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Hammarsund, Marianne. "Genetic changes in lymphoid leukemia /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-628-5841-6/.
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HODGES-GARCIA, YVONNE KATHLEEN. "PURIFICATION AND CHARACTERIZATION OF BACTERIAL PHAGE PHI29 GENE 6 PROTEIN." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/183864.
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A DNA fragment containing the coding region for gene 6 of Bacterial phage ϕ29 was placed into an expression vector. The ϕ29 gene 6 protein was isolated in large amounts by chromatography on double-stranded DNA cellulose and DE52 cellulose. The ϕ29 gene 6 protein was determined to be greater 95% pure and has a molecular weight of approximately 16,000. The ϕ29 gene 6 protein is thought to be a dimer in its native form. The partial N-terminal amino acid sequence of the purified protein is identically to the inferred amino acid sequence from the nucleotide sequence of ϕ29 gene 6. Gene 6 protein of ϕ29 aggregates in a more purified state which suggest protein to protein interactions. Purified gene 6 protein did not stimulate the ϕ29 in vitro DNA replication system and may require binding with other replication proteins to enable it to function. Gene 6 protein binds weakly to double-stranded and single-strand DNA cellulose. There is segmental amino acid sequence and secondary structure homology with adenovirus DNA binding protein Antibody to gene 6 protein inhibits it from binding to ϕ29 DNA. The results presented in this dissertation suggest that ϕ29 gene 6 protein is a weak DNA bind protein and may not be required for the in vitro ϕ29 DNA replication system.
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Holm, Sofia. "Molecular genetic studies of psoriasis susceptibility in 6p21.3 /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-225-X.
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Kholodnyuk, Irina. "A microcell hybrid based elimination test to identify human chromosome 3 regions that antagonize tumor growth /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-581-6/.
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Calero, Moreno Teresa. "Genetic changes in childhood acute lymphoblastic leukaemia and other lymphoid malignancies /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4625-6/.
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Johonnett, Peter. "Replication timing analysis of the major histocompatibility complex on human chromosome 6." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395158.
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Kabir, Sadia. "Molecular analysis of structure of chromosome 6R of triticale T701-4-6 /." Title page, summary and contents only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phk108.pdf.
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DUGAST, ISABELLE. "Genetique moleculaire de l'hemochromatose idiopathique : etude du gene ferritine h du chromosome 6." Rennes 1, 1988. http://www.theses.fr/1988REN10062.
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Recherche d'une forme nouvelle de ferritine, attribuee au chromosome 6, dans la region du locus hi, marquee par les haplotypes hla. Mise en evidence d'un gene de grande taille dont les coupures enzymatiques suggerent la presence possible d'introns. Ce clone permet de decrire un polymorphisme possible du gene ferritine h sur le chromosome 6
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BLANCHE, HELENE. "Cartographie du chromosome 6 humain, localisation et etude d'homologues du complexe t murin." Paris 6, 1991. http://www.theses.fr/1991PA066421.
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Nous avons construit une carte genetique du bras court du chromosome 6 humain (6p), composee de 17 loci lies les uns aux autres, qui s'etend d'une region proche du telomere jusqu'au centromere. Les marqueurs y sont particulierement denses dans la partie proximale aux trois loci les plus telomeriques, constituant un outil tres utile pour la localisation de genes d'interet. Du fait de l'homologie entre le chromosome 6 humain et le chromosome 17 murin dans la region du complexe t, nous avons localise genetiquement trois homologues humains de genes murins de la partie proximale de ce complexe. Les genes humains, localises vers la region telomerique du bras long du chromosome 6, sont organises de maniere semblable aux homologues murins portes par les haplotypes t murins. Deux homologues humains d'une sequence murine de la partie distale du complexe t, ont ete clones. Un a ete localise genetiquement sur le bras long du chromosome 9. L'autre, exprime dans les testicules, a ete localise, par hybridation in situ et genetiquement, a proximite de la region hla-classe i du cote distal
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Miyagi, Mikiko. "Exploitation of bacterial artificial chromosome (BAC) libraries to enhance the efficiency of genome mapping." Thesis, Queensland University of Technology, 2002. https://eprints.qut.edu.au/37140/6/37140_Digitised%20Thesis.pdf.
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MAUVIEUX-LELAURE, VALERIE. "Pseudogene h-ferritine du chromosome 6 (locus fthp1) : sequence, localisation, description de deux marqueurs polymorphiques." Rennes 1, 1991. http://www.theses.fr/1991REN10122.
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L'hemochromatose est une maladie hereditaire a transmission autosomique recessive caracterisee par une surcharge tissulaire en fer. L'anomalie genomique en cause a ete localisee sur le bras court du chromosome 6 a moins d'un centimorgan du locus hla-a. La mise en evidence dans cette meme region d'une sequence h-ferritine (la feritine etant une proteine majeure du metabolisme du fer) a constitue le point de depart de notre sujet de recherche. Afin d'isoler et d'etudier cette sequence h-ferritine du chromosome 6, differentes etapes ont ete menees a bien: 1) realisation d'une banque partielle d'adn genomique provenant d'un sujet hemochromatosique (l'adn du sujet normal etant etudie en parallele a boston) en phage lambda l147-1. 2. Isolement d'un clone contenant un insert de 12 kb possedant la sequence h-ferritine cible et sous-clonage de la sequence interessante. 3. Sequencage des sous-clones obtenus. 4. Analyse de la sequence h-ferritine chromosome 6 par comparaison avec l'acdn h-ferritine et avec certains retrogenes h-ferritine deja decrits. 5. Etude de deux marqueurs polymorphiques specifiques du locus fthp1. En conclusion, ce travail a permis d'eliminer l'hypothese d'une identite entre le pseudogene h-ferritine caracterise ici et le gene de l'hemochromatose, de preciser genetiquement la localisation du locus fthp1 et d'apporter certains elements en faveur de l'existence d'un deuxieme gene h-ferritine fonctionnel
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ESTEVE, VILETTE PASCALE. "Leucemie lymphoblastique aigue de l'enfant avec deletion du bras long du chromosome 6 : a propos d'un cas." Aix-Marseille 2, 1989. http://www.theses.fr/1989AIX20050.
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Bäckesjö, Carl-Magnus. "Molecular biology of Bruton's tyrosine kinase /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-693-6.
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Footz, Tim. "Mapping of the region of mouse chromosome 6 homologous to the human cat eye syndrome critical region." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0020/MQ47030.pdf.
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Bäckdahl, Liselotte. "Genetic dissection of experimental arthritis in the DA rat /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-227-6/.
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Deberdt, Péninna. "Analyse de la résistance au flétrissement bactérien (Ralstonia solanacearum - Race 1) gouvernée par le chromosome 6 chez la tomate." Montpellier 2, 1999. http://www.theses.fr/1999MON20005.
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Le fletrissement bacterien cause par ralstonia solanacearum est une phytobacteriose vasculaire largement distribuee dans le monde qui provoque des degats considerables sur les solanacees. Les nematodes phytoparasites sont aussi distribues dans les sols et mettent en echec l'expression de la resistance au fletrissement. L'objectif a ete l'analyse de la resistance au fletrissement conferee par le chromosome 6, en utilisant deux couples de lignees de tomate quasi-isogeniques sauf pour l'introgression portant le gene mi (caraibo / carmido) et (cra 66 / cranita). Mi confere la resistance contre les nematodes a galles et il est aussi localise sur ce chromosome. Nous avons d'abord demontre que la neoformation des galles sur le systeme racinaire est le facteur determinant l'echec de la resistance au fletrissement. En presence de r. Solanacearum et suite a la surinfection par m. Incognita, la plante n'est plus capable de gerer simultanement les mecanismes de resistance pour controler la colonisation bacterienne et les changements physiologiques imposes par la neoformation des galles. Ensuite, nous avons confirme le caractere quasi-isogenique des lignees caraibo et carmido, ce qui n'est pas le cas pour cra 66 et cranita. Enfin, la cartographie moleculaire des populations f2 combinee aux analyses phenotypiques des descendants f3 a permis de detecter dans le croisement caraibo x carmido un locus fortement associe a la region cf-2mi sur le chromosome 6 qui controle plus de 56% de la resistance. Un locus a effet mineur a aussi ete detecte dans le croisement cra 66 x cranita. Cette etude a demontre que l'introgression du gene mi par retrocroisements s'accompagne incontestablement de la baisse du niveau de resistance a r. Solanacearum du fait de la liaison etroite entre ces deux loci.
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Ferfouri, Fatma. "Anomalies génétiques et épigénétiques de l’ADN spermatique et infertilité masculine." Versailles-St Quentin en Yvelines, 2012. http://www.theses.fr/2012VERS0054.
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L’infertilité masculine parait augmenter depuis plusieurs décennies. Ses étiologies sont multiples, mais les causes génétiques et épigénétiques paraissent importantes. Nous avons dans cette thèse étudié différentes causes génétiques et épigénétiques d’infertilité en mettant en évidence les anomalies portées par les spermatozoïdes et parfois transmissibles au conceptus. Ce travail comporte trois parties, à savoir, tout d'abord, les infertilités associées à des anomalies du caryotype constitutionel en étudiant les conséquences pour le risque chromosomique porté par les spermatozoïdes avec le risque évalué sur tous les spermatozoïdes puis, les infertilités, à caryotype constitutionel normal, dont l’origine génique a parfois été démontrée et où la morphologie spermatique est altérée avec les spermatozoïdes macrocéphales, les spermatozoïdes globozoocéphales et les spermatozoïdes à larges ou petites vacuoles et enfin, les anomalies de la méthylation de l’ADN dans les différentes étiologies d’azoospermie. Ces approches ont un triple intérêt car elles permettent d'évaluer les risques pour le conceptus, de guider la prise en charge des patients et le choix des spermatozoïdes à injecter dans l’ovocyte. A plus long terme grâce à une compréhension des mécanismes en jeu, prévenir des infertilités et proposer de véritables solutions thérapeutiquesThe male infertility seems to increase for several decades. Infertility etiologies are multiple, but the genetic and epigenetic causes are important. Here, we tried to study, the abnormalities carried by spermatozoa and sometimes transmissible in the conceptus. This work contains three parts, in a first time, the infertility linked with abnomalities of constitutionel karyotype by studying the consequences for the chromosomal risk with the risk estimated on all spermatozoa, in a second time, the infertility, with normal constitutionel karyotype, where the genetic origin was sometimes demonstrated and sperm morphology altered with macrocephalic sperm, Globozoospermia and spermatozoa with large or small vacuoles and in fine, DNA methylation abnormalities in various azoospermic aetiologies. These approaches have a triple interest because, it estimate the risks for conceptus and advice patients care, guide the choice of spermatozoa to be injected in the oocyte
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Flordal, Thelander Emma. "Genetic characterization of hematological malignancies with focul on mantle cell lymphoma /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-161-6/.
