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)

Donor leukocyte therapy has resulted in a remission rate in excess of 70% in patients with relapse of chronic myeloid leukaemia (CML) following allogeneic bone marrow transplantation (BMT). Induction of remission with donor leukocyte infusions has been primarily successful for CML patients who have cytogenetic relapse or those with chronic-phase haematological relapse. Response rates appear to be lower in patients who have advanced-phase CML. The majority of patients with CML who enter remission have no detectable minimal residual disease when analysed for BCR-ABL mRNA transcripts by reverse-transcription polymerase chain reaction. The efficacy of donor leukocyte infusions and the ease of therapy are balanced by the potential for significant toxicity. The reported treatment-related mortality rate is almost 20%. The major toxicities of this treatment are secondary to marrow aplasia and graft-versus-host disease (GVHD) which may occur in up to 50% and 90% of responders respectively. Donor leukocytes with a T-cell content of only 1 x 10(7)/kg, approximately a factor of 10 fewer T cells than used in most early studies, are capable of inducing remissions in some patients. The use of lower doses of T cells or CD8+ depleted T cells may be associated with less GVHD. The optimal treatment schedule using donor leukocytes has yet to be determined. Factors which might influence outcome include phase of disease, use of interferon alpha, use of unrelated donors and human leukocyte antigen disparity, T-cell dose, CD8+ depletion of leukocytes and time from BMT to leukocyte infusion.
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PMID:Donor leukocyte infusions. 937 69

Human natural killer (NK) cells specifically interact with major histocompatibility complex (MHC) class I molecules employing different receptor systems, shared with subsets of alphabeta and gammadelta T lymphocytes. Killer cell immunoglobulin-like receptors (KIRs) recognize groups of human leukocyte antigen (HLA) class Ia proteins displaying common structural features at the alpha-1 domain; among them, KIR2DL4 has been proposed to specifically interact with the class Ib molecule HLA-G1. Members of a related family of immunoglobulin (Ig)-like receptors (ILT2 or LIR-1 and ILT4 or LIR-2), expressed by other leukocyte lineages, interact with a broad spectrum of class Ia molecules and HLA-G1. On the other hand, CD94/NKG2-A(-C) and NKG2D lectin-like receptors, respectively, recognize the class Ib molecules HLA-E and MICA. A recurrent finding within the different receptor families is the existence of pairs of homologous molecules that often share the same ligands but display divergent functions. Inhibitory receptors tend to exhibit an affinity for HLA molecules higher than their activating counterparts. Recruitment of SH2 domain-bearing tyrosine phosphatases (SHP) by cytoplasmic phosphorylated immunoreceptor tyrosine-based inhibition motifs (ITIMs) is a crucial event for the inhibitory signalling pathway. By contrast, triggering receptors assemble with homodimers of immune tyrosine-based activation motif (ITAM)-bearing adaptor molecules (i.e., DAP12, CD3 xi) that engage tyrosine kinases (ZAP70 and syk).
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PMID:Paired inhibitory and triggering NK cell receptors for HLA class I molecules. 1065 73

Chronic myeloid leukemia (CML) is a clonal disease of hematopoietic stem cells caused by a reciprocal translocation of the long arms of chromosomes 9 and 22. In human leukocyte antigen A*0201(+) (HLA-A*0201(+)) individuals, response after interferon-alpha (IFN-alpha) was shown to be associated with the emergence of CML-specific cytotoxic T cells that recognize PR-1, a myeloblastin (MBN)-derived nonapeptide. In contrast, imatinib potently induces remissions from CML by specific inhibition of the ABL tyrosine kinase. Here, we explored molecular regulations associated with CML responses under different treatment forms using cDNA-array. Expression of MBN was found to be down-regulated in remission under imatinib therapy (0 of 7 MBN(+) patients). In contrast, MBN transcription was readily detectable in the peripheral blood in 8 of 8 tested IFN-alpha patients in complete remission (P =.0002). IFN-alpha-dependent MBN transcription was confirmed in vitro by stimulation of peripheral blood mononuclear cells (PBMCs) with IFN-alpha and by IFN-alpha-mediated activation of the MBN promoter in reporter gene assays. Finally, with the use of HLA-A*0201-restricted, MBN-specific tetrameric complexes, it was demonstrated that all of 4 IFN-alpha-treated patients (100%), but only 2 of 11 imatinib patients (19%), in complete hematological or cytogenetic remission developed MBN-specific cytotoxic T cells (P =.011). Together, the induction of MBN expression by IFN-alpha, but not imatinib, may contribute to the specific ability of IFN-alpha to induce an MBN-specific T-cell response in CML patients. This also implies that the character of remissions achieved with either drug may not be equivalent and therefore a therapy modality combining IFN-alpha and imatinib may be most effective.
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PMID:Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. 1239 22

