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Sample records for protein flt 1-3

  1. Neutralizing VEGF bioactivity with a soluble chimeric VEGF receptor protein flt (1-3) IGG inhibits testosterone stimulated prostate growth in castrated mice

    International Nuclear Information System (INIS)

    Hammarsten, P.; Lissbrant, E.; Lissbrant, I.-F.; Haeggstroem-Rudolfsson, S.; Bergh, A.; Ferrara, N.

    2003-01-01

    Recent studies show that testosterone stimulated growth of the glandular tissue in the ventral prostate in adult castrated rats is preceded by increased epithelial VEGF synthesis, endothelial cell proliferation, vascular growth, and increased blood flow. These observations suggest that testosterone stimulated prostate growth could be angiogenesis dependent, and that VEGF could play a central role in this. To test this hypothesis adult male mice were castrated and after one week treated with testosterone and vehicle, or with testosterone and a soluble chimeric VEGF-receptor flt(1-3)IgG protein. Treatment with testosterone markedly increased endothelial cell proliferation, vascular volume and organ weight in the ventral prostate lobe in the vehicle groups, but these responses were inhibited but not fully prevented by anti-VEGF treatment. The testosterone stimulated increase in epithelial cell proliferation was unaffected by flt(1-3)IgG, but endothelial and epithelial cell apoptosis were increased in the anti-VEGF compared to the vehicle treated group. This study, together with our previous observations, suggest that testosterone stimulates vascular growth in the ventral prostate lobe indirectly by increasing epithelial VEGF synthesis and that this is a necessary component in testosterone stimulated prostate growth

  2. Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity.

    Science.gov (United States)

    Palmer, Kirsten R; Kaitu'u-Lino, Tu'uhevaha J; Hastie, Roxanne; Hannan, Natalie J; Ye, Louie; Binder, Natalie; Cannon, Ping; Tuohey, Laura; Johns, Terrance G; Shub, Alexis; Tong, Stephen

    2015-12-01

    In preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT-1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a-specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a. © 2015 American Heart Association, Inc.

  3. Pre-apoptotic response to therapeutic DNA damage involves protein modulation of Mcl-1, Hdm2 and Flt3 in acute myeloid leukemia cells

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    Hovland Randi

    2007-05-01

    Full Text Available Abstract Background Acute myeloid leukemia (AML cells are characterized by non-mutated TP53, high levels of Hdm2, and frequent mutation of the Flt3 receptor tyrosine kinase. The juxtamembrane mutation of FLT3 is the strongest independent marker for disease relapse and is associated with elevated Bcl-2 protein and p53 hyper-phosphorylation in AML. DNA damage forms the basic mechanism of cancer cell eradication in current therapy of AML. Hdm2 and pro-apoptotic Bcl-2 members are among the most intensely induced genes immediately after chemotherapy and Hdm2 is proposed a role in receptor tyrosine kinase regulation. Thus we examined the DNA damage related modulation of these proteins in relation to FLT3 mutational status and induction of apoptosis. Results Within one hour after exposure to ionizing radiation (IR, the AML cells (NB4, MV4-11, HL-60, primary AML cells showed an increase in Flt3 protein independent of mRNA levels, while the Hdm2 protein decreased. The FLT3 mutant MV4-11 cells were resistant to IR accompanied by presence of both Mcl-1 and Hdm2 protein three hours after IR. In contrast, the FLT3 wild type NB4 cells responded to IR with apoptosis and pre-apoptotic Mcl-1 down regulation. Daunorubicin (DNR induced continuing down regulation of Hdm2 and Mcl-1 in both cell lines followed by apoptosis. Conclusion Both IR and DNR treatment resulted in concerted protein modulations of Mcl-1, Hdm2 and Flt3. Cell death induction was associated with persistent attenuation of Mcl-1 and Hdm2. These observations suggest that defining the pathway(s modulating Flt3, Hdm2 and Mcl-1 may propose new strategies to optimize therapy for the relapse prone FLT3 mutated AML patients.

  4. Survey of activated FLT3 signaling in leukemia.

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    Ting-lei Gu

    Full Text Available Activating mutations of FMS-like tyrosine kinase-3 (FLT3 are found in approximately 30% of patients with acute myeloid leukemia (AML. FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3 and B cell acute lymphoblastic leukemia (normal and amplification of FLT3 cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC, we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia.

  5. FLT3 mutations in canine acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    Suter, Steven E; Small, George W; Seiser, Eric L; Thomas, Rachael; Breen, Matthew; Richards, Kristy L

    2011-01-01

    FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated protein in a variety of human acute leukemias. Mutations leading to constitutively active FLT3, including internal tandem duplications of the juxtamembrane domain (ITD), result in continuous cellular proliferation, resistance to apoptotic cell death, and a poorer prognosis. A better understanding of the molecular consequences of FLT3 activation would allow improved therapeutic strategies in these patients. Canine lymphoproliferative diseases, including lymphoma and acute leukemias, share evolutionarily conserved chromosomal aberrations and exhibit conserved mutations within key oncogenes when compared to their human counterparts. A small percentage of canine acute lymphocytic leukemias (ALL) also exhibit FLT3 ITD mutations. We molecularly characterized FLT3 mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real-time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via in vitro proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting. The canine B-cell leukemia cell line, GL-1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have FLT3 ITD mutations and FLT3 mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the FLT3 mutation. Finally, western blots were used to confirm the conserved downstream mediators of FLT3 activating mutations. These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias

  6. Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.

    Science.gov (United States)

    Kapoor, Shivani; Natarajan, Karthika; Baldwin, Patrick R; Doshi, Kshama A; Lapidus, Rena G; Mathias, Trevor J; Scarpa, Mario; Trotta, Rossana; Davila, Eduardo; Kraus, Manfred; Huszar, Dennis; Tron, Adriana E; Perrotti, Danilo; Baer, Maria R

    2018-01-01

    Purpose: fms -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G 1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR . ©2017 American Association for Cancer Research.

  7. Targeting oncoprotein stability overcomes drug resistance caused by FLT3 kinase domain mutations.

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    Chuanjiang Yu

    Full Text Available FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML. Internal tandem duplications (ITDs in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.

  8. Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia.

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    Reiter, K; Polzer, H; Krupka, C; Maiser, A; Vick, B; Rothenberg-Thurley, M; Metzeler, K H; Dörfel, D; Salih, H R; Jung, G; Nößner, E; Jeremias, I; Hiddemann, W; Leonhardt, H; Spiekermann, K; Subklewe, M; Greif, P A

    2018-02-01

    The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization. Here, we analyzed the effect of tyrosine kinase inhibitors (TKIs) on the localization of the FLT3 receptor and its mutants. TKI treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D835Y mutants. In T cell-mediated cytotoxicity (TCMC) assays, using a bispecific FLT3 × CD3 antibody construct, the combination with TKI treatment increased TCMC in the FLT3-ITD-positive AML cell lines MOLM-13 and MV4-11, patient-derived xenograft cells and primary patient samples. Our findings provide the basis for rational combination of TKI and FLT3-directed immunotherapy with potential benefit for FLT3-ITD-positive AML patients.

  9. All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.

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    Ma, Hayley S; Greenblatt, Sarah M; Shirley, Courtney M; Duffield, Amy S; Bruner, J Kyle; Li, Li; Nguyen, Bao; Jung, Eric; Aplan, Peter D; Ghiaur, Gabriel; Jones, Richard J; Small, Donald

    2016-06-09

    FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)(+) LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD(+) cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD(+) cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD(+) LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD(+) patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein Bcl6, limiting the drug's apoptotic effect. However, cotreatment with ATRA reduces Bcl6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD(+) LSCs and reduce the rate of relapse in AML patients with FLT3 mutations.

  10. Low-molecular weight heparin increases circulating sFlt-1 levels and enhances urinary elimination.

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    Henning Hagmann

    Full Text Available RATIONALE: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1, an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. OBJECTIVE: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. METHODS AND RESULTS: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. CONCLUSION: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.

  11. Production of Protein Concentrate and 1,3-Propanediol by Wheat-Based Thin Stillage Fermentation.

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    Ratanapariyanuch, Kornsulee; Shim, Youn Young; Emami, Shahram; Reaney, Martin J T

    2017-05-17

    Fermentation of wheat with yeast produces thin stillage (W-TS) and distiller's wet grains. A subsequent fermentation of W-TS (two-stage fermentation, TSF) with endemic bacteria at 25 and 37 °C decreased glycerol and lactic acid concentrations, while 1,3-propanediol (1,3-PD) and acetic acid accumulated with greater 1,3-PD and acetic acid produced at 37 °C. During TSF, W-TS colloids coagulated and floated in the fermentation medium producing separable liquid and slurry fractions. The predominant endemic bacteria in W-TS were Lactobacillus panis, L. gallinarum, and L. helveticus, and this makeup did not change substantially as fermentation progressed. As nutrients were exhausted, floating particles precipitated. Protein contents of slurry and clarified liquid increased and decreased, respectively, as TSF progressed. The liquid was easily filtered through an ultrafiltration membrane. These results suggested that TSF is a novel method for W-TS clarification and production of protein concentrates and 1,3-PD from W-TS.

  12. Inhibitory effect of turmeric curcuminoids on FLT3 expression and cell cycle arrest in the FLT3-overexpressing EoL-1 leukemic cell line.

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    Tima, Singkome; Ichikawa, Hideki; Ampasavate, Chadarat; Okonogi, Siriporn; Anuchapreeda, Songyot

    2014-04-25

    Leukemia is a hematologic malignancy with a frequent incidence and high mortality rate. Previous studies have shown that the FLT3 gene is overexpressed in leukemic blast cells, especially in acute myeloid leukemia. In this study, a commercially available curcuminoid mixture (1), pure curcumin (2), pure demethoxycurcumin (3), and pure bisdemethoxycurcumin (4) were investigated for their inhibitory effects on cell growth, FLT3 expression, and cell cycle progression in an FLT3-overexpressing EoL-1 leukemic cell line using an MTT assay, Western blotting, and flow cytometry, respectively. The mixture (1) and compounds 2-4 demonstrated cytotoxic effects with IC50 values ranging from 6.5 to 22.5 μM. A significant decrease in FLT3 protein levels was found after curcuminoid treatment with IC20 doses, especially with mixture 1 and compound 2. In addition, mixture 1 and curcumin (2) showed activity on cell cycle arrest at the G0/G1 phase and decreased the FLT3 and STAT5A protein levels in a dose-dependent manner. Compound 2 demonstrated the greatest potential for inhibiting cell growth, cell cycle progression, and FLT3 expression in EoL-1 cells. This investigation has provided new findings regarding the effect of turmeric curcuminoids on FLT3 expression in leukemic cells.

  13. Serum Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1 Predicts the Severity of Acute Pancreatitis

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    Paulina Dumnicka

    2016-12-01

    Full Text Available Organ failure is the most important determinant of the severity of acute pancreatitis (AP. Soluble fms-like tyrosine kinase 1 (sFlt-1 is positively associated with organ failure in sepsis. Our aim was to evaluate the diagnostic utility of automated sFlt-1 measurements for early prediction of AP severity. Adult patients (66 with AP were recruited, including 46 with mild (MAP, 15 with moderately-severe (MSAP and 5 with severe AP (SAP. Serum and urine samples were collected twice. Serum sFlt-1 was measured with automated electrochemiluminescence immunoassay. Serum concentrations of sFlt-1 were significantly higher in patients with MSAP and SAP as compared to MAP. SAP patients had the highest concentrations. At 24 and 48 h, sFlt-1 positively correlated with inflammatory markers (leukocyte count, C-reactive protein, kidney function (creatinine, urea, cystatin C, serum and urine neutrophil gelatinase-associated lipocalin, urine albumin/creatinine ratio, D-dimer and angiopoietin-2. sFlt-1 positively correlated with the bedside index of severity in AP (BISAP score and the duration of hospital stay. Serum sFlt-1 above 139 pg/mL predicted more severe AP (MSAP + SAP. In the early phase of AP, sFlt-1 is positively associated with the severity of AP and predicts organ failure, in particular kidney failure. Serum sFlt-1 may be a practical way to improve early assessment of AP severity.

  14. Flt3 ligand-eGFP-reporter expression characterizes functionally distinct subpopulations of CD150+ long-term repopulating murine hematopoietic stem cells.

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    Tornack, Julia; Kawano, Yohei; Garbi, Natalio; Hämmerling, Günter J; Melchers, Fritz; Tsuneto, Motokazu

    2017-09-01

    The pool of hematopoietic stem cells (HSCs) in the bone marrow is a mixture of resting, proliferating, and differentiating cells. Long-term repopulating HSCs (LT-HSC) are routinely enriched as Lin - Sca1 + c-Kit + CD34 - Flt3 - CD150 + CD48 - cells. The Flt3 ligand (Flt3L) and its receptor Flt3 are important regulators of HSC maintenance, expansion and differentiation. Using Flt3L-eGFP reporter mice, we show that endogenous Flt3L-eGFP-reporter RNA expression correlates with eGFP-protein expression. This Flt3L-eGFP-reporter expression distinguishes two LT-HSC populations with differences in gene expressions and reconstituting potential. Thus, Flt3L-eGFP-reporter low cells are identified as predominantly resting HSCs with long-term repopulating capacities. In contrast, Flt3L-eGFP-reporter high cells are in majority proliferating HSCs with only short-term repopulating capacities. Flt3L-eGFP-reporter low cells express hypoxia, autophagy-inducing, and the LT-HSC-associated genes HoxB5 and Fgd5, while Flt3L-eGFP-reporter high HSCs upregulate genes involved in HSC differentiation. Flt3L-eGFP-reporter low cells develop to Flt3L-eGFP-reporter high cells in vitro, although Flt3L-eGFP-reporter high cells remain Flt3L-eGFP-reporter high . CD150 + Flt3L-eGFP-reporter low cells express either endothelial protein C receptor (EPCR) or CD41, while Flt3L-eGFP-reporter high cells do express EPCR but not CD41. Thus, FACS-enrichment of Flt3/ Flt3L-eGFP-reporter negative, Lin - CD150 + CD48 - EPCR + CD41 + HSCs allows a further 5-fold enrichment of functional LT-HSCs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR1/sFlt1 requires Arf1, Arf6, and Rab11 GTPases.

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    Jae-Joon Jung

    Full Text Available The soluble form of vascular endothelial growth factor receptor 1 (sVEGFR-1/sFlt1 is generated by alternative splicing of the FLT1 gene. Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with diseases such as preeclampsia and chronic kidney disease. To date, the secretory transport process involved in the secretion of sFlt1 is poorly understood. In the present study, we investigated the itinerary of sFlt1 trafficking along the secretory pathway. To understand the timecourse of sFlt1 secretion, endothelial cells stably expressing sFlt1 were metabolically radiolabeled with [(35S]-methionine and cysteine. Our results indicate that after initial synthesis the levels of secreted [(35S]-sFlt1 in the extracellular medium peaks at 8 hours. Treatment with brefeldin A (BFA, a drug which blocks trafficking between the endoplasmic reticulum (ER and the Golgi complex, inhibited extracellular release of sFlt1 suggesting that ER to Golgi and intra-Golgi trafficking of sFlt1 are essential for its secretion. Furthermore, we show that ectopic expression of dominant-negative mutant forms of Arf1, Arf6, and Rab11 as well as siRNA-mediated knockdown of these GTPases block secretion of sFlt1 during normoxic and hypoxic conditions suggesting role for these small GTPases. This work is the first to report role of regulatory proteins involved in sFlt1 trafficking along the secretory pathway and may provide insights and new molecular targets for the modulation of sFlt-1 release during physiological and pathological conditions.

  16. Lipoprotein(a) and dietary proteins: casein lowers lipoprotein(a) concentrations as compared with soy protein1-3

    DEFF Research Database (Denmark)

    Nilausen, Karin Johanne; Meinertz, H.

    1999-01-01

    Lipoprotein(a), plasma lipoproteins, dietary proteins, soy protein, casein, liquid-formula, coronary artery disease, men, Denmark......Lipoprotein(a), plasma lipoproteins, dietary proteins, soy protein, casein, liquid-formula, coronary artery disease, men, Denmark...

  17. Proteomic analysis of tissue from α1,3-galactosyltransferase knockout mice reveals that a wide variety of proteins and protein fragments change expression level.

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    Louise Thorlacius-Ussing

    Full Text Available A barrier in a pig-to-man xenotransplantation is that the Galα1-3Galβ1-4GlcNAc-R carbohydrate (α-Gal epitope expressed on pig endothelial cells reacts with naturally occurring antibodies in the recipient's blood leading to rejection. Deletion of the α1,3-galactosyltransferase gene prevents the synthesis of the α-Gal epitope. Therefore, knockout models of the α1,3-galactosyltransferase gene are widely used to study xenotransplantation. We have performed proteomic studies on liver and pancreas tissues from wild type and α1,3-galactosyltransferase gene knockout mice. The tissues were analyzed by two-dimensional polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry. The analyses revealed that a wide variety of proteins and protein fragments are differentially expressed suggesting that knockout of the α1,3-galactosyltransferase gene affects the expression of several other genes.

  18. Unlocking the potential of translation for FLT

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    Alenka Kocbek

    2014-12-01

    Full Text Available The paper proposes unlocking the potential of translation for foreign language teaching (FLT by seeking to create synergies with the related discipline of translation science (TS. This aim is in keeping with the guidelines for language teaching provided in the Common European Framework of Languages, which introduced a model of communicative competences including communicative language competences as those which enable a person to act by drawing on specific linguistic means. First, an overview of the changing status of translation in FLT is presented – from its being considered a fundamental teaching method and basic skill in the Grammar-Translation Method, to its being all but outlawed in more recent communicative and task-based approaches, to its final rehabilitation in recent decades. It is then shown that, in the development of FLT, the parallel evolution of TS somehow failed to be acknowledged and, consequently, the opportunity to create valuable synergies between the two disciplines was missed. Following the stance of authors who have advocated the use of translation in FLT, it is argued that translation can effectively supplement the development of the four traditional language skills and, moreover, that some of the insights developed by TS can effectively be integrated into FLT as strategies aimed at enhancing leaners’ cross-cultural communicative competences. To this purpose, selected insights from TS (e.g. the functional approach and the skopos theory, the cultureme model, the theory of memes are discussed and their potential for creating synergies with FLT are explored. Finally, the paper discusses the omnipresence of different forms of translation and interpreting in contemporary societies and shows that this naturally and logically calls for a systematic inclusion of translation in FLT.

  19. The juxtamembrane domain in ETV6/FLT3 is critical for PIM-1 up-regulation and cell proliferation

    International Nuclear Information System (INIS)

    Vu, Hoang Anh; Xinh, Phan Thi; Kano, Yasuhiko; Tokunaga, Katsushi; Sato, Yuko

    2009-01-01

    We recently reported that the ETV6/FLT3 fusion protein conferred interleukin-3-independent growth on Ba/F3 cells. The present study has been conducted to assess role of the juxtamembrane domain of FLT3 for signal transduction and cell transformation. The wild-type ETV6/FLT3 fusion protein in transfected cells was a constitutively activated tyrosine kinase that led to up-regulation of PIM-1 and activations of STAT5, AKT, and MAPK. Deletion of the juxtamembrane domain abrogated interleukin-3-independent growth of the transfected cells and PIM-1 up-regulation, whereas it retained compatible levels of phosphorylations of STAT5, AKT, and MAPK. Further deletion of N-terminal region of the tyrosine kinase I domain of FLT3 completely abolished these phosphorylations. Our data indicate that the juxtamembrane domain of FLT3 in ETV6/FLT3 fusion protein is critical for cell proliferation and PIM-1 up-regulation that might be independent of a requirement for signaling through STAT5, MAPK, and AKT pathways.

  20. Protein design and engineering of a de novo pathway for microbial production of 1,3-propanediol from glucose.

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    Chen, Zhen; Geng, Feng; Zeng, An-Ping

    2015-02-01

    Protein engineering to expand the substrate spectrum of native enzymes opens new possibilities for bioproduction of valuable chemicals from non-natural pathways. No natural microorganism can directly use sugars to produce 1,3-propanediol (PDO). Here, we present a de novo route for the biosynthesis of PDO from sugar, which may overcome the mentioned limitations by expanding the homoserine synthesis pathway. The accomplishment of pathway from homoserine to PDO is achieved by protein engineering of glutamate dehydrogenase (GDH) and pyruvate decarboxylase to sequentially convert homoserine to 4-hydroxy-2-ketobutyrate and 3-hydroxypropionaldehyde. The latter is finally converted to PDO by using a native alcohol dehydrogenase. In this work, we report on experimental accomplishment of this non-natural pathway, especially by protein engineering of GDH for the key step of converting homoserine to 4-hydroxy-2-ketobutyrate. These results show the feasibility and significance of protein engineering for de novo pathway design and overproduction of desired industrial products. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Protein binding of N-2-mercaptoethyl-1,3-diaminopropane via mixed disulfide formation after oral administration of WR 2721

    Energy Technology Data Exchange (ETDEWEB)

    Tabachnik, N.F.; Blackburn, P.; Peterson, C.M.; Cerami, A.

    1982-02-01

    Earlier studies have shown that WR 2721 (H2N-(CH2)3-NH(CH2)2SPO3H2) is converted to its free thiol form, N-2-mercaptoethyl-1,3-diaminopropane (MDP), at the acidic pH of the stomach. MDP is a radioprotective compound and a mucolytic agent capable of decreasing sputum viscosity in the lungs of patients with cystic fibrosis. Conversion of WR 2721 and MDP to the corresponding sulfonic acid (MDP-SO3H) permits quantitative determination of these compounds in physiological fluids by use of an automatic amino acid analyzer. After oral administration of WR 2721 to human patients and rabbits it is converted to MDP and the free thiol form of the drug associates with plasma proteins by mixed disulfide linkage. The plasma proteins serve as a depot and reservoir of MDP for potential exchange at the tissues. When incubated with whole sputum or with purified mucin solutions in vitro, MDP decreased the viscosity of these solutions by reduction of the accessible disulfide bonds of the mucin molecule and was subsequently found in mixed disulfide association with the mucin molecule. The association of MDP with proteins via mixed disulfide linkage has important implications for the development of optimal dose regimens for administration of WR 2721 to patients.

  2. Protein binding of N-2-mercaptoethyl-1,3-diaminopropane via mixed disulfide formation after oral administration of WR 2721

    International Nuclear Information System (INIS)

    Tabachnik, N.F.; Blackburn, P.; Peterson, C.M.; Cerami, A.

    1982-01-01

    Earlier studies have shown that WR 2721 [H2N-(CH2)3-NH(CH2)2SPO3H2] is converted to its free thiol form, N-2-mercaptoethyl-1,3-diaminopropane (MDP), at the acidic pH of the stomach. MDP is a radioprotective compound and a mucolytic agent capable of decreasing sputum viscosity in the lungs of patients with cystic fibrosis. Conversion of WR 2721 and MDP to the corresponding sulfonic acid (MDP-SO3H) permits quantitative determination of these compounds in physiological fluids by use of an automatic amino acid analyzer. After oral administration of WR 2721 to human patients and rabbits it is converted to MDP and the free thiol form of the drug associates with plasma proteins by mixed disulfide linkage. The plasma proteins serve as a depot and reservoir of MDP for potential exchange at the tissues. When incubated with whole sputum or with purified mucin solutions in vitro, MDP decreased the viscosity of these solutions by reduction of the accessible disulfide bonds of the mucin molecule and was subsequently found in mixed disulfide association with the mucin molecule. The association of MDP with proteins via mixed disulfide linkage has important implications for the development of optimal dose regimens for administration of WR 2721 to patients

  3. Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions

    Directory of Open Access Journals (Sweden)

    Caroline Benedicte Nitter Engen

    2014-12-01

    Full Text Available Internal tandem duplications (ITDs of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3 receptor are present in approximately 25% of patients with acute myeloid leukemia (AML. The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML.

  4. Soluble Flt-1 and PlGF: new markers of early pregnancy loss?

    LENUS (Irish Health Repository)

    Muttukrishna, Shanthi

    2012-01-31

    Recent data have indicated a relationship between placental oxygen and angiogenic protein levels in the first trimester of normal pregnancies. Our objective was to investigate if maternal serum levels of angiogenic factors Soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1), soluble Endoglin and placental growth factor (PlGF) are altered in women with symptoms of threatened miscarriage (TM) and if they are predictive of a subsequent miscarriage. Blood samples were collected at 6-10 weeks from women presenting with TM (n = 40), from asymptomatic controls (n = 32) and from non- pregnant women in their luteal phase (n = 14). All samples were assayed for serum level of sFLT-1, PlGF, sEndoglin and HSP70 using commercial ELISAs. Samples were analysed retrospectively on the basis of pregnancy outcome. TM group included 21 women with a normal pregnancy outcome and 19 with subsequent complete miscarriage. The latter subgroup had significantly lower mean maternal serum (MS) sFlt-1 (83%, P<0.001) and PlGF (44%, P<0.001) compared to those with a normal pregnancy outcome. Asymptomatic control pregnant women had similar MS levels of sFlt-1 and PlGF compared to the TM patients with a normal outcome. The mean MS sFlt-1 (>10 fold) and MS PlGF ( approximately 2 fold) levels were significantly (P<0.001) higher in control pregnant women compared to the non-pregnant group in the luteal phase of the menstrual cycle. Soluble Endoglin was not altered in the normal pregnant women compared to non pregnant women, although lower in the TM subgroup with a subsequent miscarriage ( approximately 25%, P<0.001) compared to TM with a live birth. There was no significant difference in the mean MS HSP 70 levels between the different groups. This study shows that sFlt1 and PlGF MS levels are increased by several folds in early pregnancy and that MS sFlt-1 and MS PlGF are markedly decreased in threatened miscarriage patients who subsequently have a miscarriage suggesting these

  5. Soluble Flt-1 and PlGF: new markers of early pregnancy loss?

    LENUS (Irish Health Repository)

    Muttukrishna, Shanthi

    2011-01-01

    Recent data have indicated a relationship between placental oxygen and angiogenic protein levels in the first trimester of normal pregnancies. Our objective was to investigate if maternal serum levels of angiogenic factors Soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1), soluble Endoglin and placental growth factor (PlGF) are altered in women with symptoms of threatened miscarriage (TM) and if they are predictive of a subsequent miscarriage. Blood samples were collected at 6-10 weeks from women presenting with TM (n = 40), from asymptomatic controls (n = 32) and from non- pregnant women in their luteal phase (n = 14). All samples were assayed for serum level of sFLT-1, PlGF, sEndoglin and HSP70 using commercial ELISAs. Samples were analysed retrospectively on the basis of pregnancy outcome. TM group included 21 women with a normal pregnancy outcome and 19 with subsequent complete miscarriage. The latter subgroup had significantly lower mean maternal serum (MS) sFlt-1 (83%, P<0.001) and PlGF (44%, P<0.001) compared to those with a normal pregnancy outcome. Asymptomatic control pregnant women had similar MS levels of sFlt-1 and PlGF compared to the TM patients with a normal outcome. The mean MS sFlt-1 (>10 fold) and MS PlGF (∼2 fold) levels were significantly (P<0.001) higher in control pregnant women compared to the non-pregnant group in the luteal phase of the menstrual cycle. Soluble Endoglin was not altered in the normal pregnant women compared to non pregnant women, although lower in the TM subgroup with a subsequent miscarriage (∼25%, P<0.001) compared to TM with a live birth. There was no significant difference in the mean MS HSP 70 levels between the different groups. This study shows that sFlt1 and PlGF MS levels are increased by several folds in early pregnancy and that MS sFlt-1 and MS PlGF are markedly decreased in threatened miscarriage patients who subsequently have a miscarriage suggesting these proteins are

  6. Soluble FLT-1 rules placental destiny.

    Science.gov (United States)

    Yamashita, Michiko; Kumasawa, Keiichi; Nakamura, Hitomi; Kimura, Tadashi

    2018-02-19

    Placenta previa is an abnormality in which the placenta covers the internal uterine os, and it can cause serious morbidity and mortality in both mother and fetus due to catastrophic hemorrhage. Some pregnant women recover from placenta previa due to a phenomenon called "migration." However, the mechanism of "migration" of the placenta has not been elucidated. Human placentas were collected from patients with placenta previa and those with no abnormal placentation (control). A microarray analysis was performed to detect the genes up- or down-regulated only in the caudal part in the previa group. Specific mRNA expression was evaluated using real-time quantitative reverse transcription PCR (qRT-PCR). Unilateral uterine artery ablation of 8.5 dpc mice was performed to reproduce the reduction of placental blood supply, and weights of the placentas and fetuses were evaluated in 18.5 dpc. Specific mRNA expression was also evaluated in mice placentas. According to the result of the microarray analysis, we focused on soluble fms-like tyrosine kinase-1 (sFLT-1) and hypoxia-inducible factor-1 (HIF-1) alpha. The sFLT-1 expression level is locally high in the caudal part of the human placenta in patients with placenta previa. In mice experiments, the weights of the placentas and fetuses were significantly smaller in the ablation side than those in the control side, and the sFlt-1 expression level was significantly higher in the ablation side than in the control side. Our study suggests that "migration" of the placenta is derived from placental degeneration at the caudal part of the placenta, and sFlt-1 plays a role in this placental degeneration. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc

    Directory of Open Access Journals (Sweden)

    Marks David R

    2009-01-01

    Full Text Available Abstract Background Neurotrophins are important regulators of growth and regeneration, and acutely, they can modulate the activity of voltage-gated ion channels. Previously we have shown that acute brain-derived neurotrophic factor (BDNF activation of neurotrophin receptor tyrosine kinase B (TrkB suppresses the Shaker voltage-gated potassium channel (Kv1.3 via phosphorylation of multiple tyrosine residues in the N and C terminal aspects of the channel protein. It is not known how adaptor proteins, which lack catalytic activity, but interact with members of the neurotrophic signaling pathway, might scaffold with ion channels or modulate channel activity. Results We report the co-localization of two adaptor proteins, neuronal Src homology and collagen (nShc and growth factor receptor-binding protein 10 (Grb10, with Kv1.3 channel as demonstrated through immunocytochemical approaches in the olfactory bulb (OB neural lamina. To further explore the specificity and functional ramification of adaptor/channel co-localization, we performed immunoprecipitation and Western analysis of channel, kinase, and adaptor transfected human embryonic kidney 293 cells (HEK 293. nShc formed a direct protein-protein interaction with Kv1.3 that was independent of BDNF-induced phosphorylation of Kv1.3, whereas Grb10 did not complex with Kv1.3 in HEK 293 cells. Both adaptors, however, co-immunoprecipitated with Kv1.3 in native OB. Grb10 was interestingly able to decrease the total expression of Kv1.3, particularly at the membrane surface, and subsequently eliminated the BDNF-induced phosphorylation of Kv1.3. To examine the possibility that the Src homology 2 (SH2 domains of Grb10 were directly binding to basally phosphorylated tyrosines in Kv1.3, we utilized point mutations to substitute multiple tyrosine residues with phenylalanine. Removal of the tyrosines 111–113 and 449 prevented Grb10 from decreasing Kv1.3 expression. In the absence of either adaptor protein

  8. A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia.

    Science.gov (United States)

    Shanmugam, Rajasubramaniam; Gade, Padmaja; Wilson-Weekes, Annique; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A; Baghdadi, Tareq Al; Sargent, Katie J; Cripe, Larry D; Kalvakolanu, Dhananjaya V; Boswell, H Scott

    2012-01-15

    Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB-and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD(+) cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD(+) AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD(+) human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD(+) AMLs had selective nuclear activation of p52NF-κB. Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD(+) AML. ©2011 AACR.

  9. Heterogeneity in stabilization phenomena in FLT PET images of canines

    International Nuclear Information System (INIS)

    Simoncic, Urban; Jeraj, Robert

    2014-01-01

    3'-( 18 F)fluoro-3'-deoxy-L-thymidine (FLT) is a PET marker of cellular proliferation. Its tissue uptake rate is often quantified with a Standardized Uptake Value (SUV), although kinetic analysis provides a more accurate quantification. The purpose of this study is to investigate the heterogeneity in FLT stabilization phenomena. The study was done on 15 canines with spontaneously occurring sinonasal tumours. They were imaged dynamically for 90 min with FLT PET/CT twice; before and during the radiotherapy. Images were analyzed for kinetics on a voxel basis through compartmental analysis. Stabilization curves were calculated as a time-dependant correlation between the time-dependant SUV and the kinetic parameters (voxel values within the tumour were correlated). Stabilization curves were analyzed for stabilization speed, maximal correlation and correlation decrease following the maximal correlation. These stabilization parameters were correlated with the region-averaged kinetic parameters. The FLT SUV was highly correlated with vasculature fraction immediately post-injection, followed by maximum in correlation with the perfusion/permeability. At later times post-injection the FLT SUV was highly correlated (Pearson correlation coefficient above 0.95) with the FLT influx parameter for cases with tumour-averaged SUV 30–50 min above 2, while others were indeterminate (correlation coefficients from 0.1 to 0.97). All cases with highly correlated SUV and FLT influx parameter had correlation coefficient within 0.5% of its maximum in the period of 30–50 min post-injection. Stabilization time was inversely proportional to the FLT influx rate. Correlation between the FLT SUV and FLT influx parameter dropped at later times post-injection with drop being proportional to the dephosphorylation rate. The FLT was found to be metabolically stable in canines. FLT PET imaging protocol should define minimal and maximal FLT uptake period, which would be 30–50

  10. Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

    NARCIS (Netherlands)

    Holwerda, Kim M.; Burke, Suzanne D.; Faas, Marijke M.; Zsengeller, Zsuzsanna; Stillman, Isaac E.; Kang, Peter M.; van Goor, Harry; McCurley, Amy; Jaffe, Iris Z.; Karumanchi, S. Ananth; Lely, A. Titia

    Soluble fms-like tyrosine kinase 1 (sFlt1), a circulating antiangiogenic protein, is elevated in kidney diseases and contributes to the development of preeclampsia. Hydrogen sulfide is a vasorelaxant and proangiogenic gas with therapeutic potential in several diseases. Therefore, we evaluated the

  11. Regulation mechanisms of the FLT3-ligand after irradiation

    International Nuclear Information System (INIS)

    Prat-Lepesant, M.

    2005-06-01

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  12. Sparse "1"3C labelling for solid-state NMR studies of P. pastoris expressed eukaryotic seven-transmembrane proteins

    International Nuclear Information System (INIS)

    Liu, Jing; Liu, Chang; Fan, Ying; Munro, Rachel A.; Ladizhansky, Vladimir; Brown, Leonid S.; Wang, Shenlin

    2016-01-01

    We demonstrate a novel sparse "1"3C labelling approach for methylotrophic yeast P. pastoris expression system, towards solid-state NMR studies of eukaryotic membrane proteins. The labelling scheme was achieved by co-utilizing natural abundance methanol and specifically "1"3C labelled glycerol as carbon sources in the expression medium. This strategy improves the spectral resolution by 1.5 fold, displays site-specific labelling patterns, and has advantages for collecting long-range distance restraints for structure determination of large eukaryotic membrane proteins by solid-state NMR.

  13. Regulation mechanisms of the FLT3-ligand after irradiation; Mecanismes de regulation du FLT3-ligand apres irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Prat-Lepesant, M

    2005-06-15

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  14. Activation of PAR-1/NADPH oxidase/ROS signaling pathways is crucial for the thrombin-induced sFlt-1 production in extravillous trophoblasts: possible involvement in the pathogenesis of preeclampsia.

    Science.gov (United States)

    Huang, Qi-Tao; Chen, Jian-Hong; Hang, Li-Lin; Liu, Shi-San; Zhong, Mei

    2015-01-01

    Preeclampsia was characterized by excessive thrombin generation in placentas and previous researches showed that thrombin could enhance soluble Fms-like tyrosine kinase 1 (sFlt-1) expression in first trimester trophoblasts. However, the detailed mechanism for the sFlt-1 over-production induced by thrombin was largely unknown. The purpose of this study was to explore the possible signaling pathway of thrombin-induced sFlt-1 production in extravillous trophoblasts (EVT). An EVT cell line (HRT-8/SVneo) was treated with various concentrations of thrombin. The mRNA expression and protein secretion of sFlt-1 in EVT were detected with real-time polymerase chain reaction and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production were determined by DCFH-DA. Exposure of EVT to thrombin induced increased intracellular ROS generation and overexpression of sFlt-1 at both mRNA and protein levels in a dose dependent manner. Short interfering RNA (siRNA) directed against PAR-1 or apocynin (an inhibitor of NADPH oxidase) could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. Our results suggested that thrombin increased sFlt-1 production in EVT via the PAR-1 /NADPH oxidase /ROS signaling pathway. This also highlights the PAR-1 / NADPH oxidase / ROS pathway might be a potential therapeutic target for the prevention of preeclampsia in the future. © 2015 S. Karger AG, Basel.

  15. An initial event in the insect innate immune response: structural and biological studies of interactions between β-1,3-glucan and the N-terminal domain of β-1,3-glucan recognition protein.

    Science.gov (United States)

    Dai, Huaien; Hiromasa, Yasuaki; Takahashi, Daisuke; VanderVelde, David; Fabrick, Jeffrey A; Kanost, Michael R; Krishnamoorthi, Ramaswamy

    2013-01-08

    In response to invading microorganisms, insect β-1,3-glucan recognition protein (βGRP), a soluble receptor in the hemolymph, binds to the surfaces of bacteria and fungi and activates serine protease cascades that promote destruction of pathogens by means of melanization or expression of antimicrobial peptides. Here we report on the nuclear magnetic resonance (NMR) solution structure of the N-terminal domain of βGRP (N-βGRP) from Indian meal moth (Plodia interpunctella), which is sufficient to activate the prophenoloxidase (proPO) pathway resulting in melanin formation. NMR and isothermal calorimetric titrations of N-βGRP with laminarihexaose, a glucose hexamer containing β-1,3 links, suggest a weak binding of the ligand. However, addition of laminarin, a glucose polysaccharide (~6 kDa) containing β-1,3 and β-1,6 links that activates the proPO pathway, to N-βGRP results in the loss of NMR cross-peaks from the backbone (15)N-(1)H groups of the protein, suggesting the formation of a large complex. Analytical ultracentrifugation (AUC) studies of formation of the N-βGRP-laminarin complex show that ligand binding induces self-association of the protein-carbohydrate complex into a macro structure, likely containing six protein and three laminarin molecules (~102 kDa). The macro complex is quite stable, as it does not undergo dissociation upon dilution to submicromolar concentrations. The structural model thus derived from this study for the N-βGRP-laminarin complex in solution differs from the one in which a single N-βGRP molecule has been proposed to bind to a triple-helical form of laminarin on the basis of an X-ray crystallographic structure of the N-βGRP-laminarihexaose complex [Kanagawa, M., Satoh, T., Ikeda, A., Adachi, Y., Ohno, N., and Yamaguchi, Y. (2011) J. Biol. Chem. 286, 29158-29165]. AUC studies and phenoloxidase activation measurements conducted with the designed mutants of N-βGRP indicate that electrostatic interactions involving Asp45, Arg54

  16. The biology and targeting of FLT3 in pediatric leukemia

    Directory of Open Access Journals (Sweden)

    Colleen eAnnesley

    2014-09-01

    Full Text Available Despite remarkable improvement in treatment outcomes in pediatric leukemia over the past several decades, the prognosis for high risk groups of acute myeloid leukemia (AML and acute lymphoblastic leukemia (ALL, as well as for relapsed leukemia, remains poor. Intensified chemotherapy regimens have somewhat improved success rates, but at the cost of drastically increased morbidity and long term adverse effects. With the success of imatinib in Philadelphia-chromosome positive leukemia and all-trans retinoic acid in acute promyelocytic leukemia, the quest to find additional molecularly targeted therapies has generated much excitement over the past 15 years. Another such possible target in pediatric acute leukemia is FMS-like tyrosine kinase 3 (FLT3. FLT3 aberrations are among the most frequently identified transforming events in AML, and have significant clinical implications in both high risk pediatric AML and in certain high risk groups of pediatric ALL. Therefore, the successful targeting of FLT3 has tremendous potential to improve outcomes in these subsets of patients. This article will give an overview of the molecular function and signaling of the FLT3 receptor, as well as its pathogenic role in leukemia. We review the discovery of targeting FLT3, discuss currently available FLT3 inhibitors in pediatric leukemia and results of clinical trials to date, and finally, consider the future promise and challenges of FLT3 inhibitor therapy.

  17. Targeting FLT3 Signaling in Childhood Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Amy N. Sexauer

    2017-11-01

    Full Text Available Acute myeloid leukemia (AML is the second most common leukemia of childhood and is associated with high rates of chemotherapy resistance and relapse. Clinical outcomes for children with AML treated with maximally intensive multi-agent chemotherapy lag far behind those of children with the more common acute lymphoblastic leukemia, demonstrating continued need for new therapeutic approaches to decrease relapse risk and improve long-term survival. Mutations in the FMS-like tyrosine kinase-3 receptor gene (FLT3 occur in approximately 25% of children and adults with AML and are associated with particularly poor prognoses. Identification and development of targeted FLT3 inhibitors represents a major precision medicine paradigm shift in the treatment of patients with AML. While further development of many first-generation FLT3 inhibitors was hampered by limited potency and significant toxicity due to effects upon other kinases, the more selective second- and third-generation FLT3 inhibitors have demonstrated excellent tolerability and remarkable efficacy in the relapsed/refractory and now de novo FLT3-mutated AML settings. While these newest and most promising inhibitors have largely been studied in the adult population, pediatric investigation of FLT3 inhibitors with chemotherapy is relatively recently ongoing or planned. Successful development of FLT3 inhibitor-based therapies will be essential to improve outcomes in children with this high-risk subtype of AML.

