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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently identified the chimeric kinase FIP1L1-platelet-derived growth factor receptor alpha (PDGFRalpha) as a cause of the hypereosinophilic syndrome and of chronic eosinophilic leukemia. To investigate the role of FIP1L1-PDGFRA in the pathogenesis of acute leukemia, we screened 87 leukemia cell lines for the presence of FIP1L1-PDGFRA. One cell line, EOL-1, expressed the FIP1L1-PDGFRA fusion. Three structurally divergent kinase inhibitors--imatinib (STI-571), PKC412, and SU5614--inhibited the growth of EOL-1 cells. These results indicate that the fusion of FIP1L1 to PDGFRA occurs rarely in leukemia cell lines, but they identify EOL-1 as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and for the analysis of small molecule inhibitors of FIP1L1-PDGFRalpha.
...
PMID:The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. 1463 Jul 92

Gastrointestinal stromal tumours (GISTs), the most common mesenchymal tumours of the digestive tract, are largely resistant to chemo- and radiotherapy. They are currently defined by their overexpression of the KIT receptor tyrosine kinase (CD117), a member of the family of receptor tyrosine kinases (RTKs), and exhibit KIT mutations in more than 85% of cases. Additionally, in more than one-third of KIT wild-type GISTs, mutations of platelet-derived growth factor receptor alpha (PDGF-R alpha), which also belongs to the family of RTKs, were recently found. Since these data indicate that uncontrolled RTK signalling may be implicated in the pathogenesis of GISTs, RTKs and the activated downstream signalling cascades are attractive targets in the therapy of these tumours. Imatinib is a small-molecule inhibitor that selectively blocks the activity of the PDGF-R, ABL and KIT receptor tyrosine kinases by competitive binding to the adenosine triphosphate binding site of their catalytic domains. We herein review the molecular pathological, preclinical and clinical data that identify imatinib as a valuable new agent in the treatment of GISTs.
...
PMID:Gastrointestinal stromal tumours and their response to treatment with the tyrosine kinase inhibitor imatinib. 1473 60

Recent animal studies suggested that deregulated expression of the platelet-derived growth factor receptor alpha (PDGFRalpha) may contribute to the failure of normal neural tube closure (NTC). There is also suggestive evidence that the promoter haplotype of the PDGFRA is associated with genetic susceptibility in human neural tube defects (NTDs). The purpose of our study was to investigate the association between promoter haplotype combinations of the human PDGFRA gene and risk for NTDs in a Hispanic population from the Texas-Mexico border region. This population has a considerably higher prevalence of NTDs (16/10,000 live births) than that generally reported in the United States (8-10/10,000 live births). In the present study, NTDs were defined as spina bifida or anencephaly. The haplotype of PDGFRA gene promoter was determined by direct DNA sequence analysis. Two novel haplotypes, H2epsilon and H1beta, were found. We observed significant differences among variable haplotype groups from in vitro transient transfection studies in U2-OS osteosarcoma cell and two other cell lines (HeLa cell and MCF7 cell). Result from our case-control study demonstrated that the frequencies of haplotypes with low transcription activity were significantly higher in NTD mothers than that observed in control mothers (odds ratio=2.2, 95% CI=1.0-4.6). Infants with at least one low activity allele showed slightly higher risk (odds ratio=1.5, 95%=0.8-3.1). Our study suggests that the reduced transcriptional activity of PDGFRA gene could increase the risk of having an NTD-affected pregnancy.
...
PMID:Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects. 1474 Nov 94

We analyzed 30 gastrointestinal stromal tumors (GISTs) that were immunohistochemically weak or negative for KIT. Histologically, all 30 GISTs consisted of epithelioid tumor cells in at least a part of the tumor. The tumor cells showed different morphologies and arranged themselves in different histological patterns. In 20 of the 30 GISTs, round or oval epithelioid tumor cells often showed a less cohesive pattern of growth and showed eosinophilic cytoplasm and peripherally placed nuclei with myxoid stroma, whereas in the remaining 10 cases, tumor cells were arranged in a more cohesive pattern without myxoid stroma. The former type of tumors is called myxoid epithelioid GISTs in this study. Subsequent mutational analyses showed that the platelet-derived growth factor receptor alpha (PDGFRA) gene mutations in exon 12 or exon 18 were identified in 20 (66.7%) of the 30 GISTs, and especially in 18 (90%) of the 20 myxoid epithelioid GISTs. Moreover, 17 (85%) of the 20 myxoid epithelioid GISTs were accompanied by mast cell infiltrations within the tumor nodules. In the remaining cases, 2 (6.7%) of the 30 GISTs had c-kit gene mutations in exon 11, and no mutation was found in 8 (26.7%) of 30 GISTs. None of the patients with myxoid epithelioid GISTs died of disease. These results suggest that myxoid epithelioid GISTs are a distinct subtype of GISTs that are closely correlated with the PDGFRA gene mutation and that recognition of such histological characteristics should be helpful for molecular subclassification of GISTs that are important for molecular targeting therapy by imatinib mesylate (STI571).
...
PMID:Myxoid epithelioid gastrointestinal stromal tumor (GIST) with mast cell infiltrations: a subtype of GIST with mutations of platelet-derived growth factor receptor alpha gene. 1549 89

