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

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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)

It has been supposed in de novo AML that malignant transformation occurs at the level of committed progenitors. Recent data of our group and others provide evidence that in AML malignant transformation may regularly occur at the level of stem cells. These cells can be discriminated by function and specific surface molecules. CD34, a glycophosphoprotein, is a cellular surface antigen characteristically expressed by stem cells. CD34+ stem cells can be further subdivided by the expression of additional surface molecules like CD38 and CD117. In this article we present results from cytogenetic examinations of FACS-isolated stem cell subpopulations in eight patients (four AML and four MDS). Six of them displayed clonal karyotype abnormalities at the time of first diagnoses in the native bone marrow (5q-; 5q- and complex abnormalities; +8; inv(16) and +8; i(17q) and -21; i(21q)). We used CD117, the receptor for the stem cell factor (also KIT oncogene) as a new cellular surface marker. CD34+/CD117+/- stem cell subpopulations were examined in two patients with AML and three patients with MDS. We found leukemic stem cells in every type of stem cell subpopulation examined (CD34+/CD38-, CD34+/CD38+, CD34+/CD117-, CD34+/CD117+). Secondary, progression-associated chromosome abnormalities likewise were demonstrable in CD34+ cells. In three patients a mosaic of normal and abnormal metaphases was found in the highly purified stem cell subpopulations. We conclude that in AML and MDS stem cells are the target of leukemogenic genetic defects. CD117 as a new marker to isolate different CD34+ subpopulations was not sufficient to discriminate between normal and leukemic stem cells. Our findings have implications for autologous stem cell transplantation, high-dose chemotherapy and the pathogenetic concept of leukemogenesis.
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PMID:Cytogenetic analysis of CD34+ subpopulations in AML and MDS characterized by the expression of CD38 and CD117. 918 Feb 91

The class III receptor tyrosine kinase FLT3/FLK2 (FLT3; CD135) represents an important molecule involved in early steps of hematopoiesis. Here we compare cell-surface expression of FLT3 on bone marrow (BM) and cord blood (CB) cells using monoclonal antibodies (MoAbs) specific for the extracellular domain of human FLT3. Flow cytometric analysis of MACS-purified BM and CB cells showed that 63% to 82% of BM CD34+ and 88% to 95% of the CB CD34+ cells coexpress FLT3. Clonogenic assays and morphological characterization of FACS-sorted BM CD34+ cells demonstrate that colony-forming unit-granulocyte-macrophage (CFU-GM) and immature myelo-monocytic precursor cells are enriched in the subpopulation staining most brightly with the FLT3 MoAb whereas the majority of the burst-forming units-erythroid (BTU-E) and small cells with lymphoid morphology are found in the FLT3- population. In contrast, statistically indistinguishable proportions of CFU-granulocyte-erythrocyte-megakaryocyte-macrophage (CFU-GEMM) and more primitive cobblestone area forming cells (CAFC) were detected in both fractions, albeit the FLT3+ fraction consistently showed more CAFC activity than the FLT3- fraction. Although in both, BM and CB the majority of CD34+CD117+ (KIT+), CD34+CD90+ (Thy-1+), and CD34+CD109+ cells coexpress FLT3, three-color phenotypic analyses are consistent with the functional findings and suggest that the most primitive cells defined as CD34+CD38-, CD34+CD71low, CD34+HLA-DR-, CD34+CD117low, CD34+CD90+, and CD34+CD109+ express low levels of cell-surface FLT3 and were therefore not enriched to a statistically significant extent with the bright versus negative sorting scheme. Thus, clear segregation of the most primitive progenitors from BM CD34+ cells was confounded by low apparent levels of FLT3 cell-surface expression on these cells, whereas myeloid progenitors unambiguously segregated with the FLT3 brightest cells and erythroid progenitors with the FLT3 dimmest. Additional phenotypic analyses using MoAbs against progenitor/stem cell markers including the mucinlike molecule MGC-24v (CD164), the receptor tyrosine kinases TIE, FMS (CD115), and KIT (CD117) further illustrate the differences in surface antigen expression profiles of BM and CB CD34+ cells. Notably, CD115 is rarely detected on CB CD34+ cells, whereas 20% to 25% of the BM CD34+FLT3+ cells are CD115+. Furthermore, 80% to 95% of the CB CD34+CD117+ but only 60% to 75% of the BM CD34+CD117+ cells coexpress FLT3. Only a negligible amount of CD34+CD19+ are detected in CB, while in BM 20% to 30% of CD34+CD19+ presumed pro/pre-B cells coexpress FLT3. In contrast, the majority of the CD34+CD164+ and CD34+TIE+ subsets in both CB and BM coexpress FLT3. Analysis of unseparated cells showed that FLT3 expression is not restricted to CD34+ subsets. About 65% to 70% of lymphocyte-gated BM CD34-FLT3+ cells are positive for the monocytic marker CD115 whereas 25% to 30% of these cells consist of CD10 expressing B-cell precursors. Finally, CD34- monocytes in BM, CB, and PB express FLT3 whereas granulocytes are FLT3-. Our data show that detectable FLT3 appears first at low levels on the surface of primitive multilineage progenitor cells and disappears during defined stages of B-cell development, but is upregulated and maintained during monocytic maturation.
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PMID:Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase. 920 45

