Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP. Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.
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PMID:Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. 1288 62

Thrombin and lysophosphatidic acid (LPA) receptors play important roles in vascular biology, development, and cancer. These receptors activate rho via G(12/13) family heterotrimeric G proteins, which are known to directly activate three distinct rho guanine nucleotide exchange factors (rhoGEFs) that contain a regulator of G protein signaling (RGS) domain (RGS-rhoGEFs). However, it is not known which, if any, of these RGS-rhoGEFs (LARG (leukemia-associated rhoGEF), p115rhoGEF, or PDZrhoGEF) plays a role in G protein-coupled receptor-stimulated rho signaling. Using oligonucleotide small interfering RNAs that suppress specific RGS-rhoGEF expression, we show that thrombin receptor stimulation of rho is primarily mediated by LARG in HEK293T and PC-3 prostate cancer cell lines. In contrast, the LPA-stimulated rho response in PC-3 cells is dependent on PDZrhoGEF expression. Suppression of p115rhoGEF had no effect. Thus different rhoGEFs (LARG and PDZrhoGEF) mediate downstream rho signaling by the thrombin and LPA receptors.
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PMID:Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells. 1514 72

For a long time fibrinopeptide A(FPA), fibrinopeptide B(FPB), D-dimer, FM test, serum FDP, and thrombin anti-thrombin complex(TAT) are being used as molecular markers to for sure diagnose hypercoagulable state and thrombus formation. Indeed these molecular markers are very useful for diagnosing thrombus formation, disseminated intravascular coagulation(DIC), and the indicator of treatment of DIC. But these molecular parameters are not enough and difficult for prognosis of the disease or predicting the complication of patients as the most important subject for clinicians. The soluble fibrin monomer-fibrinogen complex (SF) is a complex coupling fibrin monomer and fibrinogen molecules to be formed in the early-activated state of blood coagulation. Thus such a molecular complex is expected to serve as a parameter for the diagnosis of thrombus formation and DIC, in particular its early stage. The aim of the present study is to evaluate a potential usefulness of a newly developed SF test utilizing an SF specific monoclonal antibody (IF-43). We measured SF together with established other parameters in 195 patients with DIC, subclinical DIC/hypercoagulable state, and non-DIC. The diagnosis of DIC was made based on a modified version of the criteria established by the Ministry of Health, Labor and Welfare of Japan. Underlying disease includes leukemia, malignant lymphoma, myelodysplastic syndrome (MDS), multiple injury, giant ovarian tumor, prostatic cancer with multiple bone metastasis, lung cancer, breast cancer with multiple lung and bone metastasis, severe pneumoniae, sepsis, hemophagocytic syndrome (HPS), and rheumatoid arthritis. The SF levels in DIC patients were significantly higher than those in the subclinical DIC/hypercoagulable state, and the non-DIC patients. Receiver operating characteristic (ROC) analysis shows that the specificity and sensitivity of the SF assay appears to be satisfactory. As the level of SF reflects the thrombin generation activity in plasma, it would serve as a strong tool to selectively kick up the state of thrombin generation. These results indicate that the SF could be a specific and reliable parameter for the diagnosis of DIC and contribute to legitimate managements of patients with DIC. The excessive life response to serious clinical insults, such as sepsis, severe pancreatitis, trauma and shock, is called systemic inflammatory response syndrome (SIRS). Once SIRS occurs, people may often die from serious complications such as adult respiratory distress syndrome (ARDS), acute lung injury (ALI), disseminated intravascular coagulation (DIC) and multiple organ failure (MOF). Especially, ALI followed by pneumoniae associated with SIRS could depend on patient's prognosis and life. That is to say, it seems to be urgent for clinicians to make differential diagnosis between Pneumoniae associated with SIRS and Coagulopathy (PASC) and Simple Pneumoniae (SP). Soluble fibrin monomer-fibrinogen complex(SF) is formed in the early-activated state of blood coagulation. Thus such a molecular complex is expected to serve as a parameter for the diagnosis of coagulopathy, in particular its early stage. The aim of the present study is to make differential diagnosis between Pneumoniae associated with SIRS and Coagulopathy (PASC) and Simple Pneumoniae(SP) by using a newly developed SF test utilizing an SF specific monoclonal antibody (IF-43). We measured SF together with established other parameters, hemogram, blood laboratory items in 7 patients with PASC and 17 patients with SP. The diagnosis of Pneumoniae was defined according to the criteria: clinical symptoms abnormal shadow in both Chest X-p and Chest CT, increased level of CRP, number of WBC. The diagnosis of SIRS was based on the criteria established by American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) Consensus Conference held in August of 1991 in Northbrook, IL (USA). Underlying disease includes leukemias, malignant lymphoma, myelodysplastic syndrome (MDS), multiple myeloma, idiopathic thrombocytopenia purpura(ITP), multiple injury (bone fracture), cerebral hemorrhage, enterocolitis, Appendicitis, lung cancer, larynx cancer, bronchiolitis obliterans organizing pneumonia(BOOP), chronic obstructive pulmonary disease(COPD), sepsis. The SF levels in PASC patients are significantly higher than those in SP patients (p < 0.001). Otherwise, there is no significant difference of the CRP levels between in PASC group and SP group (p < ns). There is no co-relationship between SF level and D-dimer level. Receiver operating characteristic (ROC) analysis shows that the specificity and sensitivity of the SF assay appears to be quite satisfactory. As the level of SF reflects the thrombin generation activity in plasma, it would serve as a strong tool to selectively kick up the state of thrombin generation. These results indicate that the SF could be a specific and reliable parameter for the diagnosis of PASC and contribute to legitimate managements of patients with PASC.
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PMID:[A novel molecular marker for thrombus formation and life prognosis--clinical usefulness of measurement of soluble fibrin monomer-fibrinogen complex (SF)]. 1516 5

