Rozprawy doktorskie: „Human chromosomes”

1

Downie, Sarah Elizabeth. "Detection of chromosomes and chromosomal abnormalities in human sperm". Title page, contents and overview only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phd751.pdf.

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Bibliography: leaves 135-151. A study of chromosomal abnormalities and the localisation of chromosomes in human sperm, especially from men with TSD, using fluorescence in situ hybridization (FISH). The project entailed: 1. development of reliable FISH protocols, 2. determination of basline frequencies of aneuploidy, 3. analysis of chromosomal abnormalities in men with severe TSD and 4. assessment of the localisation of individual chromosomes within the sperm head.

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2

Vásárhelyi, Krisztina. "Statistical study of human constitutional chromosome rearrangement breakpoint distributions". Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/29201.

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In this study the question of nonrandomness in the distribution of human constitutional rearrangements was evaluated. The distribution of breakpoints were analysed in three groups of reciprocal translocations and three groups of inversions, subdivided according to method of ascertainment of cases for study. In addition, one data set of structural aberrations obtained from sperm chromosomes was also analysed. The method of statistical analysis, based on the binomial distribution, was developed specifically to allow testing distributions in chromosome segments as small as chromosome bands. The distribution of breakpoints was analysed in all data sets using this method, in addition to testing for overall nonrandomness using goodness of fit statistics. Nonrandomness in breakpoint distributions was found in reciprocal translocations (rcp) and inversions ascertained through abnormalities and through incidental events. However, random distribution was observed in incidentally ascertained de novo rearrangements as well as in sperm chromosome aberrations. The nonrandomness in the distribution of rcp breakpoints can be largely attributed to a bias in ascertainment of cases based on the phenotypic manifestations of chromosomal imbalance resulting from a rearrangement. A dependence of the probability of producing specific types of balanced or unbalanced progeny on the position of breakpoints is a likely explanation for the nonrandomness produced in breakpoint distributions. However, some bands including, 5q35, 7p22, 9p22, 13ql4, and 17q25, were observed in different ascertainment groups, excluding selection bias as a likely explanation for this observation. These bands may represent true sites of nonrandom rearrangement due to some factor associated with an underlying DNA sequence or structural characteristic of chromatin that predisposes to rearrangement at specific sites. The nonrandomness observed in the distribution of inversion breakpoints is most likely the product of a founder effect. Many identical inversions in apparently unrelated individuals have been found suggesting that a few ancestral mutations have become widespread in the population. A large data set of incidentally ascertained de novo inversions is required to distinguish between sites of frequent breakage and nonrandomness produced by the ascertainment of related cases. All evidence considered together, indisputable predisposition to rearrangement at specific sites was not found in this study. Furthermore, an overall random association of constitutional rearrangement breakpoints in bands with known oncogenes and fragile sites was observed. However, the possibility of oncogenes and fragile sites as factors involved in constitutional rearrangements in a few isolated cases cannot be excluded. Nonrandomness was found when distribution of breakpoints in light and dark G bands was compared. An excess of breakpoints in some light G bands was observed even after a conservative correction for a possible pattern recognition bias which may lead to the overascertainment of breakpoints in light G bands.
Medicine, Faculty of
Medical Genetics, Department of
Graduate

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3

Kulharya, Anita S. (Anita Singh). "Cytogenetics of chromosome 22 and its clinical relevance". Thesis, University of North Texas, 1990. https://digital.library.unt.edu/ark:/67531/metadc798385/.

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This investigation reorganizes and identifies chromosomal anomalies and delineates the associated clinical findings. The present investigation involved 37 individuals with anomalies of chromosome 22. The clinical profile with the corresponding cytogenetic anomalies was studied.

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4

Heller, Raoul. "Engineering of human artificial mini-chromosomes". Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360317.

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5

Ross, Mark T. "Molecular studies of the human sex-chromosomes". Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.258353.

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6

Bhatt, Samarth. "Segregation analysis of paracentric inversions in human sperm". Montpellier 1, 2008. http://www.theses.fr/2008MON1T002.

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Les inversions paracentriques sont des anomalies chromosomiques généralement considérées comme inoffensives. Toutefois, des cas de porteurs de chromosomes remaniés issus d'inversions paracentriques ont été rapportés, soulignant la nécessité d'étudier le comportement méiotique de ces anomalies. Seules quelques études ont été pratiquées, utilisant la technique de fécondation croisée Homme-Hamster, le typage génétique des spermatozoïdes (sperm typing) ou l'hybridation in situ fluorescente (FISH) par marquages centromériques ou télomériques. Afin d'améliorer l'efficacité de l'étude méiotique des inversions paracentriques, nous avons développé l'utilisation des sondes BAC qui permettent une localisation chromosomique précise des points de cassures chromosomiques et l'identification de tous les produits méiotiques des inversions dans le sperme humain. Les points de cassures et la ségrégation méiotique de 3 inversions paracentriques, inv(5)(q13. 2q33. 1), inv(9)(q21. 2q34. 13) et inv(14)(q23. 2q32. 13), ont ainsi été déterminés. Les taux de recombinants observés dans ces 3 inversions varient de 3,72% à12,55%. Cette localisation des points de cassures et l'analyse des séquences d'ADN adjacentes sont essentielles pour mettre en évidence la formation de boucles d'inversion, pour déterminer le risque de recombinaison à terme, ainsi que pour étudier les mécanismes méiotiques de formation des recombinaisons. Ainsi, la présence de régions d'ADN riches en recombinaisons et en duplications inter-chromosomiques a été mise en évidence, en complément de la formation de recombinants chromosomiques. Par ailleurs, une nouvelle technique de FISH multi-couleurs 3D (3D MCB FISH) a été adaptée aux spermatozoïdes humains pour l'analyse in situ des ségrégations. Cette approche permet de visualiser in situ les inversions paracentriques et d'estimer la fréquence de tous les types de recombinants issus de boucles d'inversion, de recombinaisons U-loop ou de processus de cassure/fusion des chromatides-soeurs.

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7

Dunn, Alison M. "Cloning of human DNA repair genes". Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301385.

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8

Coultas, Susan L. (Susan Lynette). "A comparison of straight-stained, Q-stained, and reverse flourescent-stained cell lines for detection of fragile sites on the human X chromosome". Thesis, North Texas State University, 1985. https://digital.library.unt.edu/ark:/67531/metadc798127/.

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Cell cultures were examined for percentage of fragile sites seen in straight-stained, Q-stained and reverse fluorescent-stained preparations. In all cases, percentage of fragile site expression was decreased when compared to straight-stained preparations. However, fragile sites seen in Q- and RF-stain could be identified as on X chromosomes.