  18. CSF neurofilament light chain but not FLT3 ligand discriminates Parkinsonian disorders

    Directory of Open Access Journals (Sweden)

    Megan Kristy Herbert

    2015-05-01

    Full Text Available The differentiation between multiple system atrophy (MSA and Parkinson’s disease (PD is difficult, particularly in early disease stages. Therefore, we aimed to evaluate the diagnostic value of neurofilament light chain (NFL, fms-like tyrosine kinase ligand (FLT3L and total tau protein (t-tau in cerebrospinal fluid (CSF as biomarkers to discriminate MSA from PD. Using commercially available enzyme-linked immunoassays (ELISAs, we measured CSF levels of NFL, FLT3L and t-tau in a discovery cohort of 36 PD patients, 27 MSA patients and 57 non-neurological controls and in a validation cohort of 32 PD patients, 25 MSA patients, 15 PSP patients, 5 CBS patients, and 56 non-neurological controls. Cut-offs obtained from individual assays and binary logistic regression models developed from combinations of biomarkers were assessed. CSF levels of NFL were substantially increased in MSA and discriminated between MSA and PD with a sensitivity of 74% and specificity of 92% (AUC = 0.85 in the discovery cohort and with 80% sensitivity and 97% specificity (AUC = 0.94 in the validation cohort. FLT3L levels in CSF were significantly lower in both PD and MSA compared to controls in the discovery cohort, but not in the validation cohort. T-tau levels were significantly higher in MSA than PD and controls. Addition of either FLT3L or t-tau to NFL did not improve discrimination of PD from MSA above NFL alone. Our findings show that increased levels of NFL in CSF offer clinically relevant, high accuracy discrimination between PD and MSA.

  19. Protein cross-linking, peroxidase and beta-1,3-endoglucanase involved in resistance of pea against Orobanche crenata.

    Science.gov (United States)

    Pérez-de-Luque, Alejandro; González-Verdejo, Clara I; Lozano, M Dolores; Dita, Miguel A; Cubero, José I; González-Melendi, Pablo; Risueño, María C; Rubiales, Diego

    2006-01-01

    Root holoparasitic angiosperms, like Orobanche spp, completely lack chlorophyll and totally depend on their host for their supply of nutrients. O. crenata is a severe constraint to the cultivation of legumes and breeding for resistance remains the most economical, feasible, and environmentally friendly method of control. Due to the lack of resistance in commercial pea cultivars, the use of wild relatives for breeding is necessary, and an understanding of the mechanisms underlying host resistance is needed in order to improve screening for resistance in breeding programmes. Compatible and incompatible interactions between O. crenata and pea have been studied using cytochemical procedures. The parasite was stopped in the host cortex before reaching the central cylinder, and accumulation of H2O2, peroxidases, and callose were detected in neighbouring cells. Protein cross-linking in the host cell walls appears as the mechanism of defence, halting penetration of the parasite. In situ hybridization studies have also shown that a peroxidase and a beta-glucanase are differently expressed in cells of the resistant host (Pf651) near the penetration point. The role of these proteins in the resistance to O. crenata is discussed.

  20. The Coordinated P53 and Estrogen Receptor Cis-Regulation at an FLT1 Promoter SNP Is Specific to Genotoxic Stress and Estrogenic Compound

    Science.gov (United States)

    Langen, Jan-Stephan; Schoenfelder, Gilbert; Resnick, Michael A.; Inga, Alberto

    2010-01-01

    Background Recently, we established that a C>T single nucleotide polymorphism (SNP) in the promoter of the VEGF receptor FLT1 gene generates a ½ site p53 response element (RE-T) that results in p53 responsiveness of the promoter. The transcriptional control required an estrogen receptor (ER) ½ site response element (ERE1) 225 nt upstream to the RE-T. Methodology/Principal Findings Here we report the identification of a second ER ½ site (ERE2) located 145 bp downstream of the RE-T and establish that both EREs can impact p53-mediated transactivation of FLT1-T in a manner that is cell type and ER level dependent. Gene reporter assays and ChIP experiments conducted in the breast cancer-derived MCF7 cells revealed that the ERE2 site was sufficient for p53-mediated ERα recruitment and transactivation of the FLT1-T promoter/reporter construct. Surprisingly, unlike the case for other p53 target promoters, p53-mediated transactivation of FLT1-T constructs or expression of the endogenous FLT1 gene, as well as binding of p53 and ER at the promoter constructs, was inducible by doxorubicin but not by 5-fluorouracil. Furthermore, ER activity at FLT1-T was differentially affected by ER ligands, compared to a control TFF1/pS2 ER target promoter. The p53-related transcription factors (TFs) p73 and p63 had no effect on FLT1 transactivation. Conclusions/Significance We establish a new dimension to the p53 master regulatory network where p53-mediated transcription from a ½ site RE can be determined by ER binding at one or more cis-acting EREs in manner that is dependent on level of ER protein, the type of ER ligand and the specific p53-inducing agent. PMID:20422012

  1. Flt3/Flt3L Participates in the Process of Regulating Dendritic Cells and Regulatory T Cells in DSS-Induced Colitis

    Directory of Open Access Journals (Sweden)

    Jing-Wei Mao

    2014-01-01

    Full Text Available The immunoregulation between dendritic cells (DCs and regulatory T cells (T-regs plays an important role in the pathogenesis of ulcerative colitis (UC. Recent research showed that Fms-like tyrosine kinase 3 (Flt3 and Flt3 ligand (Flt3L were involved in the process of DCs regulating T-regs. The DSS-induced colitis model is widely used because of its simplicity and many similarities with human UC. In this study, we observe the disease activity index (DAI and histological scoring, detect the amounts of DCs and T-regs and expression of Flt3/Flt3L, and investigate Flt3/Flt3L participating in the process of DCs regulating T-regs in DSS-induced colitis. Our findings suggest that the reduction of Flt3 and Flt3L expression may possibly induce colonic immunoregulatory imbalance between CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs in DSS-induced colitis. Flt3/Flt3L participates in the process of regulating DCS and T-regs in the pathogenesis of UC, at least, in the acute stage of this disease.

  2. An Assessment of Early Response to Targeted Therapy via Molecular Imaging: A Pilot Study of 3′-deoxy-3′[(18F]-Fluorothymidine Positron Emission Tomography 18F-FLT PET/CT in Prostate Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Kalevi Kairemo

    2017-04-01

    Full Text Available Fluorothymidine is a thymidine analog labeled with fluorine-18 fluorothymidine for positron emission tomography (18F-FLT-PET imaging. Thymidine is a nucleic acid that is used to build DNA. Fluorine-18 fluorothymidine (18F-FLT utilizes the same metabolic pathway as does thymidine but has a very low incidence of being incorporated into the DNA (<1%. 18F-FLT-PET could have a role in the evaluation of response to targeted therapy. We present here a pilot study where we investigated cellular metabolism and proliferation in patients with prostate cancer before and after targeted therapy. Seven patients with Stage IV prostate adenocarcinoma, candidates for targeted therapy inhibiting the hepatocyte growth factor/tyrosine-protein kinase Met (HGF/C-MET pathway, were included in this study. The HGF/C-MET pathway is implicated in prostate cancer progression, and an evaluation of the inhibition of this pathway could be valuable. 18F-FLT was performed at baseline and within four weeks post-therapy. Tumor response was assessed semi-quantitatively and using visual response criteria. The range of SUVmax for 18F-FLT at baseline in the prostate varied from 2.5 to 4.2. This study demonstrated that 18F-FLT with positron emission tomography/computerized tomography (18F-FLT PET/CT had only limited applications in the early response evaluation of prostate cancer. 18F-FLT PET/CT may have some utility in the assessment of response in lymph node disease. However, 18F-FLT PET/CT was not found to be useful in the evaluation of the prostate bed, metastatic skeletal disease, and liver disease.

  3. Sequence/structural analysis of xylem proteome emphasizes pathogenesis-related proteins, chitinases and β-1, 3-glucanases as key players in grapevine defense against Xylella fastidiosa

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    Sandeep Chakraborty

    2016-05-01

    Full Text Available Background. Xylella fastidiosa, the causative agent of various plant diseases including Pierce’s disease in the US, and Citrus Variegated Chlorosis in Brazil, remains a continual source of concern and economic losses, especially since almost all commercial varieties are sensitive to this Gammaproteobacteria. Differential expression of proteins in infected tissue is an established methodology to identify key elements involved in plant defense pathways. Methods. In the current work, we developed a methodology named CHURNER that emphasizes relevant protein functions from proteomic data, based on identification of proteins with similar structures that do not necessarily have sequence homology. Such clustering emphasizes protein functions which have multiple copies that are up/down-regulated, and highlights similar proteins which are differentially regulated. As a working example we present proteomic data enumerating differentially expressed proteins in xylem sap from grapevines that were infected with X. fastidiosa. Results. Analysis of this data by CHURNER highlighted pathogenesis related PR-1 proteins, reinforcing this as the foremost protein function in xylem sap involved in the grapevine defense response to X. fastidiosa. β-1, 3-glucanase, which has both anti-microbial and anti-fungal activities, is also up-regulated. Simultaneously, chitinases are found to be both up and down-regulated by CHURNER, and thus the net gain of this protein function loses its significance in the defense response. Discussion. We demonstrate how structural data can be incorporated in the pipeline of proteomic data analysis prior to making inferences on the importance of individual proteins to plant defense mechanisms. We expect CHURNER to be applicable to any proteomic data set.

  4. Abundance of Flt3 and its ligand in astrocytic tumors

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    Eßbach C

    2013-05-01

    Full Text Available C Eßbach,1 N Andrae,1 D Pachow,1 J-P Warnke,2 A Wilisch-Neumann,1 E Kirches,1 C Mawrin11Department of Neuropathology, Otto-von-Guericke University, Magdeburg, 2Department of Neurosurgery, Paracelsus Hospital, Zwickau, GermanyBackground: Molecular targeted therapies for astrocytic tumors are the subject of growing research interest, due to the limited response of these tumors, especially glioblastoma multiforme, to conventional chemotherapeutic regimens. Several of these approaches exploit the inhibition of receptor tyrosine kinases. To date, it has not been elucidated if fms-like tyrosine kinase-3 (Flt3 and its natural ligand (Flt3L are expressed in astrocytic tumors, although some of the clinically intended small-molecule receptor tyrosine kinase inhibitors affect Flt3, while others do not. More importantly, the recent proof of principle for successful stimulation of the immune system against gliomas in preclinical models via local Flt3L application requires elucidation of this receptor tyrosine kinase pathway in these tumors in more detail. This therapy is based on recruitment of Flt3-positive dendritic cells, but may be corroborated by activity of this signaling pathway in glioma cells.Methods: Receptor and ligand expression was analyzed by real-time polymerase chain reaction in 31 astrocytic tumors (six diffuse and 11 anaplastic astrocytomas, 14 glioblastomas derived from patients of both genders and in glioblastoma cell lines. The two most common activating mutations of the Flt3 gene, ie, internal tandem duplication and D835 point mutation, were assessed by specific polymerase chain reaction.Results: A relatively high abundance of Flt3L mRNA (4%–6% of the reference, β2 microglobulin could be demonstrated in all tumor samples. Flt3 expression could generally be demonstrated by 40 specific polymerase chain reaction cycles and gel electrophoresis in 87% of the tumors, including all grades, although the small quantities of the receptor did

  5. Specific expression of GFPuv-β1,3-N-acetylglucosaminyltransferase 2 fusion protein in fat body of Bombyx mori silkworm larvae using signal peptide

    International Nuclear Information System (INIS)

    Kato, Tatsuya; Park, Enoch Y.

    2007-01-01

    Bombyxin (bx) and prophenoloxidase-activating enzyme (ppae) signal peptides from Bombyx mori, their modified signal peptides, and synthetic signal peptides were investigated for the secretion of GFP uv -β1,3-N-acetylglucosaminyltransferase 2 (GGT2) fusion protein in B. mori Bm5 cells and silkworm larvae using cysteine protease deficient B. mori multiple nucleopolyhedrovirus (BmMNPV-CP - ) and its bacmid. The secretion efficiencies of all signal peptides were 15-30% in Bm5 cells and 24-30% in silkworm larvae, while that of the +16 signal peptide was 0% in Bm5 cells and 1% in silkworm larvae. The fusion protein that contained the +16 signal peptide was expressed specifically in the endoplasmic reticulum (ER) and in the fractions of cell precipitations. Ninety-four percent of total intracellular β1,3-N-acetylglucosaminyltransferase (β3GnT) activity was detected in cell precipitations following the 600, 8000, and 114,000g centrifugations. In the case of the +38 signal peptide, 60% of total intracellular activity was detected in the supernatant from the 114,000g spin, and only 1% was found in the precipitate. Our results suggest that the +16 signal peptide might be situated in the transmembrane region and not cleaved by signal peptidase in silkworm or B. mori cells. Therefore, the fusion protein connected to the +16 signal peptide stayed in the fat body of silkworm larvae with biological function, and was not secreted extracellularly

  6. Expression of the sFLT1 gene in cord blood cells is associated to maternal arsenic exposure and decreased birth weight

    DEFF Research Database (Denmark)

    Remy, Sylvie; Govarts, Eva; Bruckers, Liesbeth

    2014-01-01

    that birth weight decreased with 47 g (95% CI: 16-78 g) for an interquartile range increase of 0.99 μg/L arsenic. The model was adjusted for child's sex, maternal smoking during pregnancy, gestational age, and parity. Higher arsenic concentrations and reduced birth weight were positively associated...... with changes in expression of the sFLT1 (soluble fms-like tyrosine kinase-1) gene in cord blood cells in girls. The protein product of sFLT1 is a scavenger of vascular endothelial growth factor (VEGF) in the extracellular environment and plays a key role in the inhibition of placental angiogenesis. In terms...

  7. A non-canonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia (AML)

    Science.gov (United States)

    Shanmugam, Rajasubramaniam; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A.; Baghdadi, Tareq Al; Sargent, Katie J.; Cripe, Larry D.; Kalvakolanu, Dhananjaya V.; Boswell, H. Scott

    2014-01-01

    Purpose DAPK1, a tumor suppressor, is a rate-limiting effector in an ER stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of AML with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB- and c- jun-responsive genes, was studied. RNAi knockdown studies were performed in Flt3ITD+ve cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were performed to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. Results AMLs characterized by normal karyotype with Flt3ITD were found to have 10-100-fold lower DAPK1 transcripts normalized to the expression of c-jun, a transcriptional activator of DAPK1, as compared to a heterogeneous cytogenetic category. Meis1, a c-jun-responsive adverse AML prognostic gene signature was also measured as control. These Flt3ITD+ve AMLs over-express relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter along with HDAC2 and HDAC6 in the Flt3ITD+ve human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NIK, de-repressed DAPK1. DAPK1-repressed primary Flt3ITD+ve AMLs had selective nuclear activation of p52NF-κB. Conclusions Flt3ITD promotes a non-canonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD+ve AML. PMID:22096027

  8. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

    NARCIS (Netherlands)

    J.E. Park (Julie E.); H.F. Yuen (Hiu Fung); J.B. Zhou (Jian Biao); A.Q.O. Al-aidaroos (Abdul Qader); K. Guo (Ke); P.J.M. Valk (Peter); S.D. Zhang (Shu Dong); W.J. Chng (Wee); C.W. Hong (Cheng William); K. Mills (Ken); Q. Zeng (Qi)

    2013-01-01

    textabstractFLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD

  9. Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones.

    Science.gov (United States)

    Spicer, Julie A; Huttunen, Kristiina M; Miller, Christian K; Denny, William A; Ciccone, Annette; Browne, Kylie A; Trapani, Joseph A

    2012-02-01

    An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure-activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. 1,3,5-Trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone directly targets heat shock protein 27 in hepatocellular carcinoma.

    Science.gov (United States)

    Fu, Wei-Ming; Wang, Wei-Mao; Wang, Hua; Zhu, Xiao; Liang, Yan; Kung, Hsiang-Fu; Zhang, Jin-Fang

    2014-02-01

    We previously showed that the small molecule 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP) induces apoptosis in hepatocellular carcinoma (HCC) by suppressing Hsp27 expression, although the mechanism is not fully understood. To investigate the functional association between TDP and Hsp27 protein in HCC, recombinant Hsp27 protein was incubated with TDP at room temperature, and assayed by mass spectrum (MS) and natural electrophoresis. TDP effectively stimulated Hsp27 to form aggregates ex vitro, leading to suppression of its chaperone activity. The aggregates were degraded by the ubiquitin-proteasome (UPS) pathway. TDP directly interacted with Asp17 and Phe55 in chain C of Hsp27 on the basis of bioinformatic prediction. In conclusion, Hsp27 is a direct target of TDP in its anti-cancer activity, which provides strong support for a clinical application. © 2013 International Federation for Cell Biology.

  11. Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice.

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    Gabor Szalai

    Full Text Available Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1 not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1 develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a in preeclampsia; 2 determine blood pressures in non-stressed conditions; and 3 develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP monitoring.Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11 or green fluorescent protein (GFP; n = 9 on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18. Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3 ± 51.7 μg/mg vs. 19.3 ± 5.6 μg/mg, p = 4.4 x 10(-2; GD18. Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2 x 10(-2. Placental and fetal weights did not differ between the groups

  12. Full-Length Human Placental sFlt-1-e15a Isoform Induces Distinct Maternal Phenotypes of Preeclampsia in Mice

    Science.gov (United States)

    Szalai, Gabor; Romero, Roberto; Chaiworapongsa, Tinnakorn; Xu, Yi; Wang, Bing; Ahn, Hyunyoung; Xu, Zhonghui; Chiang, Po Jen; Sundell, Birgitta; Wang, Rona; Jiang, Yang; Plazyo, Olesya; Olive, Mary; Tarca, Adi L.; Dong, Zhong; Qureshi, Faisal; Papp, Zoltan; Hassan, Sonia S.; Hernandez-Andrade, Edgar; Than, Nandor Gabor

    2015-01-01

    Objective Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring. Methods Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia. Results Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10-2). Placental and fetal weights did not differ between the

  13. Dual Tracer PET Imaging with FDG and FLT Differentiates Tuberculous Lymphadenopathy from Metastases in a Case of Carcinoma Cervix

    Energy Technology Data Exchange (ETDEWEB)

    Joshi, Prathamesh; Lele, Vikram; Aland, Parag; Gemawat, Shilpa [Jaslok Hospital and Research Centre, Woril (India)

    2013-09-15

    A forty-year-old woman with a known case of carcinoma cervix underwent 18-fluorodeoxyglucose positron emission tomography.computed tomography (18-FDG PET/CT) for evaluation of abdominal lymphadenopathy. Her treatment history included radical hysterectomy and radiotherapy 6 months ago. She complained of weight loss of 7 kg over last 5 months. The maximum intensity projection (MIP) image (Fig. 1a, arrows) revealed multiple areas of intense FDG uptake, which on CT and fused PET/CT images were localized to multiple lymph nodes in bilateral cervical region, right axilla, mediastinum and abdomen. The SUVmax of right axillary lymph nodes (most FDG avid of all lymph node groups) was 15.3. There was no evidence of metabolically active disease or CT demonstrable abnormality in rest of the body. Presence of metabolically active disease in extensive supradiaphramatic lymphadenopathy was unusual for a case of carcinoma cervix. This finding, along with history of significant weight loss and absence of extranodal disease, was suspicious for unrelated pathology like lymphoproliferative disorder or granulomatous disease. Mixed malignant and benign lymphadenopathy was also considered a possibility. To solve the conundrum, 18-fluoro-L-thymidine (FLT) PET/CT was performed on the next day. This scan was performed to assess the proliferation rate in various above-mentioned lymph nodes, and to plan the optimum site of biopsy. The FLT PET scan (Fig. 1b) showed physiological distribution of the tracer in bone marrow, liver, gall bladder and urinary bladder. There was minimal FLT uptake in the enlarged, FDG avid lymph nodes (Fig. 1c and d). SUVmax of FLT uptake in right axillary lymph nodes was 1.4 (SUVmax of FDG uptake = 15.8). The SUVmax of FLT uptake in cervical, mediastinal and abdominal lymph nodes were 1.3, 1.4 and 1.0 respectively. (SUVmax of FDG uptake 12.1, 12.7 and 11.9, respectively). Considering avidity for FDG and non-avidity of proliferation marker tracer (FLT), possibility of

  14. Frequency and Prognostic Relevance of FLT3 Mutations in Saudi Acute Myeloid Leukemia Patients

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    Ghaleb Elyamany

    2014-01-01

    Full Text Available The Fms-like tyrosine kinase-3 (FLT3 is a receptor tyrosine kinase that plays a key role in cell survival, proliferation, and differentiation of hematopoietic stem cells. Mutations of FLT3 were first described in 1997 and account for the most frequent molecular mutations in acute myeloid leukemia (AML. AML patients with FLT3 internal tandem duplication (ITD mutations have poor cure rates the prognostic significance of point mutations; tyrosine kinase domain (TKD is still unclear. We analyzed the frequency of FLT3 mutations (ITD and D835 in patients with AML at diagnosis; no sufficient data currently exist regarding FLT3 mutations in Saudi AML patients. This study was aimed at evaluating the frequency of FLT3 mutations in patients with AML and its significance for prognosis. The frequency of FLT3 mutations in our study (18.56% was lower than many of the reported studies, FLT3-ITD mutations were observed in 14.4%, and FLT3-TKD in 4.1%, of 97 newly diagnosed AML patients (82 adult and 15 pediatric. Our data show significant increase of FLT3 mutations in male more than female (13 male, 5 female. Our results support the view that FLT3-ITD mutation has strong prognostic factor in AML patients and is associated with high rate of relapse, and high leucocytes and blast count at diagnosis and relapse.

  15. Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.

    Science.gov (United States)

    Lau, Colleen M; Nish, Simone A; Yogev, Nir; Waisman, Ari; Reiner, Steven L; Reizis, Boris

    2016-03-07

    A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. © 2016 Lau et al.

  16. Antimicrobial and Antitumor Activities of Novel Peptides Derived from the Lipopolysaccharide- and β-1,3-Glucan Binding Protein of the Pacific Abalone Haliotis discus hannai

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    Bo-Hye Nam

    2016-12-01

    Full Text Available Antimicrobial peptides are a pivotal component of the invertebrate innate immune system. In this study, we identified a lipopolysaccharide- and β-1,3-glucan-binding protein (LGBP gene from the pacific abalone Haliotis discus hannai (HDH, which is involved in the pattern recognition mechanism and plays avital role in the defense mechanism of invertebrates immune system. The HDH-LGBP cDNA consisted of a 1263-bp open reading frame (ORF encoding a polypeptide of 420 amino acids, with a 20-amino-acid signal sequence. The molecular mass of the protein portion was 45.5 kDa, and the predicted isoelectric point of the mature protein was 4.93. Characteristic potential polysaccharide binding motif, glucanase motif, and β-glucan recognition motif were identified in the LGBP of HDH. We used its polysaccharide-binding motif sequence to design two novel antimicrobial peptide analogs (HDH-LGBP-A1 and HDH-LGBP-A2. By substituting a positively charged amino acid and amidation at the C-terminus, the pI and net charge of the HDH-LGBP increased, and the proteins formed an α-helical structure. The HDH-LGBP analogs exhibited antibacterial and antifungal activity, with minimal effective concentrations ranging from 0.008 to 2.2 μg/mL. Additionally, both were toxic against human cervix (HeLa, lung (A549, and colon (HCT 116 carcinoma cell lines but not much on human umbilical vein cell (HUVEC. Fluorescence-activated cell sorter (FACS analysis showed that HDH-LGBP analogs disturb the cancer cell membrane and cause apoptotic cell death. These results suggest the use of HDH-LGBP analogs as multifunctional drugs.

  17. Activation of PAR-1/NADPH Oxidase/ROS Signaling Pathways is Crucial for the Thrombin-Induced sFlt-1 Production in Extravillous Trophoblasts: Possible Involvement in the Pathogenesis of Preeclampsia

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    Qi-tao Huang

    2015-03-01

    Full Text Available Backgrounds/Aims: Preeclampsia was characterized by excessive thrombin generation in placentas and previous researches showed that thrombin could enhance soluble Fms-like tyrosine kinase 1 (sFlt-1 expression in first trimester trophoblasts. However, the detailed mechanism for the sFlt-1 over-production induced by thrombin was largely unknown. The purpose of this study was to explore the possible signaling pathway of thrombin-induced sFlt-1 production in extravillous trophoblasts (EVT. Methods: An EVT cell line (HRT-8/SVneo was treated with various concentrations of thrombin. The mRNA expression and protein secretion of sFlt-1 in EVT were detected with real-time polymerase chain reaction and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS production were determined by DCFH-DA. Results: Exposure of EVT to thrombin induced increased intracellular ROS generation and overexpression of sFlt-1 at both mRNA and protein levels in a dose dependent manner. Short interfering RNA (siRNA directed against PAR-1 or apocynin (an inhibitor of NADPH oxidase could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. Conclusions: Our results suggested that thrombin increased sFlt-1 production in EVT via the PAR-1 /NADPH oxidase /ROS signaling pathway. This also highlights the PAR-1 / NADPH oxidase / ROS pathway might be a potential therapeutic target for the prevention of preeclampsia in the future.

  18. Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors.

    Science.gov (United States)

    Pietschmann, Kristin; Bolck, Hella Anna; Buchwald, Marc; Spielberg, Steffi; Polzer, Harald; Spiekermann, Karsten; Bug, Gesine; Heinzel, Thorsten; Böhmer, Frank-Dietmar; Krämer, Oliver H

    2012-11-01

    Activating mutations of the class III receptor tyrosine kinase FLT3 are the most frequent molecular aberration in acute myeloid leukemia (AML). Mutant FLT3 accelerates proliferation, suppresses apoptosis, and correlates with poor prognosis. Therefore, it is a promising therapeutic target. Here, we show that RNA interference against FLT3 with an internal tandem duplication (FLT3-ITD) potentiates the efficacy of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) against AML cells expressing FLT3-ITD. Similar to RNA interference, tyrosine kinase inhibitors (TKI; AC220/cpd.102/PKC412) in combination with LBH589 exhibit superior activity against AML cells. Median dose-effect analyses of drug-induced apoptosis rates of AML cells (MV4-11 and MOLM-13) revealed combination index (CI) values indicating strong synergism. AC220, the most potent and FLT3-specific TKI, shows highest synergism with LBH589 in the low nanomolar range. A 4-hour exposure to LBH589 + AC220 already generates more than 50% apoptosis after 24 hours. Different cell lines lacking FLT3-ITD as well as normal peripheral blood mononuclear cells are not significantly affected by LBH589 + TKI, showing the specificity of this treatment regimen. Immunoblot analyses show that LBH589 + TKI induce apoptosis via degradation of FLT3-ITD and its prosurvival target STAT5. Previously, we showed the LBH589-induced proteasomal degradation of FLT3-ITD. Here, we show that activated caspase-3 also contributes to the degradation of FLT3-ITD and that STAT5 is a direct target of this protease. Our data strongly emphasize HDACi/TKI drug combinations as promising modality for the treatment of FLT3-ITD-positive AMLs. ©2012 AACR.

  19. The sFlt-1/PlGF ratio as a predictor for poor pregnancy and neonatal outcomes

    Directory of Open Access Journals (Sweden)

    Yu-Shan Chang

    2017-12-01

    Full Text Available Background: Soluble fms-like tyrosine kinase receptor-1 (sFlt-1/placental growth factor (PlGF ratio has been studied extensively as a predictive marker for pre-eclampsia. However, its usefulness for predicting neonatal outcomes remains unknown. This study aimed to evaluate the association of sFlt-1/PlGF ratio with pregnancy outcomes, neonatal morbidities and short-term postnatal growth patterns in pregnant women and their babies. Methods: sFlt-1 and PlGF were measured in women with fetal intrauterine growth retardation (IUGR or pre-eclampsia during gestational age (GA of 16–36 weeks. These women were classified into high- and low-ratio groups with a sFlt-1/PlGF cut-off ratio of 85. The maternal and neonatal outcomes were retrospectively reviewed and compared between the two groups. Results: A total of 25 pregnant women were recruited. Thirteen of them had a sFlt-1/PlGF ratio over 85 and twelve had a ratio of less than 85. The median duration from elevation of sFlt-1/PlGF to delivery was 4.5 weeks. Women in the high SFlt-1/PlGF ratio group had higher rates of intrauterine fetal demise (2/13 vs. 0/12 and early termination (1/13 vs. 0/12. The surviving offspring in this group had a higher incidence of preterm birth (GA: 31.4 ± 2.9 weeks vs. 37.3 ± 1.3 weeks, p < 0.001, lower birth weight (1142 ± 472 g vs. 2311 ± 236 g, p < 0.001, higher incidence of respiratory distress syndrome (6/10 vs. 0/12, p = 0.002 and bronchopulmonary dysplasia (4/10 vs. 0/12, p = 0.01. However, the percentile of body weight, height and head circumference at 28 days of age, 56 days of age and the corrected age of 6 months were comparable between groups. Conclusions: High sFlt-1/PlGF ratio in pregnant women is associated with poor pregnancy and neonatal outcomes. Therefore, the monitoring of sFlt-1/PlGF ratio in pregnant women with fetal IUGR and timely management for placenta-associated diseases are

  20. Soluble Flt-1 links microvascular disease with heart failure in CKD.

    Science.gov (United States)

    Di Marco, Giovana S; Kentrup, Dominik; Reuter, Stefan; Mayer, Anna B; Golle, Lina; Tiemann, Klaus; Fobker, Manfred; Engelbertz, Christiane; Breithardt, Günter; Brand, Eva; Reinecke, Holger; Pavenstädt, Hermann; Brand, Marcus

    2015-05-01

    Chronic kidney disease (CKD) is associated with an increased risk of heart failure (HF). Elevated plasma concentrations of soluble Flt-1 (sFlt-1) have been linked to cardiovascular disease in CKD patients, but whether sFlt-1 contributes to HF in CKD is still unknown. To provide evidence that concludes a pathophysiological role of sFlt-1 in CKD-associated HF, we measured plasma sFlt-1 concentrations in 586 patients with angiographically documented coronary artery disease and renal function classified according to estimated glomerular filtration rate (eGFR). sFlt-1 concentrations correlated negatively with eGFR and were associated with signs of heart failure, based on New York Heart Association functional class and reduced left ventricular ejection fraction (LVEF), and early mortality. Additionally, rats treated with recombinant sFlt-1 showed a 15 % reduction in LVEF and a 29 % reduction in cardiac output compared with control rats. High sFlt-1 concentrations were associated with a 15 % reduction in heart capillary density (number of vessels/cardiomyocyte) and a 24 % reduction in myocardial blood volume. Electron microscopy and histological analysis revealed mitochondrial damage and interstitial fibrosis in the hearts of sFlt-1-treated, but not control rats. In 5/6-nephrectomised rats, an animal model of CKD, sFlt-1 antagonism with recombinant VEGF121 preserved heart microvasculature and significantly improved heart function. Overall, these findings suggest that a component of cardiovascular risk in CKD patients could be directly attributed to sFlt-1. Assessment of patients with CKD confirmed that sFlt-1 concentrations were inversely correlated with renal function, while studies in rats suggested that sFlt-1 may link microvascular disease with HF in CKD.

  1. FLT3/ITD associated with an immature immunophenotype in PML-RARα leukemia

    Directory of Open Access Journals (Sweden)

    Mariko Takenokuchi

    2012-10-01

    Full Text Available Acute promyelocytic leukemia (APL is characterized by the specific PML-RARa fusion gene resulting from translocation t(15;17 (q22;q12. Internal tandem duplication (ITD of the FLT3 gene has been observed in approximately 35% of APLs, and large-scale studies have identified the presence of ITD as an adverse prognostic factor for acute myeloblastic leukemia (AML patients. Aberrant expressions of surface antigens, such as CD2, CD34, and CD56, have been found in APL, but the implications of this are not well understood. We investigated the incidence of the FLT3/ITD mutation and FLT3/D835 (I836 point mutation in 25 APL patients. Incidence ratios of FLT3/ITD, D835 (I836, and both FLT3/ITD and D835 (I836 were 36%, 36% and 8%, respectively. FLT3/ITD+ cases showed a predominance of the bcr3 isoform (P=0.008 and M3v morphology (P<0.001. We found that all FLT3/ITD+ cases expressed CD2 (9 of 9 more frequently than that of FLT3/ITD- (1 of 16 (P<0.001, while only one of the CD2+ cases (1 of 10, 10% did not harbor FLT3/ITD, and all CD2+CD34+ cases (5 of 5, 100% harbored FLT3/ITD. In addition, quantitative polymerase chain reaction analysis showed that FLT3 mRNA was more abundantly expressed in FLT3/ITD+ than that in FLT3/ITD- (P=0.025, while there was no difference between D835(I836+ and D835(I836- with regards to aberrant surface-antigen expression, expression levels of FLT3 mRNA, M3v morphology, and the bcr3 isoform of PML-RARa mRNA. This study demonstrates that the presence of FLT3/ITD, but not D835 (I836, is closely related to aberrant CD2 expression and high expression levels of FLT3 mRNA. Our findings also suggest that FLT3/ITD as a secondary genetic event may block differentiation at the immature stage of APL.

  2. Microwave mediated radiosynthesis of [F-18] FLT and its in-vitro study with androgen independent human prostate cancer cell line (PC-3)

    International Nuclear Information System (INIS)

    Ponde, D.E.; Dence, C.S.; Oyama, N.; Welch, M.J.

    2003-01-01

    The aim of this work was to improve the radiosynthesis of [F-18] FLT and to study its usefulness in monitoring change of proliferative activity of prostate cancer cells in the early phase of therapy. Method: Starting with anhydrothymidine, [F-18] FLT was synthesized by microwave mediated nucleophilic displacement by fluoride ion followed by acid hydrolysis in a synthesis time of just 55 minutes, which included Oasis solid phase and HPLC purification. The total radiochemical yield was 10-15% (at EOS), and the radiochemical purity was >99%. An in vitro study was carried out with androgen-independent human prostate cancer cell line PC-3. Two X 10e5 cells were seeded in 6 well plates with Ham's F-12K medium with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate supplemented with 10% heat activated FBS. One day later, PC-3 cells were at 50% confluent, the media was removed and the cells divided into two groups. In one group, cells were suspended in fresh media as above with 10% FBS, whereas in the other group cells were suspended in fresh media as above but without serum. Twenty-four hours later, [F-18] FLT was added to each flask (n=3). The cell-associated uptake of [F-18] FLT at 37 deg C was determined at 0, 1, 3, and 6 h after incubation. [F-18] FLT uptake in PC-3 cells decreased by 55% (from 9% to 4%) after 24h incubation with serum free media, indicating its potential usefulness to monitor cell proliferation in androgen-independent human prostate cancer. Studies to ascertain the uptake-mechanism are in the way. NIH grant HL13851

  3. Genome-wide in silico identification of GPI proteins in Mycosphaerella fijiensis and transcriptional analysis of two GPI-anchored β-1,3-glucanosyltransferases.

    Science.gov (United States)

    Kantún-Moreno, Nuvia; Vázquez-Euán, Roberto; Tzec-Simá, Miguel; Peraza-Echeverría, Leticia; Grijalva-Arango, Rosa; Rodríguez-García, Cecilia; James, Andrew C; Ramírez-Prado, Jorge; Islas-Flores, Ignacio; Canto-Canché, Blondy

    2013-01-01

    The hemibiotrophic fungus Mycosphaerella fijiensis is the causal agent of black Sigatoka (BS), the most devastating foliar disease in banana (Musa spp.) worldwide. Little is known about genes that are important during M. fijiensis-Musa sp. interaction. The fungal cell wall is an attractive area of study because it is essential for maintenance of cellular homeostasis and it is the most external structure in the fungal cell and therefore mediates the interaction of the pathogen with the host. In this manuscript we describe the in silico identification of glycosyl phosphatidylinositol-protein (GPI) family in M. fijiensis, and the analysis of two β-1,3-glucanosyltrans-ferases (Gas), selected by homology with fungal pathogenicity factors. Potential roles in pathogenesis were evaluated through analyzing expression during different stages of black Sigatoka disease, comparing expression data with BS symptoms and fungal biomass inside leaves. Real-time quantitative RT-PCR showed nearly constant expression of MfGAS1 with slightly increases (about threefold) in conidia and at speck-necrotrophic stage during banana-pathogen interaction. Conversely, MfGAS2 expression was increased during biotrophy (about seven times) and reached a maximum at speck (about 23 times) followed by a progressive decrease in next stages, suggesting an active role in M. fijiensis pathogenesis.

  4. FLT3 mutation incidence and timing of origin in a population case series of pediatric leukemia

    Directory of Open Access Journals (Sweden)

    Chang Jeffrey

    2010-09-01

    Full Text Available Abstract Background Mutations in FLT3 result in activated tyrosine kinase activity, cell growth stimulation, and a poor prognosis among various subtypes of leukemia. The causes and timing of the mutations are not currently known. We evaluated the prevalence and timing of origin of FLT3 mutations in a population series of childhood leukemia patients from Northern California. Methods We screened and sequenced FLT3 mutations (point mutations and internal tandem duplications, ITDs among 517 childhood leukemia patients, and assessed whether these mutations occurred before or after birth using sensitive "backtracking" methods. Results We determined a mutation prevalence of 9 of 73 acute myeloid leukemias (AMLs, 12% and 9 of 441 acute lymphocytic leukemias (ALLs, 2%. Among AMLs, FLT3 mutations were more common in older patients, and among ALLs, FLT3 mutations were more common in patients with high hyperdiploidy (3.7% than those without this cytogenetic feature (1.4%. Five FLT3 ITDs, one deletion mutation, and 3 point mutations were assessed for their presence in neonatal Guthrie spots using sensitive real-time PCR techniques, and no patients were found to harbor FLT3 mutations at birth. Conclusions FLT3 mutations were not common in our population-based patient series in California, and patients who harbor FLT3 mutations most likely acquire them after they are born.

  5. Hypoxic regulation of β-1,3-glucuronyltransferase 1 expression in nucleus pulposus cells of the rat intervertebral disc: role of hypoxia-inducible factor proteins.

    Science.gov (United States)

    Gogate, Shilpa S; Nasser, Rena; Shapiro, Irving M; Risbud, Makarand V

    2011-07-01

    To determine whether hypoxia and hypoxia-inducible factor (HIF) proteins regulate expression of β-1,3-glucuronyltransferase 1 (GlcAT-1), a key enzyme in glycosaminoglycan synthesis in nucleus pulposus cells. Real-time reverse transcriptase-polymerase chain reaction and Western blotting were used to measure GlcAT-1 expression. Transfections were performed to determine the effect of HIF-1α and HIF-2α on GlcAT-1 promoter activity. Under hypoxic conditions there was an increase in GlcAT-1 expression; a significant increase in promoter activity was seen both in nucleus pulposus cells and in N1511 chondrocytes. We investigated whether HIF controlled GlcAT-1 expression. Suppression of HIF-1α and HIF-2α induced GlcAT-1 promoter activity and expression only in nucleus pulposus cells. Transfection with CA-HIF-1α as well as with CA-HIF-2α suppressed GlcAT-1 promoter activity only in nucleus pulposus cells, suggesting a cell type-specific regulation. Site-directed mutagenesis and deletion constructs were used to further confirm the suppressive effect of HIFs on GlcAT-1 promoter function in nucleus pulposus cells. Although it was evident that interaction of HIF with hypoxia-responsive elements resulted in suppression of basal promoter activity, it was not necessary for transcriptional suppression. This result suggested both a direct and an indirect mode of regulation, possibly through recruitment of a HIF-dependent repressor. Finally, we showed that hypoxic expression of GlcAT-1 was also partially dependent on MAPK signaling. These studies demonstrate that hypoxia regulates GlcAT-1 expression through a signaling network comprising both activator and suppressor molecules, and that this regulation is unique to nucleus pulposus cells. Copyright © 2011 by the American College of Rheumatology.

  6. The Important Role of FLT3-L in Ex Vivo Expansion of Hematopoietic Stem Cells following Co-Culture with Mesenchymal Stem Cells.

