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Hofstra, Robert Martinus Wouter. "The RET gene and its associated diseases." [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1995. http://irs.ub.rug.nl/ppn/142201383.
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Carter, Melissa Terry. "Characterization of the mouse RET gene and a cross-species comparison of RET isoforms." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ63279.pdf.
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Lee, King-yiu. "The Ret gene in the enteric nervous system expression analysis and generation of ret deficient mice /." Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B31449669.
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Lee, King-yiu, and 李景耀. "The Ret gene in the enteric nervous system: expression analysis and generation of ret deficient mice." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31449669.
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Guo, Kexiao. "DNA Secondary Structures in the Promoters of Human VEGF and RET Genes and Their Roles in Gene Transcriptional Regulation." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/195943.
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Unusual DNA secondary structures, especially G-quadruplexes and i-motifs, play important roles in gene transcriptional regulation and have been identified as novel drug targets. In this dissertation, I explored their formation in the human VEGF and RET promoters and their roles in gene transcriptional regulation. VEGF is a key regulator of angiogenesis and is up-regulated in many types of tumors. A poly-guanine/poly-cytosine (polyG/polyC) tract in its proximal promoter (-85 to -50 base pairs relative to the transcription starting site) is essential for both basal and inducible VEGF expression. I demonstrated that the guanine-rich (G-rich) and cytosine-rich (C-rich) strands in the VEGF proximal promoter are able to form G-quadruplex and i-motif structures, respectively. The major G-quadruplex formed by the VEGF G-rich sequence is an intramolecular parallel G-quadruplex containing three G-tetrads and a 1:4:1 arrangement of three double-chain-reversal loops (two single-base loops and one loop with four bases). The complementary C-rich sequence in the same region forms an intramolecular i-motif containing six semiprotonated cytosine-cytosine⁺ base pairs and a 2:3:2 loop configuration (two double-base loops and one loop with three bases). The Gquadruplexes formed by the native VEGF G-rich and its derivative sequences were also confirmed by NMR. In addition, various transcription factors including Sp1, hnRNP K, CNBP and nucleolin, which recognize different DNA structural elements including single-stranded, double-stranded or G-quadruplex/i-motif DNA in the VEGF proximal promoter, have been confirmed by EMSA, siRNA and chromatin immunoprecipitation (ChIP) assay, suggesting that the DNA in the VEGF proximal promoter region is capable of undergoing transitions between those three structures. Based on my studies, I have proposed a model to describe how various transcription factors recognize different DNA structures in the VEGF proximal promoter to regulate transcription. In the proximal promoter of another important oncogene RET, I demonstrated that the guanine-rich strand forms an intramolecular parallel G-quadruplex containing three G-tetrads and a 1:3:1 arrangement of three double-chain-reversal loops. The complementary cytosine-rich strand forms an i-motif structure containing six semiprotonated cytosine-cytosine⁺ base pairs and a 2:3:2 loop configuration. Moreover, G-quadruplex-interactive compounds TMPyP4 and telomestatin were shown to further stabilize the RET G-quadruplex structure.
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Santos, Marina Silva dos. "Genetic susceptibility to thyroid cancer: contributions of RET polymorphisms." Master's thesis, Universidade da Beira Interior, 2012. http://hdl.handle.net/10400.6/1199.
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Thyroid cancer is the most common malignancy of the endocrine system, represents more than 1% of all malignancies and has an estimated annual incidence of 212,000 cases worldwide. The term differentiated thyroid carcinoma (DTC) comprises the subtypes papillary thyroid carcinoma (PTC) and follicular thyroid carcinomas (FTC), these subtypes represent the two most common subtypes of thyroid cancer (approximately 80% and 10% respectively). Despite its incidence DTCs have a good prognosis with relatively few metastases and deaths associated. The polymorphisms (variants in DNA sequence among individuals that have a frequency of at least 1% in a population) of RET proto-oncogene have been studied in different populations for association with susceptibility to thyroid cancer, but with inconsistent findings mainly in DTC. To clarify the contribution of single locus or haplotypes (polymorphisms that are transmitted through generations as a unit) of RET polymorphisms to genetic susceptibility to DTC among Portuguese patients, we conducted a case–control study by analyzing four well-characterized RET polymorphisms (G691S, L769L, S836S and S904S).
To achieve this aim, the RET polymorphisms were genotyped and haplotype frequencies were estimated in a population of 282 individuals with DTC and in a control population of 254 individuals. Allele, genotype and haplotype distributions were compared among cases and controls. Patient population was subdivided according to several clinical parameters and allele, genotype and haplotype distributions were compared among the subgroups.
The single locus analysis showed an overrepresentation of the S836S polymorphism in patients when compared to controls. Also the heterozygous genotypes of the G691S/S904S polymorphisms were overrepresented in cases diagnosed after the age of 45 years and the heterozygous genotype of G691S polymorphism revealed an overrepresentation in patients with tumors larger then 10mm of diameter at diagnosis. The haplotype analysis showed an overrepresentation of GGTC haplotype in patients particularly in those diagnosed after the age of 45 years.
In conclusion, our data suggest that the S836S polymorphism may be associated with increased risk of DTC. Also the heterozygous genotype of the G691S/S904S polymorphisms seems to be associated with age of onset of DTC and additionally the heterozygous genotype of G691S polymorphism appeared to be in association with tumor size. Finally, one haplotype appears to be associated with increased risk of DTC particularly in those developed in later age (after the age of 45 years). These findings need to be confirmed by larger studies in order re-evaluate the role of these variants in the susceptibility to DTC.Thyroid cancer is the most common malignancy of the endocrine system, represents more than 1% of all malignancies and has an estimated annual incidence of 212,000 cases worldwide. The term differentiated thyroid carcinoma (DTC) comprises the subtypes papillary thyroid carcinoma (PTC) and follicular thyroid carcinomas (FTC), these subtypes represent the two most common subtypes of thyroid cancer (approximately 80% and 10% respectively). Despite its incidence DTCs have a good prognosis with relatively few metastases and deaths associated. The polymorphisms (variants in DNA sequence among individuals that have a frequency of at least 1% in a population) of RET proto-oncogene have been studied in different populations for association with susceptibility to thyroid cancer, but with inconsistent findings mainly in DTC. To clarify the contribution of single locus or haplotypes (polymorphisms that are transmitted through generations as a unit) of RET polymorphisms to genetic susceptibility to DTC among Portuguese patients, we conducted a case–control study by analyzing four well-characterized RET polymorphisms (G691S, L769L, S836S and S904S). To achieve this aim, the RET polymorphisms were genotyped and haplotype frequencies were estimated in a population of 282 individuals with DTC and in a control population of 254 individuals. Allele, genotype and haplotype distributions were compared among cases and controls. Patient population was subdivided according to several clinical parameters and allele, genotype and haplotype distributions were compared among the subgroups. The single locus analysis showed an overrepresentation of the S836S polymorphism in patients when compared to controls. Also the heterozygous genotypes of the G691S/S904S polymorphisms were overrepresented in cases diagnosed after the age of 45 years and the heterozygous genotype of G691S polymorphism revealed an overrepresentation in patients with tumors larger then 10mm of diameter at diagnosis. The haplotype analysis showed an overrepresentation of GGTC haplotype in patients particularly in those diagnosed after the age of 45 years. In conclusion, our data suggest that the S836S polymorphism may be associated with increased risk of DTC. Also the heterozygous genotype of the G691S/S904S polymorphisms seems to be associated with age of onset of DTC and additionally the heterozygous genotype of G691S polymorphism appeared to be in association with tumor size. Finally, one haplotype appears to be associated with increased risk of DTC particularly in those developed in later age (after the age of 45 years). These findings need to be confirmed by larger studies in order re-evaluate the role of these variants in the susceptibility to DTC.
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Le, Hir Hervé. "Etude de l'epissage alternatif des arn pre-messagers du gene ret et du gene de la tyrosine hydroxylase dans les pheochromocytomes." Paris 7, 1998. http://www.theses.fr/1998PA077089.
