Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.
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2005 Jan 15;105(2):821-6. Epub
2004 Sep 23.Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.1, , , , , , , , , , , .1Department of Pediatric Hematology and Oncology, Institute for Cell and Molecular Pathology, Hannover Medical School, Germany.AbstractTreatment resistance, as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation, is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells reflected in the gene expression pattern and that resistance to chemotherapy can be predicted before treatment. To test these hypotheses, gene expression signatures of ALL samples with high MRD load were compared with those of samples without measurable MRD during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes with low expression in resistant samples were predominantly associated with cell-cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. Because treatment response could be predicted with high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.PMID:
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External link. Please review our .The effects of iodine on intelligence in children: a meta-analysis of studies conducted in China.
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):32-42.The effects of iodine on intelligence in children: a meta-analysis of studies conducted in China.1, , , , , , .1The Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China. AbstractThis study quantifies the effects of iodine on the intellectual development of children using a systematic manual literature search of Chinese publications related to iodine deficiency disorders. The Chinese Medical Reference Database, Medline, and Cochrane library were searched electronically in Chinese and English. Inclusion criteria included: studies conducted in China, comparing children (&16 ys) living in naturally iodine sufficient (IS) with those in severely iodine deficient (ID) areas, or children in ID areas born before and after the introduction of iodine supplementation. Intelligent Quotient (IQ) was measured using Binet or Raven Scales. The iodine sufficient control groups were comparable socially, economically, and educationally with the study groups. Random effects models were used in the meta-analysis. Effect size was the standard deviation IQ point (SIQP), which is equivalent to 15 IQ. Thirty-seven reported studies, total 12,291 children, were analysed. The effect size was an increase of 0.83, 0.82, and 0.32 SIQP respectively, for the children living in IS communities compared with those living in ID areas with no iodine supplementation, with inadequate iodine supplementation, or children who had received iodine during their mothers' pregnancy and after birth. These equal to 12.45, 12.3, 4.8 IQ points. Compared with that of children whose mothers were persistently exposed to ID, the total effect size of the 21 entries was an increase of 0.58 SIQP (8.7 IQ points) in the group receiving iodine supplementation during pregnancy. Furthermore, there was an increase on 1.15 SIQP of Binet or 0.8 SIQP on Raven Scale (17.25 or 12 IQ points) for children born more than 3.5 years after iodine supplementation program was introduced. The level of iodine nutrition plays a crucial role in the intellectual development of children. The intelligence damage of children exposed to severe ID was profound, demonstrated by 12.45 IQ points loss and they recovered 8.7 IQ points with iodine supplementation or IS before and during pregnancy. Iodine supplementation before and during pregnancy to women living in severe ID areas could prevent their children from intelligence deficit. This effect becomes evident in children born 3.5 years after the iodine supplementation program was introduced.PMID:
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External link. Please review our .Organic dipole layers for ultralow work function electrodes.
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2014 Sep 23;8(9):9173-80. doi: 10.1021/nn502794z. Epub
2014 Aug 27.Organic dipole layers for ultralow work function electrodes.1, , , , , , , , , , .1Materials Science Laboratory, Sony Deutschland GmbH , Hedelfinger Strasse 61, 70327 Stuttgart, Germany.AbstractThe alignment of the electrode Fermi level with the valence or conduction bands of organic semiconductors is a key parameter controlling the efficiency of organic light-emitting diodes, solar cells, and printed circuits. Here, we introduce a class of organic molecules that form highly robust dipole layers, capable of shifting the work function of noble metals (Au and Ag) down to 3.1 eV, that is, ~1 eV lower than previously reported self-assembled monolayers. The physics behind the considerable interface dipole is elucidated by means of photoemission spectroscopy and density functional theory calculations, and a polymer diode exclusively based on the surface modification of a single electrode in a symmetric, two-terminal Au/poly(3-hexylthiophene)/Au junction is presented. The diode exhibits the remarkable rectification ratio of ~2·10(3), showing high reproducibility, durability (&3 years), and excellent electrical stability. With this evidence, noble metal electrodes with work function values comparable to that of standard cathode materials used in optoelectronic applications are demonstrated. KEYWORDS:
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External link. Please review our .v-Src phosphorylation of connexin 43 on Tyr247 and Tyr265 disrupts gap junctional communication.