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Amadou, Claire. "Structure et évolution du bras court du chromosome 6 humain : la région de classe I du complexe majeur d'histocompatibilité et sa partie distale." Toulouse 3, 1996. http://www.theses.fr/1996TOU30039.
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Le principe de cartographie comparative a ete suivi pour etudier l'evolution de la region de classe i du complexe majeur d'histocompatibilite (cmh). L'auteur a identifie et localise de nouveaux marqueurs conserves entre l'homme et la souris, qui ont permis une comparaison de la moitie distale du cmh entre les deux especes. Cette carte comparative met en evidence une structure conservee de la region de classe i, malgre l'absence d'orthologie entre les genes de classe i. L'auteur postule que les sequences non apparentees aux sequences de classe i sont representatives d'une structure ancestrale, dans laquelle les sequences de classe i auraient evolue independamment. Parmi les sequences conservees, un regroupement de genes de recepteurs olfactifs a ete identifie. Plusieurs hypotheses sont proposees quant a la fonction et l'evolution de ces genes
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FOISSAC, ALEXANDRA. "Analyse de microsatellites et genetique humaine utilisations en immunogenetique et etude du chromosome 6 potentialites d'applications en transplantation de moelle osseuse." Toulouse 3, 1999. http://www.theses.fr/1999TOU30037.
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En genetique humaine, c'est dans les annees 1980 que s'ouvre l'ere de l'analyse de microsatellites, sequences repetees et nouveaux marqueurs. Dans une optique de caracterisation de l'analyse de microsatellites, trois approches : _ etat de l'art : microsatellites et analyse de microsatellites a travers une synthese bibliographique des etudes de microsatellites au sein du complexe majeur d'histocomptabilite, 104 marqueurs et une variete d'applications, est revele un developpement intense ; un essai de caracterisation en analyse microsatellite soulignant la necessite de standardisation. _ exemples d'application : genetique fondamentale et medicale a travers une etude des phenomenes de recombinaison en region hla ou du profil de susceptibilite genetique en 6q au diabete insulino-dependant, l'analyse microsatellite apparait un outil interessant, permettant la precision des intervalles de recombinaison ou la detection d'une heterogeneite d'association entre populations. _ perspectives d'application : analyse microsatellite et recherche de comptabilite en transplantation de moelle osseuse par une etude-pilote, avec genotypage d'un panel de donneurs du fichier francais, une description des profils de distribution et d'association pour 3 genes hla et 6 microsatellites hla est explicitee. Consequence d'un desequilibre de liaison, existe une possibilite de prediction des specificites hla et d'amelioration de la definition de comptabilite haplotypique grace a une caracterisation microsatellite. Par une integration du concept au sein du contexte de greffe, aspect gestion du processus de recherche de comptabilite (modalites de typage, economie) ou aspects legislation et ethique, et malgre un besoin d'optimisation et d'evaluation de faisabilite, apparait une opportunite d'innovation en greffe de moelle osseuse. En strategie de recherche ou de valorisation et application, c'est une illustration des potentialites d'exploitation d'une analyse de microsatellites qui est apportee.
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Elves, Rachel Leigh. "Consequences of mitotic loss of heterozygosity on genomic imprinting in mouse embryonic stem cells." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/1564.
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Epigenetic differences between maternally inherited and paternally inherited chromosomes, such as CpG methylation, render the maternal and paternal genome functionally inequivalent, a phenomenon called genomic imprinting. This functional inequivalence is exemplified with imprinted genes, whose expression is parent-of-origin specific. The dosage of imprinted gene expression is disrupted in cells with uniparental disomy (UPD), which is an unequal parental contribution to the genome. I have derived mouse embryonic stem (ES) cell sub-lines with maternal UPD (mUPD) for mouse chromosome 6 (MMU6) to characterize regulation and maintenance of imprinted gene expression.
The main finding from this study is that maintenance of imprinting in mitotic UPD is extremely variable. Imprint maintenance was shown to vary from gene to gene, and to vary between ES cell lines depending on the mechanism of loss of heterozygosity (LOH) in that cell line. Certain genes analyzed, such as Peg10, Sgce, Peg1, and Mit1 showed abnormal expression in ES cell lines for which they were mUPD. These abnormal expression levels are similar to that observed in ES cells with meiotically-derived full genome mUPD (parthenogenetic ES cells).
Imprinted CpG methylation at the Peg1 promoter was found to be abnormal in all sub-lines with mUPD for Peg1. Two cell sub-lines which incurred LOH through mitotic recombination showed hypermethylation of Peg1, consistent with the presence of two maternal alleles. Surprisingly, a cell sub-line which incurred LOH through full chromosome duplication/loss showed hypomethylation of Peg1. The levels of methylation observed in these sub-lines correlates with expression, as the first two sub-lines showed a near-consistent reduction of Peg1, while the latter showed Peg1 levels close to wild-type.
Altogether these results suggest that certain imprinted genes, like Peg1 and Peg10, have stricter imprinting maintenance, and as a result show abnormal expression in UPD. This strict imprint maintenance is disrupted, however, in UPD incurred through full chromosome duplication/loss, possibly because of the trisomic intermediate stage which occurs in this mechanism.
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Konyukh, Marina. "Copy number variations in autism spectrum disorders : identification and characterization of new candidate genes ( SEZ6L2 ans CNTN3-6)." Paris 7, 2010. http://www.theses.fr/2010PA077235.
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Les troubles du spectre autistique (TSA) sont caractérisés par un déficit de la communication sociale et des comportements stéréotypés. Des études d'agrégation familiales et sur les jumeaux ont indiqué que les TSA ont une composante génétique forte. Récemment, l'étude du génome à grande échelle et à haute résolution a révélé des variations du nombre de copies (CNV). Un des CNV les plus fréquemment observés chez les patients atteints de TSA est la délétion/duplication localisée dans la région chromosomique 16pl 1. 2. Parmi les gènes situés dans ce CNV, des analyses montre que SEZ6L2, pourrait être associé aux TSA. J'ai recherché des mutations dans SEZ6L2 sur un group de 170 patients et sur un panel de 282 personnes de différentes origines ethniques. J'ai trouvé des variations qui sont prédites comme ayant un impact sur la fonction de la protéine, mais ne montrant aucun enrichissement significatif chez les patients comparé aux témoins. J'ai été impliquée dans L'analyse des CNV du génome entier pour des patients atteints de TSA (n=347) et pour des contrôles (n=338). J'ai pu détecter les CNV dans des gènes candidats potentiels, notamment dans les contactines, de protéines impliquées dans le guidage axonal et dans la connexion entre les axones et les cellules gliales. J'ai séquence la partie codante des gènes CNTN3-6 et CNTNAP2 dans des groupes patients et contrôles et j'ai pu identifier des variations rares et une mutation non-sens dans des familles avec TSA. Nos données in vitro, suggèrent que plusieurs variations ont pour conséquence une altération de la morphologie des neurones. Ces résultats confirment le câblage anormal du cerveau comme un facteur de risque pour les TSAAutism spectrum disorders (ASD) are characterised by impaired reciprocal social communication, and stereotyped behaviour. Twin and familial studies have indicated that ASD are among the most genetic neuropsychiatric disorders. Recently, large-scale and high-resolution genome wide analyses revealed multiple copy number variations (CNV). Among the more frequently observed CNV associated with ASD are deletions/duplications, located on chromosome 16pl 1. 2. A primary analysis indicated that SEZ6L2 gene could be associated with ASD. During my thesis, I first screened for mutations in SEZ6L2 in a sample of 170 patients with ASD and in a panel of 282 individuals from different ethnic backgrounds. I was able to find mutations predicted as deleterious, but no significant enrichment compared with controls. I was also involved in the whole genome CNV screening of a large group of ASD patients (n=347) and controls (n=338). Using genome wide analysis, I could detect CNV altering compelling candidate genes. We could identify CNV altering several members of the contactins, a family of proteins involved in axonal guidance and the connection between axons and glial cells. I then screened for coding variations in CNTN3-6 and CNTNAP2. This screening revealed rare variants and a stop mutation present in ASD families. Our in vitro studies suggested that several variations had a functional consequence on neuronal morphology. These results further support abnormal brain wiring as a risk factor for ASD
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McDowell, Erin. "Characterization of a bacterial artificial chromosome (BAC)-based infectious clone of a low passage Marek's disease virus (MDV) vaccine strain, CVI988." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 106 p, 2009. http://proquest.umi.com/pqdweb?did=1885544371&sid=6&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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King, Stephanie. "Capillary Electrophoresis Single-Strand Conformation Polymorphism Analysis for Monitoring Bacteria during the Remediation of TNT-Contaminated Soil." Ohio University / OhioLINK, 2004. http://www.ohiolink.edu/etd/view.cgi?ohiou1108061640.
