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61.
To investigate the role of ERK signaling in human skin responses to wounding, organ cultures of human skin were maintained for 0.5-24 h in the presence of various inhibitors, followed by measurement of ERK phosphorylation or mRNA levels. The MEK inhibitor PD98059 produced near-complete (97-98%) inhibition of ERK phosphorylation, whereas inhibition of c-Fos, c-Jun, HB-EGF, AR, and VEGF mRNA by this compound was incomplete (41-65%). PD98059 was significantly more effective than either PD158780 or BB2516 as an inhibitor of ERK phosphorylation and of the rapid rise in c-Fos and c-Jun mRNA expression. In contrast, all three compounds inhibited the more delayed rise in HB-EGF mRNA to the same extent. Exogenous epidermal growth factor abrogated the inhibition of ERK phosphorylation caused by BB2516. These data indicate that one or more metalloproteinases activate ErbB signaling in skin organ culture, that ErbB signaling plays an important but not exclusive role in the activation of ERK, and that non-ERK pathways contribute to gene expression in this system. Because metalloproteinase-mediated cleavage of the HB-EGF transmembrane precursor is known to be ERK-dependent, our data suggest that ERK activation resulting from initial trauma leads to metalloproteinase-mediated cleavage of HB-EGF, thereby triggering the ErbB signaling cascade. 相似文献
62.
Human trophoblast cells are known to release a range of arachidonic acid metabolites into culture medium, including cyclo-oxygenase, lipoxygenase and epoxygenase products. In this study we investigated the effects of dibutyryl cyclic AMP (db cAMP) on arachidonic acid metabolism in human first trimester trophoblast cells, and also determined the distribution of metabolites between intracellular and extracellular compartments. db cAMP increased intracellular levels of radioactivity within 2 min, and extracellular levels of radioactivity were increased after 30 min. These changes were reflected in increased levels of arachidonic acid metabolites in both compartments, indicating that arachidonic acid was metabolised. db cAMP increased intracellular levels of 5,6-epoxyeicosatrienoic acid (5,6-EpETrE) within 2 min of addition to cultured cells. No changes were detected after 5-10 min, but substantial changes were found 30 min after the addition of db cAMP. The dihydroxyeicosatrienoic acid (DiHETrE) breakdown products also increased with similar kinetics. In contrast, levels of 14,15-EpETrE increased after 5-10 min. 相似文献
63.
Schmidt M Carbonaro DA Speckmann C Wissler M Bohnsack J Elder M Aronow BJ Nolta JA Kohn DB von Kalle C 《Nature medicine》2003,9(4):463-468
A clinical trial of retroviral-mediated transfer of the adenosine deaminase (ADA) gene into umbilical cord blood CD34(+) cells was started in 1993. ADA-containing peripheral blood mononuclear cells (PBMCs) have persisted in patients from this trial, with T lymphocytes showing the highest prevalence of gene marking. To gain a greater understanding of the nature and number of the transduced cells that were engrafted, we used linear amplification-mediated PCR (LAM-PCR) to identify clonal vector proviral integrants. In one patient, a single vector integrant was predominant in T lymphocytes at a stable level over most of the eight-year time span analyzed and was also detected in some myeloid samples. T-cell clones with the predominant integrant, isolated after eight years, showed multiple patterns of T-cell receptor (TCR) gene rearrangement, indicating that a single pre-thymic stem or progenitor cell served as the source of the majority of the gene-marked cells over an extended period of time. It is important to distinguish the stable pattern of monoclonal gene marking that we observed here from the progressive increase of a T-cell clone with monoclonal gene marking that results from leukemic transformation, as observed in two subjects in a clinical trial of gene therapy for X-linked severe combined immunodeficiency (SCID). 相似文献
64.
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66.
Kumud Majumder William Shawlot Gabriele Schuster Wilbur Harrison Frederick F.B. Elder Paul A. Overbeek 《Mammalian genome》1998,9(11):863-868
Mice with mutations at the downless (dl) locus have defects in hair follicle, tooth, sweat gland, preputial gland, Meibomian gland, and tail development. The dl phenotype is analogous to the human genetic disorder termed autosomal hypohidrotic (or anhidrotic) ectodermal dysplasia (HED).
On the basis of the identification of two related transgenic insertional mutations in the downless gene, yeast artificial
chromosomes (YACs) were identified that map to the critical region of mouse Chromosome (Chr) 10. To determine which of the
YACs contain the dl gene, we generated YAC transgenic mice by mouse embryo microinjections. The 200-kb YAC B25.D9 was found to rescue all of
the downless defects. In addition, the transgenic YAC rescued the dominant Sleek (Dl
slk
) allele. Since the sequences within the YAC are entirely deleted in one of the transgenic mutants, our results establish
that Sleek encodes a dominant-negative protein whose effects can be reversed by expression of extra copies of the wild-type
locus.
