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)

The molecular basis of polycythemia vera is discussed in the context of the JAK2 V617F mutation, in our view the most important advance in understanding the pathogenesis of polycythemia vera. This chapter discusses the nature of the JAK2 V617F mutation including the studies demonstrating its role in erythropoietin independence and hypersensitivity and endogenous erythroid colony formation. The evolving evidence that JAK2 V617F is not specific for polycythemia vera pathogenesis and the development of disease phenotype is presented as well as alternative candidates for pathogenic mutations such as the protein tyrosine phosphatases and SOCS-3. Finally, the clinical correlations and implications of the JAK2 V617F mutation are discussed.
Best Pract Res Clin Haematol 2006
PMID:Polycythemia vera and its molecular basis: an update. 1678 79

Essential thrombocythaemia is a myeloproliferative disorder that results from the transformation of a multipotent haematopoietic progenitor. Its diagnosis can be challenging and its optimal management has been controversial, largely because of a virtual absence of randomised trials. However, this situation will be dramatically altered by two recent developments. First, the Medical Research Council Primary Thrombocythaemia 1 (PT-1) trial-the largest and most comprehensive randomised study of any myeloproliferative disorder-provides clear guidance on the management of patients with high-risk essential thrombocythaemia. Second, identification of a unique JAK2 mutation in a substantial proportion of patients with essential thrombocythaemia (and also other myeloproliferative disorders) has resulted in a powerful diagnostic tool and is likely to alter approaches to both the classification and management of the myeloproliferative disorders.
Best Pract Res Clin Haematol 2006
PMID:Essential thrombocythaemia. 1678 82

Pathogenetically fundamental observations have identified polycythemia vera (PV) as a clonal stem cell disease with bone marrow histological and other biological features that distinctly differentiate it from other causes of 'increased' hematocrit. However, relatively little attention has been given to the effective utilization of pathology and laboratory markers of clonal myeloproliferation as diagnostic tools in PV. In contrast, the diagnostic use of red cell mass (RCM) measurement in PV stemmed from the accidental endorsement, as 'diagnostic criteria', of 'study eligibility criteria' that were formulated for clinical trials. It has since become evident that RCM measurement is a tedious procedure that is fraught with multiple-level imprecision, as well as suboptimal diagnostic accuracy. Therefore, it is reasonable to consider dispensing with RCM measurement as a diagnostic test for PV and instead utilize a diagnostic algorithm that combines clinical information with easily accessible laboratory data, including serum erythropoietin level and bone marrow histology. Recent discoveries of myeloproliferative-disease-specific molecular markers, including the JAK2 V617F tyrosine kinase mutation that is found in the majority of patients with PV, provide further support for such a measure.
Best Pract Res Clin Haematol 2006
PMID:The diagnosis of polycythemia vera: new tests and old dictums. 1678 83

The development of cancer vaccines directed against myeloid leukaemias has been a research area of intense interest in the past decade. Both human studies in vitro and mouse models in vivo have demonstrated that leukaemia-associated antigens (LAAs), such as the fusion protein BCR-ABL, Wilms' tumour protein and proteinase 3, may serve as effective targets for cellular immunotherapy. Peptide-based vaccines are able to induce cytotoxic T-lymphocyte responses that kill leukaemia cells. Based on these results, pilot clinical trials have been initiated in chronic and acute myeloid leukaemia and other haematological malignancies, which include vaccination of patients with synthetic peptides derived from these LAAs. Results from these trials show that peptide vaccines are able to induce immune responses that are sometimes associated with clinical benefit. These early clinical results are promising and provide valuable information for future improvement of the vaccines. This chapter will focus mainly on discussing the preclinical studies of peptide vaccines in human systems, the results from clinical trials and the future prospects for vaccine therapy for myeloid leukaemia.
Best Pract Res Clin Haematol 2008 Sep
PMID:Peptide vaccines for myeloid leukaemias. 1879 Apr 45

Allogeneic stem cell transplantation remains a curative treatment for haematological malignancies resistant to other treatment approaches through the unique graft-versus-leukaemia effect (GvL). However, the lack of specificity of this response results in the targeting of normal tissue, and the morbidity and mortality associated with graft-versus-host disease (GvHD). Further improvements in exploiting the GvL effect to prevent relapse in high-risk leukaemias while minimizing toxicity have focused on the use of targeted anti-leukaemic immunotherapy. These strategies include the use of vaccines against minor histocompatibility antigens (HA-1, HA-2 and H-Y) and leukaemia-specific antigens (proteinase 3, Wilms' tumour 1 and BCR-ABL), and the adoptive transfer of leukaemia-specific T cells. The unique post-transplant milieu, which is characterized by lymphopenia, regulatory T-cell depletion and the release of growth factors, offers the opportunity to promote the expansion of engrafted T cells and enhance the specific GvL response. Techniques to reduce regulatory T-cell control over T-cell responses to leukaemia antigens could further enhance GvL reactivity. Finally, these approaches to increase GvL effects would be facilitated by transplant approaches to deplete GvHD alloresponses selectively while preserving GvL reactivity.
Best Pract Res Clin Haematol 2008 Sep
PMID:Characterizing and optimizing immune responses to leukaemia antigens after allogeneic stem cell transplantation. 1879 Apr 48