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9

Laval, S. H. "Molecular analysis of mammalian sex chromosomes". Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302954.

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10

Mandegar, Mohammad Ali. "Analysis of artificial chromosomes in human embryonic stem cells". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:81d118c3-dd01-40e4-9fea-2c335d9f3101.

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The development of safe and efficient gene delivery systems in pluripotent human embryonic stem cells (hESc) is essential to realising their full potential for basic and clinical research. The purpose of this study was to develop an efficient, non-integrating gene expression system in pluripotent hESc using human artificial chromosomes (HAC). Similar to endogenous chromosomes, HAC are capable of gene expression, replication and segregation during cell division. Unlike retroviral-mediated gene delivery vectors, HAC do not integrate into the host genome and can encompass large genomic regions for the delivery of multiple genes. Despite the advantages HAC offer, their use has been limited due to laborious cloning procedures and poor transfection efficiencies, and thus only studied in immortalised and tumour-derived human cell lines. In this study, the high transduction efficiency of herpes simplex virus type-1 (HSV-1) amplicons was utilised to overcome the described difficulties and delivered HAC vectors into pluripotent hESc. Analysis of stable hESc clones showed that de novo gene-expressing HAC were present at high frequencies ranging from 10-70% of metaphases analysed, without integrating into the genome. The established HAC contained an active centromere, and were stably maintained without integration or loss in the absence of selection for 90 days. Stable HAC-containing hESc clones retained their pluripotency as demonstrated by neuronal differentiation, in vitro germ layer and teratoma formation assays. HAC gene expression persisted, with some variation, post-differentiation in the various deriving cell types. This is the first report of successful de novo HAC formation in hESc for gene expression studies. These findings show potential for delivering high-capacity genomic constructs safely and efficiently into pluripotent cells for the purpose of genetic manipulation and ultimately patient-specific somatic gene therapy.

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11

Chan, David Yiu Leung. "Analysis of artificial chromosomes and factors affecting stability in murine and human cultured and embryonic stem cells". Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568074.

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Human Artificial Chromosomes (HAC) are fascinating extrachromosomal molecules that stay independently from the host genome and are capable of segregating as efficiently as endogenous chromosomes. It has been proven that HAC are potential tools for both basic chromosome behavioural research and agents for gene therapy purposes. My DPhil project is divided into two main themes. The first theme was to develop a novel artificial chromosome in mouse embryonic stem cells. The second theme was to understand the factors affecting chromosome stability which may also affect the efficiency of artificial chromosome formation. so that our protocol for better HAC preparation can be refined. There are six results chapters in my thesis. The first three chapters described how I developed human artificial chromosomes in mouse embryonic stem cells. Initially, vectors containing a long stretch of human alphoid DNA were delivered to mouse cells using the Herpes Simplex Virus-I (HSV-l) amplicon system but the efficiency was low. Next, mouse pericentromeric and centromeric DNAs were employed for mouse artificial chromosome (MAC) via HSV-l system. However, the efficiency remained the same. Finally, I used the Microcell-Mediated Chromosome Transfer (MMCT) system to transfer HAC from HTl 080 cells into mouse ES cells and successfully established HAC in ES which were highly stable. The results obtained in this first part of my thesis suggested that to increase HAC formation efficiency it would be necessary to improve the techniques of HSV-I delivery and MMCT. Moreover, it would also be important to better characterize factors affecting chromosome behaviour. The last three results chapters focus on factors affecting chromosomes stability and improving the HSV -1 delivery system and MMCT. I undertook an in vivo study of whole cell fusion experiments with the aid of live cell irnaging system, and found that histone H2B proteins underwent a dynamic assembly/disassembly processes. Live cell imaging of MMCT suggested that the microcell delivery is a very slow process and the results may lead to a refinement of the MMCT protocol. I found it is possible to generate a single HAC using two HSV-l amplicons containing two different constructs, potentially doubling the HSV-l HAC capacity from 150 kb to 300 kb. The last chapter illustrated how the expression of non- coding centromeric satellites impaired chromosome stability in both human cultured and human embryonic stem cells. The findings revealed that non-coding centromeric RNA plays an important role on chromosome stability that might be important for artificial chromosome development.

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12

Nelson, Tanya N. "Molecular genetic analysis of human 8p inversion duplication chromosomes". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ34598.pdf.

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13

Kvaloey, Kirsti. "The long arm telomeres of the human sex chromosomes". Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358686.

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14

Fraser, Neil J. "Molecular studies of the human x and y chromosomes". Thesis, University of Oxford, 1987. http://ora.ox.ac.uk/objects/uuid:e22e64bb-64e5-4474-86e2-1c3d5eb6155a.

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The isolation and characterisation of sequences from the X and Y chromosomes will give some insight into the evolutionary relationship between these chromosomes, and may be of use in the study of X-linked disorders. The availability of cDNA and genomic sequences for the human STS locus (associated with the disorder, X-linked ichthyosis) has allowed a preliminary investigation of this locus in man and other species. The localisation of these sequences to Xp22.3, provides confirmation of the sub-regional assignment of the structural gene for STS. STS homologous sequences have been identified on the long arm of the Y chromosome. These sequences also appear present on the X and Y chromosomes of the chimpanzee. In other higher primates, they appear to be X-, but not Y-, linked, suggesting that the situation in man and chimpanzee is the result of a rearrangement between the X and Y chromosomes during the past 15 million years. Another region of X Y homology has been analysed. The locus DXYS27 maps to Yp and Xq21. Restriction enzyme analysis and direct sequence comparison has shown the two loci to be «99% homologous. Phylogenetic studies suggest that the locus is X-, but not Y-, linked in the chimpanzee, suggesting an evolutionarily recent transposition of material from the X to the Y chromosome. The mutations resulting in the X-Y differences appear to have occurred on both the X and Y chromosomes. It has been possible to demonstrate that the Y-specific locus is transferred to the X chromosome in many, but not all, aberrant X-Y interchanges resulting in XX maleness. A sequence has been isolated that detects a hypervariable locus at Xp11.3→Xcen (DXS255) . The hypervariability appears to be due to the presence of a tandemly repeated sequence of variable length. Attempts to clone this repeat have been unsuccessful, as it appears to be unstable in the vector/host systems employed. This sequence will be of value in linkage studies of disease loci known to be present in this region. Hypervariability at this locus has not been identified in other species, suggesting that the repeat sequence is an evolutionarily recent acquisition by the X chromosome. Taken together, the results obtained suggest that the simple model predicting an ancient origin for the bulk of the Y chromosome will have to be reassessed.