    Science.gov (United States)

    Oubari, Farhad; Amirizade, Naser; Mohammadpour, Hemn; Nakhlestani, Mozhdeh; Zarif, Mahin Nikougoftar

    2015-01-01

    Hematopoietic stem cells (HSCs) transplantation using umbilical cord blood (UCB) has improved during the last decade. Because of cell limitations, several studies focused on the ex vivo expansion of HSCs. Numerous investigations were performed to introduce the best cytokine cocktails for HSC expansion The majority used the Fms-related tyrosine kinase 3 ligand (FLT3-L) as a critical component. According to FLT3-L biology, in this study we have investigated the hypothesis that FLT3-L only effectively induces HSCs expansion in the presence of a mesenchymal stem cell (MSC) feeder. In this experimental study, HSCs and MSCs were isolated from UCB and placenta, respectively. HSCs were cultured in different culture conditions in the presence and absence of MSC feeder and cytokines. After ten days of culture, total nucleated cell count (TNC), cluster of differentiation 34+(CD34(+)) cell count, colony forming unit assay (CFU), long-term culture initiating cell (LTC-IC), homeobox protein B4 (HoxB4) mRNA and surface CD49d expression were evaluated. The fold increase for some culture conditions was compared by the t test. HSCs expanded in the presence of cytokines and MSCs feeder. The rate of expansion in the co-culture condition was two-fold more than culture with cytokines (Pculture condition at a level of 20-fold equal to the presence of stem cell factor (SCF), thrombopoietin (TPO) and FLT3-L without feeder cells. The number of extracted colonies from LTC-IC and CD49d expression compared with a cytokine cocktail condition meaningfully increased (Pculture with MSCs can induce high yield expansion of HSCs and be a substitute for the universal cocktail of SCF, TPO and FLT3-L in feeder-free culture.

  7. Chemical Space of FLT3 Inhibitors as Potential Anti-AML Drugs.

    Science.gov (United States)

    Lan, Qing-Yuan; Zhi, Yan-Le; Heng, Hao; Tian, Jie-Yi; Guo, Xiao-Xing; Liu, Hai-Chun; Chen, Ya-Dong; Lu, Tao; Lu, Shuai

    2017-11-20

    FLT3 is a member of receptor tyrosine kinase III family, mainly expressed in hematopoietic cells. The aberrant expression and function of FLT3 are strongly related to leukemia, especially acute myeloid leukemia. Its varieties of amino-acid residues mutations, such as FLT3-ITDs and -TKDs, can induce constant proliferation of hematological tumor cells with poor prognosis. Hence FLT3 serves as a promising target in AML chemotherapy. This review focused on the progress of FLT3 inhibitors study including those that have entered clinical trials or were reported in numerous patents all over the world. Thus, we provided a useful reference for the development of new anti-leukemia drugs. Through a comprehensive retrospective study, FLT3 inhibitors in several patent applications were identified and classified into five categories, including quinolone-related, indole-related, ureas, pyrimidines and other compounds. For each category of compounds, the structural feature, SAR, biological activity and current research status were thoroughly reviewed and analyzed. Although some of those compounds expressed potent bioactivities and have reached the advanced clinical trials for the treatment of leukemia, there are still several problems need to be faced before they enter the market eventually, especially the drug resistance issue. The improvement of therapeutic potency for FLT3 inhibitors might depend on the useful combination therapy and further refinement of the intrinsic properties of FLT3 inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Association of whirlin with Cav1.3 (alpha1D) channels in photoreceptors, defining a novel member of the usher protein network.

    NARCIS (Netherlands)

    Kersten, F.F.J.; Wijk, E. van; Reeuwijk, J. van; Zwaag, B. van der; Marker, T.; Peters, T.A.; Katsanis, N.; Wolfrum, U.; Keunen, J.E.E.; Roepman, R.; Kremer, J.M.J.

    2010-01-01

    PURPOSE: Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize

  9. FLT-PET for early response evaluation of colorectal cancer patients with liver metastases

    DEFF Research Database (Denmark)

    Mogensen, Marie Benzon; Loft, Annika; Aznar, Marianne

    2017-01-01

    BACKGROUND: Fluoro-L-thymidine (FLT) is a positron emission tomography/computed tomography (PET/CT) tracer which reflects proliferative activity in a cancer lesion. The main objective of this prospective explorative study was to evaluate whether FLT-PET can be used for the early evaluation...... standardised uptake values (SUVmax, SUVmean) were measured. After three cycles of chemotherapy, treatment response was assessed by CT scan based on RECIST 1.1. RESULTS: Thirty-nine consecutive patients were included of which 27 were evaluable. Dropout was mainly due to disease complications. Nineteen patients...... between the response according to RECIST and the early changes in FLT uptake measured as SUVmax(p = 0.24). CONCLUSIONS: No correlation was found between early changes in FLT uptake after the first cycle of treatment and the response evaluated from subsequent CT scans. It seems unlikely that FLT-PET can...

  10. Neurotrophin-3 and FLT3 Tyrosine Kinase Receptor in Perinatal Life

    Directory of Open Access Journals (Sweden)

    Ariadne Malamitsi-Puchner

    2005-01-01

    Full Text Available Our aim is to determine—in 30 healthy full-term infants and their mothers—circulating levels of neurotrophin-3 (NT-3 (important for antenatal and postnatal brain development and implicated in the immune response and FLT3 tyrosine kinase receptor (FLT3 (controlling hematopoiesis and found in the nervous tissue, in the fetal and neonatal life. NT-3 levels, in contrast to FLT3 ones, increased significantly on the fourth postnatal day in relation to the low levels found in the mother, fetus, and day 1 neonate (P=.03, respectively. Maternal and umbilical NT3 levels positively correlated with respective FLT3 levels (P=.003 and P=.03. Circulating NT-3 levels increased in early neonatal life, possibly due to exposure to various stimuli soon after birth. FLT3 levels do not seem to behave accordingly, although these two substances probably synergize.

  11. Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model

    Science.gov (United States)

    Poitras, Jennifer L.; Heiser, Diane; Li, Li; Nguyen, Bao; Nagai, Kozo; Duffield, Amy S.; Gamper, Christopher; Small, Donald

    2016-01-01

    Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3/ITD) are among the most common mutations in Acute Myeloid Leukemia (AML). Resulting in constitutive activation of the kinase, FLT3/ITD portends a particularly poor prognosis, with reduced overall survival and increased rates of relapse. We previously generated a knock-in mouse, harboring an internal tandem duplication at the endogenous Flt3 locus, which develops a fatal myeloproliferative neoplasm (MPN), but fails to develop acute leukemia, suggesting additional mutations are necessary for transformation. To investigate the potential cooperativity of FLT3/ITD and mutant DNMT3A, we bred a conditional Dnmt3a knockout to a substrain of our Flt3/ITD knock-in mice, and found deletion of Dnmt3a significantly reduced median survival of Flt3ITD/+ mice in a dose dependent manner. As expected, pIpC treated Flt3ITD/+ mice solely developed MPN, while Flt3ITD/+;Dnmt3af/f and Flt3ITD/+;Dnmt3af/+ developed a spectrum of neoplasms, including MPN, T-ALL, and AML. Functionally, FLT3/ITD and DNMT3A deletion cooperate to expand LT-HSCs, which exhibit enhanced self-renewal in serial re-plating assays. These results illustrate that DNMT3A loss cooperates with FLT3/ITD to generate hematopoietic neoplasms, including AML. In combination with FLT3/ITD, homozygous Dnmt3a knock-out results in reduced time to disease onset, LT-HSC expansion, and a higher incidence of T-ALL compared with loss of just one allele. The co-occurrence of FLT3 and DNMT3A mutations in AML, as well as subsets of T-ALL, suggests the Flt3ITD/+;Dnmt3af/f model may serve as a valuable resource for delineating effective therapeutic strategies in two clinically relevant contexts. PMID:27636998

  12. Inhibition of MEK5 by BIX02188 induces apoptosis in cells expressing the oncogenic mutant FLT3-ITD

    International Nuclear Information System (INIS)

    Razumovskaya, Elena; Sun, Jianmin; Roennstrand, Lars

    2011-01-01

    Highlights: → In this study we have demonstrated that FLT3 activation leads to activation of ERK5. → We have demonstrated that ERK5 is involved in activation of AKT downstream of FLT3. → (BIX02188) blocks activation of ERK5 and induces apoptosis in FLT3 Ba/F3 cells. → (BIX02188) induce apoptosis in the two leukemic cell lines MV4-11 and MOLM-13. -- Abstract: Fms-like tyrosine kinase-3 (FLT3) is a growth factor receptor normally expressed on hematopoietic progenitor cells. Approximately one third of all patients with AML carry an activating mutation in FLT3 that drives proliferation and survival of the leukemic cells. The most common activating mutation is the so-called internal tandem duplication (ITD), which involves an in-frame duplication of a segment of varying length in the region of the FLT3 gene that encodes the juxtamembrane domain. The pathways downstream of FLT3-ITD are partially known but further knowledge regarding the downstream signal transduction molecules is important in order to develop alternative strategies for pharmacological intervention. In this paper we have studied the role of MEK/ERK5 in FLT3-ITD mediated transformation. We have found that both wild-type FLT3 and FLT3-ITD activate MEK5 leading to the activation of ERK5. By use of the selective inhibitor of MEK5, (BIX02188), we have shown that activation of AKT downstream of FLT3 is partially dependent on ERK5. Furthermore, inhibition of MEK5/ERK5 induces apoptosis of both FLT3-ITD transfected Ba/F3 cells as well as the FLT3-ITD carrying leukemic cell lines MV4-11 and MOLM-13. These results suggest that MEK5/ERK5 is important for FLT3-ITD induced hematopoietic transformation and may thus represent an alternative therapeutic target in the treatment of FLT3-ITD positive leukemia.

  13. Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors.

    Science.gov (United States)

    Frett, Brendan; McConnell, Nick; Smith, Catherine C; Wang, Yuanxiang; Shah, Neil P; Li, Hong-yu

    2015-04-13

    The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  14. Intraindividual comparison of F-18-FLT PET and F-18 FET PET in brain tumor patients

    International Nuclear Information System (INIS)

    Kim, Sung Eun; Cheon, G. J.; Cho, Y. S.; Kwak, H. S.; Lee, C. H.; Choi, C. W.; Lim, S. M.

    2003-01-01

    To compare findings on FLT PET with FET PET, we prospectively undertaken FLT, FET and FDG PET in same patient with suspected primary/metastatic and recurrent brain tumors. Seventeen studies in 16 patients (47 8.3 years, M: F 10: 6) with brain tumor (3 for initial diagnosis, 6 for therapeutic response, 6 for detecting recurrence, 1 for diagnosis and recurrence both) were included. Brain tumors were 14 gliomas (6 high- grade 9 low-grade by the WHO classification), 2 metastatic brain tumors and 1 CNS lymphoma. 18F-FDG, FLT and FET PET were performed within two weeks. Attenuation-corrected brain images were acquired 30 minutes after injection of 370-555 MBq FDG, FLT and FET with a dedicated PET scanner (ECAT HR scanner, Siemens-CTI). Maximum SUV (max SUV) and relative uptake defined by FLT and FET accumulation within the tumor in relation to a contralateral control region (max SUV for tumor/ mean SUV for contralateral normal gray matter) were calculated. 26 tumor foci were analyzed. Relative FLT uptake (4.17 2.4, 0.58 to 7.45) was grater than than FET uptake (2.03 1.17, 0.92 to 4.53 (p<0.0006)) and FDG uptake (1.16 0.34, 0.76 to 2.08). Among FLT, FET and FDG uptakes in 20 tumor foci, correlation were poor. the relative FLT uptake of high-grade glioma was higher than low-glioma (6.070.76 vs 3.11 2.15, p=0.002), however, relative FET uptake was not different significantly (2.68 1.51, high-grade vs 1.970.78, low-grade). The correlation between tumor grade (high vs low grade) and relative uptake (FLT and FET) was shown only with relative FLT uptake (r=0.62, p=0.002). The best cut off value of relative FLT uptake between high-grade and low-grade glioma was 4.54 (AUC: 0.89 sensitivity: 100 specificity: 86.7%). Compared with FET uptake, FLT uptake showed much higher contrast and associated with tumor grade. Further study, evaluation of proliferative index of Ki-67 and its relationship with FLT and FET uptake, are ongoing

  15. Visualization of endothelial cell cycle dynamics in mouse using the Flt-1/eGFP-anillin system.

    Science.gov (United States)

    Herz, Katia; Becker, Alexandra; Shi, Chenyue; Ema, Masatsugo; Takahashi, Satoru; Potente, Michael; Hesse, Michael; Fleischmann, Bernd K; Wenzel, Daniela

    2018-05-01

    Endothelial cell proliferation is a key process during vascular growth but its kinetics could only be assessed in vitro or ex vivo so far. To enable the monitoring and quantification of cell cycle kinetics in vivo, we have generated transgenic mice expressing an eGFP-anillin construct under control of the endothelial-specific Flt-1 promoter. This construct labels the nuclei of endothelial cells in late G1, S and G2 phase and changes its localization during the different stages of M phase, thereby enabling the monitoring of EC proliferation and cytokinesis. In Flt-1/eGFP-anillin mice, we found eGFP + signals specifically in Ki67 + /PECAM + endothelial cells during vascular development. Quantification using this cell cycle reporter in embryos revealed a decline in endothelial cell proliferation between E9.5 to E12.5. By time-lapse microscopy, we determined the length of different cell cycle phases in embryonic endothelial cells in vivo and found a M phase duration of about 80 min with 2/3 covering karyokinesis and 1/3 cytokinesis. Thus, we have generated a versatile transgenic system for the accurate assessment of endothelial cell cycle dynamics in vitro and in vivo.

  16. Andrographolide Suppresses MV4-11 Cell Proliferation through the Inhibition of FLT3 Signaling, Fatty Acid Synthesis and Cellular Iron Uptake

    Directory of Open Access Journals (Sweden)

    Xiao Chen

    2017-08-01

    Full Text Available Background: Andrographolide (ADR, the main active component of Andrographis paniculata, displays anticancer activity in various cancer cell lines, among which leukemia cell lines exhibit the highest sensitivity to ADR. In particular, ADR was also reported to have reduced drug resistance in multidrug resistant cell lines. However, the mechanism of action (MOA of ADR’s anticancer and anti-drug-resistance activities remain elusive. Methods: In this study, we used the MV4-11 cell line, a FLT3 positive acute myeloid leukemia (AML cell line that displays multidrug resistance, as our experimental system. We first evaluated the effect of ADR on MV4-11 cell proliferation. Then, a quantitative proteomics approach was applied to identify differentially expressed proteins in ADR-treated MV4-11 cells. Finally, cellular processes and signal pathways affected by ADR in MV4-11 cell were predicted with proteomic analysis and validated with in vitro assays. Results: ADR inhibits MV4-11 cell proliferation in a dose- and time-dependent manner. With a proteomic approach, we discovered that ADR inhibited fatty acid synthesis, cellular iron uptake and FLT3 signaling pathway in MV4-11 cells. Conclusions: ADR inhibits MV4-11 cell proliferation through inhibition of fatty acid synthesis, iron uptake and protein synthesis. Furthermore, ADR reduces drug resistance by blocking FLT3 signaling.

  17. Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia

    Directory of Open Access Journals (Sweden)

    Colby A. Souders

    2015-06-01

    Full Text Available Angiogenic biomarkers, including soluble fms-like tyrosine kinase 1 (sFlt1, are thought to be predictors of preeclampsia onset; however, improvement is needed before a widespread diagnostic test can be utilized. Here we describe the development and use of diagnostic monoclonal antibodies specific to the two main splice variants of sFlt1, sFlt1-1 and sFlt1-14. These antibodies were selected for their sensitivity and specificity to their respective sFlt1 isoform in a capture ELISA format. Data from this pilot study suggest that sFlt1-1 may be more predictive of preeclampsia than total sFlt1. It may be possible to improve current diagnostic platforms if more specific antibodies are utilized.

  18. Molecular imaging of proliferation with [{sup 18}F]FLT-PET; Molekulare Bildgebung der Proliferation mit [{sup 18}F]FLT-PET

    Energy Technology Data Exchange (ETDEWEB)

    Buck, A.K.; Herrmann, K.; Schwaiger, M.; Wester, H.J. [Klinikum rechts der Isar, Technische Univ. Muenchen (Germany). Nuklearmedizinische Klinik und Poliklinik; Dechow, T.; Graf, N. [Klinikum rechts der Isar, Technische Univ. Muenchen (Germany). Medizinische Klinik III, Haematologi/Onkologie

    2009-06-15

    An increased proliferation fraction is a hallmark of malignant cells and a specific feature of malignant tumors which potentially allows more specific tumor imaging compared to increased glucose consumption (FDG-PET). The majority of therapeutic approaches aim at inhibition of proliferation or induction of apoptosis. Accordingly, non-invasive assessment of the proliferation fraction is also of interest for monitoring response to treatment and to early detect resistance to a specific kind of therapy. In clinical studies it has been demonstrated that the radiotracer 3'-deoxy-3'-[{sup 18}F]fluorothymidine (FLT) accumulates specifically in malignant tumors. Regression analysis of tumoral FLT-uptake and immunohistochemically detected proliferation fraction (PCNA, Ki-67) resulted in a significant correlation (e.g., in lung cancer, correlation coefficient r=0.87, p<0.0001). The possibility to non-invasively assess the proliferation fraction with FLT-PET has been shown in a variety of solid cancers. Compared to the standard radiotracer FDG, superior demonstration of the proliferative activity using FLT as the tracer has been demonstrated. On the other hand, accumulation of FLT was significantly lower compared to FDG. Malignant tumors with low proliferation rates did not present with increased FLT-uptake resulting in a reduced sensitivity. In lung cancer for example, the sensitivity was 86% of FLT-PET compared to 100% of FDG-PET. Also, regarding detection of locoregional lymph node metastases or distant metastases, FDG-PET was shown to have a higher sensitivity. Due to the reduced sensitivity, there is no advantage of specific imaging of tumor proliferation regarding tumor staging. In malignant lymphoma, FLT was similar effective for tumor staging as compared to FDG-PET. In a pilot study comprising 34 patients, both tracers showed a similar sensitivity regarding detection of lymphoma. An observed specificity of 100% indicates that FLT-PET represents a diagnostic

  19. [Use of sFlt-1/PlGF ratio in preeclampsia : a monocentric retrospective analysis].

    Science.gov (United States)

    Verbeurgt, L; Chantraine, F; De Marchin, J; Minon, J-M; Nisolle, M

    2017-09-01

    Soluble Fms-like tyrosine kinase 1 (sFlt-1) is an anti-angiogenic factor released in higher amounts in preeclampsia and implicated in endothelial dysfunction. sFlt-1/PlGF ratio is used in the prediction of preeclampsia. An sFlt-1/PlGF ratio inferior to 38 predicts the short-term absence of preeclampsia. A ratio ? 85 (early-onset PE) or ? 110 (late-onset of PE) could diagnose preeclampsia. In this study, sFlt-1/PlGF ratio has been measured in 183 patients. Sixty-seven preeclampsia have been diagnosed preeclamptic at delivery. The median sFlt-1/PlGF ratio was 100.3. The median ratio among women with preeclampsia (N=67) versus no preeclampsia (N=116) was 212.7 versus 35.4. In accordance with this analysis, an sFlt-1/PlGF ratio ? 38 has a sensibility of 95,5 % and a specificity of 73.3 %. The positive predictive value and the negative predictive value were 67.4 % and 96.6 %, respectively. These results suggest that sFlt-1/PlGF ratio is helpful in the diagnosis of preeclampsia.

  20. Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

    Science.gov (United States)

    Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

    2016-03-15

    Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life. Copyright © 2016 by The American Association of Immunologists, Inc.

  1. Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD.

    Science.gov (United States)

    Kazi, Julhash U; Chougule, Rohit A; Li, Tianfeng; Su, Xianwei; Moharram, Sausan A; Rupar, Kaja; Marhäll, Alissa; Gazi, Mohiuddin; Sun, Jianmin; Zhao, Hui; Rönnstrand, Lars

    2017-07-01

    The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.

  2. Temporal Changes in FLT3 ITD Regulation of Stem Cell Self Renewal and Leukemogenesis

    Science.gov (United States)

    2016-11-01

    AML) more frequently in adults than in children. FLT3-ITD encodes a constitutively active FLT3 tyrosine kinase. This mutation occurs in ~30% of adult...2006). FLT3ITD encodes a constitutively active tyrosine kinase 87   receptor that has been shown to activate the STAT5, MAP-kinase (MAPK), PI3-88...define cell populations: HSCs (CD150+, CD48-Lineage-, Sca1+, c-kit+), HPCs 570   (CD48-Lineage-, Sca1+, c-kit+), and GMPs (Lineage-, Sca1-, CD127-, c

  3. Transcriptional regulation of fksA, a β-1,3-glucan synthase gene, by the APSES protein StuA during Aspergillus nidulans development.

    Science.gov (United States)

    Park, Bum-Chan; Park, Yun-Hee; Yi, Soohyun; Choi, Yu Kyung; Kang, Eun-Hye; Park, Hee-Moon

    2014-11-01

    The temporal and spatial regulation of β-1,3-glucan synthesis plays an important role in morphogenesis during fungal growth and development. Northern blot analysis showed that the transcription of fksA, the gene encoding β-1,3-glucan synthase in Aspergillus nidulans, was cell-cycle-dependent and increased steadily over the duration of the vegetative period, but its overall expression during the asexual and sexual stages was fairly constant up until the time of transcription cessation. In an A. nidulans strain mutated in the eukaryotic bHLH-like APSES transcription factor stuA1, the transcriptional level of fksA, and consequently the content of alkali-insoluble cell wall β-glucan, significantly increased at the conidial chain formation and maturation stage. Electrophoretic mobility shift assays revealed that StuA was bound to StREs (StuA Response Elements) on the fksA promoter region. Promoter analysis with sGFP-fusion constructs also indicated the negative regulation of fksA expression by StuA, especially during asexual development. Taken together, these data suggest that StuA plays an important role in cell wall biogenesis during the development of A. nidulans, by controlling the transcription level of fksA.

  4. Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia

    Science.gov (United States)

    Major, Heather D.; Cambell, Robert A.; Silver, Robert M.; Branch, D. Ware; Weyrich, Andrew S.

    2014-01-01

    Objective Soluble fms-like tyrosine kinase (sFlt-1) is an important mediator in the pathogenesis of preeclampsia. We sought to determine if platelet-monocyte aggregates (PMAs) produced sFlt-1 and if PMAs contributed to sFlt-1 production in preeclampsia. Study Design Case-control study of sFlt-1 release from PMAs using blood samples from women with preeclampsia matched by gestational age to pregnant controls. A third group of nonpregnant, reproductive-age women comprised an additional control group. Experiments were also performed using blood from non-pregnant women to elucidate if inducing PMAs could stimulate sFlt-1 production, and if so, to determine the necessary receptors and pathways. Results Women with preeclampsia had increased total Flt-1 concentrations in platelets and monocytes at baseline compared to pregnant controls (25 vs. 10 pg/ml, p=0.0003). sFlt-1 production was elicited from monocytes incubated with thrombin-activated platelets from non-pregnant women. sFlt-1 production was regulated at the transcriptional level by p38 and NF-κB dependent pathways. Conclusion Activated platelets in preeclampsia bind monocytes to generate sFlt-1. PMAs are a previously unrecognized source of sFlt-1 that may contribute to endothelial dysfunction and systemic inflammation commonly observed in preeclampsia. PMID:24440566

  5. Monitoring of the spatial and temporal dynamics of BER/SSBR pathway proteins, including MYH, UNG2, MPG, NTH1 and NEIL1-3, during DNA replication.

    Science.gov (United States)

    Bj Rås, Karine Ø; Sousa, Mirta M L; Sharma, Animesh; Fonseca, Davi M; S Gaard, Caroline K; Bj Rås, Magnar; Otterlei, Marit

    2017-08-21

    Base lesions in DNA can stall the replication machinery or induce mutations if bypassed. Consequently, lesions must be repaired before replication or in a post-replicative process to maintain genomic stability. Base excision repair (BER) is the main pathway for repair of base lesions and is known to be associated with DNA replication, but how BER is organized during replication is unclear. Here we coupled the iPOND (isolation of proteins on nascent DNA) technique with targeted mass-spectrometry analysis, which enabled us to detect all proteins required for BER on nascent DNA and to monitor their spatiotemporal orchestration at replication forks. We demonstrate that XRCC1 and other BER/single-strand break repair (SSBR) proteins are enriched in replisomes in unstressed cells, supporting a cellular capacity of post-replicative BER/SSBR. Importantly, we identify for the first time the DNA glycosylases MYH, UNG2, MPG, NTH1, NEIL1, 2 and 3 on nascent DNA. Our findings suggest that a broad spectrum of DNA base lesions are recognized and repaired by BER in a post-replicative process. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  6. Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization

    DEFF Research Database (Denmark)

    Wild, Raphael; Klems, Alina; Takamiya, Masanari

    2017-01-01

    Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa......-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss...... of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviours including nuclear positioning and a molecular signature distinct from primary arterial or secondary venous sprouting. Manipulation of arteriovenous identity or Notch signalling established that ectopic sprouting...

  7. Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells.

    Directory of Open Access Journals (Sweden)

    Mariko Abe

    Full Text Available Internal tandem duplication (ITD mutations in the Fms-related tyrosine kinase 3 (FLT3 gene (FLT3-ITD are associated with poor prognosis in patients with acute myeloid leukemia (AML. Due to the development of drug resistance, few FLT3-ITD inhibitors are effective against FLT3-ITD+ AML. In this study, we show that FLT3-ITD activates a novel pathway involving p21Cdkn1a (p21 and pre-B cell leukemia transcription factor 1 (Pbx1 that attenuates FLT3-ITD cell proliferation and is involved in the development of drug resistance. FLT3-ITD up-regulated p21 expression in both mouse bone marrow c-kit+-Sca-1+-Lin- (KSL cells and Ba/F3 cells. The loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of concomitantly enriching the S+G2/M phase population and significantly increasing the expression of Pbx1, but not Evi-1, in FLT3-ITD+ cells. This enhanced cell proliferation following the loss of p21 was partially abrogated when Pbx1 expression was silenced in FLT3-ITD+ primary bone marrow colony-forming cells and Ba/F3 cells. When FLT3-ITD was antagonized with AC220, a selective inhibitor of FLT3-ITD, p21 expression was decreased coincident with Pbx1 mRNA up-regulation and a rapid decline in the number of viable FLT3-ITD+ Ba/F3 cells; however, the cells eventually became refractory to AC220. Overexpressing p21 in FLT3-ITD+ Ba/F3 cells delayed the emergence of cells that were refractory to AC220, whereas p21 silencing accelerated their development. These data indicate that FLT3-ITD is capable of inhibiting FLT3-ITD+ cell proliferation through the p21/Pbx1 axis and that treatments that antagonize FLT3-ITD contribute to the subsequent development of cells that are refractory to a FLT3-ITD inhibitor by disrupting p21 expression.

  8. Predictive modelling of the exposure to steviol glycosides in Irish patients aged 1-3 years with phenylketonuria and cow's milk protein allergy.

    Science.gov (United States)

    O'Sullivan, Aaron J; Pigat, Sandrine; O'Mahony, Cian; Gibney, Michael J; McKevitt, Aideen I

    2018-01-01

    Children with Phenylketonuria (PKU) and severe cow's milk protein allergy (CMPA) consume prescribed, specially formulated, foods for special medical purposes (FSMPs) as well as restricted amounts of normal foods. These patients are exposed to artificial sweeteners from the consumption of a combination of free and prescribed foods. Young patients with PKU and CMPA have a higher risk of exceeding acceptable daily intakes (ADI) for additives than age-matched healthy children. A predictive modelling approach has been adapted successfully to assess the additive exposure of young patients with PKU and CMPA to artificial sweeteners. Steviol glycosides (E960) are at various stages of regulatory approval for the various food categories in the EU but are not as yet permitted for use in products intended for young children. The aim of this study was to predict potential steviol glycoside exposure in young children with PKU and CMPA considering the potential for future provisions for the use of this sweetener. The recent introduction of steviol glycosides means that no exposure data are available for children with CMPA and PKU. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010-11). Specially formulated amino acid-based FSMPs are used to replace whole or milk protein foods and were included in the exposure model to replace restricted foods. The recommendations to ensure adequate protein intake in these patients were used to determine FSMP intake. Exposure assessment results indicated that the maximum permitted level (MPL) for FSMPs would warrant careful consideration to avoid exposures above the ADI. These data can be used to inform recommendations for the medical nutrition industry.

  9. Maternal circulating levels of activin A, inhibin A, sFlt-1 and endoglin at parturition in normal pregnancy and pre-eclampsia.

    Directory of Open Access Journals (Sweden)

    Aparna Reddy

    Full Text Available Maternal circulating levels of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1, endoglin (sEng and placental proteins like activin A and inhibin A are increased before the onset of pre-eclampsia. There is evidence for oxidative stress in pre eclampsia. Recently it was shown that placental oxygen concentration is related to sFlt-1 and inhibin A. In addition it is reported that oxidative stress markers are increased in placental tissue delivered after labour. Therefore, the objective of this study is to investigate if these proteins are altered in maternal circulation of labouring pre-eclampsia and normal pregnancies.To assess the effects of labour, samples were taken from 10 normal pregnant (NP and 10 pre-eclamptic (PE women pre-labour, full dilation, placental delivery and 24 h. To assess the effects of placental delivery, plasma samples were taken from 10NP and 10PE women undergoing elective Caesarean section, pre-delivery, placental delivery and 10 min, 60 min and 24 h post delivery. SFlt-1 and sEng and activin A and inhibin A were measured using commercial and in house ELISA's respectively.The levels of sFlt-1 and sEng were significantly higher in PE compared to NP women in both groups. In labour, sFlt-1 levels increased significantly at full dilatation in PE women, before declining by 24 hr. However there was no significant rise in sEng levels in labour. Activin A and inhibin A levels declined rapidly with placental delivery in NP and PE pregnancies. There was a significant rise in activin A levels during labour in PE compared to pre labour, but inhibin levels did not increase.Labour in pre-eclamptic women increases the levels of sFlt-1 and activin A. This pilot data suggests that increase in the maternal levels of these factors in labour could predict and/or contribute to the maternal syndrome postpartum.

  10. 18F-FDG and 18F-FLT-PET imaging for monitoring everolimus effect on tumor-growth in neuroendocrine tumors: studies in human tumor xenografts in mice.

    Directory of Open Access Journals (Sweden)

    Camilla Bardram Johnbeck

    Full Text Available The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily for 10 days. PET/CT scans were repeated at day 1,3 and 10.Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016, day 7 (164±7% vs. 226±13%; p<0.001 and at day 10 (194±10% vs. 281±18%; p<0.001. Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034, 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019 and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001 and day 10 (r2 = 0.58; P = 0.027.Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.

  11. Release of soluble vascular endothelial growth factor receptor-1 (sFlt-1 during coronary artery bypass surgery

    Directory of Open Access Journals (Sweden)

    Orsel Isabelle

    2007-09-01

    Full Text Available Abstract Background This study was conducted to follow plasma concentrations of sFlt-1 and sKDR, two soluble forms of the vascular endothelial growth factor (VEGF receptor in patients undergoing coronary artery bypass graft (CABG surgery with extracorporeal circulation (ECC. Methods Plasma samples were obtained before, during and after surgery in 15 patients scheduled to undergo CABG. Levels of sFlt-1 and KDR levels were investigated using specific ELISA. Results A 75-fold increase of sFlt-1 was found during cardiac surgery, sFlt-1 levels returning to pre-operative values at the 6th post-operative hour. In contrast sKDR levels did not change during surgery. The ECC-derived sFlt-1 was functional as judge by its inhibitory effect on the VEGF mitogenic response in human umbilical vein endothelial cells (HUVECs. Kinetic experiments revealed sFlt-1 release immediately after the beginning of ECC suggesting a proteolysis of its membrane form (mFlt-1 rather than an elevated transcription/translation process. Flow cytometry analysis highlighted no effect of ECC on the shedding of mFlt-1 on platelets and leukocytes suggesting vascular endothelial cell as a putative cell source for the ECC-derived sFlt-1. Conclusion sFlt-1 is released during CABG with ECC. It might be suggested that sFlt-1 production, by neutralizing VEGF and/or by inactivating membrane-bound Flt-1 and KDR receptors, might play a role in the occurrence of post-CABG complication.

  12. Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD–induced myeloproliferation

    Science.gov (United States)

    Matsuoka, Sahoko; Thongjuea, Supat; Jamieson, Lauren; Atkinson, Deborah; Kharazi, Shabnam; Suda, Toshio

    2017-01-01

    Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell-extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD–driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology. PMID:28637883

  13. Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia

    International Nuclear Information System (INIS)

    Al-Jamal, Hamid Ali Nagi; Mat Jusoh, Siti Asmaa; Hassan, Rosline; Johan, Muhammad Farid

    2015-01-01

    Tumor-suppressor genes are inactivated by methylation in several cancers including acute myeloid leukemia (AML). Src homology-2 (SH2)-containing protein-tyrosine phosphatase 1 (SHP-1) is a negative regulator of the JAK/STAT pathway. Transcriptional silencing of SHP-1 plays a critical role in the development and progression of cancers through STAT3 activation. 5-Azacytidine (5-Aza) is a DNA methyltransferase inhibitor that causes DNA demethylation resulting in re-expression of silenced SHP-1. Lestaurtinib (CEP-701) is a multi-targeted tyrosine kinase inhibitor that potently inhibits FLT3 tyrosine kinase and induces hematological remission in AML patients harboring the internal tandem duplication of the FLT3 gene (FLT3-ITD). However, the majority of patients in clinical trials developed resistance to CEP-701. Therefore, the aim of this study, was to assess the effect of re-expression of SHP-1 on sensitivity to CEP-701 in resistant AML cells. Resistant cells harboring the FLT3-ITD were developed by overexposure of MV4-11 to CEP-701, and the effects of 5-Aza treatment were investigated. Apoptosis and cytotoxicity of CEP-701 were determined using Annexin V and MTS assays, respectively. Gene expression was performed by quantitative real-time PCR. STATs activity was examined by western blotting and the methylation profile of SHP-1 was studied using MS-PCR and pyrosequencing analysis. Repeated-measures ANOVA and Kruskal–Wallis tests were used for statistical analysis. The cytotoxic dose of CEP-701 on resistant cells was significantly higher in comparison with parental and MV4-11R-cep + 5-Aza cells (p = 0.004). The resistant cells showed a significant higher viability and lower apoptosis compared with other cells (p < 0.001). Expression of SHP-1 was 7-fold higher in MV4-11R-cep + 5-Aza cells compared to parental and resistant cells (p = 0.011). STAT3 was activated in resistant cells. Methylation of SHP-1 was significantly decreased in MV4-11R-cep + 5-Aza cells (p = 0

  14. sFlt-1 and PlGF kinetics during and after pregnancy in women with suspected or confirmed preeclampsia.

    Science.gov (United States)

    Saleh, Langeza; van den Meiracker, Anton H; Geensen, Roos; Kaya, Aslihan; van Lennep, Jeanine E Roeters; Duvekot, Johannes J; Verdonk, Koen; Steegers, Eric A P; Russcher, Henk; Danser, Jan A H; Visser, Willy

    2017-06-10

    To assess the evolution of the sFlt-1/PlGF ratio in women with suspected or with confirmed preeclampsia and to investigate the changes in sFlt-1 and PlGF levels in preeclamptic women after delivery. In this exploratory tertiary referral university centre study, using the Roche Diagnostics Elecsys assay, sFlt-1 and PlGF were determined in two groups of patients. In the first group of 46 patients with suspected or confirmed preeclampsia, sFlt-1 and PlGF were measured at least twice during their pregnancy. Women had singleton pregnancies and a median pregnancy duration of 26 weeks (range 18 - 40 weeks). In the second group, sFlt-1 and PlGF of 26 preeclamptic patients were determined before and after delivery. The median gestational age at inclusion was 29 weeks (16 - 37) and the median days between antepartum measurement and delivery was 2 days (1 - 7). In the first group, 90% of patients with a sFlt-1/PlGF ratio ≤38 at baseline (n = 30), ruling out PE, the sFlt-1/PlGF ratio remained stable for up to 100 days. In 16 patients with a sFlt-1/PlGF ratio >38 and in 10% of those with a sFlt-1/PlGF ratio <38 at baseline the ratio increased further. In the second group, after delivery, sFlt-1 dropped to <1% of its pre-delivery values with a half-life of 1.4 ± 0.3 days, while PlGF dropped to ≈ 30% of its pre-delivery values with a half-life of 3.7 ± 4.3 days. Based on this small cohort, up to 10% of women admitted with suspected or confirmed PE presenting with a sFlt-1/PlGF ratio ≤38 display a rise of this sFlt-1/PlGF ratio in subsequent weeks, implying that repeated determination of the sFlt-1/PlGF ratio is required to reject this condition definitively. Furthermore, the rapid and pronounced decline of sFlt-1 values after delivery in patients with PE/HELLP suggests that sFlt-1, in contrast with PlGF, is almost entirely placenta-derived. This article is protected by copyright. All rights reserved.

  15. Spatiotemporal Stability of Cu-ATSM and FLT Positron Emission Tomography Distributions During Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Bradshaw, Tyler J.; Yip, Stephen; Jallow, Ngoneh [Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States); Forrest, Lisa J. [Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin (United States); Jeraj, Robert, E-mail: rjeraj@wisc.edu [Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States); Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States)

    2014-06-01

    Purpose: In dose painting, in which functional imaging is used to define biological targets for radiation therapy dose escalation, changes in spatial distributions of biological properties during treatment can compromise the quality of therapy. The goal of this study was to assess the spatiotemporal stability of 2 potential dose painting targets—hypoxia and proliferation—in canine tumors during radiation therapy. Methods and Materials: Twenty-two canine patients with sinonasal tumors (14 carcinoma and 8 sarcoma) were imaged before hypofractionated radiation therapy with copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) for hypoxia and 3′-deoxy-3′-{sup 18}F-fluorothymidine (FLT) PET/CT for proliferation. The FLT scans were repeated after 2 fractions and the Cu-ATSM scans after 3 fractions. Midtreatment PET/CT images were deformably registered to pretreatment PET/CT images. Voxel-based Spearman correlation coefficients quantified the spatial stability of Cu-ATSM and FLT uptake distributions between pretreatment and midtreatment scans. Paired t tests determined significant differences between the patients' respective Cu-ATSM and FLT correlations coefficients. Standardized uptake value measures were also compared between pretreatment and midtreatment scans by use of paired t tests. Results: Spatial distributions of Cu-ATSM and FLT uptake were stable through midtreatment for both sarcomas and carcinomas: the population mean ± standard deviation in Spearman correlation coefficient was 0.88 ± 0.07 for Cu-ATSM and 0.79 ± 0.13 for FLT. The patients' Cu-ATSM correlation coefficients were significantly higher than their respective FLT correlation coefficients (P=.001). Changes in Cu-ATSM SUV measures from pretreatment to midtreatment were histology dependent: carcinomas experienced significant decreases in Cu-ATSM uptake (P<.05), whereas sarcomas did not (P>.20). Both histologies

  16. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML

    DEFF Research Database (Denmark)

    Knapper, Steven; Russell, Nigel; Gilkes, Amanda

    2017-01-01

    The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activ...

  17. Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia.

    Science.gov (United States)

    Yunus, Noraini Mat; Johan, Muhammad Farid; Ali Nagi Al-Jamal, Hamid; Husin, Azlan; Hussein, Abdul Rahim; Hassan, Rosline

    2015-01-01

    Mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor gene may promote proliferation via activation of multiple signaling pathways. FLT3-internal tandem duplication (FLT3-ITD) is the most common gene alteration found in patients diagnosed with acute myeloid leukaemia (AML) and has been associated with poor prognosis. We performed mutational analysis of exons 14-15 and 20 of the FLT3 gene in 54 AML patients using PCR-CSGE (conformational sensitive gel electrophoresis) followed by sequencing analysis to characterise FLT3 mutations in adult patients diagnosed with AML at Hospital USM, Kelantan, Northeast Peninsular Malaysia. FLT3 exon 14-15 mutations were identified in 7 of 54 patients (13%) whereas no mutation was found in FLT3 exon 20. Six ITDs and one non-ITD mutation were found in exon 14 of the juxtamembrane (JM) domain of FLT3. FLT3-ITD mutations were associated with a significantly higher blast percentage (p-value=0.008) and white blood cell count (p-value=0.023) but there was no significant difference in median overall survival time for FLT3-ITD+/FLT3-ITD- within 2 years (p-value=0.374). The incidence of FLT3-ITD in AML patients in this particular region of Malaysia is low compared to the Western world and has a significant association with WBC and blast percentage.

  18. Immunotherapeutical role of Flt3 ligand amplification of pulmonary dendritic cells in murine multiple organ dysfunction syndrome in vivo

    Directory of Open Access Journals (Sweden)

    Hong-wei WANG

    2012-08-01

    Full Text Available Objective To explore the therapeutic effect of Flt3 ligand (Flt3L on multiple organ dysfunction syndrome (MODS model via amplification of lung dendritic cells. Methods Animal model of MODS was replicated by injecting zymosan into the peritoneal cavity of BALB/c mice, and then the mice were randomly divided into Flt3L treatment group, MODS group, Flt3L group and control group. Mortality rate was observed. After 12 days, lung mononuclear cells were isolated by density gradient centrifugation and analyzed with flow cytometry. Blood AST, ALT, creatinine, lipase, amylase and glucose were determined by automatic biochemical analyzer. Pathological changes in lung tissue were observed under light microscope. Results Mortality in Flt3L treatment group decreased dramatically compared with MODS group. The proportions of myeloid, plasmacytoid and I-Ad+ DCs in Flt3L group were remarkably increased compared with control group, and the proportion of the three DC subsets in MODS group was much lower than that in control group. Howerver, Flt3L treatment dramatically increased the proportion of them in MODS group. In MODS group, the level of ALT, AST, lipase, amylase and creatinine remarkably increased and blood glucose decreased compared with that of Flt3L and control groups; but in Flt3L treatment group, the level of ALT, AST, lipase, amylase and creatinine decreased and blood glucose increased dramatically, and lung injury mitigated obviously compared with MODS group. Conclusion Flt3L could attenuate lung tissue injury in MODS model, improve organ function, and lower the mortality of experimental animals, thus exerting its immunotherapeutic effects by in vivo amplification of lung dendritic cells.

