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

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

High oxygen affinity hemoglobin (Hb) variants are an important and well characterized cause of secondary erythrocytosis. We tested 22 patients with high oxygen affinity beta chain variants for the presence of the JAK2 V617F mutation that has been reported in chronic myeloproliferative disorders, particularly polycythemia vera. All specimens showed the absence of this mutation. This observation contributes to the overall clinical specificity of the JAK2 V617F mutation.
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PMID:The JAK2 V617F mutation is absent in patients with erythrocytosis due to high oxygen affinity hemoglobin variants. 1698 4

In this study, we provide a molecular signature of highly enriched CD34+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34+ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.
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PMID:Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. 1725 12

The Val617Phe point mutation of Janus kinase 2 gene is believed to participate in the pathogenesis of myeloproliferative syndrome characterised by the clonal alteration of hematopoietic stem cells. According to current results, the frequency of Val617Phe activating mutation is around 80% in polycythaemia vera, 35% in essential thrombocythemia, and 50% in chronic idiopathic myelofibrosis. The diagnoses of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis were so far based on the exclusion of secondary factors as well as bone marrow biopsy histology. The goal of the present work was to establish simple molecular genetic techniques for the routine testing of Janus kinase 2 gene Val617Phe mutation, and to compare the clinical phenotypes of Val617Phe mutation positive and negative myeloproliferative syndromes. We employed the allele specific polymerase chain technique for detection of Val617Phe mutation in 252 patients with myeloproliferative syndrome. We measured Val617Phe frequency as 85,4% (117/137) in polycythemia vera, 56,6% (56/99) in essential thrombocythemia, and 87,5% (14/16) in idiopathic myelofibrosis. We found significantly elevated hemoglobin levels and white blood cell counts (measured at the time of diagnosis) in Val617Phe-positive polycythemia vera and essential thrombocythemia patient groups compared to Val617Phe-negative patients. However, the frequencies of splenomegaly and other complications (thrombosis, bleeding, transformation to acute leukemia) were not significantly different between the mutation-positive and negative groups. In conclusion, the non-invasive mutation analysis of the Janus kinase 2 Val617Phe is suitable for routine laboratory application and helps the differential diagnosis of myeloproliferative syndrome. Although the exact role of Val617Phe mutation testing has not yet been identified on the basis of a broad professional consensus, the testing is suggested in cases of erythrocytoses and thrombocytoses of unknown origin.
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PMID:[Role of the activating mutation Val617Phe of Janus kinase 2 gene in myeloproliferative diseases and significance of its detection]. 1734 40

We report a novel TaqMan assay for JAK2 V617F that measures averaged copies per cell in absolute terms, as opposed to a ratio of mutant to wild-type alleles. Measurements were obtained by comparing the JAK2 V617F signal generated by the test samples to that generated by a set of external plasmid standards containing the sequence of interest. Specificity of the assay was demonstrated above 36 cycles of amplification, and endpoint titration experiments indicated sensitivity down to 0.05% clinical dilutions. The test measured linearly over a wide logarithmic range and exhibited good reproducibility. Combination of this assay with another TaqMan method for determining cell number allowed identification of 14 cases of myeloproliferative disease with greater than two copies per cell. Mutational frequency was 68% among polycythemia vera (n=44), 59% (n=37) among essential thrombocythemia and 46% (n=13) among idiopathic myelofibrosis. Levels of the mutation were significantly higher in polycythemia vera compared with essential thrombocythemia (P=0.0005) and correlated with the following jointly significant variables at diagnosis: PRV-1, hemoglobin, white cell count, neutrophil count, and red cell count, using multiple regression analyses (P=0.015). This method should be useful for assessing the relationship of gene dose to phenotype and possibly for monitoring therapy.
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PMID:Quantitative determination of JAK2 V617F by TaqMan: An absolute measure of averaged copies per cell that may be associated with the different types of myeloproliferative disorders. 1738 17