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2001 Aug 20;154(4):815-27.v-Src phosphorylation of connexin 43 on Tyr247 and Tyr265 disrupts gap junctional communication.1, , , .1Molecular Carcinogenesis Section, Cancer Research Center of Hawaii, Honolulu, HI 96813, USA.AbstractThe mechanism by which v-Src disrupts connexin (Cx)43 intercellular gap junctional communication (GJC) is not clear. In this study, we determined that Tyr247 (Y247) and the previously identified Tyr265 (Y265) site of Cx43 were the primary phosphorylation targets for activated Src in vitro. We established an in vivo experimental system by stably expressing v-Src and wild-type (wt) Cx43, or Y247F, Y265F, or Y247F/Y265F Cx43 mutants in a Cx43 knockout mouse cell line. Wt and mutant Cx43 localized to the plasma membrane in the absence or presence of v-Src. When coexpressed with v-Src, the Y247F, Y265F, and Y247F/Y265F Cx43 mutants exhibited significantly reduced levels of tyrosine phosphorylation compared with wt Cx43, indicating that Y247 and Y265 were phosphorylation targets of v-Src in vivo. Most importantly, GJC established by the Y247F, Y265F, and Y247F/Y265F Cx43 mutants was resistant to disruption by v-Src. Furthermore, we did not find evidence for a role for mitogen-activated protein kinase in mediating the disruption of GJC by v-Src. We conclude that phosphorylation on Y247 and Y265 of Cx43 is responsible for disrupting GJC in these mammalian cells expressing v-Src.PMID:
[PubMed - indexed for MEDLINE] Analysis of the phosphorylation of GST–Cx43CT by activated Src in vitro. (A) Amino acid sequence of two predicted tryptic peptides of Cx43CT (S244-K258 and Y265-K287) that contain the putative pTyr sites (Y247 and Y265) in the phosphorylated GST–Cx43CT fusion protein. Cx43CT fused to GST begins at V236 in the cytoplasmic tail of Cx43. The amino acids deleted in the Cx43CT deletion mutant are bracketed (P253LSP256). (B) Two-dimensional phosphotryptic peptide analysis of GST fusion proteins with wt or the Cx43CT deletion mutation phosphorylated by activated Src. Phosphotryptic peptides were resolved by electrophoresis (dimension 1) followed by ascending chromatography (dimension 2). Major phosphotryptic peptides are numbered. (C) Phosphoamino acid content of wt or site-directed mutant GST–Cx43CT phosphorylated by activated Src. Equal amounts of the GST–Cx43CT substrates were phosphorylated by Src, acid-hydrolyzed, and separated by electrophoresis at pH 1.9 (dimension 1) followed by electrophoresis at pH 3.5 (dimension 2). The migration positions of the unlabeled pSer, pThr, and pTyr standards are indicated. (D) Phosphotryptic peptide maps of wt and mutant GST–Cx43CT phosphorylated by activated Src. Resolved peptides were from one type of GST–Cx43CT or a mixture of wt and the Y265F GST–Cx43CT mutant. Peptides are numbered as in B.J Cell Biol. 2001 August 20;154(4):815-828.Levels of v-Src kinase activity and Cx43 in the cell clones. (A) In vitro v-Src protein kinase activities. The same amounts of anti-Src TBR serum 6-1-4 were reacted with equal amounts of cell lysate from each clone. The ability of v-Src to phosphorylate the heavy chain of IgG in an immune complex kinase assay was examined. Clone wtC1 infected by the pLXSH vector alone served as a negative control. Asterisks indicate the clones chosen for further biochemical analysis. (B) Expression of Cx43. 