Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of imatinib mesylate (imatinib) therapy on angiogenesis and myelofibrosis was investigated and compared with interferon (IFN) and hydroxyurea (HU) in 98 patients with newly diagnosed Philadelphia chromosome-positive/BCR-ABL(+) (Ph(+)/BCR-ABL(+)) chronic myeloid leukemia in first chronic phase and no other pretreatment. By means of immunostaining (CD34) and morphometry, a relationship between microvessel frequency and fiber density was detectable in initial bone marrow (BM) biopsies and sequential examinations after at least 8 months of therapy. First-line monotherapy with imatinib induced a significant reduction (normalization in comparison with controls) of microvessels and reticulin fibers. In most patients, decrease in BM vascularity was associated with a complete cytogenetic response. A significant anti-angiogenic effect was also observed after HU treatment, contrasting with IFN administration or combination regimens (IFN plus HU). In conclusion, our data support the anti-angiogenic capacity of imatinib by normalization of vascularity. In contrast, hematologic response following IFN treatment is independent from BM angiogenesis.
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PMID:Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy. 1472 1

The role of allogeneic transplantation for myeloproliferative diseases other than chronic myeloid leukemia is not well established. In all, 20 patients with a median age of 51 years underwent allogeneic hematopoietic stem cell transplantation (HSCT) for myelofibrosis (n=5), chronic myelomonocytic leukemia (CMML) (n=8) and Philadelphia (Ph) chromosome-negative/BCR-ABL-negative chronic myeloid leukemia (CML) (n=7) in our institution. Patients who developed acute leukemia prior to HSCT were excluded from this analysis. A total of 15 patients received related and five patients received unrelated donor transplants. One patient failed to engraft. After a median follow-up of 17.5 months, actuarial survival at 2 years was 47% (95% CI 2%-67%), and disease-free survival 37% (95% CI 17-58%). Allogeneic transplantation may provide a therapeutic option for patients with myelofibrosis, CMML and Ph chromosome-negative/BCR-ABL-negative CML.
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PMID:Allogeneic transplantation: a therapeutic option for myelofibrosis, chronic myelomonocytic leukemia and Philadelphia-negative/BCR-ABL-negative chronic myelogenous leukemia. 1504 41

The objective of the study was to determine the association of neurocognitive impairment with health-related quality of life (HRQoL) in patients receiving highly active antiretroviral therapy (HAART). Seventy subjects were cross-sectionally analysed with a standardized neuropsychological test battery and a questionnaire including an Italian translation of the MOS-HIV Health Survey. The presence of neurocognitive impairment was significantly associated with lower HRQoL scores: pain (P = 0.03), physical functioning (P = 0.01), role functioning (P = 0.01), social functioning (P = 0.029), mental health (P = 0.001), energy (P = 0.036), health distress (P = 0.002), cognitive functioning (P = 0.05), current health perception (P <0.001), physical health summary score (PHS) (P = 0.005), mental health summary score (MHS) (P = 0.002). Years of education (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.65-0.96), PHS (OR 0.71; 95% CI 0.54-0.95) and MHS (OR 0.67; 95% CI 0.51-0.88) were also associated with cognitive impairment. Neurocognitive impairment in patients receiving HAART was associated with reduced HRQoL. Identifying cognitive impairment may provide motivation for additional treatment to help patients to compensate for deficits in functioning.
Int J STD AIDS 2004 Apr
PMID:Neurocognitive impairment influences quality of life in HIV-infected patients receiving HAART. 1507 20

To clarify the genetic aberrations involved in the development and progression of hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC), we investigated DNA copy number aberrations (DCNAs) in 19 surgically resected HCCs by conventional CGH and array CGH. Conventional CGH revealed that increases of DNA copy number were frequent at 1q (79% of the cases), 8q (37%), 6p (32%), and 10p (32%) and that decreases were frequent at 17p (79%), 16q (58%), 4q (53%), 13q (42%), 10q (37%), 1p (32%), and 8p (32%). In general, genes that showed DCNAs by array CGH were usually located in chromosomal regions with DCNAs detected by conventional CGH analysis. Increases in copy numbers of the LAMC2, TGFB2, and AKT3 genes (located on 1q) and decreases in copy numbers of FGR/SRC2 and CYLD (located on 1p and 16q, respectively) were observed in more than 30% of tumors, including small, well-differentiated carcinomas. These findings suggest that these genes are associated with the development of HCV-HCC. Increases of MOS, MYC, EXT1, and PTK2 (located on 8q) were detected exclusively in moderately and poorly differentiated tumors, suggesting that these alterations contribute to tumor progression. In conclusion, chromosomal and array CGH technologies allow identification of genes involved in the development and progression of HCV-HCC.
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PMID:Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH. 1513 72