Anti-human leukocyte antigen (HLA) antibodies (Ab) have long been implicated in the process of acute and chronic allograft rejection, yet their mechanism(s) of action is not well understood. The aim of this study was to determine whether ligation of HLA class I molecules by anti-HLA Ab on the surface of human endothelial cells (EC) activates the PI3 Kinase (PI3K)/Akt signaling pathway and downstream target proteins of the cell death apparatus. We report that Ab ligation of major histocompatibility complex (MHC) class I molecules on the surface of EC triggers phosphorylation of Akt, PI3K, and recruitment of PI3K and Akt into a signaling unit with focal adhesion kinase. Signaling through class I also stimulated phosphorylation of Bad and upregulated expression of Bcl-2 and Bcl-xL. Pretreatment of EC with the PI3K inhibitor wortmannin blocked class I-mediated expression of Bcl-2, but not Bcl-xL, suggesting a role for the PI3K/Akt signaling pathway in regulation of class I-induced Bcl-2 expression. The intracellular events initiated by class I ligation were influenced by the concentration of the anti-HLA Ab with the lowest tested concentrations of Ab stimulating the highest level of Akt phosphorylation, Bcl-xL and Bcl-2 expression. Consistent with the in vitro experiments, analysis of biopsy samples from heart transplant recipients with evidence of Ab-mediated rejection exhibited increased Bcl-2 expression on the vascular endothelium. These results suggest that exposure of the graft endothelium to low concentrations of anti-HLA Ab may promote cell survival by transducing signals resulting in upregulation of cell survival genes.
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PMID:Anti-HLA class I antibody-mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells. 1512 Jan 84

The prognosis for patients with chronic myeloid leukemia (CML) in blast crisis (BC) remains dismal even with the availability of the BCR-ABL tyrosine kinase inhibitor imatinib, since it only offers short-term benefit in most cases. Allogeneic hematopoietic stem cell transplantation (HSCT) seems to be a viable option for BC-CML patients who attained remission. We treated ten patients with ablative allogeneic HSCT, who achieved second chronic phase (CP) by the use of imatinib after onset of BC. Median patient age was 32 years (range 17-46). Among them, four patients received HSCT from human leukocyte antigen mismatched haplo-identical family donors. After a median follow-up of 24 months (range 8-42), six out of the ten patients were alive in durable complete cytogenetic remission, one patient died in relapse 4 months after transplantation, the others died of severe acute graft-versus-host disease and associated infections. No unusual organ toxicities and engraftment difficulties were observed. Extensive chronic GVHD developed in three of six patients who could be evaluated. Patients transplanted with haplo-identical donors had a high treatment-related modality. Allogeneic HSCT may represent a feasible treatment for patients with CML in second CP attained by imatinib after onset of BC especially when a suitable donor is available.
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PMID:Allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in second chronic phase attained by imatinib after onset of blast crisis. 1828 66

Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.
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PMID:Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. 1855 48

The use of highly active antiretroviral therapy in the treatment of HIV infection has resulted in significant reductions in mortality and morbidity worldwide. However, there is considerable interindividual variability in patient outcomes in terms of drug disposition, drug efficacy and adverse events. The basis of these differences is multifactorial, but host genetics are believed to play a significant part. To date, most attempts to explain this variability have focused on isolated single nucleotide polymorphisms. The most exciting development to date is the discovery of human leukocyte antigen subtype B*5701 (HLA B*5701) as a strong predictor of the abacavir hypersensitivity reaction. There is a gradual move away from single candidate gene analyses towards a high throughput whole genome approach. These studies must be performed on well characterized cohorts and reported associations must be validated in independent, ethnically diverse populations.
Int J STD AIDS 2009 Mar
PMID:The impact of pharmacogenetics on HIV therapy. 1925 58

The most serious adverse event caused by abacavir is the hypersensitivity reaction, which is usually associated with the presence of the human leukocyte antigen (HLA) subtype B*5701, as shown in recent studies. We describe the case of a 41-year-old Caucasian female patient, who tested HLA-B*5701 negative and developed fever and severe skin rash 10 weeks after the start of abacavir therapy. Similar reports suggest that not all severe abacavir-induced adverse events occur as a result of classic hypersensitivity reactions, and can present also in HLA-B*5701-negative patients.
Int J STD AIDS 2009 Apr
PMID:Abacavir-induced reaction with fever and severe skin rash in a patient tested human leukocyte antigen-B*5701 negative. 1930 78

Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.
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PMID:Recent insights into the genetic basis of systemic lupus erythematosus. 1944 Jan 99

Chronic rejection manifests as transplant vasculopathy, which is characterized by intimal thickening of the vessels of the allograft. Intimal thickening is thought to result from the migration and proliferation of vascular smooth muscle cells (SMC) in the vessel media, followed by deposition of extracellular matrix proteins. The development of post-transplantation anti-human leukocyte antigen (HLA) antibodies (Ab) is strongly correlated with the development of transplant vasculopathy and graft loss. Here we demonstrate that cross-linking of HLA class I molecules on the surface of human SMC with anti-HLA class I Ab induced cell proliferation and migration. Class I ligation also increased phosphorylation of focal adhesion kinase (FAK), Akt, and ERK1/2 in SMC. Knockdown of FAK by siRNA attenuated class I-induced phosphorylation of Akt and ERK1/2, as well as cell proliferation and migration. These results indicate that ligation of HLA class I molecules induces SMC migration and proliferation in a FAK-dependent manner, which may be important in promoting transplant vasculopathy.
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PMID:Antibody ligation of human leukocyte antigen class I molecules stimulates migration and proliferation of smooth muscle cells in a focal adhesion kinase-dependent manner. 2200 Oct 78


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