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    ABSTRACT: We have shown previously that in T cells, LAT co-immunoprecipitates with the active but not the inactive-'closed' form of Lck, and that this interaction impacts negatively on Lck activity. Here we confirm that activation of T cells induced a transient LAT/Lck association within 4 min after stimulation, returning to basal levels by 30 min. Interestingly, autoimmune T cells isolated from patients with systemic lupus erythematosus, which contain a larger pool of active Lck and LAT, exhibited increased LAT/Lck association compared to healthy controls. To identify the domain of LAT responsible for its interaction with active Lck, a series of LAT truncation mutants were constructed and tested in co-immunoprecipitation experiments. We found that the segment comprising residues 112-126 of human LAT is required for its interaction with Lck. This domain is rich in negatively charged amino acids and is conserved among different species. Therefore, in addition to the conserved tyrosines, the 112-126 domain identified here could be important for certain functions of LAT in T cells.
    Molecular Membrane Biology 10/2011; 28(7-8):487-94. DOI:10.3109/09687688.2011.624990
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    ABSTRACT: A bone marrow examination in a young woman with anemia and β-thalassemia trait showed dyserythropoiesis in less than 10% of erythroblasts without other myelodysplastic changes, and cytogenetic analysis revealed trisomy of chromosome 8. Although she did not fulfill the current World Health Organization (WHO) criteria for diagnosis of a myelodysplastic syndrome, her acquired bone marrow disorder behaved as such, and she later developed acute myeloid leukemia.
    Leukemia & lymphoma 03/2011; 52(3):515-6. DOI:10.3109/10428194.2010.545464

  • Clinical advances in hematology & oncology: H&O 12/2010; 8(12):901-3.
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    ABSTRACT: The basis of treatment for immune thrombocytopenic purpura (ITP) has conventionally relied on nonspecific immune suppression designed to reduce platelet destruction. As a consequence, at least half of the morbidity and mortality in this condition is related to infection secondary to treatment, and alternative treatments are desirable. It has been shown that ITP is not purely due to platelet destruction, and in a significant proportion platelet production is suboptimal. Further interest developed with the discovery that the recombinant thrombopoietins (TPOs) could enhance platelet production in a variety of thrombocytopenic states. With the development of the second generation of TPOs, which had no sequence homology to endogenous TPOs, studies confirmed clinical effect. Two agents, romiplostim and eltrombopag, are now licensed and their place in the treatment is being evaluated. Platelet responses to romiplostim and eltrombopag are seen in a much greater percentage than in other second-line studies, and these are maintained while the drugs continue to be administered. Both are well tolerated, with no significant adverse effects over placebo, and have an effect both presplenectomy or postsplenectomy. An interesting initial observation has been that the platelet response is associated with an improved quality of life in many patients when compared with conventional management.
    Current opinion in hematology 07/2009; 16(5):357-64. DOI:10.1097/MOH.0b013e32832e06e4
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    ABSTRACT: This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2.5-10.0 mg/m(2)) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7.5 mg/m(2) and bortezomib 1.3 mg/m(2). The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD (n = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD (P < 0.05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.
    British Journal of Haematology 03/2009; 144(6):887-94. DOI:10.1111/j.1365-2141.2008.07572.x
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    ABSTRACT: Immune (idiopathic) thrombocytopenic purpura (ITP) is an autoantibody-mediated condition characterized by an abnormally low number of platelets in the circulating blood. Originally, the cause of ITP was attributed to accelerated antibody-mediated platelet destruction where the rate of thrombopoiesis was inadequate to offset the increased rate of platelet destruction. However, new evidence has indicated that insufficient or inadequate platelet production is also responsible for low platelet counts, and research has focused on the development of treatments that increase platelet production. ITP affects both children and adults and can be either acute or chronic. To manage and treat ITP effectively, an exhaustive assessment of the signs and symptoms must be undertaken because the clinical manifestation of ITP can be highly variable among patients. At the moment, the diagnostic approach in ITP is based largely on a process of exclusion due to the lack of available data regarding clinical and laboratory parameters. The diagnostic procedures used in children and adults are similar and involve collecting the patient's history and performing a physical examination. Laboratory investigations are kept simple in patients with suspected ITP and include a full blood count and peripheral blood smear. A number of specialized laboratory assays have been developed with varying degrees of success. There remains scope for improving and simplifying the diagnostic process to identify ITP.
