugo J; Tan, Change

    2013-01-01

    Germline cyst formation is essential for the propagation of many organisms including humans and flies. The cytoplasm of germline cyst cells communicate with each other directly via large intercellular bridges called ring canals. Ring canals are often derived from arrested contractile rings during incomplete cytokinesis. However how ring canal formation, maintenance and growth are regulated remains unclear. To better understand this process, we carried out an unbiased genetic screen in Drosophila melanogaster germ cells and identified multiple alleles of flapwing (flw), a conserved serine/threonine-specific protein phosphatase. Flw had previously been reported to be unnecessary for early D. melanogaster oogenesis using a hypomorphic allele. We found that loss of Flw leads to over-constricted nascent ring canals and subsequently tiny mature ring canals, through which cytoplasmic transfer from nurse cells to the oocyte is impaired, resulting in small, non-functional eggs. Flw is expressed in germ cells undergoing incomplete cytokinesis, completely colocalized with the Drosophila myosin binding subunit of myosin phosphatase (DMYPT). This colocalization, together with genetic interaction studies, suggests that Flw functions together with DMYPT to negatively regulate myosin activity during ring canal formation. The identification of two subunits of the tripartite myosin phosphatase as the first two main players required for ring canal constriction indicates that tight regulation of myosin activity is essential for germline cyst formation and reproduction in D. melanogaster and probably other species as well.

  17. Protein phosphatase 1ß limits ring canal constriction during Drosophila germline cyst formation.

    Directory of Open Access Journals (Sweden)

    Shinya Yamamoto

    Full Text Available Germline cyst formation is essential for the propagation of many organisms including humans and flies. The cytoplasm of germline cyst cells communicate with each other directly via large intercellular bridges called ring canals. Ring canals are often derived from arrested contractile rings during incomplete cytokinesis. However how ring canal formation, maintenance and growth are regulated remains unclear. To better understand this process, we carried out an unbiased genetic screen in Drosophila melanogaster germ cells and identified multiple alleles of flapwing (flw, a conserved serine/threonine-specific protein phosphatase. Flw had previously been reported to be unnecessary for early D. melanogaster oogenesis using a hypomorphic allele. We found that loss of Flw leads to over-constricted nascent ring canals and subsequently tiny mature ring canals, through which cytoplasmic transfer from nurse cells to the oocyte is impaired, resulting in small, non-functional eggs. Flw is expressed in germ cells undergoing incomplete cytokinesis, completely colocalized with the Drosophila myosin binding subunit of myosin phosphatase (DMYPT. This colocalization, together with genetic interaction studies, suggests that Flw functions together with DMYPT to negatively regulate myosin activity during ring canal formation. The identification of two subunits of the tripartite myosin phosphatase as the first two main players required for ring canal constriction indicates that tight regulation of myosin activity is essential for germline cyst formation and reproduction in D. melanogaster and probably other species as well.

  18. Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene.

    Science.gov (United States)

    Hirota, Seiichi; Nishida, Toshirou; Isozaki, Koji; Taniguchi, Masahiko; Nishikawa, Kazuhiro; Ohashi, Akiko; Takabayashi, Arimichi; Obayashi, Tadashi; Okuno, Tomoko; Kinoshita, Kazuo; Chen, Hui; Shinomura, Yasuhisa; Kitamura, Yukihiko

    2002-05-01

    A family with multiple gastrointestinal stromal tumors (GISTs), a new type of germline mutation of KIT gene, and dysphagia is reported. The mutation was observed at Asp-820 in tyrosine kinase (TK) II domain. Mutations in TK II domain have been found in mast cell and germ cell tumors but not in GISTs, and the present family members are the first reported cases of GISTs with TK II domain mutations, including sporadic GISTs. Because interleukin 3-dependent Ba/F3 murine lymphoid cells transfected with the mutant KIT complementary DNA grew autonomously without any growth factors and formed tumors in nude mice, the mutation was considered to be gain-of-function type. Family members with the germline KIT mutation reported dysphagia, but those without the mutation did not. The mechanism of dysphagia was examined with gastrointestinal fiberscopy, endoscopic ultrasonography, and esophageal manometry. No mechanical obstruction was found, and the esophagus was not remarkably dilated. In the family members with dysphagia, endoscopic ultrasonography at the esophagocardiac junction showed a thickened hyperechoic layer between the circular and longitudinal muscle layers, suggesting hyperplasia of interstitial cells of Cajal at the myenteric plexus layer. Manometry showed low resting lower esophageal sphincter pressure and abnormal simultaneous contractions of the esophagus without normal peristalsis. These findings indicate that the dysphagia of the present family is different from typical achalasia. This is the first report of familial dysphagia caused by germline gain-of-function mutation of the KIT gene at the TK II domain.