  19. Intra-individual comparison of F-18-FLT PET and F-18 FET PET in brain tumor patients

    International Nuclear Information System (INIS)

    Kim, S.; Cheon, G.J.; Cho, Y.S.; Kwak, H.S.; Lee, C.H.; Choi, C.W.; Lim, S.M.

    2004-01-01

    Full text: The nucleoside analogue 18F-3'-deoxy-3'-fluorothymidine (FLT) for cellular proliferation and the amino acid analogue O- (2'18F-fluoroethyl)-L-tyrosine (FET) are recently developed PET-tracer for tumor imaging. Previous studies have demonstrated that the diagnostic ability of FET PET better than FDG PET in patient with newly diagnosed or recurrent brain tumors after radiation therapy. To compare findings on FLT PET with FET PET, we prospectively undertook FLT, FET and FDG PET in same patient with suspected primary/metastatic and recurrent brain tumors. Seventeen studies (FLT +FET + FDG: 13, FLT+FDG: 3, FLT +FET: 1) in 16 consecutive patients (47 ± 8.3 years, M: F 10: 6) with brain tumor (3 for initial diagnosis, 6 for therapeutic response, 6 for detecting recurrence, 1 for diagnosis and recurrence both) were included. Brain tumors were 14 gliomas (6 high-grade, 9 low-grade by the WHO classification), 2 metastatic brain tumors and 1 CNS lymphoma. 18F-FDG, FLT and FET PET were performed within two weeks. Attenuation-corrected brain images were acquired 30 minutes after injection of 370-555 MBq FDG, FLT and FET with a dedicated PET scanner (ECAT HR+ scanner, Siemens-CTI, Knoxville, Tenn., USA). Maximum SUV (max SUV) and relative uptake defined by FLT and FET accumulation within the tumor in relation to a contra lateral control region (max SUV for tumor/mean SUV for contra lateral normal gray matter) were calculated. A total of 26 tumor foci (26 on FLT and FDG, 22 on FET) in 17 studies were analysed. In most of tumor foci (20 of 22) FLT and FET PET images showed a similar extent of tumor activity. In 2 tumor foci discrepant findings were noticed; intense FLT uptake with negative FLT uptake in primary CNS lymphoma and negative FLT uptake with mild FET uptake in low-grade astrocytoma. Overall positive FLT, FET and FDG uptakes were 85 % (22/26), 90 % (18/ 20) and 58 % (15/26) respectively. Max SUV and relative FLT/FET uptake: The mean max SUV of FLT (0.97 ± 0

  20. Heat shock protein 27 mediates the effect of 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone on mitochondrial apoptosis in hepatocellular carcinoma.

    Science.gov (United States)

    Fu, Wei-ming; Zhang, Jin-fang; Wang, Hua; Xi, Zhi-chao; Wang, Wei-mao; Zhuang, Peng; Zhu, Xiao; Chen, Shih-chi; Chan, Tak-ming; Leung, Kwong-Sak; Lu, Gang; Xu, Hong-Xi; Kung, Hsiang-fu

    2012-08-03

    Hepatocellular carcinoma (HCC) is a global public health problem which causes approximately 500,000 deaths annually. Considering that the limited therapeutic options for HCC, novel therapeutic targets and drugs are urgently needed. In this study, we discovered that 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP), isolated from the traditional Chinese medicinal herb, Garcinia oblongifolia, effectively inhibited cell growth and induced the caspase-dependent mitochondrial apoptosis in HCC. A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics were performed to find the molecular targets of TDP in HCC cells. Eighteen proteins were identified as differently expressed, with Hsp27 protein being one of the most significantly down-regulated proteins induced by TDP. In addition, the following gain- and loss-of-function studies indicated that Hsp27 mediates mitochondrial apoptosis induced by TDP. Furthermore, a nude mice model also demonstrated the suppressive effect of TDP on HCC. Our study suggests that TDP plays apoptosis-inducing roles by strongly suppressing the Hsp27 expression that is specifically associated with the mitochondrial death of the caspase-dependent pathway. In conclusion, TDP may be a potential anti-cancer drug candidate, especially to cancers with an abnormally high expression of Hsp27. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Expression of the sFLT1 gene in cord blood cells is associated to maternal arsenic exposure and decreased birth weight.

    Directory of Open Access Journals (Sweden)

    Sylvie Remy

    Full Text Available There is increasing epidemiologic evidence that arsenic exposure in utero is associated with adverse pregnancy outcomes and may contribute to long-term health effects. These effects may occur at low environmental exposures but the underlying molecular mechanism is not clear. We collected cord blood samples of 183 newborns to identify associations between arsenic levels and birth anthropometric parameters in an area with very low arsenic exposure. Our core research aim was to screen for transcriptional marks that mechanistically explain these associations. Multiple regression analyses showed that birth weight decreased with 47 g (95% CI: 16-78 g for an interquartile range increase of 0.99 μg/L arsenic. The model was adjusted for child's sex, maternal smoking during pregnancy, gestational age, and parity. Higher arsenic concentrations and reduced birth weight were positively associated with changes in expression of the sFLT1 (soluble fms-like tyrosine kinase-1 gene in cord blood cells in girls. The protein product of sFLT1 is a scavenger of vascular endothelial growth factor (VEGF in the extracellular environment and plays a key role in the inhibition of placental angiogenesis. In terms of fetal development, inhibition of placental angiogenesis leads to impaired nutrition and hence to growth retardation. Various genes related to DNA methylation and oxidative stress showed also changed expression in relation to arsenic exposure but were not related to birth outcome parameters. In conclusion, this study suggests that increased expression of sFLT1 is an intermediate marker that points to placental angiogenesis as a pathway linking prenatal arsenic exposure to reduced birth weight.

  2. Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, Michael Højby; Juul, Anders; Kjems, Lise Lund

    2006-01-01

    , no published data exist on free IGF-I levels, acid labile subunit (ALS), or IGFBP protease activity in relation to GH release during a hypocaloric diet. The main purpose of this study was to determine free IGF-I, ALS, IGFBPs-1-4, and IGFBPs-1-3 protease activity in relation to 24-h GH release before and after......Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However...... a short-term very low-calorie diet (VLCD)....

  3. Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, Michael Højby; Juul, Anders; Kjems, Lise Lund

    2006-01-01

    Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However......, no published data exist on free IGF-I levels, acid labile subunit (ALS), or IGFBP protease activity in relation to GH release during a hypocaloric diet. The main purpose of this study was to determine free IGF-I, ALS, IGFBPs-1-4, and IGFBPs-1-3 protease activity in relation to 24-h GH release before and after...... a short-term very low-calorie diet (VLCD)....

  4. MAML2 rearrangement in primary pulmonary mucoepidermoid carcinoma and the correlation with FLT1 expression.

    Directory of Open Access Journals (Sweden)

    Fen Zhu

    Full Text Available INTRODUCTION: Primary pulmonary mucoepidermoid carcinoma (PMEC is an uncommon neoplasm with remarkable resemblance to mucoepidermoid carcinoma of the salivary glands. The latter has been shown to harbor t(11,19 resulting in MECT1-MAML2 fusion, which may be of diagnostic and prognostic values. However, the importance of such feature in PMEC has not been well studied. METHODS: We detected MAML2 rearrangement using fluorescence in situ hybridization (FISH in tissue samples from 42 cases of PMEC and 40 of adenosquamous carcinoma (ASC, and the expression of potential downstream targets of MECT1-MAML2, including HES1, FLT1 and NR4A2 with immunohistochemistry (IHC. The findings were then examined regarding the clinicopathological parameters and patient outcomes. RESULTS: FISH analysis revealed MAML2 rearrangement in 50% of the PMEC cases, and such property was prominent in considerable younger patients (33 versus 60 years; p = 0.001 and restricted to cases of low and intermediate grades. IHC analysis showed that FLT1 and HES1 were expressed at lower level in MAML2 rearranged group than MAML2 non-rearranged group (p<0.001 and p = 0.023, respectively. Survival analysis showed significant correlation between MAML2 rearrangement and overall survival (p = 0.023 or disease-free survival (p = 0.027 as well as correlation between FLT1 and overall survival (p = 0.009. CONCLUSIONS: MAML2 rearrangement appears frequent in PMEC and specific with this tumor. Both the presence of MAML2 rearrangement and absence of FLT1 tend to confer a favorable clinical outcome. These findings suggest that molecular detection of MAML2 rearrangement combined with FLT1 may be of important clinical value for PMEC.

  5. Activation of 5-[125I]iodonaphthyl-1-azide via excitation of fluorescent (N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)) lipid analogs in living cells. A potential tool for identification of compartment-specific proteins and proteins involved in intracellular transport and metabolism of lipids

    International Nuclear Information System (INIS)

    Rosenwald, A.G.; Pagano, R.E.; Raviv, Y.

    1991-01-01

    We describe a new technique for analysis of proteins located near fluorescent lipid analogs in intact living cells using the membrane-permeant, photoactivatable probe, 5-[ 125 I]iodonaphthyl-1-azide ([ 125 I]INA). [ 125 I] INA can be activated directly with UV light or indirectly through excitation of adjacent fluorophores (photosensitizers) with visible light to modify nearby proteins covalently with 125 I. In this report we demonstrate that fluorescent phospholipids and sphingolipids containing N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-6-aminocaproic acid serve as appropriate photosensitizers for [ 125 I]INA. Using Chinese hamster ovary fibroblasts, we optimized the labeling conditions with respect to lipid concentration and time of irradiation and then examined the profiles of cellular proteins that were labeled when fluorescent analogs of ceramide, sphingomyelin, and phosphatidic acid were used as photosensitizers in living cells. The use of different fluorescent lipids, which label different subcellular compartments of cells as determined by fluorescence microscopy, derivatized different sets of cellular proteins with 125 I. The labeled proteins were subsets of the total set of proteins available for derivatization as determined by direct activation of [ 125 I]INA. Most proteins labeled by this procedure were pelleted by centrifugation of cell lysates at high speed (260,000 x g), but several soluble proteins were also labeled under these conditions. The implications of using this technique for identification of compartment-specific proteins and proteins involved in lipid metabolism and transport are discussed

  6. FLT3-ITD and MLL-PTD influence the expression of MDR-1, MRP-1, and BCRP mRNA but not LRP mRNA assessed with RQ-PCR method in adult acute myeloid leukemia.

    Science.gov (United States)

    Nasilowska-Adamska, Barbara; Solarska, Iwona; Paluszewska, Monika; Malinowska, Iwona; Jedrzejczak, Wieslaw W; Warzocha, Krzysztof

    2014-04-01

    Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene-partial tandem duplication (MLL-PTD) are aberrations associated with leukemia which indicate unsatisfactory prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. We have analyzed the expression of MDR-1, multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) messenger RNA (mRNA) in relation to the mutational status of FLT3-ITD and MLL-PTD in 185 acute myeloid leukemia (AML) adult patients. The real-time quantitative polymerase chain reaction method was performed to assess the expression of the MDR-1, MRP-1, BCRP, and LRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule. Significantly higher expressions of MDR-1 mRNA were found in patients who did not harbor FLT3-ITD (0.20 vs. 0.05; p = 0.0001) and MRP-1 mRNA in patients with this mutation (0.96 vs. 0.70; p = 0.002) and of BCRP mRNA in patients with MLL-PTD (0.61 vs. 0.38; p = 0.03). In univariate analysis, the high expression of MDR-1 mRNA (≥0.1317) negatively influenced the outcome of induction therapy (p = 0.05), whereas the high expression of BCRP mRNA (≥1.1487) was associated with a high relapse rate (RR) (p = 0.013). We found that the high expression of MDR-1 (≥0.1317), MRP-1 (≥0.8409), and BCRP mRNA (≥1.1487) significantly influenced disease-free survival (DFS; p = 0.059, 0.032, and 0.009, respectively) and overall survival (0.048, 0.014, and 0.059, respectively). Moreover, a high expression of BCRP mRNA (≥1.1487) proved to be an independent prognostic factor for RR (p = 0.01) and DFS (p = 0.002) in multivariate analysis. The significant correlation between the expression of MDR-1, MRP-1, and BCRP mRNA and FLT3-ITD or MLL-PTD in AML patients requires further investigation.

  7. Incidence and significance of FLT3-ITD and NPM1 mutations in patients with normal karyotype acute myeloid leukaemia.

    LENUS (Irish Health Repository)

    Haslam, K

    2012-02-01

    BACKGROUND: Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis. AIMS: To determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML. METHODS: FLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients. RESULTS: FLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype. CONCLUSIONS: FLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.

  8. Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.

    Science.gov (United States)

    Ukon, Naoyuki; Zhao, Songji; Yu, Wenwen; Shimizu, Yoichi; Nishijima, Ken-Ichi; Kubo, Naoki; Kitagawa, Yoshimasa; Tamaki, Nagara; Higashikawa, Kei; Yasui, Hironobu; Kuge, Yuji

    2016-12-01

    Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl- 3 H(N)]-3'-fluoro-3'-deoxythythymidine ([ 3 H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [ 18 F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [ 18 F]FLT. The dynamic pattern of [ 18 F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [ 18 F]FLT phosphorylation (k 3 ) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [ 18 F]FLT forward transport (K 1 ) to reverse transport (k 2 ), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group). Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic

  9. FLT-PET for early response evaluation of colorectal cancer patients with liver metastases: a prospective study.

    Science.gov (United States)

    Mogensen, Marie Benzon; Loft, Annika; Aznar, Marianne; Axelsen, Thomas; Vainer, Ben; Osterlind, Kell; Kjaer, Andreas

    2017-12-01

    Fluoro-L-thymidine (FLT) is a positron emission tomography/computed tomography (PET/CT) tracer which reflects proliferative activity in a cancer lesion. The main objective of this prospective explorative study was to evaluate whether FLT-PET can be used for the early evaluation of treatment response in colorectal cancer patients (CRC) with liver metastases. Patients with metastatic CRC having at least one measurable (>1 cm) liver metastasis receiving first-line chemotherapy were included. A FLT-PET/CT scan was performed at baseline and after the first treatment. The maximum and mean standardised uptake values (SUV max , SUV mean ) were measured. After three cycles of chemotherapy, treatment response was assessed by CT scan based on RECIST 1.1. Thirty-nine consecutive patients were included of which 27 were evaluable. Dropout was mainly due to disease complications. Nineteen patients (70%) had a partial response, seven (26%) had stable disease and one (4%) had progressive disease. A total of 23 patients (85%) had a decrease in FLT uptake following the first treatment. The patient with progressive disease had the highest increase in FLT uptake in SUV max . There was no correlation between the response according to RECIST and the early changes in FLT uptake measured as SUV max (p = 0.24). No correlation was found between early changes in FLT uptake after the first cycle of treatment and the response evaluated from subsequent CT scans. It seems unlikely that FLT-PET can be used on its own for the early response evaluation of metastatic CRC.

  10. Potent Activity of Ponatinib (AP24534) in Models of FLT3-Driven Acute Myeloid Leukemia and Other Hematologic Malignancies

    Science.gov (United States)

    Gozgit, Joseph M.; Wong, Matthew J.; Wardwell, Scott; Tyner, Jeffrey W.; Loriaux, Marc M.; Mohemmad, Qurish K.; Narasimhan, Narayana I.; Shakespeare, William C.; Wang, Frank; Druker, Brian J.; Clackson, Tim; Rivera, Victor M.

    2011-01-01

    Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and mutant BCR-ABL at clinically achievable drug levels. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). Here, using leukemic cell lines containing activated forms of each of these receptors, we show that ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L). The activity of ponatinib against the FLT3-ITD mutant, found in up to 30% of acute myeloid leukemia (AML) patients, was particularly notable. In MV4-11 (FLT3-ITD+/+) but not RS4;11 (FLT3-ITD−/−) AML cells, ponatinib inhibited FLT3 signaling and induced apoptosis at concentrations of less than 10 nmol/L. In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib led to a dose-dependent inhibition of signaling and tumor regression. Ponatinib inhibited viability of primary leukemic blasts from a FLT3-ITD positive AML patient (IC50 4 nmol/L) but not those isolated from 3 patients with AML expressing native FLT3. Overall, these results support the investigation of ponatinib in patients with FLT3-ITD–driven AML and other hematologic malignancies driven by KIT, FGFR1, or PDGFRα. PMID:21482694

  11. In-vivo imaging of cellular proliferation in renal cell carcinoma using 18F-fluorothymidine (FLT) PET

    International Nuclear Information System (INIS)

    Wong, P.; Lee, S. T.; Eng, J.; Berlangieri, S. U.; Pathmaraj, K.; O'Keefe, G. J.; Lawrentschuk, N.

    2009-01-01

    Full text:Background: The ability to measure cellular proliferation non-invasively in renal cell carcinoma may allow prediction of tumour aggressiveness and response to therapy. The aim of this study was to evaluate the uptake of 18F-fluorothymidine (FLT) in renal cell carcinoma, and to compare this to 18F-fluorodeoxyglucose (FDG), and to an immunohistochemical measure of cellular proliferation (Ki-67). Methods: Twenty seven patients (16 men, 11 women; age 42-77) with newly diagnosed renal cell carcinoma suitable for resection were prospectively enrolled. All patients had preoperative FLT and FDG PET scans. After surgery tumour was taken for histologic analysis and immunohistochemical staining by Ki-67. Results: The mean SUVmax (maximum standardized uptake value) ± SD for FLT in tumour was 2.53 ± 1.26, compared to normal kidney (2.47 ± 0.34). The mean SUVmax for FDG in tumour was similar to FLT (2.60 ± 1.08). Visual identification of tumour using FLT PET compared to normal kidney was facilitated by the use of a pre-operative contrast enhanced CT scan. There was a significant correlation between FLT uptake and the immunohistochemical marker Ki-67 (r=0.624, p=0.0008) in RCC. Ki-67 labelling index was mean ± SD of 13.3% ± 9.2 (range 2.2% to 36.3%). Conclusion: There is detectable uptake of FLT in primary renal cell carcinoma, which correlates with cellular proliferation as assessed by Ki-67 labelling index. This finding has relevance to the use of FLT PET in molecular imaging studies of renal cell carcinoma biology.

  12. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial.

    Science.gov (United States)

    Heier, Jeffrey S; Kherani, Saleema; Desai, Shilpa; Dugel, Pravin; Kaushal, Shalesh; Cheng, Seng H; Delacono, Cheryl; Purvis, Annie; Richards, Susan; Le-Halpere, Annaig; Connelly, John; Wadsworth, Samuel C; Varona, Rafael; Buggage, Ronald; Scaria, Abraham; Campochiaro, Peter A

    2017-07-01

    Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration. This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2 × 10 8 vector genomes (vg); cohort 2, 2 × 10 9 vg; cohort 3, 6 × 10 9 vg; and cohort 4, 2 × 10 10 vg, n=3 per cohort) and one maximum tolerated dose cohort (cohort 5, 2 × 10 10 vg, n=7) and followed up for 52 weeks. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, number NCT01024998. 19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-week trial period. Two patients in cohort 4 (2 × 10 10 vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2 × 10 10 vg had aqueous humour concentrations of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to

  13. FDG-PET/CT and FLT-PET/CT for differentiating between lipid-poor benign and malignant adrenal tumours

    Energy Technology Data Exchange (ETDEWEB)

    Nakajo, Masatoyo; Jinguji, Megumi; Fukukura, Yoshihiko; Nakabeppu, Yoshiaki; Nakamura, Fumihiko; Yoshiura, Takashi [Kagoshima University, Department of Radiology, Graduate School of Medical and Dental Sciences, Kagoshima (Japan); Kajiya, Yoriko; Tani, Atushi; Nakajo, Masayuki [Nanpuh Hospital, Department of Radiology, Kagoshima (Japan); Arimura, Hiroshi; Nishio, Yoshihiko [Kagoshima University, Department of Diabetes and Endocrine Medicine, Graduate School of Medical and Dental Sciences, Kagoshima (Japan)

    2015-12-15

    To compare F-18-fluorodeoxyglucose (FDG) and F-18-fluorothymidine (FLT) PET/CT examinations for differentiating between benign and malignant adrenal tumours. Thirty lipid-poor benign and 11 malignant tumours of 40 patients were included. FDG- and FLT-based indices including visual score, maximum standardized uptake value (SUVmax) and FDG adrenal lesion/liver SUVmax (A/L SUVmax) or FLT adrenal lesion/back muscle SUVmax (A/B SUVmax) ratio were compared between benign and malignant tumours using the Mann-Whitney's U or Wilcoxon signed-rank test, and their diagnostic performances were evaluated by means of the area under the curve (AUC) values derived from the receiver operating characteristic analysis. All indices were significantly higher in malignant than benign tumours on both images (p < 0.05 each). On FDG-PET/CT, the sensitivity, specificity, and accuracy were 91 %, 63 % and 71 % for visual score, 91 %, 67 % and 73 % for SUVmax, and 100 %, 70 % and 78 % for A/L SUVmax ratio, respectively. On FLT-PET/CT, they were 100 %, 97 % and 98 % for visual score, SUVmax and A/B SUVmax ratio, respectively. All FLT indices were significantly higher than those of FDG in AUC (p < 0.05 each). FLT-PET/CT may be superior to FDG-PET/CT in differentiating lipid-poor benign from malignant adrenal tumours because of higher specificity and accuracy. (orig.)

  14. Flt3 ligand-receptor interaction is important for maintenance of early thymic progenitor numbers in steady-state thymopoiesis.

    Science.gov (United States)

    Kenins, Linda; Gill, Jason W; Holländer, Georg A; Wodnar-Filipowicz, Aleksandra

    2010-01-01

    T-cell production throughout life depends on efficient colonization and intrathymic expansion of BM-derived hematopoietic precursors. After irradiation-induced thymic damage, thymic recovery is facilitated by Flt3 ligand (FL), expressed by perivascular fibroblasts surrounding the thymic entry site of Flt3 receptor-positive progenitor cells. Whether intrathymic FL-Flt3 interactions play a role in steady-state replenishment of T cells remains unknown. Here, using competitive BM transplantation studies and fetal thymic organ cultures we demonstrated the continued numerical advantage of Flt3+ intrathymic T-cell precursors. Sub-kidney capsule thymic transplantation experiments, in which WT and FL-/- thymic lobes were grafted into FL-/- recipients, revealed that FL expression by the thymic microenvironment plays a role in steady-state thymopoiesis. The deficiency of the most immature thymic T-cell precursors correlated to upregulation of FL by thymic MTS15+ fibroblasts, suggesting that the number of Flt3+ progenitor cells may regulate the thymic expression of this cytokine. Together, these results show that FL expression by thymic stromal fibroblasts interacting with Flt3+ T-cell progenitors is important for the physiological maintenance of early T-cell development.

  15. 1-3 Composites Study

    National Research Council Canada - National Science Library

    Gabrielson, Thomas B

    2003-01-01

    ...) In a transducer in which the active material is sandwiched between mass elements, the filler in a 1-3 composite degrades performance with respect to an unfilled array of piezoelectric rods. (3...

  16. Prognostic value of 18F-FLT PET in patients with neuroendocrine neoplasms

    DEFF Research Database (Denmark)

    Johnbeck, Camilla B.; Knigge, Ulrich; Langer, Seppo W.

    2016-01-01

    Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors arising in various organs and with a large span of aggressiveness and survival rates. The Ki-67 proliferation index is presently used as the key marker of prognosis, and treatment guidelines are largely based on this index...... study was to investigate 18F-FLT PET as a prognostic marker for NENs in comparison with 18F-FDG PET and Ki-67 index. Methods: One hundred patients were PET-scanned with both 18F-FLT and 18F-FDG within the same week, and the prognostic value of a positive scan was examined in terms of progression...... prognostic value in NEN patients but when 18F-FDG PET and Ki-67 index are also available, a multivariate model revealed that 18F-FLT PET only adds information regarding PFS but not OS, whereas 18F-FDG PET remains predictive of both PFS and OS. However, a clinically robust algorithm including 18F...

  17. Comparison of [18F]FLT and [18F]FDG in in vitro cancer cell uptake and glucose effect

    International Nuclear Information System (INIS)

    Soo Jung Lim; Jin-Sook Ryu; Heuiran Lee; Seok Young Kim; Seung Jun Oh; Dae Hyuk Moon

    2004-01-01

    [18F]FLT is a new radiopharmaceutical for cell proliferation. We compared [18F]FLT and [18F]FDG in in vitro cancer cell uptake and glucose effect. Method: In vitro cancer cell uptake of [18F]FLT was evaluated using SCC7(mouse squamous cell carcinoma). At 24 hours after seeding 1 x 106 cells/well in 6 well plates with RPMI 1640 medium, culture media were changed to medium with glucose free or glucose concentration of 100 mg/dl. Then, [18F]FLT 5 μCi/50 ml was added to each well. After incubation for 30, 60, 90, 120 minutes, cells were washed twice by PBS, and harvested using 0.25% trypsin-EDTA. After centrifugation and counting at gamma counter, cell uptake was calculated by % activity of cellular uptake to total activity of cell and supernatant. For comparison, same tumor cell uptake experiment was performed with [18F]FDG. Results: After incubation with SCC7 cell line for 30, 60, 90, 120 minutes, [18F]FLT showed 1.95%, 2.17%, 2.10% and 2.80% of cell uptake in glucose free media, respectively. The results [18F]FLT uptake in glucose 100 mg/dl media were 1.82%, 1.87%, 1.97%, and 2.94%, respectively. The results of [18F]FDG in glucose free media were 2.50%, 3.47%, 5.04%, and 10.4%, whereas those in glucose 100 mg/dl media were 1.60%, 1.79%, 1.53%, and 1.82%, respectively. Conclusion: In contrast to [18F]FDG, [18F]FLT uptake in cancer cell was not affected by glucose concentration. In physiologic glucose concentration, [18F]FLT uptake in SCC7 cell line was significantly higher than [18F]FDG uptake after 120 minutes incubation. In [18F]FLT PET imaging may not need fasting for preparation before imaging study. (authors)

  18. Performance of FLT-PET for pulmonary lesion diagnosis compared with traditional FDG-PET: A meta-analysis

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zixing; Wang, Yuyan [Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, 100005 (China); Sui, Xin; Zhang, Wei [Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100005 (China); Shi, Ruihong [National Institutes for Food and Drug Control, Beijing, 100000 (China); Zhang, Yingqiang; Dang, Yonghong; Qiao, Zhen [Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100005 (China); Zhang, Biao [Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, 100005 (China); Song, Wei, E-mail: cjr.songwei@vip.163.com [Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100005 (China); Jiang, Jingmei, E-mail: jingmeijiang238@hotmail.com [Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, 100005 (China)

    2015-07-15

    Highlights: • FDG PET is more sensitive compared with FLT for detecting small and early staged lung cancers. • FLT can reduce false positives of FDG for inflammation-based lesions such as tuberculosis. • FLT shows comparable accuracies for diagnoses of late stage tumors and larger pulmonary lesions. - Abstract: Purpose: Widely used {sup 18}F 2′-deoxy-2′-fluoro-D-glucose (FDG) positron emission tomography (PET) can be problematic with false positives in cancer imaging. This study aims to investigate the diagnostic accuracy of a candidate PET tracer, {sup 18}F 2′,3′-dideoxy-3′-fluoro-2-thiothymidine (FLT), in diagnosing pulmonary lesions compared with FDG. Materials and methods: After comprehensive search and study selection, a meta-analysis was performed on data from 548 patients pooled from 17 studies for evaluating FLT accuracy, in which data from 351 patients pooled from ten double-tracer studies was used for direct comparison with FDG. Weighted sensitivity and specificity were used as main indicators of test performance. Individual data was extracted and patient subgroup analyses were performed. Results: Overall, direct comparisons showed lower sensitivity (0.80 vs. 0.89) yet higher specificity (0.82 vs. 0.66) for FLT compared with FDG (both p < 0.01). Patient subgroup analysis showed FLT was less sensitive than FDG in detecting lung cancers staged as T1 or T2, and those ≤2.0 cm in diameter (0.81 vs. 0.93, and 0.53 vs. 0.78, respectively, both p < 0.05), but was comparable for cancers staged as T3 or T4, and those >2.0 cm in diameter (0.95 vs. 1.00, 0.96 vs. 0.88, both p > 0.05). For benignities, FLT performed better compared with FDG in ruling out inflammation-based lesions (0.57 vs. 0.32, p < 0.05), and demonstrated greater specificity regardless of lesion sizes. Conclusions: Although FLT cannot replace FDG in detecting small and early lung cancers, it may help to prevent patients with larger or inflammatory lesions from cancer misdiagnosis

  19. Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

    Science.gov (United States)

    Doshi, Kshama A.; Trotta, Rossana; Natarajan, Karthika; Rassool, Feyruz V.; Tron, Adriana E.; Huszar, Dennis; Perrotti, Danilo; Baer, Maria R.

    2016-01-01

    Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD. PMID:27374090

  20. Early detection of response to experimental chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in human ovary cancer xenografts in mice

    DEFF Research Database (Denmark)

    Jensen, Mette Munk; Erichsen, Kamille Dumong; Björkling, Fredrik

    2010-01-01

    3'-Deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use (18)F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects...

  1. SOCS1 cooperates with FLT3-ITD in the development of myeloproliferative disease by promoting the escape from external cytokine control

    DEFF Research Database (Denmark)

    Reddy, P.N.G.; Serve, H.; Brandts, C.H.

    2012-01-01

    Activating mutations in the receptor tyrosine kinase FLT3 are frequently found in acute myelogenous leukemia patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control that regulates normal hematopoiesis. We have recently demonstrated that FLT3-internal...

  2. Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3 inhibitor therapy with evolving actionable targets

    Directory of Open Access Journals (Sweden)

    Pashtoon M. Kasi

    2016-01-01

    Full Text Available For acute myeloid leukemia (AML, identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3 has led to the development of several FLT3-inhibitors. Here we present clinical and next generation sequencing data at the time of progression of a patient on a novel FLT3-inhibitor clinical trial (ASP2215 to show that employing therapeutic interventions with these novel targeted therapies can lead to consequences secondary to selective pressure and clonal evolution of cancer. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process. (Clinical Trial: NCT02014558; registered at: 〈https://clinicaltrials.gov/ct2/show/NCT02014558〉

  3. 18F-FLT uptake kinetics in head and neck squamous cell carcinoma: A PET imaging study

    International Nuclear Information System (INIS)

    Liu, Dan; Fenwick, John D.; Chalkidou, Anastasia; Landau, David B.; Marsden, Paul K.

    2014-01-01

    Purpose: To analyze the kinetics of 3 ′ -deoxy-3 ′ -[F-18]-fluorothymidine (18F-FLT) uptake by head and neck squamous cell carcinomas and involved nodes imaged using positron emission tomography (PET). Methods: Two- and three-tissue compartment models were fitted to 12 tumor time-activity-curves (TACs) obtained for 6 structures (tumors or involved nodes) imaged in ten dynamic PET studies of 1 h duration, carried out for five patients. The ability of the models to describe the data was assessed using a runs test, the Akaike information criterion (AIC) and leave-one-out cross-validation. To generate parametric maps the models were also fitted to TACs of individual voxels. Correlations between maps of different parameters were characterized using Pearson'sr coefficient; in particular the phosphorylation rate-constants k 3-2tiss and k 5 of the two- and three-tissue models were studied alongside the flux parameters K FLT-2tiss and K FLT of these models, and standardized uptake values (SUV). A methodology based on expectation-maximization clustering and the Bayesian information criterion (“EM-BIC clustering”) was used to distil the information from noisy parametric images. Results: Fits of two-tissue models 2C3K and 2C4K and three-tissue models 3C5K and 3C6K comprising three, four, five, and six rate-constants, respectively, pass the runs test for 4, 8, 10, and 11 of 12 tumor TACs. The three-tissue models have lower AIC and cross-validation scores for nine of the 12 tumors. Overall the 3C6K model has the lowest AIC and cross-validation scores and its fitted parameter values are of the same orders of magnitude as literature estimates. Maps ofK FLT and K FLT-2tiss are strongly correlated (r = 0.85) and also correlate closely with SUV maps (r = 0.72 for K FLT-2tiss , 0.64 for K FLT ). Phosphorylation rate-constant maps are moderately correlated with flux maps (r = 0.48 for k 3-2tiss vs K FLT-2tiss and r = 0.68 for k 5 vs K FLT ); however, neither phosphorylation

  4. A Pilot Study for the Feasibility of F-18 FLT-PET in Locally Advanced Breast Cancer: Comparison with F-18 FDG-PET

    International Nuclear Information System (INIS)

    Lee, Jai Hyuen; Kim, Euy Nyong; Hong, Il Ki

    2008-01-01

    The aim of this study was to investigate the feasibility of 3'-[F-18]fluoro-3'-deoxythymidine positron emission tomography(FLT-PET) for the detection of locally advanced breast cancer and to compare the degree of FLT and 2'-deoxy-2'-[F-18]fluoro-d-glucose(FDG) uptake in primary tumor, lymph nodes and other normal organs. The study subjects consisted of 22 female patients (mean age; 42±6 years) with biopsy-confirmed infiltrating ductal carcinoma between Aug 2005 and Nov 2006. We performed conventional imaging workup, FDG-PET and FLT PET/CT. Average tumor size measured by MRI was 7.2±3.4 cm. With visual analysis, Tumor and Lymph node uptakes of FLT and FDG were determined by calculation of standardized uptake value (SUV) and tumor to background (TB) ratio. We compared FLT tumor uptake with FDG tumor uptake. We also investigated the correlation between FLT tumor uptake and FDG tumor uptake and the concordant rate with lymph node uptakes of FLT and FDG. FLT and FDG uptakes of bone marrow and liver were measured to compare the biodistribution of each other. All tumor lesions were visually detected in both FLT-PET and FDG-PET. There was no significant correlation between maximal tumor size by MRI and SUVmax of FLT-PET or FDG-PET (p>0.05). SUVmax and SUV75 (average SUV within volume of interest using 75% isocontour) of FLT-PET were significantly lower than those of FDG-PET in primary tumor (SUVmax; 6.3±5.2 vs 8.3±4.9, p=0.02 / SUV75; 5.3±4.3 vs 6.9 4.2, p=0.02). There is significant moderate correlation between uptake of FLT and FDG in primary tumor (SUVmax; rho=0.450, p=0.04 / SUV75; rho=0.472, p=0.03). But, TB ratio of FLT-PET was higher than that of FDG-PET(11.7±7.7 vs 6.3±3.8, p=0.001). The concordant rate between FLT and FDG uptake of lymph node was reasonably good (33/34). The FLT SUVs of liver and bone marrow were 4.2±1.2 and 8.3±4.9. The FDG SUVs of liver and bone marrow were 1.8±0.4 and 1.6±0.4. The uptakes of FLT were lower than those of FDG, but all

  5. Evaluation of an automated double-synthesis module: efficiency and reliability of subsequent radiosyntheses of FHBG and FLT

    International Nuclear Information System (INIS)

    Niedermoser, Sabrina; Pape, Manuela; Gildehaus, Franz Josef; Wängler, Carmen; Hartenbach, Markus; Schirrmacher, Ralf; Bartenstein, Peter; Wängler, Björn

    2012-01-01

    We optimized the synthesis methods for 3′-deoxy-3′-[ 18 F]fluorothymidine ([ 18 F]FLT) and 9-(4-[ 18 F]fluoro-3-[hydroxymethyl]butyl)guanine) ([ 18 F]FHBG) and automated them on an Explora General Nucleophilic double-synthesis module. Furthermore, the synthesis efficiency and reliability and the formation of cross-contaminations of the products when preparing two consecutive batches were evaluated. Whereas the preinstalled FLT synthesis conditions required substantial modification in reaction and neutralization conditions to achieve radiochemical yields of up to 60% within 70±10 min including high-performance liquid chromatography purification, the synthesis of FHBG had to be implemented to the module to obtain competitive radiochemical yields of up to 40% in an overall synthesis time of 60±10 min. The radiochemical purities obtained were ≥99% and ≥96% for the synthesis of [ 18 F]FLT and [ 18 F]FHBG, respectively. No significant changes in yield or purity could be observed between both batch productions. We found that the yields and purities also did not change when performing FLT after FHBG syntheses and vice versa. Hence, we developed a synthesis setup that offers the opportunity to perform two subsequent syntheses of either [ 18 F]FLT, [ 18 F]FHBG or [ 18 F]FLT after [ 18 F]FHBG without decrease in radiochemical yields and purities. Also, no cross-contaminations were observed, which can be attributed to the use of separate product delivery tubes, purification columns and an automated intermediate cleaning program. These results open up the possibility of producing consecutively either two equal 18 F-fluorinated tracers or two different ones in high yields on the same synthesis module.

  6. Dinucleotide repeat polymorphism in Fms-like tyrosine kinase-1 (Flt-1 gene is not associated with preeclampsia

    Directory of Open Access Journals (Sweden)

    Park So-Yeon

    2008-07-01

    Full Text Available Abstract Background Preeclampsia is a major cause of maternal and perinatal mortality and morbidity. The etiology of preeclampsia remains unclear. Recently, it was shown that misregulation of fms-like tyrosine kinase-1 (Flt-1 in the peripheral blood mononuclear cells of pregnant women results in over-expression of the soluble splice variant of Flt-1, sFlt-1, producing an additional (extra-placental source of sFlt-1 that can contribute to the etiology of preeclampsia. The aim of this study was to investigate the relationship between preeclampsia and a dinucleotide (threonine-glycine; TGn repeat polymorphism in the 3' non-coding region of the Flt-1 gene. Methods The number of the d(TGn repeats was analyzed in 170 patients with preeclampsia and in 202 normotensive pregnancies. The region containing the dinucleotide repeat polymorphism of the Flt-1 gene was amplified by polymerase chain reaction (PCR from the DNA samples and was analyzed by direct PCR sequencing. Results We found 10 alleles of the dinucleotide repeat polymorphism and designated these as allele*12 (A1 through allele*23 (A12 according to the number of the TG repeats, from 12 to 23. The frequency of the 14-repeat allele (A3 was most abundant (63.82% in preeclampsia and 69.06% in controls, followed by the 21-repeat allele (A10; 28.53% in preeclampsia and 23.76% in controls. There was no significant difference in the allele frequency between patients with preeclampsia and normal controls. The most common genotype in preeclamptic and normotensive pregnancies was heterozygous (TG14/(TG21 (41.76% and homozygous (TG14/(TG14 (45.05%, respectively. However, the genotype frequencies were not significantly different between preeclamptic patients and controls. Conclusion This is the first study to characterize the dinucleotide repeat polymorphism of the Flt-1 gene in patients with preeclampsia. We found no differences in the allele or genotype frequencies between patients with preeclampsia and

  7. FLT3 and JAK2 Mutations in Acute Myeloid Leukemia Promote Interchromosomal Homologous Recombination and the Potential for Copy Neutral Loss of Heterozygosity.

    Science.gov (United States)

    Gaymes, Terry J; Mohamedali, Azim; Eiliazadeh, Anthony L; Darling, David; Mufti, Ghulam J

    2017-04-01

    Acquired copy neutral LOH (CN-LOH) is a frequent occurrence in myeloid malignancies and is often associated with resistance to standard therapeutic modalities and poor survival. Here, we show that constitutive signaling driven by mutated FLT3 and JAK2 confers interchromosomal homologous recombination (iHR), a precedent for CN-LOH. Using a targeted recombination assay, we determined significant iHR activity in internal tandem duplication FLT3 (FLT3-ITD) and JAK2V617F-mutated cells. Sister chromatid exchanges, a surrogate measure of iHR, was significantly elevated in primary FLT3-ITD normal karyotype acute myeloid leukemia (NK-AML) compared with wild-type FLT3 NK-AML. HR was harmonized to S phase of the cell cycle to repair broken chromatids and prevent iHR. Increased HR activity in G 0 arrested primary FLT3-ITD NK-AML in contrast to wild-type FLT3 NK-AML. Cells expressing mutated FLT3-ITD demonstrated a relative increase in mutation frequency as detected by thymidine kinase (TK) gene mutation assay. Moreover, resistance was associated with CN-LOH at the TK locus. Treatment of FLT3-ITD- and JAK2V617F-mutant cells with the antioxidant N -acetylcysteine diminished reactive oxygen species (ROS), restoring iHR and HR levels. Our findings show that mutated FLT3-ITD and JAK2 augment ROS production and HR, shifting the cellular milieu toward illegitimate recombination events such as iHR and CN-LOH. Therapeutic reduction of ROS may thus prevent leukemic progression and relapse in myeloid malignancies. Cancer Res; 77(7); 1697-708. ©2017 AACR . ©2017 American Association for Cancer Research.

