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)

In a patient with precursor B-cell acute lymphoblastic leukemia (ALL) associated with eosinophilia that completely responded to induction chemotherapy, we assayed serial remission cerebrospinal fluid and bone marrow specimens for minimal residual disease using a quantitative polymerase chain reaction assay to assess for clone-specific immunoglobulin heavy-chain gene cluster (IGH) gene rearrangement. Cerebrospinal fluid eosinophilia and minimal residual disease were detected on day 406, preceding the morphologic diagnosis of central nervous system relapse on day 578. By day 841, the bone marrow had 35% blasts. Despite aggressive therapy, including unrelated umbilical cord blood transplantation, the patient developed testicular and bone marrow relapses and died of disease. We conclude that increasing levels of minimal residual disease in cerebrospinal fluid can predict recurrence of ALL prior to clinical and morphologic relapse. Furthermore, we demonstrate a novel translocation in this tumor, the t(5;9)(q31;p24), that possibly led to fusion of the interleukin-3 (IL3) (5q31) and JAK2 (9p24) genes and may explain the concomitant appearance of eosinophilia and ALL.
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PMID:Molecular monitoring of cerebrospinal fluid can predict clinical relapse in acute lymphoblastic leukemia with eosinophilia. 1270 6

Based on its ability to inhibit the tyrosine kinase activity of ABL, as well as the c-kit and the Platelet Derived Growth Factor Receptor tyrosine kinases, the spectrum of diseases that may respond to STI571 is increasing. A recently recognized subgroup of myeloproliferative disorders/myelodysplastic syndromes (MPD/MDS) has a t(5;12)(q33;p13) with the activation of the gene for PDGFBR which encodes a receptor tyrosine kinase. Here, we present the case of a patient, with MPD/MDS, and eosinophilia, carrying a translocation t(5;12)(q33;p13) who achieved a complete remission following treatment with STI571, 400 mg daily. At the time of writing he still remains in complete remission with an excellent performance status. There is clearly a need for further studies of STI 571in MPD/MDS with chromosomal translocations involving PDGFBR to confirm this promising initial result.
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PMID:Response to STI571 in chronic myelomonocytic leukemia with platelet derived growth factor beta receptor involvement: a new case report. 1274 87

To examine the participation of transcription factor GATA-3 in Th2 immune responses in vivo, we generated transgenic mice having several copies of GATA-3 with LCK promotor. Mice were infected with the intestinal nematode Heligmosomoides polygyrus to induce Th2 immune responses. Upon antigen stimulation, IL-5 and IL-13 production of mesenteric lymph node cells from H. polygyrus-infected mice, was significantly enhanced in GATA-3-transgenic mice compared with nontransgenic control mice. However, IL-4 production was the same in GATA-3-transgenic and control mice. H. polygyrus-infected GATA-3-transgenic mice exhibited significantly more peripheral blood eosinophils and total IgE levels compared with control mice. These results suggest that GATA-3 promotes IL-5 and IL-13 production, and that the function of these cytokines results in eosinophilia and hyper-IgE, respectively.
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PMID:Th2 immune responses in GATA-3-transgenic mice infected with Heligmosomoides polygyrus. 1277 43

A cross sectional survey was conducted to determine the association between enteric parasites and diarrhoea in HIV-infected adults in Caracas. Three hundred and four patients were evaluated: 104 had acute diarrhoea, 113 chronic diarrhoea and 87 were controls. Isopora belli infection was associated with acute (P = 0.022) and chronic diarrhoea (P = 0.003), Entamoeba histolytica/dispar infection was also associated with both acute (P = 0.015) and chronic diarrhoea (P = 0.017). Strongyloides stercoralis (P = 0.003), and Cryptosporidium parvum (P = 0.017) infections were associated mainly with chronic episodes. Weight loss (P < 0.001), a non-infectious factor investigated, was significantly associated with diarrhoea. Eosinophilia, a laboratory parameter studied, was found to be associated with strongyloidiasis (P = 0.001), giardiasis (P = 0.001) and isoporiasis (P = 0.003). In summary, the presence of enteric parasites in HIV-infected patients from tropical urban areas with diarrhoea, with or without significant weight loss, must be considered. Similarly, eosinophilia might suggest parasitic infection in these patients.
Int J STD AIDS 2003 Jul
PMID:Association between parasitic intestinal infections and acute or chronic diarrhoea in HIV-infected patients in Caracas, Venezuela. 1286 31