Activating mutations of KIT and platelet-derived growth factor receptor alpha (PDGFRA) are known to be alternative and mutually exclusive genetic events in the development of gastrointestinal stromal tumors (GISTs). We examined the effect of the mutations of these two genes on the gene expression profile of 22 GISTs using the oligonucleotide microarray. Mutations of KIT and PDGFRA were found in 17 cases and three cases, respectively. The remaining two cases had no detectable mutations in either gene. The mutation status of KIT and PDGFRA was directly related to the expression levels of activated KIT and PDGFRA, and was also related to the different expression levels of activated proteins that play key roles in the downstream of the receptor tyrosine kinase III family. To evaluate the impact of mutation status and the importance of the type of mutation in gene expression and clinical features, microarray-derived data from 22 GISTs were interpreted using a principal component analysis (PCA). Three relevant principal component representing mutation of KIT, PDGFRA and chromosome 14q deletion were identified from the interpretation of the oligonucleotide microarray data with PCA. After supervised analysis, there was at least a two fold difference in expression between GISTs with KIT and PDGFRA mutation in 70 genes. Our findings demonstrate that mutations of KIT and PDGFRA affect differential activation and expression of some genes, and can be used for the molecular classification of GISTs.
...
PMID:Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors. 1569 55

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the digestive tract and the majority of GIST has characteristic gain-of-function mutations of the c-kit gene, which encodes the KIT receptor for stem cell factor. The present study aimed to establish the usefulness of protein kinase C theta (PKC theta) as an immunohistochemical marker for GIST in comparison with KIT immunohistochemistry. PKC theta immunohistochemistry was carried out not only on 48 cases of GIST and another 40 cases of gastrointestinal mesenchymal tumors, but also on 24 cases of various tumors known to be immunohistochemically positive for KIT. Immunohistochemically, 41 out of 48 cases (85%) of GIST were positive for PKC theta, and its expression was confirmed by Western blot analysis using six cases of surgically resected GIST. In the present study there were six GIST immunohistochemically negative for KIT, which histologically revealed a myxoid epithelioid appearance characteristic to that of GIST with platelet-derived growth factor receptor alpha mutation. All six GIST were immunohistochemically positive for PKC theta. No PKC theta immunoreactivity was observed in other gastrointestinal mesenchymal tumors and various KIT-positive tumors except for three cases (14%) of gastrointestinal schwannomas. The present study revealed that PKC theta is an immunohistochemically novel and useful marker for GIST, especially for GIST negative for KIT.
...
PMID:PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumors. 1574 18

Gastrointestinal stromal tumors (GIST), KIT-positive and KIT signaling driven or platelet-derived growth factor receptor alpha (PDGFRA) signaling driven mesenchymal tumors, are poorly known in nonhuman primates. Availability of KIT- and PDGFRA-inhibitor drug imatinib mesylate has greatly raised the interest for these tumors. At necropsy of a 22-year-old male chimpanzee, a round, firm 2-cm intramural tumor was incidentally found in the midbody of the stomach and diagnosed as a GIST. Histologically, the mass was composed of spindle to polygonal epithelioid cells arranged in short to intermediate-length, interlacing streams, bundles, and nodular whorls often separated by hyalinized eosinophilic matrix. The mitotic rate was a maximum 1/50 high-power field. Immunohistochemically, the tumor cells were diffusely positive for KIT and CD34, focally positive for alpha-smooth muscle actin, and negative for muscle specific actin, desmin, S-100 protein, synaptophysin, and glial fibrillary acidic protein. Because the majority of human GISTs have gain-of-function KIT or PDGFRA mutations, genomic sequences of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 from this chimpanzee GIST were polymerase chain reaction amplified and sequenced. However, no mutation was identified in the analyzed "mutational hot spots." This study is the first extensive histomorphologic, immunohistochemical, and molecular genetic analysis of a chimpanzee GIST. More cases of nonhuman primate GISTs should be analyzed to discover the clinicopathologic spectrum of GISTs in these species.
...
PMID:KIT-positive gastrointestinal stromal tumor in a 22-year-old male chimpanzee (Pan troglodites). 1587 85

