Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone marrow-derived endothelial progenitor cells (EPC) play an important role in neovascularisation and tumor growth. However, the clinical relevance of EPCs on blood vessel formation in non-small cell lung cancer (NSCLC) is unclear. EPC numbers in circulation are very low and therefore their detection is technically challenging. In the present study, 10 NSCLC patients and 5 healthy controls were included. Patients underwent blood analyses before and after surgery. EPCs were isolated from whole blood by magnetic cell sorting to CD34 (MACS). Afterwards, FACS analyses using antibodies against CD133, CD34, VEGFR2 and CD45 and and immunocytological staining to CD133 on cytospins (MCA) were performed. Cryostat sections of tumor samples were stained for CD133, CD31 and cytokeratin A7. Serum levels of the vascular endothelial growth factor (VEGF) were quantified by sandwich ELISA. Compared to the control group NSCLC patients showed significantly elevated EPC counts and VEGF levels in peripheral blood before and after surgery. From a methodological point of view, the tested procedure (MCA) was validated as compared to the standard FACS analyses (CD34+/VEGFR2+). MCA proved to have a very high sensitivity and even allowed the identification of singular positive EPCs.
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PMID:Increased numbers of endothelial progenitor cells in peripheral blood and tumor specimens in non-small cell lung cancer: a methodological challenge and an ongoing debate on the clinical relevance. 1820 80

Somatic stem cell transplantation holds great promise in regenerative medicine. The best-characterized adult stem cells are mesenchymal stem cells (MSCs), neural stem cells (NSCs), and CD133(+) hematopoietic stem cells (HSCs). The applications of HSCs are hampered since these cells are difficult to maintain in an undifferentiated state in vitro. Understanding genes responsible for stem cell properties and their interactions will help on this issue. The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem-like state. We performed a systemic study on human CD133(+) HSCs, NSCs, MSCs, and embryonic stem cells and two different progenies of CD133(+) HSCs, microvascular endothelial cells (MVECs) and peripheral blood mononuclear cells. Genes abundant in each or in all three somatic stem cells were identified. We also observed complex genetic networks functioning in postnatal stem cells, in which several genes, such as PTPN11 and DHFR, acted as hubs to maintain the stability and connectivity of the whole genetic network. Eighty-seven HSC genes, including ANGPT1 and GATA2, were independently identified by comparing CD34(+)CD33(-)CD38(-) hematopoietic stem cells with CD34(+) precursors and various matured progenies. Introducing GATA2 into MVECs resulted in dedifferentiation-like transcriptome reprogramming, with HSC genes (such as ANGPT1) being up and endothelial genes (such as EPHB2) being down. This study provides a foundation for a more detailed understanding of human somatic stem cells. Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem-like status.
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PMID:Functional network reconstruction reveals somatic stemness genetic maps and dedifferentiation-like transcriptome reprogramming induced by GATA2. 1830 45

BAALC expression is considered an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML), but has yet to be investigated together with multiple other established prognostic molecular markers in CN-AML. We analyzed BAALC expression in 172 primary CN-AML patients younger than 60 years of age, treated similarly on CALGB protocols. High BAALC expression was associated with FLT3-ITD (P = .04), wild-type NPM1 (P < .001), mutated CEBPA (P = .003), MLL-PTD (P = .009), absent FLT3-TKD (P = .005), and high ERG expression (P = .05). In multivariable analysis, high BAALC expression independently predicted lower complete remission rates (P = .04) when adjusting for ERG expression and age, and shorter survival (P = .04) when adjusting for FLT3-ITD, NPM1, CEBPA, and white blood cell count. A gene-expression signature of 312 probe sets differentiating high from low BAALC expressers was identified. High BAALC expression was associated with overexpression of genes involved in drug resistance (MDR1) and stem cell markers (CD133, CD34, KIT). Global microRNA-expression analysis did not reveal significant differences between BAALC expression groups. However, an analysis of microRNAs that putatively target BAALC revealed a potentially interesting inverse association between expression of miR-148a and BAALC. We conclude that high BAALC expression is an independent adverse prognostic factor and is associated with a specific gene-expression profile.
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PMID:High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. 1837 53