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J'ai etudie la regulation de l'epissage en relation avec le processus de tumorigenese, et choisi pour cela les pheochromocytomes (tumeurs de la medullo-surrenale). Ces tumeurs sont dans certains cas d'origine familiale, associees a des mutations activatrices du proto-oncogene ret. Ce gene code pour un recepteur a activite tyrosine-kinase agissant dans la voie de signalisation de ret avec le ligand gdnf et le co-recepteur gdnfr-. L'epissage alternatif de l'arn pre-messager ret conduit a la production de nombreux arnm codant pour dix isoformes du recepteur. Pour deux de celle-ci il a ete montre qu'elles possedent des activites transformantes differentes. J'ai mesure la quantite des arnm ret, gdnf et gdnfr- et montre que ces trois genes sont exprimes simultanement et que les genes ret et gdnf sont surexprimes dans la majorite des pheochromocytomes compare aux tissus sains. J'ai mesure l'abondance des divers arnm ret et montre que seuls les arnm codant pour deux isoformes de ret sont exprimes dans les tissus sains aussi bien que dans les tumeurs et ainsi que l'epissage alternatif du pre-messager ret n'est pas specifiquement altere dans les cellules tumorales. J'ai observe dans les pheochromocytomes la presence d'une nouvelle classe de transcrits contenant des introns non excises. En parallele du gene ret, j'ai etudie le patron d'epissage du gene de la tyrosine hydroxylase (th) dans ces tumeurs, dont le pre-messager est egalement sujet a un epissage alternatif. J'ai montre (i) que la moitie des introns ret et th sont retenus en quantite significative dans les arn cellulaires totaux et polyadenyles. (ii) peu ou pas de retention est detectee dans les tissus sains comme la medullo-surrenale et la substance noire. (iii) la majorite des introns sont retenus dans les memes molecules. Nous proposons que ce phenomene resulte d'une alteration generale de la machinerie d'epissage dans les pheochromocytomes.
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La, Perle Krista Marie DuBray. "Characterization of ret/PTC1 Transgenic-p53 knockout mice and sodium/iodide symporter gene transfer for Prostate Cancer /." The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486457871785739.
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Marsee, Derek K. "Exploration of novel therapies for thyroid cancer adenoviral gene therapy and 17-allylamino-17-demethoxygeldanamycin /." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1087497053.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xv, 118 p.; also includes graphics (some col.) Includes bibliographical references (p. 106-118). Available online via OhioLINK's ETD Center
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Pasini, Andrea. "Bases biologiques des néoplasies endocriniennes multiples de type 2 et de la maladie de Hirschsprung : étude des conséquences fonctionnelles des mutations du gène RET." Lyon 1, 1997. http://www.theses.fr/1997LYO1T249.
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Tong, Qiang. "Molecular mechanism of the activation of the ret/ptc1 oncogene in papillary thyroid carcinomas and characterization of the promoter of the rat sodium iodide symporter gene /." The Ohio State University, 1997. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487947501136078.
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Lau, Ming-fung Anson, and 劉銘豐. "Regulation of gene expression by NF-kB and STATs downstream of RET receptor tyrosine kinase in Hirschsprung's disease and thyroid cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B29976911.
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Hatanaka, Roxanne. "Rastreamento de variantes de significado desconhecido (VUS) no gene RET em indivíduos-controle e em pacientes com carcinoma medular de tireoide." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-24022016-111259/.
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Introdução: A Neoplasia endócrina múltipla do tipo 2 (NEM-2) é uma síndrome tumoral de herança autossômica dominante, na qual os tumores associados são carcinoma medular de tireoide (CMT), feocromocitoma (FEO) e hiperparatireoidismo primário (HPT). Esta síndrome ocorre devido a mutações ativadoras no proto-oncogene RET que alteram a via do receptor tirosina quinase RET. Essas mutações levam à ativação constitutiva de vias de sinalização desregulando o ciclo celular. Segundo os Consensos Internacionais de 2001 e 2009 sobre CMT/NEM-2, portadores de mutações no gene RET, inclusive indivíduos assintomáticos, devem ser submetidos a tireoidectomia total (TT) preventiva, aumentando a chance de cura da doença. Não é recomendado rastreamento clínico em portadores que apresentem somente polimorfismos isolados (variante não patogênica). No entanto, existem indivíduos que carregam variantes genéticas de significado clínico desconhecido (VUS), gerando dúvida quanto à conduta clínica. Atualmente, não se tem conhecimento se essas variantes podem ou não estar envolvidas no aumento do risco ao desenvolvimento de CMT. Dessa forma, o presente projeto analisou diversos aspectos como frequência alélica, estudo in silico, dados na literatura e nos bancos genéticos com o intuito de abranger o entendimento dessas variantes e auxiliar na indicação de conduta clínica adequada aos portadores de RET VUS. Objetivo: Expandir o conhecimento do potencial patogênico das VUS do gene RET, focando na classificação controversa da variante p.Y791F. Métodos: Foi realizado o rastreamento dos exons hotspots do gene RET em indivíduos adultos/idosos-controle e em pacientes com CMT através da técnica de Sequenciamento de Nova Geração (NGS) e Sequenciamento de Sanger. Foi também analisada a predição computacional da patogenicidade dessas variantes em seis diferentes programas preditivos. Foi feito o levantamento de dados em diversos bancos genéticos. Resultados: As variantes p.Y791N, p.Y791F e p.E511K foram encontradas no rastreamento genético das amostras-controle sequenciadas. Além dessas variantes, foram identificadas e estudadas famílias de pacientes com CMT portadoras das variantes p.V648I e p.K666N. A variante p.Y791F foi identificada em um novo caso somente com FEO. A análise in silico demonstrou que 4/6 programas foram mais informativos, e que 25/48 VUS demonstram alterar a estrutura físico-química da proteína RET. A frequência alélica encontrada nos bancos de dados de indivíduos-controle e indivíduos com tumores foram bastante baixas. Apenas 15/48 VUS possuem dados sobre estudos in vitro. Conclusão: Nossos dados sugerem que a variante RET p.Y791F, quando isolada e sem coocorrência com mutações conhecidas RET, se comporta como um polimorfismo benigno raro, sem associação do aumento do risco ao CMT. Já a associação de p.Y791F com mutações conhecidas RET, como a C634Y, pode levar ao desenvolvimento de fenótipos atípicos, como maior risco ao feocromocitoma. A variante p.V648I é provavelmente um polimorfismo benigno raro, evidenciado pelo seguimento clínico de aproximadamente 15 anos de uma família portadora dessa variante, sem evidências de CMT, FEO ou HPT. Há necessidade de mais dados para classificar apropriadamente as demais VUS; no entanto, devido a possibilidade das variantes p.E511K, K666N e Y791N poderem ser patogênicas, portadores devem ser monitorados clinicamenteIntroduction: Multiple endocrine neoplasia type 2 (MEN-2) is a tumor syndrome with autosomal dominant inheritance, in which tumors are associated with medullary thyroid carcinoma (MTC), pheochromocytoma (FEO) and primary hyperparathyroidism (HPT). This syndrome occurs due to activating mutations in the RET proto-oncogene, which lead to constitutive activation of tyrosine kinase signaling pathways that deregulate the cell cycle. According to the International Consensus on MTC/MEN-2 of 2001 and 2009 one should recommend that RET mutation carriers, including asymptomatic individuals, should undergo prophylactic total thyroidectomy (TT), increasing the chance of cure of the disease. It is not recommended clinical screening in patients that show only isolated polymorphisms (non-pathogenic variant). However, there are individuals who carry genetic variants of unknown clinical significance (VUS), generating doubt about the best clinical management. Currently, there is no consistent knowledge whether these variants may or may not be involved with the increased risk to MTC. The present project has approached the several aspects of these VUS, such as the allele frequency, in silico pathogenic prediction, published data and public databases, in order to increase our knowledge about VUS, in an attempt to contribute by offering appropriate clinical management to VUS carriers. Objective: To expand the knowledge of the pathogenic potential of some of the VUS of the RET gene, focusing especially on the controversial genetic variant p.Y791F. Methods: We performed the mutation screening of hotspots exons of the RET gene of DNA samples of 2061 adult/elderly healthy individuals and of patients with CMT by Sanger sequencing and Next Generation Sequencing (NGS) techniques. Pathogenic predictions of the studied variants were generated using six genetic softwares. Allelic frequency of RET VUS was assessed in different public databanks. Results: Genetic screening of control samples identified the presence of p.Y791N, p.Y791F and p.E511K germline variants. Patients with MTC carrying p.V648I and p.K666N germline variants were localized and family members were screened and clinically investigated. In addition, a new case with pheochromocytoma was found to carry the p.Y791F germline variant. The in silico analyses showed that 4 out of 6 packages were more informative, suggesting physico-chemical structure alteration caused by 25 out of 48 RET VUS. Very low allele frequencies were found in the public databases including healthy individuals and tumor samples. In vitro studies have been performed only for 15 out of 48 RET VUS. Conclusion: Our data strongly suggest that the p.Y791F variant, when occurring in an isolated form, is a benign polymorphism not associated with increased risk of MTC. Conversely, its co-occurrence with bona fide RET mutations as C634Y may lead to modulation of the phenotype, as increasing the frequencies of large and bilateral pheochromocytomas in MEN2A families. Family members carrying the p.V648I variant isolate have been followed clinically for approximately 15 years. As no indication of MCT, pheochromocytoma or hyperparathyroidism development has been documented, we conclude that this variant is a rare RET benign polymorphism. More information is needed to a better characterization of other VUS as E511K, K666N and Y791N. Thus, carriers with these variants should be necessarily examined through a periodic clinical follow up
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Lamazière, Frédéric. "Formes familiales de néoplasie endocrinienne multiple 2A : intérêt du dépistage des mutations du gène RET, à propos d'un cas familial." Bordeaux 2, 1995. http://www.theses.fr/1995BOR2M179.
