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| 2. |
- Brenne, AT, et al.
(författare)
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Low serum level of soluble tumor necrosis factor receptor p55 predicts response to thalidomide in advanced multiple myeloma
- 2004
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Ingår i: Haematologica. - 1592-8721 .- 0390-6078. ; 89:5, s. 552-556
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives. Thalidomide modulates the production of tumor necrosis factor (TNF-alpha). Soluble TNF receptors, TNFR p55 and TNFR p75, modify TNF-a activity. In this study, we explored the relation between soluble TNF receptors and outcome in patients with advanced multiple myeloma treated with thalidomide. Design and Methods. The levels of soluble TNF receptor p55 and p75 were assessed in serum from 34 myeloma patients with relapsed or refractory disease before starting thalidomide treatment. Serial measurements were performed for 16 patients in serum collected during treatment. Results. The pre-treatment serum level of soluble TNFR p55 in thalidomide responders was significantly lower than that in non-responders (median 1.75 ng/mL (range 1.19-2.84) vs. 2.79 ng/mL (1.36-5.51), p=0.004). The levels of p55 declined significantly during treatment. The levels of p75 showed the same pattern as p55, but the differences were not significant. The median survival of myeloma patients with pre-treatment levels of p55 less than or equal to 2.79 ng/mL was 404 days; the median survival of patients with pre-treatment levels less than or equal to 2.79 ng/mL was shorter (65 days, log-rank test p=0.02). Interpretation and Conclusions. We conclude that soluble TNFR p55 is an adverse prognostic factor in myeloma patients with relapsed or refractory disease treated with thalidomide. Patients with a low pre-treatment level of this receptor have a better response rate and a longer overall survival.
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| 3. |
- Knaust, Eva, 1944-, et al.
(författare)
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Heterogeneity of isolated mononuclear cells from patients with acute myeloid leukemia affects cellular accumulation and efflux of daunorubicin
- 2000
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Ingår i: Haematologica. - 0390-6078 .- 1592-8721. ; 85:2, s. 124-132
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVE: Pharmacologic studies on blasts from patients with leukemia are generally performed on density gradient isolated blood or bone marrow cells. Thereby, cellular drug accumulation and efflux are determined as mean values of the entire cell population. The objective of the present study was to characterize the heterogeneity in the accumulation and efflux of daunorubicin in various subpopulations of mononuclear cells isolated from patients with acute myeloid leukemia (AML).DESIGN AND METHODS: Mononuclear cells from 33 patients with AML were isolated from peripheral blood by density gradient centrifugation on Lymphoprep (1. 077 g/mL). Cellular accumulation of fluorescent daunorubicin was determined by flow cytometry after incubation of the cells at +37C for 1 hour. Thereafter, the cells were washed and reincubated in drug-free medium. Kinetics of drug efflux were determined by frequent determination of cellular fluorescence during 30 min. Daunorubicin accumulation and efflux were compared in the total isolated mononuclear cell population and in the various blast cell populations gated on FSC/SSC according to the results of immunophenotyping.RESULTS: In 8 of these 33 (24%) patient samples, two distinct blast cell populations could be identified. In 7 out of 8 these cases the more immature blasts had a lower drug accumulation and in 6 out of the 8 cases also a higher efflux rate than the differentiating cell population. Cyclosporin A increased daunorubicin accumulation and reduced efflux in the immature blast population. In the differentiating cell population cyclosporin A increased both the accumulation and the efflux. In patients with a single blast cell population, the gated blast cells had a significantly lower drug accumulation but also a lower drug efflux rate than the total cell population.INTERPRETATION AND CONCLUSIONS: The results imply that drug transport studies on cells isolated from patients with AML give somewhat different results depending on the cell population studied. Some, but not all, of these differences in daunorubicin accumulation and efflux as well as in the effect of cyclo-sporin A can be explained by a heterogenous expression of the mdr1-gene. The observed heterogeneity may be of special relevance with regard to drug resistance. The presence of even a small resistant cell clone may jeopardize the effect of the chemotherapy due to expansion resulting in relapse of disease.
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| 4. |
- Lindemalm, Synnove, et al.
