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)

Chronic myeloid leukemia (CML) relapse after allogeneic stem cell transplantation (SCT) is a relatively frequent situation, which is correlated to disease status, time from diagnosis to transplant and T-cell depletion. We evaluated the potential for early minimal residual disease (MRD) BCR-ABL quantification to predict relapse of CML patients receiving allogeneic SCT. Minimal residual disease was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) at day 100 (d100) in 38 patients with >1 year follow-up after conventional non-T-cell-depleted SCT. Normal ABL control values from 1724 follow-up blood samples were used to define an RQ-PCR amplifiability index and the limits of reliable use of BCR-ABL ratios. We then compared the 14 patients with a high-level d100 BCR-ABL/ABL ratio (> or = 10(-4)) to that of the 24 patients with a negative/low-level ratio (<10(-4)). Despite being comparable for all classical parameters, the incidence of relapse was significantly higher in the high MRD group (11/14 (79%)) compared to that of the low/negative MRD group (7/24 (29%)) (P = 0.009), with d100 MRD values representing an independent risk factor of relapse and disease-free survival, but not of overall survival, in multivariate analysis. These data should facilitate risk-adapted post-transplant immunosuppression and/or tyrosine kinase inhibitor therapy based on an early evaluation of MRD.
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PMID:Prediction of relapse by day 100 BCR-ABL quantification after allogeneic stem cell transplantation for chronic myeloid leukemia. 1654 Nov 40

Molecular monitoring of the BCR-ABL transcript in chronic myelogenous leukemia (CML) using quantitative RT-PCR provides clinicians with important diagnostic and prognostic information. To determine whether molecular detection and monitoring of CML is comparable using peripheral blood (PB) and bone marrow (BM) aspirate samples, we performed a prospective study using quantitative real-time RT-PCR (QRT-PCR) of paired PB and BM samples from 41 patients with CML entered onto a single Cancer and Leukemia Group B (CALGB) treatment study. QRT-PCR analysis of PB and BM samples was performed prior to initiation of, and during, treatment with homoharringtonine and cytarabine on a CALGB study for previously untreated CML. Statistical analyses demonstrated good agreement of PB and BM pre-treatment samples. However, using the Bland-Altman statistical method that measures true agreement between PB and BM values, we found that there was only modest agreement of BCR-ABL measurements in PB and BM for samples obtained during treatment. PB values obtained during treatment tended to be lower than the corresponding BM values [average difference = -0.37 (p<0.001) in 36 paired samples] and the 95% limits of agreement ranged from -1.23 to 0.48. Nevertheless, our study demonstrates that BM and PB QRT-PCR values followed a similar trend during treatment (Spearman correlation coefficient, 0.83; 95% CI, 0.70, 0.96). Our data suggest that, quantitatively, PB and BM measurements of BCR-ABL are frequently disparate. Since BM values tended to be higher than PB values, BM sampling provides the most accurate assessment of minimal residual disease (MRD). Based on these results, we caution against interchanging BM with PB sampling for MRD monitoring during treatment of CML since this may lead to misinterpretation of treatment results.
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PMID:Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples. 1659 25

Universal Russian reagents for real time PCR were tested and compared with reference reagents provided by foreign companies. Testing was carried out on plasmids with cloning fragments (DNA-standards) of cDNA with chimeric (fusion) gene PML-RARalpha. Values of amplification efficiency of Russian and foreign reagents were measured on samples with serial dilutions (30-300000 copies) of cloned cDNA fragments of PML-RARalpha and internal control gene ABL. Amplification efficiencies of Russian and foreign reagents were found to be close one to another. Russian universal reagent kit RealityTM and ABI TaqMan Core Reagent Kit have amplification efficiencies 1.919 and 1.929, and correlation coefficients of copy numbers PML-RARalpha0.999 and 0.996, respectively. These values were determined by construction of a standard curve. To verify these results we studied also the samples of cDNA from blood and bone marrow of patients with acute promyelocytic leukemia. All samples posses translocation t(15;17), and appropriate chimeric gene PML-RARalpha. copy number in 1 microg of total RNA was in range 5.86 x 10(4)-8.315 x 10(5) before chemotherapy. No symptoms of minimal residual disease were found after 3.5 months since chemotherapy - fusion gene PML-RARalpha was not detected by real time PCR method. These results are in agreement with clinical data. Our investigations tend to show that application of RealityTM reagent set in real timePCR experiments gives correct results and may be used in molecular oncodiagnostics.
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PMID:[Characterization of the universal Russian reagent sets for real-time PCR and its application for molecular oncodiagnostic]. 1663 76