  8. Preliminary 19F-MRS Study of Tumor Cell Proliferation with 3′-deoxy-3′-fluorothymidine and Its Metabolite (FLT-MP

    Directory of Open Access Journals (Sweden)

    In Ok Ko

    2017-01-01

    Full Text Available The thymidine analogue 3′-deoxy-3′-[18F]fluorothymidine, or [18F]fluorothymidine ([18F]FLT, is used to measure tumor cell proliferation with positron emission tomography (PET imaging technology in nuclear medicine. FLT is phosphorylated by thymidine kinase 1 (TK1 and then trapped inside cells; it is not incorporated into DNA. Imaging with 18F-radiolabeled FLT is a noninvasive technique to visualize cellular proliferation in tumors. However, it is difficult to distinguish between [18F]FLT and its metabolites by PET imaging, and quantification has not been attempted using current imaging methods. In this study, we successfully acquired in vivo F19 spectra of natural or nonradioactive 3′-deoxy-3′-fluorothymidine ([19F]FLT and its monophosphate metabolite (FLT-MP in a tumor xenograft mouse model using 9.4T magnetic resonance imaging (MRI. This preliminary result demonstrates that 19F magnetic resonance spectroscopy (MRS with FLT is suitable for the in vivo assessment of tumor aggressiveness and for early prediction of treatment response.

  9. Alterations in plasma soluble vascular endothelial growth factor receptor-1 (sFlt-1 concentrations during coronary artery bypass graft surgery: relationships with post-operative complications

    Directory of Open Access Journals (Sweden)

    Orsel Isabelle

    2008-04-01

    Full Text Available Abstract Background Plasma concentrations of sFlt-1, the soluble form of the vascular endothelial growth factor receptor (VEGF, markedly increase during coronary artery bypass graft (CABG surgery with extracorporeal circulation (ECC. We investigated if plasma sFlt-1 values might be related to the occurrence of surgical complications after CABG. Methods Plasma samples were collected from the radial artery catheter before vascular cannulation and after opening the chest, at the end of ECC just before clamp release, after cross release, after weaning from ECC, at the 6th and 24th post-operative hour. Thirty one patients were investigated. The presence of cardiovascular, haematological and respiratory dysfunctions was prospectively assessed. Plasma sFlt-1 levels were measured with commercially ELISA kits. Results Among the 31 investigated patients, 15 had uneventful surgery. Patients with and without complications had similar pre-operative plasma sFlt-1 levels. Lowered plasma sFlt-1 levels were observed at the end of ECC in patients with haematological (p = 0.001, ANOVA or cardiovascular (p = 0.006 impairments, but not with respiratory ones (p = 0.053, as compared to patients with uneventful surgery. Conclusion These results identify an association between specific post-CABG complication and the lower release of sFlt-1 during ECC. sFlt-1-induced VEGF neutralisation might, thus, be beneficial to reduce the development of post-operative adverse effects after CABG.

  10. Metabolically active tumour volume segmentation from dynamic [(18)F]FLT PET studies in non-small cell lung cancer.

    Science.gov (United States)

    Hoyng, Lieke L; Frings, Virginie; Hoekstra, Otto S; Kenny, Laura M; Aboagye, Eric O; Boellaard, Ronald

    2015-01-01

    Positron emission tomography (PET) with (18)F-3'-deoxy-3'-fluorothymidine ([(18)F]FLT) can be used to assess tumour proliferation. A kinetic-filtering (KF) classification algorithm has been suggested for segmentation of tumours in dynamic [(18)F]FLT PET data. The aim of the present study was to evaluate KF segmentation and its test-retest performance in [(18)F]FLT PET in non-small cell lung cancer (NSCLC) patients. Nine NSCLC patients underwent two 60-min dynamic [(18)F]FLT PET scans within 7 days prior to treatment. Dynamic scans were reconstructed with filtered back projection (FBP) as well as with ordered subsets expectation maximisation (OSEM). Twenty-eight lesions were identified by an experienced physician. Segmentation was performed using KF applied to the dynamic data set and a source-to-background corrected 50% threshold (A50%) was applied to the sum image of the last three frames (45- to 60-min p.i.). Furthermore, several adaptations of KF were tested. Both for KF and A50% test-retest (TRT) variability of metabolically active tumour volume and standard uptake value (SUV) were evaluated. KF performed better on OSEM- than on FBP-reconstructed PET images. The original KF implementation segmented 15 out of 28 lesions, whereas A50% segmented each lesion. Adapted KF versions, however, were able to segment 26 out of 28 lesions. In the best performing adapted versions, metabolically active tumour volume and SUV TRT variability was similar to those of A50%. KF misclassified certain tumour areas as vertebrae or liver tissue, which was shown to be related to heterogeneous [(18)F]FLT uptake areas within the tumour. For [(18)F]FLT PET studies in NSCLC patients, KF and A50% show comparable tumour volume segmentation performance. The KF method needs, however, a site-specific optimisation. The A50% is therefore a good alternative for tumour segmentation in NSCLC [(18)F]FLT PET studies in multicentre studies. Yet, it was observed that KF has the potential to subsegment

  11. Interstitial diffusion and the relationship between compartment modelling and multi-scale spatial-temporal modelling of (18)F-FLT tumour uptake dynamics.

    Science.gov (United States)

    Liu, Dan; Chalkidou, Anastasia; Landau, David B; Marsden, Paul K; Fenwick, John D

    2014-09-07

    Tumour cell proliferation can be imaged via positron emission tomography of the radiotracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT). Conceptually, the number of proliferating cells might be expected to correlate more closely with the kinetics of 18F-FLT uptake than with uptake at a fixed time. Radiotracer uptake kinetics are standardly visualized using parametric maps of compartment model fits to time-activity-curves (TACs) of individual voxels. However the relationship between the underlying spatiotemporal accumulation of FLT and the kinetics described by compartment models has not yet been explored. In this work tumour tracer uptake is simulated using a mechanistic spatial-temporal model based on a convection-diffusion-reaction equation solved via the finite difference method. The model describes a chain of processes: the flow of FLT between the spatially heterogeneous tumour vasculature and interstitium; diffusion and convection of FLT within the interstitium; transport of FLT into cells; and intracellular phosphorylation. Using values of model parameters estimated from the biological literature, simulated FLT TACs are generated with shapes and magnitudes similar to those seen clinically. Results show that the kinetics of the spatial-temporal model can be recovered accurately by fitting a 3-tissue compartment model to FLT TACs simulated for those tumours or tumour sub-volumes that can be viewed as approximately closed, for which tracer diffusion throughout the interstitium makes only a small fractional change to the quantity of FLT they contain. For a single PET voxel of width 2.5-5 mm we show that this condition is roughly equivalent to requiring that the relative difference in tracer uptake between the voxel and its neighbours is much less than one.

  12. Conformation of glycomimetics in the free and protein-bound state: structural and binding features of the C-glycosyl analogue of the core trisaccharide alpha-D-Man-(1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man.

    Science.gov (United States)

    Mikkelsen, Lise Munch; Hernáiz, María José; Martín-Pastor, M; Skrydstrup, Troels; Jiménez-Barbero, Jesús

    2002-12-18

    The conformational properties of the C-glycosyl analogue of the core trisaccharide alpha-D-Man-(1 --> 3)-[alpha-D-Man-(1 --> 6)]-D-Man in solution have been carefully analyzed by a combination of NMR spectroscopy and time-averaged restrained molecular dynamics. It has been found that both the alpha-1,3- and the alpha-1,6-glycosidic linkages show a major conformational averaging. Unusual Phi ca. 60 degrees orientations for both Phi torsion angles are found. Moreover, a major conformational distinction between the natural compound and the glycomimetic affects to the behavior of the omega(16) torsion angle around the alpha-1 --> 6-linkage. Despite this increased flexibility, the C-glycosyl analogue is recognized by three mannose binding lectins, as shown by NMR (line broadening, TR-NOE, and STD) and surface plasmon resonance (SPR) methods. Moreover, a process of conformational selection takes place, so that these lectins probably bind the glycomimetic similarly to the way they recognize the natural analogue. Depending upon the architecture and extension of the binding site of the lectin, loss or gain of binding affinity with respect to the natural analogue is found.

  13. Transfer of the human NKG2D ligands UL16 binding proteins (ULBP) 1-3 is related to lytic granule release and leads to ligand retransfer and killing of ULBP-recipient natural killer cells.

    Science.gov (United States)

    López-Cobo, Sheila; Romera-Cárdenas, Gema; García-Cuesta, Eva M; Reyburn, Hugh T; Valés-Gómez, Mar

    2015-09-01

    After immune interactions, membrane fragments can be transferred between cells. This fast transfer of molecules is transient and shows selectivity for certain proteins; however, the constraints underlying acquisition of a protein are unknown. To characterize the mechanism and functional consequences of this process in natural killer (NK) cells, we have compared the transfer of different NKG2D ligands. We show that human NKG2D ligands can be acquired by NK cells with different efficiencies. The main findings are that NKG2D ligand transfer is related to immune activation and receptor-ligand interaction and that NK cells acquire these proteins during interactions with target cells that lead to degranulation. Our results further demonstrate that NK cells that have acquired NKG2D ligands can stimulate activation of autologous NK cells. Surprisingly, NK cells can also re-transfer the acquired molecule to autologous effector cells during this immune recognition that leads to their death. These data demonstrate that transfer of molecules occurs as a consequence of immune recognition and imply that this process might play a role in homeostatic tuning-down of the immune response or be used as marker of interaction. © 2015 John Wiley & Sons Ltd.

  14. Bone marrow stromal cells spontaneously produce Flt3-ligand: influence of ionizing radiations and cytokine stimulation.

    Science.gov (United States)

    Bertho, Jean Marc; Demarquay, Christelle; Mouiseddine, Moubarak; Douenat, Noémie; Stefani, Johanna; Prat, Marie; Paquet, François

    2008-08-01

    To define the ability of human bone marrow (BM) stromal cells to produce fms-like tyrosine kinase 3 (Flt3)-ligand (FL), and the effect of irradiation, tumour necrosis factor-alpha (TNFalpha) or tumour growth factor beta (TGFbeta) on FL production. Primary BM stromal cell cultures were irradiated at 2-10 Gy or were stimulated with TNFalpha or TGFbeta1. The presence of FL was tested in culture supernatants and in cell lysate. The presence of a membrane-bound form of FL and the level of gene expression were also tested. Primary BM stromal cells spontaneously released FL. This production was increased by TNFalpha but not by TGFbeta1 or by irradiation. Chemical induction of osteoblastic differentiation from BM stromal cells also induced an increase in FL release. Our results suggest that the observed increase in FL concentration after in vivo irradiation is an indirect effect. The possible implication of BM stromal cells in these mechanisms is discussed.

  15. Mathemimetics II. Demonstratio Mirabilis of FLT by infinitely ascending cubical crystal growth

    Science.gov (United States)

    Trell, Erik

    2012-09-01

    Emulating Nature by observation and ground-up application of its patterns, structures and processes is a classical scientific practice which under the designation of Biomimetics has now been brought to the Nanotechnology scale where even highly complex systems can be realized by continuous or cyclically reiterated assembly of the respective self-similar eigen-elements, modules and algorithms right from their infinitesimal origin. This is actually quite akin to the genuine mathematical art and can find valuable renewed use as here exemplified by the tentatively original Demonstratio Mirabilis of FLT (Fermat's Last Theorem, or, in that case, Triumph) by infinitely ascending sheet-wise cubical crystal growth leading to the binomial `magic triangle' of his close fellow Blaise Pascal.

  16. Uteroplacental arterio-venous difference in soluble VEGFR-1 (sFlt-1), but not in soluble endoglin concentrations in preeclampsia.

    Science.gov (United States)

    Paasche Roland, M C; Lorentzen, B; Godang, K; Henriksen, T

    2012-03-01

    The aim was to determine plasma levels of sFlt-1 and sEng on the arterial and venous side of the uteroplacental circulation in preeclamptic patients and healthy controls. Preeclamptic patients had higher arterial concentrations than controls of sFlt-1 (17,450 vs. 5055 pg/ml, p = 0.003) and sEng (68.7 vs. 28.7 ng/ml, p = 0.003). In the preclampsia group sFlt-1 was higher in the uterine vein than in the radial artery (22,450 vs. 17,450 pg/ml, p = 0.005). We found no gradient for sEng. Our results support the hypothesis that excess sFlt-1 at least partly originates in placenta, while excess sEng appears to have a different origin. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Alterations of plasma nitric oxide, vascular endothelial growth factor, and soluble form of its receptor (sFlt-1 after resistance exercise: An experimental study

    Directory of Open Access Journals (Sweden)

    Parivash Shekarchizadeh Esfahanni

    2014-01-01

    Conclusion: Resistance training does not alter plasma angiogenic factors (NO, VEGF, and sFlt-1, at least in normal rats. More studies are needed to show the effect of resistance training on angiogenesis process.

  18. Human Flt3L generates dendritic cells from canine peripheral blood precursors: implications for a dog glioma clinical trial.

    Directory of Open Access Journals (Sweden)

    Weidong Xiong

    2010-06-01

    Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumor in adults and carries a dismal prognosis. We have developed a conditional cytotoxic/immunotherapeutic approach using adenoviral vectors (Ads encoding the immunostimulatory cytokine, human soluble fms-like tyrosine kinase 3 ligand (hsFlt3L and the conditional cytotoxic molecule, i.e., Herpes Simplex Type 1- thymide kinase (TK. This therapy triggers an anti-tumor immune response that leads to tumor regression and anti-tumor immunological memory in intracranial rodent cancer models. We aim to test the efficacy of this immunotherapy in dogs bearing spontaneous GBM. In view of the controversy regarding the effect of human cytokines on dog immune cells, and considering that the efficacy of this treatment depends on hsFlt3L-stimulated dendritic cells (DCs, in the present work we tested the ability of Ad-encoded hsFlt3L to generate DCs from dog peripheral blood and compared its effects with canine IL-4 and GM-CSF.Our results demonstrate that hsFlT3L expressed form an Ad vector, generated DCs from peripheral blood cultures with very similar morphological and phenotypic characteristics to canine IL-4 and GM-CSF-cultured DCs. These include phagocytic activity and expression of CD11c, MHCII, CD80 and CD14. Maturation of DCs cultured under both conditions resulted in increased secretion of IL-6, TNF-alpha and IFN-gamma. Importantly, hsFlt3L-derived antigen presenting cells showed allostimulatory potential highlighting their ability to present antigen to T cells and elicit their proliferation.These results demonstrate that hsFlt3L induces the proliferation of canine DCs and support its use in upcoming clinical trials for canine GBM. Our data further support the translation of hsFlt3L to be used for dendritic cells' vaccination and gene therapeutic approaches from rodent models to canine patients and its future implementation in human clinical trials.

  19. Altered hemodynamics and hyperuricemia accompany an elevated sFlt-1/PlGF ratio before the onset of early severe preeclampsia.

    LENUS (Irish Health Repository)

    Doherty, Anne

    2014-08-01

    Early identification of women at risk of developing early-onset severe preeclampsia (sPE) is a key objective in obstetrics. An elevated ratio of serum soluble fms-like tyrosine kinase (sFlt-1) to placenta-like growth factor (PlGF) (sFlt-1\\/PlGF ratio) precedes overt hypertension. The longitudinal relationship between this biomarker, maternal hemodynamics, and maternal serum uric acid during the pre-clinical phase is unknown.

  20. Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model

    Directory of Open Access Journals (Sweden)

    Chen X-C

    2008-10-01

    Full Text Available Abstract Background Bone marrow-derived stromal cells (BMSCs are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor. Methods Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1. The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models. Results BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors. Conclusion We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.

  1. Monitoring of anti-cancer treatment with (18)F-FDG and (18)F-FLT PET

    DEFF Research Database (Denmark)

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

    treatment effect early in a treatment course and by that to stratify patients into responders and non-responders. With 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine((18)F-FLT) two of the cancer hallmarks, altered energy metabolism and increased cell proliferation, can......Functional imaging of solid tumors with positron emission tomography (PET) imaging is an evolving field with continuous development of new PET tracers and discovery of new applications for already implemented PET tracers. During treatment of cancer patients, a general challenge is to measure...... be visualized and quantified non-invasively by PET. With (18)F-FDG and (18)F-FLT PET changes in energy metabolism and cell proliferation can thereby be determined after initiation of cancer treatment in both clinical and pre-clinical studies in order to predict, at an early time-point, treatment response...

  2. FLT-PET/CT as a Biomarker of Therapeutic Response in Pemetrexed Therapy for Non-Small Cell Lung Cancer

    Science.gov (United States)

    2016-12-01

    Teva Pharmaceuticals , Petach Tikva Israel) were provided freshly prepared as a 1mg/ml sterile saline solution by the Abramson Cancer Center...human and murine, pemetrexed (ALIMTA; Eli Lilly and Company, Indianapolis, IN) and cisplatin (Teva Pharmaceuticals , PetachTikva Israel) were provided...Griffiths JR, Doblas S, Sinkus R, Laverman P, Oyen WJ, Heerschap A, Boerman OC. Response Monitoring with [18F]FLT PET and Diffusion-Weighted MRI

  3. Intratumoral heterogeneity of 18F-FLT uptake predicts proliferation and survival in patients with newly diagnosed gliomas

    International Nuclear Information System (INIS)

    Mitamura, Katsuya; Yamamoto, Yuka; Kudomi, Nobuyuki; Norikane, Takashi; Miyake, Keisuke; Nishiyama, Yoshihiro; Maeda, Yukito

    2017-01-01

    The nucleoside analog 3'-deoxy-3'- 18 F-fluorothymidine (FLT) has been investigated for evaluating tumor proliferating activity in brain tumors. We evaluated FLT uptake heterogeneity using textural features from the histogram analysis in patients with newly diagnosed gliomas and examined correlation of the results with proliferative activity and patient prognosis, in comparison with the conventional PET parameters. FLT PET was investigated in 37 patients with newly diagnosed gliomas. The conventional parameters [tumor-to-contralateral normal brain tissue (T/N) ratio and metabolic tumor volume (MTV)] and textural parameters (standard deviation, skewness, kurtosis, entropy, and uniformity) were derived from FLT PET images. Linear regression analysis was used to compare PET parameters and the proliferative activity as indicated by the Ki-67 index. The associations between parameters and overall survival (OS) were tested by Cox regression analysis. Median OS was 662 days. For the conventional parameters, linear regression analysis indicated a significant correlation between T/N ratio and Ki-67 index (p = 0.02) and MTV and Ki-67 index (p = 0.02). Among textural parameters, linear regression analysis indicated a significant correlation for kurtosis (p = 0.003), entropy (p < 0.001), and uniformity (p < 0.001) as compared to Ki-67 index, exceeding those of the conventional parameters. The results of univariate analysis suggested that skewness and kurtosis were associated with OS (p = 0.03 and 0.02, respectively). Mean survival for patients with skewness values less than 0.65 was 1462 days, compared with 917 days for those with values greater than 0.65 (p = 0.02). Mean survival for patients with kurtosis values less than 6.16 was 1616 days, compared with 882 days for those with values greater than 6.16 (p = 0.006). Based on the results of this preliminary study in a small patient population, textural features reflecting heterogeneity on FLT PET images seem to be

  4. Early assessment of the efficacy of temozolomide chemotherapy in experimental glioblastoma using [18F]FLT-PET imaging.

    Directory of Open Access Journals (Sweden)

    Thomas Viel

    Full Text Available UNLABELLED: Addition of temozolomide (TMZ to radiation therapy is the standard treatment for patients with glioblastoma (GBM. However, there is uncertainty regarding the effectiveness of TMZ. Considering the rapid evolution of the disease, methods to assess TMZ efficacy early during treatment would be of great benefit. Our aim was to monitor early effects of TMZ in a mouse model of GBM using positron emission tomography (PET with 3'-deoxy-3'-[(18F]fluorothymidine ([(18F]FLT. METHODS: Human glioma cells sensitive to TMZ (Gli36dEGFR-1 were treated with sub-lethal doses of TMZ to obtain cells with lower sensitivity to TMZ (Gli36dEGFR-2, as measured by growth and clonogenic assays. Gli36dEGFR-1 and Gli36dEGFR-2 cells were subcutaneously (s.c. or intracranially (i.c. xenografted into nude mice. Mice were treated for 7 days with daily injection of 25 or 50 mg/kg TMZ. Treatment efficacy was measured using [(18F]FLT-PET before treatment and after 2 days. Computed Tomography (CT or Magnetic Resonance Imaging (MRI were used to determine tumor volumes before treatment and after 7 days. RESULTS: A significant difference was observed between TMZ and DMSO treated tumors in terms of variations of [(18F]FLT T/B ratio as soon as day 2 in the i.c. as well as in the s.c. mouse model. Variations of [(18F]FLT T/B uptake ratio between days 0 and 2 correlated with variations of tumor size between days 0 and 7 (s.c. model: n(tumor = 17 in n(mice = 11, P<0.01; i.c. model: n(tumor/mice = 9, P<0.01. CONCLUSIONS: Our results indicate that [(18F]FLT-PET may be useful for an early evaluation of the response of GBM to TMZ chemotherapy in patients with glioma.

  5. FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors.

    Directory of Open Access Journals (Sweden)

    Martin Neumann

    Full Text Available Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68 in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%. Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-, a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3 and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements. The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%. To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup.

  6. Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

    Science.gov (United States)

    Grudzinski, Joseph J.; Floberg, John M.; Mudd, Sarah R.; Jeffery, Justin J.; Peterson, Eric T.; Nomura, Alice; Burnette, Ronald R.; Tomé, Wolfgang A.; Weichert, Jamey P.; Jeraj, Robert

    2012-03-01

    We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a ‘slow-clearing’ agent, 124I-NM404 (n = 10), or a ‘fast-clearing’ agent, 18F-FLT (3‧-deoxy-3‧-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k12/k21), central elimination rate constant (kel), and tumor influx-to-efflux ratio (k34/k43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, kel (0.009 ± 0.003 h-1), normal body retention, k12/k21 (0.69 ± 0.16), tumor retention, k34/k43 (1.44 ± 0.46) and predicted dosimetry, Dtumor (3.47 ± 1.24 Gy). The PK parameter estimation of FLT

  7. Imaging Cellular Proliferation During Chemo-Radiotherapy: A Pilot Study of Serial 18F-FLT Positron Emission Tomography/Computed Tomography Imaging for Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Everitt, Sarah; Hicks, Rodney J.; Ball, David; Kron, Tomas; Schneider-Kolsky, Michal; Walter, Tania; Binns, David; Mac Manus, Michael

    2009-01-01

    Purpose: To establish whether 18 F-3'-deoxy-3'-fluoro-L-thymidine ( 18 F-FLT) can monitor changes in cellular proliferation of non-small-cell lung cancer (NSCLC) during radical chemo-radiotherapy (chemo-RT). Methods and Materials: As part of a prospective pilot study, 5 patients with locally advanced NSCLC underwent serial 18 F-FLT positron emission tomography (PET)/computed tomography (CT) scans during treatment. Baseline 18 F-FLT PET/CT scans were compared with routine staging 18 F-FDG PET/CT scans. Two on-treatment 18 F-FLT scans were performed for each patient on Days 2, 8, 15 or 29, providing a range of time points for response assessment. Results: In all 5 patients, baseline lesional uptake of 18 F-FLT on PET/CT corresponded to staging 18 F-FDG PET/CT abnormalities. 18 F-FLT uptake in tumor was observed on five of nine (55%) on-treatment scans, on Days 2, 8 and 29, but not Day 15. A 'flare' of 18 F-FLT uptake in the primary tumor of one case was observed after 2 Gy of radiation (1.22 x baseline). The remaining eight on-treatment scans demonstrated a mean reduction in 18 F-FLT tumor uptake of 0.58 x baseline. A marked reduction of 18 F-FLT uptake in irradiated bone marrow was observed for all cases. This reduction was observed even after only 2 Gy, and all patients demonstrated a complete absence of proliferating marrow after 10 Gy. Conclusions: This proof of concept study indicates that 18 F-FLT uptake can monitor the distinctive biologic responses of epithelial cancers and highly radiosensitive normal tissue changes during radical chemo-RT. Further studies of 18 F-FLT PET/CT imaging during therapy may suggest that this tracer is useful in developing response-adapted RT for NSCLC.

  8. Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML.

    Science.gov (United States)

    Sayar, Hamid; Liu, Yan; Gao, Rui; Zaid, Mohammad Abu; Cripe, Larry D; Weisenbach, Jill; Sargent, Katie J; Nassiri, Mehdi; Li, Lang; Konig, Heiko; Suvannasankha, Attaya; Pan, Feng; Shanmugam, Rajasubramaniam; Goswami, Chirayu; Kapur, Reuben; Xu, Mingjiang; Boswell, H Scott

    2018-01-19

    Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3 , occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3 /Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.

  9. Study of the production of the radiopharmaceutical {sup 18}F-FLT in automated system: contribution for process validation; Estudo da producao do radiofarmaco FLT-{sup 18}F em sistema automatizado: contribuicao para a validacao do processo

    Energy Technology Data Exchange (ETDEWEB)

    Zanette, Camila

    2013-07-01

    Radiopharmaceutical {sup 18}F-FLT is a thymidine nucleoside analogue and a promising tumor proliferation marker for PET images. The synthesis of this radiopharmaceutical is not simple, and often has low yields. This radiopharmaceutical has already been studied for some years; however, there is no production, nor are there clinical studies in Brazil. The study of the production process and its compliance with the guidelines of Good Manufacturing Practices (ANVISA) are of extreme importance. This study aimed to investigate the synthesis of this radiopharmaceutical, evaluate methods of quality control that will be used in future production routines, perform cytotoxicity studies, biodistribution studies and PET imaging in animals, thereby contributing to the development and elaboration of the process validation protocol and to the establishment of analytical methods to be used during production routines. Initially, we studied the synthesis and production of {sup 18}F-FLT, with the evaluation of three different temperatures of radiolabeling to check the behavior of the radiochemical yield and stability of the nal product. Studies of analytical methodology comprised the analysis of radionuclide identification, determination of chromatographic profiles, radiochemical purity, residual solvents, and pH. In vitro studies of internalization and cytotoxicity were also carried out. In in vivo studies, we evaluated the pharmacokinetics, biodistribution in healthy animals and in animals with tumor models, in addition to PET/CT images in animals with melanomas. The final product had high radiochemical purity and was stable for up to 10 hours after the synthesis, but got a relatively low radiochemical yield, as described in the literature. The tested analytical methods proved suitable for use in the quality control of {sup 18}F-FLT. In in vitro studies, {sup 18}F-FLT showed a significant percentage of binding to tumor cells, and the nonradiolabeled molecule was not considered toxic

  10. Soluble vascular endothelial growth factor (VEGF) receptor-1 inhibits migration of human monocytic THP-1 cells in response to VEGF.

    Science.gov (United States)

    Zhu, Cansheng; Xiong, Zhaojun; Chen, Xiaohong; Lu, Zhengqi; Zhou, Guoyu; Wang, Dunjing; Bao, Jian; Hu, Xueqiang

    2011-08-01

    We aimed to investigate the regulation and contribution of vascular endothelial growth factor (VEGF) and sFlt-1(1-3) to human monocytic THP-1 migration. Ad-sFlt-1/FLAG, a recombinant adenovirus carrying the human sFlt-1(1-3) (the first three extracellular domains of FLT-1, the hVEGF receptor-1) gene, was constructed. L929 cells were infected with Ad-sFlt-1/FLAG and the expression of sFlt-1 was detected by immunofluorescent assay and ELISA. Corning(®) Transwell(®) Filter Inserts containing polyethylene terephthalate (PET) membranes with pore sizes of 3 μm were used as an experimental model to simulate THP-1 migration. Five VEGF concentrations (0, 0.1, 1, 10 and 100 ng/ml), four concentrations of sFlt-1(1-3)/FLAG expression supernatants (0.1, 1, 10 and 100 ng/ml), and monocyte chemoattractant protein-1 (MCP-1, 10 ng/ml) were used to test the ability of THP-1 cells to migrate through PET membranes. The sFlt-1(1-3) gene was successfully recombined into Ad-sFlt-1/FLAG. sFlt-1(1-3) was expressed in L929 cells transfected with Ad-sFlt-1/FLAG. THP-1 cell migration increased with increasing concentrations of VEGF, while cell migration decreased with increasing concentrations of sFlt1(1-3)/FLAG. sFlt1(1-3)/FLAG had no effect on MCP-1-induced cell migration. This study demonstrated that VEGF is able to elicit a migratory response in THP-1 cells, and that sFlt-1(1-3) is an effective inhibitor of THP-1 migration towards VEGF.

  11. Stable curcumin-loaded polymeric micellar formulation for enhancing cellular uptake and cytotoxicity to FLT3 overexpressing EoL-1 leukemic cells.

    Science.gov (United States)

    Tima, Singkome; Anuchapreeda, Songyot; Ampasavate, Chadarat; Berkland, Cory; Okonogi, Siriporn

    2017-05-01

    The present study aims to develop a stable polymeric micellar formulation of curcumin (CM) with improved solubility and stability, and that is suitable for clinical applications in leukemia patients. CM-loaded polymeric micelles (CM-micelles) were prepared using poloxamers. The chemical structure of the polymers influenced micellar properties. The best formulation of CM-micelles, namely CM-P407, was obtained from poloxamer 407 at drug to polymer ratio of 1:30 and rehydrated with phosphate buffer solution pH 7.4. CM-P407 exhibited the smallest size of 30.3±1.3nm and highest entrapment efficiency of 88.4±4.1%. When stored at -80°C for 60days, CM-P407 retained high protection of CM and had no significant size change. In comparison with CM solution in dimethyl sulfoxide (CM-DMSO), CM kinetic degradation in both formulations followed a pseudo-first-order reaction, but the half-life of CM in CM-P407 was approx. 200 times longer than in CM-DMSO. Regarding the activity against FLT3 overexpressing EoL-1 leukemic cells, CM-P407 showed higher cytotoxicity than CM-DMSO. Moreover, intracellular uptake to leukemic cells of CM-P407 was 2-3 times greater than that of CM-DMSO. These promising results for CM-P407 will be further investigated in rodents and in clinical studies for leukemia treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Assessment of glucose metabolism and cellular proliferation in multiple myeloma: a first report on combined 18F-FDG and 18F-FLT PET/CT imaging.

    Science.gov (United States)

    Sachpekidis, C; Goldschmidt, H; Kopka, K; Kopp-Schneider, A; Dimitrakopoulou-Strauss, A

    2018-04-10

    Despite the significant upgrading in recent years of the role of 18 F-FDG PET/CT in multiple myeloma (MM) diagnostics, there is a still unmet need for myeloma-specific radiotracers. 3'-Deoxy-3'-[ 18 F]fluorothymidine ( 18 F-FLT) is the most studied cellular proliferation PET agent, considered a potentially new myeloma functional imaging tracer. The aim of this pilot study was to evaluate 18 F-FLT PET/CT in imaging of MM patients, in the context of its combined use with 18 F-FDG PET/CT. Eight patients, four suffering from symptomatic MM and four suffering from smoldering MM (SMM), were enrolled in the study. All patients underwent 18 F-FDG PET/CT and 18 F-FLT PET/CT imaging by means of static (whole body) and dynamic PET/CT of the lower abdomen and pelvis (dPET/CT) in two consecutive days. The evaluation of PET/CT studies was based on qualitative evaluation, semi-quantitative (SUV) calculation, and quantitative analysis based on two-tissue compartment modeling. 18 F-FDG PET/CT demonstrated focal, 18 F-FDG avid, MM-indicative bone marrow lesions in five patients. In contrary, 18 F-FLT PET/CT showed focal, 18 F-FLT avid, myeloma-indicative lesions in only two patients. In total, 48 18 F-FDG avid, focal, MM-indicative lesions were detected with 18 F-FDG PET/CT, while 17 18 F-FLT avid, focal, MM-indicative lesions were detected with 18 F-FLT PET/CT. The number of myeloma-indicative lesions was significantly higher for 18 F-FDG PET/CT than for 18 F-FLT PET/CT. A common finding was a mismatch of focally increased 18 F-FDG uptake and reduced 18 F-FLT uptake (lower than the surrounding bone marrow). Moreover, 18 F-FLT PET/CT was characterized by high background activity in the bone marrow compartment, further complicating the evaluation of bone marrow lesions. Semi-quantitative evaluation revealed that both SUV mean and SUV max were significantly higher for 18 F-FLT than for 18 F-FDG in both MM lesions and reference tissue. SUV values were higher in MM lesions than in

  13. Angiogenesis-Related Biomarkers (sFlt-1/PLGF in the Prediction and Diagnosis of Placental Dysfunction: An Approach for Clinical Integration

    Directory of Open Access Journals (Sweden)

    Ignacio Herraiz

    2015-08-01

    Full Text Available Placental dysfunction is involved in a group of obstetrical conditions including preeclampsia, intrauterine growth restriction, and placental abruption. Their timely and accurate recognition is often a challenge since diagnostic criteria are still based on nonspecific signs and symptoms. The discovering of the role of angiogenic-related factors (sFlt-1/PlGF in the underlying pathophysiology of placental dysfunction, taking into account that angiogenesis-related biomarkers are not specific to any particular placental insufficiency-related disease, has marked an important step for improving their early diagnosis and prognosis assessment. However, sFlt-1/PlGF has not been yet established as a part of most guidelines. We will review the current evidence on the clinical utility of sFlt-1/PlGF and propose a new protocol for its clinical integration.

  14. Mutation Analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese Patients with Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Min Wang

    2014-01-01

    Full Text Available Since the discovery of JAK2V617F tyrosine kinase-activating mutation, several genes have been found mutated in myeloproliferative neoplasms (MPNs. FLT3-ITD, NPM1, and DNMT3A mutations frequently occurred in AML patients and have been found conferred with myeloproliferative neoplasms in mouse model. Therefore, we sought to search for mutations in JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in 129 cases including 120 classic MPN cases and 9 MDS/MPN cases. JAK2V617F mutation was found in 60% of the 120 classic MPNs. However, none of the patients displayed FLT3-ITD and NPM1 mutations; only 2 patients harbored DNMT3A R882 mutation. Further studies including whole-genome sequence will be conducted to investigate the possible involvement of these genes in MPN.

  15. Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group.

    Science.gov (United States)

    Manara, E; Basso, G; Zampini, M; Buldini, B; Tregnago, C; Rondelli, R; Masetti, R; Bisio, V; Frison, M; Polato, K; Cazzaniga, G; Menna, G; Fagioli, F; Merli, P; Biondi, A; Pession, A; Locatelli, F; Pigazzi, M

    2017-01-01

    Recurrent molecular markers have been routinely used in acute myeloid leukemia (AML) for risk assessment at diagnosis, whereas their post-induction monitoring still represents a debated issue. We evaluated the prognostic value and biological impact of minimal residual disease (MRD) and of the allelic ratio (AR) of FLT3-internal-tandem duplication (ITD) in childhood AML. We retrospectively screened 494 children with de novo AML for FLT3-ITD mutation, identifying 54 harboring the mutation; 51% of them presented high ITD-AR at diagnosis and had worse event-free survival (EFS, 19.2 versus 63.5% for low ITD-AR, <0.05). Forty-one percent of children with high levels of MRD after the 1st induction course, measured by a patient-specific real-time-PCR, had worse EFS (22.2 versus 59.4% in low-MRD patients, P<0.05). Next, we correlated these parameters with gene expression, showing that patients with high ITD-AR or persistent MRD had characteristic expression profiles with deregulated genes involved in methylation and acetylation. Moreover, patients with high CyclinA1 expression presented an unfavorable EFS (20.3 versus 51.2% in low CyclinA1 group, P<0.01). Our results suggest that ITD-AR levels and molecular MRD should be considered in planning clinical management of FLT3-ITD patients. Different transcriptional activation of epigenetic and oncogenic profiles may explain variability in outcome among these patients, for whom novel therapeutic approaches are desirable.

  16. TU-F-12A-02: Quantitative Characterization of Normal Bone Marrow Proliferative Activity with FLT PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Weisse, N; Jeraj, R [Department of Medical Physics, University of Wisconsin, Madison, WI (United States)

    2014-06-15

    Purpose: [F-18]FLT PET is a tool for assessing health of bone marrow by evaluating its proliferative activity. This study establishes a baseline quantitative characterization of healthy marrow proliferation to aid in diagnosis of hematological disease. Methods: 31 patients (20 male, 11 female, 41–76 years) being treated for solid cancers with no history of hematological disease, osseous metastatic disease, or radiation therapy received pre-treatment FLT PET/CT scans. Total bone marrow was isolated from whole body FLT PET images by manually removing organs and applying a standardize uptake value (SUV) threshold of 1.0. Because adult marrow is concentrated in the axial skeleton, quantitative total bone marrow analysis (QTBMA) was used to isolate marrow in the lumbar spine, thoracic spine, sacrum, and pelvis for analysis. SUVmean, SUVmax, and SUVCV were used to quantify bone marrow proliferation. Correlations were explored between SUV and patient characteristics including age, weight, height, and BMI using the Spearman coefficient (ρ). Results: The population-averaged whole-skeleton SUVmean, SUVmax, and SUVCV were 3.0±0.6, 18.4±5.7, and 0.6±0.1, respectively. Uptake values in the axial skeleton were similar to the whole-skeleton demonstrated by SUVmean in the thoracic spine (3.6±0.6), lumbar spine (3.3±0.5), sacrum (3.0±0.6), and pelvis regions (2.8±0.5). Whole-skeleton SUVmax correlated with patient weight (ρ=0.47, p<0.01) and BMI (ρ=0.60, p<0.01), suggesting marrow activity is related to the body's burden. SUV measures in the thoracic spine, lumbar spine, sacrum, and pelvis were negatively correlated with age (ρ:−0.41 to −0.46, p≤0.02). These negative correlations reflect the fact that active marrow in the adult skeleton is localized in the axial skeleton and decreases with age. Conclusions: Normal bone marrow characterizations were determined using FLT

  17. Study of the production of the radiopharmaceutical 18F-FLT in automated system: contribution for process validation

    International Nuclear Information System (INIS)

    Zanette, Camila

    2013-01-01

    Radiopharmaceutical 18 F-FLT is a thymidine nucleoside analogue and a promising tumor proliferation marker for PET images. The synthesis of this radiopharmaceutical is not simple, and often has low yields. This radiopharmaceutical has already been studied for some years; however, there is no production, nor are there clinical studies in Brazil. The study of the production process and its compliance with the guidelines of Good Manufacturing Practices (ANVISA) are of extreme importance. This study aimed to investigate the synthesis of this radiopharmaceutical, evaluate methods of quality control that will be used in future production routines, perform cytotoxicity studies, biodistribution studies and PET imaging in animals, thereby contributing to the development and elaboration of the process validation protocol and to the establishment of analytical methods to be used during production routines. Initially, we studied the synthesis and production of 18 F-FLT, with the evaluation of three different temperatures of radiolabeling to check the behavior of the radiochemical yield and stability of the nal product. Studies of analytical methodology comprised the analysis of radionuclide identification, determination of chromatographic profiles, radiochemical purity, residual solvents, and pH. In vitro studies of internalization and cytotoxicity were also carried out. In in vivo studies, we evaluated the pharmacokinetics, biodistribution in healthy animals and in animals with tumor models, in addition to PET/CT images in animals with melanomas. The final product had high radiochemical purity and was stable for up to 10 hours after the synthesis, but got a relatively low radiochemical yield, as described in the literature. The tested analytical methods proved suitable for use in the quality control of 18 F-FLT. In in vitro studies, 18 F-FLT showed a significant percentage of binding to tumor cells, and the nonradiolabeled molecule was not considered toxic for these studied

  18. HANSF 1.3 user's manual

    International Nuclear Information System (INIS)

    PLYS, M.G.

    1999-01-01

    The HANSF analysis tool is an integrated model considering phenomena inside a multi-canister overpack (MCO) spent nuclear fuel container such as fuel oxidation, convective and radiative heat transfer, and the potential for fission product release. It may be used for all phases of spent fuel disposition including cold vacuum drying, transportation, and storage. This manual reflects HANSF version 1.3, a revised version of version 1.2a. HANSF 1.3 was written to add new models for axial nodalization, add new features for ease of usage, and correct errors. HANSF 1.3 is intended for use on personal computers such as IBM-compatible machines with Intel processors running under a DOS-type operating system. HANSF 1.3 is known to compile under Lahey TI and Digital Visual FORTRAN, Version 6.0, but this does not preclude operation in other environments

  19. HANSF 1.3.2 User's Manual

    International Nuclear Information System (INIS)

    DUNCAN, D.R.

    1999-01-01

    The HANSF analysis tool is an integrated model considering phenomena inside a multi-canister overpack (MCO) spent nuclear fuel container such as fuel oxidation, convective and radiative heat transfer, and the potential for fission product release. This manual reflects the HANSF version 1.3.2, a revised version of 1.3.1. HANSF 1.3.2 was written to correct minor errors and to allow modeling of condensate flow on the MCO inner surface. HANSF 1.3.2 is intended for use on personal computers such as IBM-compatible machines with Intel processors running under Lahey TI or digital Visual FORTRAN, Version 6.0, but this does not preclude operation in other environments

  20. HANSF 1.3 user's manual; TOPICAL

    International Nuclear Information System (INIS)

    PLYS, M.G.