We report a case of BCR-ABL-negative atypical chronic myeloid leukemia (CML) with translocation t(4;22) (q12;q11.2) juxtaposing the breakpoint cluster region (BCR) and platelet-derived growth factor receptor-alpha (PDGFRA) genes. The patient was a 57-year-old man with a history of stage IV diffuse large B-cell lymphoma, status post-6 cycles of combination chemotherapy in 1999, who presented in August 2002 with enlarged lymph nodes, anemia, and marked leukocytosis (50 x 10(9) g/dL) consistent with a myeloproliferative disorder (MPD). A bone marrow biopsy showed granulocytic hyperplasia, neutrophilia, and mild eosinophilia. Initial cytogenetic evaluation by interphase FISH for BCR-ABL, to rule out a translocation 9;22, showed a variant signal pattern consistent with rearrangement of BCR at 22q11.2, but not ABL at 9q34. Analysis of the patient's cDNA by polymerase chain reaction (PCR) for BCR-ABL was negative. Cytogenetic analysis showed an abnormal karyotype with rearrangement of chromosomes 4 and 22. PCR amplification and subsequent sequence analysis demonstrated an in-frame 5'-BCR/3'-PDGFRA fusion in the patient's cDNA. PDGFRA encodes a receptor tyrosine kinase and shares structural and organizational homology with the KIT and CSf1R receptor genes. However, although the incidence of MPD involving translocations of PDGFRB has been well established, to our knowledge there are only two previous reports describing a BCR-PDGFRA fusion gene, in 3 patients diagnosed with atypical CML. Here, we report the molecular and cytogenetic characterization of a patient with BCR-PDGFRA-positive MPD who had a complete hematologic response after treatment with imatinib mesylate.
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PMID:Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia. 1503 67

Bruton's tyrosine kinase (Btk) is thought to positively regulate mast cell activation, implying a role in allergic responses. We have compared acute and late phase allergic airway reactions in mice lacking either Btk or interleukin-2-inducible T cell kinase (Itk), another Tec kinase expressed in mast cells. Btk(-/-) mice showed minor protection against allergic symptoms when challenged with allergen via the airways. In sharp contrast, both acute and late phase inflammatory allergic responses were markedly reduced in Itk(-/-) mice. Notably, airway mast cell degranulation in Itk(-/-) mice was severely impaired, despite wild-type levels of allergen-specific IgE and IgG1. The degranulation defect was confirmed in DNP-conjugated human serum albumin-challenged mice passively sensitized with anti-DNP IgE antibodies, and was also observed after direct G-protein stimulation with the mast cell secretagogue c48/80. Moreover, late phase inflammatory changes, including eosinophilia, lymphocyte infiltration, and Th2 cytokine production in the lungs, was eliminated in Itk(-/-) mice. Collectively, our data suggest a critical role of Itk in airway mast cell degranulation in vivo that together with an impaired T cell response prevents the development of both acute and late phase inflammatory allergic reactions.
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PMID:Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses. 1577 96