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Carvalho, Beatriz Pinto Morais de. "Chromosome 6q deletions in gastric carcinoma : A Positional cloning approach to isolate cDNAs at 6q16.3-q23.3 = Delecções do braço longo do cromossoma 6 em carcinomas gástricos : Isolamento de cDNAs em 6q16.3-q23.3 por clonagem posicional." Doctoral thesis, Universidade do Porto. Reitoria, 2000. http://hdl.handle.net/10216/10097.
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Dissertação de Doutoramento em Biologia Humana apresentada à Faculdade de Medicina da Universidade do PortoO cromossoma 6 é um dos cromossomas mais frequentemente envolvido em alterações estruturais em tumores gástricos. De todas as anomalias descritas deste cromossoma, a delecção parcial do braço longo representa é a alteração mais vezes detectada, tanto por análise citogenética como por estudos de perda de heterozigotia (LOH).A perda de heterozigotia em 6q ocorre em todos os tipos histológicos de carcinoma gástrico, incluindo tumores precoces.O objectivo "major" deste estudo foi isolar genes localizados em 6q que podem estar envolvidos no desenvolvimento e progressão de tumores gástricos. Em estudos anteriormente realizados pelo nosso grupo, foram definidas duas regiões de delecção mínima uma intersticial em 6q16.3-q23.1 (15 cM) e uma distal em 6q27 (> 30 cM). No entanto, como a extensão destas duas regiões não permitia ainda o início de pesquisa de genes, o nosso primeiro objectivo foi delimitar a região intersticial. Para isso, foram seleccionados novos marcadores localizados na região (marcadores microssatélites), que viriam a ser aplicados na análise de um painel alargado de tumores primários. Do mapeamento detalhado da região foi possível restringir a região intersticial de 15 cM para uma nova região de apenas 2 cM (aproximadamente 3 Mb) (Artigo I).No sentido de ultrapassar os problemas de análise e interpretação decorrentes da contaminação estromal em tumores primários, procedemos ao estudo de tumores xenografados em ratinhos atímicos e linhas celulares derivadas dos xenografos, estabelecidos no nosso Instituto. Este estudo, envolvendo análise de microssatélites e FISH, permitia verificar se as linhas celulares em causa apresentavam as mesmas alterações em 6q detectadas nos tumores primários, o que, a verificar-se, permitiria utilizar este material como para estudos futuros, nomeadamente estudos funcionais.Verificámos que, tal como nos tumores primários, duas linhas celulares apresentavam uma delecção distal (6q27). Estes resultados apoiam a existência d ...
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Carvalho, Beatriz Pinto Morais de. "Chromosome 6q deletions in gastric carcinoma : A Positional cloning approach to isolate cDNAs at 6q16.3-q23.3 = Delecções do braço longo do cromossoma 6 em carcinomas gástricos : Isolamento de cDNAs em 6q16.3-q23.3 por clonagem posicional." Tese, Universidade do Porto. Reitoria, 2000. http://hdl.handle.net/10216/10097.
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Dissertação de Doutoramento em Biologia Humana apresentada à Faculdade de Medicina da Universidade do PortoO cromossoma 6 é um dos cromossomas mais frequentemente envolvido em alterações estruturais em tumores gástricos. De todas as anomalias descritas deste cromossoma, a delecção parcial do braço longo representa é a alteração mais vezes detectada, tanto por análise citogenética como por estudos de perda de heterozigotia (LOH).A perda de heterozigotia em 6q ocorre em todos os tipos histológicos de carcinoma gástrico, incluindo tumores precoces.O objectivo "major" deste estudo foi isolar genes localizados em 6q que podem estar envolvidos no desenvolvimento e progressão de tumores gástricos. Em estudos anteriormente realizados pelo nosso grupo, foram definidas duas regiões de delecção mínima uma intersticial em 6q16.3-q23.1 (15 cM) e uma distal em 6q27 (> 30 cM). No entanto, como a extensão destas duas regiões não permitia ainda o início de pesquisa de genes, o nosso primeiro objectivo foi delimitar a região intersticial. Para isso, foram seleccionados novos marcadores localizados na região (marcadores microssatélites), que viriam a ser aplicados na análise de um painel alargado de tumores primários. Do mapeamento detalhado da região foi possível restringir a região intersticial de 15 cM para uma nova região de apenas 2 cM (aproximadamente 3 Mb) (Artigo I).No sentido de ultrapassar os problemas de análise e interpretação decorrentes da contaminação estromal em tumores primários, procedemos ao estudo de tumores xenografados em ratinhos atímicos e linhas celulares derivadas dos xenografos, estabelecidos no nosso Instituto. Este estudo, envolvendo análise de microssatélites e FISH, permitia verificar se as linhas celulares em causa apresentavam as mesmas alterações em 6q detectadas nos tumores primários, o que, a verificar-se, permitiria utilizar este material como para estudos futuros, nomeadamente estudos funcionais.Verificámos que, tal como nos tumores primários, duas linhas celulares apresentavam uma delecção distal (6q27). Estes resultados apoiam a existência d ...
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Zeller, Constanze. "Isolierung und Charakterisierung tumorsupprimierender Gene aus der Chromosomenregion 6q23-q25 beim primären Mammakarzinom des Menschen." Berlin wvb, Wiss. Verl, 2007. http://www.wvberlin.de/data/inhalt/zeller.html.
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Gilbert-Girard, Shella. "Étude de l'intégration chromosomique de l'herpèsvirus humain de type 6 et impact de son infection sur la reconnaissance des dommages aux télomères." Master's thesis, Université Laval, 2016. http://hdl.handle.net/20.500.11794/27414.
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L’herpèsvirus humain de type 6B (HHV-6B) infecte près de 100% des humains et établit une latence pour le reste de la vie de l’hôte. L’épidémiologie d’HHV-6A est moins connue. Ces deux virus sont capables d’intégrer leur génome dans les télomères des chromosomes humains. Lorsque cette intégration a lieu dans une cellule germinale et qu’il y a fécondation, ceci mène à un individu portant une copie du génome viral dans chacune des cellules de son corps. Cette condition, appelée inherited chromosomally-integrated HHV-6 (iciHHV-6), résulte en une transmission du génome viral intégré à 50% des descendants et est retrouvée chez environ 1% des humains. Malgré cette importante fréquence dans la population, l’intégration de HHV-6, de même que son infection et son effet sur ses cellules hôtes, demeurent peu caractérisés. Dans ce travail, nous avons étudié l’effet de l’infection d’HHV-6A et HHV-6B sur la réponse de dommages à l’ADN (DDR). Nous avons observé une forte réponse DDR localisée dans les compartiments de la réplication virale (RC), colocalisant avec une grande quantité d’ADN télomérique d’origine virale. De plus, les niveaux des ARNm des gènes TRF1, TRF2 et TPP1, membres du complexe shelterin protégeant les télomères, étaient surexprimés dans les cellules infectées. Cette augmentation se traduit par une surexpression de la protéine TRF2, recrutée aux séquences télomériques virales dans les RC. Finalement, nous avons étudié l’effet de BRACO-19, un inhibiteur de la télomérase, sur l’intégration d’HHV-6A et sa persistance. En utilisant un essai d’intégration récemment mis au point dans notre laboratoire, nous avons démontré que l’inhibition de la télomérase menait à une diminution significative de la fréquence de cellules porteuses d’intégration. Ce travail apporte de nouvelles connaissances sur l’infection de HHV-6 et sur son mécanisme d’intégration potentiel, de même que la première observation d’une possible participation des protéines du complexe shelterin dans l’infection de HHV-6.Human herpesviruse 6B (HHV-6B) is a very prevalent virus that infect nearly 100% of humans and establish a life-long latency. Much less is known regarding HHV-6A epidemiology. Both viruses can integrate their genome into the telomeres of human chromosomes. When this integration occurs in a germinal cell, it can lead to an individual carrying one copy of the viral genome in every cell of its body. This condition, called inherited chromosomally-integrated HHV-6 (iciHHV-6), will then be transmitted to 50% of offspring and is found in approximately 1% of individuals across the world. Despite being so frequent, much remains to be studied on HHV-6 infection and integration processes. In this work, we studied the effects of viral infection on DNA damage response (DDR) signaling. We observed a DDR located in viral replication compartments (RC), together with a large amount of telomeric sequences that we confirmed to be of viral origin. In addition, mRNAs coding for TRF1, TRF2 and TPP1, members of the shelterin complex protecting telomeres, were upregulated during infection. Consequently, TRF2 protein was overexpressed and relocated to viral telomeric sequences in RC. Lastly, we’ve examined the effects of BRACO-19, a compound that affects telomerase activity, on HHV-6 integration and persistence. Using an integration assay recently developed in our laboratory, we could demonstrate that in the presence of the telomerase inhibitor, the frequency of cells containing integrated HHV-6 was significantly reduced. This work brings new knowledge regarding HHV-6 infection and its potential integration mechanism, as well as the first observation of a possible participation of the shelterin complex proteins during HHV-6 infection.
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Trempe, Frédéric. "Étude du rôle de la protéine U94 de l'herpèsvirus humain de type 6 dans le processus de l'intégration chromosomique." Thesis, Université Laval, 2013. http://www.theses.ulaval.ca/2013/29539/29539.pdf.
Full textAbstract:
L’herpèsvirus humain de type 6 (HHV-6) infecte les enfants en bas âge et sa prévalence est estimée à près de 95% dans la population mondiale. Ce virus se distingue des autres membres de la famille des herperviridae par sa capacité à s’intégrer aux chromosomes cellulaires. On estime qu’environ 1% de la population mondiale serait porteuse d’une copie du génome du HHV-6 par cellule (52, 73, 100, 119, 131). Le mécanisme de cette intégration est toujours inconnu.