(författare)
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Comparison of cytotoxicity of 2-chloro- 2'-arabino-fluoro-2'-deoxyadenosine (clofarabine) with cladribine in mononuclear cells from patients with acute myeloid and chronic lymphocytic leukemia
- 2003
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Ingår i: Haematologica. - 0390-6078 .- 1592-8721. ; 88:3, s. 324-332
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Clofarabine (CAFdA), one of the newer nucleoside drugs is undergoing a phase II clinical trial for the treatment of pediatric refractory/relapsed acute myeloid and lymphocytic leukemia. Although CAFdA is structurally similar to the clinically established analogs fludarabine and cladribine (CdA), its metabolism and mechanism of actions are significantly different. The present study investigates the in vitro cytotoxicity of CAFdA and CdA in mononuclear cells isolated from 52 patients with chronic lymphocytic (CLL) and acute myeloid leukemia (AML). DESIGN AND METHODS: We incubated the leukemic cells with drugs for 48 hours and cytotoxicity was then evaluated by the MTT dye assay. We also determined the levels of deoxycytidine and deoxyguanosine kinase with radio-chemical substrate-based assays and used a high performance liquid chromatographic method to measure cellular nucleotides in leukemia cells after 2 hours' incubation. RESULTS: Using equimolar concentrations of CAFdA and CdA, the in vitro cytotoxicity for the population was significantly higher with CAFdA than with CdA (median EC50 for CAFdA 0.12 microM and for CdA 0.15 microM, p<0.001). From the individual estimates the difference in cytotoxicity between CAFdA and CdA was more pronounced in cells from CLL patients (median EC50 for CAFdA 0.08 microM and for CdA 0.16 microM p<0.001) than in those from AML patients. We also found that CAFdA was phosphorylated more efficiently than CdA. No correlations were detected in this study between the levels of CdA and CAFdA nucleotides, enzymes levels and the in vitro responses. INTERPRETATION AND CONCLUSIONS: The greater in vitro cytotoxicity and cell metabolism of CAFdA compared to CdA confirm the high activity of CAFdA and encourage clinical trials with CAFdA in leukemic patients.
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| 5. |
- Nilsson, Ulrika K., et al.
(författare)
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Synergistic activation of human platelets by adrenaline and lysophosphatidic acid
- 2002
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Ingår i: Haematologica. - 0390-6078 .- 1592-8721. ; 87:7, s. 730-739
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Platelet reactivity is regulated by various important bioactive and physiologic substances. The objective of this study was to characterize lysophosphatidic acid (LPA)-triggered responses in human platelets. In addition, the effect of LPA was compared with that of other activators and possible synergistic interactions were evaluated. DESIGN AND METHODS: LPA-triggered cytosolic Ca(2+) responses were measured using fura-2-loaded platelets in a spectrofluorometer. Furthermore, platelet aggregation and secretion were analyzed in a lumi-aggregometer and protein tyrosine phosphorylation was detected with the Western blot technique. RESULTS: LPA dose-dependently increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in platelets. This response involved both influx of extracellular Ca(2+) and release of Ca(2+) from intracellular stores. However, in comparison with other platelet agonists, i.e. thrombin and adenosine 5'-diphosphate (ADP), LPA was a very weak Ca(2+)-elevating agent. Furthermore, we observed that the LPA-induced rise in [Ca(2+)](i) was markedly suppressed by cyclic nucleotide-elevating agents. In functional studies, LPA failed to stimulate platelet aggregation and secretion. However, in combination with adrenaline, another weak platelet agonist, LPA could induce an irreversible and complete aggregatory response. There was an individual variation in aggregatory response and tyrosine phosphorylation when LPA and adrenaline were combined. These agents induced a powerful response on platelets from some individuals, but had a weak or no effect on others. INTERPRETATION AND CONCLUSIONS: The present study shows, for the first time, that isolated platelets from some healthy blood donors respond synergistically to a combination of LPA and adrenaline. Platelet activation is a key step in distinguishing normal hemostasis from pathologic hemostasis. Increased knowledge about this mechanism might help to predict individual responses and provide new insights into molecular mechanisms responsible for pathologic thrombosis.
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| 7. |
- Sandström, Herbert, et al.
(författare)
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Congenital dyserythropoietic anemia type III.
