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)

We studied 36 DNA samples of 18 patients affected with chronic myeloid leukemia (CML) for the presence of mutations in the first exon of the BCR gene was divided into four regions amplified by polymerase chain reaction (PCR). By single strand conformation polymorphism analysis (SSCP) and direct sequencing of amplified fragments, we found different banding profiles in 9 out of 18 patients in the PCR fragment spanning nucleotide 506-826. In one patient, sequence analysis revealed the presence of a point mutation at nucleotide 669 (A-T; Gln-Leu). No difference was found between DNA samples collected during the chronic phase and the blastic transformation. No different mobility shifts of single stranded PCR products were found in the other amplified fragments. The activation of BCR-ABL involves direct interaction between BCR first exon sequences and the tyrosine kinase regulatory domains of ABL. In the first BCR exon, and around the mutated sequences two SH-2-binding sites, are retained. These domains are essential for BCR-ABL-mediated transformation. Our results demonstrate the presence of point mutation in this regulatory region, which may suggest a role for the altered BCR sequence in activation of the BCR-ABL oncogene.
Leuk Lymphoma 1993
PMID:Structural organization of BCR-ABL gene in chronic phase and blast transformation in chronic myeloid leukemia patients. 825 17

The Philadelphia chromosome (t9;22)(q34;q11) is a characteristic abnormality in chronic myeloid leukemia. In greater than 95% of the cases, the breakpoint occurs with the M-bcr region of the BCR gene on chromosome 22. Several studies have attempted to correlate the location of the breakpoint within the M-bcr with a clinical parameter. The majority of studies have examined the relationship between the site of breakpoint and the median chronic phase duration (CPD). Some studies have reported a correlation, with 5' breakpoint patients who have a longer median CPD than patients with a 3' breakpoint. However, other groups have reported that no correlation exists. Furthermore, data from some of the latter groups have suggested that a correlation may exist with the lineage of blast crisis which developed and 3' breakpoint patients had a higher than expected number of lymphoid blast crisis. A correlation between high platelet counts at diagnosis and patients with a 3' breakpoint or those who expressed a b3-a2 BCR-ABL mRNA has also been described. No consistent conclusion from any of these studies can be drawn. This may due, in part, to some degree of patient and sample selection, although environmental, genetic or life-style factors may also contribute.
Leuk Lymphoma 1993
PMID:The relationship between the location of the breakpoint within the M-bcr and clinical parameters. 825 22

Human T cell lymphotropic virus type I (HTLV-I) infection in India has been found to be associated with adult T cell leukaemia/lymphoma (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) among life-long residents of southern India. To examine the heterogeneity of HTLV-I strains from southern India and to determine their relationship with the sequence variants of HTLV-I from Melanesia, 1149 nucleotides spanning selected regions of the HTLV-I gag, pol, env and pX genes were amplified and directly sequenced from DNA extracted from whole blood blotted onto filter paper and from peripheral blood mononuclear cells, obtained from one patient with HAM/TSP, two with ATLL and eight asymptomatic carriers from Andhra Pradesh, Kerala and Tamil Nadu. Sequence alignments and comparisons indicated that the 11 HTLV-I strains from southern India were 99.2% to 100% identical among themselves and 98.7% to 100% identical to the Japanese prototype HTLV-I ATK. The majority of base substitutions were transitions and silent. No frameshifts, insertions, deletions or possibly disease-specific base changes were found in the regions sequenced. The observed clustering of the Indian HTLV-I strains with those from Japan, as determined by the maximum parsimony method, suggested a common source of HTLV-I infection with subsequent parallel evolution. Amplification of DNA from blood specimens collected on filter paper may be useful for the study of other blood-borne pathogens.
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PMID:Sequence analysis of human T cell lymphotropic virus type I strains from southern India: gene amplification and direct sequencing from whole blood blotted onto filter paper. 827 90

Antisense oligonucleotides were used to determine the role of the BCR-ABL gene in the proliferation of chronic myeloid leukaemia (CML) clonogenic cells. Peripheral blood Philadelphia chromosome positive cells were obtained from eight CML patients at diagnosis (chronic phase = 7; accelerated phase = 1). Mononuclear cells were incubated with synthetic antisense 18-mer oligonucleotides complementary to the two different junctions b2a2 or b3a2. The type of junction (b2a2 or b3a2) was previously determined by RT-PCR techniques. Cells incubated for 12 to 14 hours with or without sense oligonucleotides served as controls. After incubation with oligonucleotides, the cell DNA synthesis was analysed by flow cytometry using the BrdUrd/DNA method and the cell plating efficiency in methylcellulose was determined. In six of the seven patients in chronic phase, there was a significant inhibition of CFU-GM production which was only 68.4 +/- 19%; (p < .01) of that found in controls. The S phase index, which depends upon the percentage of S phase cells as well as the fluorescence intensity, was 48 +/- 29% (p < .01) of the control values for the seven patients in chronic phase. Interestingly, for the only CML patient in accelerated phase, antisense oligomers had no inhibitory effect on either the production of CFU-GM or the number of S phase cells. In improving the specificity of oligomers, it might be useful for gene-targeted anti-leukemic therapy and/or bone marrow purging.
Leuk Lymphoma 1995 Nov
PMID:Specific antisense oligomer anti Bcr-abl junctions in chronic myeloid leukemia: a cell cycle analysis and CFU-GM study. 859 Aug 42