We investigated whether KIT signaling was sufficient to maintain human hematopoietic stem cells in culture or whether, as with murine stem cells, signaling through glycoprotein 130 (gp130) is additionally required. Sorted CD34(+)CD133(+)(CD33/CD38/CD71)(-) cells from human umbilical cord blood (UCB) were cultured in the presence of combinations of KIT-ligand (KL) and the gp130 stimulating molecule oncostatin M (OSM). We found that OSM increased KL-induced proliferation, which was accompanied by an expansion in numbers of mature progenitors colony-forming cells (CFC, CAFCw2). More primitive progenitors, CAFCw6 and long-term culture-CFC, were not maintained by KL as a single factor. Although addition of OSM did not improve survival, the KL/OSM combination showed improved maintenance of immature progenitors as well as higher CD34 expression. Similarly, both KL and OSM were required to maintain NOD/SCID-repopulating activity. In experiments to investigate the underlying mechanism, we found that extracellular signal-regulated kinase (ERK) and its downstream target p90 ribosomal S6 kinase were activated by KL and downregulated by the inclusion of OSM during stimulation. The p38 mitogen-activated protein kinase (p38 MAPK) was not modulated by either KL or OSM. Indeed, many of the effects of OSM (increased cell division, maintenance of CFC, and maintenance of high CD34 expression) could be mimicked by using the mitogen-activated protein kinase kinase inhibitor U0126. More importantly, NOD/SCID-repopulating activity was preserved in the KL/U0126-stimulated cells, but not in cells stimulated with a combination of KL and the p38 MAPK inhibitor SB203580. Our results show that the loss of repopulating activity during KL stimulation is counteracted by OSM through the downregulation of ERK pathway signaling. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Oncostatin M-mediated regulation of KIT-ligand-induced extracellular signal-regulated kinase signaling maintains hematopoietic repopulating activity of Lin-CD34+CD133+ cord blood cells. 1849 91

Stem cells are self-renewing multipotent progenitors with the broadest developmental potential in a given tissue at a given time. Normal stem cells in the adult organism are responsible for renewal and repair of aged or damaged tissue. Adult stem cells are present in virtually all tissues and during most stages of development. In this review, we introduce the reader to the basic information about the field. We describe selected stem cell isolation techniques and stem cell markers for various stem cell populations. These include makers for endothelial progenitor cells (CD146/MCAM/MUC18/S-endo-1, CD34, CD133/prominin, Tie-2, Flk1/KD/VEGFR2), hematopoietic stem cells (CD34, CD117/c-Kit, Sca1), mesenchymal stem cells (CD146/MCAM/MUC18/S-endo-1, STRO-1, Thy-1), neural stem cells (CD133/prominin, nestin, NCAM), mammary stem cells (CD24, CD29, Sca1), and intestinal stem cells (NCAM, CD34, Thy-1, CD117/c-Kit, Flt-3). Separate section provides a concise summary of recent clinical trials involving stem cells directed towards improvement of a damaged myocardium. In the last part of the review, we reflect on the field and on future developments.
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PMID:Adult stem cells and their trans-differentiation potential--perspectives and therapeutic applications. 1862 66

Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/- neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/- cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas, and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker CD133, and resistance to oxidative stress and ionizing radiation. The RAS/mitogen-activated protein kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways were activated, and checkpoint kinase 1 (Chk1), the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/- cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, glial fibrillary acidic protein-positive, nestin-positive tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability.
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PMID:EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors. 1881 21

Our objective was to determine the relationships between levels of different dietary nutrients intake with circulating endothelial progenitor cells (EPC) and vascular endothelial function in type II diabetic patients. We studied the daily dietary nutrients intake, the numbers of circulating CD34(+)/KDR(+) EPC and CD133(+)/KDR(+) EPC and brachial artery flow-mediated dilation (FMD) in 88 diabetic patients without prior cardiovascular diseases and 91 sex- and age-matched controls. Compared with controls, diabetic patients had lower CD133(+)/KDR(+) EPC count (48.3 +/- 5.2 vs. 84.6 +/- 7.6/microL, p < 0.001), CD34(+)/KDR(+) EPC count (311 +/- 41 vs. 412 +/- 36/microL, p = 0.045), and FMD (2.54 +/- 0.37% vs. 5.46 +/- 0.47%, p < 0.001). After adjusted for age, sex, smoking history, body weight, hemoglobin A1c level, total calorie intake, other dietary vitamin intake, use of antihypertensives, and lipid lowering agents, a higher intake of thiamine was significantly associated with a higher level of circulating CD34(+)/KDR(+) EPC (beta = 0.49, p = 0.028) and CD133(+)/KDR(+) EPC (beta = 0.45, p = 0.037) in diabetic patients, but not in controls. Furthermore, an increased intake of thiamine from 1st to 4th quartile in diabetic patients independently predicted an absolute increase in FMD by 1.29% (p = 0.026, relative increase = 63.5%). This study demonstrated that daily thiamine intake was positively correlated with the circulating number of EPCs and FMD in patients with type II diabetes, independent of other dietary nutrients intake.
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PMID:Daily intake of thiamine correlates with the circulating level of endothelial progenitor cells and the endothelial function in patients with type II diabetes. 1892 14