Nous pensons que la protéine U94 du HHV-6 joue un rôle important dans l'intégration chromosomique du génome viral. Elle serait nécessaire à l'éxécution d'une recombinaison homologue entre les séquences télomériques cellulaires et virales (motif TTAGGG). U94 a une homologie de séquence de 24% avec la protéine Rep68 responsable de l'intégration du génome de l’adeno-associated virus 2 (AAV-2) au chromosome 19 (123). Pour ce faire, quatre activités intrinsèques à la protéine Rep68 lui sont nécessaires : la liaison à l'ADN simple et double brin, l'ATPase, l'hélicase et l'endonucléase (54, 97).
Le but de ce projet de recherche était de caractériser les activitités biochimiques de la protéine U94. Tout d’abord, nous avons démontré que la protéine U94A est localisée au noyau en accord avec les résultats obtenus par le laboratoire du Dr. Mori (87). Pour réaliser nos études, nous avons exprimé et purifié U94 chez E. coli en fusion avec la protéine maltose-binding protein (MPB). Nos résultats démontrent que les protéines MBP-U94A et MBP-U94B sont capables de lier préférentiellement l'ADN simple brin avec un motif CCCTAA (complément du motif télomérique TTAGGG). L’essai de liaison sur le Proteon™ XPR36 démontre également que la protéine MBP-U94B lie un ADN double brin ayant le motif télomérique cellulaire. Nos résultats nous ont amenés à vérifier si l'ARN de la télomérase, qui contient un motif CCCTAA, pouvait aussi être lié par les protéines MBP-U94A et MBP-U94B. Les résultats obtenus indiquent que MBP-U94 ne lie pas l'ARN, ni la séquence équivalente en ADN ce qui suggère que la liaison de U94 requiert plus d’une répétition du motif CCCTAA. En se basant sur des études de mutagenèse réalisées sur la protéine Rep68 (128, 129), nous avons générés des mutants U94A et U94B. Les résultats démontrent que la mutation K395A affecte négativement la capacité de liaison à l’ADN de U94.
Les essais d'ATPase indiquent que MBP-U94A et MBP-U94B hydrolysent l'ATP en ADP et AMP en présence d'un ADN simple brin ou d’un ADN double brin. Divers mutants des activités d’ATPase/Hélicase et d’endonucléase présumées furent générés et devront être caractérisés.
Ces résultats suggèrent que U94 possède les activités biochimiques nécessaires à l'intégration du génome viral aux chromosomes cellulaires.Human herpesvirus 6 infects young children with an estimated prevalence of 95% in the world population. It differs from the other members of the herperviridae family by its capacity to integrate cell's chromosomes. It is estimated that approximately 1% of the world population carries a copy of the HHV-6 genome per cell (52, 73, 100, 119, 131). The chromosomal integration mechanisms used by HHV-6 are currently unknown. Our hypothesis is that the HHV-6 U94 protein plays an important role in chromosomal integration that we suspect occur through homologous recombination between cellular and viral telomeric sequences (TTAGGG). The U94 gene product shares 24% sequence homology with Rep68, a responsible for the genomic integration of adeno-associated virus 2 (AAV-2) (123). To promote integration, Rep68 relies on four intrinsic activities: binding to single and double stranded DNA, ATPase activity, helicase and endonuclease (54, 97). The goal of this research project is to characterize the biochemical properties of U94 and determine whether it posseses activities similar to Rep68. First, we confirmed the results of Dr. Mori's laboratory by showing that U94 is localized in the nucleus (87). Next, to conduct our studies, we’ve expressed and purified maltose-binding-U94 recombinant proteins (MBP-U94) in E. coli. Our results suggest that MBP-U94A and MBP-U94B preferentially bind single-strandred DNA containing the CCCTAA motif (complement to the TTAGGG telomeric motif). Surface plasmon resonance (SPR) experiments also indicate that MBP-U94B binds double-stranded DNA containing telomeric motifs. Since the telomerease RNA component TERC contains the CCCTAA motif, we investigated whether MBP-U94 could bind a single-stranded RNA molecule containing the CCCTAA motif. SPR analysis clearly indicates that MBP-U94 does not bind such RNA nor a single-stranded DNA molecule having a single CCCTAA motif, suggesting that more than one motif is required for proper binding. Based on published work on Rep68 (128, 129), we generated specific U94 mutants. Our results indicate that the K395A mutation greatly diminishes U94 binding to DNA pointing out the importance of this residue. ATPase assays were also performed and indicate that both MBP-U94A and MBP-U94B possess the ability to hydrolyze ATP into ADP and AMP when incubated in the presence of DNA. Several other mutants targeting the helicase and endonuclease activities were generated and will be tested in the near future. Altogether these results suggest that U94 has biological properties that are consistent with a role for this protein in the process of chromosomal integration of the HHV-6 genome into the host chromosomes.
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Kuhn, Kristina [Verfasser]. "Charakterisierung des doppelkonsomen Rattenstamms MWF-6SHR8SHR zur Analyse der Albuminurie-QTL auf Chromosom 6 und Chromosom 8 bei der MWF-Ratte / Kristina Kuhn." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1026789885/34.
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Duscher, Sonja. "Vergleichende Genomanalyse bei Mensch und Schwein am Beispiel ausgewählter syntenischer Regionen des humanen Chromosoms 6." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=962093890.
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Tsao, E. H. F. "Gene expression studies of lytic infection and chromosomal integration of human herpesvirus 6." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445129/.
Full textAbstract:
Human herpesvirus 6 (HHV-6) was discovered in 1986 in patients with lymphoproliferative diseases and it has a predominant tropism for CD4+ T cells in vitro and in vivo. The virus can be divided into two variants: HHV-6A and 6B, based on the differences in biological properties and DNA sequences. HHV-6B has been shown to be the causative agent of exanthem subitum while HHV-6A has no clear association with any disease yet. The genome for both variants has been defined and each encodes just over 100 open readings frames (ORFs). However, there is limited knowledge regarding the functions and transcription kinetics of most ORFs. This thesis discusses the development of DNA microarrays for HHV-6 and the application of the arrays to characterise HHV-6B gene expression in the SupT1 cell line. The expression pattern of individual viral genes over a 60h time course (<1 replication cycle) was profiled. Viral genes were further classified into three kinetic groups: immediately-early (IE), early (E), and late (L), according to their transcriptional activity in the absence of de novo protein synthesis or DNA replication. In addition, HHV-6 presents an atypical stage in the herpesvirus life cycle in which the viral genome is integrated into host chromosomes. The prevalence of HHV-6 integration was estimated to be between 0.21% to 3%. An individual harbouring integrated HHV-6 was previously identified. The molecular biology and gene expression of this integrated HHV-6 DNA were characterised. Expression of viral genes belonging to all three kinetic classes (IE, E, and L) was detected in vitro and ex vivo. The data strongly suggest that the chromosomal HHV-6 sequence is transcriptionally active and the implications of this are discussed.
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Arbuckle, Jesse Herbert. "Identification and Characterization of the Human Herpesviruses 6A and 6B Genome Integration into Telomeres of Human Chromosomes during Latency." Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/2989.
Full textAbstract:
While the latent genome of most Herpesviruses persists as a nuclear circular episome, previous research has suggested that Human Herpesvirus 6 (HHV-6) may integrate into host cell chromosomes, and be vertically transmitted in the germ-line. Because the HHV-6 genome encodes a perfect TTAGGG telomere repeat array at the right end direct repeat (DRR) and an imperfect TTAGGG repeat at the end of the left end direct repeat (DRL), we established a hypothesis that during latency, the HHV-6A and HHV-6B genome integrates into the telomeres of human chromosomes through homologous recombination with the n(TTAGGG) viral repeats, and the integrated virus can be induced to lytic replication.
We sought, first, to definitively illustrate the in vitro and in vivo integration of HHV-6A and HHV-6B. Following infection of naïve Jjhan and HEK-293 cell lines by HHV-6A and Molt3 cell line by HHV-6B, the virus integrated into telomere of chromosomes. Next, peripheral blood mononuclear cells (PBMCs) were isolated from families in which several members, including at least one parent and child, had unusually high copy numbers of HHV-6 DNA per ml of blood. FISH confirmed that HHV-6 DNA co-localized with telomeric regions of one allele on chromosomes 17p13.3, 18q23, and 22q13.3, while the integration site was identical among members of the same family. Partial sequencing of the viral genome identified the same integrated HHV-6A strain within members of families, confirming vertical transmission of the viral genome through the germ-line [inherited HHV-6 (iHHV-6)].
Amplification and sequencing of the HHV-6A and more recently HHV-6B viral-chromosome junction identified DRR integrated into the telomere directly adjacent to the subtelomere of the chromosome. After mapping the DRR of iHHV-6, we subsequently focused on determining if the DRL was present in the integrated genome and whether the remaining telomere sequence of the chromosome was extended beyond the DRL. Southern hybridization of PCR amplified HHV-6 integrated cell lines and iHHV-6 patients PBMCs indicate the presence of DRL within the integrated viral genome. Therefore, the genomic structure of the iHHV-6 is as follows: chromosome-subtelomere-(TTAGGG)5-41-DRR-U-DRL-(TTAGGG)n.
During latent integration, no circular episomes were detected even by PCR. However, trichostatin-A treatment of PBMCs and in vitro integrated HEK-293 cells induced the reactivation of iHHV-6 from its latent integrated state. We demonstrated the induction of integrated iHHV-6 with trichostatin-A lead to the excision of the integrated genome and generation of the U-DR-U junction which signifies circularization and/or concatemer formation of the viral genome through rolling-circle replication. Taken together, the data suggests that HHV-6A and HHV-6B are unique among human herpesviruses: they specifically and efficiently integrate into telomeres of chromosomes during latency rather than forming episomes, and the integrated viral genome is capable of producing virions.