  19. MORC-1 Integrates Nuclear RNAi and Transgenerational Chromatin Architecture to Promote Germline Immortality.

    Science.gov (United States)

    Weiser, Natasha E; Yang, Danny X; Feng, Suhua; Kalinava, Natallia; Brown, Kristen C; Khanikar, Jayshree; Freeberg, Mallory A; Snyder, Martha J; Csankovszki, Györgyi; Chan, Raymond C; Gu, Sam G; Montgomery, Taiowa A; Jacobsen, Steven E; Kim, John K

    2017-05-22

    Germline-expressed endogenous small interfering RNAs (endo-siRNAs) transmit multigenerational epigenetic information to ensure fertility in subsequent generations. In Caenorhabditis elegans, nuclear RNAi ensures robust inheritance of endo-siRNAs and deposition of repressive H3K9me3 marks at target loci. How target silencing is maintained in subsequent generations is poorly understood. We discovered that morc-1 is essential for transgenerational fertility and acts as an effector of endo-siRNAs. Unexpectedly, morc-1 is dispensable for siRNA inheritance but is required for target silencing and maintenance of siRNA-dependent chromatin organization. A forward genetic screen identified mutations in met-1, which encodes an H3K36 methyltransferase, as potent suppressors of morc-1(-) and nuclear RNAi mutant phenotypes. Further analysis of nuclear RNAi and morc-1(-) mutants revealed a progressive, met-1-dependent enrichment of H3K36me3, suggesting that robust fertility requires repression of MET-1 activity at nuclear RNAi targets. Without MORC-1 and nuclear RNAi, MET-1-mediated encroachment of euchromatin leads to detrimental decondensation of germline chromatin and germline mortality. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Comprehensive assessment of germline chemical toxicity using the nematode Caenorhabditis elegans.

    Science.gov (United States)

    Parodi, Daniela A; Damoiseaux, Robert; Allard, Patrick

    2015-02-22

    Identifying the reproductive toxicity of the thousands of chemicals present in our environment has been one of the most tantalizing challenges in the field of environmental health. This is due in part to the paucity of model systems that can (1) accurately recapitulate keys features of reproductive processes and (2) do so in a medium- to high-throughput fashion, without the need for a high number of vertebrate animals. We describe here an assay in the nematode C. elegans that allows the rapid identification of germline toxicants by monitoring the induction of aneuploid embryos. By making use of a GFP reporter line, errors in chromosome segregation resulting from germline disruption are easily visualized and quantified by automated fluorescence microscopy. Thus the screening of a particular set of compounds for its toxicity can be performed in a 96- to 384-well plate format in a matter of days. Secondary analysis of positive hits can be performed to determine whether the chromosome abnormalities originated from meiotic disruption or from early embryonic chromosome segregation errors. Altogether, this assay represents a fast first-pass strategy for the rapid assessment of germline dysfunction following chemical exposure.

  1. Fitness loss and germline mutations in barn swallows breeding in Chernobyl

    Energy Technology Data Exchange (ETDEWEB)

    Ellegren, Hans; Lindgren, Gabriella; Primmer, C.R. [Swedish Univ. of Agricultural Sciences, Animal Breeding and Genetics Dept., Uppsala (Sweden); Moeller, A.P. [Universite Pierre et Marie Curie. Lab. d`Ecologie, Paris, 75 (France)