- 2000
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Ingår i: Haematologica. - 0390-6078 .- 1592-8721. ; 85:7, s. 753-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Congenital dyserythropoietic anemia type III (CDA-III) is a group of very rare disorders characterized by similar bone marrow morphology. The clinical picture is characterized by hemolytic anemia and dramatic bone marrow changes dominated by active erythropoiesis with big multinucleated erythroblasts. The aim of this review is to describe the clinical manifestations, laboratory findings, and management CDA-III.EVIDENCE AND INFORMATION SOURCES: The present review critically examines relevant articles and abstracts published in journals covered by the Science Citation Index and Medline. The authors have performed several studies on CDA-III.STATE OF ART AND PERSPECTIVES: The clinical and laboratory manifestations of CDA-III indicate that the gene responsible for it, which has been mapped to chromosome 15q22, is expressed not only in erythroblasts during mitosis but also in B-cells, and in cells of the retina. Preliminary results indicate genetic and phenotypic similarities between a Swedish and an American family, both with an autosomally dominant inherited form of CDA-III. It is possible that the genetic lesion is identical in these families, but the different phenotypes and modes of inheritance reported among some other cases of CDA-III are probably the results of other genetic lesions. At present, the function of the gene responsible for the Swedish (V sterbotten) variant of CDA-III (CDAN3) is unknown and it is an important goal to characterize and clone this gene in order to study its function.
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| 8. |
- Berntorp, Erik, et al.
(författare)
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Immune tolerance induction and the treatment of hemophilia. Malmo protocol update
- 2000
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Ingår i: Haematologica. - 1592-8721. ; 85:10 Suppl, s. 48-48
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Tidskriftsartikel (refereegranskat)abstract
- The Malmo protocol for immune tolerance induction includes high doses of Factor VIII/IX, intravenous IgG and cyclophosphamide. If the inhibitor titer exceeds 10 Bethesda units at start, extracorporeal adsorption of IgG is performed using protein A. The protocol sometimes has to be repeated. A successful response may occur within a few weeks. In hemophilia A the success rate so far is 10/17 patients (15 high-responders, 2 low-responders) or 59%, whereas in hemophilia B 6/9 patients (8 high-responders, 1 low-responder), or 67%, have become tolerant. In one hemophilia B patient, a relapse occurred after 6 months. During a second treatment episode he developed an acute myocardial infarction, probably caused by replacement with prothrombin complex concentrate. We conclude that the Malmo protocol is efficient for induction of immune tolerance but the patients must be selected particularly with regard to inhibitor duration and time of last booster.
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| 9. |
- Berntorp, Erik
(författare)
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Regimens of factor VIII administration--continuous infusion vs. bolus
- 2000
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Ingår i: Haematologica. - 1592-8721. ; 85:10 Suppl, s. 69-69
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Tidskriftsartikel (refereegranskat)abstract
- The Malmo protocol for immune tolerance induction uses intermittent injections of factor VIII/IX together with intravenous IgG and cyclophosphamide. In order to increase the production of antigen-antibody complexes, and also to improve cost-efficacy, we applied continuous infusion instead of intermittent injection in 5 high-responders (3 hemophilia A and 2 hemophilia B). All treatment attempts failed. However, we conclude that continuous infusion may play a role in immune tolerance induction, and the treatment failures in our study could probably be explained by the fact that the patients were partially selected to be resistant cases.
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| 10. |
- Berntorp, Erik
(författare)
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Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations: is it of clinical importance?
- 2003
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Ingår i: Haematologica. - 1592-8721. ; 88:6, s. 3-3
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Tidskriftsartikel (refereegranskat)abstract
- Factor VIII inhibitors may interfere with several important functional binding sites on the factor VIII molecule including that of von Willebrand factor, which binds to the C2 domain. There are in vitro and in vivo observations that inhibitors reacting against the factor VIII light-chain C2 domain may display a lower inhibitor titer against von Willebrand factor containing concentrates as compared to pure products. In low titer inhibitor patients it can be anticipated that von Willebrand factor containing concentrates give a better hemostatic effect. The role in immune tolerance induction is of great interest as an increased success rate and decreased treatment time may have a substantial impact on the cost of treatment. Case reports and treatment experience from some centers indicate a better success rate with von Willebrand factor containing concentrates. Even if formal, well-controlled studies are needed, it can already be recommended that inhibitor plasma should be tested against a panel of concentrates in order to select the less neutralized concentrate for use in inhibitor patients.
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