We have recently found that diethylstilbestrol (DES), a synthetic estrogen agonist, inhibits thrombin-induced Ca(2+) influx in human platelets, but it remains unclear to what extend this effect might be related to the store-operated Ca(2+) influx pathway. To study the effect of DES on store-operated channels and capacitative Ca(2+) influx, we used rat basophilic leukemia (RBL) cells, vascular smooth muscle cells (SMC), and human platelets, and recorded whole-cell Ca(2+) release-activated Ca(2+) (CRAC) currents and thapsigargin (TG)-induced capacitative Ca(2+) influx. In this study, we demonstrate that extracellular DES produces a dose-dependent and reversible inhibition of CRAC currents in RBL cells (IC(50), approximately 0.5 microM), whereas intracellular DES (25 microM) has no effect. Extracellular DES (up to 30 microM) inhibited only CRAC but did not affect a whole-cell monovalent cation current mediated by TRPM7 channels. DES effectively inhibited TG-induced capacitative Ca(2+) influx in a dose-dependent manner with an IC(50) values of approximately 0.1 microM in RBL cells, <0.1 microM in SMC, and approximately 1 microM in human platelets. It is noteworthy that trans-stilbene, a close structural analog of DES that lacks hydroxyl and ethyl groups, had no effect on CRAC current and on store-operated Ca(2+) influx. Thus, we found DES to be a very effective inhibitor of store-operated channels and Ca(2+) influx in a variety of cell types.
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PMID:Diethylstilbestrol is a potent inhibitor of store-operated channels and capacitative Ca(2+) influx. 1532 63

Regulated exocytosis is a process in which a physiological trigger initiates the translocation, docking, and fusion of secretory granules with the plasma membrane. A class of proteins termed SNAREs (including SNAP-23, syntaxins, and VAMPs) are known regulators of secretory granule/plasma membrane fusion events. We have investigated the molecular mechanisms of regulated exocytosis in mast cells and find that SNAP-23 is phosphorylated when rat basophilic leukemia mast cells are triggered to degranulate. The kinetics of SNAP-23 phosphorylation mirror the kinetics of exocytosis. We have identified amino acid residues Ser(95) and Ser(120) as the major phosphorylation sites in SNAP-23 in rodent mast cells. Quantitative analysis revealed that approximately 10% of SNAP-23 was phosphorylated when mast cell degranulation was induced. These same residues were phosphorylated when mouse platelet degranulation was induced with thrombin, demonstrating that phosphorylation of SNAP-23 Ser(95) and Ser(120) is not restricted to mast cells. Although triggering exocytosis did not alter the absolute amount of SNAP-23 bound to SNAREs, after stimulation essentially all of the SNAP-23 bound to the plasma membrane SNARE syntaxin 4 and the vesicle SNARE VAMP-2 was phosphorylated. Regulated exocytosis studies revealed that overexpression of SNAP-23 phosphorylation mutants inhibited exocytosis from rat basophilic leukemia mast cells, demonstrating that phosphorylation of SNAP-23 on Ser(120) and Ser(95) modulates regulated exocytosis by mast cells.
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PMID:Phosphorylation of SNAP-23 regulates exocytosis from mast cells. 1561 Oct 44

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an L-asparaginase-induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0.53 U/ml). LMWH 0.3 and 0.7 U/ml or melagatran 0.3 and 0.5 micromol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno-depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66-88% decrease in ETGC in AT-normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT-depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.
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PMID:Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with L-asparaginase: an in vitro study. 1685 90

