Search

Haematopoiesis is the process of generation of blood cells. Lymphopoiesis generates lymphocytes, the cells in charge of the adaptive immune response. Disruptions of this process are associated with diseases like leukaemia, which is especially incident in children. The characteristics of self-regulation of this process make them suitable for a mathematical study. In this paper we develop mathematical models of lymphopoiesis using currently available data. We do this by drawing inspiration from existing structured models of cell lineage development and integrating them with paediatric bone marrow data, with special focus on regulatory mechanisms. A formal analysis of the models is carried out, giving steady states and their stability conditions. We use this analysis to obtain biologically relevant regions of the parameter space and to understand the dynamical behaviour of B-cell renovation. Finally, we use numerical simulations to obtain further insight into the influence of proliferation and maturation rates on the reconstitution of the cells in the B line. We conclude that a model including feedback regulation of cell proliferation represents a biologically plausible depiction for B-cell reconstitution in bone marrow. Research into haematological disorders could benefit from a precise dynamical description of B lymphopoiesis., Comment: Submitted to Journal of Theoretical Biology

Artificial intelligence methods may help in unveiling information that is hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data, but they have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell Acute Lymphoblastic Leukaemia. In this paper, we analysed flow cytometry data that were obtained at diagnosis from 56 paediatric B-cell Acute Lymphoblastic Leukaemia patients from two local institutions. Our aim was to assess the prognostic potential of immunophenotypical marker expression intensity. We constructed classifiers that are based on the Fisher&rsquo, s Ratio to quantify differences between patients with relapsing and non-relapsing disease. We also correlated this with genetic information. The main result that arises from the data was the association between subexpression of marker CD38 and the probability of relapse.

Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow. The transcription factor PRDM1 is a master regulator of plasma cell development and is considered to be an oncosuppressor in several lymphoid neoplasms. The PRDM1β isoform is an alternative promoter of the PRDM1 gene that may interfere with the normal role of the PRDM1α isoform. To explain the induction of the PRDM1β isoform in MM and to offer potential therapeutic strategies to modulate its expression, we characterized the cis regulatory elements and epigenetic status of its promoter. We observed unexpected patterns of hypermethylation and hypomethylation at the PRDM1α and PRDM1β promoters, respectively, and prominent H3K4me1 and H3K9me2 enrichment at the PRDM1β promoter in non-expressing cell lines compared to PRDM1β-expressing cell lines. After treatment with drugs that inhibit DNA methylation, we were able to modify the activity of the PRDM1β promoter but not that of the PRDM1α promoter. Epigenetic drugs may offer the ability to control the expression of the PRDM1α/PRDM1β promoters as components of novel therapeutic approaches.

Resumen Objetivo Determinar los niveles en los titulos de anticuerpos antinucleares (ANA) observados por inmunofluorescencia indirecta en sustrato de celula HEp-2, y su asociacion con el diagnostico de enfermedad del tejido conectivo sistemica en las pruebas solicitadas por una Unidad de Reumatologia. Metodo Se seleccionaron muestras de pacientes que acudian por primera vez a consulta de reumatologia, sin prueba de ANA previa, durante el periodo comprendido entre enero de 2010 y diciembre de 2012. Se registro el titulo de dilucion, patron y especificidad antigenica. En enero de 2015 se valoraron los diagnosticos de los pacientes y se clasificaron en conectivopatias sistemicas (lupus eritematoso sistemico, sindrome de Sjogren, esclerosis sistemica, conectivopatia indiferenciada, sindrome antifosfolipido, enfermedad mixta del tejido conectivo y miopatia inflamatoria) o no conectivopatia sistemica. Resultado De un total de 1.282 pruebas solicitadas por la Unidad de Reumatologia en sujetos sin estudio previo 293 resultaron positivas, predominando las mujeres (81,9%). Con conectivopatia sistemica se registraron 105 pacientes y 188 sin conectivopatia. En diluciones 1/640 el valor predictivo positivo en las conectivopatias fue de 73,3% frente al 26,6% de las no conectivopatias, y para valores ≥ 1/1.280, 85% frente al 15% respectivamente. Al realizar el analisis multivariante se observo una asociacion positiva entre las diluciones 1/320 OR 3,069 (IC 95%: 1,237-7,614; p = 0,016), 1/640 OR 12,570 (IC 95%: 3,659-43,187; p = 0,000) y ≥ 1/1.280 OR 42,136 (IC 95%: 8,604-206,345; p = 0,000). Conclusion Estos resultados muestran asociacion de titulos de dilucion ≥ 1/320 para la primera prueba de ANA realizada en una Unidad de Reumatologia con pacientes con conectivopatia sistemica. El VPP en estos pacientes resulto superior a estudios previos desarrollados por otras especialidades medicas. Esto puede indicar la importancia de una solicitud de la prueba de forma dirigida.

Objective To determine the dilution titles at antinuclear antibodies (ANA) by indirect immunofluorescence observed in cell substrate HEp-2 and its association with the diagnosis of systemic connective tissue disease in ANA test requested by a Rheumatology Unit. Method Samples of patients attended for the first time in the rheumatology unit, without prior ANA test, between January 2010 and December 2012 were selected. The dilution titers, immunofluorescence patterns and antigen specificity were recorded. In January 2015 the diagnosis of the patients were evaluated and classified in systemic disease connective tissue (systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, undifferentiated connective, antiphospholipid syndrome, mixed connective tissue and inflammatory myophaty) or not systemic disease connective tissue. Result A total of 1282 ANA tests requested by the Rheumatology Unit in subjects without previous study, 293 were positive, predominance of women (81.9%). Patients with systemic connective tissue disease were recorded 105, and 188 without systemic connective tissue disease. For 1/640 dilutions the positive predictive value in the connective was 73.3% compared to 26.6% of non-connective, and for values ≥1/1280 85% versus 15% respectively. When performing the multivariate analysis we observed a positive association between 1/320 dilution OR 3.069 (95% CI: 1.237–7.614; P = .016), 1/640 OR 12.570 (95% CI: 3.659–43.187; P = .000) and ≥ 1/1280 OR 42.136 (95% CI: 8.604–206.345; P = .000). Conclusion These results show association titles dilution ≥1/320 in ANA's first test requested by a Rheumatology Unit with patients with systemic connective tissue disease. The VPP in these patients was higher than previous studies requested by other medical specialties. This may indicate the importance of application of the test in a targeted way.