BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice.

In this study, we describe the successful use of a gene transfer approach to demonstrate the ability of forced BCR-ABL expression to deregulate the growth and differentiation of primitive naive human hematopoietic cells after their transplantation into immunodeficient mice. Human CD34+ cord blood cells were exposed to an MSCV retrovirus containing a BCR-ABL-IRES-GFP (P210) cassette and then injected immediately into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) or NOD/SCID-beta2microglobulin-/- mice. P210- and control-transduced (GFP+) human hematopoietic cells were produced in the bone marrow of the mice at similar levels until termination of the experiments 5-6 months later. However, the P210-transduced cells produced a markedly different spectrum of progeny, with an increased ratio of myeloid to B-lymphoid cells and a frequently prolonged increase in erythroid and megakaryocytic cells. After 5 months, several of the mice transplanted with P210-transduced cells developed an increased WBC count and/or splenomegaly due to an expansion of the human GFP+ population. These findings demonstrate that forced expression of BCR-ABL in primitive transplantable human hematopoietic cells is sufficient to cause a rapid and persistent deregulation of their growth and differentiation in vivo with occasional evidence after several months of progression to an early stage of disease.     

The safety profile of imatinib in CML and GIST: long-term considerations

Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST) by targeting BCR-ABL and c-KIT tyrosine kinases, respectively. Indeed, imatinib has substantially changed the clinical management and improved the prognosis of both diseases. Treatment with imatinib is generally well tolerated, and the risk for severe adverse effects is low, generally occurring during the early phase of treatment and correlating with imatinib dose, phase of disease and patient’s characteristics. This article summarises recent data on safety profile of imatinib for the treatment of CML and GIST, including long-term side effects. Prolonged treatment with imatinib in both diseases demonstrates excellent tolerability. There are few significant concerns and those that have emerged, like cardiotoxicity, have far turned out to be exaggerated.     

Impaired generation of bone marrow CD34-derived dendritic cells with low peripheral blood subsets in patients with myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by ineffective haematopoiesis and blood cytopenias. The present study investigated the potential of bone marrow CD34(+) progenitors in MDS patients to proliferate and differentiate into dendritic cells (DCs) in a cytokine-supplemented liquid culture system and analysed the status of blood DC subsets in these patients. CD34(+) progenitors had low potential to generate DCs in vitro, as the number of DCs obtained from one CD34(+) cell was significantly lower compared with controls (median value 0.2 vs. 4, P = 0.003). In patients, the survival and proliferation of CD34(+) cells in culture was not correlated to the degree of apoptosis. Phenotypically and functionally CD34(+)-derived DCs were similar in MDS patients and normal subjects. The percentage of both circulating DC subsets in patients was extremely diminished compared with controls (myeloid DC: 0.10 +/- 0.10% vs. 0.35 +/- 0.13%, P < 0.001; plasmacytoid DC: 0.11 +/- 0.10% vs. 0.37 +/- 0.14%, P < 0.001). In cases with the 5q deletion both CD34-derived DCs and blood DCs harboured the cytogenetic abnormality. Our results indicate that, in MDS, the production of DCs is affected by the neoplastic process resulting in ineffective 'dendritopoiesis' with low blood DC precursor numbers. This quantitative DC defect probably contributes to the poor immune response against infectious agents and to the escape of the malignant clone from immune recognition with disease progression towards acute leukaemia.     

Spontaneous bacterial peritonitis (SBP): clinical,laboratory, and prognostic features. A single-center experience

BACKGROUND: The aim of the present study was to assess the clinical and laboratory characteristics, the course, and the factors influencing the hospital mortality and relapse rate of spontaneous bacterial peritonitis (SBP) in cirrhotic patients admitted in a single University Hospital in Greece. METHODS: The study comprises the evaluation of 81 cirrhotic patients who developed SBP during a 30-month period. RESULTS: The occurrence of SBP was independent of the etiology of liver disease and was symptomatic in 66/81 patients (82%). Encephalopathy, as presenting symptom, occurred mainly in Child C patients. Ascitic fluid culture was positive in 20 patients (25%); E. coli (60%) and Enterococcus faecalis (14%) were the most common bacteria isolated. Empirical treatment was effective in 94% of patients. Renal impairment was observed in 21 patients (26%), six of whom developed hepatorenal syndrome. Total mortality was 10% and was related to the existence of symptoms (P<0.01), ascetic fluid polymorphonuclear cell count (P<0.05), bilirubin levels (P<0.01), and kidney function at the beginning of the episode (P<0.01). The relapse rate was 24.6% and was related to the Child stage (P<0.01). CONCLUSIONS: SBP was asymptomatic in a substantial number of patients. Deterioration of renal function was frequently observed and was the main cause of death. The low (10%) in-hospital mortality seems to be related to earlier diagnosis and treatment. Relapse was associated with the severity of liver disease.     

A natural alternative to sulphur dioxide for red wine production: Influence on colour, antioxidant activity and anthocyanin content

An alternate to sulphur dioxide natural antioxidant was tested during 2005 harvest on four different red vinifications, and was applied in each winemaking batch in combination with sulphur dioxide and on its own. Responses measured and analysed with uni- and multivariate statistics were: anthocyanin content, antioxidant capacity and classic oenological parameters. ANOVA revealed no significant effect of treatment in the antioxidant values of RA or diphenylpicrylhydrazyl (DPPH) of wines, but a paired t-test could differentiate wines treated only with SO₂ from those treated only with the novel product according to their RA values. Principal component analysis (PCA) of anthocyanin content of the treated wines gave five significant components, explaining 100% of variance and differentiating products treated only with SO₂ from those treated only with new product. PCA of oenological data explained 72% of variance in the first two components and wines were clearly differentiated on the basis of SO₂ or alternative treatment. In all cases, commercially acceptable red wines were produced, giving a possibility for partial substitution of SO₂ by a natural product.     

Engraftment of NOD/SCID-beta2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome

The development of immunodeficient mouse xenograft models has greatly facilitated the investigation of some human hematopoietic malignancies, but application of this approach to the myelodysplastic syndromes (MDSs) has proven difficult. We now show that cells from most MDS patients (including all subtypes) repopulate nonobese diabetic-severe combined immunodeficient (scid)/scid-beta2 microglobulin null (NOD/SCID-beta2m(-/-)) mice at least transiently and produce abnormal differentiation patterns in this model. Normal marrow transplants initially produce predominantly erythroid cells and later predominantly B-lymphoid cells in these mice, whereas most MDS samples produced predominantly granulopoietic cells. In 4 of 4 MDS cases, the regenerated cells showed the same clonal markers (trisomy 8, n = 3; and 5q-, n = 1) as the original sample and, in one instance, regenerated trisomy 8(+) B-lymphoid as well as myeloid cells were identified. Interestingly, the enhanced growth of normal marrow obtained in NOD/SCID-beta2m(-/-) mice engineered to produce human interleukin-3, granulocyte-macrophage colony-stimulating factor, and Steel factor was seen only with 1 of 7 MDS samples. These findings support the concept that human MDS originates in a transplantable multilineage hematopoietic stem cell whose genetic alteration may affect patterns of differentiation and responsiveness to hematopoietic growth factors. They also demonstrate the potential of this new murine xenotransplant model for future investigations of MDS.