Two leukaemia inhibitory factor (LIF) mutants, designated MH35-BD and LIF05, have been shown to have a capacity to inhibit the biological activities of not only human LIF (hLIF) but also other interleukin-6 (IL-6) subfamily cytokines such as human oncostatin M (hOSM). These cytokines share the same receptor complex in which the glycoprotein 130 (gp130) subunit is a common constituent. However, at low concentrations and in their monomeric forms, such molecules have a relatively short plasma half-life due to rapid clearance from the kidneys. Here, to prolong their serum half-lives, we have used a multi-step polymerase chain reaction (PCR) to fuse each of the LIF05 and MH35-BD cDNA fragments to a sequence encoding the Fc portion, and the hinge region, of the human immunoglobulin G (hIgG) heavy chain. The linking was achieved through an oligomer encoding a thrombin-sensitive peptide linker thus generating MH35-BD:Fc and LIF05:Fc, respectively. Both Fc fusion constructs were expressed in insect cell Sf21 and the proteins were purified by two successive affinity chromatography steps using nickel-nitrilotriacetic acid (Ni-NTA) agarose and protein A beads. The Ba/F3 cell-based proliferation assay was used to confirm that the proteins were biologically active. In addition, preliminary pharmacokinetics indicates that the Fc fusion constructs have a longer serum half-life compared to their non-fusion counterparts.
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PMID:Generation of mutant leukaemia inhibitory factor (LIF)-IgG heavy chain fusion proteins as bivalent antagonists of LIF. 1740 87

The minor histocompatibility antigen HA-1H is a potential immunotherapeutic molecule. It can be used as a target for graft versus leukaemia reactions to eliminate residual HA-1H expressing leukaemic cells in patients following haemopoietic stem cell transplantation, whereby HA-1H primed donor cells can be transferred into a patient via adoptive immunotherapy. However, thus far only synthetic peptides corresponding to a HLA-A *0201 restricted HA-1H epitope have been used to generate HA-1H specific T cells. We are the first laboratory to clone, express and purify a region of HA-1H using an Escherichia coli expression system. The recombinant HA-1H protein was purified under denaturing conditions and the affinity purification tag removed using thrombin to remove non-specific amino acids. The 92 amino acid recombinant protein was characterised by mass spectrometry. Our rationale is that by using a recombinant HA-1H protein rather than peptide, HA-1H specific T cells may be generated from presentation of multiple HA-1H epitopes complexed in different HLA molecules. A multi-epitope approach may have wider applicability and maybe more effective at leukaemia control. The recombinant HA-1H protein may also be used as a research tool to identify novel CD4(+) helper T cell and CD8(+) cytotoxic T cell epitopes.
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PMID:Expression and purification of the minor histocompatibility antigen, HA-1H generated in Escherichia coli. 1742 78

Hemostatic disorders can be found in approximately 90% of cancer patients, but clinical expression in only 15%. Hemorrhagic complications are more frequent in acute leukaemia; solid tumors are often associated with deep venous thromboses (DVP). Disseminated intravascular coagulation syndrome (DICS) can be latent or acute, and has various clinical presentations, occurring in the course of many serious conditions including cancer. Patients have higher morbidity and mortality. Irrespective of the etiology, DICS can be revealed by a wide variety of clinical manifestations, from mild biological hemostasis disorders, to intravascular or extravascular microthromboses or lethal hemorrhagic events. We report the case of a 45-year-old female with non-small-cell lung cancer with metastases at diagnosis. The patient developed and finally died of numberous thromboembolic events subsequent to DICS. This case illustrates some rather rare complications of DICS and offers the opportunity to discuss the main therapeutic goal in this situation, i.e. to modulate the disproportionate production of thrombin, inducing thromboses and/or hemorrhages by consumption of the cellular and plasmatic coagulation factors. This means a symptomatic and mostly etiologic treatment, especially chemotherapy which can in itself provoke thromboembolic events.
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PMID:[Disseminated intravascular coagulation syndrome and thromboembolic complications of non-small-cell lung cancer. A case report]. 1745 85

Thromboembolism (TE) is an uncommon entity in childhood. Overall 25% of children with thrombosis and more than 40% of children with central venous line (CVL) -related TE enrolled on the Canadian Pediatric Thrombophilia Registry had underlying diagnosis of cancer. However, so far there are very little data describing the epidemiology of TE in children with cancer. Most of the available information in this area originates mainly from retrospective and some prospective observational cohort studies conducted in children with acute lymphoblastic leukemia (ALL). Although ALL has been the most common cancer reported in association with thrombosis in children, available data from small studies indicate that TE is equally common in children with acute myeloid leukemia and lymphoma. TE in association with leukemia and lymphoma seems to be a multifactorial entity. Potential risk factors include increased thrombin generation related to leukemia, age of the patients, use of CVL, chemotherapy including asparaginase and corticosteroids, infections, and inherited prothrombotic state. Management of TE in a child with cancer presents a unique challenge in terms of balancing risk versus benefit. Conservative therapy could lead to clot extension and risks of additional morbidity or mortality; however, chemotherapy-related thrombocytopenia and coagulopathy increase the risk of bleeding complications. In summary, TE is a frequent and serious complication in children with hematologic malignancies. More prospective studies are required to define the epidemiology, pathogenesis, and management of TE in children with hematologic malignancies.
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PMID:Thromboembolic complications in pediatric hematologic malignancies. 1752 99


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