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15

Shemilt, L. A. "Coherent diffraction imaging and ptychography of human metaphase chromosomes". Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1455381/.

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Mitotic chromosome structure is highly important in the packing and safe separation of DNA during cell division. The chromatin fibre, the first packaging of DNA around histone proteins, is coiled into a highly condensed state during the metaphase stage of mitosis where the chromosomes form their characteristic ’X’ shape in order to be split into two daughter cells on cell division. Accessing the 3D structure of the condensed chromatin could provide high resolution information on the location of the genes inside the chromosome during metaphase and the placement of the proteins used in the packaging mechanism. We apply lensless X-ray imaging techniques to chromosomes in an attempt to access their structure. Coherent Diffraction Imaging and Ptychography have potential to achieve wavelength limited resolution in 3D. The techniques directly measure phase that can be used to map the electron density in the sample. Sample preparation is highly important to obtain good quality images from any microscopy technique. We start with studying sample preparations with Fluorescence and Scanning Electron Microscopy to observe the suitability and effects of the protocols. We perform lensless imaging on nuclei and chromosomes prepared with newly designed protocols for this type of X-ray imaging. Images of nuclei were retrieved from the ptychography experiments at 34-ID-C, I-13 and cSAXS. Ptychography was performed with a visible light source on a set of 46 human chromosomes. The images provide a map of electron density that can be used to calculate the mass of chromosomes and nuclei. Mass is a macroscopic structural quantity that can be used to observe the changes to the protein and DNA content in the nucleus during the cell cycle given a high enough resolution. The nuclei measured in this work were in an early mitotic state and gave consistent mass values calculated from the phase measured by ptychography. In the case of chromosomes mass calculated from the ptychography images was used to sort and identify them in a form of karyotyping. This method of identification is novel because it takes into account the whole of the chromosome contents, both protein and DNA, whereas standard methods of karyotyping look at positions of bandsin the chromosomes.

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16

Jobling, Mark A. "Molecular studies of the human Y chromosome". Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302791.

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17

Curwen, Gillian B. "G₂ chromosomal radiosensitivity in childhood and adolescent cancer survivors and their offspring". Thesis, St Andrews, 2008. http://hdl.handle.net/10023/425.

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18

Rudd, Mary Katharine. "Organization, evolution and function of alpha satellite DNA at human centromeres". Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1091493781.

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19

Tapia, Páez Isabel. "Characterization of human chromosome 22 : cloning of breakpoints of the constitutional translocation t(11;22)(q23;q11) and detection of small constitutional deletions by microarray CGH /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-505-0.

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20

Lähdesmäki, R. (Raija). "Sex chromosomes in human tooth root growth:radiographic studies on 47,XYY males, 46,XY females, 47,XXY males and 45,X/46,XX females". Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514281705.

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Abstract Studies on families and individuals with sex chromosome abnormalities and 46,XY females, together with molecular research, have provided proof that both X and Y chromosome genes are expressed in human tooth crown growth. The Y chromosome promotes the formation of both permanent tooth crown enamel and dentin, whereas the effect of the X chromosome is seen mainly in enamel formation. In particular, the effect of the Y chromosome on dentin formation explains the expression of sexual dimorphism in crown size. When crown growth is complete, root dentin is formed and requires proliferation of epithelial cells in Hertwig's epithelial root sheath to initiate the differentiation of root odontoblasts. These epithelial cells determine the size, shape and number of the roots. There is a clear sex difference in tooth crown sizes, men have larger teeth than women. The aim of this research was to study completed permanent tooth root lengths in individuals with sex chromosome abnormalities and 46,XY females, an approach which might also provide some clues for a further insight into the development of sexual dimorphism in human growth. The underlying hypothesis was that the effect of the X and Y chromosomes on crown growth is also expressed in root growth. The subjects were participants of L. Alvesalo's research project, Kvantti, and comprised 45,X/46,XX females, 47,XYY and 47,XXY males and female sex reversals with insensitivity to androgens (46,XY females). The root lengths were measured from dental panoramic radiographs with a sliding digital calliper. All available teeth (except third molars) with complete root formation on both sides of the jaws were measured. The results showed longer final permanent tooth root lengths in 47,XYY and 47,XXY males, while the roots in 45,X/46,XX females were shorter compared with the values of normal men and women, respectively. The root lengths of 46,XY females were longer compared to normal women and placed on a level with normal men. The root morphology did not reveal any major deviations from normal variation. In terms of population dental developmental standards it is conceivable that changes in these study groups in final size of their permanent tooth roots become evident during a period beginning eight years after birth and continuing up to the age of 14 years, at least. It became clear that the effect of the Y chromosome on tooth root growth is greater than that of the X chromosome, and this may cause the observed sexual dimorphism, males having longer roots than females. It is suggested that root growth may be affected by the same genes on the X and Y chromosomes which promote crown growth.

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21

Stephens, Sarah H. "Fine mapping of the chromosome 15q13-14 schizophrenia linkage region /". Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.

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Thesis (Ph.D. in Human Medical Genetics) -- University of Colorado Denver, 2008.
Typescript. Includes bibliographical references (leaves 112-128). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;

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22

Rosser, Zoë H. "Human Y chromosomes and the origins of modern European populations". Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/30329.

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Three different studies examining Y-chromosomal diversity have been undertaken: a large continent-wide study examining the distribution of biallelic haplogroup diversity within 48 European and circum-European populations; a micro-geographic study examining the haplogroup distribution and diversity within a linguistic isolate of the Italian Alps; and finally, a global study of a single lineage, employing biallelic and multiallelic markers, to try to explain the unusual global distribution of this lineage. Within the European study, five haplogroups showed significant clinal patterns. Two major continent-wide clines are consistent with the migration of farmers from the Near East. Statistical analyses confirm that populations are related primarily on the basis of geography rather than language. The second study shows that Ladin-speakers have low haplography diversity when compared to neighbouring populations however, a high level of internal diversity was observed using the multiallelic markers. Minisatellite MSY1 examination shows unique alleles within Ladin valleys which suggests either in situ differentiation of an isolated population, or a small, already diverse founding population. Within the final study additional biallelic markers were incorporated using a new typing methodology, enabling the further sub-division of the YAP branch, and some new haplogroups showed population specificity. Increasing the number of microsatellite loci from seven to seventeen allowed improved discrimination within the haplogroups. The dating of mutations enabled historical events to be proposed to explain the unusual geographical distribution of this lineage.

