Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical and haematological phenotype of patients with myelofibrosis harbouring MPL(W515L/K) mutation has not been thoroughly investigated. Of 217 myelofibrosis subjects, 18 (8.2%) had an MPL mutation, four of which (22%) co-existed with JAK2(V617F) mutation. When compared with MPL wild-type patients, irrespective of JAK2(V617F) status, those with MPL(W515L/K), were more frequently female, were older (61 years vs. 57 years; P = 0.02), presented with more severe anaemia (haemoglobin, 101 g/l vs. 121 g/l; P = 0.002) and were more likely to require regular transfusional support (P = 0.012). These data indicate that MPL mutation in myelofibrosis characterises patients with more severe anaemic phenotype.
...
PMID:Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. 1740 65

Patients with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) have limited therapeutic options. The farnesyltransferase-inhibitor tipifarnib inhibits in vitro proliferation of myeloid progenitors from such patients. In the current phase II clinical trial, single-agent oral tipifarnib (300 mg twice daily x 21 of 28 days) was given to 34 symptomatic patients with either PMF (n=28) or post-PV/ET MF (n=6). Median time to discontinuation of protocol therapy was 4.6 months; reasons for early termination (n=19; 56%) included disease progression (21%) and adverse drug effects (18%). Toxicities (>/=grade 3) included myelosuppression (n=16), neuropathy (n=2), fatigue (n=1), rash (n=1) and hyponatremia (n=1). Response rate was 33% for hepatosplenomegaly and 38% for transfusion-requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis or cytogenetic status. Pre- and post-treatment patient sample analysis for in vitro myeloid colony growth revealed substantial reduction in the latter. Clinical response did not correlate with either degree of colony growth, measurable decrease in quantitative JAK2(V617F) levels or tipifarnib IC(50) values (median 11.8 nM) seen in pretreatment samples. The current study indicates both in vitro and in vivo tipifarnib activity in PMF and post-PV/ET MF.
...
PMID:A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. 1758 8

The discovery of the Janus kinase 2 gain-of-function V617F mutation (JAK2(V617F)) provided a major breakthrough in the understanding of Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph(-) CMPD). Among haematologic neoplasm the mutation appears to be almost specific for Ph(-) CMPD but the different entities comprising polycythaemia vera (PV), essential thrombocythaemia and chronic idiopathic myelofibrosis (CIMF) are not discriminated by the mutation. It is unclear how the diversity with heterogeneous clinical and pathoanatomical presentations comes about. It has been suggested that differences in JAK2(V617F) gene dosage or different degrees to which the haematologic lineages are affected by the mutation could explain the heterogeneity of morphology and prognosis. Indeed the mutation mediates a PV-like phenotype but with regard to myelofibrosis JAK2(V617F) does not appear to be a causative factor. Megakaryocytes are homozygous in the majority of fibrotic CIMF and PV, whereas JAK2(V617F) heterozygosity is predominantly encountered in prefibrotic CIMF and essential thrombocythaemia but transition from hetero- to homozygosity with onset of fibrosis is rare. In conclusion, JAK2(V617F) provides a valuable adjunct to the diagnosis of Ph(-) CMPD, in particular with regard to discrimination from reactive proliferations, but the challenge of correct subtyping and hence prognostication persists for clinicians and bone marrow pathologists.
...
PMID:Histological and molecular classification of chronic myeloproliferative disorders in the age of JAK2: persistence of old questions despite new answers. 1758 78

Idiopathic myelofibrosis (IM) is likely the consequence of both the acquisition of genetic mutations and epigenetic changes that silence critical genes that control cell proliferation, differentiation, and apoptosis. We have explored the effects of the sequential treatment with the DNA methyltransferase inhibitor, decitabine [5-aza-2'-deoxycytidine (5azaD)], followed by the histone deacetylase inhibitor, trichostatin A (TSA), on the behavior of IM CD34(+) cells. Unlike normal CD34(+) cells where 5azaD/TSA treatment leads to the expansion of CD34(+) cells and marrow-repopulating cells, treatment of IM CD34(+) cells results in a reduction of the number of total cells, CD34(+) cells, and assayable hematopoietic progenitor cells (HPC). In IM, HPCs are either heterozygous or homozygous for the JAK2V617F mutation or possess wild-type JAK2 in varying proportions. Exposure of IM CD34(+) cells to 5azaD/TSA resulted in a reduction of the proportion of JAK2V617F-positive HPCs in 83% of the patients studied and the reduction in the proportion of homozygous HPCs in 50% of the patients. 5azaD/TSA treatment led to a dramatic reduction in the number of HPCs that contained chromosomal abnormalities in two JAK2V617F-negative IM patients. IM is characterized by constitutive mobilization of HPCs, which has been partly attributed to decreased expression of the chemokine receptor CXCR4. Treatment of IM CD34(+) cells with 5azaD/TSA resulted in the up-regulation of CXCR4 expression by CD34(+) cells and restoration of their migration in response to SDF-1. These data provide a rationale for sequential therapy with chromatin-modifying agents for patients with IM.
...
PMID:Effects of chromatin-modifying agents on CD34+ cells from patients with idiopathic myelofibrosis. 1761 2

