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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
41

Prevalência e genotipagem do papilomavírus humano em carcinomas epidermóides penianos de pacientes do Estado do Maranhão Prevalence and genotyping of human papillomavirus in squamous cell carcinomas of patients from the state of Maranhão

RAMOS, Walna Luisa Barros e 28 April 2017 (has links)
Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-09-12T19:35:08Z No. of bitstreams: 1 WalnaRamos.pdf: 1885249 bytes, checksum: a716015a5d512aaba735cf4af13d0e13 (MD5) Made available in DSpace on 2017-09-12T19:35:08Z (GMT). No. of bitstreams: 1 WalnaRamos.pdf: 1885249 bytes, checksum: a716015a5d512aaba735cf4af13d0e13 (MD5) Previous issue date: 2017-04-28 Human papillomavirus (HPV) is the etiologic agent of one of the most common sexually transmitted infections (STIs). According to the oncogenic potential, it is classified in low risk and high risk; high risk subtypes cause lesions that may progress to invasive carcinomas and has been recognized as a possible etiologic agent in penile carcinoma. Brazil has one of the highest incidences of penile cancer in the world. The general objective of this work is associate HPV infection with the histopathological profile of squamous cell carcinomas in patients from the State of Maranhão. This is a prospective analytical study of 29 samples of patients who underwent penectomy surgery at the Aldenora Bello Institute of Oncology of Maranhão. Sociodemographic data were collected through a questionnaire applied to the patients, clinical and histopathological data were collected from the medical records. Tumor samples were collected during penectomy surgeries, and the following steps were performed at the laboratory: DNA extraction and quantification, Nested PCR with PGMY and GP + primers for HPV detection, visualization of amplified products, purification of the PCR product and automated sequencing. The sequencing products were decoded through the BLAST program. Data were analyzed through the SPSS statistical program, with a 5% level of significance. It was observed that the majority of the men were over 60 years of age (69%), had stable marital union (75.9%), family income of up to one minimum wage (75.9%), were illiterate (55. 2%), lived in countryside towns (79.3%), reported using tobacco at some moment in their lives (62%). Regarding sexual habits, 62.1% reported not having performed circumcision, 41.4% had a previous STD, 72.4% had never used a condom, 48.3% had the first intercourse before age 18. The presence of HPV was detected in 69% of the cases, among the viral types, HPV 16 was the most prevalent (55.5%). Regarding to lesion, 51.7% of the cases presented more than one affected region, and the glans was affected in 93.1% of the cases. The most prevalent type of lesion was ulceration (51.7%). Among the histopathological classifications, 41.4% of the samples were classified in degree I of the Broders scale, 27.7% in stage T1 of the TNM staging and according to the Jackson classification, both stages I and II presented the same prevalence, 27.6% of samples. There was no statistically significant difference between the variables evaluated and the presence of HPV. Low education, low income and no circumcision were highly observed in the study, being possible to correlate such variables with the increase of the risk of penile cancer development. The presence of HPV in 69% of the samples and the prevalence of high risk subtypes suggest the need for more actions to prevent the spread of HPV over the population O papilomavírus humano (HPV) é o agente etiológico de umas das infecções sexualmente transmissíveis (ISTs) mais comuns. É classificado de acordo com o potencial oncogênico em baixo risco e alto risco, os subtipos de alto risco causam lesões que podem progredir para carcinomas invasivos e vem sendo reconhecido como possível agente etiológico no carcinoma peniano. O Brasil tem uma das maiores incidências de câncer de pênis do mundo. O objetivo geral deste trabalho é associar a infecção do HPV com o perfil histopatológico de carcinomas epidermóides penianos em pacientes do Estado do Maranhão. Trata-se de um estudo analítico prospectivo de 29 amostras de pacientes que foram submetidos a cirurgia de penectomia no Instituto Maranhense de Oncologia Aldenora Bello. Dados sociodemográficos foram coletados através de um questionário aplicado aos paciente, os dados clínicos e histopatológicos foram coletados dos prontuários. As amostras tumorais foram coletadas durante as cirurgias de penectomia, e em laboratório foram realizadas as etapas de: extração e quantificação do DNA, PCR Nested com os primers PGMY e GP+ para detecção do HPV, visualização dos produtos amplificados, purificação do produto da PCR e sequenciamento automatizado. Os produtos do sequenciamento foram decodificados através do programa BLAST. Os dados foram analisados através do programa estatístico SPSS, o nível de significância foi de 5%. Foi observado que a maioria dos homens estava na faixa etária acima de 60 anos (69%), apresentavam união conjugal estável (75,9%), renda familiar de até um salário mínimo (75,9%), eram analfabetos (55,2%), residiam em municípios do interior do Estado (79,3%), relataram o uso de tabaco em algum momento da vida (62%). Em relação aos hábitos sexuais, 62,1% relataram não ter realizado circuncisão, 41,4 % a ocorrência de DST prévia, 72,4% nunca fizeram uso de preservativo, 48,3% tiveram o 1º coito antes dos 18 anos. A presença de HPV foi detectada em 69% dos casos, dentre os tipos virais, o HPV 16 foi o mais prevalente (55,5%). Em relação a lesão, 51,7% dos casos apresentou mais de uma região afetada, estando a glande afetada em 93,1% dos casos. O tipo de lesão mais prevalente foi a do tipo ulceração (51,7%). Dentre as classificações histopatológicas, 41,4% das amostras foram classificadas no grau I da escala de Broders, 27,7% no estágio T1 do estadiamento TNM e na classificação de Jackson, os estágios I e II apresentam a mesma prevalência, 27,6% das amostras. Não houve diferença estatisticamente significante entre as variáveis avaliadas e a presença de HPV. A baixa escolaridade, a baixa renda e a não circuncisão foram observados no estudo com um percentual elevado, sendo possível correlacionar tais variáveis com o aumento no risco de desenvolvimento do câncer de pênis. A presença de HPV em 69% das amostras e a prevalências dos subtipos de alto risco sugerem a necessidade de mais ações de prevenção da disseminação desse vírus na população.
42

