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)

The molecular mechanism of anemia that is hyporesponsive to recombinant human erythropoietin (rHuEPO) in hemodialysis patients without underlying causative factors has not been investigated fully in hematopoietic stem cell system. Circulating CD34+ cells (1 x 10(4)) were isolated from rHuEPO hyporesponsive hemodialysis patients (EPO-H; n = 9), patients who were responsive to rHuEPO (EPO-R; n = 9), and healthy control subjects (n = 9). The patients with known causes of EPO hyporesponsiveness were eliminated from the current study. The cells were cultured in STEM PRO 34 liquid medium, supplemented with rHuEPO, IL-3, stem cell factor, and granulocyte-macrophage colony stimulating factor for 7 d and then transferred to a semisolid methylcellulose culture medium for performing burst forming unit-erythroid (BFU-E) colony assay. Expression of src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), phosphorylated Janus kinase 2 (p-JAK2), and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) was assessed with Western blot analysis. In EPO-H patients, SHP-1 antisense or scrambled S-oligos were included in the culture medium, and its effects were evaluated. The number of circulating CD34+ cells was not statistically different among the three groups, and their proliferation rates were similar for 7 d in culture. However, BFU-E colonies were significantly decreased in EPO-H patients compared with EPO-R and control groups. The mRNA and protein expression of SHP-1 and p-SHP-1 was significantly increased, whereas that of p-STAT5 was reduced in EPO-H patients. The inclusion of SHP-1 antisense S-oligo in culture suppressed SHP-1 protein expression associated with p-STAT5 upregulation, increase in p-STAT5-regulated genes, and partial recovery of BFU-E colonies. In EPO-H hemodialysis patients, the EPO signaling pathway is attenuated as a result of dephosphorylation of STAT5 via upregulation of SHP-1 phosphatase activity, and SHP-1 may be a novel target molecule to sensitize EPO action in these patients.
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PMID:The critical role of SRC homology domain 2-containing tyrosine phosphatase-1 in recombinant human erythropoietin hyporesponsive anemia in chronic hemodialysis patients. 1557 25

The immediate protective effect of erythropoietin (EPO) against ischemia in heart suggests a role beyond hematopoiesis and the treatment of anemia. We determined the role of JAK/STAT and Ras/Rac/MAPK in the protective effect of EPO against ischemia-reperfusion injury in infant rabbit heart. EPO (1.0 U/ml) administered 15 minutes prior to 30-minutes global ischemia and 35 minutes reperfusion resulted in increased recovery of postischemic ventricular developed pressure in rabbit hearts. EPO exerted its immediate cardioprotective effect via activation of multiple signaling pathways by: 1) phosphorylation and activation of JAK1/2, STAT3 and STAT5A but not of STAT1alpha and STAT5B, 2) phosphorylation and activation of PI(3) kinase and its downstream kinases Akt and Rac, 3) activation of PKCepsilon, Raf, MEK1/2, p42/44 MAPK and p38 MAPK. Pretreatment with Wortmannin abolished EPO-induced Akt activation and phosphorylation. Pretreatment with Chelerythrine followed by EPO treatment resulted in partial inhibition of Raf activation, and abolished PKCepsilon and p38 MAPK activation without any effect on Akt, MEK1/2 and p42/44 MAPK. PD98059 abolished MEK1/2 and p42/44 MAPK activation with no effect on Akt, Raf and p38 MAPK activation. SB203580 inhibited only p38 MAPK activation by EPO. We can conclude EPO increases immediate cardioprotection through the activation of multiple signal transduction pathways.
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PMID:Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. 1561 43