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Raouane, Mouna. "Vectorisation de siRNA dirigés contre l'oncogène de fusion RET/PTC1 impliqué dans le carcinome papillaire de la thyroïde par des nanoparticules de squalène." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T077.
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Le cancer papillaire de la thyroïde (PTC) représente 70-80% des cas de cancers de la thyroïde. Il est principalement caractérisé par des réarrangements chromosomiques affectant le gène RET. Le réarrangement RET/PTC1, dans lequel RET est réarrangé avec un gène proapoptotique H4, représente 30% des cas sporadiques et jusqu’à 60% des cas survenus après irradiation. Afin d’inhiber l’oncogène de fusion RET/PTC1, nous avons utilisé un siRNA ciblant la zone de jonction RET/PTC1 (siRNA RET/PTC1) au niveau de l’ARN messager des cellules tumorales et montré sa spécificité et son efficacité. Néanmoins, le développement des siRNAs comme molécule d’intérêt thérapeutique se heurte in vivo à des difficultés liées à leur administration. Sous forme libre, ces molécules sont, en effet, très vite dégradées par les nucléases extracellulaires et leur pénétration intracellulaire est limitée. C’est la raison pour laquelle il est nécessaire de les vectoriser. Nous avons choisi de le faire par la méthode de « squalénisation » et avons couplé d’une manière covalente le squalène, un lipide naturel précurseur de la biosynthèse du cholestérol, au siRNA RET/PTC1. Le bioconjugué formé s’autoassemble spontanément en milieu aqueux sous forme de nanoparticules stables de 170 nm de diamètre. L’efficacité et la toxicité des nanoparticules siRNA RET/PTC1-squalène ont été étudiées in vitro dans deux lignées de PTC exprimant RET/PTC1 (BHP10-3 et TPC-1) et l’activité antitumorale a été évaluée in vivo sur des souris athymiques xénogreffées par BHP10-3 puis traitées en i.v. par ces nanoparticules. Les nanoparticules siRNA RET/PTC1-squalène ont montré une bonne efficacité antitumorale. En revanche, aucune activité inhibitrice n’a été retrouvée in vitro. En conclusion, nous avons réussi à vectoriser le siRNA RET/PTC1 par la méthode de squalénisation. Cette étude ouvre des perspectives thérapeutiques pour certains patients atteints de PTC et réfractaires au traitement conventionnelThe papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. This tumour is associated with somatic mutations of the RET proto-oncogene, due to gene rearrangements of the proto-RET. RET/PTC1 rearrangement is the most common genetic alteration identified to date, it is formed by an intra chromosomic rearrangement which leads to the juxtaposition of the RET Tyrosine Kinase domain of the proto-RET with the gene H4. The fusion RET/PTC1 oncogene represents an interesting target for small interfering RNA (siRNA) strategies since it is present only in the tumour cells and not in the surrounding normal cells. However, the biological efficacy of the siRNAs is hampered by their short plasma half-life due to poor stability in biological fluids and low intracellular penetration. In order to protect siRNA from degradation, and to improve their intracellular capture, we applied the concept of “squalenoylation”, ie. The bioconjugation of a drug substance to squalene, for the delivery of siRNA targeted toward the RET/PTC1 fusion oncogene. The acyclic isoprenoid chain of squalene was covalently coupled with RET/PTC1 siRNA at the 3’-terminus of the sense strand via a stable thioether linkage. The linkage of RET/PTC1 siRNA to squalene leads to an amphiphilic molecule that self-organise in water as RET/PTC1 siRNA-SQ nanoassemblies of 170 nm and Zeta potential of -26.4 mV. These RET/PTC1 siRNA-SQ NPs did not showed any cytotoxicity in vitro. Interestingly, in vivo, in a mouse xenografted RET/PTC1 experimental model, RET/PTC1 siRNA-SQ nanoparticles inhibited tumour growth, RET/PTC1 oncogene and oncoprotein expression, after intravenous injections of 2.5 mg/kg cumulative dose. In the last of this work, GALA-cholesterol combination with siRNA-SQ NPs further enhanced nucleic acid internalization, promoted their escape into the cytosol and consequently their gene silencing efficiency in vitro. In conclusion, these results showed that the “squalenoylation” offers a new non cationic plate-form for the siRNA delivery
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Boichard, Amélie. "Caractérisation moléculaire des formes métastatiques de carcinome médullaire de la thyroïde." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T015/document.