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Schrempf, Matthias Christian [Verfasser], Adnan [Akademischer Betreuer] Kastrati, and Karl-Ludwig [Akademischer Betreuer] Laugwitz. "Assoziation der SLC22A3-LPAL2-LPA-Genregion auf dem Chromosom 6 mit dem akuten Myokardinfarkt / Matthias Christian Schrempf. Gutachter: Adnan Kastrati ; Karl-Ludwig Laugwitz. Betreuer: Adnan Kastrati." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1062700821/34.
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Eberhardt, Andrea. "Auf der Suche nach frühen Gendefekten beim sporadischen Mammakarzinom: Identifizierung zweier 4 und 6 Mb großer Deletionen auf Chromosom 6q24 bei einzelnen disseminierten Tumorzellen mit normalem CGH-Profil." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-63556.
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Toyama, Julio Mitsutomo. "O papel da dopplervelocimetria do ducto venoso de 11 a 13 6/7 semanas no rastreamento de anomalias cromossômicas, malformações estruturais e prognóstico fetal." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-13102014-101232/.
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Objetivos: avaliar a contribuição do fluxo anormal no ducto venoso de 11 a 13 6/7 semanas no rastreamento de anomalias cromossômicas, defeitos estruturais e prognóstico gestacional. Método: 1221 gestações únicas foram submetidas a Dopplervelocimetria do ducto venoso após o rastreamento pela translucência nucal (TN). Resultados: os defeitos cromossômicos foram diagnosticados em 22 fetos. O fluxo no ducto venoso estava anormal em 84 fetos, a TN estava acima do 95o percentil em 160 casos e ambos marcadores estiveram anormais em 41 fetos. A sensibilidade, especificidade, valores preditivos positivo e negativo para defeitos cariotípicos corresponderam respectivamente a 86,4%, 86,9%, 11,9% e 99,7% considerando a TN aumentada, 68,2%, 96,9%, 31,3%, 99,3% para anomalias do fluxo do ducto venoso e 68,2%, 97,6%, 36,6%, 99,3% analisando ambos os marcadores. Investigando malformações estruturais, esses valores foram de 43,8%, 92,9%, 8,3%, 99,1% para uma TN aumentada, 25%, 92,6%, 4,8%, 98,8% para anomalias do fluxo do ducto venoso e 25%, 97,9%, 15,4%, 98,9% para ambos os marcadores. Nos casos com TN aumentada, a proporção de nascidos vivos morfológica e cariotipicamente normais diminui de 93,8% nos fetos com fluxo no ducto venoso normal para 77,3%, quando anormal. Conclusão: a avaliação do ducto venoso de 11 a 13 6/7 semanas de gestação pode ser utilizada no rastreamento de anomalias cromossômicas fetais e pode ajudar a reduzir a taxa de falso-positivo quando combinado com a medida da TN. Em fetos com TN aumentada o fluxo anormal no ducto venoso aumenta a probabilidade de resultados gestacionais adversosObjective: To evaluate the association between abnormal ductus venosus at 11 - 13 6/7 weeks\' gestation and chromosomal abnormalities, structural defects and fetal outcome. Methods: Ductus venosus waveform (DVFVW) and nuchal translucency (NT) thickness were prospectively evaluated in 1221 singleton pregnancies. Results: The DVFVW was abnormal in 84 cases, NT was above the 95th centile in 160 cases and both markers were observed in 41 fetuses. Chromosomal defects were diagnosed in 22 fetuses. The sensitivity, specificity and positive predictive values for an abnormal karyotype were respectively 86.4%, 86.9%, 11.9% for an increased NT; 68.2%, 96.9%, 31.3% for DVFVW abnormalities and 68.2%, 97.6%, 36.6% for both markers. Regarding structural defects, this values were 43.8%, 92.9%, 8.3% for an abnormal NT, 25%, 92.6%, 4.8% for DVFVW abnormalities and 25%, 97.9%, 15.4% for both. Considering those cases of unexplained fetal demise, the percentages were 44.4%, 85.9%, 5% for NT abnormalities, 22.2%, 92.6%, 4.8% for an abnormal DVFVW and 22.2%, 98%, 15.4% for both. In cases with increased NT measurement, the percentage of livebirths with normal karyotype and no major fetal structural defects decreased from 93.8% in normal DVFVW fetuses to 77.3%, when abnormal. Conclusion: Ductus venosus assessment at 11 - 13 6/7 weeks\' gestation is useful in screening for fetal chromosomal abnormalities and may help to reduce the false-positive rate when combining with NT thickness measurement. Abnormal DVFVW is also associated with an increase of adverse perinatal outcome in fetuses with enlarged NT. However, the value of DVFVW assessment in cases with normal NT measurement is unclear
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Cooke, Peter Henry. "Electrophoretic and nucleotide polymorphism at the esterase-6 locus of drosophila melanogaster." Phd thesis, 1988. http://hdl.handle.net/1885/141092.
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"Loss of chromosome 6q is frequently seen in gastric carcinoma of all stages." 2001. http://library.cuhk.edu.hk/record=b5890914.
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Li Chung Yi.Thesis (M.Phil.)--Chinese University of Hong Kong, 2001.
Includes bibliographical references (leaves 110-123).
Abstracts in English and Chinese.
ABSTRACT --- p.i
ACKNOWLEDGEMENTS --- p.iv
TABLE OF CONTENTS --- p.v
LIST OF FIGURES --- p.ix
LIST OF TABLES --- p.xi
Chapter I. --- INTRODUCTION --- p.1
Chapter I.1 --- Gastric Carcinoma --- p.1
Chapter I.2 --- Etiology of Gastric Carcinoma --- p.2
Chapter I.2.1 --- Environmental Factors: --- p.2
Chapter I.2.2 --- Helicobacter Pylori Infection: --- p.2
Chapter I.2.3 --- Genetic Factors: --- p.3
Chapter I.2.4 --- Other Factors: --- p.4
Chapter I.3 --- The Lauren Classification of Gastric carcinoma --- p.5
Chapter I.3.1 --- Histolopathology of Intestinal Type of Gastric Carcinoma --- p.5
Chapter I.3.2 --- Histopathology of Diffuse Type of Gastric Carcinoma --- p.8
Chapter I.4 --- Cytogenetics Studies in Gastric Carcinoma --- p.10
Chapter I.4.1 --- Cytogenetic Studies of Gastric carcinoma --- p.10
Chapter I.5 --- Molecular Studies of Gastric Carcinoma --- p.14
Chapter I.5.1 --- Genetic Instability --- p.14
Chapter I.5.2 --- Amplification/ Mutation of Oncogenes --- p.15
Chapter I.5.3 --- Alterations of Tumor Suppressor Genes --- p.20
Chapter I.5.4 --- Cell Adhesion Molecules --- p.23
Chapter I.5.5 --- Molecular Studies on Intestinal Metaplasia --- p.27
Chapter II. --- LONG ARM OF CHROMOSOME 6 --- p.28
Chapter III. --- BRIEF REVIEWS OF THE TECHNIQUES USED IN THIS STUDY --- p.34
Chapter III.1 --- Comparative Genomic Hybridization (CGH) --- p.34
Chapter III.2 --- Loss of Heterozygosity (LOH) --- p.37
Chapter III.3 --- Methylation-Specific PCR (MSP) --- p.38
Chapter IV. --- OBJECTIVES OF STUDY --- p.40
Chapter V. --- MATERIALS AND METHODS --- p.41
Chapter V.l --- Sample Collections --- p.41
Chapter V.1.1 --- Patients Information for CGH Studies --- p.42
Chapter V. 1.2 --- Patients Information for LOH Studies --- p.42
Chapter V.2 --- Extraction of Genomic DNA for Tumor and Normal Tissues --- p.47
Chapter V.2.1 --- Extraction of Genomic DNA from Frozen Tissues or Paraffin Embedded Sections --- p.47
Chapter V.2.2 --- Extraction of Genomic DNA from Blood --- p.48
Chapter V.3 --- Comparative Genomic Hybridization (CGH) of Gastric Carcinoma --- p.49
Chapter V.3.1 --- Preparation of Normal Metaphase Slides --- p.49
Chapter V.3.2 --- Metaphase Slide Denaturation --- p.49
Chapter V.3.3 --- Nick Translation for DNA Labeling --- p.50
Chapter V.3.4 --- Dot Blot Assay for Biotin and Digoxigenin-Labeled DNA --- p.51
Chapter V.3.5 --- "Probe Preparation, Denaturation and Hybridization" --- p.51
Chapter V.3.6 --- Post hybridization Washing and Detection --- p.52
Chapter V.3.7 --- Image Acquisition and Analysis of CGH Images --- p.53
Chapter V.4 --- Loss of Heterozygosity (LOH) Analysis on Chromosome 6q --- p.55
Chapter V.4.1 --- Microsatellite Markers --- p.55
Chapter V.4.2 --- Polymerase Chain Reaction (PCR) --- p.57
Chapter V.4.3 --- Denaturing Polyacrylamide Gel Electrophoresis --- p.58
Chapter V.4.4 --- SYBR Gold Nucleic Acid Gel Staining and Image Viewing --- p.58
Chapter V.4.5 --- Assessment of Loss of Heterozygosity (LOH) --- p.59
Chapter V.4.6 --- Statistical Analysis --- p.61
Chapter V.5 --- Methylation Specific Polymerase Chain Reaction (MSP) --- p.62
Chapter V.5.1 --- Bisulfite Modification of DNA --- p.62
Chapter V.5.2 --- Mehtylation Specific PCR --- p.63
Chapter VI. --- RESULTS --- p.66
Chapter VI.1 --- Results of CGH --- p.66
Chapter VI. 1.1 --- Chromosomal Copy Number Aberrations in Gastric Carcinoma --- p.66
Chapter VI. 1.2 --- Comparison of CGH Results with Intestinal and Diffuse Type of Gastric Carcinoma --- p.67
Chapter VI.2 --- LOH Analysis of Chromosome 6q --- p.73
Chapter VII. --- DISCUSSIONS --- p.83
Chapter VII.l --- Discussions on CGH --- p.83
Chapter VII.2 --- Discussions on LOH Study --- p.89
Chapter VII.2.1 --- Two Distinct Deletion Regions --- p.89
Chapter VII.2.2 --- Possible Candidate Suppressor Genes in Two Deletion Regions --- p.93
Chapter VII.2.3 --- Infrequent Loss of IGF2R Gene --- p.95
Chapter VII.3 --- Relationship Between Intestinal Metaplasia and Gastric Carcinoma --- p.99
Chapter VII.4 --- Microsatellite Instability --- p.100
Chapter VII.5 --- Correlations --- p.103
Chapter VII.6 --- Comparison Between CGH and LOH Results on Chromosome 6 --- p.104
Chapter VII.7 --- Conclusions --- p.106
Chapter VII.8 --- Limitations of the Study --- p.107
Chapter VII.8.1 --- Limitation of CGH --- p.107
Chapter VII.8.2 --- Limited Information Supply by LOH Analysis --- p.107
Chapter VII.8.3 --- Small Sample Size --- p.107
Chapter VII.9 --- Future Studies --- p.108
Chapter VIII. --- REFERENCES --- p.110
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Lin, Hong-Mao, and 林弘茂. "Mapping the centromere of chromosome 6 by using B-A translocation in maize." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/36059718582810762849.