V617F JAK2 mutation is a reliable molecular marker of polycythemia vera (PV), potentially useful to monitor the effect of treatments in this disease. In a phase 2 study of pegylated (peg) IFN-alpha-2a in PV, we performed prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%V617F) by real-time polymerase chain reaction (PCR). The %V617F decreased in 24 (89%) of 27 treated patients, from a mean of 49% to a mean of 27% (mean decrease of 44%; P < .001), and no evidence for a plateau was observed. In one patient, mutant JAK2 was no longer detectable after 12 months. In 3 patients homozygous for the mutation, reappearance of 50% of wild-type allele was observed during treatment. The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV. This trial was registered at www.clinicaltrials.gov as #NCT00241241.
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PMID:High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. 1670 29

Despite of postoperative radiotherapy plus temozolomide for newly diagnosed glioblastoma multiforme (GBM) and improvements in the molecular characterization of high-grade glioma, these tumors continue to relapse. We reviewed all clinical studies of re-treatment published between May 2000 and September 2005. In groups of highly selected patients with re-treatment for GBM, median survival reaches 26-27 months. Re-treatment was stereotactic radiotherapy (mostly with additional chemotherapy) or re-resection plus either photodynamic treatment, radioimmunotherapy and temozolomide, or systemic and local chemotherapy. Thus, intense local treatment was always a component of more successful strategies. Additional data suggest that chemotherapy is more efficacious when minimal residual disease is present, although the recent trials have not uncovered a clear regimen of choice. Early trials of immunotherapy and toxin-delivery demonstrate the feasibility of these approaches and encouraging median survival times. Response to erlotinib was more common if tumors had epidermal growth factor receptor gene amplification, protein overexpression and low levels of phosphorylated PKB/Akt. Individual tailoring of such strategies based on molecular profiling is hoped to improve the outcome.
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PMID:Therapeutic options for recurrent high-grade glioma in adult patients: recent advances. 1687 33

The PAXgene RNA blood collection tube is used for RNA of peripheral blood (PB) and the stability of PB RNA in this tube has already been reported. However, the stability of bone marrow blood (BM) RNA in the PAXgene tube is unknown. Thus, we examined the stability of BM RNA in the PAXgene tubes. BM from leukemia patients was collected into PAXgene and EDTA tubes and stored at 4 degrees C for 5 days. RNA isolated from both tubes was analyzed by a quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. Porphobilinogen deaminase (PBGD) mRNA of BM (as high-expression mRNA) and Wilms tumor suppressor (WT1) mRNA of BM (as low-expression mRNA) and very low copies of major BCR-ABL mRNA (as minimal residual disease of leukemia) of leukemia of BM were quantified by a LightCycler system. RNA yield from the PAXgene tubes and the intensity of 28S rRNA bands on RNA electrophoresis showed a degradation trend. However, the intensity of 18S rRNA bands from the PAXgene tubes remained. The expression of PBGD and WT1 of BM in the PAXgene tubes did not decrease for 5 days. The very low copies of major BCR-ABL mRNA in the PAXgene tubes were detectable on day 5 but those in the EDTA tubes were not detectable. Therefore, the PAXgene tube can be used for BM samples in a quantitative RT-PCR of the fusion gene transcripts of leukemia.
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PMID:Examination of stability of bone marrow blood RNA in the PAXgene tube. 1695 Jun 75

Imatinib mesylate, binding to the inactive conformation of Bcr-Abl tyrosine kinase and suppressing the Ph chromosome positive clone, has revolutionized the treatment of chronic myeloid leukaemia (CML) patients. Given the high rates of clinical and cytogenetic remission achieved, the molecular monitoring of BCR-ABL transcript levels by RT-qPCR has become always more important to assess minimal residual disease. Recently, recommendations for harmonizing current methodologies for detecting and measuring BCR-ABL transcripts in CML patients have been suggested. Studies of imatinib-treated patients have determined that the BCR-ABL levels measured early in therapy may predict durable cytogenetic remission and in turn prolonged progression free-survival or acquisition of resistance. The major mechanism of imatinib resistance is clonal expansion of leukaemia cells with mutations in the Bcr-Abl fusion tyrosine kinase. The early reduction of such mutations may allow timely treatment intervention to prevent or overcome resistance. We review current trends in the management of chronic myeloid leukaemia patients undergoing treatment with tyrosine kinase inhibitors.
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PMID:Monitoring minimal residual disease and controlling drug resistance in chronic myeloid leukaemia patients in treatment with imatinib as a guide to clinical management. 1698 30