Coronary Artery Diseases (CAD) is the first mortality cause in industrialized countries. The possibility of regenerating myocardium injured tissue using the cell therapy is a promising option to regenerate cardiac tissue. Currently, a variety of adult stem/ progenitor cells are undergoing clinical evaluation, but it is very important to study and characterize the bone marrow-derived progenitor/ stem cells, the main source of cells used for human cardiac repair, before their clinical use. Bone marrow-derived endothelial progenitor cells (EPC) home sites of ischemia and differentiate into endothelial cells, increase the neovascularization of ischemic tissue. Moreover recently, it has been observed that EPC can be able to differentiate or transdifferentiate to like-adult cells resident in cardiac tissues. The characterization of phenotype EPC is complex, because express hematopoietic stem cells (CD133 and/or CD34) and endothelial markers such as vascular endothelial growth factor receptor 2 (KDR). Several studies described subpopulation of EPC expressing CD34+D133+KDR+ phenotype in literature, but some other authors suggest other phenotype. The EPC capacity of mobilization or recruitment/ homing to ischemic tissue areas by cytokines are reviewed. Finally are described clinical studies in CAD using bone marrow-derived progenitor cells permitting human cardiac tissue repair.
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PMID:Endothelial progenitor cells in cell-based therapy for cardiovascular disease. 1895 47

Endothelial progenitor cells (EPCs) are important initiators of vasculogenesis in the process of tumor neovascularization. However, it is unclear how circulating EPCs contribute to the formation of tumor microvessels. In this study, we isolated CD34(+)/CD133(+) cells from human umbilical cord blood (HUCB) and obtained EPCs with the capacities of forming colonies, uptaking acetylated low-density lipoprotein (ac-LDL), binding lectins and expressing vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2, KDR), CD31 and von Willebrand factor (vWF). These EPCs were actively proliferative and migratory, and could formed capillary-like tubules in response to VEGF. When injected into mice bearing subcutaneously implanted human malignant glioma, EPCs specifically accumulated at the sites of tumors and differentiated into mature endothelial cells (ECs), which accounted for 18% ECs of the tumor microvessels. The incorporation of circulating EPCs into tumor vessel walls significantly affected the morphology and structure of the vasculature. Our results suggest that circulating EPCs constitute important components of tumor microvessel network and contribute to tumor microvascular architecture phenotype heterogeneity.
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PMID:Incorporation of endothelial progenitor cells into the neovasculature of malignant glioma xenograft. 1905 96

A newly established GM7 cell line was derived from the tumor tissue of a 65-year-old man surgically treated for a relapse of glioblastoma multiforme that occurred 10 months after first surgery following radiotherapy. GM7 cells exhibit spindle or glia-like morphology, and multinucleated giant cells are also present in the culture. The cells proliferate rapidly (PDT is about 18 h) and tend to grow in multilayer without contact inhibition. Using G-banding and SKY, the GM7 cell line was identified as near-triploid with a large number of structural and numerical abnormalities. Repeated karyotyping during long-term cultivation confirmed a chromosome number of 70+/-3 chromosomes per cell. Special attention was paid to the immunocytochemical analysis of protein markers in this cell line; GM7 cells showed strong positivity for CD133, vimentin, nestin, NF-160 and S-100 protein and weak positivity for GFAP and NSE, but were negative for synaptophysin. The most important features of the GM7 cell line are its stable phenotype CD133+/nestin+, which are accepted as stem cell markers in neural stem/progenitor cells, and especially unusual intracellular localization of the IF protein nestin, which was detected and repeatedly confirmed both in the cytoplasm and cell nucleus. For this reason, the new GM7 glioblastoma cell line represents an important model suitable not only for further studies on glioblastoma biology and cancer stem cells, but particularly for the detailed investigation of the role of nestin in transformed cells.
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PMID:Characterization of a GM7 glioblastoma cell line showing CD133 positivity and both cytoplasmic and nuclear localization of nestin. 1908 52


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