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碩士國立中興大學
分子生物學研究所
87
Abstract The centromere of chromosome 6 was physically mapped by hypoploids of TB-6Lc and TB-6Sa generated by maize B-A translocations. The hypoploid from TB-6Lc is deficient for almost the entire length of the paternal long arm, while the hypoploid TB-6Sa is deficient for the paternal short arm. RFLP markers located on the long arm will lose the paternal signal on hypoploid from TB-6Lc , and those RFLP markers located on short arm will not possess the paternal signal on hypoploid from TB-6Sa . Then the map position of the centromere is located between two RFLP markers close to the translocation breakpoints on both arms. The result of this study maps the centromere of chromosome 6 in the bnl6.29-bnl7.28 region , an interval of about 2 to 3 cM. The position of traslocation breakpoint was also defined, TB-6Lc in the csu71-bnl7.28 region, TB-6Sa in the uaz102-bnl6.29 region. In addition to centromeric location other interesting observations were found in this study. The hypoploids of TB-6Lc and TB-6Sa werefound to be associated with the chromosome rearrangement near or at the translocation breakpoint. The other observation is that the RFLP marker bnl7.28 shows homology with the B chromosome.
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Chen, Yen-Jiun, and 陳彥君. "physical mapping of RFLP markers on the long arm of chromosome 6 in maize." Thesis, 1996. http://ndltd.ncl.edu.tw/handle/76989219332864837115.
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碩士國立中興大學
分子生物研究所
84
The X-ray-induced r-X1 deletion generates a low frequency of chromosome breakage. The resulting fragment carrying the centromere is retained in the cell to become a terminal deficiency called partial monosomy ( PM ). This thesis aims to isolate PMs associated with the long arm of chromosome 6 ( 6L ) and to use them for physical mapping RFLP probes. These PMs were isolated from crossing r-X1/R-r plants as pistillate parents with r/r plants carrying recessive pigmy 1 ( py1 ) gene. Among the F1 progeny, majority expressed py1 phenotype. These py1 plants are deficient for the maternal dominant Py1 allele. Of 105 py1 recessive progenies produced from the cross, eight were PMs with the deletion of a large portion of 6L idetified by subsequent cytological examination and Southern hybridization. These PMs were used to map eleven RFLP probes. Their breakpoints divided 6L into six region C with only five PM breakpoints. The order of the RFLP probes mapped in the thesis was parallel to genetic linkage maps with the exception of umc137 and umc133. Both of them are not located physically on the long arm of chromosome 6.
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Kabir, Sadia. "Molecular analysis of structure of chromosome 6R of triticale T701-4-6 / by Sadia Kabir." Thesis, 1997. http://hdl.handle.net/2440/19234.
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Errata slip inserted.Bibliography: leaves 68-93.
viii, 93, [42] leaves, [15] leaves of plates : ill. ; 30 cm.
Rye chromosome 6R in triticale contains a gene useful for resistance to cereal cyst nematode. This study shows that the complex structure of this chromosome may prevent render its use impracticle in introgression of this resistance into wheat.
Thesis (Ph.D.)--University of Adelaide, Dept. of Plant Science, 1998
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Cordero, Guzmán Gustavo Segundo. "Reassembly and biochemical characterization of the human Smc5/6 complex." Thèse, 2017. http://hdl.handle.net/1866/20396.
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Wani, Saima Masood. "Elucidation of the Role of Nse1, a RING Domain Containing Component of Smc5/6 complex, in Maintenance of Chromosome Stability in Saccharomyces cerevisiae." Thesis, 2017. http://etd.iisc.ernet.in/2005/3570.
Full textAbstract:
Structural Maintenance of Chromosomes (SMC) proteins are a highly conserved class of proteins required for the maintenance of genome stability and regulate nearly all aspects of chromosome biology. Eukaryotes, such as the budding yeast Saccharomyces cerevisiae, have six Smc proteins that form three SMC complexes in association with non-SMC proteins, i.e., the cohesin complex, the condensin complex and the Smc5/6 complex. The yeast Smc5/6 complex consists of Smc5, Smc6 and six non-Smc elements (Nse1-6) that are all essential for the survival of cells.
Nse1 is the first non-smcelement that was identified associated with the Smc5/6 complex. Nse1 has a C-terminal RING-domain, which is a characteristic feature of some E3 ubiquitin ligases. A RING domain consists of eight conserved Zn-coordinating residues arranged in a cross-brace conformation. To understand the importance of this domain, we created site directed mutations in conserved residues identified by sequence alignment of the budding yeast Nse1 RING domain with that of other species. We found a new RING domain mutant nse1-103that was temperature sensitive at 37°C and showed an increased sensitivity towards genotoxic agents such as hydroxyurea (HU), methyl methane sulfonate (MMS) and ultraviolet (UV) radiation. Thense1-103 mutant cells are slow growing and show delayed chromosomal replication at the restrictive temperature. Genetic interactions with replication factors such as RRM3, TOF1 etc. revealed thatnse1-103shows a synthetic sick growth defect in combination with rrm3∆ that is partially suppressed by deletion of TOF1. We found an enhancement in chromosome loss in nse1-103 compared to wild type cells. This was accompanied by a slight reduction in cohesion between the sister chromatids in nse1-103,suggesting a plausible mechanism for the chromosome destabilization observed in the mutant.
Since Nse1 forms part of a trimeric sub-complex with Nse3 and Nse4 in the Smc5/6 complex, we performed a yeast two hybrid assay to test the interaction of nse1-103 with Nse3 or Nse4, and found a defect in interaction of nse1-103 with Nse3 and Nse4. In addition, a defect in association of nse1-103 with Smc5 or Smc6 could be observed by performing co-immunoprecipitation from yeast cell lysates, suggesting that the integrity of the RING-domain is critical for the interaction of Nse1 with other subunits of the Smc5/6 complex. However, there was no defect in the interaction between Nse3 and Smc5 in nse1-103, indicating that the interaction of these components within the complex isindependent of Nse1.
We also identified a novel sequence motif near the RING domain of Nse1, deletion of which leads to an increased sensitivity towards genotoxic stressors and higher temperature. Biochemical characterization of this mutant also suggests a defect ininteraction with Nse3 or Nse4, and also with Smc5. The nse1 mutants also showed defects in post translational modification of Smc5 and other proteins.
Since the Smc5/6 complex also has a SUMO E3 ligase, Mms21/Nse2, we also investigated genetic interactions between the RING domain mutant,nse1-103 and the SUMO ligase RING domain defective mutant,mms21∆sl, and found an exacerbation of the drug sensitive phenotypes in thense1-103 mms21∆sl double mutant relative to either of the single mutants nse1-103 or mms21∆sl, indicating that the two proteins contribute independently to the function of Smc5/6 complex in resisting genotoxic stress.
In conclusion, the present study emphasizes the role of the RING domain of budding yeast Nse1 in resisting genotoxic stress and maintaining chromosome stability and reveals that the integrity of the RING-domain is critical for interactions of Nse1 with Nse3 and other Smc5/6 complex components. In addition, we report identification of another novel sequence motif in Nse1 that is also crucial for its interaction with other subunits of the Smc5/6 complex and for maintenance of post-translational modifications of some cellular proteins.
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Toledo-Flores, Deborah Fernanda. "Evolution of mammalian sex chromosomes and sex determination genes: insights from monotremes." Thesis, 2015. http://hdl.handle.net/2440/97382.