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Le carcinome médullaire de la thyroïde (CMT) est une tumeur neuroendocrine rare, se développant à partir des cellules sécrétant la calcitonine. Cette tumeur survient dans un contexte familial dans un tiers des cas. Toutes les formes germinales et près de 40% des formes sporadiques sont causées par une mutation ponctuelle activatrice de l’oncogène RET, codant pour un récepteur membranaire à activité tyrosine kinase. Les événements oncogéniques à l’origine des formes sporadiques non mutées RET restent mal définis, à l’exception de mutations activatrices des oncogènes RAS découvertes récemment.Le pronostic péjoratif du CMT est essentiellement lié à un envahissement ganglionnaire précoce. A ce titre, la chirurgie initiale est souvent insuffisante et les formes métastatiques ont longtemps été considérées en impasse thérapeutique. L’avènement récent des inhibiteurs séléctifs de tyrosine kinases (ITK) a apporté un nouvel élan à la prise en charge des tumeurs réfractaires, certains d’entre eux incluant dans leur spectre d’action le récepteur RET. Mais l’optimisation de ces traitements requiert une connaissance préalable des mécanismes moléculaires sous-jacents au développement tumoral.Dans ce contexte et en nous appuyant sur une collection importante de prélèvements humains, nous avons cherché à approfondir la decription du ‘paysage génomique’ du CMT.Dans un premier temps, nous avons évalué les anomalies structurales ponctuelles et chromosomiques présentées par les CMT. Nous avons montré, par optimisation de méthodes de séquençage, que les mutations des gènes RET et RAS interviennent dans plus de 96% des cas et que ces évènements sont mutuellement exclusifs. Ces mutations permettent de distinguer plusieurs groupes d’agressivité et de réponse aux traitements par ITK. Nous avons également observé - par technique d’hybridation génomique comparative - des anomalies de grande ampleur récurrentes dans cette pathologie : les délétions du bras court du chromosome 1 et des chromosomes entiers 4 et 22 apparaissent comme étant des évènements précoces et indépendants de la tumorigenèse du CMT.Dans un second temps, nous avons déterminé - par approche de type biopuce - les profils d’expression de microARN dans les CMT. Certains de ces régulateurs post-transcriptionnels majeurs semblent liés au caractère invasif de la tumeur, et notamment les miR-21, miR-199 et miR-129. Nous avons également démontré le potentiel d’utilisation des microARN miR-21 et miR-199 en tant que biomarqueurs circulants du CMT. L’impact fonctionnel des formes précurseurs mir-21 et mir-129 a ensuite été évalué par transfection dans les modèles cellulaires TT et MZ-CRC1.Les observations ainsi obtenues offrent de nombreuses perspectives d’études. Elles permettent la définition de marqueurs tissulaires distinguant a priori les tumeurs métastatiques et/ou réfractaires aux thérapies. Enfin, elles mettent en lumière de nouvelles pistes pour la découverte de cibles thérapeutiques additionnelles dans cette pathologieMedullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor, arising from calcitonin-secreting cells. This cancer occurs in a family context in a third of cases. All inherited forms and nearly 40% of sporadic forms are caused by activating point-mutations in the RET oncogene, coding for a tyrosine-kinase receptor. Other oncogenic events causing sporadic cases remain unclear, but activating mutations of RAS oncogenes have been discovered recently.Prognosis of MTC is essentially linked to early lymph node occurrence. Initial surgery of metastatic forms is often insufficient and patients are considered in therapeutic dead-end. The recent advent of selective tyrosine-kinase inhibitors (TKIs) has brought a new impetus to the management of refractory tumors, some of them targeting the RET receptor. Optimization of these treatments require improving knowledge of the underlying molecular mechanisms of tumor development.In this context and helped by a large collection of human specimens, we have sought to deepen the description of genomic landscape of MTC.At first, we evaluated the structural and chromosomal abnormalities presented by MTC. We showed, by optimizing sequencing methods, that RET and RAS mutations are involved in over 96% of the cases, these events are mutually exclusives. These mutations can distinguish several groups of aggressiveness and of response to TKI treatments. We also observed, by comparative genomic hybridization techniques, recurrent abnormalities such as deletion of the short arm of chromosome 1 and loss of entire chromosomes 4 and 22. These losses appear to be early events of tumorigenesis MTC.In a second step, we determined - by a microarray approach – the microRNA expression profile of MTC. Some of these post-transcriptional regulators seem related to tumor invasiveness, such as miR-21, miR-199 and miR-129. We demonstrated the potential of microRNAs miR-21 and miR-199 as circulating diagnosis biomarkers of MTC. The functional impact of the precursor forms mir-21 and mir-129 was then evaluated by transfection in TT and MZ- CRC1 cellular models.Observations obtained pave the way for a lot of new potential studies. They allow the definition of tissue biomarkers distinguishing metastatic forms or refractory patients. Finally, they highlight new pathways for the discovery of additional therapeutic targets in this disease
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Sekiya, Tomoko. "Análise do gene CDKN1B/p27kip1 em pacientes com neoplasia endócrina múltipla tipo 2." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-26022014-112355/.
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INTRODUÇÃO: Na Neoplasia Endócrina Múltipla tipo 2 (NEM2), o desenvolvimento do Carcinoma Medular de Tireoide (CMT), Feocromocitoma (FEO) e Hiperparatireoidismo primário (HPT) está associado à mutações germinativas ativadoras no proto-oncogene RET. Casos de CMT esporádico podem apresentar mutações somáticas no RET (~40%). A variabilidade fenotípica observada em casos de CMT e FEO familiais associados à NEM2 indica o envolvimento de eventos genéticos adicionais que seriam responsáveis pelas diferenças clínicas observadas nos indivíduos afetados (idade de desenvolvimento, progressão e agressividade do tumor). Outras alterações genéticas no RET como duplas mutações, SNPs e haplótipos específicos podem influenciar na susceptibilidade, agressividade e modulação do fenótipo NEM2. Entretanto, os estudos de outros genes envolvidos no processo da tumorigênese NEM2 ainda estão em andamento. Recentemente foi mostrado que RET ativado controla a expressão de proteínas inibidoras do ciclo celular (p18 e p27). Mutações germinativas no gene p27 foram recentemente associadas à susceptibilidade de tumores neuroendócrinos e estão associadas à síndrome NEM4 (Neoplasia endócrina múltipla tipo 4). Mutações somáticas, inativadoras de p27, são raramente encontradas em vários tipos de tumores. Entretanto, diversos estudos documentaram que a redução na expressão e a sublocalização citoplamática de p27 são controladas por alterações pós-transducionais e/ou epigenéticas. OBJETIVOS: o estudo teve como objetivos avaliar a participação de genes, recentemente associados ao RET ativado, em tumores de pacientes com NEM2 e também verificar se polimorfismos no gene p27 estariam atuando como moduladores de fenótipo em uma grande família com NEM2. CASUÍTICA: foram analisadas 66 amostras tumorais advindas de 36 pacientes com diagnóstico clínico e genético de NEM2 e 28 indivíduos pertencentes a uma grande família com NEM2A-CMTF e mutação C620R no gene RET. MÉTODOS: As análises somáticas do p27 e também de p15, p18 e RET foram realizadas por PCR e sequenciamento direto de DNA e análise de microssatélites para p27 foi realizada por PCR e eletroforese capilar. Análises de expressão e localização da proteína p27 celular foram realizadas por Western blot e imunohistoquímica. A análise da modulação de fenótipo na família com NEM2A foi realizada por meio da amplificação do éxon 1 do gene p27 na amostra de sangue total. RESULTADOS: Não foram encontradas mutações somáticas no gene p27 e também nos genes p15 e p18. Entretanto, verificamos baixa expressão proteica de p27 em tumores CMT e FEO, a qual se encontrava relacionada com o tipo e agressividade do códon mutado no RET, principalmente em tumores que apresentavam mutação RET no códon 634 (controle x 634 p=0,05; controle x 634/791 p= 0,032; 620 x 634 p=0,045; 620 x 634/791 p= 0,002; 620 x 634 + 634/791 p=0,036). Notou-se também correlação positiva entre os níveis de expressão de p27 na localização nuclear, analisada por imunohistoquímica, e o genótipo TT do SNP p27 p.V109G (p=0,03). CONCLUSÕES: Alterações moleculares somáticas no gene p27 nos tumores NEM2 não são frequentes. Entretanto, a redução na expressão e a localização citoplasmática de p27 provavelmente estão associadas a alterações somáticas em outros genes que controlam os processos de fosforilação da proteína p27 (eventos pós-transducionais)INTRODUCTION: In Multiple Endocrine Neoplasia type 2 (MEN2) the development of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and primary hyperparathyroidism (HPT) are associated with activating germline mutations in RET proto-oncogene. Cases of sporadic MTC may have somatic RET mutations (~ 40%). The phenotypic variability observed in cases with familial MTC/MEN2 and PHEO/MEN2 indicates the probable involvement of additional genetic events that could be responsible for the clinical differences observed in the affected individuals (age development, progression and aggressiveness of the tumor). Other genetic alterations such as RET double mutations, SNPs and specific haplotypes may influence susceptibility, aggressiveness and MEN2 phenotype modulation. However, studies of other genes involved in the tumorigenesis of MEN2 are still in progress. Recently, it was shown that the activated RET controls the expression of cell cycle inhibitory proteins (p18 and p27). Germline mutations in the p27 gene have recently been associated with the susceptibility to neuroendocrine tumors and are associated with the MEN4 syndrome (Multiple endocrine neoplasia type 4). Somatic inactivating mutations p27 are rarely found in many types of tumors. However, several studies have documented that reduced expression and subcellular location of p27 is controlled by post-transductional changes and/or epigenetic factors. OBJECTIVES: This study aimed to evaluate the role of genes recently associated with RET activated in tumors from MEN2 patients and also check whether polymorphisms in the p27 gene would be acting as modulators of phenotype in a large MEN2 family. PATIENTS: We analyzed 66 tumor samples from 36 patients with clinical and genetic diagnosis of MEN2 and from 28 individuals belonging to a large family with FMTC/MEN2A and RET C620R mutation. METHODS: The analyses of somatic p27, p15, p18 and RET were performed by PCR and direct sequencing of DNA and microsatellite analysis was performed for p27 by PCR and capillary electrophoresis. Expression analysis and subcellular localization of p27 protein were performed by Western blot and immunohistochemistry. The analysis of phenotype modulation in MEN2A families was performed by the amplification of exon 1 of the p27 gene in a whole blood sample. RESULTS: There were no somatic mutations in the p27 gene and also in the p15 and p18 genes. However, we verified a low p27 protein expression in MTC/MEN2 and PHEO/MEN2 that showed a definite correlation with the type and aggressiveness of the mutated RET codon, mainly in those tumors from cases with germline RET codon 634 mutations (control vs 634, p=0,05; control vs 634/791, p= 0,032; 620 vs 634, p=0,045; 620 vs 634/791, p= 0,002; 620 vs 634 + 634/791, p=0,036). It was also verified a positive correlation between the immunohistochemistry expression of nuclear p27 subcellular location and the p27 p.V109G TT genotype (p=0,03). CONCLUSIONS: The reduction in the expression of p27 and its subcellular localization are likely to be associated with somatic changes in other genes that control the processes of phosphorylation of p27 protein through post-transductional events
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Lioupis, Alexandros. "Studies on non-primate growth hormones : molecular evolution and structure-function relationships." Thesis, University of Sussex, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263869.