At present, allogeneic bone marrow transplantation (BMT) seems to be the only curative treatment for patients with chronic myeloid leukemia (CML). The mechanisms of this therapeutic approach probably include anti-leukemic immune response or "graft-versus-leukemia" (GVL) reaction against leukemic cell clones, since even aggressive chemotherapy is not sufficient per se to cure this type of disease. In many patients, allogeneic BMT results in the disappearance of the Ph chromosome; this negativity does not exclude the presence of residual leukemic cells since sensitivity of cytogenetic analysis is low. The chimeric BCR-ABL gene in CML is a tumor-specific marker that is well suited to allowing detection of low numbers of residual leukemic cells through the extremely sensitive detection method of polymerase chain reaction (PCR). Using this method, 1 leukemic cell in 10(5) or 10(6) normal cells can be detected. Many studies have evaluated the clinical significance and predictive value of BCR-ABL gene rearrangement detected by PCR assay after BMT, most often on heterogeneous populations. Results from such studies have been conflicting. We have conducted a review of the literature, focussing on long-term survivors (> 3 years from BMT) of CML to determine the value of PCR in such patients (n = 183). With the consideration that such a population is obviously heterogenous, long-term PCR negativity strongly correlated with achieving a cure since no patient relapsed in this population (n = 117). Among the PCR positive patients (n = 66), only 5 (8%) relapsed, suggesting a poor prognostic value for a PCR+ test > 36 months post-transplant. Besides the potential clinical value of these data, they contribute to the understanding of the biology of the disease and may suggest a crucial role for the long term GVL effect of marrow transplantation.
Leuk Lymphoma 1996 Jan
PMID:Value of PCR analysis for long term survivors after allogeneic bone marrow transplant for chronic myelogenous leukemia: a comparative study. 862 62

Bruton's tyrosine kinase (BTK) is a member of the SRC-related TEC family of protein tyrosine kinases (PTKs). DT-40 lymphoma B cells, rendered BTK-deficient through targeted disruption of the btk gene by homologous recombination knockout, did not undergo radiation-induced apoptosis, but cells with disrupted lyn or syk genes did. Introduction of the wild-type, or a SRC homology 2 domain or a plecstrin homology domain mutant (but not a kinase domain mutant), human btk gene into BTK-deficient cells restored the apoptotic response to radiation. Thus, BTK is the PTK responsible for triggering radiation-induced apoptosis of lymphoma B cells, and its kinase domain is indispensable for the apoptotic response.
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PMID:BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells. 868 94

Interleukin-9 (IL-9), a T-cell-derived cytokine, interacts with a specific receptor associated with the IL-2 receptor gamma chain. In this report, we analyze the functional domains of the human IL-9 receptor transfected into mouse lymphoid cell lines. Three different functions were examined: growth stimulation in factor-dependent pro-B Ba/F3 cells, protection against dexamethasone-induced apoptosis, and Ly-6A2 induction in BW5147 lymphoma cells. The results indicated that a single tyrosine, at position 116 in the cytoplasmic domain, was required for all three activities. In addition, we observed that human IL-9 reduced the proliferation rate of transfected BW5147 cells, an effect also dependent on the same tyrosine. This amino acid was necessary for IL-9-mediated tyrosine phosphorylation of the receptor and for STAT activation but not for IRS-2/4PS activation or for JAK1 phosphorylation, which depended on a domain closer to the plasma membrane. We also showed that JAK1 was constitutively associated with the IL-9 receptor. Activated STAT complexes induced by IL-9 were found to contain STAT1, STAT3, and STAT5 transcription factors. Moreover, sequence homologies between human IL-9 receptor tyrosine 116 and tyrosines (of other receptors activating STAT3 and STAT5 were observed. Taken together, these data indicate that a single tyrosine of the IL-9 receptor, required for activation of three different STAT proteins, is necessary for distinct activities of this cytokine, including proliferative responses.
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PMID:A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. 875 28