    1997-10-09

    The severe nuclear accident at Chernobyl in 1986 resulted in the worst reported accidental exposure of radioactive material to free-living organisms. Short-term effects on human populations inhabiting polluted areas include increased incidence of thyroid cancer, infant leukaemia, and congenital malformations in newborns. Two recent studies have reported, although with some controversy, that germline mutation rates were increased in humans and voles living close to Chernobyl, but little is known about the viability of the organisms affected. Here we report an increased frequency of partial albinism, a morphological aberration associated with a loss of fitness, among barn swallows, Hirundo rustica, breeding close to Chernobyl. Heretability estimates indicate that mutations causing albinism were at least partly of germline origin. Furthermore, evidence for an increased germline mutation rate was obtained from segregation analysis at two hypervariable microsatellite loci, indicating that mutation events in barn swallows from Chernobyl were two- to tenfold higher than in birds from control areas in Ukraine and Italy. (author).

  2. A germline polymorphism of DNA polymerase beta induces genomic instability and cellular transformation.

    Directory of Open Access Journals (Sweden)

    Jennifer Yamtich

    Full Text Available Several germline single nucleotide polymorphisms (SNPs have been identified in the POLB gene, but little is known about their cellular and biochemical impact. DNA Polymerase β (Pol β, encoded by the POLB gene, is the main gap-filling polymerase involved in base excision repair (BER, a pathway that protects the genome from the consequences of oxidative DNA damage. In this study we tested the hypothesis that expression of the POLB germline coding SNP (rs3136797 in mammalian cells could induce a cancerous phenotype. Expression of this SNP in both human and mouse cells induced double-strand breaks, chromosomal aberrations, and cellular transformation. Following treatment with an alkylating agent, cells expressing this coding SNP accumulated BER intermediate substrates, including single-strand and double-strand breaks. The rs3136797 SNP encodes the P242R variant Pol β protein and biochemical analysis showed that P242R protein had a slower catalytic rate than WT, although P242R binds DNA similarly to WT. Our results suggest that people who carry the rs3136797 germline SNP may be at an increased risk for cancer susceptibility.

  3. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations.

    Science.gov (United States)

    Snow, Andrew L; Xiao, Wenming; Stinson, Jeffrey R; Lu, Wei; Chaigne-Delalande, Benjamin; Zheng, Lixin; Pittaluga, Stefania; Matthews, Helen F; Schmitz, Roland; Jhavar, Sameer; Kuchen, Stefan; Kardava, Lela; Wang, Wei; Lamborn, Ian T; Jing, Huie; Raffeld, Mark; Moir, Susan; Fleisher, Thomas A; Staudt, Louis M; Su, Helen C; Lenardo, Michael J

    2012-11-19

    Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions, but constitutive NF-κB activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)-induced NF-κB activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-κB activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.

  4. Germline allele-specific expression of DAPK1 in chronic lymphocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Quan-Xiang Wei

    Full Text Available We previously reported a rare germline variant (c.1-6531 that resulted in allele-specific expression (ASE of death-associated protein kinase 1 (DAPK1 and predisposition to chronic lymphocytic leukemia (CLL. We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE with MALDI-TOF mass spectrometry, and detected germline DAPK1 ASE in 17 out of 120 (14.2% CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the DAPK1 5' upstream regulatory region, within distinct exons or in the 3'-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL.

  5. Establishment of Germ-line Competent C57BL/6J Embryonic Stem Cell Lines

    Institute of Scientific and Technical Information of China (English)

    Gui-jun YAN; Zheng GU; Jian WANG; Jia-ke TSO

    2004-01-01

    Objective To establish C57BL/6J embryonic stem (ES) cell lines with potential germline contribution Methods ES cells were isolated from blastocyst inner cell mass of C57BL/6J mice, and cultured for 15 passages, and then injected into blastococels of lCR mice blastocysts to establish chimeric mice.Results Three ES cell lines (mC57ESl,mC57ES3, mC57ES7) derived from the inner cell mass of C57BL/6J mice blastocysts were established. They were characteristic of undifferentiated state, including normal XY karyotype, expression of a specific cell surface marker "stage-specific embryonic antigen-1" and alkaline phosphatase in continuous passage. When injected into immunodeficient mice, mC5 7ES1 cells consis tently differentiated into derivatives of all three embryonic germ layers. When mC57ES1cells were transferred into ICR mice blastocysts, 4 chimeric mice have been obtained.One male of them revealed successful germ-line transmission. Conclussion We have obtained C57BL/6J ES cell lines with a potential germ-line contribution, which can be used to generate transgenic and gene knock-out mice.