The JAK2 617V>F mutation is frequent in polycythemia vera (PV) and essential thrombocythemia (ET). Using quantitative polymerase chain reaction (PCR), we found that high levels of JAK2 617V>F in PV correlate with increased granulocytes and high levels of hemoglobin and endogenous erythroid colony formation. We detected normal progenitors and those that were heterozygous or homozygous for the mutation by genotyping ET and PV clonal immature and committed progenitors. In PV patients, we distinguished homozygous profiles with normal, heterozygous, and homozygous progenitors from heterozygous profiles with only heterozygous and normal progenitors. PV patients with a heterozygous profile had more mutated, committed progenitors than did other PV and ET patients, suggesting a selective amplification of mutated cells in the early phases of hematopoiesis. We demonstrated that mutated erythroid progenitors were more sensitive to erythropoietin than normal progenitors, and that most homozygous erythroid progenitors were erythropoietin independent. Moreover, we observed a greater in vitro erythroid amplification and a selective advantage in vivo for mutated cells in late stages of hematopoiesis. These results suggest that, for PV, erythrocytosis can occur through two mechanisms: terminal erythroid amplification triggered by JAK2 617V>F homozygosity, and a 2-step process including the upstream amplification of heterozygous cells that may involve additional molecular events.
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PMID:The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. 1738 63

The purpose of this study was to compare the variation in hemoglobin (Hgb) values among various point-of-care (POC) analyzers available on the market. Eight analyzers (Gem 3000, ABL 720, ABL 77, Rapidpoint 405, IL 682, GemOPL, Hb 201+, and manual/centrifugation) were compared with the Hgb values from the Beckman Coulter LH750. A total of 72 patient samples were analyzed on each test instrument. The samples were obtained after intubation, after heparinization, during cardiopulmonary bypass, and after protamine administration. Four of the samples were excluded from the study because of delayed sample analysis. The calculated mean differences of reference test method Hgb (mean +/- SD) for all samples (n = 68) were Gem 3000 = 1.431 +/- 0.396 g/dL; ABL 720 = -0.224 +/- 0.240 g/dL; ABL 77 = 0.341 +/- 0.578 g/dL; Rapidpoint 405 = 0.001 +/- 0.205 g/dL; IL 682 = -0.137 +/- 0.232 g/dL; GemOPL = 0.774 +/- 0.427 g/dL; Hb 201+ = 0.110 +/- 0.524 g/dL; and manual/ centrifugation = 0.547 +/- 0.499 g/dL. Cumulative results indicated that the bias in Hgb values from the Gem 3000, ABL720, ABL 77, IL 682, GemOPL, and the manual method were statistically significant (p < .05), compared with the Coulter LH750. Additionally, only the Rapidpoint 405 and Hb 201+ most closely matched the values from the Coulter LH750 (p > .05). Some of the methodologies have previously been shown to be affected during hemodilution, hypoproteinemia, and/or after blood transfusion. There is variability among methodologies, which can give rise to statistically different Hgb values, and one should consider the "ideal" instrument based on this and many other factors. Based on our results, the rank order of closest approximation to the Coulter LH750 measurement was Rapidpoint 405, Hb 201+, IL 682, ABL 720, ABL 77, manual/centrifugation, GemOPL, and Gem 3000.
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PMID:Hemoglobin test result variability and cost analysis of eight different analyzers during open heart surgery. 1748 68

In order to explore the application of real-time quantitative reverse-transcription polymerase chain reaction (Q-PCR) for detecting PML/RARalpha gene transcripts in patients with acute promyelocytic leukemia (APL), the bone marrow samples from 46 newly diagnosed APL patients were collected for analysis. Three plasmids containing cDNA fragments of the bcr1-, bcr3-form PML/RARalpha and ABL control gene were constructed respectively. The ABI Prism 7500 Sequence Detection System using Taqman fluorogenic probes was used to quantify target gene. PML/RARalpha mRNA was detected by Q-PCR in 46 APL patients and 40 non-APL patients. The normalized quotient (NQ) of PML/RARalpha mRNA was calculated as followings: NQ = PML/RARalpha mRNA copy numbers/ABL mRNA copy numbers. Immunophenotype of acute promyelocytic leukemia was determined by four-color flow cytometry. The results showed that the coefficients of variation (CV) of inter-day assay and intra-day assay by using Q-PCR were 1.58% and 0.88% respectively. Q-PCR could detect reproducibly 5 copies of target gene per 100 ng RNA and no pseudopositive results were found. The median NQ of PML/RARalpha mRNA was 0.450 (0.084 - 1.082) in 46 APL patients. There was no indication of any correlation of PML/RARalpha mRNA type with age, sex, hemoglobin, platelet count, percentage of promyelocytes in bone marrow detected by morphology or flow cytometry, PML/RARalpha NQ, or signs of clinically diagnosed coagulation/bleeding disorders. Compared with bcr1-form cases, bcr3-form cases had more M(3v) phenotype (42.9% vs 9.4%, P = 0.015) and higher WBC count (9.35 x 10(9)/L vs 2.15 x 10(9)/L, P = 0.038). APL cells could be classified into large side scatter population (L-SSC) and non-large side scatter population (NL-SSC) in CD45/SSC histogram of flow cytometry. 87.50% patients with bcr1-form showed L-SSC phenotype and 64.29% patients with bcr3-form showed NL-SSC phenotype. It is concluded that a sensitive Q-PCR method is established. The median NQ of PML/RARalpha mRNA was 0.450 in newly diagnosed APL patients. There was no significant difference about PML/RARalpha mRNA expression of both bcr3-form and bcr1-form APL patients. Type of PML/RARalpha transcripts is related with the morphology and immunophenotype.
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PMID:[Detection of PML/RARalpha gene transcripts in 46 newly diagnosed acute promyelocytic leukemia patients by real-time quantitative reverse-transcription polymerase chain reaction]. 1749 May 9