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23

Baker, Elizabeth Gay. "The mapping of human chromosomes by fluorescence in situ hybridization /". Title page, contents and summary only, 1996. http://web4.library.adelaide.edu.au/theses/09MSM/09msmb167.pdf.

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Thesis (M. Med. Sc.)--University of Adelaide, Dept. of Pediatrics and Dept. of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, Adelaide, 1996.
Copies of author's previously published articles inserted. Includes bibliographical references (leaves 122-142).

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24

Yu, Zhiling. "Interactions and architecture of human MCM proteins in vitro and in vivo /". View Abstract or Full-Text, 2003. http://library.ust.hk/cgi/db/thesis.pl?BICH%202003%20YU.

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Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2003.
Includes bibliographical references (leaves 118-137). Also available in electronic version. Access restricted to campus users.

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Al-Shammari, Mohamad H. "Integrated data analytics of germline mutation classes in human cancers. An integrated bioinformatics analysis to investigate associations between germline mutation classes and human cancers". Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6318.

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Biological and environmental factors contribute collectively to the development of human cancers. The primary focus of this research project was to investigate the impact of germline gene mutations, as a significant biological factor, on 29 major primary human cancers. For this I obtained data from multiple databases, including the Genetic Association Database (GAD), Sanger database (COSMIC), HGMD database, OMIM data and PubMed literature. Using the Extraction Transform and Load (ETL) process, 424 genes were obtained with 8,879 cancer mutation records. By integrating these gene mutation records a Human Cancer Map (HCM) was constructed, from which several sub-maps were derived based on particular mutation classes. Furthermore, a Protein-Protein Interaction Map (PPIM) was constructed based on the encoded proteins of the 424 gene set. Several key questions were addressed using the HCM and its sub-maps including the following: (i) Are individual groups of primary cancers associated with specific subset of genes (within the 424 full set)? (ii) Are groups of primary cancers associated with particular mutation classes? (iii) If both questions prove to be true, are groups of cancers associated with particular mutation class of target genes? This project also explored whether a corresponding Protein-Protein Interaction Map, derived from the Missense/Non-sense Mutation portion of the HCM gene set, would provide further information on gene associations between primary cancers in terms of the consequent identical amino acid changes involved. Results showed that: (1) closely-connected human cancers in the HCM exhibited a strong association with a particular mutation class; (2) Missense /Nonsense and Regulatory mutations played a central role in connecting cancers (i.e. via primary nodes) and so significantly influenced the construction of the HCM; (3) Genes with Missense/Nonsense and Regulatory mutations tended to be involved in cancer-associated pathways; (4) Using the kappa test to measure the extent of agreement between two connected primary cancers in the sub-HCMs, BRCA1, BRCA2, PALB2, MSH2, MSH6, MLH1, CDKN2A, and TP53 showed highest agreement for 5 of 10 mutation classes; (5) From the PIPM, it was evident that BRCA1, MSH6, BARD1, TP53, MSH2 and CHEK2 proteins best connected Breast, Ovarian, Prostate and Bowel primary cancers, and so the latter could represent ¿driver proteins¿ for these cancers. In summary, this project has approached the analysis of gene involvement in human primary cancers from the starting position of the mutation class that harbours the specific gene mutation. Together with their downstream resultant alterations in the associated proteins, this analysis can provide insights into the relatedness of primary human cancers and their potential gene hierarchies. These data may therefore help us to understand more fully the etiology, diagnosis and potentially personalized treatments for cancer.

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Wittwer, Pia Ethena. "Physical and genetical investigation of the Xp11.3 region on the short arm of the human X-chromosome". Thesis, University of the Western Cape, 2004. http://etd.uwc.ac.za/index.php?module=etd&amp.

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The pattern of inactivation in the DXS8237E-UBE1-PCTK1 region is of particular interest, since the mechanisms of X chromosome inactivation and the escape from inactivation are, as yet, not fully understood. The inactivation status of the DXS8237E and PCTKl gene differ: the first undergoes normal inactivation and the second escapes this process. The status of the UBEl gene has been controversial, although it is widely excepted that it does escape X chromosome inactivation. Physical mapping of the region employing YACs and subsequently P ACs has been undertaken, but was restricted in scope by the high frequency of rearrangements occurring. DNA sequences between DXS8237E, UBE1, PCTKl and the distal gene, UHX1, have been investigated with regard to LINEI elements, which are thought to playa role in X-inactivation. The results obtained strongly suggest a link between LINE1 elements and X chromosome inactivation. Sequence analysis results also contributed to the understanding of difficulties with restriction mapping of the region. Further, this work includes the first reported establishment of the UBEl exonintron boundaries. Additionally, genomic sequence analysis showed that only 46kb separate DXS8237E from UHX1, which confirms that this region is extremely gene rich.

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27

Kedra, Darek. "Characterization of candidate disease genes from human chromosomes 11g13 and 22q /". Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3792-3/.

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28

Fang, Yu-Yan. "Microdissection and molecular cloning of extra small ring chromosomes of human /". Title page, contents and summary only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phf211.pdf.

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Thesis (Ph. D.)--University of Adelaide, Dept. of Paediatrics, 1998.
Copies of author's previously published articles inserted. Errata pasted onto front end-paper. Includes bibliographical references (leaves 111-139).

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29

Cheung, Kwok Leung. "Investigation of candidate tumor suppressor genes on chromosomes 3 and 14 in nasopharyngeal carcinoma /". View abstract or full-text, 2009. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202009%20CHEUNG.

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30

Al-Shammari, Mohamad Hilal. "Integrated data analytics of germline mutation classes in human cancers : an integrated bioinformatics analysis to investigate associations between germline mutation classes and human cancers". Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6318.