  6. Aspirin increases metabolism through germline signalling to extend the lifespan of Caenorhabditis elegans.

    Science.gov (United States)

    Huang, Xiao-Bing; Mu, Xiao-Hui; Wan, Qin-Li; He, Xiao-Ming; Wu, Gui-Sheng; Luo, Huai-Rong

    2017-01-01

    Aspirin is a prototypic cyclooxygenase inhibitor with a variety of beneficial effects on human health. It prevents age-related diseases and delays the aging process. Previous research has shown that aspirin might act through a dietary restriction-like mechanism to extend lifespan. To explore the mechanism of action of aspirin on aging, we determined the whole-genome expression profile of Caenorhabditis elegans treated with aspirin. Transcriptome analysis revealed the RNA levels of genes involved in metabolism were primarily increased. Reproduction has been reported to be associated with metabolism. We found that aspirin did not extend the lifespan or improve the heat stress resistance of germline mutants of glp-1. Furthermore, Oil Red O staining showed that aspirin treatment decreased lipid deposition and increased expression of lipid hydrolysis and fatty acid β-oxidation-related genes. The effect of germline ablation on lifespan was mainly mediated by DAF-12 and DAF-16. Next, we performed genetic analysis with a series of worm mutants and found that aspirin did not further extend the lifespans of daf-12 and daf-16 single mutants, glp-1;daf-12 and glp-1;daf-16 double mutants, or glp-1;daf-12;daf-16 triple mutants. The results suggest that aspirin increase metabolism and regulate germline signalling to activate downstream DAF-12 and DAF-16 to extend lifespan.

  7. The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer

    Science.gov (United States)

    Esteban-Jurado, Clara; Franch-Expósito, Sebastià; Muñoz, Jenifer; Ocaña, Teresa; Carballal, Sabela; López-Cerón, Maria; Cuatrecasas, Miriam; Vila-Casadesús, Maria; Lozano, Juan José; Serra, Enric; Beltran, Sergi; Brea-Fernández, Alejandro; Ruiz-Ponte, Clara; Castells, Antoni; Bujanda, Luis; Garre, Pilar; Caldés, Trinidad; Cubiella, Joaquín; Balaguer, Francesc; Castellví-Bel, Sergi

    2016-01-01

    Colorectal cancer (CRC) is one of the most common neoplasms in the world. Fanconi anemia (FA) is a very rare genetic disease causing bone marrow failure, congenital growth abnormalities and cancer predisposition. The comprehensive FA DNA damage repair pathway requires the collaboration of 53 proteins and it is necessary to restore genome integrity by efficiently repairing damaged DNA. A link between FA genes in breast and ovarian cancer germline predisposition has been previously suggested. We selected 74 CRC patients from 40 unrelated Spanish families with strong CRC aggregation compatible with an autosomal dominant pattern of inheritance and without mutations in known hereditary CRC genes and performed germline DNA whole-exome sequencing with the aim of finding new candidate germline predisposition variants. After sequencing and data analysis, variant prioritization selected only those very rare alterations, producing a putative loss of function and located in genes with a role compatible with cancer. We detected an enrichment for variants in FA DNA damage repair pathway genes in our familial CRC cohort as 6 families carried heterozygous, rare, potentially pathogenic variants located in BRCA2/FANCD1, BRIP1/FANCJ, FANCC, FANCE and REV3L/POLZ. In conclusion, the FA DNA damage repair pathway may play an important role in the inherited predisposition to CRC. PMID:27165003

  8. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma.