Prospecção de assinaturas de seleção em regiões de QTL associadas com características reprodutivas em novilhas Nelore Prospection of selection signatures in QTL regions associated to reproductive features in Nelore heifers

Montes Vergara, Donicer Eduardo [UNESP] 24 March 2016 (has links)
Submitted by DONICER EDUARDO MONTES VERGARA null (donicer.montes@unisucre.edu.co) on 2016-04-11T17:24:33Z No. of bitstreams: 1 H.Tese-Donicer- Defensa Definitivo -08-04-2016.pdf: 1794206 bytes, checksum: a97a3f4dcd0f3e1489260272006d51af (MD5) Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-04-12T14:43:11Z (GMT) No. of bitstreams: 1 montesvergara_de_dr_jabo.pdf: 1794206 bytes, checksum: a97a3f4dcd0f3e1489260272006d51af (MD5) Made available in DSpace on 2016-04-12T14:43:11Z (GMT). No. of bitstreams: 1 montesvergara_de_dr_jabo.pdf: 1794206 bytes, checksum: a97a3f4dcd0f3e1489260272006d51af (MD5) Previous issue date: 2016-03-24 Características reprodutivas, como a ocorrência de prenhez precoce, são mais importantes economicamente ao comparar-se com as características de crescimento. Desta forma, o aumento da taxa de fertilidade e emprego de animais geneticamente superiores é determinante no progresso da produtividade nas fazendas comerciais de produção de carne bovina. A seleção modifica as frequências alélicas de uma população ao transmitir as variantes gênicas mais interessantes. Considerando o desequilíbrio de ligação, alguns locos adjacentes às mutações favoráveis são transmitidos ao longo das gerações. Estes são conhecidos como assinaturas de seleção e podem ser identificados com o uso de “chips” de SNP e metodologias estatísticas adequadas. Com o objetivo de identificar assinaturas de seleção recentes em QTL previamente mapeados para características reprodutivas de fêmeas bovinas ligadas à precocidade sexual, foram genotipadas 2.035 fêmeas da raça Nelore (Bos taurus indicus) com o chip “Illumina BovineHD BeadChip”. Posteriormente foi inferida a fase de ligação dos SNPs e a reconstrução dos haplótipos. A detecção de assinaturas de seleção foi realizada por meio da aplicação da metodologia “Relative Extended Haplotype Homozygosity” (REHH). A identificação de genes que contribuem para a importância da característica nestas regiões foi feita com a ferramenta Map Viewer do “National Center for Biotechnology Information”- NCBI e GBrowse carregada com o genoma bovino versão UMD 3.1. Foram detectadas 2.756 regiões núcleo, com tamanho médio 27,6 ± 29,1 Kb, abrangendo 70,1 Mb dos 25 cromossomos estudados. Dos SNPs utilizados, 17.312 participaram da formação das regiões núcleo, com o mínimo de 10 no BTA27 e o máximo de 20 SNPs nos cromossomos 1, 3-7, 9-15,18-21, e 23-24. Foram identificadas 40 assinaturas de seleção recentes com diferentes níveis de significância e 56 genes A maioria dos genes localizados nas regiões de assinaturas de seleção tem relação com os processos biológicos de metabolismo mitocondrial, desenvolvimento pós-embrionário, regulação da taxa de ovulação e fertilidade, resposta imune, metabolismo de triglicerídeo, proliferação celular e neurônios receptores olfativos. A investigação de mecanismos regulatórios da expressão dos genes associados aos processos biológicos descritos pode oferecer conhecimentos sobre os mecanismos moleculares que afetam a característica ocorrências de prenhez precoce, na raça Nelore. Some reproductive traits such as early pregnancy are more profitable than those related to growth. Increasing fertility rate and using genetically superior animals are crucial in productivity of meat commercial farms. Artificial selection modifies allele frequencies of a cattle population by transmitting the most significant gene variants. Considering linkage disequilibrium, some loci adjacent to favorable mutations are transmitted across generations. Known as signatures of selection, such locations can be identified by the SNP chips, and appropriate statistical methods. To determine recent selection signature in quantitative trait loci (QTL) previously mapped for reproductive cow features linked to sexual precocity, 2,035 Nelore (Bos taurus indicus) females were genotyped by Illumina Bovine chip. After, inferring the connection phase of SNPs allowed haplotype reconstruction. Selection signatures were detected by Relative Extended Haplotype Homozygosity (REHH) method. Genes supposedly important were recognized by Map Viewer from the National Center for Biotechnology Information (NCBI), and also through a loaded GBrowse with bovine genome UMD, version 3.1. A total of 2,756 core regions were detected, with an average size of 27.6 ± 29.1 Kb, covering 70.1 Mb of 25 chromosomes. 