Full textAbstract:
Genetic sex determination systems are generally based on the presence of differentiated sex chromosomes. Birds have a ZZ/ZW sex chromosome system in which males are ZZ and females ZW, whereas mammals have an XX/XY system with males being XY and females XX. Monotremes have an extraordinary sex chromosome system that consists of multiple sex chromosomes: 5X5Y in platypus and 5X4Y in echidna. Intriguingly, the monotreme sex chromosomes show extensive homology to the bird ZW and not to the therian XY. However, sex determination in monotremes is still a mystery; the Y-specific Sry gene that triggers male sex determination in therian mammals is absent and so far very few genes have been identified on Y chromosomes in monotremes. To gain more insights into the gene content of Y-chromosomes and to identify potential sex determination genes in the platypus a collaborative large scale transcriptomic approach led to the identification of new male specific genes including the anti-Muellerian hormone AMH that I mapped to Y₅, this makes Amhy an exciting new candidate for sex determination in monotremes. Platypus chromosome 6 is largely homologous to the therian X and therefore it represents the therian proto sex chromosome. In addition, this autosome features a large heteromorphic nucleolus organizer region (NOR) and associates with the sex chromosomes during male meiosis (Casey and Daish personal communication). I investigated chromosome 6 heteromorphism in both sexes and found a number of sex-specific characteristics related to the extent of the NOR heteromorphism, DNA methylation, silver staining patterns and interestingly, meiotic segregation bias. This raises the possibility that chromosome 6 may have commenced differentiation prior to monotreme therian divergence. These results led me to investigate the chromosome 6 borne gene Sox3, from which Sry evolved in therian mammals. This revealed a platypus male-specific Sox3 allele, which differs from the alleles observed also in females on the length of one of the Sox3
polyalanine tracts. This raises the possibility that Sox3 may be working differently in males and females. We have used our unique knowledge of monotreme sex chromosomes to determine the sex of captively bred echidnas. I used a PCR based genetic sexing technique that utilizes DNA from small hair samples and primers that amplify male-specific genes. Interestingly, I found that seven out of eight echidnas born in captivity were females. Furthermore, I found a Sox3 deletion in the only male echidna born in captivity. This gives us the unique opportunity to investigate the sexual development of an animal in which this gene is naturally deleted providing an exceptional situation in which to study monotreme sex determination. Furthermore, this sexing technique has the potential of being applied in the wild to investigate sex ratio in natural populations of monotremes, including the critically endangered long-beaked echidna.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2015
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Rai, Ragini. "Molecular Genetic Analysis Of The Role Of Nse2, A SUMO E3 Ligase Of The Smc5/6 Complex, In Resisting Genotoxic Stress And Maintaining Chromosome Stability In Saccharomyces Cerevisiae." Thesis, 2009. http://hdl.handle.net/2005/1020.
Full textAbstract:
DNA repair pathways have evolved to protect the genome from damage caused by intrinsic and extrinsic factors. Although numerous DNA repair mechanisms have been studied and reported, information regarding how they coordinate with the necessary changes in chromatin structure is scarce. Smc (structural maintenance of chromosomes) proteins are a conserved, essential family of proteins required for chromosome organization and accurate segregation. The budding yeast, Saccharomyces cerevisiae has three Smc-protein complexes: Smc1/3 complex (cohesin), Smc2/4 complex (condensin) and the Smc5/6 complex, required for sister chromatid cohesion, condensation and DNA repair, respectively. The chromatin associated Smc5/6 complex consists of Smc5, Smc6 and six non-smc elements (Nse1-Nse6). Smc5 and Smc6 are required for stability of repetitive chromosomal regions and sister chromatid recombination-mediated repair of double-strand breaks.
Mms21/Nse2, a subunit of the Smc5/6 complex, is a SUMO E3-ligase, which conjugates SUMO (small ubiquitin-like modifier) to Smc5 and Yku70 (DNA repair protein) and its SUMO ligase activity protects the cells from extrinsic DNA damage. To address the role of Nse2 SUMO ligase in cellular events, we isolated mutants (nse2∆sl and nse2C221A) defective in the E3-ligase domain of Nse2 and found that these mutants are sensitive to genotoxic agents, for example MMS, UV or bleomycin, as expected. We found that cysteine 221 present in the SP-RING domain of Nse2 is required in the function of Nse2 in resisting genotoxic stress. We found that nse2∆sl cultures are slow growing and show increased abundance of cells having 2N DNA content (indicative of a G2-M cell cycle delay or arrest) relative to wild type cells. The DNA damage checkpoint pathway is activated to a limited extent in unchallenged nse2∆sl mutant cells indicating that cells lacking the SUMO ligase activity of Nse2 incur spontaneous DNA damage. Furthermore nse2∆sl cells are exquisitely sensitive to caffeine, an agent known to override the DNA damage checkpoint in a number of organisms by inhibiting the DNA damage checkpoint transducer ATR (Homo sapiens), Mec1 (Saccharomyces cerevisiae) and Rad3 (Schizosaccharomyces pombe). In order to investigate the importance of the DNA damage checkpoint pathway for nse2∆sl cells, we employed a genetic approach. We found that nse2∆sl exhibits synthetic sick interaction with mec1∆ but not tel1∆ (defective in Mec1 or Tel1 PI kinases) or mrc1∆ (defective in Mrc1 or mediator of replication checkpoint 1) indicating that the DNA damage induced Mec1 dependent checkpoint pathway is selectively required but the replication stress checkpoint pathway is dispensable for optimal growth of unchallenged nse2∆sl cells.
In order to further investigate the role of Nse2 in S phase events, we used camptothecin (CPT), a drug that induces S phase specific double strand breaks. CPT inhibits topoisomerase I by trapping the covalent Top1-DNA intermediate. Collision of a DNA replication fork with such a complex results in double-strand and single-strand breaks in DNA. We found that nse2∆sl is CPT-sensitive and that nse2∆sl top1-8 has a synthetic sick phenotype. Thus, our chemical and genetic interaction studies suggest that the SUMO ligase activity of Nse2 may be required when Top1 function is compromised. Interestingly, human and yeast Top1 proteins are known to be sumoylated. Our findings suggest that MMS-induced enhancement of Top1 sumoylation in budding yeast is partially dependent on SUMO ligase activity of Nse2. Since both sumoylation and Top1 play a role in telomere maintenance, we also examined the telomere length in single as well as double mutants and found that there is slight telomere lengthening in nse2∆sl top1-8 double mutant. To gain further insight into the genetic interaction between Nse2 and other proteins which affect DNA topology, we also investigated genetic interaction of Nse2 with other topoisomerases. We found that top3-2 nse2∆sl exhibited a synthetic sick phenotype but nse2∆sl top2-4 showed partial rescue of temperature sensitivity.
In order to investigate whether chromosome integrity is compromised in nse2∆sl cells we employed a YAC (yeast artificial chromosome) based assay to examine GCRs (gross chromosomal rearrangements). We found elevated levels of GCR in nse2∆sl cells compared to wild type cells. Furthermore, deletion of DNA Topoisomerase1 in nse2∆sl background selectively destabilizes a longer YAC relative to shorter YACs. We also examined the effect of varying origin number on YAC stability in nse2∆sl as well as top1∆ and nse2∆sl top1∆ cells. We found that a YAC having fewer origins is not destabilized in nse2∆sl and top1∆ single mutants but is destabilized in the nse2∆sl top1∆ double mutant. Since Nse2 is a non-SMC member of the Smc5/6 complex, we also investigated the effect of varying origin number on YAC stability in smc6-56 and smc656 top1∆ mutants. We found that the stability of a YAC is modestly compromised in the smc6-56 mutant but its derivative having fewer origins is not further destabilized, rather it seems to be stabilized.
In order to gain molecular insights into the involvement of the SUMO ligase activity of Nse2 in maintenance of chromosome integrity, we examined sumoylation of specific substrates following a candidate approach. Smc5 and Yku70 are known targets of Nse2dependent sumoylation. We found that Smc6 is also sumoylated and that the MMS-induced enhancement of Smc6 sumoylation in budding yeast is partially dependent on Nse2. To understand the functional significance of Smc5 sumoylation, we mutated lysine residues of all the four predicted sumoylation sites ψKXE/D, individually as well as all four together. We found that all the single as well as quadruple mutants were weakly sensitive to MMS suggesting that these putative sumoylation sites of Smc5 may contribute towards countering MMS-induced DNA damage. Interestingly, we found that Smc5 sumoylation is enhanced when treated with MMS (methyl methane sulfonate) but not significantly with HU (hydroxyurea) and CPT (camptothecin). We also generated putative ATP-binding defective mutants in Smc5. Previous studies suggest that the ATPase motif is required for the essential function of some Smc proteins (for example, Smc1 and Smc6). We found that smc5K75E and smc5K75Q, having a mutation in the lysine residue of the conserved GXGKS motif present in the Walker A type box at the Nterminus exhibited a null phenotype implying that this conserved lysine residue is required for essential function of Smc5.
In this study, employing genetic and biochemical methods, we have characterized the Nse2 SUMO ligase defective mutant and analyzed its role in the unperturbed mitotic cell cycle and in genome maintenance. We have also employed genetic methods to study the involvement of both Nse2 and DNA Topoisomerase I in maintaining genomic stability. Lastly, we have addressed the functional significance of Lysine residues of putative sumoylation sites and the conserved ATP-binding motif of Smc5 by mutational analysis.
In conclusion, our study highlights an important role for the SUMO ligase activity of Nse2 in maintaining genomic stability and suggests that sumoylation of Smc5 may be important for resisting MMS-induced genotoxic stress.
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Yu, Chih-kai, and 游智凱. "The investigation in the correlation of IL-6 -572 C/G, IL-10 -792 T/G, chromosome 9P21.3 polymorphisms/ periodontitis with cardiac artery stenosis and acute myocardial infraction." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/21522248736764094101.
Full textAbstract:
碩士高雄醫學大學
牙醫學研究所
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Object: The purpose of this study is to investigate the relationship of IL-6 -572 C/G、IL-10-592 T/G and chromosome 9P21.3 gene polymorphism in periodontitis and cardiovascular disease. Materials and methods: According to the result of cardiac catheterization and CT scan and number of artery stenosis, we divided 222 patients whom had cardiovascular disease into 3 group. We also recorded the periodontal status including the numbers of missing tooth, probing depth, clinical attachment loss, bleeding on probing and plaque record. Single nucleotide polymorphisms were based on samples of IL-6 -572 (rs1800796), IL-10 -592 (rs1800872), 9P21.3 (rs10757278) gene polymorphism analysis. The relationship between single nucleotide polymorphisms, periodontitis and cardiovascular disease were analysed. Result: Three artery stenosis group had more tooth loss, higher average loss of clinical attachment level and higher level of clinical attachment loss ≧ 5 mm percentage. There were statistically significantly higher levels of clinical attachment loss and loss of clinical attachment level ≧ 5 mm percentage in group whom with history of myocardial infarction than that with no history of myocardial infarction.IL-6 -572 G genotype has a protective effect on severity of periodontoitis and gender, history of diabetes, pack-year> 30 had statistically significantly association with heart artery stenosis. But single nucleotide polymorphisms did not reach a statistically significant correlation with heart artery stenosis. Conclusion: The results indicated that there were more advanced periodontal breakdown in more artery stenosis group and with history of myocardial infarction group.IL-6 -572 G genotype has a protective effect on severity of periodontitis but single nucleotide polymorphism did not reach a statistically significant correlation with severity of more artery stenosis and with history of myocardial infarction.