We compared virus-specific antibody and T-cell responses to influenza virus vaccination in 32 caregivers of Alzheimer's disease (AD) patients and matched control subjects. Caregivers showed a poorer antibody response and virus-specific T-cell response following vaccination compared to the control subjects as measured by fourfold increases in antibody titers to the vaccine and lower levels of virus-induced IL-2 levels in vitro. We performed a second study in which forty-eight medical students were inoculated with a series of three injections of the hepatitis-B (HEP-B) vaccine to coincide with the third day of three, three-day examination blocks. Twelve of the 48 medical students seroconverted after the first injection; these students were characterized by falling into the lower stressed/lower anxiety group of students. Students who reported greater social support and lower anxiety and stress demonstrated a higher antibody response to the vaccine and a more vigorous T-cell response to HEP-B surface antigen at the end of the third examination experience. The differences in antibody and T-cell responses to HEP-B and influenza virus vaccinations provide a demonstration of how stress may be able to alter both the cellular and humoral immune responses to vaccines and novel pathogens in both younger and older adults.
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PMID:The influence of psychological stress on the immune response to vaccines. 962 91

The rapid degradation and subsequent lack of efficacy of n-butyric acid in vivo has been improved by the synthesis of monosaccharide stable pro-drugs of butyric acid. We studied the effects of D1 (O-n-butanoyl-2,3-O-isopropylidene-alpha-D-mannofuranoside), G1 (1-O-n-butanoyl-D,L-xylitol), and F1 (1-O-n-butanoyl 2,3-O-isopropylidene-D,L-xylitol) on the maturation and proliferation of AML cell lines HL 60 and FLG 29.1 and of purified blast cells from 10 cases of de novo acute myeloid leukaemia (AML). AML cell maturation was measured by surface antigen expression, morphology and cytochemistry. Toxicology in mice was also evaluated (DL50 1000 mg/kg). In HL 60 cells G1 and D1 increased the expression of CD15 and CD11a (presenting 62% of promyelo-metamyelocytes), and in 7/10 cases of primary AMLs that of CD11a, CD11b, CD15, and myeloperoxidase. D1, G1 and F1 induced a dose-dependent inhibition of tritiated thymidine uptake. Apoptosis (evaluated by flow cytometry and agarose gel electrophoresis) was induced in AML blasts by D1 and F1 (79% and 94% respectively for HL 60 cells) and, with less effect, by G1 (27%). The persistence of maturative and apoptotic activity in these new pro-drugs of butyric acid, hydrolysed only inside the tumour cell, suggests a possible use in differentiation therapy of myelodysplastic syndromes and AMLs.
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PMID:Butyrate-stable monosaccharide derivatives induce maturation and apoptosis in human acute myeloid leukaemia cells. 963 98