    Science.gov (United States)

    Betti, Marta; Casalone, Elisabetta; Ferrante, Daniela; Aspesi, Anna; Morleo, Giulia; Biasi, Alessandra; Sculco, Marika; Mancuso, Giuseppe; Guarrera, Simonetta; Righi, Luisella; Grosso, Federica; Libener, Roberta; Pavesi, Mansueto; Mariani, Narciso; Casadio, Caterina; Boldorini, Renzo; Mirabelli, Dario; Pasini, Barbara; Magnani, Corrado; Matullo, Giuseppe; Dianzani, Irma

    2017-10-01

    Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p = 0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  9. BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing

    Science.gov (United States)

    Mafficini, Andrea; Simbolo, Michele; Parisi, Alice; Rusev, Borislav; Luchini, Claudio; Cataldo, Ivana; Piazzola, Elena; Sperandio, Nicola; Turri, Giona; Franchi, Massimo; Tortora, Giampaolo; Bovo, Chiara; Lawlor, Rita T.; Scarpa, Aldo

    2016-01-01

    BRCA mutated ovarian cancers respond better to platinum-based therapy and to the recently approved PARP-inhibitors. There is the need for efficient and timely methods to detect both somatic and germline mutations using formalin-fixed paraffin-embedded (FFPE) tissues and commercially available technology. We used a commercial kit exploring all exons and 50bp exon-intron junctions of BRCA1 and BRCA2 genes, and semiconductor next-generation sequencing (NGS) on DNA from 47 FFPE samples of high-grade serous ovarian cancers. Pathogenic mutations were found in 13/47 (28%) cancers: eight in BRCA1 and five in BRCA2. All BRCA1 and two BRCA2 mutations were germline; three BRCA2 mutations were somatic. All mutations were confirmed by Sanger sequencing. To evaluate the performance of the NGS panel, we assessed its capability to detect the 6,953 variants described for BRCA1 and BRCA2 in ClinVar and COSMIC databases using callability analysis. 6,059 (87.1%) variants were identified automatically by the software; 829 (12.0%) required visual verification. The remaining 65 (0.9%) variants were uncallable, and would require 15 Sanger reactions to be resolved. Thus, the sensitivity of the NGS-panel was 99.1%. In conclusion, NGS performed with a commercial kit is highly efficient for detection of germline and somatic mutations in BRCA genes using routine FFPE tissue. PMID:26745875

  10. Proven germline mosaicism in a father of two children with CHARGE syndrome.

    Science.gov (United States)

    Pauli, S; Pieper, L; Häberle, J; Grzmil, P; Burfeind, P; Steckel, M; Lenz, U; Michelmann, H W

    2009-05-01

    CHARGE syndrome is an autosomal dominant malformation syndrome caused by mutations in the CHD7 gene. The majority of cases are sporadic and only few familial cases have been reported. In these families, mosaicism in one parent, as well as parent- to-child transmission of a CHD7 mutation, has been described. In some further cases, germline mosaicism has been suggested. Here, we report the first case in which germline mosaicism could be demonstrated in a father of two affected children with CHARGE syndrome. The truncating mutation c.7302dupA in exon 34 of the CHD7 gene was found in both affected children but was not detected in parental lymphocytes. However, in DNA extracted from the father's spermatozoa, the c.7302dupA mutation could be identified. Furthermore, mutation analysis of DNA isolated from 59 single spermatozoa revealed that the c.7302dupA mutation occurs in 16 spermatozoa, confirming germline mosaicism in the father of the affected children. This result has a high impact for genetic counselling of the family and for their recurrence risk in further pregnancies.

  11. BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing.

    Science.gov (United States)

    Mafficini, Andrea; Simbolo, Michele; Parisi, Alice; Rusev, Borislav; Luchini, Claudio; Cataldo, Ivana; Piazzola, Elena; Sperandio, Nicola; Turri, Giona; Franchi, Massimo; Tortora, Giampaolo; Bovo, Chiara; Lawlor, Rita T; Scarpa, Aldo