Clinical research evidence on outcomes of using epoetin (EPO) to treat or prevent anemia in oncology has recently been systematically synthesized to provide a scientific foundation for developing and implementing clinical practice guidelines. Two groups have distinguished themselves by their meticulous research methods, the Blue Cross and Blue Shield Association Technology Evaluation Center (BCBSA TEC) and the Cochrane Review Group (CRG), and have summarized existing research evidence on the role of EPO in anemia associated with cancer treatment. An ASH/ASCO (American Society of Hematology/American Society of Clinical Oncology) panel has used the BCBSA TEC review to develop practice guidelines on the use of EPO in patients with cancer. The ASH/ASCO guideline panel identified eight important clinical circumstances for which use of EPO in oncology might be considered and used the BCBSA TEC evidence review to formulate evidence-based guidelines that support use of EPO. Both BCBSA TEC and CRG found solid evidence exists to show that EPO improves hemoglobin levels and reduce the risk for transfusion. The ASH/ASCO panel concluded that best empirical evidence exists to support the use of EPO to correct anemia due to chemotherapy if Hgb</=10g/dl. In other clinical circumstances the ASH/ASCO panel made recommendations either by extrapolating evidence from similar settings or relied on expert opinion since sufficient evidence was lacking. Both BCBSA TEC and CRG also concluded that limited evidence exists that EPO improves symptoms, fatigue, or quality of life, particularly when anemia is less severe. The finding from these systematic reviews are also reflected in the opinion of the ASH/ASCO guidelines panel, which also concluded that better evidence is needed to support use of EPO in oncology under these circumstances. In this paper, the findings from the guidelines set by ASH/ASCO that were culled from systematic reviews by BCBSA TEC and the Cochrane Review are compared and contrasted.
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PMID:Erythropoietin use in oncology: a summary of the evidence and practice guidelines comparing efforts of the Cochrane Review group and Blue Cross/Blue Shield to set up the ASCO/ASH guidelines. 1579 20

Chronic lymphocytic leukemia follows an extremely variable clinical course with survival range from months to decades. Some patients present minimal symptoms and others organomegaly requiring rapidly therapy. Therapeutic options take into account efficacy, toxicity and prognostic factors. One of the well known prognosis factor is the clinical staging developed either by Rai et al. or by Binet et al. However, there is an important heterogeneity concerning the course of the disease among patients within a single stage group. Recently, several important observations related to the biologic significance of VH gene mutational status, expression of CD38, over-expression of ZAP-70 and chromosomal aberrations have led to the ability to identify high risk patients with rapid disease progression and lower survival. It has been demonstrated that the VH mutation status is clinically highly relevant. CLL patients with unmutated VH gene show an unfavourable course with a very rapid progression. Specific genomic aberrations have been associated with disease characteristics such as lymphadenopathy related to 11q deletion and resistance to treatment related to 17p deletion. VH gene mutation status and genomic aberrations appear separate parameters when considering their prognostic relevance but nevertheless they are correlated: unfavourable aberrations (11q- and 17p-) occur more frequently in VH unmutated CLL patients. According to these prognostic factors, several treatments including purine analogues and/or monoclonal antibodies have been tested with different schedules and doses of monoclonal antibodies (rituximab and alemtuzumab) considering safety to determine the better efficacy. Infections and haemolytic anemia remain the most frequent complications during conventional chemotherapy. In autologous transplant setting, the transplant related mortality is less than 10%, but survival curve do not show a plateau with about 50% of patients relapsing at 4 years. Conventional allogeneic transplantation could achieve durable remission and probably cure the disease but at the price of a too high transplant related mortality related to depressive immune status and old age of CLL population. In order to minimize the toxicity and to improve graft-versus-leukemia effect, development of reduced intensity conditioning (RIC) regimens appear particularly important for CLL patients. Recent studies, although a still short follow-up show very promising results and use of monoclonal antibodies in the conditioning or just after transplant could improve the results of allogeneic stem cell transplantation and cure a larger number of CLL patients. Recent advances to categorize CLL patients according to risk stratification regarding new prognostic factors (FISH, CD38, ZAP70, Ig mutational status) should allow to define better the best therapeutic strategy. In parallel, age, co morbidities and the notion of the risk-adapted strategy have also an important impact adding.
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PMID:[News in therapeutic management of chronic lymphoid leukemia]. 1582 Sep 19

