RESUMEN
The Nordic Lymphoma Study Group has performed two randomized clinical trials with chemotherapy-free first-line treatment (rituximab +/- interferon) in follicular lymphoma (FL), with 73% of patients alive and 38% without any need of chemotherapy after 10.6 years median follow-up. In order to identify predictive markers, that may also serve as therapeutic targets, gene expression- and copy number profiles were obtained from 97 FL patients using whole genome microarrays. Copy number alterations (CNAs) were identified, e.g. by GISTIC. Cox Lasso Regression and Lasso logistic regression were used to determine molecular features predictive of time to next therapy (TTNT). A few molecular changes were associated with TTNT (e.g. increased expression of INPP5B, gains in 12q23/q24), but were not significant after adjusting for multiple testing. Our findings suggest that there are no strong determinants of patient outcome with respect to GE data and CNAs in FL patients treated with a chemotherapy-free regimen (i.e. rituximab +/- interferon).
Asunto(s)
Linfoma Folicular , Humanos , Rituximab , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/genética , Variaciones en el Número de Copia de ADN , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Interferones/uso terapéutico , Biopsia , Expresión GénicaRESUMEN
Depending on disease stage follicular lymphoma (FL) lack the t(14;18) in ~15-~50% of cases. Nevertheless, most of these cases express BCL2. To elucidate mechanisms triggering BCL2 expression and promoting pathogenesis in t(14;18)-negative FL, exonic single-nucleotide variant (SNV) profiles of 28 t(14;18)-positive and 13 t(14;18)-negative FL were analyzed, followed by the integration of copy-number changes, copy-neutral LOH and published gene-expression data as well as the assessment of immunoglobulin N-glycosylation sites. Typical FL mutations also affected t(14;18)-negative FL. Curated gene set/pathway annotation of genes mutated in either t(14;18)-positive or t(14;18)-negative FL revealed a strong enrichment of same or similar gene sets but also a more prominent or exclusive enrichment of immune response and N-glycosylation signatures in t(14;18)-negative FL. Mutated genes showed high BCL2 association in both subgroups. Among the genes mutated in t(14;18)-negative FL 555 were affected by copy-number alterations and/or copy-neutral LOH and 96 were differently expressed between t(14;18)-positive and t(14;18)-negative FL (P<0.01). N-glycosylation sites were detected considerably less frequently in t(14;18)-negative FL. These results suggest a diverse portfolio of genetic alterations that may induce or regulate BCL2 expression or promote pathogenesis of t(14;18)-negative FL as well as a less specific but increased crosstalk with the microenvironment that may compensate for the lack of N-glycosylation.
Asunto(s)
Biomarcadores de Tumor , Linfoma Folicular/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Biología Computacional/métodos , Variaciones en el Número de Copia de ADN , Glicosilación , Humanos , Región Variable de Inmunoglobulina/genética , Linfoma Folicular/metabolismo , Mutación , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Translocación Genética , Secuenciación del ExomaRESUMEN
A screening procedure for highly thermostable yeast superoxide dismutase was developed. Growth yields at various temperatures were estimated for ten mesophilic and thermotolerant strains, belonging to the genera Saccharomyces, Kluyveromyces and Pichia. Higher yields at 45 degrees C were obtained for K. lactis 90-3 and 90-4. A correlation between the ability to grow at higher temperature and the thermostability of the superoxide dismutase enzyme synthesized was observed. A comparison of the operational stability of the superoxide dismutase of all tested strains suggests that the enzyme of K. lactis strains was more thermostable than that of the other tested microorganisms.
Asunto(s)
Proteínas Fúngicas/análisis , Kluyveromyces/enzimología , Pichia/enzimología , Saccharomyces/enzimología , Superóxido Dismutasa/análisis , CalorAsunto(s)
Evolución Biológica , Genes Fúngicos , Saccharomyces cerevisiae/enzimología , Schizosaccharomyces/enzimología , Acetiltransferasas/genética , Aspartato Carbamoiltransferasa/genética , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante)/genética , Dihidroorotasa/genética , Complejos Multienzimáticos/genética , Saccharomyces cerevisiae/genética , Schizosaccharomyces/genéticaRESUMEN
The organisation of the URA1 gene of Schizosaccharomyces pombe was determined from the entire cDNA cloned by the transformation of an ATCase-deficient strain of Saccharomyces cerevisiae. The URA1 gene encodes the bifunctional protein GLNase/CPSase-ATCase which catalyses the first two steps of the pyrimidine biosynthesis pathway. The complete nucleotide sequence of the URA1 cDNA was elucidated and the deduced amino-acid sequence was used to define four domains in the protein; three functional domains, corresponding to GLNase (glutamine amidotransferase), CPSase (carbamoylphosphate synthetase) and ATCase (aspartate transcarbamoylase) activities, and one cryptic DHOase (dihydroorotase) domain. Genetic investigations confirmed that both GLNase/CPSase and ATCase activities are carried out by the same polypeptide. They are also both feedback-inhibited by UTP (uridine triphosphate). Its organization and regulation indicate that the S. pombe URA1 gene product appears very similar to the S. cerevisiae URA2 gene product.