Processed complementary foods (PCF) might mitigate several complementary feeding barriers in developing countries. Efficacy trials, however, have not shown substantial improvements in child growth, possibly due to inadequate formative research to assess acceptability and identify pitfalls. Milk powder might improve palatability of PCF but incurs a higher cost. We compared the acceptability of an instant soy-rice PCF without (SR) and with (SRM) milk powder. Best practices for formative evaluation of PCF are not established. We therefore compared findings from randomized trials of SR vs. SRM in 1-d sensory tests (n = 71 mother-infant dyads) vs. Trials of Improved Practices (TIPs), a 2-wk in-home mixed methods evaluation (n = 54 dyads). TIPs included interviews, disappearance rates, observations, and 24-h dietary recalls to assess acceptance, consumption of the 50 g/d ration, and impact on diet. Although mothers preferred SRM to SR in the sensory tests, children in the TIPs consumed >50 g/d of SR (87 +/- 9 g/d) and SRM (89 +/- 8 g/d) with no difference between the foods (P = 0.55). Despite some replacement of family food, energy (574 kJ/d; P < 0.001) and protein (19 g protein/d; P < 0.001) increased in both groups. Mothers' preferences for milk, more sugar in SR, and preparation with hot water were concerns raised in the sensory tests that proved insignificant in TIPs. However, TIPs uncovered new concerns of overconsumption and food safety. We found milk did not improve the acceptability of the soy-rice PCF and recommend TIPs as a useful tool for formative research of PCF interventions.
 ...
PMID:Soy- and rice-based processed complementary food increases nutrient intakes in infants and is equally acceptable with or without added milk powder. 1880 8

CARD9 is a caspase recruitment domain-containing signaling protein that is highly expressed in dendritic cells and in macrophages. Work over the last two years has identified CARD9 as a central regulator of innate immunity. Best characterized is CARD9's function downstream of ITAM-bearing or ITAM-coupled receptors in myeloid cells, including its essential role downstream of the antifungal pattern-recognition receptor Dectin-1. In the ITAM receptor pathway, CARD9 couples receptor proximal splenic tyrosine kinase SYK activation to the canonical NF-kappaB pathway. In addition, CARD9 is involved in the activation of p38 and JNK kinases and it can function downstream of cytosolic pattern-recognition receptors. CARD9 signaling mediates mammalian innate immune responses against selected fungi, bacteria, and viruses and can prime and shape adaptive immunity. This review will summarize current knowledge on CARD9 signaling and its function in the innate immune response.
 ...
PMID:CARD9 signaling in the innate immune response. 1907 43

The use of microarray technology in chronic myeloid leukaemia (CML) has increased our understanding of the biology of this disease. From early studies of gene expression profiling in BCR-ABL-positive cell lines to samples from patients in different disease phases of CML, using resting cells or cells treated with a variety of therapeutic agents, the field has now moved on to profiling microRNA and single nucleotide polymorphisms of CML cells. With the advent of tyrosine kinase inhibitors, several groups have also attempted to use microarray profiling to ascertain if particular gene expression profiles pre-existing in patients' CML cells, which could reflect intrinsic disease biology, would predict for response to treatment. This could streamline patients for alternative treatments upfront should a poor risk profile be found. In this article, we provide an overview of the progress made so far in this field, and outline the more substantial results of available microarray studies to date.
Best Pract Res Clin Haematol 2009 Jun
PMID:The impact of gene profiling in chronic myeloid leukaemia. 1969 27

The discovery of the Philadelphia (Ph) chromosome represented the first step towards understanding the molecular basis of haematological malignancies. Subsequent developments including the characterisation of t(9;22)(q34;q11) translocation, the identification of the breakpoint cluster region as well as the demonstration that retrovirally mediated insertion of a human BCR-ABL gene into murine haematopoietic stem cells induced a leukaemia-like picture and the creation of BCR-ABL transgenic mice established the central role of BCR-ABL in chronic myeloid leukaemia (CML) beyond all reasonable doubt. Many years later an important goal was achieved, that is, the use of BCR-ABL as a therapeutic target. However, it is uncertain whether the BCR-ABL fusion gene is really the initiating lesion for the chronic phase of CML. There is an incomplete understanding of the so-called genomic instability that underlies the production of the fusion gene and predisposes the Ph-positive clone to acquire further genetic events leading to advanced-phase disease.
Best Pract Res Clin Haematol 2009 Sep
PMID:CML: a model for targeted therapy. 1995 80

Reliable epidemiological information on chronic myeloproliferative disorders (CMPDs), notably Philadelphia (Ph)/BCR-ABL-positive chronic myeloid leukaemia (CML), is rare. Incidence rates vary from 0.6 to 2.0 cases per 100 000 inhabitants, increase with age and are higher in men than in women. Geographic and/or ethnic variations might contribute to the variability of incidences among registries. Prevalence rate has increased by use of tyrosine kinase inhibitors. In daily clinical practice, some CML management areas are not in line with the current recommendations. Problematic areas are sub-optimal timing of treatment decisions under monitoring, and unawareness of new molecular monitoring techniques and of beneficial new tyrosine kinase inhibitors. Median age differs between cancer registries and clinical trials by 10-20 years. Reports of clinical studies underestimate the true age of the CML population. Elderly CML patients are underrepresented in clinical studies and thus have a reduced access to investigational therapies.
Best Pract Res Clin Haematol 2009 Sep
PMID:Epidemiology of chronic myeloid leukaemia (CML). 1995 81


<< Previous 1 2 3 4 5 6 7 Next >>