    2016-01-12

    BRCA mutated ovarian cancers respond better to platinum-based therapy and to the recently approved PARP-inhibitors. There is the need for efficient and timely methods to detect both somatic and germline mutations using formalin-fixed paraffin-embedded (FFPE) tissues and commercially available technology. We used a commercial kit exploring all exons and 50bp exon-intron junctions of BRCA1 and BRCA2 genes, and semiconductor next-generation sequencing (NGS) on DNA from 47 FFPE samples of high-grade serous ovarian cancers. Pathogenic mutations were found in 13/47 (28%) cancers: eight in BRCA1 and five in BRCA2. All BRCA1 and two BRCA2 mutations were germline; three BRCA2 mutations were somatic. All mutations were confirmed by Sanger sequencing. To evaluate the performance of the NGS panel, we assessed its capability to detect the 6,953 variants described for BRCA1 and BRCA2 in ClinVar and COSMIC databases using callability analysis. 6,059 (87.1%) variants were identified automatically by the software; 829 (12.0%) required visual verification. The remaining 65 (0.9%) variants were uncallable, and would require 15 Sanger reactions to be resolved. Thus, the sensitivity of the NGS-panel was 99.1%. In conclusion, NGS performed with a commercial kit is highly efficient for detection of germline and somatic mutations in BRCA genes using routine FFPE tissue.

  12. Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain

    Institute of Scientific and Technical Information of China (English)

    Ana Sánchez de Abajo; Trinidad Caldes; Miguel de la Hoya; Alicia Tosar; Javier Godino; Juan Manuel Fernández; Jose Lopez Asenjo; Beatriz Perez Villamil; Pedro Perez Segura; Eduardo Diaz-Rubio

    2005-01-01

    AIM: To investigate the prevalence and penetrance of hMSH6 mutations in Spanish HNPCC families that was negative for mutation in hMLH1 or hMSH2.METHODS: We used PCR-based DGGE assay and direct Sequencing to screen for hMSH6 gene in 91 HNPCC families.RESULTS: we have identified 10 families with germ-line mutations in the DNA sequence. These mutations included two intronic variation, three missense mutation, one nonsense mutation, and four silent mutations. Among the 10 germ-line mutations identified in the Spanish cohort,8 were novel, perhaps, suggesting different mutational spectra in the Spanish population. Detailed pedigrees were constructed for the three families with a possible pathogenic hMSH6 mutation. The two silent mutations H388H and L758L, detected in a person affected of colorectal cancer at age 29, produce loss of the wild-type allele in the tumor sample. Immunohistochemical analysis showed that expression of MSH6 protein was lost only in the tumors from the carriers of V878A and Q263X mutations.CONCLUSION: Altogether, our results indicate that disease-causing germ-line mutations of hMSH6 are very less frequent in Spanish HNPCC families.

  13. Bridging the generation gap: flowering plant gametophytes and animal germlines reveal unexpected similarities.

    Science.gov (United States)

    Dickinson, Hugh G; Grant-Downton, Robert

    2009-11-01

    Alternation of generations underpins all plant life histories and is held to possess important adaptive features. A wide range of data have accumulated over the past century which suggest that alternation from sporophyte to gametophyte in angiosperms includes a significant phase of 'informational reprogramming', leaving the founder cells of the gametophyte developmentally uncommitted. This review attempts to bring together results from these historic studies with more recent data on molecular and epigenetic events which accompany alternation, gametophyte development and gametogenesis in angiosperms. It is striking that most members of the other principal group of multicellular eukaryotes--the animals--have a completely different a life history: animals generate their gametes directly from diploid germlines, often set aside early in development. Nevertheless, a comparison between animal germlines and angiosperm gametophyte development reveals a number of surprising similarities at the cytological and molecular levels. This difference in life history but similarity in developmental process is reviewed in the context of the very different life strategies adopted by plants and animals, and particularly the fact that plants do not set aside diploid germlines early in development.

  14. POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.

    Science.gov (United States)

    Lessel, Davor; Hisama, Fuki M; Szakszon, Katalin; Saha, Bidisha; Sanjuanelo, Alexander Barrios; Salbert, Bonnie A; Steele, Pamela D; Baldwin, Jennifer; Brown, W Ted; Piussan, Charles; Plauchu, Henri; Szilvássy, Judit; Horkay, Edit; Högel, Josef; Martin, George M; Herr, Alan J; Oshima, Junko; Kubisch, Christian

    2015-11-01

    Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

  15. RetCam 3 screening fundus lesions in in 2 800 neonates%应用RetCam3筛查2800例新生儿眼底病变分析

    Institute of Scientific and Technical Information of China (English)