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Shoja, Valia. "A Broad Analysis of Tandemly Arrayed Genes in the Genomes of Human, Mouse, and Rat." Thesis, Virginia Tech, 2006. http://hdl.handle.net/10919/35800.
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Tandemly arrayed genes (TAG) play an important functional and physiological role in the genome. Most previous studies have focused on individual TAG families in a few species, yet a broad characterization of TAGs is not available. We identified all the TAGs in the genomes of human, chimp, mouse, and rat and performed a comprehensive analysis of TAG distribution, TAG sizes, TAG gene orientations and intergenic distances, and TAG gene functions. TAGs account for about 14-17% of all the genomic genes and nearly one third of all the duplicated genes in the four genomes, highlighting the predominant role that tandem duplication plays in gene duplication. For all species, TAG distribution is highly heterogeneous along chromosomes and some chromosomes are enriched with TAG forests while others are enriched with TAG deserts. The majority of TAGs are of size two for all genomes, similar to the previous findings in C. elegans, A. thaliana, and O. sativa, suggesting that it is a rather general phenomenon in eukaryotes.
The comparison with the genome patterns shows that TAG members have a significantly higher proportion of parallel gene orientation in all species, corroborating Graham's claim that parallel orientation is the preferred form of orientation in TAGs. Moreover, TAG members with parallel orientation tend to be closer to each other than all neighboring genes with parallel orientation in the genome. The analysis of GO function indicate that genes with receptor or binding activities are significantly over-represented by TAGs. Simulation reveals that random gene rearrangements have little effect on the statistics of TAGs for all genomes. It is noteworthy to mention that gene family sizes are significantly correlated with the extent of tandem duplication, suggesting that tandem duplication is a preferred form of duplication, especially in large families.
There has not been any systematic study of TAG genes' expression patterns in the genome. Taking advantage of recent large-scale microarray data, we were able to study expression divergence of some of the TAGs of size two in human and mouse for which the expression data is available and examine the effect of sequence divergence, gene orientation, and physical proximity on the divergence of gene expression patterns. Our results show that there is a weak negative correlation between sequence divergence and expression similarity between the two members of a TAG, and also a weak negative correlation between physical proximity of two genes and their expression similarity. No significant relationship was detected between gene orientation and expression similarity. Moreover, we compared the expression breadth of upstream and downstream duplicate copies and found that downstream duplicate does not show significantly narrower expression breadth. We also compared TAG gene pairs with their neighboring non-TAG pairs for both physical proximity and expression similarity. Our results show that TAG gene pairs do not show any distinct differences in the two aspects from their neighboring gene pairs, suggesting that sufficient divergence has occurred to these duplicated genes during evolution and their original similarity conferred by duplication has decayed to a level that is comparable to their surrounding regions.Master of Science
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Banister, Susan H. "Regenerating gene (reg) expression : studies in the BB rat and man." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296263.
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McSweeny, Andrew J. "Identification of Candidate Genes within Blood Pressure QTL Containing Regions Using Gene Expression Data." University of Toledo Health Science Campus / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=mco1212501779.
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Allan, G. "Gene expression during keratinocyte differentiation." Thesis, University of Newcastle Upon Tyne, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233424.
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Zablocki, Destinee Elizabeth. "Differential Expression of Calsarcin Genes in Orthognathic Surgery Patients with ACTN3 R577X Gene Deviations." Master's thesis, Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/405298.
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Oral BiologyM.S.
Objective: Malocclusion is a complex musculoskeletal trait, with muscle playing an integral role in vertical facial development. A single nucleotide polymorphism (SNP) produces the R577XX nonsense mutation in the alpha-actinin-3 (ACTN3) gene, creating a stop codon and loss of its protein. With loss of ACTN3, alpha-actinin-2 (ACTN2) is upregulated. Calsarcins, known inhibitors of calcineurin activation, preferentially bind ACTN2 leading to a surge in free calcineurin. The increase in calcineurin activity produces the phenotypic shift of fast muscle fibers toward the slow myogenic program seen in the ACTN3 null genotype (Seto et al., 2013). Here, we have tested whether calsarcin gene expression is affected by ACTN3 genotypes in human masseter muscle. Methods: Subjects undergoing orthodontic treatment and orthognathic surgery were recruited from the University of Lille, Department of Oral and Maxillofacial Surgery in Northern France. During the bilateral sagittal split osteotomy, masseter muscle samples were collected from the discarded section of deep anterior superficial masseter muscle, snap frozen, and shipped to Dr. Sciote’s lab at Temple University. RNA from masseter muscle samples was isolated from 41 subjects using TRIzolTM reagent. MYOZ gene expression was quantified by RT-PCR using an adult skeletal muscle reference standard (commercially prepared skeletal muscle RNA; Ambion, Inc), and individual primer-probe sets for MYOZ1, MYOZ2, MYOZ3, and HPRT1 (utilized for normalization of data). ANOVA and unpaired t-tests were used to determine the significance of expression differences between MYOZ genes and by ACTN3 R577X genotypes, as well as by malocclusion classes. Pearson analyses were used to determine correlations between MYOZ expression and fiber type mean percent occupancies. Results: The main aim of this project was to determine whether expression of the three calsarcin genes, MYOZ1, 2, and 3, differs between subjects with RR, RX and XX genotypes for the ACTN3 gene, as well as between sagittal and vertical classes of malocclusion, asymmetries and TMD. Differences were found for MYOZ3 expression where relative quantities in males, but not females, decreased progressively from the ACTN3 RR, to RX, and XX genotypes. Among subjects with the RX genotype, expression differed significantly between males and females by an unpaired t-test. A statistically significant difference was detected between MYOZ2 and Class II, Class III malocclusions (p=0.05). Sagittal differences were compared further by ANOVA analyses with a statistically significant difference detected for MYOZ3 with a probability of 0.02. Correlation analyses comparing fiber type mean % occupancy with calsarcin gene expression revealed a significant positive relationship between MYOZ2 and type I (slow-twitch) fibers. Correspondingly, a significant correlation of MYOZ2 expression with type IIA and IIX (fast-twitch) fibers was negative. Conclusions: The greatest relative quantity of RNA for the three calsarcin genes was found in MYOZ3, suggesting more calsarcin-3 may be needed in masticatory muscle structure and function than other calsarcin isoforms. Alternatively, high expression of MYOZ3 in the masseter samples may indicate that there are relatively greater amounts of that isoform in cranial muscle than in the limb skeletal muscle standard used in these studies. Also, relative quantities of MYOZ3 expression in males decreased progressively from the ACTN3 RR, to RX, and XX genotypes. While this data may suggest that the ACTN3 R577X polymorphism may affect MYOZ3 expression in males of the malocclusion patient population, an increased sample of male subjects would be needed to determine if this trend has true significance. Expression of MYOZ2 (calsarcin-1) was strongly correlated with slow fiber-type occupancy in masseter muscle of our patient population. The muscle-specific expression of each calsarcin may lend to the understanding of this result. MYOZ2 is the only isoform found in both cardiac muscle and slow-twitch skeletal muscle, while MYOZ1 and MYOZ3 are both found in skeletal muscle with a predilection towards fast-twitch skeletal muscle (Frey et al., 2004).