40 μg of whole cell lysates was resolved by SDS-PAGE and electrotransferred to Immobilon-P membranes.J Cell Biol. 2001 August 20;154(4):815-828.Localization of wt or mutant Cx43 to the plasma membrane. Top, cells lacking v-S bottom, cells expressing v-Src. Cells were grown to subconfluence on coverslips before being fixed and permeabilized. Cx43CT368 antiserum was used to detect Cx43. Arrowheads indicate the positions of some Cx43 gap junction plaques.J Cell Biol. 2001 August 20;154(4):815-828.Phosphorylation of wt or mutant Cx43 in v-Src–expressing cells. (A) Immunoprecipitation of Cx43. Confluent cells were metabolically labeled with 32Pi. Cx43 was immunoprecipitated from cell lysates with Cx43CT368 antiserum under conditions of antigen excess. The positions of multiple isoforms of phosphorylated Cx43 are shown by brackets. (B) Phosphoamino acid content of Cx43 immunoprecipitated from the cell clones. Immunoprecipitated 32P- labeled Cx43 was acid hydrolyzed and separated in two dimensions as indicated. (C) pTyr content of Cx43 from the cell clones. Cells were grown to confluence and the same amount of Cx43CT368 antiserum was used to immunoprecipitate Cx43 from cell lysates under conditions of antigen excess. The pTyr content of Cx43 was detected with a pTyr antibody (top). Quantitation of pTyr in Cx43 is shown in the bottom part of the figure. The average relative amounts of pTyr of Cx43 were obtained from scans of the Cx43 images of the top and from a second experiment. The levels of pTyr of Cx43 from wtC1 and wtS2 were normalized to 0 and 100%, respectively.J Cell Biol. 2001 August 20;154(4):815-828.Two-dimensional phosphotryptic peptide analysis of wt and mutant forms of Cx43 isolated from cells metabolically labeled with 32Pi. Phosphotryptic peptides were resolved by electrophoresis (dimension 1) followed by ascending chromatography (dimension 2). Boxes show phosphopeptides tentatively ascribed to the Y247 or the Y265 containing peptides.J Cell Biol. 2001 August 20;154(4):815-828.Fluorescent images from microinjection of the v-Src– expressing cell clones. Fluorescent images were captured and recorded at 4–6 min after microinjections of single cells with Lucifer yellow dye.J Cell Biol. 2001 August 20;154(4):815-828.The role of MAP kinase in the disruption of GJC by v-Src. Cells were untreated or treated with EGF or the MEK inhibitor before being lysed. The same amount of whole cell lysate was loaded for each sample. Activated MAP kinase was detected with an antibody recognizing phosphorylated MAP kinase. Lane 1, untreated wtC1; lane 2, wtC1 treated with 100 ng/ml EGF for 2 lane 3, untreated wtS2; and lanes 4 and 5, duplicate plates of wtS2 treated with 100 μM MEK inhibitor for 1 h. The same membrane used to detect active MAP kinase was stripped and reprobed with an antibody recognizing all isoforms of p42 MAP kinase. The ratios of active MAP kinase to total MAP kinase were determined and normalized to the untreated wtS2 cells set as 100%. Average GJC values obtained from multiple plates are reported for lanes 1, 3, and 4, and the GJC value from a single plate that was also used to measure the level of activated MAP kinase is shown for lane 5. The number of injections contributing to the determination of GJC is shown in brackets. Active MAP kinase was reduced to 5 and 2% of the starting level by the 1 h treatment with MEK inhibitor as shown in lanes 4 and 5, respectively.J Cell Biol. 2001 August 20;154(4):815-828.A model for the interaction of v-Src with Cx43. In this model, the binding of Cx43 to v-Src is dependent upon SH3 and SH2 domain interactions, which are important for v-Src–induced phosphorylation of Cx43 at the Y265 site and the subsequent phosphorylation at the Y247 site, leading to closure of the Cx43 channel (details described in Discussion). PXXP denotes the proline-rich sequence of Cx43 P274–P284 that interacts with the SH3 domain of v-Src. For simplicity, gap junction channels are represented as cylinders. PM stands for plasma membrane.J Cell Biol. 2001 August 20;154(4):815-828.Publication TypesMeSH TermsSubstancesGrant SupportFull Text SourcesOther Literature SourcesMolecular Biology DatabasesMiscellaneous
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