Atopic dermatitis (AD) is an allergic disease that has recently shown a dramatic increase of incidence in developed countries. Eosinophilia, the accumulation of eosinophils, occurs in AD patients through an anti-apoptotic mechanism. To understand the target proteins involved in the anti-apoptotic signaling of eosinophilia, we used a proteomic approach to analyze eosinophil proteins from AD patients with eosinophilia and healthy donors. Protein spots in two-dimensional electrophoresis (2-DE) gels were identified with peptide mass fingerprinting (PMF) based on matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and database searching. More spots were observed in the 2-DE proteome map from AD patient samples (1310 +/- 58 spots) than in those from healthy donors (1121 +/- 40 spots). We identified 51 proteins affected by eosinophilia: 19 related to signaling, 8 involved in regulation of metabolism, 4 related to apoptosis, and 3 involved in inflammation. The other identified proteins were associated with transcription, RNA processing, translation, the cytoskeleton, and unknown functions. Among the identified proteins, we observed prominent increases in the expressions of cyclinA2, voltage-dependent anion channel protein 2, and 38 kDa FK506 binding protein 8 in eosinophils from AD patients in comparison to healthy donors. PMF and immunoblotting of a single spot that was expressed in eosinophils from healthy individuals but not in AD patients identified the protein as phosphorylated growth receptor binding 7 (Grb7) adaptor protein. Increased phosphorylation of Grb7 and its upstream signaling protein, focal adhesion kinase (FAK), was detected in low viability eosinophils such as those from healthy donors or in cultured eosinophils (AML14.3D10 cells) treated with dexamethasone. These results suggest that phosphorylation of Grb7 and the expressions of cyclinA2, voltage-dependent anion channel protein 2, and 38 kDa FK506 binding protein 8 may be related with the anti-apoptosis mechanism of eosinophilia.
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PMID:Comparative proteomic analysis of peripheral blood eosinophils from healthy donors and atopic dermatitis patients with eosinophilia. 1583 65

We report on a patient fulfilling the diagnostic criteria of unclassifiable myelodysplastic/myeloproliferative diseases with prominent erythropoietic hyperplasia/dysplasia (erythroid preleukemia) and the unique translocation (8;9)(p23;p24). The patient presented with B-symptoms, erythroblastemia, thrombopenia, marked eosinophilia, presence of myeloid precursors in the peripheral blood, and decreased erythropoietin level. Nodular peritrabecular polymorphous blasts, dysplastic megakaryocytes, and a diffuse argyrophilic fibrosis were detected in the trephine bone marrow biopsy. Immunohistochemically, the blasts stained positively for glycophorin C and hemoglobin A; the proliferation fraction was nearly 90% in the Ki-67 stain. Expression of the phosphorylated Janus kinase 2 was detected in almost all megakaryocytes and in isolated erythroblast islets, suggesting a probable activation of Janus kinase 2, the jak-2 gene being mapped on 9p24. Ten months after initial diagnosis, the disease progressed to frank acute erythroid leukemia. We report for the first time a myelodysplastic/myeloproliferative disease (erythroid preleukemia) accompanied by the specific chromosomal aberration t(8;9)(p23;p24), distinct histopathology, and clinical and laboratory symptoms, and progress to acute erythroid leukemia.
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PMID:Myelodysplastic/myeloproliferative disease with erythropoietic hyperplasia (erythroid preleukemia) and the unique translocation (8;9)(p23;p24): first description of a case. 1656 30

To evaluate the frequency of clonal abnormalities in patients with unexplained persisting eosinophilia we analyzed 40 patients (27 males, 13 females) using cytomorphology, cytogenetic analysis, interphase fluorescence in situ hybridization (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR). Cytogenetic analysis revealed clonal abnormalities in five patients (four of whom were males) including t(8;9)(p21;p24), ins(9;4)(q34;q12q31), del(6)(q24), and trisomy 8 (n=2). RT-PCR confirmed a PCM1-JAK2 fusion underlying the t(8;9). FISH analysis suggested a rearrangement involving PDGFRA in the ins(9;4). A FIP1L1-PDGFRA fusion gene was identified in four male patients by interphase FISH and RT-PCR. These methods in combination demonstrated clonality in 8/40 patients (20%) with a male predominance (6/8; 75%).
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PMID:A combination of cytomorphology, cytogenetic analysis, fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction for establishing clonality in cases of persisting hypereosinophilia. 1676 84

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.
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PMID:Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. 1696 Jan 51


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