DFMO is an irreversible inhibitor of ornithine decarboxilase (ODC), the key enzyme in mammalian polyamine biosynthesis, and has been shown to induce apoptosis. In this paper, the relation between the effects of DFMO on the polyamine content, apoptotic index and Fas expression in HEP-2 cells was determined. Fas is a type I membrane protein with a molecular mass of 45 kDa, which mediates apoptosis. The results suggest that the treatment with the polyamine inhibitor DFMO induced the expression of the surface antigen Fas, which could be responsible for trigger apoptosis in these cells.
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PMID:Effects of alpha-difluoromethylornithine on the Fas expression and apoptosis in Hep-2 cells. 1120 56

Hepatitis A and B viruses are threats to deployed military forces. The objective of this study was to determine the feasibility of concurrent vaccination against hepatitis A and B viruses. One hundred five healthy persons, 20 to 49 years of age and without serologic markers to hepatitis A or B viruses, were randomized to receive an inactivated hepatitis A vaccine (HEP A; 25 units in 0.5 mL), recombinant hepatitis B vaccine (HEP B; 10 micrograms in 1.0 mL), or both (HEP A & B) concurrently in separate arms. Vaccines were administered intramuscularly at 0, 1, and 6 months. Sera obtained at 1, 2, 6, 7, and 12 months after the first dose were tested for quantitative antibody to hepatitis A virus (anti-HAV) and antibody to hepatitis B surface antigen. Local reactions (e.g., pain) were reported by less than half of the volunteers and were similar at the site of HEP A, whether given alone or concurrently. However, more persons complained of pain (usually mild) at the HEP B site when HEP B was given concurrently with HEP A compared with HEP B alone (43% vs. 15%, 34% vs. 9%, and 42% vs. 15% for doses 1, 2, and 3, respectively; p < 0.05 for each dose). Among persons immunized with HEP A alone or HEP A & B, the proportion with > or = 10 mIU/mL anti-HAV was 83% in both groups 1 month after dose 1 and 100% at months 2, 7, and 12. The geometric mean concentrations of anti-HAV increased from 21 mIU/mL at month 1 to 2,649 and 2,312 mIU/mL in the HEP A and HEP A & B groups, respectively, at month 7. The response to HEP B was similar whether administered alone or concurrently. Antibody responses were similar in those receiving HEP A or HEP B concurrently or alone, but more subjects reported pain (usually mild) at the HEP B site after concurrent vaccination than after HEP B alone. Further work should be conducted to approve HEP A for patients younger than 2 years of age and to develop combined HEP A and HEP B vaccines in the United States.
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PMID:Randomized controlled trial of concurrent hepatitis A and B vaccination. 1127 21

Tumour cells transfected with cDNAs encoding non-self proteins were used to investigate the ability of the immune system to respond to immunogenic antigens expressed by tumours. Secreted, intracellular and surface proteins were used as model antigens, as these reflect the potential forms of tumour antigens. Syngeneic BALB/c mice injected with viable line 1 lung carcinoma or EMT6 mammary tumour cells secreting ovalbumin (OVA) or prostate-specific antigen (PSA) produced very high immunoglobulin G (IgG) antibody titres, equivalent to those of mice injected with protein in Freund's complete adjuvant (FCA). Secretion of the antigens was not necessary as tumour cells expressing a cell-surface antigen (HER-2/Neu) or an intracellular antigen - green fluorescence protein (GFP) - also generated high-titre antigen-specific IgG antibodies. In interleukin-4 (IL-4)-deficient mice, both IgG1 and IgG2a were produced in response to OVA administered in FCA, whereas in response to tumour-produced antigen, the antibodies switched from predominantly IgG1 to IgG2a, indicating that the mechanisms responsible for antibody induction differed between these forms of immunization. In contrast to the line 1 and EMT6 tumours, which are of BALB/c origin, OVA- or PSA-producing B16 melanoma cells, which are of C57BL/6 origin, failed to elicit antibody production. This was not the result of strain differences, as a similar finding was observed when the tumours were grown in (BALB/c x C57BL/6)F1 mice, but appeared to be caused by intrinsic differences in the tumours. Furthermore, co-injection of both B16/OVA and line 1 tumours resulted in production of anti-OVA antibody, indicating that B16 tumours were not immunosuppressive, but instead line 1 tumours appear to exert an adjuvant effect.
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PMID:Tumours can act as adjuvants for humoral immunity. 1132 83