A somatic mutation in the JH2 autoinhibitory domain of the Janus kinase 2 (JAK2) tyrosine kinase was recently described in polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia. The prevalence of this mutation in either "atypical" myeloproliferative disorders (MPDs) or the myelodysplastic syndromes (MDSs) is unknown. Bone marrow-derived genomic DNA from 245 patients--119 with chronic myelomonocytic leukemia (CMML), 101 with MDS, 11 with hypereosinophilic syndrome (HES), 8 with systemic mastocytosis (SM), and 6 with chronic neutrophilic leukemia (CNL)--was screened for the JAK2 V617F mutation. A mutant allele was detected in 11 patients: 3 with CMML (3%), 5 with MDS (5%), 2 with SM, and 1 with CNL. Interestingly, one of the patients with SM and the patient with CNL with JAK2 V617F had a history of lymphoma, and this patient with SM also had associated myelofibrosis and CMML. The current observation strengthens the specific association between JAK2 V617F and classic MPD, but also suggests an infrequent occurrence in other myeloid disorders.
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PMID:The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes. 1586 Jun 61

Essential thrombocythaemia was first described over 70 years ago. This condition is dominated by thrombotic and haemorrhagic complications and, in the long-term, by risk of transformation to myelofibrosis and/or acute leukaemia. However, it is heterogeneous both clinically and biologically. Here, a review of current concepts in disease aetiology and management is offered with reference to recent focused reviews where appropriate. In addition, five specific areas are discussed in detail: the role of the trephine biopsy, the disease entity prefibrotic myelofibrosis; the recently described Janus kinase 2 (JAK2) mutations; the leukaemogenicity of hydroxyurea (hydroxycarbamide); and lastly, the implications of the results of the Medical Research Council Primary Thrombocythaemia 1 study are explored.
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PMID:Essential thrombocythaemia: challenges and evidence-based management. 1602 44

An activating 1849G>T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)-negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph(+)CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G>T mutation is common in Ph(-) MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.
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PMID:JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. 1603 87

Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML)/atypical chronic myelogenous leukemia (aCML), myelodysplastic syndrome (MDS), B-lineage acute lymphoblastic leukemia (ALL), T-cell ALL, and chronic lymphocytic leukemia (CLL). Analysis of 222 patients with AML identified JAK2V617F mutations in 4 patients with AML, 3 of whom had a preceding MPD. JAK2V617F mutations were identified in 9 (7.8%) of 116 CMML/a CML samples, and in 2 (4.2%) of 48 MDS samples. We did not identify the JAK2V617F disease allele in B-lineage ALL (n = 83), T-cell ALL (n = 93), or CLL (n = 45). These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in lymphoid malignancies.
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PMID:The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. 1608 87

The combined use of bone marrow histopathology, biomarkers and clinical features has the potential to diagnose, stage and distinguish early and overt stages of ET, PV and idiopathic myelofibrosis, that has an important impact on prognosis and treatment of MPD patients. As the extension of the PVSG and WHO for ET, PV and agnogenic myeloid metaplasia (AMM), a new set of European clinical and pathological (ECP) criteria clearly distinct true ET from early or latent PV mimicking true ET, overt and advanced polycythemia vera (PV), and from thrombocythemia associated with prefibotic, early fibrotic stages of chronic megakaryocytic granulocytic metaplasia (CMGM) or chronic idiopathic myelofibrosis (CIMF). Cases of atypical MPD and masked PV are usually overlooked by clinicians and pathologists. Bone marrow biopsy will not differentiate between post-PV myelofibrosis versus so-called classical agnogenic myeloid metaplasia. The recent discovery of the JAK2 V617F mutation can readily explain the trilinear megakaryocytic, erythroid and granulocytic proliferation in the bone marrow, but also the etiology of the platelet-mediated microvascular thrombotic complications at increased platelet counts and red cell mass in essential thrombocythemia and polycythemia vera.
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PMID:Clinical, pathological and molecular features of the chronic myeloproliferative disorders: MPD 2005 and beyond. 1618 76

The discovery this year of a single mutation in the Janus Kinase (JAK)-2 gene in a high percentage of cases of polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis suggests that it maybe the underlying molecular mechanism for these disorders. Different approaches from the inhibition of the tyrosine kinase JAK2, widespread search for mutations in tyrosine kinases, and investigation of the short arm of chromosome 9 where JAK2 is located all led to the discovery of the V617F JAK2 mutation. Substitution of a valine for a phenylalanine destabilizes the JH2 domain of JAK2 causes loss of the auto-inhibitory activity of this domain and explains some of the biological phenomena observed in patients with myeloproliferative disorders (MPD). The V617F JAK2 mutation can be detected by PCR-direct sequencing using DNA from the granulocyte lineage or with increased sensitivity by the amplification refractory mutation system using DNA from unfractionated blood. Pyrosequencing assays can be used to quantitate allele ratios to accurately define homozygote and heterozygote status. This single mutation is widespread having been detected in related MPD and other haematological malignancies. This leads to a number of further questions about the role of this single mutation in the clinical pattern of disease.
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PMID:The V617F JAK2 mutation and the myeloproliferative disorders. 1628 6


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