Received: 26 June 1998 / Accepted: 17 July 1998 相似文献
67.
Alkylpurine–DNA–N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate 下载免费PDF全文
68.
Li-Nien Chien Quinn T. Ostrom Haley Gittleman Jia-Wei Lin Andrew E. Sloan Gene H. Barnett J. Bradley Elder Christopher McPherson Ronald Warnick Yung-Hsiao Chiang Chieh-Min Lin Lisa R. Rogers Hung-Yi Chiou Jill S. Barnholtz-Sloan 《PloS one》2015,10(6)
Background
High grade gliomas are the most common type of malignant brain tumor, and despite their rarity, cause significant morbidity and mortality. This study aimed to compare the treatment patterns of high grade glioma to examine survival patterns in patients who receive specific treatments between cohorts in Ohio and Taiwan.Method
Patients aged 18 years and older at age of diagnosis with World Health Organization (WHO) grade III or IV astrocytoma from 2007-2012 were selected from the Ohio Brain Tumor Study and the Taiwan Cancer Registry. The treatment information was derived from medical chart reviews in Ohio and National Health Insurance Research Data in Taiwan. Treatment examined included surgical procedure (brain biopsy and/or resection), radiotherapy (radiation and/or radiosurgery), and alkylating chemotherapy. Kaplan-Meier and parametric survival models were used to examine the effect of treatment on survival, adjusted for age, sex, and comorbidities.Results
294 patients in Ohio and 1,097 patients in Taiwan met the inclusion criteria. 70.3% patients in Ohio and 51.4% in Taiwan received surgical resection, followed by concurrent chemoradiation. Patients who received this treatment had the highest survival rate, with a 1-year survival rate of 72.8% in Ohio and 73.4% in Taiwan. Patients who did not receive surgical resection, followed by concurrent chemoradiation had an increased risk of death (hazard ratio of 5.03 [95% confidence interval (CI): 3.61-7.02] in Ohio and 1.49 [95% CI: 1.31-1.71] in Taiwan) after adjustment for age, sex, and comorbidities.Conclusion
Surgical resection followed by concurrent chemoradiation was associated with higher survival rate of patients with high grade glioma in both Ohio and Taiwan; however, one-third of patients in Ohio and half in Taiwan did not receive this treatment. 相似文献69.
Seasonal patterns in soil surface CO<Subscript>2</Subscript> flux under snow cover in 50 and 300 year old subalpine forests 总被引:2,自引:0,他引:2
Robert ?M.?HubbardEmail author Michael G.?Ryan Kelly?
Elder Charles C.?Rhoades 《Biogeochemistry》2005,73(1):93-107
Soil CO2 flux can contribute as much as 60–80% of total ecosystem respiration in forests. Although considerable research has focused on quantifying this flux during the growing season, comparatively little effort has focused on non-growing season fluxes. We measured soil CO2 efflux through snow in 50 and ~300 year old subalpine forest stands near Fraser CO. Our objectives were to quantify seasonal patterns in wintertime soil CO2 flux; determine if differences in soil CO2 flux between the two forest ages during the growing season persist during winter; and to quantify the sample size necessary to discern treatment differences. Soil CO2 flux during the 2002–2003 and 2003–2004 snow season averaged 0.31 and 0.35 μmols m−2 s−1 for the young and old forests respectively; similar to the relative difference observed during summer. There was a significant seasonal pattern of soil CO2 flux during the winter with fluxes averaging 0.22 μmols m−2 s−1 in December and January and increasing to an average of 0.61 μmols m−2 s−1 in May. Within-plot variability for measurements used in calculating flux was low. The coefficients of variation (CV) for CO2 concentration, snowpack density, and snow depth were 17, 8 and 14%, respectively, yielding a CV for flux measurements within-plot of 29%. A within plot CV of 29% requires 8 sub-samples per plot to estimate the mean flux with a standard error of ±10% of the mean. Variability in CO2 flux estimates among plots (size = 400 m2) was similar to that within plot and was also low (CV = ~28%). With a CV of 28% among plots, ten plots per treatment would have a 50% probability of detecting a 25% difference in treatment means for α = 0.05. 相似文献
70.
Aletaha D Nell VP Stamm T Uffmann M Pflugbeil S Machold K Smolen JS 《Arthritis research & therapy》2005,7(4):R796-R806