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Biological and environmental factors contribute collectively to the development of human cancers. The primary focus of this research project was to investigate the impact of germline gene mutations, as a significant biological factor, on 29 major primary human cancers. For this I obtained data from multiple databases, including the Genetic Association Database (GAD), Sanger database (COSMIC), HGMD database, OMIM data and PubMed literature. Using the Extraction Transform and Load (ETL) process, 424 genes were obtained with 8,879 cancer mutation records. By integrating these gene mutation records a Human Cancer Map (HCM) was constructed, from which several sub-maps were derived based on particular mutation classes. Furthermore, a Protein-Protein Interaction Map (PPIM) was constructed based on the encoded proteins of the 424 gene set. Several key questions were addressed using the HCM and its sub-maps including the following: (i) Are individual groups of primary cancers associated with specific subset of genes (within the 424 full set)? (ii) Are groups of primary cancers associated with particular mutation classes? (iii) If both questions prove to be true, are groups of cancers associated with particular mutation class of target genes? This project also explored whether a corresponding Protein-Protein Interaction Map, derived from the Missense/Non-sense Mutation portion of the HCM gene set, would provide further information on gene associations between primary cancers in terms of the consequent identical amino acid changes involved. Results showed that: (1) closely-connected human cancers in the HCM exhibited a strong association with a particular mutation class; (2) Missense /Nonsense and Regulatory mutations played a central role in connecting cancers (i.e. via primary nodes) and so significantly influenced the construction of the HCM; (3) Genes with Missense/Nonsense and Regulatory mutations tended to be involved in cancer-associated pathways; (4) Using the kappa test to measure the extent of agreement between two connected primary cancers in the sub-HCMs, BRCA1, BRCA2, PALB2, MSH2, MSH6, MLH1, CDKN2A, and TP53 showed highest agreement for 5 of 10 mutation classes; (5) From the PIPM, it was evident that BRCA1, MSH6, BARD1, TP53, MSH2 and CHEK2 proteins best connected Breast, Ovarian, Prostate and Bowel primary cancers, and so the latter could represent 'driver proteins' for these cancers. In summary, this project has approached the analysis of gene involvement in human primary cancers from the starting position of the mutation class that harbours the specific gene mutation. Together with their downstream resultant alterations in the associated proteins, this analysis can provide insights into the relatedness of primary human cancers and their potential gene hierarchies. These data may therefore help us to understand more fully the etiology, diagnosis and potentially personalized treatments for cancer.

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31

Raja, Kimenthra. "The influence of sex chromosomes on the outcome of human embryo development". Thesis, Link to the online version, 2005. http://hdl.handle.net/10019/1173.

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32

Holm, Pernilla. "Genetic studies of susceptibility to diabetes mellitus with emphasis on type 1 diabetes /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-527-1/.

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33

Åkesson, Eva. "Genetic mapping and association analysis in multiple sclerosis /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-174-1/.

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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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35

Davies, Nicholas Paul. "Modification, transfer and expression of yeast artificial chromosomes carrying human immunoglobulin genes". Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318326.

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36

Simopoulou, Maria. "Molecular cytogenetic approaches to the analysis of chromosomes in human preimplantation embryos". Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418296.

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37

Gillet-Markowska, Alexandre. "Etude quantitative des variations structurelles des chromosomes chez Saccharomyces cerevisiae". Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066233/document.

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L’accumulation de remaniements de la structure des chromosomes aussi appelés variations structurelles (SV) est un important contributeur à la transformation des cellules malignes et à la constitution d’une hétérogénéité intratumorale. Nous avons développé un outil bio-informatique qui permet désormais d’obtenir une image fine de ces SV qui se produisent dans le génome humain. Nous avons ainsi pu démontrer l’existence de SV présentes à de faibles fréquences dans différentes populations cellulaires supposées clonales montrant que les taux de formation des SV pourraient être grandement sous-estimés. Parallèlement, nous avons montré que le niveau d’instabilité des individus dépend de facteurs génétiques de prédisposition. Pour les identifier, nous avons développé des systèmes génétiques de mesure des taux de SV chez la levure qui vont nous permettre d'identifier les gènes contrôlant l'instabilité chromosomique par analyse de liaison à grande échelle. Ces régulateurs représenteront de nouveaux gènes candidats impliqués dans le développement du cancer chez l’homme, car les déterminants génétiques impliqués dans le métabolisme de l'ADN sont très conservés entre la levure et les mammifères
The accumulation of chromosomal rearrangements also called Structural Variations (SV) is a major contributor to the transformation of tumoral cells and to the constitution of intratumoral heterogeneity. We have developed a bio-informatic tool that can now provide a sharp image of SV that occur in the human genome. We have demonstrated the existence of SV present in low proportions in different supposedly clonal cell populations showing that the rates of SV formation could be greatly underestimated. In parallel, we have shown that the level of instability of the genome depends on predisposition factors. To identify those, we have developed genetic assays to measure the rate of SV in yeast that will allow us to identify new genes controlling the stability of the genome using large scale linkage analysis. These regulators represent new gene-candidates involved in the development of cancer in human as the determinants involved in DNA metabolism are very conserved between yeast and mammals

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38

Ko, Josephine Mun Yee. "Tumor suppressive role of chromosomes 11, 13, and 14 in esophageal squamous cell carcinoma studied by functional complementation /". View abstract or full-text, 2005. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202005%20KO.

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39

Peat, D. S. "The effect of herpes simplex virus type 1 on chromosomes of human cells". Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383841.

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40

Daphnis, Danny Diamantis. "Molecular and cytogenetic approaches to the analysis of chromosomes in human preimplantation embryos". Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444371/.