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.
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PMID:Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines. 1587 Jul 11

Erythropoietin (Epo) is used for managing anemia in cancer patients. However, recent studies have raised concerns for this practice. We investigated the expression and function of Epo and the erythropoietin receptor (EpoR) in tumor biopsies and cell lines from human head and neck cancer. Epo responsiveness of the cell lines was assessed by Epoetin-alpha-induced tyrosine phosphorylation of the Janus kinase 2 (JAK2) protein kinase. Transmigration assays across Matrigel-coated filters were used to examine the effects of Epoetin-alpha on cell invasiveness. In 32 biopsies, we observed a significant association between disease progression and expression of Epo and its receptor, EpoR. Expression was highest in malignant cells, particularly within hypoxic and infiltrating tumor regions. Although both Epo and EpoR were expressed in human head and neck carcinoma cell lines, only EpoR was upregulated by hypoxia. Epoetin-alpha treatment induced prominent JAK2 phosphorylation and enhanced cell invasion. Inhibition of JAK2 phosphorylation reduced both basal and Epo-induced invasiveness. Our findings support a role for autocrine or paracrine Epo signaling in the malignant progression and local invasiveness of head and neck cancer. This mechanism may also be activated by recombinant Epo therapy and could potentially produce detrimental effects in rhEpo-treated cancer patients.
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PMID:Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. 1596 6

The regeneration of circulating red blood cells in response to anaemia associated with blood loss or haemolysis involves an increased rate of erythropoiesis and expansion of proerythroblasts, the bone marrow precursor cells that terminally differentiate into mature erythrocytes. This study investigated the mechanisms by which erythropoietin (Epo) and stem cell factor (Scf) modulate the expansion of proerythroblasts. Homogenous populations of primary human proerythroblasts were generated in liquid cultures of CD34(+) cells. In serum-free cultures, proerythroblasts failed to survive in the presence of Epo or Scf alone, but exhibited synergistic proliferation in response to combined Epo and Scf treatment, exhibiting one-log expansion in 5 d. Intracellular signal transduction in response to Epo and Scf revealed that tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5, a downstream target for the non-receptor tyrosine kinase, Janus kinase 2 (Jak2), was mediated by Epo but not Scf. The mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) 1-2 were phosphorylated in response to either Epo or Scf. Phosphorylation of Akt, a signalling molecule downstream of phosphatidylinositol 3-kinase (PI3K), was observed following Scf but not Epo treatment. To determine the contribution of specific signalling pathways to synergistic expansion of proerythroblasts in response to co-operative effects of Epo and Scf, cells were treated with kinase inhibitors targeting Jak2, PI3K and MAPK kinase. There was a significant, dose-dependent inhibition of proerythroblast expansion in response to all three kinase inhibitors. In conclusion, Epo- and Scf-mediated co-operative, synergistic expansion of primary erythroid precursors requires selective activation of multiple signalling pathways, including the Jak-Stat, PI3K and MAPK pathways.
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PMID:Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor. 1598 54