Temple University--Theses
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Johnson, Rory. "Molecular mechanisms of REST-mediated repression of RE1 target genes in neural cells." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435796.
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Clark, Allan F. "Disruption of the Ren-1d gene." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/13405.
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Physiologically, JG cells are the mot important sites of renin expression since they are the only cells known to convert prorenin to the active enzyme, renin, and to secrete it into the plasma in large amounts. Present data indicate that most mammals possess a single renin gene, however in most strains of mice there exists an additional gene, Ren-2, encoding a highly homologous but physically distinct enzyme renin-2. The two genes have different but often overlapping expression patterns, with both being expression at equal levels in the JG cells of the kidney (mRNA level). A major difference between the two enzyme is their capacity for N-linked glycosylation, renin-1d being glycosylated at one or more of its three potential glycosylation sites, whereas renin-2 is not glycosylated, lacking any N-linked glycosylation consensus sequences. To facilitate studies of the physiological significance of the two renin genes in mice, we have disrupted the Ren-1d gene by gene targeting, leaving renin-2 as the only functional renin isozyme capable of participating in the renin-angiotensin system. The targeting construct used to disrupt the Ren-1d gene was assembled using homology arms of 3.7 and 3.6kb generated by PCR. Ren-1d-/- animals are viable, display no gross, visible abnormalities and express Ren-2 as the only renin mRNA. The kidneys of all adult homozygous mutant animals display altered morphology of the macula densa and complete absence of JG cell granulation. Blood pressure homeostasis in these animals displays a sexual dimorphism, with female, but not male, Ren-1d-/- animals showing a reduced blood pressure. These results prove that renin-1d and renin-2 are not functionally equivalent enzymes, Ren-1d being required for normal macula densa cell morphology, granulation of JG cells and the maintenance of normal blood pressure in female Ren-1d-/- animals.
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TRONCHE, FRANCOIS. "Regulation de la transcription des genes specifiques de tissus : le promoteur du gene de l'albumine du rat." Paris 7, 1992. http://www.theses.fr/1992PA077199.
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Les genes hepatiques fournissent un systeme attrayant pour l'etude du controle de la specificite tissulaire de l'expression genique. Nous avons choisi, comme modele, l'etude la regulation de la transcription du gene de l'albumine du rat. Un promoteur albumine de 68 pb est efficace et specifique des hepatocytes. C'est un promoteur fort dans l'hepatome differencie h4ii mais inactif dans les hepatomes dedifferencies h5. Il n'est constitue que de deux elements: un motif tata et l'element pe, responsable du comportement specifique de tissu. Il a par ailleurs ete montre que: 1) pe est reconnu par hnf1, une proteine presente dans les cellules h4ii mais absente des autres lignees cellulaires et que, 2) des sites homologues a pe sont presents dans de nombreux promoteurs de genes hepatiques. L'organisation de promoteur albumine est plus complexe: lorsque l'affinite de hnf1 pour pe est artificiellement reduite, l'activite promotrice est abolie. La presence des 83 nucleotides en amont de pe restaure, par synergie, cette activite. Cette region distale (-151/-69) contient quatre elements capables de cooperer avec pe: deiii, deii, dei et ccaat (reconnu in vitro et in vivo par le facteur ubiquitaire nfy). Les promoteurs hepatiques reconnus par hnf1 semblent donc regules par un double jeu faisant intervenir des variations d'affinite de hnf1 pour ses diverses cibles naturelles, modulees par une cooperation avec d'autres facteurs. Hnf1 est une homeo-proteine dont la capacite a activer un promoteur albumine est dependante du type cellulaire. Hnf1, exprime de facon stable dans h5 ou c2, n'est pas capable d'activer l'expression du gene endogene de l'albumine et donc, a fortiori, d'imposer un phenotype hepatique aux cellules dedifferentiees. Ce qui est compatible avec la caracterisation recente de hnf1 dans des types cellulaires autres que les hepatocytes (epithelia du rein et de l'intestin). D'autres facteurs de transcription hepatiques (hnf3, hnf4, c/ebp) ont ete decrits. Le phenotype hepatique pourrait resulter de leur expression simultanee, a un niveau particulier, dans une cellule
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Piton, Nicolas. "Optimisation de la prise en charge diagnostique, pronostique et théranostique des carcinomes broncho-pulmonaires humains : des techniques d’imagerie in vivo à la biologie moléculaire. Ligation -dependent RT-PCR : a new specific and low-cost technique to detect ALK, ROS and RET rearrangements in lung adenocarcinoma A new assay for detection of theranostic gene translocations and MET exon 14 skipping in thoracic oncology. One-year perspective routine LD-RT-PCR in 413 newly diagnosed lung tumors STK11 mutations are associated with lower PDL1 expression in lung adenocarcinoma BRAF V600E mutation is not always present as expected ! A case report of lung and thyroid carcinomas A novel method for in vivo imaging of solitary lung nodules using navigational bronchoscopy and confocal laser microendoscopy." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR119.
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Le carcinome pulmonaire est une affection grave et fréquente dont la prise en charge a été bouleversée ces dernières années, tant sur le plan diagnostique que pronostique ou « théranostique » avec l’avènement des « thérapies ciblées ». Ces dernières permettent une nette amélioration de la survie et du confort des patients éligibles, mais ne sont pas sans compliquer le travail médical, depuis le diagnostic de la maladie jusqu’au suivi régulier du patient, sans oublier le choix des traitements ou les problèmes techniques posés par la multiplication arborescente des altérations moléculaires à rechercher à partir d’un tissu tumoral souvent peu abondant dans ce contexte particulier de l’oncologie thoracique. Ce travail de thèse collige 5 travaux de recherche selon deux angles d’approche : les marqueurs moléculaires pronostiques et « théranostiques » du cancer pulmonaire, et les procédures de diagnostic in vivo de cette pathologie. Le premier axe comporte 4 articles. Les deux premiers concernent l’évaluation d’une nouvelle technique moléculaire, la LD-RT-PCR, dans la détection des translocation géniques du cancer pulmonaire : la première étude est une étude de faisabilité, la deuxième est un travail de validation. Le troisième article explore l’association entre la présence d’une mutation STK11 dans les carcinomes pulmonaires et l’expression de PDL1. Enfin, le quatrième article est une étude de cas illustrant l’importance de l’approche morphologique du cancer pulmonaire. Le second axe est représenté par un travail comparant une technique d’imagerie in vivo par voie endoscopique utilisant la micro-endoscopie confocale par laser avec l’approche microscopique conventionnelleLung cancer is a serious and frequent condition for which the management strategies have been dramatically modified in recent years, from a diagnostic, prognostic and “theranostic” perspective, most notably with the introduction of “targeted therapies”. The latter have demonstrated dramatic improvement in both quality of life and survival rates of eligible patients, yet consequently highlight new complications in diagnosis, treatment options or technical considerations which can be attributed to the growing number of molecular alterations to be detected from limited tissue samples frequently encountered in thoracic oncology. This work combines 5 different research papers from 2 different angles: prognostic and “theranostic” molecular markers of lung cancer, as well as in vivo diagnostic procedures of lung cancer. The first angle encompasses 4 articles. The first two evaluate a new molecular technique, LD-RT-PCR, to detect gene translocation in lung cancer. The third article explores the association between STK11 mutations in lung cancer and the expression of PDL1. Finally, the fourth article is a case report illustrating the importance of a morphological approach to lung cancer. The second angle compares in vivo imaging techniques by endoscopy using confocal laser microendoscopy alongside a conventional microscopic approach
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Brug, Marcel Patrick van der. "Excitotoxic induced gene expression in the adult rat brain /." [St. Lucia, Qld.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17077.pdf.