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The original focus of the research for this thesis was concentrated on establishing strategies to detect chromosome imbalance as well as exploring the phenomenon of mosaicism and its underlying mechanisms in human preimplantation embryos. High levels of chromosomal mosaicism have been detected in human preimplantation embryos mostly by fluorescent in situ hybridisation (FISH) but also by comparative genomic hybridisation (CGH) and karyotyping. Mosaicism could arise through several mechanisms including abnormal cell divisions (mitotic non-disjunction or anaphase lag), failure of cytokinesis or endoreduplication. The FISH procedure has been criticised, as it is prone to failure. Two separate studies were developed and carried out in order to detect the level of mosaicism in embryos. In the first study a FISH protocol for the use of two different probes per chromosome was developed. The aim was to gain information on mechanisms leading to aneuploidy mosaicism and its true incidence. Three colour FISH was performed in three sequential rounds. In the first and second round different probes were used for chromosomes 1, 11, 18. In the third round probes were used for chromosomes X, Y and 18. Each FISH procedure included a control slide to assess FISH efficiency in all rounds of FISH. Two groups of embryos were spread on day 5 of development embryos grown in cleavage media throughout and embryos transferred to blastocyst media after day 3. A total of 21 embryos were analysed in each Group. The FISH results revealed one uniformly diploid and 20 mosaic embryos for Group I and 2 uniformly diploid and 19 mosaic embryos for Group II. Use of 2 different probes per chromosome was able to detect FISH artefacts and failure of hybridisation. Post- zygotic chromosome loss was the predominant mechanism leading to aneuploidy mosaicism for both groups, followed by chromosome gain, with only a few examples of mitotic non-disjunction. The relatively high percentage of tetraploidy in the blastocyst medium group was considered to reflect normal embryonic development. The use of CGH was investigated as an alternative strategy to detect the true level of mosaicism in the whole genome. The second part of the research for this thesis involved assessing the efficiency of CGH, improving the protocol for optimised use on single cells, and its application to human embryonic material. Results suggested that CGH is a laborious and technically demanding technique however, can provide extra information when used as a research tool. CGH was combined with FISH in order to assess chromosomal abnormalities in day 3 and day 5 embryos respectively. CGH was employed in 1-2 biopsied cells from a day 3 embryo, which was grown up to day 5 and further analysed by multi-colour FISH. The aim of this study was to observe the full chromosomal status of 1 -2 blastomeres biopsied at the cleavage stage (day 3) of development followed by FISH analysis of the rest of the embryo on day 5. This would allow the assessment of abnormalities in day 3 embryos by a full karyotype and then confirm whether the abnormality persists until day 5 using FISH for the chromosome(s) involved. In summary 30 embryos were fully analysed and only 3 (10%) were uniformly normal, while the rest were mosaic or chaotic. CGH was able to provide results in 83.3% of the embryos subjected to analysis. FISH and CGH showed either agreeing or complimentary results for all embryos analysed. The predominant mechanism of aneuploidy mosaicism was whole chromosome loss. Furthermore, partial aneuploidy was also detected, with partial chromosome loss being the principal mechanism. In the final part of the thesis the development of PGD protocols for a single gene disorder, namely DM, were devised using polymerase chain reaction (PCR) techniques. Two PGD protocols were devised and employed clinically in two patients undergoing PGD for DM using fluorescent PCR. Due to the extensive workup needed to develop the specific PCR protocols for each patient, a universal-like protocol was researched. Such a protocol would involve production of a sufficient amount of DNA through whole genome amplification techniques i.e. DOP-PCR from a single cell to carry out subsequent analysis with F-PCR markers as well whole chromosome analysis using CGH. DOP-PCR amplified DNA was subjected to amplification of five markers that would have been used during a PGD workup for DM and also subjected to CGH analysis. Initially genomic DNA was tested which produced high fidelity of amplification. Single cell DNA was then utilised in order to assess the amplification rate, allele dropout (ADO) and contamination levels.

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41

White, Jacqueline Katie. "Analysis of human NRAMP, IL8R and V1L1 genes (2q35) using yeast artificial chromosomes". Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339595.

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42

Inglehearn, Christopher Francis. "Minisatellite sequences close to the short arm telomere of the human sex chromosomes". Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/14143.

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Cosmid CY29 is derived from a DNA library prepared from the human-mouse hybrid cell line 3E7, which contains multiple Y chromosomes. Sub-clone 29C1, derived from CY29, has been found to define a hypervariable locus within 23kb of the human pseudoautosomal telomere. This has been assigned the locus name DXYS14. The clone has contributed to a genetic map of the human pseudoautosomal region, and has been used to study properties of the adjacent telomere. This thesis describes an analysis of sequences at this locus. Maps of the short arm subtelomeric regions of three human sex chromosomes are presented. In addition, by following inheritance of 290 homology through selected pedigrees it has been possible to obtain data on subtelomeric regions of seven other sex chromosomes. From this data it is shown that a region containing 29C1 homologous sequence and sequence proximal to it are duplicated on some telomeres. Thus any individual may have two, three or four copies of 29C1 homologous sequence in total, with one or two on each sex chromosome. In addition, restriction fragments containing 29C1 homology vary in size due to variation in copy number of a minisatellite type repeat. Sequence data from three such fragments shows blocks of imperfect 31bp GC rich repeat units in variable numbers in a head to tail array. The consensus sequence of these repeats show some similarity to other, reported minisatellite sequences. However when used as a probe, a DXYS14 consensus repeat oligomer detects other hypervariable loci only weakly, even at low stringency. It appears therefore that the DXYS14 repeat represents a separate family of minisatellites present in one or two blocks per haploid genome, and isolated within 23kb of the human XY telomere. In one pedigree studied, a novel 29C1 homologous restriction fragment is shown to have arisen during male meiosis, probably by change in size of the repeat block. Sequence and mapping data indicate that the 29C1 repeat block and sequence proximal to it shows characteristics normally associated with a low methylation island. This region does not appear to be transcribed however, and in the light of knowledge of DNA structure around locus DXYS14, a gene at this site seems unlikely. Sequences homologous to 29C1 are found in a range of vertebrates, with strong homology in some primates yet none in others. The implications of these observations are discussed.

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43

Holland, Katalin Anna. "Analysis of the molecular structure of centromeres of Chinese hamster and human chromosomes". Thesis, University of Leicester, 1993. http://hdl.handle.net/2381/34425.

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Monoclonal anti-CHO chromosome scaffold, and polyclonal anti-centromere autoimmune antibodies were employed to investigate the molecular organisation of the centromeres of Chinese hamster and human chromosomes. The presence of a novel ring-like structure was revealed, which was conserved amongst the metaphase centromeres of two rodents, namely Chinese hamster and mouse, and in humans. In metaphase the antigen had a molecular weight of 170kD, this polypeptide may be processed from, or the stable degradation product of, a 200kD interphase precursor full-length polypeptide. The antigen could not be detected in interphase centromeres, but the ring-like structure was detected in chromosome scaffold preparations, indicating that the ring antigen resisted the 2M NaCl extraction, and hence, tightly bound the DNA of metaphase chromosomes. The possible relationship of the centromere antigen with another high molecular weight and major chromosome scaffold protein, DNA topoisomerase II, was also explored. The centromere antigen was also localised apparently to the interdigitating microtubules of the midzone, in anaphase; seemingly to the contractile ring at cytokinesis, and also to the interphase centrioles. The antigen was shown to be distinct from the microtubule-associated proteins and had non-identity with another high molecular weight protein component of the contractile ring, namely myosin. The dramatic relocation of the antigen, however, at the metaphase/anaphase transition suggests that it falls into a class of recently identified dual chromosomal and cytoplasmic components, termed the "passenger proteins". The ring antigen is postulated to be involved in holding the sister chromatids together by a strong interaction with the centromeric DNA through prometaphase to the metaphase-anaphase transition. It is suggested that the ring antigen is disengaged from the centromere prior to anaphase, and may be involved in the regulation of the metaphase-anaphase transition.