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Guedes, Ana Filipa Barata Duarte. "Estudo de marcadores de diagnóstico e prognóstico em gliomas." Master's thesis, 2010. http://hdl.handle.net/10348/538.
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Dissertação de Mestrado em Biotecnologia para as Ciências da SaúdeOs gliomas são os tumores cerebrais primários mais frequentes, representando mais de 80% de todas as neoplasias do Sistema Nervoso Central e são, actualmente, classificados, pela Organização Mundial de Saúde, em astrocitomas, oligodendrogliomas, tumores mistos e ependimomas. O diagnóstico e a classificação destes tumores são baseados nas características histopatológicas que, por vezes, são difíceis de definir. Apesar dos avanços na neurocirurgia, quimioterapia e radioterapia, o prognóstico dos doentes com gliomas é ainda muito reservado. Nos últimos anos, estudos em gliomas têm identificado marcadores de diagnóstico, de prognóstico e preditivos, susceptíveis de ajudarem a definir a classificação histológica. A codelecção 1p/19q em tumores oligodendrogliais, a presença de mutações somáticas em genes que codificam isocitrato desidrogenase 1 e 2 (IDH1 e IDH2) em astrocitomas, oligodendrogliomas e oligoastrocitomas e a hipermetilação da região promotora do gene MGMT em glioblastomas são, actualmente, considerados os três marcadores mais interessantes em gliomas. Estudos prévios sugerem que a codelecção dos braços dos cromossomas 1p e 19q tem provado ser um bom marcador de diagnóstico e prognóstico. A perda combinada de 1p e 19q tem sido associada com a morfologia de oligodendrogliomas e com o aumento da sobrevida nestes tumores. Contudo, em outros tumores, a componente oligodendroglial pode também conferir um melhor prognóstico. Assim, um dos objectivos deste Projecto, foi a avaliação de 1p/19q em relação ao diagnóstico e prognóstico dos doentes. Estudos recentemente publicados sugerem que mutações nos genes IDH1 e IDH2, podem ser marcadores úteis de diagnóstico e prognóstico, no entanto, esta relação nem sempre é consensual. Os doentes com mutação nos genes IDH1 ou IDH2 parecem ter um melhor prognóstico do que os doentes sem mutação Deste modo, pretendeu-se identificar e caracterizar as mutações encontradas para a população em estudo, e correlacionar a sua presença com a sobrevida dos respectivos doentes. Também, foi objectivo de estudo avaliar se a presença de mutações permite distinguir glioblastomas primários (de novo) de glioblastomas secundários (que progridem de gliomas de baixo grau ou anaplásicos). A proteína de reparação de DNA, MGMT, é um factor implicado na quimioresistência em gliomas. O valor preditivo e de prognóstico da hipermetilação da região promotora do gene MGMT permanece, contudo, controverso. Assim, foi também objectivo deste estudo, avaliar a importância da hipermetilação no prognóstico de doentes com glioblastomas. No total, analisaram-se 141 amostras de doentes seguidos nos Hospitais da Universidade de Coimbra, com astrocitomas (n = 111), oligoastrocitomas (n = 18), oligoastrocitomas (n = 8) e ependimomas (n = 4). No estudo realizado a perda alélica 1p/19q foi avaliada por Fluorescence In Situ Hybridization (iFISH) (n = 130), as mutações somáticas nos genes IDH1 e IDH2 foram analisadas por Sequenciação directa (n = 128) e a análise de hipermetilação foi efectuada por Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) (n = 38). Os dados obtidos sugeriram que a codelecção 1p e 19q está associada com a morfologia de oligodendrogliomas (p<0,0001), independentemente do grau do tumor. Contudo, esta alteração não foi associada com a quimiosensibilidade e aumento da sobrevida destes doentes. Mutações IDH1 foram detectadas em 17 dos 128 gliomas estudados, e encontraram-se 3 mutações diferentes no gene IDH1. Este estudo sugeriu que as mutações IDH1 são frequentes em glioblastomas secundários, mas raros em glioblastomas primários (100% vs 1,1%, p<0,0001). Além disso, mutações IDH1 parecem ser também um factor de prognóstico mais favorável. Nenhum dos 128 gliomas analisados era, todavia, portador de mutações IDH2. A região promotora do gene MGMT apresentou-se metilada em 67% dos doentes e não metilada em 33% dos doentes com glioblastomas. Verificou-se que os doentes com a região promotora hipermetilada, quando submetidos a radioterapia ou quimioterapia, apresentaram um aumento de sobrevida relativamente àqueles que também apresentavam metilação, mas que não foram submetidos a qualquer tratamento (p<0,001). Assim, através da realização deste Projecto, a implementação dos três marcadores em estudo reveste-se da maior importância, devido ao seu valor no diagnóstico e à sua utilidade para prever e controlar melhor o prognóstico de alguns destes doentes. Tem ainda, um poder preditivo da resposta ao tipo de tratamento, o qual poderá ser optimizado e ajustado para alguns doentes previamente seleccionados.
Gliomas are the most common primary brain tumors, accounting for more than 80% of all neoplasms arising in the Central Nervous System (CNS) and are currently classified by the World Health Organization (WHO) into astrocytomas, oligodendrogliomas, mixed gliomas and ependymomas. The diagnosis and classification are based on their histopathological appearance, which sometimes may be difficult. Despite advances in neurosurgery, chemotherapy and radiotherapy, the prognosis of most glioma patients remains dismal. In recent years, extensive molecular studies have identified diagnostic, prognostic and predictive markers in gliomas that reinforce the WHO histological classification. The 1p19q coleletion in oligodendroglial tumors, the presence of somatic mutations in the genes enconding isocitrate dehydrogensase 1 and 2 (IDH1 and IDH2) in astrocytomas, oligodendrogliomas e oligoastrocytomas and the hypermethylation of the promoter of O6-methylguanine DNA methyltransferase (MGMT) gene in glioblastomas are currently the three most pertinent markers in diffuse gliomas. Previous studies suggest that codeletion of chromosome arms 1p and 19q has proven to be a powerful diagnostic and prognostic marker. Combined loss of 1p and 19q has been associated with morphology of oligodendrogliomas and with enhanced survival in these tumors. However, in other glial tumors, an oligodendroglial component can mean a better prognostic. Therefore, one of the aims of this Project is the 1p/19q evaluation concerning the patients’ diagnostic and prognostic. Recent published studies considered that mutations in IDH1 and IDH2, are an important diagnostic and prognostic marker but that is still unclear. Also, patients with tumors harboring mutation of IDH1 or IDH2 genes seem to have a better outcome than patients with non mutated tumors. Thus, another goal of this study focus on the identification and characterization of mutations, difference in survival at a population level and to assess whether they allow reliable discrimination between primary (de novo) glioblastomas and secondary glioblastomas (that progressed from low-grade or anaplastic gliomas). DNA repair protein, MGMT, is one implicated factor in glioma chemoresistance. The prognostic and predictive value of MGMT promoter hypermethylation however remains controversial. An additional aim of this study regards the evaluation of the prognostic significance of MGMT in patients with glioblastomas. In total, we analysed 141 patient samples for a series of patients followed in the University Hospital of Coimbra with astrocitomas (n = 111), oligodendrogliomas (n = 18), mixed gliomas (n = 8) and ependymomas (n = 4). In our study, the 1p/19q status was assessed by interphase Fluorescence In Situ Hybridization (iFISH) (n = 130), somatic mutations analysis of IDH1 and IDH2 genes was directed sequenced (n = 128) and MGMT hypermethylation analysis was performed by using Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) on the glioma samples (n = 38). Our data suggested that deletions of chromosome arms 1p and 19q are associated with oligodendrogliomas morphology (p<0,0001), independently of tumor grade. However, this alteration is not associated with chemosensitivity and enhanced survival. IDH1 mutations were detected in 17 of 128 gliomas, in which 3 different mutations were identified. This study indicated that IDH1 mutations are frequent in secondary glioblastomas but rare in primary glioblastomas (100% vs 1,1%, p<0,0001). Therefore, IDH1 mutations also seem to be a more favorable prognostic factor. None of the 128 gliomas analyzed contained an IDH2 mutation. The MGMT gene promoter was methylated in 67% and unmethylated in 33% of glioblastoma patients. This marker can be a predictor factor of response to chemotherapy because the patients who had the promoter hypermethylation and underwent chemotherapy had increased their survival in relation to the patients who did not undergo the therapy (p<0,001). Therefore, according to these Project results, we emphasized the importance of the implementation of these three markers, in routine bases, due to their value concerning the diagnosis leading to a better understanding of the prognosis as well as the clinical course and management and also due to their predictive value of the response to chemotherapy treatments.
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Stenzel, Annette [Verfasser]. "Development of an SNP map in the peri-MHC region on the human chromosome 6 as a tool to identify candidate genes for inflammatory bowel disease / vorgelegt von Annette Stenzel." 2003. http://d-nb.info/97224865X/34.
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Anamelechi, Katja. "Lokalisation eines Psoriasissuszeptibilitätslocus auf Chromosom 6 /." 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014594230&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Abdel-Rahman, Salah Mahmoud Ali. "Analysis of microsatellites for quantitative trait loci (QTL's) for milk and growth on different chromosomes in dairy cattle /." 2003. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=012821500&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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