65 research outputs found
Serum profiling reveals distinctive proteomic markers in the serum from chronic myeloid leukaemia patients
No full textWe have shown that proteomic profiling of sera from chronic myeloid leukaemia patients at presentation identifies five serum markers whose expression profile is significantly different from that seen in normal controls, non-malignant neutrophilia and in CML patients in HR following treatment with Gleevec. Of particular interest is the persistence of three of the five biomarkers following successful induction of HR, suggesting that those changes are disease specific. We have demonstrated that serum profiling can robustly identify disease groups and disease state in patients with CML compared with non-malignant and normal controls. In addition our data suggest that serum profiling of other haematological malignancies may provide new biomarkers for disease state and stag
Leukemia associated antigens: their dual role as biomarkers and immunotherapeutic targets for acute myeloid leukemia
No full textLeukemia associated antigens (LAAs) are being increasingly identified by methods such as cytotoxic T-lymphocyte (CTL) cloning, serological analysis of recombinant cDNA expression libraries (SEREX) and mass spectrometry (MS). In additional, large scale screening techniques such as microarray, single nucleotide polymorphisms (SNPs), serial analysis of gene expression (SAGE) and 2-dimensional gel electrophoresis (2-DE) have expanded our understanding of the role that tumor antigens play in the biological processes which are perturbed in acute myeloid leukemia (AML). It has become increasingly apparent that these antigens play a dual role, not only as targets for immunotherapy, but also as biomarkers of disease state, stage, response to treatment and survival. We need biomarkers to enable the identification of the patients who are most likely to benefit from specific treatments (conventional and/or novel) and to help clinicians and scientists improve clinical end points and treatment design. Here we describe the LAAs identified in AML, to date, which have already been shown to play a dual role as biomarkers of AML diseas
Immunotherapy of myeloid leukaemias
No full textThe treatment of myeloid leukaemia has progressed in recent years with the advent of donor leukocyte infusions (DLI), haemopoietic stem cell transplants (HSCTs) and targeted therapies. However, relapse has a high associated morbidity rate and a method for removing diseased cells in first remission, when a minimal residual disease state is achieved and tumour load is low, has the potential to extend remission times and prevent relapse especially when used in combination with conventional treatments. Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are heterogeneous diseases which lack one common molecular target while chronic myeloid leukaemia (CML) patients have experienced prolonged remissions through the use of targeted therapies which remove BCR-ABL(+) cells effectively in early chronic phase. However, escape mutants have arisen and this therapy has little effectivity in the late chronic phase. Here we review the immune therapies which are close to or in clinical trials for the myeloid leukaemias and describe their potential advantages and disadvantage
Van‐den Berghe’s 5q‐ syndrome in 2008
No full textVan Den Berghe established 5q- syndrome as a discrete clinical entity in 1974 when he described patients with macrocytic anaemia, thrombocytosis, dyserythropoiesis, hypolobulated megakaryocytes and an interstitial deletion within chromosome 5q. With del(5q) as the sole cytogenetic abnormality, 5q- syndrome represents an opportunity to define precisely the molecular defect(s) underlying the pathogenesis of this disease. The commonly deleted region in 5q- syndrome, which is distinct from that in patients with complex cytogenetic changes that include del(5q), includes the ribosomal protein S14 locus and it has been proposed that that loss of an RPS14 allele accounts for the 5q- syndrome phenotype. However, this hypothesis fails to explain the growth advantage of the 5q- syndrome clone and it is evident that ribosomal protein defects are not specific to 5q- syndrome, as they are found in other bone marrow failure syndromes. Lenalidomide therapy leads to normalization of both haematological and cytogenetic parameters in the majority of 5q- syndrome patients. This review examines the potential role of several genes, including RPS14, in the pathogenesis of the 5q- syndrome and recent advances in clinical management, with particular emphasis on the role and mechanism of action of lenalidomide
IL-2 and Antisense TGF-B1 Gene Therapy of the H238 Tumor and Analysis of TGF-B Receptors
No full textTransforming growth factor-beta (TGF-p) belongs to a family of immunosuppressive cytokines, capable of regulating macrophages, T, B and NK cells. We have detected the TGF-p transcript being synthesized by H238 cells. This is herpes simplex-Type2 transformed murine fibrosarcoma cell line. The amount of TGF-p formed/106 cells was \u3e2000pg/ml. Previous attempts to control H238 tumorigenicity had sub-optimal efficacies. In addition, studies had shown that the FI238 cell line was not responsive to TGF-p. This project was an attempt to develop an improved modality to reduce H238 tumorigenicity and investigate potential abnormalities in expression of TGF-p receptors in the H238 cell line.