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44

Oakey, Rebecca. "The structure of alphoid satellite DNA on normal and abnormal human Y chromosomes". Thesis, University of Oxford, 1989. http://ora.ox.ac.uk/objects/uuid:162cb1a7-3176-4b56-be8b-353b65fee236.

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The long-range structure of the Y chromosome alphoid satellite DNA has been determined in the cell lines 3E7 and OXEN. Variation in alphoid DNA block size and restriction enzyme sites were observed. The alphoid block size and restriction enzyme site variations were determined for a collection of 42 normal Y chromosomes. The alphoid DNA polymorphisms observed denned 24 Y chromosome alleles. Unexpectedly, the Y alphoid DNA alleles analysed revealed two distinct groups of Y chromosomes indicating that most of the Caucasian and Asian men analysed were descended from one of two males. The structure of the alphoid DNA was determined for 25 cell lines expected to contain abnormal Y chromosomes. Six of the cell lines lacked Y chromosomes. Four lacked both alphoid DNA and Y a centromere. 13 out of the remaining 15 Y chromosomes had centromeres and Y alphoid DNA block sizes and restriction enzyme site variation similar to that of normal Y chromosome alphoid DNA. Two of the abnormal cell lines had alphoid DNA blocks significantly different from the normal Y alphoid DNA structure. These results confirm that alphoid DNA is located very close to, or at the centromere and make it a prime candidate for a functional mammalian centromere sequence.

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45

Han, Tie Lan. "Study of individual chromosomes in human ejaculated sperm by fluorescence in situ hybridization". Thesis, Adelaide Thesis (M.D.) -- University of Adelaide, Department of Obstetrics and Gynaecology, 1993. http://hdl.handle.net/2440/21663.

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46

Han, Tie Lan. "Study of individual chromosomes in human ejaculated sperm by fluorescence in situ hybridization". Adelaide Thesis (M.D.) -- University of Adelaide, Department of Obstetrics and Gynaecology, 1993. http://hdl.handle.net/2440/21663.

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47

Gillet-Markowska, Alexandre. "Etude quantitative des variations structurelles des chromosomes chez Saccharomyces cerevisiae". Electronic Thesis or Diss., Paris 6, 2015. http://www.theses.fr/2015PA066233.

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L’accumulation de remaniements de la structure des chromosomes aussi appelés variations structurelles (SV) est un important contributeur à la transformation des cellules malignes et à la constitution d’une hétérogénéité intratumorale. Nous avons développé un outil bio-informatique qui permet désormais d’obtenir une image fine de ces SV qui se produisent dans le génome humain. Nous avons ainsi pu démontrer l’existence de SV présentes à de faibles fréquences dans différentes populations cellulaires supposées clonales montrant que les taux de formation des SV pourraient être grandement sous-estimés. Parallèlement, nous avons montré que le niveau d’instabilité des individus dépend de facteurs génétiques de prédisposition. Pour les identifier, nous avons développé des systèmes génétiques de mesure des taux de SV chez la levure qui vont nous permettre d'identifier les gènes contrôlant l'instabilité chromosomique par analyse de liaison à grande échelle. Ces régulateurs représenteront de nouveaux gènes candidats impliqués dans le développement du cancer chez l’homme, car les déterminants génétiques impliqués dans le métabolisme de l'ADN sont très conservés entre la levure et les mammifères
The accumulation of chromosomal rearrangements also called Structural Variations (SV) is a major contributor to the transformation of tumoral cells and to the constitution of intratumoral heterogeneity. We have developed a bio-informatic tool that can now provide a sharp image of SV that occur in the human genome. We have demonstrated the existence of SV present in low proportions in different supposedly clonal cell populations showing that the rates of SV formation could be greatly underestimated. In parallel, we have shown that the level of instability of the genome depends on predisposition factors. To identify those, we have developed genetic assays to measure the rate of SV in yeast that will allow us to identify new genes controlling the stability of the genome using large scale linkage analysis. These regulators represent new gene-candidates involved in the development of cancer in human as the determinants involved in DNA metabolism are very conserved between yeast and mammals

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48

Liu, Jian. "Deletion mapping of human 3P in major epithelial malignancies and fine localization of candidate tumor suppressor genes /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-577-8/.

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49

Christoffels, Alan. "Generation of a human gene index and its application to disease candidacy". Thesis, University of the Western Cape, 2001. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_2413_1185436829.

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With easy access to technology to generate expressed sequence tags (ESTs), several groups have sequenced from thousands to several thousands of ESTs. These ESTs benefit from consolidation and organization to deliver significant biological value. A number of EST projects are underway to extract maximum value from fragmented EST resources by constructing gene indices, where all transcripts are partitioned into index classes such that transcripts are put into the same index class if they represent the same gene. Therefore a gene index should ideally represent a non-redundant set of transcripts. Indeed, most gene indices aim to reconstruct the gene complement of a genome and their technological developments are directed at achieving this goal. The South African National Bioinformatics Institute (SANBI), on the other hand, embarked on the development of the sequence alignment and consensus knowledgebase (STACK) database that focused on the detection and visualisation of transcript variation in the context of developmental and pathological states, using all publicly available ESTs. Preliminary work on the STACK project employed an approach of partitioning the EST data into arbitrarily chosen tissue categories as a means of reducing the EST sequences to manageable sizes for subsequent processing. The tissue partitioning provided the template material for developing error-checking tools to analyse the information embedded in the error-laden EST sequences. However, tissue partitioning increases redundancy in the sequence data because one gene can be expressed in multiple tissues, with the result that multiple tissue partitioned transcripts will correspond to the same gene.