Systemic mastocytosis is characterized by abnormal mast cell proliferation in different organs. The 2001 consensus classification distinguishes in separate categories indolent systemic mastocytosis, systemic mastocytosis with concomitant blood disease, aggressive systemic mastocytosis and mast cell leukemia. Clinical manifestations are caused by tissue infiltration by proliferating mastocytes and by release of mediators. The principal organs affected are the skin, bones, digestive tract, liver, spleen and lymph nodes. Diagnosis of mastocytosis is based on appropriate stains (Giemsa, toluidine blue) and immunophenotype features (tryptase, CD117, also known as c-KIT and stem cell factor receptor). Serum tryptase levels reflect the total mast cell burden. Treatment must prevent release of mast cell mediators (histamine antagonists, cromolyn sodium, corticosteroids, or leukotriene-receptor inhibitors), limit bone involvement (bisphosphonates) and reduce the number of circulating mast cells (interferon, cladribine, or tyrosine kinase inhibitors). Enhanced understanding of the pathogenic mechanisms (mutation of c-kit and platelet-derived growth factor receptor alpha has led to the development of targeted treatments, including new inhibitors of tyrosine kinase and of nuclear factor Kappa B.
...
PMID:[Systemic mastocytosis]. 1598 48

Mast cell disease (MCD) is characterized by the abnormal growth and accumulation of neoplastic mast cells (MC) in one or more organs. The diagnosis of systemic MCD is most commonly established by a thorough histological and immunohistochemical examination of a bone marrow (BM) trephine specimen. In cases with pathognomonic perivascular and -trabecular aggregates of morphologically atypical MC and significant BM involvement, the diagnosis may be relatively straightforward. In contrast, when a sparse, loose pattern of MC infiltration predominates, or when MCs are obscured by an associated non-MC hematological neoplasm, a high index of suspicion and use of adjunctive tests, including special stains, such as tryptase and CD25, may be necessary to reach a diagnosis. The updated classification for MCD clarifies the clinical and pathological criteria for categorizing patients into relatively discrete subgroups. Some cases, however, such those with Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)(+) clonal eosinophilia associated with elevated serum tryptase levels, with features that overlap MCD and chronic eosinophilic leukemia, may not be easy to categorize on the basis of this classification. There is no standard therapy for MCD and treatment has to be tailored to the needs of the individual patient. MC-cytoreductive therapies, such as interferon-alpha and chemotherapy, are generally reserved for patients with progressive disease and organopathy. A subset of MCD patients with associated eosinophilia who carry the FIP1L1-PDGFRA oncogene will achieve complete clinical, histological, and molecular remissions with imatinib mesylate therapy, in contrast to those with c-kit D816V mutations. The BM pathology, consensus classification, and current therapies for MCD are further discussed in this article.
...
PMID:Systemic mastocytosis: bone marrow pathology, classification, and current therapies. 1599 24

The recent discovery of an eosinophilia-specific, imatinib-sensitive, karyotypically occult but fluorescence in situ hybridization-apparent molecular lesion in a subset of patients with blood eosinophilia has transformed the diagnostic as well as treatment approach to eosinophilic disorders. Primary (i.e. nonreactive) eosinophilia is considered either "clonal" or "idiopathic" based on the presence or absence, respectively, of either a molecular or bone marrow histological evidence for a myeloid neoplasm. Clonal eosinophilia might accompany a spectrum of clinicopathological entities, the minority of whom are molecularly characterized; Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA(+)) systemic mastocytosis, platelet-derived growth factor receptor beta (PDGFRB)-rearranged atypical myeloproliferative disorder, chronic myeloid leukemia, and the 8p11 syndrome that is associated with fibroblast growth factor receptor 1 (FGFR1) rearrangement. Hypereosinophilic syndrome (HES) is a subcategory of idiopathic eosinophilia and is characterized by an absolute eosinophil count of > or =1.5 x 10(9)/l for at least 6 months as well as eosinophil-mediated tissue damage. At present, a working diagnosis of primary eosinophilia mandates a bone marrow examination, karyotype analysis, and additional molecular studies in order to provide the patient with accurate prognostic information as well as select appropriate therapy. For example, the presence of either PDGFRA or PDGFRB mutations warrants the use of imatinib in clonal eosinophilia. In HES, prednisone, hydroxyurea, and interferon-alpha constitute first-line therapy, whereas imatinib, cladribine, and monoclonal antibodies to either interleukin-5 (mepolizumab) or CD52 (alemtuzumab) are considered investigational. Allogeneic transplantation offers a viable treatment option for drug-refractory cases.
...
PMID:Modern diagnosis and treatment of primary eosinophilia. 1599 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---