The role of histopathology in the diagnosis of essential thrombocythemia (ET) is controversial, and there has been little attempt to quantitate interobserver variability. Diagnostic bone marrow trephine biopsy specimens from 370 patients with ET by Polycythemia Vera Study Group (PVSG) criteria were assessed by 3 experienced hematopathologists for 16 different morphologic features and overall diagnosis according to the World Health Organization (WHO) classification. Our results show substantial interobserver variability, particularly for overall diagnosis and individual cellular characteristics such as megakaryocyte morphology. Reticulin grade was the dominant independent predictor of WHO diagnostic category for all 3 hematopathologists. Factor analysis identified 3 independent factors likely to reflect underlying biologic processes. One factor related to overall and lineage-specific cellularity and was significantly associated with JAK2 V617F status (P < .001), a second factor related to megakaryocyte clustering, and a third was associated with the fibrotic process. No differences could be discerned between patients labeled as having "prefibrotic myelofibrosis" or "true ET" in clinical and laboratory features at presentation, JAK2 status, survival, thrombosis, major hemorrhage, or myelofibrotic transformation. These results show that histologic criteria described in the WHO classification are difficult to apply reproducibly and question the validity of distinguishing true ET from prefibrotic myelofibrosis on the basis of subjective morphologic criteria. This study was registered at http://isrctn.org as #72251782 and at http://eudract.emea.europa.eu/ as #2004-000245-38.
...
PMID:Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. 1788 79

US Army Medics (formerly MOS 91B) received training similar to EMT-B level but were not required to be certified. Medics additionally received training in such skills as intravenous (i.v.) line insertion and fluid resuscitation. Continuing education, although encouraged, was not required. The objective of this study was to determine the effectiveness of a focused and directed psychomotor skills continuing education program in maintaining skills performance over a 6-month period in four key resuscitation areas. The education effect was the focus of the analysis. The study population was a convenience sample of medics with 1-4 years experience assigned to field units at Ft. Hood, TX. Subjects received a pretest evaluation of skills performance in four key areas using standard NREMT skill sheets. Scores on skill evaluations represent the percentage of steps correctly performed. After pretest evaluations, subjects were required to complete a comprehensive and focused continuing education program that emphasized skill practice. After the 6-month pretest, a post-test was conducted. Pre- and post-test scores for each student were matched. A one-tailed Student's t-test was used to compare results before and after the intervention, with statistical significance set at p < 0.05. The total sample of subjects available for the post-test (n =107) was compared to the initial pretest sample (n = 127) and shown to be accurately representative. The pretest performance for the skills of i.v. insertion, airway management, patient assessment, and bleeding control was 79 +/- 11, 73 +/- 14, 44 +/- 22, and 57 +/- 13, respectively. The post-test performance for these same skills increased (p < 0.05) in all cases when compared to pretest scores: 87 +/- 9, 76 +/- 15, 73 +/- 19, and 62 +/- 14, respectively. A focused and directed continuing education program that emphasizes skill practice in key resuscitation areas can improve skills performance.
...
PMID:Effect of a focused and directed continuing education program on prehospital skill maintenance in key resuscitation areas. 1797 62

The diagnosis and management of the BCR-ABL-negative myeloproliferative disorders (MPDs) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are at an explosive crossroads of scientific investigation and evolving paradigms since the discovery of the tyrosine kinase-activating JAK2V617F mutation in 2005. Additional discovery of relevant molecular lesions (JAK2 exon 12 mutations and c-MplW515L/K) have only further enriched our understanding of MPD pathogenesis. The improved diagnostic certainty these molecular markers provide have resulted in the modification, and simplification, of the World Health Organization (WHO) diagnostic algorithms for MPDs. Despite these scientific advances, however, the initial management of MPDs continues to rely upon a risk-based strategy to minimize the risk of vascular events with control of erythrocytosis, targeted antiplatelet therapy, and risk-based myelosuppressive therapy. No current medical therapy has altered the natural trend of the MPDs to lead to overt severe myelofibrosis or acute leukemia. Investigations into targeted therapies for MPDs are proceeding at a brisk pace with agents aimed at immunomodulation, decreasing marrow stromal reaction to the aberrant clone, DNA hypomethylation, or the inhibition of tyrosine kinases. Specific inhibition of JAK2 itself appears promising by in vitro investigations, and clinical trials with multiple agents are planned to commence enrollment in 2007. The potential impact of JAK2 inhibitors on the manifestations of the MPDs is unclear, but is awaited with great interest.
...
PMID:Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. 1802 51