We created expression plasmids encoding transgenes for murine IL-2 and antisense TGF-p and stably transfected H238 cells to create populations/clones of H238 cells expressing these transgenes. In vitro, expression analysis using ELISA and RT-PCR showed that H238 cells are capable of expressing functional IL-2 and, in addition, antisense transfected H238 cells showed a significant decrease in TGF-p production. The ultimate test, was to evaluate the tumorigenicity of these stable transfected cells in an immunocompetent BALB/c host, in comparison to wild type H238 cells. Mice injected with wild type and control H238 cells, showed a 80 - 100% tumor incidence. Mice injected with either antisense TGF-p or murine IL-2 transfected H238 cells showed almost no tumor incidence (0-20%). Mitogen stimulation of splenocytes from tumor bearing and non tumor bearing animals showed significant differences. Splenocytes from non tumor bearing animals displayed a higher stimulation index than from tumor bearing animals, probably alluding to lower amounts of tumor derived systemic TGF-p.
The non-responsiveness of H238 cells to TGF-p was also confirmed. Our results corroborated Uhm, at al (1993), whereby the authors reported similar results. To evaluate this further, we hypothesized that a defect within the TGF-p receptors may be the cause of this inert response. Total H238 RNA was exctracted and mRNA for TGF-p receptors was amplified using primers specific to the Type 1 and Type 2 TGF-p receptors, these were sequenced to confirm their identity. Our sequence analysis concluded that the TGF-p receptors on H238 cells were essentially normal with no critical mutations which would validate either splicing or truncated products. Protein expression was confirmed using Western blot analysis. Whole cell lysate was also resolved into membrane and cytosolic fractions, and these probed with for the type 1 or the type2 receptor. In comparision, to positive cell lysate controls for these receptors, H238 cell lysates showed a comparitively less amount of receptor expression. Receptor expression was further quantitated using a laser scanning cytometer.
Using this procedure, H238 cells showed approximately 50% less expression of the type 2 TGF-p receptor than the type 1 TGF-p receptor. Cytochemical staining for the receptors showed little membrane puncate staining, however, distinct staining was observed in the cytosolic regions of the cells. The lack of pucntate staining may be explained by either the relatively very few numbers of TGF-p receptors expressed/cell or there may be defects in the glycosylation and receptor trafficking. In addtion, the different ratios of the type 1 and type 2 receptor expression may also account for the inertness of H238 cells to TGF-p. This has been shown to be present in other tumor models and may explain the non responsiveness of FI238 cells to TGF-p
Land Degradation in the Dinder and Rahad Basins: Interactions Between Hydrology, Morphology and Ecohydrology in the Dinder National Park, Sudan
No full textThe spatial and temporal variability of the hydro-climate as well as land use and land cover (LULC) changes are among the most challenging problems facing water resources management. Understanding the interaction between climate variability, land use and land cover changes and their links to hydrology, river morphology and ecohydrology in the Dinder and Rahad basins in Sudan is confronted by the lack of climatic, hydrological and ecological data.This book investigated the impacts of land degradation on the Dinder and Rahad hydrology and morphology, and interlinkage to the ecohydrological system of the Dinder National Park (DNP) in Sudan. It used an ensemble of techniques to improve our understanding of the hydrological processes and LULC changes in these basins. This included long-term trend analysis of hydroclimatic variables, LULC changes analysis, field measurements, rainfall-runoff modelling, hydrodynamic and morphological modelling of the Dinder river and its floodplain, with special focus on the Mayas wetlands. Moreover, this research is the first study to investigate the eco-hydrology of the DNP. It is expected that the results of the study will be beneficial to all stakeholders concerned and support decision-making processes for better management of water resources and ecosystem conservation in the area and possibly beyond.Dissertation submitted in fulfillment of the requirements of the Board for Doctorates of Delft University of Technology and of the Academic Board of IHE Delft Institute for Water Education.Water Resource
Understanding the Impact of Human Interventions on the Hydrology of Nile Basin Headwaters, the Case of Upper Tekeze Catchments
No full textThe availability and distribution of water resources in catchments are influenced by various natural and anthropogenic factors. Human-induced environmental changes are key factors controlling the hydrological flows of semi-arid catchments. Land degradation, water scarcity and inefficient utilization of available water resources continue to be important constraints for socio-economic development in the headwater catchments of the Nile river basin in particular over the Ethiopian Catchments. This research investigates the impact of landscape anthropogenic changes on the hydrological processes in the Upper Tekeze basin (A tributary of the Nile). The hydrology of the basin is investigated through analysis of hydro-climatic data, remote sensing techniques, new field measurements and parsimonious hydrological models.Dissertation submitted in fulfillment of the requirements of the Board for Doctorates of Delft University of Technology and of the Academic Board of IHE Delft Institute for Water Education.Water Resource
Recent advances in understanding the molecular pathogenesis of myelodysplastic syndromes
No full textThe advent of novel genomic sequencing technologies has aided the identification of somatically acquired genetic abnormalities up to 80% of myelodysplastic syndrome (MDS) patients. Novel recurrent genetic mutations in pathways such as RNA splicing, DNA methylation and histone modification and cohesion complexes, underscore the molecular heterogeneity seen in this clinically varied disease. Functional studies to establish a causative link between genomic aberrations and MDS biogenesis are still in their infancy. The deluge of this molecular information, once validated on a larger cohort, will be incorporated into prognostic systems and clinical practise, and also hopefully aid in MDS therapeutics, especially in guiding targeted therapy.</p
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