    1999-01-01

    The HANSF analysis tool is an integrated model considering phenomena inside a multi-canister overpack (MCO) spent nuclear fuel container such as fuel oxidation, convective and radiative heat transfer, and the potential for fission product release. It may be used for all phases of spent fuel disposition including cold vacuum drying, transportation, and storage. This manual reflects HANSF version 1.3, a revised version of version 1.2a. HANSF 1.3 was written to add new models for axial nodalization, add new features for ease of usage, and correct errors. HANSF 1.3 is intended for use on personal computers such as IBM-compatible machines with Intel processors running under a DOS-type operating system. HANSF 1.3 is known to compile under Lahey TI and Digital Visual FORTRAN, Version 6.0, but this does not preclude operation in other environments

  1. Distribution Atlas of Proliferating Bone Marrow in Non-Small Cell Lung Cancer Patients Measured by FLT-PET/CT Imaging, With Potential Applicability in Radiation Therapy Planning

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, Belinda A., E-mail: Belinda.Campbell@petermac.org [Department of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Callahan, Jason [Centre for Molecular Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Bressel, Mathias [Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne (Australia); Simoens, Nathalie [Centre for Molecular Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Everitt, Sarah [Radiotherapy Services, Peter MacCallum Cancer Centre, East Melbourne (Australia); Hofman, Michael S.; Hicks, Rodney J. [Centre for Molecular Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Burbury, Kate [Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne (Australia); MacManus, Michael [Department of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia)

    2015-08-01

    Purpose: Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)–positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility. Methods and Materials: The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status. Results: Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age. Conclusions: This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required.

  2. Distribution Atlas of Proliferating Bone Marrow in Non-Small Cell Lung Cancer Patients Measured by FLT-PET/CT Imaging, With Potential Applicability in Radiation Therapy Planning

    International Nuclear Information System (INIS)

    Campbell, Belinda A.; Callahan, Jason; Bressel, Mathias; Simoens, Nathalie; Everitt, Sarah; Hofman, Michael S.; Hicks, Rodney J.; Burbury, Kate; MacManus, Michael

    2015-01-01

    Purpose: Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)–positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility. Methods and Materials: The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status. Results: Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age. Conclusions: This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required

  3. High Level of Soluble FMS-Like Tyrosine Kinase-1 (sFlt-1 Serum in Pregnancy as a Risk Factor of Preeclampsia

    Directory of Open Access Journals (Sweden)

    I Gede Mega Putra

    2016-07-01

    Full Text Available Background: Recently, etiology and pathogenesis of preeclampsia remain unknown. One of the theory indicating that hypoxia and ischemic placenta caused by abnormal cytotrophoblast invasion in preeclampsia. Soluble Fms-like tyrosine kinase-1 (sFlt-1 serum as a laboratory marker of hypoxia condition that contributes to the occurrence of endothelial damage and clinical manifestations in preeclampsia. Objective: This study was aimed at proving that high level of soluble Fms-like tyrosine kinase-1 (sFlt-1 serum in pregnancy as a risk factor for preeclampsia. Methods: This study was a case control. Among 58 pregnant women studied, 29 women with preeclampsia as a case group and 29 women with normal pregnancy as a control group. Soluble Fms-like tyrosine kinase-1 (sFlt-1 serum was analyzed in the Prodia Laboratory. Collected data were tested for normality using Kolmogorov-Smirnov, then analyzed with independent sample test. Chi-Square test used to determine soluble Fms-like tyrosine kinase-1 (sFlt-1 serum level in preeclampsia. Results: This research concluded that the average level of soluble Fms-like tyrosine kinase-1 (sFlt-1 serum in preeclampsia were 11231.00 ± 8390.3 pg/mL and 3981.62 ± 4921.5 pg/mL in normal pregnancy. Analysis of significance with independent t-test concluded that the value of t = 4.01 and p = 0.001. This mean the average levels of soluble Fms-like tyrosine kinase-1 (sFlt-1serum levels in both groups were difference significantly (p <0.05. Based on the cut-off point of sFlt-1 serum levels was 4505.50 pg/mL with 79.3% sensitivity and 82.8% specificity, the relative risk of preeclampsia was 18 times (OR = 18.40, IK 95% = 4.93 to 68.70, p = 0.001. Conclusion:  Based on this research, high levels of soluble Fms-like tyrosine kinase-1 (sFlt-1 in pregnancy was proved as a risk factor for preeclampsia.

  4. Clinical value of 18F-FDG and 18F-FLT PET /CT for the detection of primary and regional lymph node metastasis of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    杨洋

    2014-01-01

    Objective To evaluate the value of18F-FDG and18F-FLT PET/CT for the detection of primary and regional lymph node metastasis of gastric cancer.Methods Thirty-seven patients with gastric cancer underwent preoperative18F-FLT and18F-FDG PET/CT within one week from March 2011 to April 2013.Postoperative histopathology confirmation was obtained in all patients.The PET/CT images were assessed visually and semi-quantitatively.Two-sample t andχ2tests were analyzed using SPSS overall diagnostic

  5. Repeatability of quantitative 18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis.

    Science.gov (United States)

    Kramer, G M; Liu, Y; de Langen, A J; Jansma, E P; Trigonis, I; Asselin, M-C; Jackson, A; Kenny, L; Aboagye, E O; Hoekstra, O S; Boellaard, R

    2018-06-01

    3'-deoxy-3'-[ 18 F]fluorothymidine ( 18 F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative 18 F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of 18 F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five 18 F-FLT repeatability cohorts in solid tumors. 18 F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUV max , SUV mean , SUV peak , proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all 18 F-FLT uptake metrics (R 2  ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUV peak (RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUV max  ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repeatability of SUV metrics. In multi-center studies

  6. Purification and characterization of a novel 1,3- propanediol ...

    African Journals Online (AJOL)

    A novel 1,3-propanediol oxidoreductase (YqhD-1) found in Klebsiella oxytoca M5al was purified to homogeneity with a his-tag on a Ni-NTA column. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of the purified protein showed a molecular weight of 42 kDa. When YqhD-1 was tested as a ...

  7. On D=2 (1/3,1/3) supersymmetric theories 2

    International Nuclear Information System (INIS)

    Saidi, E.H.; Zerouaoui, J.; Sedra, M.B.

    1994-06-01

    Denoting by D=2 (1/3,1/3) superalgebra; the off critical symmetry of the Φ 5/7,5/7 perturbation of the C=6/7 conformal theory, we build a new superspace solution of the (1/3,1/3) - subalgebra generated by spin ±1/3 charge operators extending the usual (1/2,1/2) supersymmetry generated by spin ±1/2 charges. This solution is based on the use of two Grassmann variables instead of one parafermionic variable θ ±1/3 satisfying the cubic nilpotency condition (θ ±1/3 ) 3 =0. Known results on the C=6/7 tricritical Potts model are recovered as special features. A relation with N=2 Landau-Ginzburg models is also discussed. (author). 17 refs, 1 tab

  8. Bis(1,3-dithiole) Compounds

    DEFF Research Database (Denmark)

    Andersen, Jan Rud; Engler, E. M.; Green, D. C.

    1977-01-01

    There is described the preparation of bis-1,3-dithiole compounds (I) which are key synthetic precursors for the preparation of new polymeric metal bis(dithiolene) (i.e., II) and tetrathiafulvalene compounds (i.e., III): (Image Omitted)...

  9. Detection of TET2, KRAS and CBL variants by Next Generation Sequencing and analysis of their correlation with JAK2 and FLT3 in childhood AML

    Directory of Open Access Journals (Sweden)

    Dilara Fatma Akin

    2016-04-01

    Conclusion: We found novel mutations for TET2, KRAS, and CBL. The detected variants in this article seem to be the first screening results of genes studied by NGS in childhood AML patients. Our results also showed some degree of association between FLT3-ITD and TET2, KRAS, CBL mutations.

  10. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

    NARCIS (Netherlands)

    Mathew, N.R.; Baumgartner, F.; Braun, L.; O'Sullivan, D.; Thomas, S.; Waterhouse, M.; Muller, T.A.; Hanke, K.; Taromi, S.; Apostolova, P.; Illert, A.L.; Melchinger, W.; Duquesne, S.; Schmitt-Graeff, A.; Osswald, L.; Yan, K.L.; Weber, A; Tugues, S.; Spath, S.; Pfeifer, D.; Follo, M.; Claus, R.; Lubbert, M.; Rummelt, C.; Bertz, H.; Wasch, R.; Haag, J.; Schmidts, A.; Schultheiss, M.; Bettinger, D.; Thimme, R.; Ullrich, E.; Tanriver, Y.; Vuong, G.L.; Arnold, R.; Hemmati, P.; Wolf, D.; Ditschkowski, M.; Jilg, C.; Wilhelm, K.; Leiber, C.; Gerull, S.; Halter, J.; Lengerke, C.; Pabst, T.; Schroeder, T.; Kobbe, G.; Rosler, W.; Doostkam, S.; Meckel, S.; Stabla, K.; Metzelder, S.K.; Halbach, S.; Brummer, T.; Hu, Z; Dengjel, J.; Hackanson, B.; Schmid, C.; Holtick, U.; Scheid, C.; Spyridonidis, A.; Stolzel, F.; Ordemann, R.; Muller, L.P.; Sicre-de-Fontbrune, F.; Ihorst, G.; Kuball, J.; Ehlert, J.E.; Feger, D.; Wagner, E.M.; Cahn, J.Y.; Schnell, J.; Kuchenbauer, F.; Bunjes, D.; Chakraverty, R.; Richardson, S.; Gill, S.; Kroger, N.; Ayuk, F.; Vago, L.; Ciceri, F.; Muller, A.M.; Kondo, T.; Teshima, T.; Klaeger, S.; Kuster, B.; Kim, D.D.H.; Weisdorf, D.; Velden, W.J. van der; Dorfel, D.; Bethge, W.; Hilgendorf, I.; Hochhaus, A.; Andrieux, G.; Borries, M.; Busch, H.; Magenau, J.; Reddy, P.; Labopin, M.; Antin, J.H., et al.

    2018-01-01

    Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a

  11. F-18 FLT PET : A Noninvasive Diagnostic Tool for Visualization of the Bone Marrow Compartment in Patients With Aplastic Anemia A Pilot Study

    NARCIS (Netherlands)

    Agool, Ali; Slart, Riemer H. J. A.; Kluin, Philip M.; de Wolf, Joost Th. M.; Dierckx, Rudi A. J. O.; Vellenga, Edo

    Rationale: A discordant relationship between bone marrow cellularity and peripheral blood findings is regularly noticed in patients with aplastic anemia (AA). Therefore, the feasibility of 3-F-18 fluoro-3-deoxy-L-thymidine (F-18 FLT PET was tested as a noninvasive tool to visualize the total

  12. Prediction of severe pre-eclampsia by a combination of sFlt-1, CT-pro ET1 and blood pressure: exploratory study

    DEFF Research Database (Denmark)

    Malte, Anne Lind; Uldbjerg, Niels; Wright, David

    2018-01-01

    gestational age 35(+6) weeks) attending the obstetrical outpatient clinic, and 99 with normal pregnancies. RESULTS: In a group of patients presenting with mild to moderate symptoms of preeclampsia, a combination of C-terminal Pro Endothelin 1 (CT-Pro-ET1), sFlt-1 and systolic blood pressure reached an Area...

  13. SU-E-J-250: A Methodology for Active Bone Marrow Protection for Cervical Cancer Intensity-Modulated Radiotherapy Using 18F-FLT PET/CT Image

    International Nuclear Information System (INIS)

    Ma, C; Yin, Y

    2014-01-01

    Purpose: The purpose of this study was to compare a radiation therapy treatment planning that would spare active bone marrow and whole pelvic bone marrow using 18F FLT PET/CT image. Methods: We have developed an IMRT planning methodology to incorporate functional PET imaging using 18F FLT/CT scans. Plans were generated for two cervical cancer patients, where pelvicactive bone marrow region was incorporated as avoidance regions based on the range: SUV>2., another region was whole pelvic bone marrow. Dose objectives were set to reduce the volume of active bone marrow and whole bone marraw. The volumes of received 10 (V10) and 20 (V20) Gy for active bone marrow were evaluated. Results: Active bone marrow regions identified by 18F FLT with an SUV>2 represented an average of 48.0% of the total osseous pelvis for the two cases studied. Improved dose volume histograms for identified bone marrow SUV volumes and decreases in V10(average 18%), and V20(average 14%) were achieved without clinically significant changes to PTV or OAR doses. Conclusion: Incorporation of 18F FLT/CT PET in IMRT planning provides a methodology to reduce radiation dose to active bone marrow without compromising PTV or OAR dose objectives in cervical cancer

  14. Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    Kranenburg, A. R.; de Boer, W. I.; Alagappan, V. K. T.; Sterk, P. J.; Sharma, H. S.

    2005-01-01

    BACKGROUND: Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in tissue remodelling and

  15. Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    A.R. Kranenburg (Andor); W.I. de Boer (Pim); V.K.T. Alagappan (Vijay Kumar Thyagarajan); P.J. Sterk (Peter); H.S. Sharma (Hari)

    2005-01-01

    textabstractBACKGROUND: Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in

  16. Budget impact analysis of sFlt-1/PlGF ratio as prediction test in Italian women with suspected preeclampsia.

    Science.gov (United States)

    Frusca, Tiziana; Gervasi, Maria-Teresa; Paolini, Davide; Dionisi, Matteo; Ferre, Francesca; Cetin, Irene

    2017-09-01

    Preeclampsia (PE) is a pregnancy disease which represents a leading cause of maternal and perinatal mortality and morbidity. Accurate prediction of PE risk could provide an increase in health benefits and better patient management. To estimate the economic impact of introducing Elecsys sFlt-1/PlGF ratio test, in addition to standard practice, for the prediction of PE in women with suspected PE in the Italian National Health Service (INHS). A decision tree model has been developed to simulate the progression of a cohort of pregnant women from the first presentation of clinical suspicion of PE in the second and third trimesters until delivery. The model provides an estimation of the financial impact of introducing sFlt-1/PlGF versus standard practice. Clinical inputs have been derived from PROGNOSIS study and from literature review, and validated by National Clinical Experts. Resources and unit costs have been obtained from Italian-specific sources. Healthcare costs associated with the management of a pregnant woman with clinical suspicion of PE equal €2384 when following standard practice versus €1714 using sFlt-1/PlGF ratio test. Introduction of sFlt-1/PlGF into hospital practice is cost-saving. Savings are generated primarily through improvement in diagnostic accuracy and reduction in unnecessary hospitalization for women before PE's onset.

  17. Synthesis and labeling 5'-O-(4-4'-dimetoxytrityl) -2,3-anhidrothymidine for preparation of radiopharmaceutical [18F]FLT

    International Nuclear Information System (INIS)

    Purwoko; Maskur; Chaeruman; Sugiarto, Yono

    2013-01-01

    It is has been known that the compound of 3'-deoxy-3,-( 18 F] Fluorothymidine or ( 18 F] FLT is a thymidine derivative radiopharmaceutical used for cancer detection based on DNA metabolism. Synthesis and labeling of 5'-0-(4,4 '-dimetoxytrityl) -2,3' anhidrothymidine precursor for preparation of the radiopharmaceutical [ 18 F]FL T was carried out. The precursor was synthesized in similar manner and procedure literature and it have been obtained a crystalline product with total yield of 32,4 %. The chemical purity of the product which determined by HPLC was found to be more than 95%. Characterization of the product was done by observing the results of the LC / MS and 1 H-NMR test, the resulted data were found to be very closed to those reported in the literature. Labeling of the precursor was done by nucleophilic fluorination reactions using 18 Fluoride at 160 °C for 15 minutes with kryptofix 2.2.2 catalyst followed hydrolysis using HCI at 100 °C for 10 minutes and then neutralized with NaOH. Purification [ 18 F]FLT was performed by single cartridge Alumina-N as a substitute HPLC methods. The results have been obtained a label compound [ 18 F]FLT with high purity as a bulk for preparation of the radiopharmaceutical [ 18 F]FLT. The label compound of [ 18 F]FLT undergone a quality test which included a clarity, pH and a radiochemical purity. The results of quality control on four batches of [ 18 F]FLT showed that these products were colorless clear solution with pH between 6.0-7.5, and radiochemical purity 97.93 ± 1,48% and showed that the label compounds have been obtained [ 18 F]FLT-free particles form a clear solution with a pH between 6,0 - 7,5, radiochemical purity of 97.93 ± 1,48 %, radiochemical yields 8.18 ± 1.54% (decay uncorrected) and processing time 73 ± 4 minutes. (author)

  18. Evaluation of 18F-fluorothymidine positron emission tomography ([18F]FLT-PET/CT) methodology in assessing early response to chemotherapy in patients with gastro-oesophageal cancer.

    Science.gov (United States)

    Sharma, R; Mapelli, P; Hanna, G B; Goldin, R; Power, D; Al-Nahhas, A; Merchant, S; Ramaswami, R; Challapalli, A; Barwick, T; Aboagye, E O

    2016-12-01

    3'-Deoxy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT) PET has limited utility in abdominal imaging due to high physiological hepatic uptake of a tracer. We evaluated [ 18 F]FLT-PET/CT combined with a temporal-intensity information-based voxel-clustering approach termed kinetic spatial filtering (KSF) to improve tumour visualisation in patients with locally advanced and metastatic gastro-oesophageal cancer and as a marker of early response to chemotherapy. Dynamic [ 18 F]FLT-PET/CT data were collected before and 3 weeks post first cycle of chemotherapy. Changes in tumour [ 18 F]FLT-PET/CT variables were determined. Response was determined on contrast-enhanced CT after three cycles of therapy using RECIST 1.1. Ten patients were included. Following application of the KSF, visual distinction of all oesophageal and/or gastric tumours was observed in [ 18 F]FLT-PET images. Among the nine patients available for response evaluation (RECIST 1.1), three patients had responded (partial response) and six patients were non-responders (stable disease). There was a significant association between Ki-67 and all baseline [ 18 F]FLT-PET parameters. Area under the curve (AUC) from 0 to 1 min was associated with treatment response. The results of this study indicate that application of the KSF allowed accurate visualisation of both primary and metastatic lesions following imaging with the proliferation marker, [ 18 F]FLT-PET/CT. However, [ 18 F]FLT-PET uptake parameters did not correlate with response. Instead, we observe significant changes in tracer delivery following chemotherapy suggesting that further [ 18 F]FLT-PET/CT studies in this tumour type should be undertaken with caution.

  19. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

    Science.gov (United States)

    Mathew, Nimitha R; Baumgartner, Francis; Braun, Lukas; O'Sullivan, David; Thomas, Simone; Waterhouse, Miguel; Müller, Tony A; Hanke, Kathrin; Taromi, Sanaz; Apostolova, Petya; Illert, Anna L; Melchinger, Wolfgang; Duquesne, Sandra; Schmitt-Graeff, Annette; Osswald, Lena; Yan, Kai-Li; Weber, Arnim; Tugues, Sonia; Spath, Sabine; Pfeifer, Dietmar; Follo, Marie; Claus, Rainer; Lübbert, Michael; Rummelt, Christoph; Bertz, Hartmut; Wäsch, Ralph; Haag, Johanna; Schmidts, Andrea; Schultheiss, Michael; Bettinger, Dominik; Thimme, Robert; Ullrich, Evelyn; Tanriver, Yakup; Vuong, Giang Lam; Arnold, Renate; Hemmati, Philipp; Wolf, Dominik; Ditschkowski, Markus; Jilg, Cordula; Wilhelm, Konrad; Leiber, Christian; Gerull, Sabine; Halter, Jörg; Lengerke, Claudia; Pabst, Thomas; Schroeder, Thomas; Kobbe, Guido; Rösler, Wolf; Doostkam, Soroush; Meckel, Stephan; Stabla, Kathleen; Metzelder, Stephan K; Halbach, Sebastian; Brummer, Tilman; Hu, Zehan; Dengjel, Joern; Hackanson, Björn; Schmid, Christoph; Holtick, Udo; Scheid, Christof; Spyridonidis, Alexandros; Stölzel, Friedrich; Ordemann, Rainer; Müller, Lutz P; Sicre-de-Fontbrune, Flore; Ihorst, Gabriele; Kuball, Jürgen; Ehlert, Jan E; Feger, Daniel; Wagner, Eva-Maria; Cahn, Jean-Yves; Schnell, Jacqueline; Kuchenbauer, Florian; Bunjes, Donald; Chakraverty, Ronjon; Richardson, Simon; Gill, Saar; Kröger, Nicolaus; Ayuk, Francis; Vago, Luca; Ciceri, Fabio; Müller, Antonia M; Kondo, Takeshi; Teshima, Takanori; Klaeger, Susan; Kuster, Bernhard; Kim, Dennis Dong Hwan; Weisdorf, Daniel; van der Velden, Walter; Dörfel, Daniela; Bethge, Wolfgang; Hilgendorf, Inken; Hochhaus, Andreas; Andrieux, Geoffroy; Börries, Melanie; Busch, Hauke; Magenau, John; Reddy, Pavan; Labopin, Myriam; Antin, Joseph H; Henden, Andrea S; Hill, Geoffrey R; Kennedy, Glen A; Bar, Merav; Sarma, Anita; McLornan, Donal; Mufti, Ghulam; Oran, Betul; Rezvani, Katayoun; Shah, Omid; Negrin, Robert S; Nagler, Arnon; Prinz, Marco; Burchert, Andreas; Neubauer, Andreas; Beelen, Dietrich; Mackensen, Andreas; von Bubnoff, Nikolas; Herr, Wolfgang; Becher, Burkhard; Socié, Gerard; Caligiuri, Michael A; Ruggiero, Eliana; Bonini, Chiara; Häcker, Georg; Duyster, Justus; Finke, Jürgen; Pearce, Erika; Blazar, Bruce R; Zeiser, Robert

    2018-03-01

    Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-γ + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

  20. Can multimodality imaging using {sup 18}F-FDG/{sup 18}F-FLT PET/CT benefit the diagnosis and management of patients with pulmonary lesions?

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Baixuan; Guan, Zhiwei; Liu, Changbin; Wang, Ruimin; Yin, Dayi; Zhang, Jinming; Chen, Yingmao; Yao, Shulin; Shao, Mingzhe; Wang, Hui; Tian, Jiahe [Chinese PLA General Hospital, Department of Nuclear Medicine, Beijing (China)

    2011-02-15

    Dual-tracer, {sup 18}F-fluorodeoxyglucose and {sup 18}F-fluorodeoxythymidine ({sup 18}F-FDG/{sup 18}F-FLT), dual-modality (positron emission tomography and computed tomography, PET/CT) imaging was used in a clinical trial on differentiation of pulmonary nodules. The aims of this trial were to investigate if multimodality imaging is of advantage and to what extent it could benefit the patients in real clinical settings. Seventy-three subjects in whom it was difficult to establish the diagnosis and determine management of their pulmonary lesions were prospectively enrolled in this clinical trial. All subjects underwent {sup 18}F-FDG and {sup 18}F-FLT PET/CT imaging sequentially. The images were interpreted with different strategies as either individual or combined modalities. The pathological or clinical evidence during a follow-up period of more than 22 months served as the standard of truth. The diagnostic performance of each interpretation and their impact on clinical decision making was investigated. {sup 18}F-FLT/{sup 18}F-FDG PET/CT was proven to be of clinical value in improving the diagnostic confidence in 28 lung tumours, 18 tuberculoses and 27 other benign lesions. The ratio between maximum standardized uptake values of {sup 18}F-FLT and {sup 18}F-FDG was found to be of great potential in separating the three subgroups of patients. The advantage could only be obtained with the full use of the multimodality interpretation. Multimodality imaging induced substantial change in clinical management in 31.5% of the study subjects and partial change in another 12.3%. Multimodality imaging using {sup 18}F-FDG/{sup 18}F-FLT PET/CT provided the best diagnostic efficacy and the opportunity for better management in this group of clinically challenging patients with pulmonary lesions. (orig.)

  1. Comparison of (18)F-FET and (18)F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma

    DEFF Research Database (Denmark)

    Nedergaard, Mette Kjoelhede; Michaelsen, Signe Regner; Perryman, Lara

    2016-01-01

    was to compare FLT and FET PET for the assessment of anti-VEGF response in glioblastoma xenografts. METHODS: Xenografts with confirmed intracranial glioblastoma were treated with anti-VEGF therapy (B20-4.1) or saline as control. Weekly bioluminescence imaging (BLI), FLT and FET PET/CT were used to follow....... Furthermore, we found a significantly lower MVD in the anti-VEGF group as compared to the control group. However, we found no difference in the Ki67 proliferation index or mean survival time. CONCLUSION: FET appears to be a more sensitive tracer than FLT to measure early response to anti-VEGF therapy with PET...

  2. Predicting location of recurrence using FDG, FLT, and Cu-ATSM PET in canine sinonasal tumors treated with radiotherapy

    International Nuclear Information System (INIS)

    Bradshaw, Tyler; Jeraj, Robert; Fu, Rau; Zhu, Jun; Bowen, Stephen; Forrest, Lisa

    2015-01-01

    Dose painting relies on the ability of functional imaging to identify resistant tumor subvolumes to be targeted for additional boosting. This work assessed the ability of FDG, FLT, and Cu-ATSM PET imaging to predict the locations of residual FDG PET in canine tumors following radiotherapy. Nineteen canines with spontaneous sinonasal tumors underwent PET/CT imaging with radiotracers FDG, FLT, and Cu-ATSM prior to hypofractionated radiotherapy. Therapy consisted of 10 fractions of 4.2 Gy to the sinonasal cavity with or without an integrated boost of 0.8 Gy to the GTV. Patients had an additional FLT PET/CT scan after fraction 2, a Cu-ATSM PET/CT scan after fraction 3, and follow-up FDG PET/CT scans after radiotherapy. Following image registration, simple and multiple linear and logistic voxel regressions were performed to assess how well pre- and mid-treatment PET imaging predicted post-treatment FDG uptake. R 2 and pseudo R 2 were used to assess the goodness of fits. For simple linear regression models, regression coefficients for all pre- and mid-treatment PET images were significantly positive across the population (P < 0.05). However, there was large variability among patients in goodness of fits: R 2 ranged from 0.00 to 0.85, with a median of 0.12. Results for logistic regression models were similar. Multiple linear regression models resulted in better fits (median R 2 = 0.31), but there was still large variability between patients in R 2 . The R 2 from regression models for different predictor variables were highly correlated across patients (R ≈ 0.8), indicating tumors that were poorly predicted with one tracer were also poorly predicted by other tracers. In conclusion, the high inter-patient variability in goodness of fits indicates that PET was able to predict locations of residual tumor in some patients, but not others. This suggests not all patients would be good candidates for dose painting based on a single biological target. (paper)

  3. WE-H-207A-03: The Universality of the Lognormal Behavior of [F-18]FLT PET SUV Measurements

    International Nuclear Information System (INIS)

    Scarpelli, M; Eickhoff, J; Perlman, S; Jeraj, R

    2016-01-01

    Purpose: Log transforming [F-18]FDG PET standardized uptake values (SUVs) has been shown to lead to normal SUV distributions, which allows utilization of powerful parametric statistical models. This study identified the optimal transformation leading to normally distributed [F-18]FLT PET SUVs from solid tumors and offers an example of how normal distributions permits analysis of non-independent/correlated measurements. Methods: Forty patients with various metastatic diseases underwent up to six FLT PET/CT scans during treatment. Tumors were identified by nuclear medicine physician and manually segmented. Average uptake was extracted for each patient giving a global SUVmean (gSUVmean) for each scan. The Shapiro-Wilk test was used to test distribution normality. One parameter Box-Cox transformations were applied to each of the six gSUVmean distributions and the optimal transformation was found by selecting the parameter that maximized the Shapiro-Wilk test statistic. The relationship between gSUVmean and a serum biomarker (VEGF) collected at imaging timepoints was determined using a linear mixed effects model (LMEM), which accounted for correlated/non-independent measurements from the same individual. Results: Untransformed gSUVmean distributions were found to be significantly non-normal (p<0.05). The optimal transformation parameter had a value of 0.3 (95%CI: −0.4 to 1.6). Given the optimal parameter was close to zero (which corresponds to log transformation), the data were subsequently log transformed. All log transformed gSUVmean distributions were normally distributed (p>0.10 for all timepoints). Log transformed data were incorporated into the LMEM. VEGF serum levels significantly correlated with gSUVmean (p<0.001), revealing log-linear relationship between SUVs and underlying biology. Conclusion: Failure to account for correlated/non-independent measurements can lead to invalid conclusions and motivated transformation to normally distributed SUVs. The log

  4. MO-AB-BRA-06: Dynamic FLT PET for Investigating Potential Synergistic Therapeutic Targets During Anti-Angiogenic Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Scarpelli, M; Perlman, S; Liu, G [University of Wisconsin-Madison, Madison, WI (United States); Simoncic, U [Jozef Stefan Institute, Ljubljana (Slovenia); Jeraj, R [University of Wisconsin-Madison, Madison, WI (United States); Jozef Stefan Institute, Ljubljana (Slovenia)

    2016-06-15

    Purpose: Novel treatment strategies for metastatic cancer patients involve synergistically combining treatments with the hope of improving outcomes. This study investigated changes in tumor proliferative and vascular characteristics derived from dynamic [F-18]FLT PET during antiangiogenic treatment with the goal of identifying synergistic treatment opportunities. Methods: Patients with various solid cancers underwent continuous three-week cycles of anti-angiogenic treatment with intermittent dosing (two-weeks-on/one-week-off). Patients received up to six dynamic FLT PET/CT scans (days 0, 14, and 21 of cycle 1 (C1) and cycle 3 (C3)). Tumor proliferative (Kflt, net uptake rate) and vascular parameters (K1 blood-to-tissue transfer; Vb, vascular fraction) were calculated using a two-tissue compartment four-rate parameter kinetic model. Relative changes in these parameters, from day 0 to 14 (TxResp) and day 14 to 21 (offTxResp), were calculated. Significant differences were tested using Wilcoxon signed-rank test and significant correlations were tested using Spearman correlation. Results: Thirty patients were evaluable for C1 offTxResp with median values for Kflt, K1, and Vb of +30%, +35% and +30%, respectively. The fractions of patients with positive C1 offTxResp were: 21/30 for Ki, 24/30 for K1, 21/30 for Vb, and 12/30 had positive offTxResp for all three kinetic parameters. The offTxResp in C3 was not significantly different from C1 for any of the kinetic parameters. Significant correlations were found between TxResp and offTxResp in C1 for Kflt (ρ=-0.52, p=0.014), K1 (ρ=−0.61, p=0.003) and Vb (ρ=−0.80, p<0.001). Similar correlations were found for Kflt (ρ=-1, p=0.017) and K1 (ρ=−1, p=0.017) for the five patients evaluable in C3. Conclusion: Dynamic FLT PET showed evidence of distinct vascular and proliferative increases during off treatment weeks that could potentially be targeted with synergistic therapy. Early changes in kinetic parameters were

  5. WE-H-207A-03: The Universality of the Lognormal Behavior of [F-18]FLT PET SUV Measurements

    Energy Technology Data Exchange (ETDEWEB)

    Scarpelli, M; Eickhoff, J; Perlman, S; Jeraj, R

    2016-06-15

    Purpose: Log transforming [F-18]FDG PET standardized uptake values (SUVs) has been shown to lead to normal SUV distributions, which allows utilization of powerful parametric statistical models. This study identified the optimal transformation leading to normally distributed [F-18]FLT PET SUVs from solid tumors and offers an example of how normal distributions permits analysis of non-independent/correlated measurements. Methods: Forty patients with various metastatic diseases underwent up to six FLT PET/CT scans during treatment. Tumors were identified by nuclear medicine physician and manually segmented. Average uptake was extracted for each patient giving a global SUVmean (gSUVmean) for each scan. The Shapiro-Wilk test was used to test distribution normality. One parameter Box-Cox transformations were applied to each of the six gSUVmean distributions and the optimal transformation was found by selecting the parameter that maximized the Shapiro-Wilk test statistic. The relationship between gSUVmean and a serum biomarker (VEGF) collected at imaging timepoints was determined using a linear mixed effects model (LMEM), which accounted for correlated/non-independent measurements from the same individual. Results: Untransformed gSUVmean distributions were found to be significantly non-normal (p<0.05). The optimal transformation parameter had a value of 0.3 (95%CI: −0.4 to 1.6). Given the optimal parameter was close to zero (which corresponds to log transformation), the data were subsequently log transformed. All log transformed gSUVmean distributions were normally distributed (p>0.10 for all timepoints). Log transformed data were incorporated into the LMEM. VEGF serum levels significantly correlated with gSUVmean (p<0.001), revealing log-linear relationship between SUVs and underlying biology. Conclusion: Failure to account for correlated/non-independent measurements can lead to invalid conclusions and motivated transformation to normally distributed SUVs. The log

  6. Synthesis 1, 3-bis (4-bromophenyl-5-isopropyl-1, 3, 5-triazacyclohexane

    Directory of Open Access Journals (Sweden)

    L. LEFRADA

    2015-03-01

    Full Text Available Condensation of an isopropylamine and an 4-bromoaniline with formaline in basic solution to give 1, 3-bis (4-bromophenyl-5- (isopropyl- 1, 3, 5- triazicyaclohexane. Through the interaction of rapid Schiff base, Structures of this compound have been elucidated by spectroscopic methods; IR, 1H NMR, 13C NMR. Their purities were confirmed by elemental analyses.

  7. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3 and KIT driven Leukemogenesis

    Science.gov (United States)

    Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar; Mali, Raghuveer Singh; Martin, Holly; Kobayashi, Michihiro; Vemula, Sasidhar; Canela, Victor H.; Waskow, Emily R.; Visconte, Valeria; Tiu, Ramon V.; Smith, Catherine C.; Shah, Neil; Bunting, Kevin D.; Boswell, H. Scott; Liu, Yan; Chan, Rebecca J.; Kapur, Reuben

    2015-01-01

    SUMMARY Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK), whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis. PMID:25456130

  8. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

    Directory of Open Access Journals (Sweden)

    Anindya Chatterjee

    2014-11-01

    Full Text Available Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML and myeloproliferative neoplasms (MPNs, and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

  9. Asymmetric oxidation of 1,3-dithianes to 1,3-dithiane 1-oxides

    OpenAIRE

    Yoshihiko, Watanabe; Yojiro, Ono; Yoshio, Ueno; Takeshi, Toru

    1998-01-01

    Oxidation of 2-(1-hydroxy-1-methylethyl)-1,3-dithiane with the Sharpless reagent has been examined under various reaction conditions. Oxidation of 2-(1-hydroxy-1-methylethyl)-1,3-dithiane with Ti(OPri)4-diethyl L-(+)-tartrate-tert-butyl hydroperoxide (1:2:1.5) in CH2Cl2 in the presence of 4 A molecular sieves gives (1S,2S)-2-(1-hydroxy-1-methylethyl)-1,3-dithiane 1-oxide with high trans selectivity and with moderate enantioselectivity. The enantioselectivity depends upon the substituent at t...

  10. Subchronic toxicity studies on 1,3,5-trinitrobenzene, 1,3-dinitrobenzene and tetryl in rats. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, T.V.; Daniel, F.B.

    1994-09-01

    Toxic effects of 1,3-Dinitrobenzene (1,3-DNB) in male and female F344 rats were evaluated by feeding powdered certified laboratory chow diet supplemented with varied concentrations of 1,3-DNB (0, 2.5, 10, 25, 75 and 150 mg/kg diet) for fourteen days. The average daily 1 ,3-DNB doses consumed were 0.21, 0.87, 2.02, 6.28 and 11.82 mg/kg b.w. for females and 0.21, 0.80, 1.98, 5.77 and 10.56 for males. Food consumption was significantly decreased in high dose animals of both sexes. Final body weights were not altered but relative organ weights were significantly changed in the 150 and 75 mg dose groups involving the spleen (males and females) and testes (males). Hematology and clinical chemistry studies indicated significantly increased values in both sexes relating to reticulocytes and methemoglobin in the 150 and 75 mg/kg dose groups while the red blood cell count, hemoglobin level and % hematocrit were decreased in these same groups. In addition, the levels of bilirubin, protein and albumin were increased in high dose males, Histopathological evaluations suggested that the susceptible organs for 1,3-DNB toxicity were kidneys (hyaline droplets), spleen (erythroid cell hyperplasia), brain (malacia and microgliosis), testes (seminiferous tubular degeneration). These changes were noted mainly in the 150 and 75 mg/kg dose groups except those changes involving the brain (150 mg/kg group only).

  11. Noninvasive quantification of 18F-FLT human brain PET for the assessment of tumour proliferation in patients with high-grade glioma

    International Nuclear Information System (INIS)

    Backes, Heiko; Ullrich, Roland; Neumaier, Bernd; Kracht, Lutz; Wienhard, Klaus; Jacobs, Andreas H.

    2009-01-01

    Compartmental modelling of 3 ' -deoxy-3 ' -[ 18 F]-fluorothymidine ( 18 F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18 F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. Based on the analysis of 11 patients with glioma (WHO grade II-IV) a procedure for the automated extraction of an input function from 18 F-FLT brain PET data was derived. The time-activity curve of the volume of interest with the maximum difference in 18 F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18 F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K 1 (transport across the blood-brain barrier) and K i (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K 1,img and K 1,sample , r = 0.95, p -5 ; K i,img and K i,sample , r = 0.86, p 1,img and K 1,sample , p = 0.20; K i,img and K i,sample , p = 0.92). Furthermore, a significant correlation between K i,img and the percentage of Ki-67-positive cells was observed (r = 0.73, p = 0.01). Kinetic modelling of 18 F-FLT brain PET data using image-derived input functions extracted from human brain PET data with the practical

  12. Serum concentrations of soluble Flt-1 are decreased among women with a viable fetus and no symptoms of miscarriage destined for pregnancy loss.

    Directory of Open Access Journals (Sweden)

    Tu'uhevaha J Kaitu'u-Lino

    Full Text Available Miscarriage is the most common complication of pregnancy. Pre-clinical miscarriage has an estimated incidence of 30%, whilst clinical miscarriage has an incidence of 12-15%. Two thirds of pregnancies lost to miscarriage are believed to be attributable to defective placentation, thus a number of studies have sought to identify markers of defective placentation that could be used as clinical biomarkers of miscarriage. Decreased soluble FMS-like tyrosine kinase-1 (sFlt1, placental growth factor (PlGF, and soluble endoglin (sEng in the maternal circulation during the first trimester have recently been proposed as potential markers of pregnancy loss. However, in these studies clinical samples were only obtained once women had presented with symptoms of miscarriage. In this study we prospectively screened serum samples collected from asymptomatic women with a viable fetus. We assessed maternal serum levels of sFlt1, PlGF and sEng across the first trimester of normal pregnancy and compared levels between women who continued to a live birth, to those who subsequently miscarried. Both sFlt1 and PlGF significantly (p≤0.05 increased across gestation in normal pregnancy with serum levels rising from 0.65±0.12 ng/ml at 6 weeks to 1.85±0.24 ng/ml at 12 weeks for sFlt1, and 57.2±19.2 pg/ml to 106±22.7 pg/ml for PlGF. sEng remained unchanged throughout the the first trimester. Importantly we detected a significant (35%, p≤0.05 decrease in sFlt1 levels between our control and miscarriage cohort, however there was significant overlap between cases and controls, suggesting serum sFlt1 is unlikely to be useful as a clinical biomarker in asymptomatic women. Nevertheless, our data suggests a dysregulation of angiogenic factors may be involved in the pathophysiology of miscarriage.

  13. An analysis on the roles of angiogenesis-related factors including serum vitamin D, soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF) in the diagnosis and severity of late-onset preeclampsia.

    Science.gov (United States)

    Cim, Numan; Kurdoglu, Mertihan; Ege, Serhat; Yoruk, Ibrahim; Yaman, Gorkem; Yildizhan, Recep

    2017-07-01

    The aim of this study was to evaluate the roles of proangiogenic factors including serum vitamin D and vascular endothelial growth factor (VEGF) and anti-angiogenic factors including soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt1) in the diagnosis and severity of late-onset preeclampsia. The study was conducted at Yuzuncu Yil University Research and Education Hospital Department of Gynecology and Obstetrics. The study included a patient group of 40 women with late-onset preeclampsia who were pregnant at ≥32 weeks of gestation according to the last menstrual period (LMP) or ultrasonographic fetal biometric measurement and a control group of 40 healthy pregnant women who presented to our clinic for routine pregnancy examination and were at the same age and gestational period with those in the patient group. The two groups were compared in terms of maternal age, gravida, parity, week of gestation, systolic/diastolic blood pressure, total protein in spot urine sample, 24-h urine protein, white blood cell (WBC), hemoglobin (Hgb), platelet count, urea, creatinine, liver function tests (AST, ALT, LDH), vitamin D 3 , 25(OH) vitamin D 3 , 1,25(OH) vitamin D 3 , sEng, sFlt1, and VEGF levels, mode of delivery, the infant APGAR score at 1 and 5 min after delivery, and infant weight at delivery. The groups were similar in terms of age, gravida, parity, week of gestation, serum vitamin D 3 , 25(OH) vitamin D 3 , 1,25(OH) 2 vitamin D 3 and VEGF levels, and infant weight at delivery (p > 0.05). Systolic/diastolic blood pressure, total protein in spot urine sample, 24-h urine protein, WBC, Hgb, serum urea, creatine, AST, ALT, and LDH were significantly higher in the preeclamptic group compared to the healthy group (p preeclampsia compared to the women with mild preeclampsia (p preeclampsia (p > 0.05). Both sEng and sFlt1 levels are remarkably high in patients with late-onset preeclampsia; however, only sEng may be a useful tool in the

  14. Pharmacokinetics and whole body distribution of elastase derived angiostatin (k1-3) in rats

    NARCIS (Netherlands)

    Molema, Grietje; van Veen-Hof, Ingrid; van Loenen - Weemaes, Anne-miek; Proost, Johannes; de Leij, Lou F.M.H.; Meijer, Dirk K.F.