Therefore, the sequence data represented by each tissue category had to be merged in order to obtain a comprehensive view of expressed transcript variation across all available tissues. The need to consolidate all EST information provided the impetus for developing a STACK human gene index, also referred to as a whole-body index. In this dissertation, I report on the development of a STACK human gene index represented by consensus transcripts where all constituent ESTs sample single or multiple tissues in order to provide the correct development and pathological context for investigating sequence variation. Furthermore, the availability of a human gene index is assessed as a diseasecandidate gene discovery resource. A feasible approach to construction of a whole-body index required the ability to process error-prone EST data in excess of one million sequences (1,198,607 ESTs as of December 1998). In the absence of new clustering algorithms, at that time, we successfully ported D2_CLUSTER, an EST clustering algorithm, to the high performance shared multiprocessor machine, Origin2000. Improvements to the parallelised version of D2_CLUSTER included: (i) ability to cluster sequences on as many as 126 processors. For example, 462000 ESTs were clustered in 31 hours on 126 R10000 MHz processors, Origin2000. (ii) enhanced memory management that allowed for clustering of mRNA sequences as long as 83000 base pairs. (iii) ability to have the input sequence data accessible to all processors, allowing rapid access to the sequences. (iv) a restart module that allowed a job to be restarted if it was interrupted. The successful enhancements to the parallelised version of D2_CLUSTER, as listed above, allowed for the processing of EST datasets in excess of 1 million sequences. An hierarchical approach was adopted where 1,198,607 million ESTs from GenBank release 110 (October 1998) were partitioned into "
tissue bins"
and each tissue bin was processed through a pipeline that included masking for contaminants, clustering, assembly, assembly analysis and consensus generation. A total of 478,707 consensus transcripts were generated for all the tissue categories and these sequences served as the input data for the generation of the wholebody index sequences. The clustering of all tissue-derived consensus transcripts was followed by the collapse of each consensus sequence to its individual ESTs prior to assembly and whole-body index consensus sequence generation. The hierarchical approach demonstrated a consolidation of the input EST data from 1,198607 ESTs to 69,158 multi-sequence clusters and 162,439 singletons (or individual ESTs). Chromosomal locations were added to 25,793 whole-body index sequences through assignment of genetic markers such as radiation hybrid markers and gé
né
thon markers. The whole-body index sequences were made available to the research community through a sequence-based search engine (http://ziggy.sanbi.ac.za/~alan/researchINDEX.html).

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50

Machado, Melissa Pereira. "Monitoramento molecular dos transcritos BCR/ABL de pacientes com leucemia mieloide cronica em uso de imatinibe atraves da tecnica de PCR quantitativo em tempo rela (real-time)". [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310185.

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Orientadores: Katia Borgia Barbosa Pagnano, Afonso Celso Vigorito
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-14T18:14:56Z (GMT). No. of bitstreams: 1 Machado_MelissaPereira_M.pdf: 1144638 bytes, checksum: c55a80d3cce151782b16b741b0f21149 (MD5) Previous issue date: 2009
Resumo: A leucemia mieloide crônica (LMC) e uma desordem mieloproliferativa caracterizada pela presença do cromossomo Philadelphia (Ph), resultado da fusão do gene abl e do gene bcr cujo produto e uma proteína de atividade de tirosina quinase, inibida pelo mesilato de imatinibe. O imatinibe e hoje o tratamento de primeira linha da LMC e o monitoramento molecular dos transcritos BCR-ABL e fundamental no acompanhamento dos pacientes e na detecção precoce da perda de resposta ao tratamento. O objetivo deste trabalho foi realizar a padronização do método de PCR quantitativo (RQPCR) para o monitoramento molecular dos transcritos BCR-ABL de pacientes com LMC em tratamento com imatinibe. Foram coletadas amostras de sangue periferico de pacientes com LMC para RQ-PCR ao diagnostico e a cada três meses apos o tratamento com imatinibe. Foi utilizado o método Taqman. Como gene controle foi utilizado o ABL. Foi criada uma curva standard com diluições de 108 a 103 de um plasmideo com os transcritos b3a2 e b2a2 e com ABL. As quantificações foram feitas em duplicatas, assim como a curva standard. O threshold utilizado foi de 0,05 e a eficiência foi determinada em 99%. Os resultados foram reportados como uma relação entre BCR-ABL/ABL. Para o valor de referencia basal do laboratório foram analisadas 30 amostras de pacientes ao diagnostico, e calculada a mediana, sendo esse valor 83,66%. Resposta molecular maior (RMM) foi definida como redução dos transcritos BCR-ABL em 3 log a partir do valor basal do laboratório. Os valores foram ajustados a escala internacional, usando-se um fator de conversão de 1.19. Apos a padronização do método, foram avaliados 60 pacientes com LMC, cujas amostras foram coletadas ao diagnostico e a cada 3 meses. Respostas hematológica, citogenetica maior e citogenetica completa foram obtidas em 57 (95%), 45 (75%) e 38 (63%) dos pacientes, respectivamente. Vinte e quatro de 60 pacientes atingiram a RMM (40%), numa mediana de 8,5 meses. A sobrevida global foi superior nos pacientes com RCC (100%) vs pacientes sem RCC (77%) em 48 meses. Pacientes com RCC e com RMM tiveram uma sobrevida livre de eventos superior em relação aos pacientes que não atingiram os dois tipos de reposta (100% vs 60% respectivamente) (p= 0.007). Em resumo, neste estudo demonstramos o impacto prognostico em atingir RCC e RMM e também a importância do acompanhamento molecular nos pacientes com LMC.
Abstract: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of Philadelphia chromosome (Ph), the result of bcr and abl gene fusion, which product is a protein with kinase activity, inhibited by imatinib. Imatinib is currently the first-line treatment of CML and molecular monitoring of BCRABL transcripts is essential in monitoring of patients and for the early detection of loss of response to treatment. The aim of this study was to standardize quantitative PCR (RQ-PCR) method for molecular monitoring of BCR-ABL transcripts in patients with CML treated with imatinib. Peripheral blood samples from chronic phase patients were collected for RQ-PCR at diagnosis and every three months after treatment with imatinib. Taqman method was used for RQ-PCR. A standard curve with dilutions of 108 to 103 of a plasmid with the b3a2 and b2a2 transcripts and ABL gene, used as the control gene, was constructed. The runs were made in duplicates. The threshold used was 0.05 and the efficiency was determined as 99%. The results were reported as a BCR-ABL/ABL ratio (%). For the reference value of the baseline of the laboratory 30 samples from patients at diagnosis were quantified and the median value calculated was 83.66%. Major molecular response (MMR) was considered a three log reduction from the baseline value. MMR values were adjusted to international scale, using a conversion factor of 1.19. After standardization, BCR-ABL levels of 60 CML patients in chronic phase treated with imatinib were measured at diagnosis and then every three months. Hematological, major cytogenetic and complete cytogenetic responses were achieved in 57 (95%), 45 (75%) and 38 (63%) patients, respectively. Twenty-four out of 60 patients achieved a MMR (40%), in a median time of 8.5 months. Overall survival was superior for patients with CCR (100%) versus patients with no CCR (77%) (p= 0.01) in 48 months. Patients with CCR and with MMR had a superior event free-survival (EFS) in comparison with patients with CCR and no MMR (p= 0.007). In conclusion, we could demonstrate the prognostic impact of achieving CCR and a major molecular response and also the importance of molecular monitoring in the follow-up of CML patients.
Mestrado
Ciencias Medicas
Mestre em Clinica Medica

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