17,312 SNPs are involved in the formation of core regions with at least 10 on BTA27, and a maximum of 20 SNPs on 1, 3-7, 9-15, 18-21, and 23-24 chromosomes. We identify 40 possible recent selection signatures, with different levels of significance, and 56 positional candidate genes. Most of genes located in selection signature regions are related to biological processes of mitochondrial metabolism, post-embryonic development, ovulation rate regulation and fertility, immune response, triglyceride metabolism, cell proliferation, and olfactory receptor neurons. The investigation of regulatory mechanisms of gene expression associated with biological processes described can provide knowledge on the molecular mechanisms affecting characteristic of early pregnancy occurrences in Nellore.
43

Comparação das técnicas micromorfológicas e moleculares na pesquisa e identificação de Malessezia spp em individuos sadios e com manifestações dermatológicas. Comparison of the techniches micromorphological and molecular in the research and identification of Malassezia spp. in healthy individuals and with dermatological manifestations.

Giovana Leticia Hernández Arriagada 27 January 2009 (has links)
Espécies de Malassezia fazem parte da microbiota de humanos e de animais. Essas leveduras lipofílicas são microrganismos oportunistas que estão associados com muitas doenças superficiais como: pitiriase versicolor, dermatite seborréica, foliculite, dermatite atópica e algumas infecções sistêmicas. As espécies de Malassezia têm sido identificadas através de procedimentos morfológicos e bioquímicos, no entanto, pequenas semelhanças entre algumas espécies estão presentes em algumas regiões do genoma. Foi avaliado o PCR-RFLP, método molecular para genotipar espécies de Malassezia obtidas de 55 amostras clinicas isoladas. Foram analisados 23 pacientes com dermatite seborréica, pitiriase versicolor e com a síndrome de Gourgerot- Carteaud. Encontramos quatro espécies diferentes: M. furfur, M. globosa, M. sympodialis and M. slooffiae. A identificação fisiológica e o PCR-RFPL foram compatíveis em 83% das amostras. M. furfur esteve presente em 52% dos casos, o que sugere que é o agente causador da pitiriase versicolor e da dermatite seborréica. Os resultados sugerem que a utilização do PCR-RFLP em amostras clínicas é importante no diagnóstico de algumas micoses causadas por esta levedura. Malassezia species are part of the microbiota of humans and other animals. These lipophilic yeasts are opportunistic microorganisms that are associated with some dermatoses including pityriasis versicolor, seborrheic dermatitis, folliculitis ptirospórica, atopic dermatitis, some systemic infections among others. The species of Malassezia have been identified by morphological and biochemical and molecular techniques currently. We identify the species of Malassezia obtained from 55 clinical samples and 15 samples that formed the control group, by conventional techniques using a medium with not described in the literature, the mixture of media and Dixon Kimming, which was higher than each when used separately. Used the molecular method of PCR-RFLP to genotype 23 of the 55 clinical samples of Malassezia spp. from patients with seborrheic dermatitis, pityriasis versicolor and Gourgerot - Carteaud syndrome. Could the isolation of four species: M. furfur, M. globosa, M. Sympodialis and M. slooffiae. The physiological identification obtained with the PCRRFLP was consistent in 83% of the samples. M. furfur was present in 52% of cases, suggesting that is the main causative agent of pityriasis versicolor and perhaps the agent most frequently found in seborrheic dermatitis. The results suggest that the use of PCR-RFLP method in clinical samples is of great use for the identification of Malassezia species associated with diseases in humans.
44

Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression

Burkhardt, Jana, Blume, Mechthild, Petit-Teixeira, Elisabeth, Teixeira, Vitor Hugo, Steiner, Anke, Quente, Elfi, Wolfram, Grit, Scholz, Markus, Pierlot, Céline, Migliorini, Paola, Bombardieri, Stefano, Balsa, Alejandro, Westhovens, René, Barrera, Pilar, Radstake, Timothy R. D. J., Alves, Helena, Bardin, Thomas, Prum, Bernard, Emmrich, Frank, Cornelis, Francois, Ahnert, Peter, Kirsten, Holger 5 September 2014 (has links) (PDF)
In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p,1026) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA.
45

Duffy ir Kidd antigenų sistemų fenotipavimo ir genotipavimo reikšmė, atliekant dažnas eritrocitų transfuzijas The value of phenotyping and genotyping of Duffy and Kidd antigen systems in case of frequent red blood cell transfusions

Remeikienė, Diana 18 June 2014 (has links)
Nors yra žinoma, kad pacientams, kuriems neseniai atliktos eritrocitų transfuzijos, kraujo grupių nustatymo hemagliutinacijos reakcija rezultatai gali būti nepatikimi dėl kraujyje cirkuliuojančių donoro ertrocitų, tačiau literatūroje nėra aiškių rekomendacijų, kuriais atvejais reikėtų naudoti molekulinius tyrimo metodus. Serologinis Duffy ir Kidd sistemų antigenų ir antikūnų prieš juos nustatymas – viena svarbiausių imunohematologinių problemų transfuzinėje medicinoje. Šiame darbe pirmą kartą Lietuvoje atlikti moksliniai tyrimai imunohematologijos srityje ir panaudoti genetiniai Duffy ir Kidd antigenų sistemų tyrimo metodai. Siekiant įvertinti Duffy ir Kidd antigenų sistemų fenotipavimo ir genotipavimo reikšmę, mes nagrinėjome klinikinių, demografinių, imunohematologinių bei su transfuzija susijusių veiksnių įtaką tyrimų rezultatams. Mūsų tyrimo metu nustatytas didesnis nei 30 proc. nesutapimų dažnis tarp Duffy ir Kidd antigenų sistemų fenotipavimo ir genotipavimo rezultatų patvirtino genetinių tyrimų naudą, atliekant dažnas eritrocitų transfuzijas. Atliekant šį darbą, pirmą kartą Lietuvoje nustatytas Duffy ir Kidd antigenų sistemų fenotipų paplitimas. Nustatytas laiko tarpas, per kurį įprastai klinikinėje praktikoje naudojamų serologinių tyrimų (hemagliutinacijos reakcijos) rezultatai gali būti patikimi, bei pateiktos atitinkamos rekomendacijos didina šio tyrimo praktinę vertę ir yra novatoriška šiuolaikinėje transfuzinėje medicinoje. Accurate phenotyping of multitransfused patients is often complicated - mostly due to the presence of circulating transfused donor’s RBCs in the recipient’s blood, leading to discrepancies in the assessment of test results. The question when genotyping including Duffy and Kidd systems should be used for patients undergoing chronic RBC transfusions is still being discussed. Serological testing and evaluation of the antigens and antibodies of Duffy and Kidd systems are among the main problems in multitransfused patients. The research on immunohematology and blood group genetics has been caried out for the first time in Lithuania. A high rate (more than 30%) of disagreements between the results of phenotyping and genotyping in our study demonstrates the benefit of DNA-based testing for chronically-transfused patients. In order to estimate the value of phenotyping and genotyping of Duffy and Kidd antigen systems in patients undergoing long-term RBC transfusions, the impact of demographic, clinical, immunohaematological or transfusion-related factors, on the discrepancy of the results, was investigated. Time frame that could be appropriate to obtain reliable results of conventionaly used serologic tests (hemmagglutination reaction) after the last transfusion was established as well as appropriate recommendations were made. We believe that these studies could be helpful for clinical practice as well as in decreasing the risk of transfusion of red blood cells.
46