Philadelphia-negative chronic myeloproliferative disorders (CMD) include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Angiogenesis is critical in the pathogenesis of PMF. We studied angiogenesis in 115 patients with CMD (23 PV, 24 ET, 46 PMF, 12 post-PV and 10 post-ET myelofibrosis) by assessment of microvessel density (MVD) in bone marrow (BM). Kruskall-Wallis analysis of variance showed that patients with PMF had significantly higher values of MVD than those with PV (P < 0.001), ET (P < 0.001) and controls (P < 0.001). Mann-Whitney U-test demonstrated that patients with PMF at the prefibrotic stage had significantly higher MVD values than those with ET (P = 0.02). Patients with post-PV myelofibrosis showed significantly higher MVD values than those with PV (P < 0.001), as did patients with post-ET myelofibrosis compared with ET (P < 0.001). In patients with CMD, the multivariate generalized linear regression model showed that the JAK2 (V617F) mutational burden (P = 0.01), serum lactate dehydrogenase level (P = 0.003), and anaemia (P < 0.001) independently correlated with MVD. In summary, this study indicates that assessment of BM angiogenesis, as measured by MVD, may be a useful additional tool in the histopathological definition of CMD.
...
PMID:Bone marrow microvessel density in chronic myeloproliferative disorders: a study of 115 patients with clinicopathological and molecular correlations. 1802 79

The clinical courses of polycythemia vera (PV) and essential thrombocythemia (ET) are characterized by an increased incidence of thrombotic and hemorrhagic complications and an inherent tendency to progress into myelofibrosis or acute myeloid leukemia. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thromboses and hemorrhages, but there is concern that their use accelerates the rate of leukemic transformation. Thus, a risk-oriented management strategy is recommended. Low-risk patients with PV should be treated with phlebotomy and low-dose aspirin, whereas those with ET can be left untreated. Cytotoxic agents are recommended in high-risk patients and hydroxyurea is the drug of choice in most patients. Interferon-alpha (IFN-alpha) or anagrelide could be considered in selected young patients or as second-line therapy in those intolerant of hydroxyurea or with refractory disease. The recent identification of the JAK2 V617F mutation in a substantial proportion of patients with PV and ET raises the possibility of a molecularly targeted therapy.
...
PMID:Expertise-based management in essential thrombocythemia and polycythemia vera. 1803 74

The treatment of primary myelofibrosis (PMF) remains essentially palliative. Conventional modalities include a wait-and-see approach for asymptomatic patients, oral cytolytic drugs such as hydroxyurea for the hyperproliferative forms of the disease, androgens or erythropoietin for the anemia, and splenectomy in selected patients. These therapeutic modalities improve the patients' quality of life but have no impact on survival. Newer therapies for PMF are currently being used. Antiangiogenic and immunomodulatory drugs such as thalidomide and lenalidomide are associated with frequent side effects but have shown certain efficacy, especially for the anemia and thrombocytopenia. The association of low-dose thalidomide with prednisone has better tolerability, and it is also effective. Tyrosine kinase inhibitors such as imatinib have also been used, but their efficacy is limited. Tipifarnib, a farnesyltransferase inhibitor, has shown certain effects in the anemia. Allogeneic stem cell transplantation (SCT) is the only curative therapy for PMF. Its standard modality has an associated mortality of 30%, and it is indicated in younger patients with high-risk disease or disease resistant to conventional treatment. Reduced-intensity conditioning allogeneic SCT is associated with low mortality while maintaining a curative potential, and until longer follow-up is available, it can be used in patients aged 45-70 years old with high- or intermediate-risk myelofibrosis or myelofibrosis resistant to treatment. Autologous SCT is a palliative measure that can be considered in patients with resistant disease, who lack a suitable donor. Newer immunomodulatory drugs, proteasome inhibitors, hypomethylating agents, and JAK2 inhibitors are currently being tested.
...
PMID:New and old treatment modalities in primary myelofibrosis. 1803 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---