The present phase II study aimed to define the application of a novel regimen incorporating methotrexate, paclitaxel, epirubicin, and carboplatin (M-TEC) in advanced bladder cancer, essentially as an M-VAC-like regimen, by substitution of cisplatin by carboplatin, doxorubicin by epirubicin and vinblastine by paclitaxel. Forty patients with advanced bladder cancer entered the study; 34 males/6 females, median age: 68 (range, 59-76), median PS (Karnovsky): 80, without receiving prior chemotherapy. Disease extention was as follows; 11/40 had local recurrence, 6/40 liver metastases, 14/40 lung metastases, bone and lymph node 8/40, bones-lymph node-lung metastases 4, lymph node and liver 4/40, lymph node-liver and lung metastases 2/40. Drug schedule and doses were as follows: paclitaxel 180 mg/m2, carboplatin AUC = 5 (according to creatinine clearance, based on Calvert's formula), and epirubicin 40 mg/m2 were administered during day 1, whereas methotrexate 30 mg/m2 and epirubicin 40 mg/m2 were administered on day 14. All patients were evaluable for response with 24/40 responding [response rate (RR) 60%]; 10/40 (25%) CR, 14/40 (35%) PR, 9/40 (22.5%) SD, and 7/40 (17.5%) PD. Symptomatic improvement was observed in 50% of patients. The median duration of response was 22 (14-32) weeks, median time-to-progression (TTP) 33 (12-44) weeks, and median survival was 56 (20-84) weeks. Toxicity was well accepted and was mainly neutropenia > grade 3: 17%, anemia >grade 3: 16%, thrombocytopenia > grade 2: 6%, nausea & vomiting mainly > grade 2: 31%, according to the administered chemotherapy cycles, whereas fatigue grade 2-3: 19%, neurotoxicity grade 1-2 13% of patients, and alopecia grade 2 was observed in all patients. The present pilot study indicates the feasibility of the M-TEC combination for bladder cancer with acceptable toxicity.
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PMID:Methotrexate-paclitaxel-epirubicin-carboplatin (M-TEC) combination chemotherapy in patients with advanced bladder cancer: an open label phase II study. 1616 25

We evaluated the analytical performance of a new, commercial, fully automated immunoturbidimetric assay for the determination of ferritin [FER-Latex(X2)CN SEIKEN, Denka Seiken, Japan] in serum on the Olympus AU2700 analyzer. The new assay is a latex-enhanced turbidimetric immunoassay with an analysis time of 10 min. The linearity of the assay was confirmed up to 2505 pmol/L (R2=0.999). The detection limit and the functional sensitivity were both 4.5 pmol/L. The intra- and inter-assay imprecision (CV) at 67, 506, 2186 pmol/L was < 1.8% and < 2.5%, respectively. Verification of the traceability to a WHO standard (80/578) showed a recovery of 102.6% (target value 449 pmol/L). No hook effect was observed in samples containing up to 33,705 pmol/L. The assay showed good correlation with the Beckman Immage nephelometric system (r=0.999). Hemoglobin (< or = 9.8 g/L), total bilirubin (< or = 113 micromol/L), conjugated bilirubin (< or = 109 micromol/L) and rheumatoid factor (< or = 5.2x10(5) IU/L) did not interfere with the assay. The reference interval (2.5-97.5 percentile) was 72-521 pmol/L for men and 27-267 pmol/L for women. The reference interval in patients with anemia, malignant tumors and hemochromatosis was 5.6-52, 130-2436 and 1465-2903 pmol/L, respectively. On the basis of the receiver operating characteristic curve, the 90% sensitivity cut-off value to distinguish between patients with and without iron deficiency was 40 pmol/L. The new latex turbidimetric procedure for ferritin assay is an attractive alternative that avoids the need for dedicated instrumentation.
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PMID:Preliminary evaluation of the performance of a new, highly sensitive commercial immunoassay for serum ferritin determination. 1620 2

Idiopathic myelofibrosis (IMF) is the least common of the chronic myeloproliferative disorders and carries the worst prognosis with a median survival of 4 years. It is a clonal haematopoietic stem-cell disorder and, although the pathogenesis remains unclear, approximately 50% of cases are known to possess an activating JAK2 V617F mutation. In contrast, the characteristic stromal proliferation is a reactive, or secondary, event that results from the aberrant release of a variety of growth factors from megakaryocytes and monocytes. Treatment for most cases is supportive, although androgens, recombinant erythropoietin, steroids and thalidomide are effective modalities for the amelioration of anaemia. Myelosuppression, splenectomy and irradiation are valuable therapeutic modalities for specific clinical situations. Prognostic scores are available to aid the identification of cases for whom bone marrow transplantation should be considered. Recently, the use of reduced intensity conditioning has resulted in prolonged survival and lower transplant-related mortality. This review summarises the recent advances in the disease's pathogenesis and discusses the role of the various therapeutic options.
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PMID:Idiopathic myelofibrosis: pathogenesis to treatment. 1647 81


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