HPV and p16 in head and neck cancer

Sailan, Ahmad Tarmidi 2010 (has links)
There is some evidence to suggest that human papilloma virus (HPV) may play a causal role in head and neck carcinoma (HNSCC). The aim of this study was to investigate the prevalence of HPV DNA in HNSCC and to determine whether any correlation exists with p16 or survival. An initial pilot study of sixty formalin-fixed HNSCC was carried out in order to optimise the methodology for the PCR and immunohistochemistry. A further 84 benign lesions, 12 dysplasias and additional 80 HNSCC were also included. In the pilot study the prevalence of all HPV types was 67% of which 18% were high risk-HPV (HR-HPV) and for the combined carcinoma sample it was 59% of which 25% were HR-HPV. The overall HPV prevalence was 51% and 42% for benign lesions and dysplasias with HR-HPV accounting for 14% and 8% respectively. A total of four alpha HPV types were identified and eleven beta HPV types. Multiple HPV types co-existed in the same tissue and in some cases both alpha and beta HPV. The results may suggest that HR-HPV may play a role in a small subset of HNSCC. An association was found between HPV status and gender, age group, survival, nodal metastasis and T3 tumour size and smoking. HPV16 was predominantly present in female patients and was associated with an improved overall survival and recurrence free survival. p16 positivity varied from 76-78% in carcinomas, 51% in benign lesions and 66% in dysplasias. p16 status was not associated with disease recurrence or nodal metastasis. Positive p16 staining and high staining intensity was associated with a poorer overall survival and the male gender, an older age group, anatomic site, and T2 tumour size. Overall HPV status was not correlated with p16 expression but a correlation found between p16 and HPV16 may suggest that p16 could potentially act as a surrogate marker of HPV16. However, the lack of concordance would suggest that in isolation p16 may not be a reliable marker for HR-HPV and should not be relied upon in isolation. Our findings could suggest that HPV16 and p16 status may be independent predictors for prognosis and disease recurrence.
47

Etude du polymorphisme associé aux répétitions en tandem pour le typage de bactéries pathogènes : Pseudomonas aeruginosa et Staphylococcus aureus

Onteniente, Lucie 13 February 2004 (has links) (PDF)
Les répétitions en tandem sont constituées de successions de motifs d'ADN. Ces structures présentes dans tous les organismes, procaryotes comme eucaryotes, ont des applications dans de nombreux domaines. Depuis quelques années seulement, les répétitions en tandem sont étudiées chez les bactéries. Le polymorphisme associé à ces séquences peut être utilisé pour le génotypage de bactéries pathogènes, permettant une identification précise au niveau de la souche. Le polymorphisme des séquences répétées est de deux types : polymorphisme de longueur et mutations internes aux motifs. Les génomes des deux bactéries pathogènes responsables d'infections nosocomiales, Staphylococcus aureus et Pseudomonas aeruginosa, ont été étudiés dans le but d'identifier des séquences répétées polymorphes. Un ensemble de marqueurs polymorphes a été validé expérimentalement pour ces deux espèces permettant un typage dit MLVA (pour « Multiple Locus VNTR Analysis »). Le travail plus classique de typage par la taille de la répétition a été complété par un travail de séquençage de certains allèles. Les résultats obtenus montrent comment le typage « MLVA » complété si nécessaire par le séquençage d'allèles, pourraient constituer de nouvelles méthodes peu coûteuses participant au contrôle des infections bactériennes.
48

Caracterización genética y molecular del linfoma de células del manto y sus implicaciones clínicas