The case records of consecutive patients admitted to a specialist HIV/AIDS inpatient unit between 1989 and 1993 with pyrexia of undetermined origin (PUO) were reviewed in order to determine the eventual diagnosis. Seventy-nine episodes occurred in 75 patients; 52 patients had a prior AIDS defining diagnosis. CD4+ lymphocyte counts ranged widely, 0-0.79 (median = 0.04) x 10(9)/l. Infections were found in 63 episodes (79%), including mycobacterial infection in 41 episodes (53%) and bacterial infection in 12 episodes (15%). Tumours were found in 6 episodes (8%), 5 of these were lymphoma. Factitious fever accounted for 2 episodes (3%) and connective-tissue disease for 1 episode (1%); no definite diagnosis was reached in 7 episodes (9%). PUO in HIV positive patients is commonly due to infection or tumour. Unexplained fever in this patient group should not be ascribed to HIV infection itself and should be vigorously investigated to find a cause.
Int J STD AIDS
PMID:Pyrexia of undetermined origin in patients with human immunodeficiency virus infection and AIDS. 879 78

We report the results of a recent trial in elderly acute lymphoblastic leukemia (ALL) patients (> or = 60 years). Initial chemotherapy consisted of one 14-day course with single-dose idarubicin plus vincristine-prednisone-L-asparaginase. Idarubicin was preferred to other anthracyclines because of its shorter time to response. Sequential outpatient postremission therapy included single-dose idarubicin plus vincristine-cyclophosphamide-L-asparaginase pulses, cranial irradiation with intrathecal methotrexate-cytarabine, flexible weekly vincristine-cyclophosphamide alternating with cytarabine-teniposide, and two-year standard maintenance with mercaptopurine-methotrexate. Granulocyte colony-stimulating factor (G-CSF) was added to induction and early consolidation courses. Twenty-two patients mainly with high-risk features entered the study: median age was 64 years (60-73), 40% of cases were CD10- B-lineage and T-lineage ALL, 38% of CD10+ B-lineage ALL carried a BCR-ABL rearrangement, while 23% coexpressed myeloid antigen, 86% had L2 morphology, 50% had a blast count greater than 10 x 10(9)/1, 54% had hepato-splenomegaly and lymphadenopathy. The complete remission (CR) rate after induction therapy was 59%. A partial remission was obtained in two cases. There were four early deaths (18%) and three refractory ALL (14%). Median time to response was 21 days. With G-CSF, the median duration of absolute neutropenia was 10.5 days. Flexible postremission therapy was very well tolerated, causing no major toxicity. With a median follow-up of 2.6 years, 3 patients remain alive in first CR (23%), 2 of whom at 21.3 months and 39.6 months, respectively. Median survival of responders was 12 months compared to only 1.2 months for nonresponders (p < 0.001). This moderate-dose idarubicin-containing and G-CSF-supported regimen was associated with a high early remission rate in elderly ALL. Postremission therapy results were modest, though not appreciably different from the general experience in this patient population. Because further escalation of drug intensity appears unjustified, attempts to document and reverse drug resistance patterns and restore a dysregulated apoptosis must be considered.
Leuk Lymphoma 1996 Jul
PMID:Age-adapted moderate-dose induction and flexible outpatient postremission therapy for elderly patients with acute lymphoblastic leukemia. 881 79

Nineteen cases of cerebral toxoplasmosis (CTOX) are reported from a group of Edinburgh AIDS patients. All patients were severely immunodeficient at the time of presentation with CD4 count < 50 cells/mm3. Thirteen patients had suffered a previous AIDS-defining illness. In Edinburgh, CTOX has developed in 48% of patients who are seropositive for toxoplasma and have a CD4 count < 50 cells/mm3. It is estimated that at least half of the toxoplasma seropositive patients will develop CTOX if they survive for 21 months after reaching a time in their illness when the CD4 count = 50 cells/mm3. The incidence of CTOX in toxoplasma-seronegative patients with a CD4 count < 50 cells/mm3 is 1.3%. All patients showed improvement on treatment and there was no correlation between clinical or radiological features and patient survival. Those patients unable to tolerate first choice anti-toxoplasma therapy had a significantly shorter survival than the remainder but there was no single therapeutic regimen which conferred a survival advantage. Eighteen patients had died at the time of study and the median survival following diagnosis of cerebral toxoplasmosis was 10 months (range 3-38 months). Postmortem examination of the brain was available in 8, 4 of whom had concomitant cerebral lymphoma. The survival from AIDS or CD4 count = 50 cells/mm3 did not differ significantly between those with treated CTOX and a control group who had no toxoplasma infection, suggesting that treatment is reasonably effective. CTOX is a disease associated with severe HIV-related immunodeficiency and, in those with a CD4 count < 50 cells/mm3, occurs more than 35 times as frequently in toxoplasma-seropositive than toxoplasma-seronegative patients. Treatment is effective but the outcome of treated disease cannot be predicted from presenting clinical or radiological features. Concomitant space-occupying cerebral pathology is evident in 50% of post-mortem examinations.
Int J STD AIDS 1996 Jul
PMID:Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients. 887 56


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