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Abankwa, Daniel. "Axotomy induced gene expression in rat brain." [S.l. : s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963458051.
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McDowell, Ian L. "Studies on the rat phenylalanine hydroxylase gene." Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260390.
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Duran, Alonso Maria Beatriz. "Genetic mapping of the rat agu gene." Thesis, University of Glasgow, 1997. http://theses.gla.ac.uk/39021/.
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In 1993, a mutant strain, AS/AGU arose spontaneously in an enclosed colony of the Albino Swiss (AS) strain of rat. AS/AGU animals exhibit a set of locomotor abnormalities. They display a general instability and whole body tremor, are slow at initiating movement, show reductions in purposeful action, and perform poorly at locomotor tests such as mid-air righting. L-dopa administration or fetal midbrain transplants reverse the majority of the symptoms, resembling the observations made on Parkinson's disease patients. These features make the AS/AGU strain a useful model for movement disorders due in significant part to failure of the dopaminergic transmission system. Crosses of AS/AGU to other laboratory rat strains point to a single recessive mutation with essentially complete penetrance (agu/agu) as the cause of the abnormal phenotype. There is no evidence of sex linkage or maternal inheritance. In the absence of any evidence of the function of the agu gene product, positional cloning of this locus was begun. The first step was the establishment of a genetic map location for the agu locus. A large series of microsatellite markers were analysed and used to identify which of the strains PVG, BN, and F344 differed to a greater extent from AS/AGU. Differences at 43%, 62% and 47% of the loci were recorded, respectively. BN and F344 were therefore selected as the reference strains in backcrosses to AS/AGU, in an attempt to maximise the number of informative markers which could be used to type the progeny.
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Hunt, Jannine M. "A psbA phylogeny for selected rhodophyceae /." Electronic version (PDF), 2006. http://dl.uncw.edu/etd/2007-2/huntj/janninehunt.pdf.
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Scott, Ian Stuart. "Regulation of hormone gene expression in normal and mutant rodents." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.258240.
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Zemmel, Rodney W. "Rev-RRE interactions in human immunodeficiency virus gene expression." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390234.
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Asfour, Boulos. "Experimental design for cardiac gene therapy : rat heart transplantation models and gene transfer techniques /." Münster : Schüling, 2000. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=008939687&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Au, Mun-yee Deborah. "Molecular studies of rat [beta]-globin gene cluster." Click to view the E-thesis via HKUTO, 1996. http://sunzi.lib.hku.hk/hkuto/record/B31234598.
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Denny, Paul. "Molecular analysis of gene expression in rat brain." Thesis, Imperial College London, 1991. http://hdl.handle.net/10044/1/46744.
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Nasa, Zeyad, and nasa zeyad@med monash edu au. "Characterization of the Rat Relaxin-like Factor Gene." RMIT University. Medical Sciences, 2006. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080514.100729.
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Relaxin-like factor (RLF), also known as Leydig insulin-like peptide (Ley-I-L) or Insulin 3 (INSL3), is a newly characterized member of the insulin peptide family. Amino acid sequence homology revealed that RLF is more closely related to relaxin than any other insulin-like hormones. The main aim of this thesis was to sequence the rat RLF (Relaxin-like factor) gene and determine the structure and organisation of the gene. Secondly to compare the structural organisation of the rat RLF/JAK3 genomic region with that of the mouse and human, using bioinformatic databases. Thirdly to further investigate the signalling pathways for the RLF receptor, in particular the NFÛB pathway. The homology between rat and mouse in the JAK3/RLF region revealed 84.4 % similarity over 1262 bp of DNA sequence, observing that unlike the mouse, the rat RLF promoter is separated from the JAK3 gene by around 700-1000 bp. Similarly in humans, the RLF gene is located around 4 kb downstre am from JAK3. Also Protein kinase A (PKA) was the only signalling pathway which dispalyed major induction and no inhibitory effects were observed through the NFÛB signalling pathway.
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Norgate, Zoe. "Gene expression in rat uterine natural killer cells." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614884.
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區敏宜 and Mun-yee Deborah Au. "Molecular studies of rat {221}-globin gene cluster." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1996. http://hub.hku.hk/bib/B31234598.
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Trickett, Jeffrey Ianto. "The arylacetamide deacetylase gene in rat and mouse." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397619.
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Rees, D. "Characterisation of the rat phenylalanine hydroxylase gene promotor." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343614.
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Au, Mun-yee Deborah. "Molecular studies of rat b-globin gene cluster /." Hong Kong : University of Hong Kong, 1996. http://sunzi.lib.hku.hk/hkuto/record.jsp?B18995779.
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McCormick, James A. "Transcriptional regulation of the rat glucocorticoid receptor gene." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/23114.
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The aims of this thesis were to investigate tissue-specific regulation of the rat GR gene and how this relates to perinatal programming of GR levels. RNase protection analysis was used to determine the relative tissue distributions of alternate exon 1-contianing GR mRNAs. One alternate exon 1, exon 110, was found to be present in the majority (56-87%) of GR mRNAs in a variety of tissues, including hippocampus, liver and thymus. Mapping of the 5' end of exon 110 revealed substantial heterogeneity in transcription initiation points. Other alternate exons 1 exhibited tissue-specific distributions. For example, exon 11-containing GR mRNAs were restricted to thymus, while exon 17-containing GR mRNAs are hippocampus-specific. To address the mechanisms of perinatal programming of GR levels, RNase protection analysis was used to assess changes in the abundances of alternate GR mRNAs in the liver of adult rats exposed to dexamethasone in utero. A significant reduction (13%, p<0.05) in the proportion of exon 110-containing GR was detected, suggesting an increase in the proportion of a minor GR mRNA variant. Further experiments, however, did not identify a variant GR mRNA upregulated by this manipulation. 5'-Rapid amplification of cDNA ends PCR performed on primary hippocampal cultures revealed that the majority of GR mRNAs expressed by these cultures contain exon 110 and strengthened the earlier finding that transcription initiation of this variant transcript exhibits considerable heterogeneity. RT-PCR performed on these culture revealed that primary hippocampal culture express GR mRNAs containing exon 17, which is specifically induced in the hippocampus by neonatal handling, suggesting that these cultures might provide a useful system to elucidate the mechanisms by which neonatal handling leads to permanently increased hippocampal GR. An understanding of the molecular mechanisms underlying programming of GR is of great importance in gaining an understanding of how tissue-specific regulation of GR occurs and how early life events influence adult disease.
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Craig, Nicola Jane. "Genetic and physical mapping of the rat agu locus." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341722.
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Davies, Janet Elizabeth. "Towards a transgenic rat model of Familial Neurohypophysial Diabetes Insipidus." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247860.