Royo Moreno, Cristina 15 January 2013 (has links)
Los resultados de esta tesis doctoral han permitido profundizar en el reconocimiento y clasificación del linfoma de células del manto (MCL), basándonos en dos subtipos poco habituales. Por un lado, hemos estudiado las muestras de los pacientes de MCL que no presentan la traslocación principal t(11;14), característica que ha sido objeto de discusión al pensar que el diagnóstico de MCL podía no ser el correcto. Por otro lado, hemos estudiado los MCL con presentación clínica indolente, larga supervivencia, y que no requieren tratamiento durante largos períodos de tiempo, particularidad llamativa en los pacientes de MCL. En las dos primeras publicaciones de esta tesis hemos profundizado en el estudio de los MCL ciclina D1 negativos. Hemos demostrado que el factor de transcripción SOX11, además de sobreexpresarse en MCL ciclina D1 positivos, es un biomarcador útil para identificar los MCL ciclina D1 negativos. Además, caracterizamos genéticamente estos casos y mostramos que el 55% presenta traslocaciones de la CCND2 predominantemente con cadenas ligeras de los genes de las inmunoglobulinas. El perfil de alteraciones genómicas estudiado con arrays de alta densidad ha demostrado que las alteraciones genéticas secundarias entre los MCL ciclina D1 negativos y positivos son muy similares. Los casos de MCL ciclina D1 negativos tienen características clínicas y patológicas similares a los ciclina D1 positivos. Las translocaciones de CCND2 junto con la expresión de SOX11 son herramientas de diagnóstico muy útiles en la identificación de los MCL ciclina D1 negativos para que éstos puedan beneficiarse de los mismos protocolos terapéuticos usados en los MCL convencionales. En el tercer trabajo de esta tesis, nos hemos centrado en el reconocimiento del grupo de pacientes de MCL que no necesita tratamiento durante largos periodos de tiempo, idea que está modificando la manera de entender el MCL, ya que en general está considerado un linfoma agresivo que requiere un tratamiento inmediato. En este trabajo nos basamos en el estudio de Fernandez et al.1 en que se comparó un grupo de pacientes de MCL con comportamiento clínico indolente con un grupo de pacientes con MCL convencional (agresivo). Ambos grupos de muestras tenían un perfil de expresión global similar, sugiriendo que pertenecen a la misma enfermedad, pero también diferían en la expresión de una pequeña firma de 13 genes que estaba altamente expresada en los casos convencionales de MCL pero era negativa en los tumores de los pacientes con comportamiento indolente. Por lo que en el presente estudio, diseñamos y validamos un ensayo de PCR cuantitativa, seleccionando tres genes de la firma de perfil de expresión génica: SOX11, HDGFRP3 y DBN1 que permiten clasificar los casos en uno de estos dos grupos. El subgrupo con baja expresión de los tres genes incluye principalmente los pacientes con clínica indolente, afectación no-ganglionar, genes de las inmunoglobulinas hipermutados, y una supervivencia significativamente superior en comparación a los casos con expresión alta. Además, los MCL leucémicos sin afectación ganglionar y con alta expresión de los tres genes tienen una supervivencia significativamente inferior y un comportamiento clínico más agresivo que los pacientes con firma de expresión baja sin afectación ganglionar. En cuanto a las alteraciones genéticas, tanto los MCL con alta o baja expresión de los tres genes tenían una supervivencia significativamente inferior si presentan alteraciones en 17p. Por tanto, concluimos que la evaluación de la firma de los tres genes junto con el estudio de 17p/TP53 en muestras leucémicas puede ayudar a identificar un subgrupo particular de MCL y determinar la evolución clínica de estos los pacientes. Por tanto, estos estudios pueden proporcionar una evaluación más precisa del MCL y una ayuda en la decisión de tratamiento más adecuado para cada paciente. In the first publication of this thesis we have studied the cyclin D1-negative mantle cell lymphomas (MCL). These cases are not well characterized due to the difficulties in their recognition. Overexpression of the transcription factor SOX11 has been observed in conventional MCL. In this study we demonstrated that SOX11 was highly expressed in cyclin D1-negative MCL, thus SOX11 expression is a highly specific marker for both cyclin D1-positive and negative MCL. In the second study we investigated 40 cyclin D1-negative MCL. Chromosomal rearrangements of CCND2 were detected in 55% of the cases and frequently with light chain immunoglobulin (IG) genes as partners. The genomic profile of the cyclin D1-negative cases analyzed by high resolution arrays were similar to the cyclin D1-positive MCL. This characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients. In the third publication, we studied the clinical and biological features of mantle cell lymphoma with a more indolent disease and long survival. The expression of 3 genes (SOX11, HDGFRP3, DBN1) selected from a gene expression signature distinguishing conventional an indolent MCL was studied in 68 leukemic MCL by quantitative PCR. An unsupervised analysis segregated two groups of MCL based on the expression levels of these genes. The tumors with low expression presented mainly with a non-nodal disease, had more frequently mutated IG, fewer genomic alterations, remained untreated more frequently and longer time, and had a better outcome than the tumors with high expression. The presence of 17p/TP53 alterations had an adverse effect on the outcome of both subgroups of MCL. The detection of the 3-gene signature may help to identify this particular subtype of MCL.
49