The JAK2-V617F mutation occurs in about 50% of patients with myelofibrosis and might be a reliable marker to monitor residual disease after allogeneic stem cell transplantation. We describe a new, highly sensitive (>or= 0.01%) real-time polymerase chain reaction (PCR) to monitor and quantify V617F-JAK2-positive cells after dose-reduced allogeneic stem cell transplantation. After 22 allogeneic stem cell transplantation procedures in 21 JAK2-positive patients with myelofibrosis, 78% became PCR negative. In 15 of 17 patients (88%), JAK2 remained negative after a median follow-up of 20 months. JAK2 negativity was achieved after a median of 89 days after allograft (range, 19-750 days). A significant inverse correlation was seen for JAK2 positivity and donor-cell chimerism (r:-0.91, P<.001). Four of 5 patients who never achieved JAK2 negativity fulfilled during the entire follow-up all criteria for complete remission recently proposed by the International Working Group, suggesting a major role for JAK2 measurement to determine depths of remission. In one case, residual JAK2-positive cells were successfully eliminated by donor lymphocyte infusion. In conclusion, allogeneic stem cell transplantation after dose-reduced conditioning induces high rates of molecular remission in JAK2-positive patients with myelofibrosis, and quantification of V617F-JAK2 mutation by real-time PCR allows the detection of minimal residual disease to guide adoptive immunotherapy.
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PMID:Monitoring of the JAK2-V617F mutation by highly sensitive quantitative real-time PCR after allogeneic stem cell transplantation in patients with myelofibrosis. 1701 57

While imatinib is highly effective therapy, with improving prospects over time for sustained remission and potential to severely limit or eliminate disease progression and transformation, a minority of patients either fail or respond suboptimally to imatinib; as well, disease eradication may not be possible with imatinib. Distinct patterns of resistance have evolved with the use of imatinib, and Abl kinase mutations, which alter imatinib binding or favor kinase conformations inaccessible to imatinib, are a common finding associated with clinical resistance. Dasatinib and nilotinib, alternate Abl kinase inhibitors, restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase disease; in advanced disease and Philadelphia chromosome (Ph)(+) ALL, responses are more limited and relapse is common. Future studies with these agents will focus on further optimizing imatinib response, reduction of minimal residual disease, and prevention of resistance. Still newer inhibitors active against T315I mutant BCR-ABL may overcome primary and secondary resistance to dasatinib and nilotinib.
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PMID:Defining and managing imatinib resistance. 1712 64

We carried out sequential molecular monitoring of different markers on two BCR-ABL positive ALL patients receiving a standard dose induction regimen, which was followed by a maintenance therapy that alternated imatinib and chemotherapy administration. Molecular study was performed at diagnosis, at the end of the induction phase, and then every three months during maintenance therapy. Each marrow sample underwent BCR-ABL analysis (p210 and p190 expression by RT-PCR and Real-time PCR) and monoclonal JH rearrangement analysis, while WT1 gene expression was detected by Real-time PCR. At diagnosis we detected high WT1 expression associated with the presence of both BCR-ABL transcripts and monoclonal JH rearrangement in both patients. Hematological remission, as well as a molecular status characterized by undetectable BCR-ABL expression, normal levels of WT1 expression, and persistence of monoclonal JH rearrangement, were achieved by both patients post-therapy. Follow up of patient 1 showed a progressive increase in WT-1 and in p-190 transcript, which was followed by cytogenetic and hematological relapse. We observed a progressive increase in the p210 transcript without a concomitant increase in WT-1 levels in patient 2. JH rearrangement was detected in all the samples analyzed. The molecular results may indicate the persistence of JH rearranged clonal cells with undetectable BCR-ABL. From a clinical point of view, our preliminary experience suggests that simultaneous analysis of BCR-ABL, JH and WT-1 expression may improve the study of MRD in Ph+ ALL.
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PMID:Monitoring molecular response by BCR-ABL, JH and WT-1 in Ph+ all treated with imatinib containing regimen: preliminary report of two cases. 1716 71


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