Hyper-transaminasemia (HT) is a well-known laboratory sign of celiac disease (CD); however, hyper-creatine phosphokinase (CK)-emia (HCK) is not so familiar. As there are reported cases of myopathy associated CD in the literature, we aimed to investigate serum CK levels of children with CD. Newly diagnosed 126 children were included. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and CK levels were determined. Mean age was 8.7+/-4.4 years (11 mo to 18 y). Of patients, 77 (61.1%) had classic form, 49 (38.9%) had atypical form. Elevated levels of AST, ALT, and CK, respectively, were found in 65 (51.6%), 45 (35.7%), and 50 (39.7%) patients. Isolated HCK was detected in 9 (7.1%) patients. AST, ALT, and CK were all elevated in 29 (23.0%) children. Mean serum AST, ALT, and CK levels were found as 56.1+/-53.7 U/L (11 to 403), 44.7+/-44.0 U/L (7 to 290), and 258.0+/-686.5 U/L (36 to 5956), respectively. In 95 (75.4%) children, AST/ALT value was greater than 1, and in 19 (15.1%) it was greater than 2. We found positive correlations with the level of CK and AST, and ALT (P=0.01). CK level was inversely correlated with hemoglobin and cholesterol levels (P=0.013 and 0.007). In conclusion, this is the first study, which determined elevated serum levels of CK in CD and demonstrated that HCK is as common as HT in children with CD. We emphasize that HT seen in CD is not necessarily a sign of liver injury, but may also be due to myopathy.
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PMID:Hyper-CK-emia in pediatric celiac disease: prevalence and clinical importance. 1766 50

Recently, an activating somatic mutation of Janus kinase 2 (JAK2V617F) was identified in the myeloproliferative disorders (MPDs). In this study, we investigated the occurrence of JAK2V617F in patients with slightly elevated platelets or hemoglobin without a secondary cause, who did not meet the criteria of polycythemia vera or essential thrombocythemia. Six out of 18 patients (33%) were positive for the JAK2 mutation, and five of these six patients had a history of thrombosis. These findings suggest that apart from thrombocytosis/erythrocytosis, other mechanisms exist that cause thrombosis, and more patients with a latent form of MPD are likely to exist. Future studies will have to elucidate how to treat these patients.
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PMID:Detection of the JAK2V617F mutation in patients with slightly elevated platelets or hemoglobin without a secondary cause. 1770 2

Few investigators have evaluated the usefulness of the JAK2 V617F mutation for explaining the phenotypic variations and for predicting the risk of major clinical events in primary myelofibrosis (PMF). In a transversal survey we assayed by allele-specific polymerase chain reaction (PCR) the JAK2 V617F mutational status in 304 patients with PMF. Multiple DNA samples were collected prospectively from 64 patients, and a highly sensitive quantitative PCR was used as a confirmatory test. In a longitudinal prospective study we determined the progression rate to clinically relevant outcomes in 174 patients who had JAK2 mutation determined at diagnosis. JAK2 V617F was identified in 63.4% of patients. None of the V617F-negative patients who were sequentially genotyped progressed to become V617F positive, whereas progression rate from heterozygous to homozygous mutation was 10 per 100 patient-years. JAK2 V617F mutation contributed to hemoglobin, aquagenic pruritus, and platelet count variability, whereas homozygous mutation was independently associated with higher white blood cell count, larger spleen size, and greater need for cytoreductive therapies. Adjusting for conventional risk factors, V617F mutation independently predicted the evolution toward large splenomegaly, need of splenectomy, and leukemic transformation. We conclude that JAK2 V617F genotype should be considered in any future risk stratification of patients with PMF.
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PMID:JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. 1771 47


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