    European journal of haematology. Supplementum 03/2009; 82(71):8-12. DOI:10.1111/j.1600-0609.2008.01207.x
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    ABSTRACT: Initially, immune (idiopathic) thrombocytopenic purpura (ITP) was considered to be a disease of increased platelet destruction. Consequently, treatments for ITP patients were focused on reducing the destruction of platelets. However, recent research on the pathogenesis of ITP points to a role of suboptimal platelet production, and this has led to the development of new treatment options which increase platelet production such as the novel thrombopoiesis-stimulating agent, romiplostim. In two, multicentre, randomized, placebo-controlled, double-blinded, phase III trials, romiplostim was able to increase and sustain platelet counts in both splenectomized and non-splenectomized patients. Eighty-three per cent (69/83) of the romiplostim-treated patients achieved an overall platelet response compared with 7% (3/42) of patients receiving placebo (P < 0.0001; Cochran-Mantel-Haenszel test controlled for splenectomy and baseline concurrent ITP therapy). Patients from the romiplostim studies, with platelet counts below 50 x 10(9)/L, were able to enter a long-term, open-label, extension study. The results of the long-term study showed that platelet counts above 50 x 10(9)/L were maintained for > or =10, > or =25 and > or =52 consecutive weeks by 78% (102/131), 54% (66/122) and 35% (29/84) of patients, respectively. Romiplostim appears to be generally well tolerated and several patients have now been treated for more than 3 yrs. Most adverse events tend to be mild to moderate in nature. Romiplostim provides a valid treatment option that may bring about a change in the way that patients with ITP are treated in the future. Further studies are now being undertaken in paediatric patients with ITP, patients with myelodysplastic syndrome and patients with chemotherapy-induced thrombocytopenia.
    European journal of haematology. Supplementum 03/2009; 82(71):20-5. DOI:10.1111/j.1600-0609.2008.01209.x
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    ABSTRACT: Neonatal/newborn haemoglobinopathy screening is being performed in an increasing number of European countries since changing patterns of immigration have led to significant numbers of neonates at risk of sickle cell disease. The purpose of screening is to improve management of sickle cell disease through early parental education and the institution of prophylaxis against infection. Some haemoglobinopathy screening programmes are stand-alone, while others are integrated into a neonatal screening programme for metabolic disorders. Despite the logistic problems and economic constraints, neonatal haemoglobinopathy screening is also being gradually introduced in a number of African countries.
    Journal of clinical pathology 02/2009; 62(1):53-6. DOI:10.1136/jcp.2008.060624
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    ABSTRACT: A diagnosis of myelodysplastic syndrome, refractory anemia subtype, was made in an elderly Indian woman on the basis of a refractory macrocytic anemia with normal vitamin B(12) and folate assays, normal thyroid function, essentially normal liver function and normal cytogenetic analysis. Disease evolution revealed that the diagnosis was erroneous.
    Leukemia & lymphoma 12/2008; 49(11):2196-7. DOI:10.1080/10428190802419665
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    ABSTRACT: Dietary flavonoids have many health-promoting actions, including anticancer activity via proteasome inhibition. Bor-tezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but is not effective in chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive in vitro to bortezomib-induced apoptosis when cultured in medium, the killing activity was blocked when cultured in 50% fresh autologous plasma. Dietary flavonoids, quercetin and myricetin, which are abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH)2, in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution is required when giving dietary advice to patients.
    Blood 11/2008; 112(9):3835-46. DOI:10.1182/blood-2008-04-150227
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