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Montgomery, Douglas S. "An investigation of rat DNA polymerase alpha." Thesis, University of Aberdeen, 1985. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU362670.
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The aim of this project was to clone the gene encoding the catalytic subunit of the rat DNA replication enzyme, DNA polymerase alpha. A strategy was adopted in which cDNA clones expressing the catalytic subunit sequences would be identified using anti-DNA polymerase antibodies. DNA polymerase alpha was partially purified from regenerating rat liver and exponentially growing rat Y3 myeloma cells. The catalytic subunit was identified as a 170-180kD polypeptide by activity gel analysis of partially purified Y3 cell fractions. The catalytic subunit was found to be susceptible to degradation but without loss of polymerase activity. Glycerol gradient analysis indicated a two stage degradation of DNA polymerase in vivo. Sera were collected from mice immunised with partially purified DNA polymerase alpha from regenerated rat liver. These sera cross-reacted with Western-blotted Y3 cell fractions; removed polymerase activity from solution in plate binding assays and bound alpha polymerase activity (140-180kD) on an immuno-adsorption column cDNA was synthesised using size selected mRNA from exponentially growing Y3 cells and cloned into the expression vectors pUC8 and ?gtll, both of which utilise the lac Z gene to express cloned DNA sequences. Immunoscreening of the ?gtll library was frustrated by non-specific binding of the serum. This non-specific binding was overcome by pre-adsorbing the serum against a lysate of E. coli JM 83. Screening of the pUC8 library revealled 27 out of 2.25x104 colonies which bound pre-adsorbed anti-DNA polymerase alpha serum.
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Costa, Marcella Motta da. "Duplicação do gene MECP2 em meninos com deficiência intelectual." reponame:Repositório Institucional da UnB, 2016. http://dx.doi.org/10.26512/2016.02.D.20076.
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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2016.A Deficiência Intelectual (DI), é um grande problema de saúde pública, visto que sua prevalência é de aproximadamente 2%-3%. Sua maior prevalência em homens se deve ao grande número de formas de DI Ligada ao cromossomo X (DILX). Essa podem ser, classificadas como sindrômicas (S-DILX) ou não-sindrômicas (NS-DILX). Uma das causas mais comuns de DILX em meninos é a duplicação do gene MECP2. Estudos anteriores relatam frequências de 1 a 15% de portadores de CNVs incluindo o gene MECP2 em coortes de meninos com DI. Este trabalho buscou rastrear a presença de microduplicações do gene MECP2 em uma população de 265 pacientes do sexo masculino, sendo 138 analisados pela técnica de qPCR e 127 pacientes provenientes do banco de dados de análise cromossômica por microarray do laboratório de Genética da UnB. Não foram identificados CNVs do gene MECP2 nos 265 pacientes estudados. A frequência de CNVs de MECP2 nesse estudo foi menor que a reportada anteriormente na literatura e sua baixa prevalência não justifica a triagem individual de alterações de número de cópias de MECP2 em meninos com DI.
The Intellectual Disability (ID) is a big problem of public health, since its prevalence is approximately 1%. Its higher prevalence in men is due to the large number of forms of ID linked to the X chromosome (DILX). It can be classified as syndromic (S-DILX) or non-syndromic (NS-DILX). One of the most common causes of DILX in boys is the duplication of the MECP2 gene. Earlier studies reported frequencies from 1 to 15% of CNVs carriers including MECP2 in cohort of boys with ID. This study aimed to trace the presence of microduplications of the MECP2 gene in a population of 265 male patients, 138 analysed by qPCR technique and 127 patients from the chromosomal analysis database by microarray from the Genetics Laboratory at UnB. We have not identified none of the MECP2 gene in 265 patients studied. The frequency of CNVs from MECP2 in this study was lower than reported previously in the literature and its low prevalence does not justify the individual triage of the alteration of MECP2 number of copies in boys with ID.
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Tang, Mei Kuen. "Applications of the subtractive hybridization method to study gene expression in rat liver after cadmium exposure." HKBU Institutional Repository, 1994. https://repository.hkbu.edu.hk/etd_ra/39.
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Rodrigues, Lucas Mateus Rivero [UNESP]. "Avaliação da agressividade e caracterização genética de linhagens de Ralstonia Solanacearum isoladas de diferentes plantas hospedeiras." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/97187.
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O presente trabalho teve como objetivo avaliar a agressividade de linhagens de Ralstonia solanacearum provenientes de solanáceas, plantas ornamentais e eucalipto, em plantas de batata, tomate e fumo, bem como caracterizar as linhagens por meio de técnicas moleculares. Vinte e duas linhagens foram utilizadas nos ensaios de avaliação da agressividade, em experimentos conduzidos em casa-de-vegetação evidenciaram alta severidade da doença pelas linhagens de R. solanacearum quando inoculadas em plantas de tomate e batata, sendo a batata mais afetada nas inoculações. Todas as linhagens mostraram-se agressivas, sendo que o fumo mostrou baixa suscetibilidade ao ataque das bactérias. As linhagens mais agressivas em plantas de tomate foram IBSBF 309, IBSBF 1712, IBSBF 1839, IBSBF 1882, IBSBF 1883 e IBSBF 2000, pertencentes às biovares I, II e III. As linhagens mais agressivas às plantas de fumo foram IBSBF 309, IBSBF 2131 e IBSBF 292T, pertencentes à biovar I. Foi efetuado também ensaio de microbiolização in vitro em sementes de eucalipto, a fim de se identificar possíveis linhagens patogênicas a esta espécie vegetal e concluiu-se que todas as linhagens utilizadas infectaram plantas de eucalipto ou afetaram seu crescimento. A caracterização molecular de 41 linhagens de Ralstonia solanacearum, provenientes de diversas plantas hospedeiras, incluindo solanáceas, bananeira, helicônia, plantas ornamentais e eucalipto, foi efetuada empregando-se ERIC e BOX-PCR e os resultados mostraram grande diversidade genética entre as linhagens. A análise de PCR-RFLP da região espaçadora 16S-23S DNAr permitiu distinguir os isolados pertencentes à biovar III das demais biovares (I, II, IIA e IIT), quando digeridos com as enzimas Taq I e Hin6 I. A análise de sequenciamento de parte dos genes Endoglucanase (Egl) e MutS possibilitou a classificação em filotipos e os resultados...
This study aimed to evaluate the aggressiveness of strains of Ralstonia solanacearum from solanaceus, ornamental and eucalyptus plants, on potato, tomato and tobacco, and to characterize the strains through molecular techniques. Twenty-two strains were used in this study to evaluate the aggressiveness and, the experiments conducted in a greenhouse revealed the high susceptibility of tomato and potato plants, with the potato being the most affected on through the inoculations. All isolates proved to be aggressive and higher tolerance to the attack of bacteria was verified on tobacco plants. Strains more aggressive on tomato were IBSBF 309, IBSBF 1712, IBSBF 1839, IBSBF 1882, IBSBF 1883 and IBSBF 2000, belonging to biovars I, II and III. The more aggressive strains on the tobacco plants were IBSBF 309, IBSBF 292T and IBSBF 2131 belonging to biovar I. Tests in vitro of microbiolization of eucalyptus seeds were also performed in order to identify possible pathogenic strains to this species and the results showed that all strains used cause infection on emerging plants or affected their growth. To molecular characterization of 41 strains of Ralstonia solanacearum from several host plants including solanaceous, banana, heliconia, ornamentals and eucalyptus were employed to ERIC and BOX-PCR, and the results showed high genetic diversity among strains. The analysis of PCR-RFLP of 16S-23S spacer region rDNA allowed us to distinguish the isolates belonging to biovar III from the others (biovars I, II, IIA and IIT) when digested with enzymes Taq I and Hin6 I. The sequence analysis of the partial of Endoglucanase (Egl) and MutS genes allowed the classification in phylotypes and the results revealed a predominance of the phylotype II in Brazil, and four isolates were classified in the phylotype I, all belonging to biovar III