    曾亚薇

    2016-01-01

    Objective To investigate the value of RetCam 3 screening fundus lesions in neonates and to analyze the incidence of fundus lesions in neonates and the influencing factors of retinopathy.Methods 2 800 neonates from our hospital were screened for fundus oculi disease by RetCam 3.The results were statistically analyzed.Results Among the 2 800 infants,473 (16.89%) were detected with fundus lesions;among which,198 (7.07%) were detected with retinopathy,234 (8.36%) retinal hemorrhage (8.36%),27 (0.96%) retinal exudative changes,2 (0.07%) retinoblastoma,4 (0.14%) familial exudative vitreoretinopathy,4 (0.14%) albinotic fundus,3 (0.11%) morning glory syndrome,and 1 (0.04%) retinoschisis.Univariate analysis revealed that gestational age,birth weight,oxygen uptaking,mechanical ventilation,and asphyxia significantly affected retinopathy (P < 0.05).Multiple logistic regression analysis showed that birth weight,gestational age,oxygen uptaking mechanical ventilation,and asphyxia were risk factors for the development ofretinopathy (P < 0.05).Conclusions Neonatal fundus diseases are various and harmful,so early fundus screening should be carried out.Preventive measures should be taken against the risk factors to decrease the incidence of retinopathy.%目的 探讨RetCam3在新生儿眼底病变筛查中的应用价值,同时分析新生儿眼底病变的发生情况及ROP发生的影响因素.方法 采用眼科广域数字成像系统(RetCam3)对本院2 800例新生儿进行眼底病筛查,并对筛查结果进行统计学分析.结果 通过RetCam3筛查的2 800例新生儿中,检查出有眼底病变473例,阳性检出率为16.89%,其中早产儿视网膜病变(ROP) 198例(7.07%),视网膜出血234例(8.36%),视网膜渗出27例(0.96%),视网膜母细胞瘤2例(0.07%),家族渗出性玻璃体视网膜病变4例(0.14%),白化病眼底4例(0.14%).牵牛花综合征3例(0.11%),视网膜劈裂1例(0.04%).单因素分析结果显示胎龄

  16. 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.

  17. 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...... 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......-PCR). Methods: A new method for RNA extraction from routine air-dried FNA smears was established, which allowed analysis for the presence of four variants of PAX8/PPARG and RET/PTC 1 and RET/PTC 3, which were analyzed in 106 routine FNA smears and the corresponding surgically obtained FFPE tissues using real...

  18. Determination of RET Sequence Variation in an MEN2 Unaffected Cohort Using Multiple-Sample Pooling and Next-Generation Sequencing

    Directory of Open Access Journals (Sweden)

    R. L. Margraf

    2012-01-01

    Full Text Available Multisample, nonindexed pooling combined with next-generation sequencing (NGS was used to discover RET proto-oncogene sequence variation within a cohort known to be unaffected by multiple endocrine neoplasia type 2 (MEN2. DNA samples (113 Caucasians, 23 persons of other ethnicities were amplified for RET intron 9 to intron 16 and then divided into 5 pools of <30 samples each before library prep and NGS. Two controls were included in this study, a single sample and a pool of 50 samples that had been previously sequenced by the same NGS methods. All 59 variants previously detected in the 50-pool control were present. Of the 61 variants detected in the unaffected cohort, 20 variants were novel changes. Several variants were validated by high-resolution melting analysis and Sanger sequencing, and their allelic frequencies correlated well with those determined by NGS. The results from this unaffected cohort will be added to the RET MEN2 database.

  19. Los Huehuetlatolli: Modelos discursivos destinados a la enseñanza retórica en la tradición indígena

    Directory of Open Access Journals (Sweden)

    Mónica Ruiz Bañuls

    2013-04-01

    Full Text Available Si  entendemos la retórica en un sentido general como una manifestación de las capacidades persuasivas de los hablantes, los pueblos indígenas habían desarrollado, sin duda, antes de la llegada de los españoles en 1492, una retórica que se transmitía por tradición oral de una generación a otra. Los huehuetlatolli constituyen verdaderos modelos de discursos destinados a la enseñanza retórica dentro de la cultura azteca, la cual ya existía como materia de estudio en los famosos calmecac prehispánicos.

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

    Directory of Open Access Journals (Sweden)

    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.