    2001-01-01

    In the current study, we determined short-term pharmacokinetics and whole body distribution of elastase derived angiostatin [angiostatin((k1-3))] in rats after i.v. injection of radiolabelled protein. Since In gamma-camera studies, no tumor specific angiostatin((k1-3)) accumulation was observed,

  15. 1-3-7 minute intravenous urography

    International Nuclear Information System (INIS)

    Bahk, Yong Whee; Yoon, Sei Chul; Lee, Myung Hee

    1980-01-01

    Intravenous urography (IVU) as it is used widely today was probably started in early 1950's after the introduction of triiodobenzoic acid compounds as contrast media. This long cherished traditional method consists of taking radiograms at 5, 15 and 25 minutes after the injection of contrast medium. There are a few modifications of this standard urographic examination such as five minute IVU (Woodruff, 1959), minute-sequence pyelogram (Maxwell et al., 1964), drip infusion pyelography (Schencker, 1964) and nephrotomography (Evans et al., 1955). The present study has been undertaken to test if the conventional standard IVU can be more rapidly performed without losing essential informational contents of urograms. In this new clinical trial, urograms were taken at the end of 1, 3 and 7 minutes instead of 5, 15 and 25 minutes after the intravenous injection of contrast medium. We injected 40 ml of meglumine diatrizoate solution within 30 seconds using an 18G iv needle. (The amount of injected contrast medium has been reduced recently to ordinary single dose of 20 ml for subjects weighing less than 8 kg). Upon viewing the 7 minute film in front of an automatic processor, the examination was terminated after obtaining an upright view unless any further radiogram was indicated. As shown in Tables and Figures, our new 1-3-7 minute method has been proven to provide us with as much essential and useful information as conventional 5-15-25 minute urography. Thus, we were able to finish one examination within 10 minutes without losing any necessary diagnostic information. In some of patients with obstructive uropathy such as stone the examination was extended as long as it was desired. Side reactions were occasional nausea, flushing and rare mild vomiting which never prevented the examination

  16. 18F-FLT Positron Emission Tomography/Computed Tomography Imaging in Pancreatic Cancer: Determination of Tumor Proliferative Activity and Comparison with Glycolytic Activity as Measured by 18F-FDG Positron Emission Tomography/Computed Tomography Imaging

    Directory of Open Access Journals (Sweden)

    Senait Aknaw Debebe

    2016-02-01

    Full Text Available Objective: This phase-I imaging study examined the imaging characteristic of 3’-deoxy-3’-(18F-fluorothymidine (18F-FLT positron emission tomography (PET in patients with pancreatic cancer and comparisons were made with (18F-fluorodeoxyglucose (18F-FDG. The ultimate aim was to develop a molecular imaging tool that could better define the biologic characteristics of pancreas cancer, and to identify the patients who could potentially benefit from surgical resection who were deemed inoperable by conventional means of staging. Methods: Six patients with newly diagnosed pancreatic cancer underwent a combined FLT and FDG computed tomography (CT PET/CT imaging protocol. The FLT PET/CT scan was performed within 1 week of FDG PET/CT imaging. Tumor uptake of a tracer was determined and compared using various techniques; statistical thresholding (z score=2.5, and fixed standardized uptake value (SUV thresholds of 1.4 and 2.5, and applying a threshold of 40% of maximum SUV (SUVmax and mean SUV (SUVmean. The correlation of functional tumor volumes (FTV between 18F-FDG and 18F-FLT was assessed using linear regression analysis. Results: It was found that there is a correlation in FTV due to metabolic and proliferation activity when using a threshold of SUV 2.5 for FDG and 1.4 for FLT (r=0.698, p=ns, but a better correlation was obtained when using SUV of 2.5 for both tracers (r=0.698, p=ns. The z score thresholding (z=2.5 method showed lower correlation between the FTVs (r=0.698, p=ns of FDG and FLT PET. Conclusion: Different tumor segmentation techniques yielded varying degrees of correlation in FTV between FLT and FDGPET images. FLT imaging may have a different meaning in determining tumor biology and prognosis.

  17. Performance comparison of 2-1-3, 1-3 and 1-3-2 piezoelectric composite transducers by finite element method

    Directory of Open Access Journals (Sweden)

    Y. Sun

    2018-03-01

    Full Text Available 1-3 type, 1-3-2 type and 2-1-3 type piezoelectric composites are three proper smart materials for the design and manufacture of ultrasonic transducers. They have been proposed in different stages but possess similar properties. Compared with the initial 1-3 type composite, 1-3-2 composite is of higher mechanical stability. Compared with 1-3-2 composite, 2-1-3 composite has lower manufacturing difficulty. In this paper, a comparative study on these three composites in terms of receiving transducer material properties is presented. Finite element method (FEM has been adopted to calculate longitudinal velocity, thickness electromechanical coupling coefficient and voltage receiving sensitivity. It is concluded that for a large aspect ratio α=1, the performance of 2-1-3 composite transducer is much better than that of 1-3 and 1-3-2 composite transducers. The thickness electromechanical coupling coefficient of 2-1-3 composite transducer is about 5.58 times that of 1-3 composite transducer and 7.42 times that of 1-3-2 composite transducer. The voltage receiving sensitivity at 2 kHz of 2-1-3 composite transducer is 13.1 dB higher than that of 1-3-2 composite transducer and 12.3 dB higher than that of 1-3 composite transducer.

  18. Fusion protein of tapasin and hepatitis B core antigen 18‑27 enhances T helper cell type 1/2 cytokine ratio and antiviral immunity by inhibiting suppressors of cytokine signaling family members 1/3 in hepatitis B virus transgenic mice.

    Science.gov (United States)

    Tang, Yuyan; Chen, Xiaohua; Zhang, Yi; Tang, Zhenghao; Zhuo, Meng; Li, Dan; Wang, Peng; Zang, Guoqing; Yu, Yongsheng

    2014-04-01

    Persistent hepatitis B virus (HBV) infection is characterized by a weak adaptive immune response, which is considered to be due to an imbalance of T helper cell types 1 and 2 (Th1/Th2). Suppressors of cytokine signaling (SOCS) family members, particularly SOCS1 and SOCS3, have been demonstrated to be important in the regulation of T cell differentiation. Previous studies by our group showed that the expressed and purified fusion protein of cytoplasmic transduction peptide (CTP) and HBV core antigen 18‑27 (HBcAg18‑27)‑tapasin was able to enter the cytoplasm of bone marrow‑derived dendritic cells (BMDCs), promoting the maturation of BMDCs and efficiently enhancing T cell immune responses in vitro. In the present study, HBcAg‑specific immune responses induced by CTP‑HBcAg18‑27‑tapasin in HBV were assessed in transgenic mice, and SOCS1 and SOCS3 were identified as negative regulators of this response. The Th1/Th2 cytokine ratio was analyzed by ELISA. The expression of T cell‑specific T‑box transcription factor (T‑bet) and GATA‑binding protein 3 (GATA‑3), SOCS1 and SOCS3 were detected by real‑time quantitative polymerase chain reaction and western blot analysis. The results demonstrated that CTP‑HBcAg18‑27‑tapasin significantly increased the Th1/Th2 cytokine ratio in HBV transgenic mice. CTP‑HBcAg18‑27‑tapasin immunization more efficiently suppressed the expression of serum hepatitis B surface antigen (HBsAg), HBV DNA as well as liver HBsAg and HBcAg in HBV transgenic mice. Furthermore, CTP‑HBcAg18‑27‑tapasin promotes T‑bet but reduces GATA‑3 expression. In addition, the expression of SOCS1 and SOCS3 was significantly downregulated in the CTP‑HBcAg18‑27‑tapasin group compared with the control groups. In conclusion, the present study demonstrated that CTP‑HBcAg18‑27‑tapasin enhanced the Th1/Th2 cytokine ratio and antiviral immunity by suppressing SOCS1/3 in HBV transgenic mice.

  19. Use of Molecular Imaging Markers of Glycolysis, Hypoxia and Proliferation (18F-FDG, 64Cu-ATSM and 18F-FLT) in a Dog with Fibrosarcoma

    DEFF Research Database (Denmark)

    Zornhagen, Kamilla; Clausen, Malene; Hansen, Anders Elias

    2015-01-01

    of cancer patients. A dog with fibrosarcoma was imaged using 18F-FDG, 64Cu-ATSM, and 18F-FLT before, during, and after 10 fractions of 4.5 Gy radiotherapy. Uptake of all tracers decreased during treatment. Fluctuations in 18F-FDG and 18F-FLT PET uptakes and a heterogeneous spatial distribution of the three......Glycolysis, hypoxia, and proliferation are important factors in the tumor microenvironment contributing to treatment-resistant aggressiveness. Imaging these factors using combined functional positron emission tomography and computed tomography can potentially guide diagnosis and management...... tracers were seen. Tracer distributions partially overlapped. It appears that each tracer provides distinct information about tumor heterogeneity and treatment response....

  20. First trimester uterine artery Doppler, sFlt-1 and PlGF to predict preeclampsia in a high-risk population.

    Science.gov (United States)

    Diguisto, Caroline; Piver, Eric; Gouge, Amélie Le; Eboue, Florence; Vaillant, Claudine Le; Maréchaud, Martine; Goua, Valérie; Giraudeau, Bruno; Perrotin, Franck

    2017-07-01

    The study aims to evaluate the accuracy of combining uterine artery Doppler (UAD), PlGF and sFlt-1 in the first trimester for preeclampsia screening. Prospectively enrolled women at high risk of preeclampsia were included. Transabdominal UAD measurements and serum biomarkers were collected between 11 and 13 weeks of gestation in three university hospitals and in one general hospital. The main outcome was preeclampsia. UAD parameters and biomarker levels among women with preeclampsia were compared with those of women in the unaffected group in univariate and multivariate analyses. Out of 226 women included from May 2007 to January 2011, 27 (11.9%) women developed preeclampsia. Among women affected by preeclampsia, the lowest pulsatility index was higher (p = 0.02), bilateral notching was more frequent (p = 0.01), and PlGF was lower (p preeclampsia, but neither sFlt-1 nor any UAD indices improved the prediction of preeclampsia.

  1. Impact of VEGF and VEGF receptor 1 (FLT1) expression on the prognosis of stage III esophageal cancer patients after radiochemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Rades, D. [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf (Germany); Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Luebeck (Germany); Golke, H. [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf (Germany); Inst. of Pathology, Univ. Medical Center Hamburg-Eppendorf (Germany); Schild, S.E. [Dept. of Radiation Oncology, Mayo Clinic, Scottsdale, AZ (United States); Kilic, E. [Inst. of Pathology, Univ. Medical Center Hamburg-Eppendorf (Germany); Inst. of Pathology, Univ. Hospital Basel-Stadt (Switzerland)

    2008-08-15

    Background and purpose: high expression of vascular endothelial growth factor (VEGF) is negatively associated with clinical outcome. The prognostic value of VEGF receptor 1 (FLT1) is unclear. This retrospective study investigated the impact of tumor expression of VEGF and FLT1 on outcome in 68 stage III esophageal cancer patients. Material and methods: the impact of tumor VEGF and FLT expression (< 10% vs. > 10%) and five additional potential prognostic factors on overall survival (OS) and locoregional control (LC) was retrospectively evaluated. These factors included T-stage (T3 vs. T4), N-stage (NO vs. N1), treatment (radiochemotherapy plus resection vs. radiochemotherapy alone), erythropoietin (ERYPO {sup registered} 10000, Janssen-Cilag, Neuss, Germany) administration during radiotherapy, and majority of hemoglobin levels during radiotherapy (< 12 vs. {>=} 12 g/dl). Subgroup analyses were performed for patients receiving resection (R0 vs. R1/2 resection). The factors found to be significant on univariate analyses (Kaplan-Meier method, log-rank test) were included in multivariate analyses performed with the Cox proportional hazard model. Results: on univariate analysis, improved OS was associated with T3 stage (p = 0.011), surgery (p = 0.019), and hemoglobin {>=} 12 g/dl (p < 0.001). Improved LC was associated with T3 stage (p = 0.025), hemoglobin {>=} 12 g/dl (p < 0.001), and VEGF negativity (p = 0.045). On multivariate analyses, only hemoglobin maintained significance. In patients having surgery, R0 resection was significantly better than R1/2 resection for OS (p < 0.001) and LC (p < 0.001). Conclusion: preradiotherapy tumor VEGF expression appears negatively correlated with outcomes, whereas FLT1 expression appears to have no significant impact on OS and LC. (orig.)

  2. Impact of VEGF and VEGF receptor 1 (FLT1) expression on the prognosis of stage III esophageal cancer patients after radiochemotherapy

    International Nuclear Information System (INIS)

    Rades, D.; Golke, H.; Schild, S.E.; Kilic, E.

    2008-01-01

    Background and purpose: high expression of vascular endothelial growth factor (VEGF) is negatively associated with clinical outcome. The prognostic value of VEGF receptor 1 (FLT1) is unclear. This retrospective study investigated the impact of tumor expression of VEGF and FLT1 on outcome in 68 stage III esophageal cancer patients. Material and methods: the impact of tumor VEGF and FLT expression ( 10%) and five additional potential prognostic factors on overall survival (OS) and locoregional control (LC) was retrospectively evaluated. These factors included T-stage (T3 vs. T4), N-stage (NO vs. N1), treatment (radiochemotherapy plus resection vs. radiochemotherapy alone), erythropoietin (ERYPO registered 10000, Janssen-Cilag, Neuss, Germany) administration during radiotherapy, and majority of hemoglobin levels during radiotherapy (< 12 vs. ≥ 12 g/dl). Subgroup analyses were performed for patients receiving resection (R0 vs. R1/2 resection). The factors found to be significant on univariate analyses (Kaplan-Meier method, log-rank test) were included in multivariate analyses performed with the Cox proportional hazard model. Results: on univariate analysis, improved OS was associated with T3 stage (p = 0.011), surgery (p = 0.019), and hemoglobin ≥ 12 g/dl (p < 0.001). Improved LC was associated with T3 stage (p = 0.025), hemoglobin ≥ 12 g/dl (p < 0.001), and VEGF negativity (p = 0.045). On multivariate analyses, only hemoglobin maintained significance. In patients having surgery, R0 resection was significantly better than R1/2 resection for OS (p < 0.001) and LC (p < 0.001). Conclusion: preradiotherapy tumor VEGF expression appears negatively correlated with outcomes, whereas FLT1 expression appears to have no significant impact on OS and LC. (orig.)

  3. [18F]FDG and [18F]FLT positron emission tomography imaging following treatment with belinostat in human ovary cancer xenografts in mice

    DEFF Research Database (Denmark)

    Jensen, Mette Munk; Erichsen, Kamille Dumong; Johnbeck, Camilla Bardram

    2013-01-01

    Belinostat is a histone deacetylase inhibitor with anti-tumor effect in several pre-clinical tumor models and clinical trials. The aim of the study was to evaluate changes in cell proliferation and glucose uptake by use of 3'-deoxy-3'-[(18)F]fluorothymidine ([18F]FLT) and 2-deoxy-2-[(18)F]fluoro-......]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) following treatment with belinostat in ovarian cancer in vivo models....

  4. Flt3 ligand synergizes with granulocyte-colony-stimulating factor in bone marrow mobilization to improve functional outcome after spinal cord injury in the rat

    Czech Academy of Sciences Publication Activity Database

    Urdzíková, Lucia; Mašínová, Katarína; Vaněček, Václav; Růžička, Jiří; Šedý, Jiří; Syková, Eva; Jendelová, Pavla

    2011-01-01

    Roč. 13, č. 9 (2011), s. 1090-1104 ISSN 1465-3249 R&D Projects: GA AV ČR IAA500390902; GA MŠk(CZ) LC554 Grant - others:GA MŠk(CZ) 1M0538 Program:1M Institutional research plan: CEZ:AV0Z50390703 Keywords : axonal sprouting * bone marrow mobilization * Flt3 ligand Subject RIV: FH - Neurology Impact factor: 3.627, year: 2011

  5. In vivo imaging of therapy response to a novel Pan-HER antibody mixture using FDG and FLT positron emission tomography

    DEFF Research Database (Denmark)

    Nielsen, Carsten H; Jensen, Mette M; Kristensen, Lotte K

    2015-01-01

    response obtained by targeting HER family members individually or simultaneously using the novel monoclonal antibody (mAb) mixture Pan-HER. EXPERIMENTAL DESIGN AND RESULTS: Mice with subcutaneous BxPC-3 pancreatic adenocarcinomas were divided into five groups receiving vehicle or mAb mixtures directed...... to Pan-HER therapy. FDG and FLT PET/CT imaging should be considered as imaging biomarkers in clinical evaluation of the Pan-HER mAb mixture....

  6. 5-Isopropylidene-1,3-dithiolo[4,5-d][1,3]dithiole-2-thione

    Directory of Open Access Journals (Sweden)

    Yoshiro Yamashita

    2009-05-01

    Full Text Available The title compound, C7H6S5, contains a 5-ylidene-1,3-dithiolo[4,5-d][1,3]dithiole-2-thione framework, which is an important synthetic precursor of multi-dimensional organic superconductors and conductors. The molecular framework is planar with an r.m.s. deviation of 0.012 Å for the non-H atoms. In the crystal structure, molecules are linked by short intermolecular S...S interactions [3.501 (5 and 3.581 (4 Å], constructing a zigzag molecular tape network along the c axis.

  7. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5 ...

    Science.gov (United States)

    The IRIS Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) was released for external peer review in September 2016. The EPA’s Science Advisory Board’s (SAB) Chemical Assessment Advisory Committee (CAAC) will conduct a peer review of the scientific basis supporting the RDX assessment and release a final report of their review. Information regarding the peer review can be found on the SAB website. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for RDX. The outcome of this project is an updated Toxicological Review and IRIS Summary for RDX that will be entered into the IRIS database.

  8. Evaluation of 18F-FDG and 18F-FLT for monitoring therapeutic responses of colorectal cancer cells to radiotherapy

    International Nuclear Information System (INIS)

    Wang, Hui; Liu, Bo; Tian, Jiahe; Xu, Baixuan; Zhang, Jinming; Qu, Baolin; Chen, Yingmao

    2013-01-01

    In order to compare the efficacy of 18 F-fluorothymidine (FLT) and 18 F-fluorodeoxyglucose (FDG) for monitoring early responses to irradiation, two human colorectal cancer (CRC) cell lines SW480 and SW620, which were derived from the primary lesions and the metastatic lymph node, underwent X-ray irradiation of 0, 10, or 20 Gy and were examined at 0, 24 and 72 h After irradiation, reduced proliferation of both SW480 and SW620 cells was observed in a dose-dependent manner (P < 0.001), G0-G1 arrest was also noted in both cell types after 72 h in the 20 Gy group (P < 0.001). Although increased apoptosis was observed in both cell lines after irradiation (P < 0.001), a greater percentage of SW480 cells underwent apoptosis in response to irradiation than SW620 cells. Increased Hsp27 and decreased integrin β 3 , Ki67 and VEGFR2 expression was observed over time via immunocytochemistry and Western blot analysis (P < 0.001), however, no significant changes were noted in response to irradiation. Finally, reduced uptake of 18 F-FLT by SW480 or SW620 cells was observed at 24-h post-irradiation, however, reduced 18 F-FDG uptake was only observed after 72 h. Therefore, we conclude that 18 F-FLT is a more suitable positron emission tomography (PET) tracer for monitoring early responses to irradiation in primary and metastatic lymph node CRC cells

  9. Mechanism and regioselectivity of 1,3-dipolar cycloaddition ...

    Indian Academy of Sciences (India)

    1,3-Dipolar cycloaddition; sulphur-centred 1,3-dipoles; regioselectivity; DFT reactivity indices;. FMO theory. 1. Introduction. Five-membered heterocyclic compounds can be gene- rated by addition of a 1,3-dipole to a dipolarophile under a 1,3-dipolar cycloaddition (1,3-DC) reaction which is well known as pericyclic reaction.

  10. ESTUDIO CONFORMACIONAL EN ALGUNAS 1,3-OXAZINAS Y 1,3-BENZOXAZINAS EMPLEANDO METODOS TEORICOS.

    OpenAIRE

    HURTADO OCAMPO, SANDRA MARCELA; HURTADO OCAMPO, SANDRA MARCELA

    2007-01-01

    En la década del cincuenta, resultados experimentales entregados por Urbanski y colaboradores [1] pusieron en evidencia propiedades antituberculósicas y antitumorales en compuestos del tipo 5-nitro-R-N-1 ,3- oxazínicos. Como resultado de un proceso relati 187p.

  11. Transcriptional activation of Mina by Sp1/3 factors.

    Science.gov (United States)

    Lian, Shangli; Potula, Hari Hara S K; Pillai, Meenu R; Van Stry, Melanie; Koyanagi, Madoka; Chung, Linda; Watanabe, Makiko; Bix, Mark

    2013-01-01

    Mina is an epigenetic gene regulatory protein known to function in multiple physiological and pathological contexts, including pulmonary inflammation, cell proliferation, cancer and immunity. We showed previously that the level of Mina gene expression is subject to natural genetic variation linked to 21 SNPs occurring in the Mina 5' region. In order to explore the mechanisms regulating Mina gene expression, we set out to molecularly characterize the Mina promoter in the region encompassing these SNPs. We used three kinds of assays--reporter, gel shift and chromatin immunoprecipitation--to analyze a 2 kb genomic fragment spanning the upstream and intron 1 regions flanking exon 1. Here we discovered a pair of Mina promoters (P1 and P2) and a P1-specific enhancer element (E1). Pharmacologic inhibition and siRNA knockdown experiments suggested that Sp1/3 transcription factors trigger Mina expression through additive activity targeted to a cluster of four Sp1/3 binding sites forming the P1 promoter. These results set the stage for comprehensive analysis of Mina gene regulation from the context of tissue specificity, the impact of inherited genetic variation and the nature of upstream signaling pathways.

  12. Preclinical FLT-PET and FDG-PET imaging of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901

    International Nuclear Information System (INIS)

    Cullinane, Carleen; Waldeck, Kelly L.; Binns, David; Bogatyreva, Ekaterina; Bradley, Daniel P.; Jong, Ron de; McArthur, Grant A.; Hicks, Rodney J.

    2014-01-01

    Introduction: The Aurora kinases play a key role in mitosis and have recently been identified as attractive targets for therapeutic intervention in cancer. The aim of this study was therefore to investigate the utility of 3′-[ 18 F]fluoro-3′-deoxythymidine (FLT) and 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) for assessment of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901. Methods: Balb/c nude mice bearing HCT116 colorectal xenografts were treated with up to 30 mg/kg TAK 901 or vehicle intravenously twice daily for two days on a weekly cycle. Tumor growth was monitored by calliper measurements and PET imaging was performed at baseline, day 4, 8, 11 and 15. Tumors were harvested at time points corresponding to days of PET imaging for analysis of ex vivo markers of cell proliferation and metabolism together with markers of Aurora B kinase inhibition including phospho-histone H3 (pHH3) and senescence associated β-galactosidase. Results: Tumor growth was inhibited by 60% on day 12 of 30 mg/kg TAK-901 therapy. FLT uptake was significantly reduced by day 4 of treatment and this corresponded with reduction in bromodeoxyuridine and pHH3 staining by immunohistochemistry. All biomarkers rebounded towards baseline levels by the commencement of the next treatment cycle, consistent with release of Aurora B kinase suppression. TAK-901 therapy had no impact on glucose metabolism as assessed by FDG uptake and GLUT1 staining by immunohistochemistry. Conclusions: FLT-PET, but not FDG-PET, is a robust non-invasive imaging biomarker of early HCT116 tumor response to the on-target effects of the multi-targeted Aurora B kinase inhibitor, TAK-901. Advances in knowledge and implications for patient care: This is the first report to demonstrate the impact of the multi-targeted Aurora B kinase inhibitor, TAK-901 on tumor FLT uptake. The findings provide a strong rationale for the evaluation of FLT-PET as an early biomarker of tumor response in the early phase

  13. Using the angiogenic factors sFlt-1 and PlGF with Doppler ultrasound of the uterine artery for confirming preeclampsia.

    Science.gov (United States)

    Bahlmann, Franz; Al Naimi, Ammar

    2016-11-01

    The aim of this study is to assess the value of the angiogenic factors for diagnosing preeclampsia and predicting the severity of manifestation. A secondary aim is assessing the combination of the uterine artery Doppler with the angiogenic factors for improving the diagnostic power. This is a prospective single center study in a tertiary referral hospital. This study includes 728 individual patients. Inclusion criteria were singleton pregnancies, a referral to the hospital with suspicion of preeclampsia and any one or combination of the following symptoms: headache, upper abdominal pain, edema, and hypertension. Patients with complications that would affect the course of the pregnancy, such as placenta praevia, premature preterm rupture of membranes, breech presentation, and fetal chromosomal or structural anomalies, were excluded from the study. Blood samples collection and uterine artery Doppler ultrasound were performed at time of recruitment. The differences in sFlt-1, PlGF, and their quotient among normal collective and patients with preeclampsia were analyzed. Doppler ultrasound was performed by one of four highly qualified sonographers. Wilcoxon-Mann-Whitney U test, Spearman's rank correlation, receiver operating characteristic curves, Chi-square test, and logistic regression were used in the analysis. A total of 1003 individual samples for the angiogenic factors were included in the analysis. 584 out of the recruited 728 patients had follow-up data with delivery information at the study hospital. Patients with preeclampsia show a significant increase in sFlt-1, which directly correlate with the increased severity of manifestation (Spearman's ρ 0.49). The sFlt-1 cut-off value of 5424 pg/ml confirms preeclampsia with 83.7 % sensitivity, 68.1 % specificity, and 24 % misclassification rate. Preeclampsia patients also show a significant decrease in PlGF, which negatively correlates with the increased severity of manifestation (Spearman's ρ -0.39). A Pl

  14. Comparison of 18F-FET and 18F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma

    International Nuclear Information System (INIS)

    Nedergaard, Mette Kjoelhede; Michaelsen, Signe Regner; Perryman, Lara; Erler, Janine; Poulsen, Hans Skovgaard; Stockhausen, Marie-Thérése; Lassen, Ulrik; Kjaer, Andreas

    2016-01-01

    Background: The radiolabeled amino acid O-(2- 18 F-fluoroethyl)-L-tyrosine (FET) and thymidine analogue 3′-deoxy-3′- 18 F-fluorothymidine (FLT) are widely used for positron emission tomography (PET) brain tumor imaging; however, comparative studies are scarce. The aim of this study therefore was to compare FLT and FET PET for the assessment of anti-VEGF response in glioblastoma xenografts. Methods: Xenografts with confirmed intracranial glioblastoma were treated with anti-VEGF therapy (B20-4.1) or saline as control. Weekly bioluminescence imaging (BLI), FLT and FET PET/CT were used to follow treatment response. Tracer uptake of FLT and FET was quantified using maximum standardized uptake (SUV max ) values and tumor-to-background ratios (TBRs). Survival, the Ki67 proliferation index and micro-vessel density (MVD) were evaluated. Results: In contrast to FLT TBRs, FET TBRs were significantly lower as early as one week after treatment initiation in the anti-VEGF group as compared to the control group. Following two weeks of treatment, both FLT and FET TBRs were significantly lower in the anti-VEGF group. In contrast, no significant difference between the treatment groups was detected using BLI. Furthermore, we found a significantly lower MVD in the anti-VEGF group as compared to the control group. However, we found no difference in the Ki67 proliferation index or mean survival time. Conclusion: FET appears to be a more sensitive tracer than FLT to measure early response to anti-VEGF therapy with PET. Advances in knowledge and implications for patient care FET PET appears to be an early predictor of anti-VEGF efficacy. Confirmation of these results in clinical studies is needed.

  15. Processing of water-based LiNi1/3Mn1/3Co1/3O2 pastes for ...

    Indian Academy of Sciences (India)

    Results show that a substitution of the conventional organic solvent-based manufacturing route for LiNi1/3Mn1/3Co1/3O2 cathodes by water-based processing exhibits a promising way to realise Li-ion batteries with comparable electrochemical behaviour, while avoiding toxic processing aids and reducing overall ...

  16. GITT studies on oxide cathode LiNi1/3Co1/3Mn1/3O2 synthesized ...

    Indian Academy of Sciences (India)

    2016-08-26

    Aug 26, 2016 ... GITT studies on oxide cathode LiNi1/3Co1/3Mn1/3O2 synthesized by citric acid assisted high-energy ball milling ... The State Key Laboratory Base of Novel Functional Materials and Preparation Science; The Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, P. R. ...

  17. GITT studies on oxide cathode LiNi1/3Co1/3Mn1/3O2 synthesized ...

    Indian Academy of Sciences (India)

    Li diffusion; LiNi1/3Co1/3Mn1/3O2; lithium ion batteries; layered structure. 1. Introduction ... The coin-type cell CR2012 consisting of a metallic- lithium foil anode ... and the polyvinylidenefluoride (PVDF) binder with a mass ratio of 4:1:1 in NMP ...

  18. Layered oxides-LiNi1/3Co1/3Mn1/3O2 as anode electrode for symmetric rechargeable lithium-ion batteries

    Science.gov (United States)

    Wang, Yuesheng; Feng, Zimin; Yang, Shi-Ze; Gagnon, Catherine; Gariépy, Vincent; Laul, Dharminder; Zhu, Wen; Veillette, René; Trudeau, Michel L.; Guerfi, Abdelbast; Zaghib, Karim

    2018-02-01

    High-performance and long-cycling rechargeable lithium-ion batteries have been in steadily increasing demand for the past decades. Nevertheless, the two dominant anodes at the moment, graphite and L4T5O12, suffer from a safety issue of lithium plating (operating voltage at ∼ 0.1 V vs. Li+/Li) and low capacity (175 mAh/g), respectively. Here, we report LiNi1/3Co1/3Mn1/3O2 as an alternative anode material which has a working voltage of ∼1.1 V and a capacity as high as 330 mAh/g at the current rate of C/15. Symmetric cells with both electrodes containing LiNi1/3Co1/3Mn1/3O2 can deliver average discharge voltage of 2.2 V. In-situ XRD, HRTEM and first principles calculations indicate that the reaction mechanism of a LiNi1/3Co1/3Mn1/3O2 anode is comprised mainly of conversion. Both the fundamental understanding and practical demonstrations suggest that LiNi1/3Co1/3Mn1/3O2 is a promising negative electrode material for lithium-ion batteries.

  19. Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis.

    Science.gov (United States)

    Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar; Mali, Raghuveer Singh; Martin, Holly; Kobayashi, Michihiro; Vemula, Sasidhar; Canela, Victor H; Waskow, Emily R; Visconte, Valeria; Tiu, Ramon V; Smith, Catherine C; Shah, Neil; Bunting, Kevin D; Boswell, H Scott; Liu, Yan; Chan, Rebecca J; Kapur, Reuben

    2014-11-20

    Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Structural and thermal stabilities of layered Li(Ni 1/3Co 1/3Mn 1/3)O 2 materials in 18650 high power batteries

    Science.gov (United States)

    He, Yan-Bing; Ning, Feng; Yang, Quan-Hong; Song, Quan-Sheng; Li, Baohua; Su, Fangyuan; Du, Hongda; Tang, Zhi-Yuan; Kang, Feiyu

    The structural and thermal stabilities of the layered Li(Ni 1/3Co 1/3Mn 1/3)O 2 cathode materials under high rate cycling and abusive conditions are investigated using the commercial 18650 Li(Ni 1/3Co 1/3Mn 1/3)O 2/graphite high power batteries. The Li(Ni 1/3Co 1/3Mn 1/3)O 2 materials maintain their layered structure even when the power batteries are subjected to 200 cycles with 10 C discharge rate at temperatures of 25 and 50 °C, whereas their microstructure undergoes obvious distortion, which leads to the relatively poor cycling performance of power batteries at high charge/discharge rates and working temperature. Under abusive conditions, the increase in the battery temperature during overcharge is attributed to both the reactions of electrolyte solvents with overcharged graphite anode and Li(Ni 1/3Co 1/3Mn 1/3)O 2 cathode and the Joule heat that results from the great increase in the total resistance (R cell) of batteries. The reactions of fully charged Li(Ni 1/3Co 1/3Mn 1/3)O 2 cathodes and graphite anodes with electrolyte cannot be activated during short current test in the fully charged batteries. However, these reactions occur at around 140 °C in the fully charged batteries during oven test, which is much lower than the temperature of about 240 °C required for the reactions outside batteries.

  1. Thermochemistry of 1,1,3,3-tetramethylguanidine and 1,1,3,3-tetramethylguanidinium nitrate

    International Nuclear Information System (INIS)

    Vitorino, Joana; Agapito, Filipe; Piedade, M. Fátima M.; Bernardes, Carlos E.S.; Diogo, Hermínio P.; Leal, João P.

    2014-01-01

    Graphical abstract: - Highlights: • The enthalpy of formation of 1,1,3,3-tetramethylguanidinium nitrate was determined by combustion calorimetry. • The cohesive energy of liquid 1,1,3,3-tetramethylguanidinium nitrate was evaluated. • The crystal structure of 1,1,3,3-tetramethylguanidinium nitrate was determined by single crystal X-ray diffraction. • Δ f H m o (l/g) of 1,1,3,3-tetramethylguanidine (tmg) were obtained by solution and Calvet calorimetry. • Δ f H m o (g) calculated by the W1-F12 procedure was in excellent agreement with the corresponding experimental value. - Abstract: Considerable efforts have recently been made to investigate how the structure of protic ionic liquids determines some of their most important properties for technological applications (e.g. low vapour pressure, conductivity). In contrast, the assessment of cohesive energies (which are also linked to those properties) based on thermodynamic results is still practically unexplored. This problem is addressed here for 1,1,3,3-tetramethylguanidinium nitrate, [Htmg][NO 3 ], through a combination of experimental and computational chemistry results at the reference temperature of 298.15 K. The standard molar enthalpies of formation, Δ f H m o ([Htmg][NO 3 ],cr)=-(311.8±2.3)kJ·mol -1 , and fusion, Δ fus H m o ([Htmg][NO 3 ])=16.2±3.8kJ·mol -1 , of solid 1,1,3,3-tetramethylguanidinium nitrate (form I polymorph) were obtained by combustion and differential scanning calorimetry, respectively. From these results Δ f H m o ([Htmg][NO 3 ],l)=-(295.6±4.4)kJ·mol -1 could be derived. Also determined were the standard molar enthalpies of formation, Δ f H m o (tmg, l)=7.7±2.8kJ·mol -1 , and vaporisation, Δ vap H m o (tmg,l)=50.0±1.2kJ·mol -1 , of 1,1,3,3-tetramethylguanidine, by reaction solution and Calvet-drop microcalorimetry, respectively, leading to Δ f H m o (tmg,g)=57.7±3.0kJ·mol -1 . This result is in excellent agreement with Δ f H m o (tmg,g)=58.4±4.0kJ·mol -1

  2. 2,4,6-Triamino-1,3,5-triazine-1,3-diium aquapentafluoridoaluminate

    Directory of Open Access Journals (Sweden)

    V. Maisonneuve

    2008-04-01

    Full Text Available The title compound, (C3H8N6[AlF5(H2O], was obtained by solvothermal synthesis from the reaction of aluminium hydroxide, 1,3,5-triazine-2,4,6-triamine (melamine, aqueous HF and water at 323 K for 48 h. The structure consists of [AlF5(H2O]2− octahedra and diprotonated melaminium cations. Cohesion is ensured by a three-dimensional network of hydrogen bonds.

  3. Preparation of layered oxide Li(Co1/3Ni1/3Mn1/3)O2 via the sol-gel process

    Institute of Scientific and Technical Information of China (English)

    ZHANG Wen; LIU Hanxing; HU Chen; ZHU Xianjun; LI Yanxi

    2008-01-01

    To obtain homogenous layered oxide Li(Co1/3Ni1/3Ni1/3Mn1/3)O2 as a lithium insertion positive electrode material,the sol-gel process using citric acid as a chelating agent was applied.The material Li(Co1/3,Ni1/3Mn1/3)O2 was synthesized at different calcination temperatures.XRD experiment indicated that the hyered Li(Co1/3Ni1/3Mn1/3)O2material could he synthesized at a lower temperature of 800℃,and the oxidation state of Co,Ni,and Mn in the cathode confirmed by XPS were +3,+2,and +4,respectively.SEM observations showed that the synthesized material could form homogenous particle morphology with the particle size of about 200nm In spite of different calcination temperatures,the charge-discharge curves of all the samples for the initial cycle were similar,and the cathode synthesized at 900℃ showed a small irreversible capacity loss of 11.24% and a high discharge capacity of 212.2 mAh.g-1 in the voltage range of 2.9-4.6 V.

  4. Water quality criteria for hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

    Energy Technology Data Exchange (ETDEWEB)

    Etnier, E.L.

    1989-04-01

    The occurrence of the munitions compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in groundwater surrounding Army ammunition plants may result in contamination of local drinking water supplies. RDX exerts its primary toxic effect in humans on the central nervous system, but also involves gastrointestinal and renal effects. Symptomatic effects following acute exposure include hyperirritability, nausea, vomiting, generalized epileptiform seizures, and prolonged postictal confusion and amnesia. Health effects data were analyzed for RDX, and although no controlled human studies exist concerning the acute or chronic toxic effects of exposure to RDX, sufficient animal toxicity data are available to derive an ambient water quality criterion for the protection of human health. This paper summarizes the available literature on metabolism of RDX and human and animal toxicity. Based on noncarcinogenic mammalian toxicity data, and following the methodologies of the U.S. Environmental Protection Agency, an ambient water quality criterion for the protection of human health of 103 micrograms/liter is proposed for ingestion of drinking water and aquatic foodstuffs. A criterion of 105 micrograms/liter is proposed for ingestion of drinking water alone.54 references.

  5. Importância da detecção das mutações no gene FLT3 e no gene NPM1 na leucemia mieloide aguda - Classificação da Organização Mundial de Saúde 2008 Importance of detecting FLT3 and NPM1 gene mutations in acute myeloid leukemia -World Health Organization Classification 2008

    Directory of Open Access Journals (Sweden)

    Marley Aparecida Licínio

    2010-01-01

    Full Text Available As leucemias mieloides agudas (LMA constituem um grupo de neoplasias malignas caracterizadas pela proliferação descontrolada de células hematopoéticas, decorrente de mutações que podem ocorrer em diferentes fases da diferenciação de células precursoras mieloides. Em 2008, a Organização Mundial da Saúde (OMS-2008 publicou uma nova classificação para neoplasias do sistema hematopoético e linfoide. De acordo com essa classificação, para um diagnóstico mais preciso e estratificação de prognóstico de pacientes com leucemias mieloides agudas, devem-se pesquisar mutações nos genes FLT3 e NPM1. Sabe-se que a presença de mutações no gene FLT3 é de prognóstico desfavorável e que as mutações no gene NPM1 do tipo A são de prognóstico favorável. Assim, nos países desenvolvidos, a análise das mutações no gene FLT3 e NPM1 tem sido considerada como um fator de prognóstico importante na decisão terapêutica em pacientes com diagnóstico de leucemias mieloides agudas. Considerando essas informações, é de extrema importância a análise das mutações no gene FLT3 (duplicação interna em tandem - DIT - e mutação pontual D835 e no gene NPM1 como marcadores moleculares para o diagnóstico, o prognóstico e a monitoração de doença residual mínima em pacientes com leucemias mieloides agudas.Acute myeloid leukemia (AML is a group of malignancies characterized by uncontrolled proliferation of hematopoietic cells resulting from mutations that occur at different stages in the differentiation of myeloid precursor cells. In 2008, the World Health Organization (WHO-2008 published a new classification for cancers of the hematopoietic and lymphoid system. According to this classification, FLT3 and NPM1 gene mutations should be investigated for a more precise diagnosis and prognostic stratification of AML patients. It is well known that the presence of FLT3 gene mutations is considered an unfavorable prognostic factor and type

  6. Hydrothermal synthesis of layered Li[Ni1/3Co1/3Mn1/3]O2 as positive electrode material for lithium secondary battery

    International Nuclear Information System (INIS)

    Myung, Seung-Taek; Lee, Myung-Hun; Komaba, Shinichi; Kumagai, Naoaki; Sun, Yang-Kook

    2005-01-01

    In attempts to prepare layered Li[Ni 1/3 Co 1/3 Mn 1/3 ]O 2 , hydrothermal method was employed. The hydrothermal precursor, [Ni 1/3 Co 1/3 Mn 1/3 ](OH) 2 , was synthesized via a coprecipitation route. The sphere-shaped powder precursor was hydrothermally reacted with LiOH aqueous solution at 170 deg. C for 4 days in autoclave. From X-ray diffraction and scanning electron microscopic studies, it was found that the as-hydrothermally prepared powders were crystallized to layered α-NaFeO 2 structure and the particles had spherical shape. The as-prepared Li[Ni 1/3 Co 1/3 Mn 1/3 ]O 2 delivered an initial discharge of about 110 mA h g -1 due to lower crystallinity. Heat treatment of the hydrothermal product at 800 deg. C was significantly effective to improve the structural integrity, which consequently affected the increase in the discharge capacity to 157 (4.3 V cut-off) and 182 mA h g -1 (4.6 V cut-off) at 25 deg. C with good reversibility

  7. Analysis of 3-MCPD and 1,3-DCP in Various Foodstuffs Using GC-MS

    OpenAIRE

    Kim, Wooseok; Jeong, Yun A; On, Jiwon; Choi, Ari; Lee, Jee-yeon; Lee, Joon Goo; Lee, Kwang-Geun; Pyo, Heesoo

    2015-01-01

    3-Monochloro-1,2-propanediol (3-MCPD) and 1,3-dichloro-2-propanol (1,3-DCP) are not only produced in the manufacturing process of foodstuffs such as hydrolyzed vegetable proteins and soy sauce but are also formed by heat processing in the presence of fat and low water activity. 3-MCPD exists both in free and ester forms, and the ester form has been also detected in various foods. Free 3-MCPD and 1,3-DCP are classified as Group 2B by the International Agency for Research on Cancer. Although th...