Gastrointestinal mesenchymal tumors (GIMTs) are the most common mesenchymal tumors of the gastrointestinal tract. RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is a cancer cell-surface antigen and has been identified as a prognostic factor in several cancer types. It is thought that tumor cells escape immune attack by expressing RCAS1, which induces apoptosis in receptor-positive immune cells. The current study was designed to elucidate the histogenesis of these tumors by using various immunohistochemical markers, and identify parameters that will help to establish the criteria of malignancy in the GIMT. We also discuss the clinicopathological significance of RCAS1 expression in the diagnosis and prognosis of GIMTs. A total of 70 cases of GIMTs were reviewed. Immunohistochemistry was performed between 1990 and 2000, with the avidin-biotin-peroxidase complex method on 3 microm-thick sections of formalin-fixed paraffin-embedded specimens of GIMTs. Antibodies to the following antigens were used: KIT (CD117), CD34 alpha-SMA, Desmin, cytokeratin, S-100 protein, p53, and RCAS1. Recurrence-free survival analysis was done with Stat View-J 5.0 statistical packages. Univariate analysis for a recurrence-free prognosis demonstrated that antibody detection of p53 expression (p=0.0333) and expression of RCAS1 (p=0.0008) is correlated with a significantly higher potential of recurrence. On multivariate analysis, tumor size and RCAS1 expression were independently and inversely correlated with recurrence-free survival. The expression of RCAS1 has not previously been reported in GIMT; indeed, our study suggests that the expression of RCAS1 is correlated with recurrence not only in carcinomas, but also in mesenchymal tumors.
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PMID:A clinical and immunohistochemical study on gastrointestinal mesenchymal tumor (GIMT): RCAS1 as a predictor for recurrence of GIMT. 1621 Dec 75

The gamma-irradiation of normal cells causes an increased synthesis of specific proteins. However, few studies have described the effects of high doses of irradiation on the expression of cell surface antigens in tumor cells. This study analyzed the effects of high doses of gamma-irradiation on the surface antigen expression of Major Histocompatability Complex (MHC) class I/II and intercellular adhesion molecule-1 (ICAM-I) in human multiple myeloma (MM) cell lines ARP-1, ARK-RS, and 10 MM primary tumors. The expression of surface antigens was evaluated by fluorescence-activated cell sorter analysis at different time points, following the exposure to high doses of gamma-irradiation. Doses of 10,000 and 15,000 cGy were not sufficient to totally block cell replication in both cell lines and primary tumors; cell replication was able to be inhibited completely only at 18,000 cGy. Lower doses (10,000 cGy) and lethal doses of irradiation (i.e., 15,000 and 18,000 cGy) increased the expression of all surface antigens present on the cells before irradiation. Essentially, such upregulation was shown to be dose dependent, with higher radiation doses resulting in higher antigen expression. Furthermore, when the kinetics of this upregulation were studied 3 and 6 d after irradiation, there was a constant increase in antigen expression in MM cells. These findings suggest that upregulation of costimulatory molecules, such as of MHC class I/II antigens and ICAM-I molecules in MM patients treated by gamma-radiation, can increase the immunogenicity of the tumor cells. In light of these findings, radiotherapy combined with immunotherapy might be considered in relapsing patients after receiving the standard treatment.
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PMID:Gamma-radiation upregulates MHC class I/II and ICAM-I molecules in multiple myeloma cell lines and primary tumors. 1675 54

FLT3 mutations and cell-surface antigen were investigated in 29 DR-negative (DR(-)) M1/M2 AML samples in comparison with 30 DR-positive (DR(+)) M1/M2 AML samples. FLT3-ITD was detected in 59.3% and D835 was detected in 7.4% of the samples. The incidence of FLT3-ITD was higher in the DR(-) group (59.3%) than in the DR(+) group (17.9%; P=0.002). The DR(-) status was associated with the CD34(-) (82.8%), CD7(-) (92.9%) and CD45RO(+) status (76%). Our results indicated that FLT3 mutation is the most common gene alteration found in the DR(-) M1/M2 AML. These results are important for further characterizing this phenotypic AML entity.
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PMID:HLA-DR-negative AML (M1 and M2): FLT3 mutations (ITD and D835) and cell-surface antigen expression. 1705 11


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