The genetic composition and diversity of Francisella tularensis

Larsson, Pär 2007 (has links)

Francisella tularensis is the causative agent of the debilitating, sometimes fatal zoonotic disease tularemia. To date, little information has been available on the genetic makeup of this pathogen, its evolution, and the genetic differences which characterize subspecific lineages. These are the main areas addressed in this thesis.

The work indicated a high degree of genetic conservation of F. tularensis, both on the sequence level as determined by sequencing and on the compositional level, determined by array-based comparative genomic hybridizations (aCGH). One striking finding was that subsp. mediasiatica was most similar to subsp. tularensis, despite their natural confinement to Central Asia and North America, respectively. All genetic Regions of Difference RD found by aCGH distinguishing lineages were had resulted from repeat-mediated excision of DNA. This was used to identify additional RDs. Such data along with a multiple locus sequence analysis suggested an evolutionary scenario for F. tularensis.

Based on genomic information, a novel typing scheme for F. tularensis was furthermore devised and evaluated. This method provided increased robustness compared to previously used methods for F. tularensis typing, while retaining a capacity for high resolution.

Finally, the genomic sequence of the highly virulent F. tularensis strain SCHU S4 was determined and analysed. Evidenced by numerous pseudogenes and disrupted metabolic pathways, the bacterium appears to be undergoing a genome reduction process whereby a large proportion of the genetic capacity gradually is lost. It is likely that F. tularensis has irreversibly has evolved into an obligate host-dependent bacterium, incapable of a free-living existence. Unexpectedly, the bacterium was found to be devoid of common virulence mechanisms such as classic toxins, or type III and IV secretion systems. Instead, the virulence of this bacterium is probably largely the result of specific and unusual mechanisms.

50

The genetic composition and diversity of Francisella tularensis

Larsson, Pär 2007 (has links)
Francisella tularensis is the causative agent of the debilitating, sometimes fatal zoonotic disease tularemia. To date, little information has been available on the genetic makeup of this pathogen, its evolution, and the genetic differences which characterize subspecific lineages. These are the main areas addressed in this thesis. The work indicated a high degree of genetic conservation of F. tularensis, both on the sequence level as determined by sequencing and on the compositional level, determined by array-based comparative genomic hybridizations (aCGH). One striking finding was that subsp. mediasiatica was most similar to subsp. tularensis, despite their natural confinement to Central Asia and North America, respectively. All genetic Regions of Difference RD found by aCGH distinguishing lineages were had resulted from repeat-mediated excision of DNA. This was used to identify additional RDs. Such data along with a multiple locus sequence analysis suggested an evolutionary scenario for F. tularensis. Based on genomic information, a novel typing scheme for F. tularensis was furthermore devised and evaluated. This method provided increased robustness compared to previously used methods for F. tularensis typing, while retaining a capacity for high resolution. Finally, the genomic sequence of the highly virulent F. tularensis strain SCHU S4 was determined and analysed. Evidenced by numerous pseudogenes and disrupted metabolic pathways, the bacterium appears to be undergoing a genome reduction process whereby a large proportion of the genetic capacity gradually is lost. It is likely that F. tularensis has irreversibly has evolved into an obligate host-dependent bacterium, incapable of a free-living existence. Unexpectedly, the bacterium was found to be devoid of common virulence mechanisms such as classic toxins, or type III and IV secretion systems. Instead, the virulence of this bacterium is probably largely the result of specific and unusual mechanisms.

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