  8. Roles of some antioxidants in modulation of cardiac myopathy induced by sodium nitrite via down-regulation of mRNA expression of NF-κB, Bax, and flt-1 and suppressing DNA damage

    Directory of Open Access Journals (Sweden)

    Laila Mohamed Fadda

    2018-02-01

    Full Text Available The underlying pathology of cardiac damage involves various molecular and signaling pathways. Therefore, this study aimed to explore the role of Quercetin (Querc, alone or in combination with Melatonin (Melat against cardiac damage induced by sodium nitrite (Sod nit, as well as to elucidate different signaling pathways. Querc and Melat were injected intraperitoneally (i.p., followed by induction of hypoxia in rats by using a single dose of Sod nit (60 mg/kg, s.c.. Treatment with Sod nit significantly decreased hemoglobin (Hb levels in blood. Pretreatment of hypoxic rats with Querc and/or Melat elevated the declined Hb concentration. The forementioned antioxidants also successfully ameliorated the alteration of heat shock protein 70 (HSP-70 and markers of cardiac injury, including troponin T (Trop. T, creatine kinase-MB (CK-MB, tumor necrosis factor-α (TNF α, and C-reactive protein (CRP in the rats serum. Furthermore, RT-PCR revealed that these antioxidants successfully modulated mRNA expression of NF-κB, Bax, Bcl-2, and flt-1. They also regulated vascular endothelial growth factor (VEGF, the apoptosis marker caspase 3, and oxidative DNA damage in cardiac tissue, compared to Sod nit-intoxicated rats. The present biochemical results are reinforced by histopathological examination. In Conclusion: The results reflected that treatment with Querc in combination with Melat was most effective in improving Sod nit-toxicity induced cardiac damage, thus confirming the promising role of this combination as an effective treatment for cardiac damage induced by other cardio-toxic agents.

  9. Evaluation of {sup 18}F-FDG and {sup 18}F-FLT for monitoring therapeutic responses of colorectal cancer cells to radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hui [Nuclear Medicine Department, The General Hospital of the Chinese People' s Liberation Army and Military Medical Postgraduate College, Beijing 100853 (China); Liu, Bo [Department of Hepatobiliary Surgery, The General Hospital of the Chinese People' s Liberation Army and Military Medical Postgraduate College, Beijing 100853 (China); Tian, Jiahe, E-mail: tianjh@vip.sina.com [Nuclear Medicine Department, The General Hospital of the Chinese People' s Liberation Army and Military Medical Postgraduate College, Beijing 100853 (China); Xu, Baixuan; Zhang, Jinming [Nuclear Medicine Department, The General Hospital of the Chinese People' s Liberation Army and Military Medical Postgraduate College, Beijing 100853 (China); Qu, Baolin [Department of Radiation Oncology, The General Hospital of the Chinese People' s Liberation Army and Military Medical Postgraduate College, Beijing 100853 (China); Chen, Yingmao [Nuclear Medicine Department, The General Hospital of the Chinese People' s Liberation Army and Military Medical Postgraduate College, Beijing 100853 (China)

    2013-09-15

    In order to compare the efficacy of {sup 18}F-fluorothymidine (FLT) and {sup 18}F-fluorodeoxyglucose (FDG) for monitoring early responses to irradiation, two human colorectal cancer (CRC) cell lines SW480 and SW620, which were derived from the primary lesions and the metastatic lymph node, underwent X-ray irradiation of 0, 10, or 20 Gy and were examined at 0, 24 and 72 h After irradiation, reduced proliferation of both SW480 and SW620 cells was observed in a dose-dependent manner (P < 0.001), G0-G1 arrest was also noted in both cell types after 72 h in the 20 Gy group (P < 0.001). Although increased apoptosis was observed in both cell lines after irradiation (P < 0.001), a greater percentage of SW480 cells underwent apoptosis in response to irradiation than SW620 cells. Increased Hsp27 and decreased integrin β{sub 3}, Ki67 and VEGFR2 expression was observed over time via immunocytochemistry and Western blot analysis (P < 0.001), however, no significant changes were noted in response to irradiation. Finally, reduced uptake of {sup 18}F-FLT by SW480 or SW620 cells was observed at 24-h post-irradiation, however, reduced {sup 18}F-FDG uptake was only observed after 72 h. Therefore, we conclude that {sup 18}F-FLT is a more suitable positron emission tomography (PET) tracer for monitoring early responses to irradiation in primary and metastatic lymph node CRC cells.

  10. Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging.

    Science.gov (United States)

    Tamura, Yasuhisa; Takahashi, Kayo; Takata, Kumi; Eguchi, Asami; Yamato, Masanori; Kume, Satoshi; Nakano, Masayuki; Watanabe, Yasuyoshi; Kataoka, Yosky

    2016-08-03

    Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [(18)F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [(18)F]FLT combined with probenecid, an inhibitor of drug transporters at the blood-brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [(18)F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment. Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of

  11. Phosphatidylinositol 3-kinase is essential for kit ligand-mediated survival, whereas interleukin-3 and flt3 ligand induce expression of antiapoptotic Bcl-2 family genes

    DEFF Research Database (Denmark)

    Karlsson, Richard; Engström, Maria; Jönsson, Maria

    2003-01-01

    Cytokines such as interleukin 3 (IL-3), kit ligand (KL), and flt3 ligand (FL) promote survival of hematopoietic stem cells and myeloid progenitor cells. In many cell types, members of the Bcl-2 gene family are major regulators of survival, but the mediating mechanisms are not fully understood....... Using two myeloid progenitor cell lines, FDCP-mix and FDC-P1, as well as primary mouse bone marrow progenitors, we demonstrate that KL-mediated survival is dependent on the activation of phosphatidylinositol-3 (PI-3) kinase. The inhibitor LY294002 was able to completely abolish survival mediated by KL...

  12. Mapping Radiation Injury and Recovery in Bone Marrow Using 18F-FLT PET/CT and USPIO MRI in a Rat Model.

    Science.gov (United States)

    Rendon, David A; Kotedia, Khushali; Afshar, Solmaz F; Punia, Jyotinder N; Sabek, Omaima M; Shirkey, Beverly A; Zawaski, Janice A; Gaber, M Waleed

    2016-02-01

    We present and test the use of multimodality imaging as a topological tool to map the amount of the body exposed to ionizing radiation and the location of exposure, which are important indicators of survival and recovery. To achieve our goal, PET/CT imaging with 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was used to measure cellular proliferation in bone marrow (BM), whereas MRI using ultra-small superparamagnetic iron oxide (USPIO) particles provided noninvasive information on radiation-induced vascular damage. Animals were x-ray-irradiated at a dose of 7.5 Gy with 1 of 3 radiation schemes-whole-body irradiation, half-body shielding (HBS), or 1-leg shielding (1LS)-and imaged repeatedly. The spatial information from the CT scan was used to segment the region corresponding to BM from the PET scan using algorithms developed in-house, allowing for quantification of proliferating cells, and BM blood volume was estimated by measuring the changes in the T2 relaxation rates (ΔR2) collected from MR scans. (18)F-FLT PET/CT imaging differentiated irradiated from unirradiated BM regions. Two days after irradiation, proliferation of 1LS animals was significantly lower than sham (P = 0.0001, femurs; P < 0.0001, tibias) and returned to sham levels by day 10 (P = 0.6344, femurs; P = 0.3962, tibias). The degree of shielding affected proliferation recovery, showing an increase in the irradiated BM of the femurs, but not the tibias, of HBS animals when compared with 1LS (P = 0.0310, femurs; P = 0.5832, tibias). MRI of irradiated spines detected radiation-induced BM vascular damage, measured by the significant increase in ΔR2 2 d after whole-body irradiation (P = 0.0022) and HBS (P = 0.0003) with a decreasing trend of values, returning to levels close to baseline over 10 d. Our data were corroborated using γ-counting and histopathology. We demonstrated that (18)F-FLT PET/CT and USPIO MRI are valuable tools in mapping regional radiation exposure and the effects of radiation on

  13. San Diego, California 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second San Diego, California Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is...

  14. Newport, Oregon 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second Newport, Oregon Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is...

  15. Hilo, Hawaii 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second Hilo, Hawaii Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is strictly...

  16. Four experimental stimulants found in sports and weight loss supplements: 2-amino-6-methylheptane (octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA).

    OpenAIRE

    Cohen, Pieter A; Travis, John C; Keizers, Peter H J; Deuster, Patricia; Venhuis, Bastiaan J

    2017-01-01

    The United States Food and Drug Administration banned the stimulant 1,3-dimethylamylamine (1,3-DMAA) from dietary supplements and warned consumers that the stimulant can pose cardiovascular risks ranging from high blood pressure to heart attacks.

  17. Southwestern Washington 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second Southwest Washington Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is...

  18. Seaside, Oregon 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second Seaside Oregon Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is...

  19. Nawiliwili, Hawaii 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second Nawiliwili Hawaii Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is...

  20. Guam 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second Guam Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is strictly for...

  1. Relationships between tobacco leaf δ"1"3C and physiological characteristics

    International Nuclear Information System (INIS)

    Wang Yi; Song Pengfei; Yan Kan; Tan Shuwen; Wu Xiaoxiao; Chen Zongyu

    2013-01-01

    In this paper, the flue-cured tobacco K326 was employed to study the abundance of carbon isotope composition, photosynthetic pigment content, soluble protein content and leaf mass per area (LMA) of tobacco leaf which were grown at four testing sites of different altitude (T_1, T_2, T_3, T_4). The correlations of carbon isotope composition with altitude, leaf position and physiological measures were understood as well. Results showed that δ"1"3C of those samples varied from -27.4‰ to -23.4‰. The δ"1"3C of samples from T_1, T_2and T_3 were increased with rising of the leaf position. δ"1"3C of middle and upper leaves from T_1, T_2and T_3 were positively correlated with altitude. However, δ"1"3C of samples from T_4 ranging from -26.8‰ to -26.4‰ was lower than the values from previous samples. The δ"1"3C also decreased with the increasing of leaf position, and was significantly negatively correlated with chlorophyll content and chlorophyll/carotinoid ratio (P < 0.05). The δ"1"3C was not significantly correlated with carotinoid content and chlorophyll a/b ratio. Meanwhile, it was positively correlated with soluble protein content and LMA significantly (P < 0.01). Generally, our findings indicated that chlorophyll content, chlorophyll/carotenoid ratio, soluble protein content, and LMA had strong relationships with δ"1"3C, whereas the relationship of δ"1"3C with altitude and leaf position was still unclear. (authors)

  2. Direct, Regioselective N-Alkylation of 1,3-Azoles.

    Science.gov (United States)

    Chen, Shuai; Graceffa, Russell F; Boezio, Alessandro A

    2016-01-04

    Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.

  3. Distribution of Proliferating Bone Marrow in Adult Cancer Patients Determined Using FLT-PET Imaging

    International Nuclear Information System (INIS)

    Hayman, James A.; Callahan, Jason W.; Herschtal, Alan; Everitt, Sarah; Binns, David S.; Hicks, Rod J.; Mac Manus, Michael

    2011-01-01

    Purpose: Given that proliferating hematopoietic stem cells are especially radiosensitive, the bone marrow is a potential organ at risk, particularly with the use of concurrent chemotherapy and radiotherapy. Existing data on bone marrow distribution have been determined from the weight and visual appearance of the marrow in cadavers. 18 F-fluoro-L-deoxythymidine concentrates in bone marrow, and we used its intensity on positron emission tomography imaging to quantify the location of the proliferating bone marrow. Methods and Materials: The 18 F-fluoro-L-deoxythymidine positron emission/computed tomography scans performed at the Peter MacCallum Cancer Centre between 2006 and 2009 on adult cancer patients were analyzed. At a minimum, the scans included the mid-skull through the proximal femurs. A software program developed at our institution was used to calculate the percentage of administered activity in 11 separately defined bony regions. Results: The study population consisted of 13 patients, 6 of whom were men. Their median age was 61 years. Of the 13 patients, 9 had lung cancer, 2 had colon cancer, and 1 each had melanoma and leiomyosarcoma; 6 had received previous, but not recent, chemotherapy. The mean percentage of proliferating bone marrow by anatomic site was 2.9% ± 2.1% at the skull, 1.9% ± 1.2% at the proximal humeri, 2.9% ± 1.3% at the sternum, 8.8% ± 4.7% at the ribs and clavicles, 3.8% ± 0.9% at the scapulas, 4.3% ± 1.6% at the cervical spine, 19.9% ± 2.6% at the thoracic spine, 16.6% ± 2.2% at the lumbar spine, 9.2% ± 2.3% at the sacrum, 25.3% ± 4.9% at the pelvis, and 4.5% ± 2.5% at the proximal femurs. Conclusion: Our modern estimates of bone marrow distribution in actual cancer patients using molecular imaging of the proliferating marrow provide updated data for optimizing normal tissue sparing during external beam radiotherapy planning.

  4. Synthesis and characterization of "1"3C_3-tristearin

    International Nuclear Information System (INIS)

    Wu Hangyu; Lin Lin; Li Lei; Chen Dazhou

    2011-01-01

    A highly efficient synthesis of "1"3C_3 labeled triglycerides of stearic acids from "1"3C_3-glycerol and stearic acids, by immobilized lipase-catalyzed in solvent-free medium was described. The structure of the product were characterized by fourier transform infrared spectrum (FT-IR), nuclear magnetic resonance (NMR), mass spectra (MS). The results showed that triglycerides of stearic acids contained three "1"3C atoms. The isotope abundance of "1"3C_3-tristearin was more than 99% and the yield was 80% of "1"3C_3-tristearin through calculation. Chemical purity (> 98%) was obtained by differential scanning calorimetry (DSC). (authors)

  5. Novel 1,3-dioxanes from apple juice and cider.

    Science.gov (United States)

    Kavvadias, D; Beuerle, T; Wein, M; Boss, B; König, T; Schwab, W

    1999-12-01

    Extracts obtained by XAD solid-phase extraction of apple juice and cider were separated by liquid chromatography on silica gel. Several new 1,3-dioxanes including the known 2-methyl-4-pentyl-1,3-dioxane and 2-methyl-4-[2'(Z)-pentenyl]-1,3-dioxane, were identified in the nonpolar fractions by GC/MS analysis and confirmed by chemical synthesis. The enantioselective synthesis of the stereoisomers of the 1,3-dioxanes was performed using (R)- and (R,S)-octane-1,3-diol and (R)- and (R,S)-5(Z)-octene-1,3-diol as starting material. Comparison with the isolated products indicated that the natural products consisted of a mixture of (2S,4R) and (2R,4R) stereoisomers in the ratio of approximately 10:1, except for 1,3-dioxanes generated from acetone and 2-butanone. It is assumed that the 1, 3-dioxanes are chemically formed in the apples and cider from the natural apple ingredients (R)-octane-1,3-diol, (R)-5(Z)-octene-1, 3-diol, (3R,7R)- and (3R,7S)-octane-1,3,7-triol, and the appropriate aldehydes and ketones, which are produced either by the apples or by yeast during fermentation of the apple juice.

  6. Italian Advisory Board: sFlt-1/PlGF ratio and preeclampsia, state of the art and developments in diagnostic, therapeutic and clinical management.

    Science.gov (United States)

    Di Martino, Daniela; Cetin, Irene; Frusca, Tiziana; Ferrazzi, Enrico; Fuse', Federica; Gervasi, Maria Teresa; Plebani, Mario; Todros, Tullia

    2016-11-01

    Extensive research has been published, showing the usefulness of angiogenic markers in both diagnosis and subsequent prediction and management of preeclampsia and placenta-related disorders. Recent evidence provides a helpful cut off for the Elecsys ratio sFlt-1 to PlGF, that predicts preeclampsia development in women with sign and symptoms, before its clinical onset in the short term. In Europe, no accordance exists for the use of such kind of test in clinical practice; only German guidelines have recently taken it into account, as a diagnostic aid for preeclampsia, in conjunction with other clinical findings. This panel of Italian experts recently met, in order to review the literature and to promote the evaluation of the clinical utility of sFlt-1/PlGF ratio at the Italian country level, as regards: prediction of preeclampsia during the first trimester, prediction or exclusion of new onset or recurrence in patients with risk factors for preeclampsia, triage of patients suffering from gestational hypertension, evaluation of disease severity, prediction of adverse maternal and fetal outcomes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Rapid Exercise-Induced Mobilization of Dendritic Cells Is Potentially Mediated by a Flt3L- and MMP-9-Dependent Process in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Nathalie Deckx

    2015-01-01

    Full Text Available In healthy individuals, one exercise bout induces a substantial increase in the number of circulating leukocytes, while their function is transiently suppressed. The effect of one exercise bout in multiple sclerosis (MS is less studied. Since recent evidence suggests a role of dendritic cells (DC in the pathogenesis of MS, we investigated the effect of one combined endurance/resistance exercise bout on the number and function of DC in MS patients and healthy controls. Our results show a rapid increase in the number of DC in response to physical exercise in both MS patients and controls. Further investigation revealed that in particular DC expressing the migratory molecules CCR5 and CD62L were increased upon acute physical activity. This may be mediated by Flt3L- and MMP-9-dependent mobilization of DC, as demonstrated by increased circulating levels of Flt3L and MMP-9 following one exercise bout. Circulating DC display reduced TLR responsiveness after acute exercise, as evidenced by a less pronounced upregulation of activation markers, HLA-DR and CD86, on plasmacytoid DC and conventional DC, respectively. Our results indicate mobilization of DC, which may be less prone to drive inflammatory processes, following exercise. This may present a negative feedback mechanism for exercise-induced tissue damage and inflammation.

  8. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain.

    Science.gov (United States)

    Anandasabapathy, Niroshana; Victora, Gabriel D; Meredith, Matthew; Feder, Rachel; Dong, Baojun; Kluger, Courtney; Yao, Kaihui; Dustin, Michael L; Nussenzweig, Michel C; Steinman, Ralph M; Liu, Kang

    2011-08-01

    Antigen-presenting cells in the disease-free brain have been identified primarily by expression of antigens such as CD11b, CD11c, and MHC II, which can be shared by dendritic cells (DCs), microglia, and monocytes. In this study, starting with the criterion of Flt3 (FMS-like receptor tyrosine kinase 3)-dependent development, we characterize the features of authentic DCs within the meninges and choroid plexus in healthy mouse brains. Analyses of morphology, gene expression, and antigen-presenting function established a close relationship between meningeal and choroid plexus DCs (m/chDCs) and spleen DCs. DCs in both sites shared an intrinsic requirement for Flt3 ligand. Microarrays revealed differences in expression of transcripts encoding surface molecules, transcription factors, pattern recognition receptors, and other genes in m/chDCs compared with monocytes and microglia. Migrating pre-DC progenitors from bone marrow gave rise to m/chDCs that had a 5-7-d half-life. In contrast to microglia, DCs actively present self-antigens and stimulate T cells. Therefore, the meninges and choroid plexus of a steady-state brain contain DCs that derive from local precursors and exhibit a differentiation and antigen-presenting program similar to spleen DCs and distinct from microglia.

  9. Hydrogenolysis of 2-tosyloxy-1,3-propanediol into 1,3-propanediol over Raney Ni catalyst

    Energy Technology Data Exchange (ETDEWEB)

    Zhi, Zheng; Jianli, Wang; Zhen, Lu; Min, Luo; Miao, Zhang; Lixin, Xu; Jianbing [Zhejiang Province Key Laboratory of Biofuel, The State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou (China)

    2013-03-15

    2-Tosyloxy-1,3-propanediol (TPD), a potential precursor for 1,3-propanediol (1,3-PD) production, is produced by the tosylation of glycerol with the help of protecting group techniques. In this work, the hydrogenolysis of TPD into 1,3-PD over Raney Ni catalyst is discussed at different reaction parameters to optimize the reaction conditions for selective formation of 1,3-PD. The mechanisms of the hydrogenolysis of TPD and the side reactions were also confirmed by gas chromatography-mass spectrometry (GC-MS) technique (author)

  10. Local atomic characterization of LiCo1/3Ni1/3Mn1/3O2 cathode material

    International Nuclear Information System (INIS)

    Nedoseykina, Tatiana; Kim, Sung-Soo; Nitta, Yoshiaki

    2006-01-01

    Co, Ni and Mn K-edge XAFS investigation of LiCo 1/3 Ni 1/3 Mn 1/3 O 2 as alternative cathode material to commercially used LiCoO 2 in lithium rechargeable battery has been performed. Parameters of a local atomic structure such as radii of metal-oxygen and metal-metal coordination shells and disorder in those shells have been determined. It has been found that the radius of the first coordination shell (metal-oxygen) as well as a local disorder in the second shell (metal-metal) around each of the 3d-metals are in a good agreement with obtained for superlattice model of √3 x √3] R30 o type in triangular lattice of sites by first principle calculation. Other parameters of the local atomic structure around Co, Ni and Mn atoms do not provide evidence for presence of superstructure in LiCo 1/3 Ni 1/3 Mn 1/3 O 2

  11. Inhibiting trophoblast PAR-1 overexpression suppresses sFlt-1-induced anti-angiogenesis and abnormal vascular remodeling: a possible therapeutic approach for preeclampsia.

    Science.gov (United States)

    Zhao, Yin; Zheng, YanFang; Liu, XiaoXia; Luo, QingQing; Wu, Di; Liu, XiaoPing; Zou, Li

    2018-03-01

    Is it possible to improve vascular remodeling by inhibiting the excessive expression of protease-activated receptor 1 (PAR-1) in trophoblast of abnormal placenta? Inhibition of trophoblast PAR-1 overexpression may promote placental angiogenesis and vascular remodeling, offering an alternative therapeutic approach for preeclampsia. PAR-1 is high-affinity receptor of thrombin. Thrombin increases sFlt-1 secretion in trophoblast via the activation of PAR-1. It is reported that the expression of both thrombin and PAR-1 expression are increased in placentas of preeclampsia patients compared with normal placentas. Trophoblast cells were transfected with PAR-1 short hairpin RNA (shRNA) or PAR-1 overexpression plasmids in vitro. Tube formation assays and a villus-decidua co-culture system were used to study the effect of PAR-1 inhibition on placental angiogenesis and vascular remodeling, respectively. Placentas from rats with preeclampsia were transfected with PAR-1 shRNA to confirm the effect of inhibiting PAR-1 overexpression in placenta. The trophoblast cell line HTR-8/SVneo was transfected with PAR-1 shRNA or PAR-1 overexpression plasmids. After 48 h, supernatant was collected and the level of sFlt-1 secretion was measured by ELISA. Human umbilical cord epithelial cells and a villus-decidua co-culture system were treated with conditioned media to study the effect of PAR-1 inhibition on tube formation and villi vascular remodeling. A preeclampsia rat model was established by intraperitoneal injection of L-NAME. Plasmids were injected into the placenta of the preeclampsia rats and systolic blood pressure was measured on Days 15 and 19. The effect of different treatments was evaluated by proteinuria, placental weights, fetal weights and fetal numbers in study and control groups. The level of serum sFlt-1 in rats with preeclampsia was also measured. Changes in the placenta microvessels were studied by histopathological staining. PAR-1 shRNA inhibited PAR-1 expression and

  12. Four experimental stimulants found in sports and weight loss supplements: 2-amino-6-methylheptane (octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA).

    Science.gov (United States)

    Cohen, Pieter A; Travis, John C; Keizers, Peter H J; Deuster, Patricia; Venhuis, Bastiaan J

    2017-11-08

    The United States Food and Drug Administration banned the stimulant 1,3-dimethylamylamine (1,3-DMAA) from dietary supplements and warned consumers that the stimulant can pose cardiovascular risks ranging from high blood pressure to heart attacks. We designed our study to determine if a new stimulant similar in structure to 1,3-DMAA has been introduced as an ingredient in supplements sold in the United States (US). We analyzed six brands of supplements that listed an ingredient on the label (e.g., Aconitum kusnezoffii, DMHA or 2-amino-isoheptane) that might refer to an analog of 1,3-DMAA. Supplements were analyzed by two separate laboratories using ultra-high-performance liquid chromatography mass spectrometry and reference standards. Two previously unidentified 1,3-DMAA analogs (2-amino-6-methylheptane [octodrine] and 1,4-dimethylamylamine [1,4-DMAA]) and two banned stimulants (1,3-DMAA and 1,3-dimethylbutylamine [1,3-DMBA]) were identified. Octodrine was found at a dose (±95% CI) of 72 ± 7.5 mg per serving. In Europe, octodrine was previously sold as a pharmaceutical in multi-ingredient medications at dosages from 8 to 33 mg. The quantity of octodrine found in our study was more than twice the largest pharmaceutical dose. The other new stimulant, 1,4-DMAA, has not previously been approved for human consumption, and its safety in humans is unknown. 1,4-DMAA was found at dosages between 21 ± 11 mg to 94 ± 48 mg per serving. In addition, two banned stimulants - 1,3-DMAA and 1,3-DMBA - were also identified: 24 ± 7.6 mg to 35 ± 11 mg of 1,3-DMAA and 51 ± 16 mg of 1,3-DMBA. In one product, 24 ± 7.6 mg of 1,3-DMAA was combined with 21 ± 11 mg of 1,4-DMAA. 1,3-DMAA has been investigated as potentially contributing to hemorrhagic strokes and sudden death, whereas the safety of 1,3-DMBA in humans is unknown. Two banned stimulants (1,3-DMAA and 1,3-DMBA) and two previously unidentified stimulants (1,4-DMAA and

  13. Purification and Characterization of β-1,3-Glucanase from the Antagonistic Fungus Trichoderma reesei

    Directory of Open Access Journals (Sweden)

    SRI WAHYUNI BUDIARTI

    2009-09-01

    Full Text Available Trichoderma enzymes that inhibit fungal cell walls have been suggested to play an important role in mycoparasitic action against fungal root rot pathogen Ganoderma philippii. This experiment was aimed to purify and characterize the β-1,3-glucanase of T. reesei. Extracellular β-1,3-glucanase was produced by growing mycoparasite T. reesei isolate T13 in colloidal chitin and sucrose as carbon sources. The enzyme was then purified to its homogeneity by precipitation with ammonium sulfate, followed by gel filtration chromatography and chromatofocusing. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE 12% was used to confirm the purity of enzyme at each stage of preparation and to characterize purified protein. The results showed that T. reesei produced at least three extracellular β-1,3-glucanases. Estimation of molecular weight based on SDS-PAGE 12% have three isoform of β-1,3-glucanase were 90 kDa for β-1,3-glucanase-I, 75 kDa for β-1,3-glucanase-II, and 64 kDa for β-1,3-glucanase-III. Their optimum pH and temperature were 5 and 50 oC, respectively.

  14. New 4-phosphino-1,3,2-dioxaborinanes

    International Nuclear Information System (INIS)

    Musina, Eh.I.; Nikonov, G.N.; Balueva, A.S.; Litvinov, I.A.

    1999-01-01

    Molecular and crystal structure of bis[(5,6-benzo-2-phenyl-1,3,2-dioxaborinane-4)phenylphosphino]methane are ascertained by the method of X-ray diffraction analysis. Interaction of methyl (phenyl) phosphine and salicyl aldehyde with phenylboric acid ester gives rise to preparation of its monoheterocyclic analog - 4-methyl(phenyl) phosphino-2-phenyl-5,6-benzo-1,3,2-dioxaborinane and its sulfide. It is shown that in the series 4-aryl(alkyl)phosphino 1,3,2-dioxaborinanes no stacking-conformations realized for 4-diarylphosphino-1,3,2-dioxaboraphosphorinanes are observed [ru

  15. A pilot study for texture analysis of {sup 18}F-FDG and {sup 18}F-FLT-PET/CT to predict tumor recurrence of patients with colorectal cancer who received surgery

    Energy Technology Data Exchange (ETDEWEB)

    Nakajo, Masatoyo; Tani, Atsushi; Jinguji, Megumi; Yoshiura, Takashi [Kagoshima University, Department of Radiology, Graduate School of Medical and Dental Sciences, Kagoshima (Japan); Kajiya, Yoriko; Nakajo, Masayuki [Nanpuh Hospital, Department of Radiology, Kagoshima (Japan); Kitazono, Masaki [Nanpuh Hospital, Department of Surgery, Kagoshima (Japan)

    2017-12-15

    This retrospective study was done to examine whether the heterogeneity in primary tumor F-18-fluorodeoxyglucose ({sup 18}F-FDG) and {sup 18}F-3'-fluoro-3'-deoxythymidine ({sup 18}F-FLT) distribution can predict prognosis of patients with colorectal cancer who received surgery. The enrolled 32 patients with colorectal cancer underwent both {sup 18}F-FDG- and {sup 18}F-FLT-PET/CT studies before surgery. Clinicopathological factors, stage, SUVmax, SUVmean, metabolic tumor volume (SUV ≥ 2.5), total lesion glycolysis, total lesion proliferation and seven texture heterogeneity parameters (coefficient of variation, local parameters: entropy, homogeneity, and dissimilarity; and regional parameters: intensity variability [IV], size-zone variability [SZV], and zone percentage [ZP]) were obtained. Progression free survival (PFS) was calculated by the Kaplan-Meier method. Prognostic significance was assessed by Cox proportional hazards analysis. Eight patients had eventually come to progression, and 24 patients were alive without progression during clinical follow-up [mean follow-up PFS; 55.9 months (range, 1-72)]. High stage (p = 0.004), high {sup 18}F-FDG-IV (p = 0.015), high {sup 18}F-FDG-SZV (p = 0.013) and high {sup 18}F-FLT-entropy (p = 0.015) were significant in predicting poor 5-year PFS. Other parameters did not predict the disease outcome. At bivariate analysis, disease event hazards ratios for {sup 18}F-FDG-IV and {sup 18}F-FDG-SZV remained significant when adjusted for stage and {sup 18}F-FLT-entropy ({sup 18}F-FDG-IV; p = 0.004 [adjusted for stage], 0.007 [adjusted for {sup 18}F-FLT-entropy]; {sup 18}F-FDG-SZV; p = 0.028 [adjusted for stage], 0.040 [adjusted for {sup 18}F-FLT-entropy]). {sup 18}F-FDG PET heterogeneity parameters, IV and SZV, have a potential to be strong prognostic factors to predict PFS of patients with surgically resected colorectal cancer and are more useful than {sup 18}F-FLT-PET/CT heterogeneity parameters. (orig.)

  16. Lithium Diffusion and Magnetism in Battery Cathode Material LixNi1/3Co1/3Mn1/3O2

    International Nuclear Information System (INIS)

    Månsson, M; Prša, K; Nozaki, H; Sugiyama, J; Wikberg, J M; Sassa, Y; Dahbi, M; Kamazawa, K; Sedlak, K; Watanabe, I

    2014-01-01

    We have studied low-temperature magnetic properties as well as high-temperature lithium ion diffusion in the battery cathode materials Li x Ni 1/3 Co 1/3 Mn 1/3 O 2 by the use of muon spin rotation/relaxation. Our data reveal that the samples enter into a 2D spin-glass state below T SG ≈ 12 K. We further show that lithium diffusion channels become active for T ≥ T diff ∼ 125 K where the Li-ion hopping-rate [v(T)] starts to increase exponentially. Further, v(T) is found to fit very well to an Arrhenius type equation and the activation energy for the diffusion process is extracted as E a ≈ 100 meV

  17. Mitochondrial ultrastructure and glucose signaling pathways attributed to the Kv1.3 ion channel

    Directory of Open Access Journals (Sweden)

    Christopher P. Kovach

    2016-05-01

    Full Text Available Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3-/- results in ‘Super-smeller’ mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, Golf. Kv1.3-/- mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE, increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4 is co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3 was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT and Kv1.3-/- male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat for 4 months and then examined OB ultrastructure using transmission microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3-/- mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3-/- mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how

  18. 26 CFR 1.3-1 - Application of optional tax.

    Science.gov (United States)

    2010-04-01

    ..., appropriate to his number of exemptions, provided for cases in which a joint return is filed. (c) Use of tax... in the case of a joint return (including the return of a surviving spouse) and lesser income... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Application of optional tax. 1.3-1 Section 1.3-1...

  19. Solar wind oscillations with a 1.3 year period

    Science.gov (United States)

    Richardson, John D.; Paularena, Karolen I.; Belcher, John W.; Lazarus, Alan J.

    1994-01-01

    The Interplanetary Monitoring Platform 8 (IMP-8) and Voyager 2 spacecraft have recently detected a very strong modulation in the solar wind speed with an approximately 1.3 year period. Combined with evidence from long-term auroral and magnetometer studies, this suggests that fundamental changes in the Sun occur on a roughly 1.3 year time scale.

  20. 21 CFR 172.712 - 1,3-Butylene glycol.

    Science.gov (United States)

    2010-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Other Specific Usage Additives § 172.712 1,3-Butylene glycol. The food additive 1,3-butylene glycol (CAS...

  1. 1,3- and 1,4-Substituted tetrazolium salts

    International Nuclear Information System (INIS)

    Voitekhovich, Sergei V; Gaponik, Pavel N; Ivashkevich, Oleg A

    2002-01-01

    The published data on the synthesis, physicochemical properties, structures and reactions of 1,3-(1,3,5)- and 1,4-(1,4,5)-substituted tetrazolium salts are systematised and generalised. Their applications as starting compounds in the preparative chemistry of heterocyclic derivatives and some other branches of science and technology are reviewed. The bibliography includes 122 references.

  2. Characterization of methacetin-methoxy-"1"3C

    International Nuclear Information System (INIS)

    Lu Weijing; Lu Hao; Yang Weicheng; Liu Weixia; Li Shuai; Xu Zhongjie; Guan Liang; Zhu Chengmo; Chen Suyun; Jiang Lei

    2010-01-01

    Methacetin-methoxy-"1"3C was synthesized by using methanol-"1"3C with a novel method, and the characterization of it was performed using HPLC, LC-MS and "1HMNR. The results indicated that the synthetic was right. And the yield of methacetin-methoxy-"1"3C was 70.0% with 99% "1"3C abundance and 99.8% purity. Compared with the classical method, there was more benefit. The methacetin "1"3C-breath test was performed with the synthetic on the live mice, which showed a precise reflection of alteration of liver function in liver injury and functional recovery. (authors)

  3. Periodic assessment of plasma sFlt-1 and PlGF concentrations and its association with placental morphometry in gestational hypertension (GH) - a prospective follow-up study.

    Science.gov (United States)

    Jeevaratnam, Kamalan; Nadarajah, Vishna Devi; Judson, John Paul; Nalliah, Sivalingam; Abdullah, Mohd Farouk

    2010-09-28

    Hypertensive disorders in pregnancy contributes to about 12% of maternal deaths in Malaysia and similarly worldwide. Early detection and adequate management are preventable strategies. Biochemical markers of abnormal angiogenesis would be more specific in early detection than routine blood pressure and proteinuria measurements. The aim of this study was to estimate maternal plasma PlGF and sFlt-1 levels in pregnant women with gestational hypertension at three intervals of pregnancy and correlate these biomarker levels with placental morphometry. Venous blood samples (antepartum, intrapartum and post partum periods) were drawn to estimate for sFlt-1 and PlGF levels while placental tissue samples were examined for placental morphometry. PlGF levels were lower in gestational hypertension (GH) compared to normotensive during antepartum and intrapartum period, whereas sFlt-1 levels were elevated in GH at antepartum, intrapartum and postpartum intervals during pregnancy. An inverse relationship between these two biomarkers was observed through correlation analysis. PlGF levels were inversely correlated with total villous surface area of the placental periphery (TCsa-C) and villous capillarization (VC-C) of the placental periphery. We established periodic values of for sFlt-1 and PlGF levels for the first time in an ethnically diverse Malaysian setting. We suggest the development of GH in women is related to defective capillarization. In demonstrating periodic changes, this study suggest the possibility of developing GH and other long term health complications as a result of prolonged exposure to sFlt-1. The correlation between PlGF levels and morphometric findings also support possible capillarization defect.

  4. Periodic assessment of plasma sFlt-1 and PlGF concentrations and its association with placental morphometry in gestational hypertension (GH - a prospective follow-up study

    Directory of Open Access Journals (Sweden)

    Nalliah Sivalingam

    2010-09-01

    Full Text Available Abstract Background Hypertensive disorders in pregnancy contributes to about 12% of maternal deaths in Malaysia and similarly worldwide. Early detection and adequate management are preventable strategies. Biochemical markers of abnormal angiogenesis would be more specific in early detection than routine blood pressure and proteinuria measurements. The aim of this study was to estimate maternal plasma PlGF and sFlt-1 levels in pregnant women with gestational hypertension at three intervals of pregnancy and correlate these biomarker levels with placental morphometry. Methods Venous blood samples (antepartum, intrapartum and post partum periods were drawn to estimate for sFlt-1 and PlGF levels while placental tissue samples were examined for placental morphometry. Results PlGF levels were lower in gestational hypertension (GH compared to normotensive during antepartum and intrapartum period, whereas sFlt-1 levels were elevated in GH at antepartum, intrapartum and postpartum intervals during pregnancy. An inverse relationship between these two biomarkers was observed through correlation analysis. PlGF levels were inversely correlated with total villous surface area of the placental periphery (TCsa-C and villous capillarization (VC-C of the placental periphery. Conclusion We established periodic values of for sFlt-1 and PlGF levels for the first time in an ethnically diverse Malaysian setting. We suggest the development of GH in women is related to defective capillarization. In demonstrating periodic changes, this study suggest the possibility of developing GH and other long term health complications as a result of prolonged exposure to sFlt-1. The correlation between PlGF levels and morphometric findings also support possible capillarization defect.

  5. Semiautomatic methods for segmentation of the proliferative tumour volume on sequential FLT PET/CT images in head and neck carcinomas and their relation to clinical outcome

    Energy Technology Data Exchange (ETDEWEB)

    Arens, Anne I.J.; Grootjans, Willem; Oyen, Wim J.G.; Visser, Eric P. [Radboud University Medical Center, Department of Nuclear Medicine, P.O. Box 9101, Nijmegen (Netherlands); Troost, Esther G.C. [Radboud University Medical Center, Department of Radiation Oncology, Nijmegen (Netherlands); Maastricht University Medical Centre, MAASTRO clinic, GROW School for Oncology and Developmental Biology, Maastricht (Netherlands); Hoeben, Bianca A.W.; Bussink, Johan; Kaanders, Johannes H.A.M. [Radboud University Medical Center, Department of Radiation Oncology, Nijmegen (Netherlands); Lee, John A.; Gregoire, Vincent [St-Luc University Hospital, Department of Radiation Oncology, Universite Catholique de Louvain, Brussels (Belgium); Hatt, Mathieu; Visvikis, Dimitris [Laboratoire de Traitement de l' Information Medicale (LaTIM), INSERM UMR1101, Brest (France)

    2014-05-15

    Radiotherapy of head and neck cancer induces changes in tumour cell proliferation during treatment, which can be depicted by the PET tracer {sup 18}F-fluorothymidine (FLT). In this study, three advanced semiautomatic PET segmentation methods for delineation of the proliferative tumour volume (PV) before and during (chemo)radiotherapy were compared and related to clinical outcome. The study group comprised 46 patients with 48 squamous cell carcinomas of the head and neck, treated with accelerated (chemo)radiotherapy, who underwent FLT PET/CT prior to treatment and in the 2nd and 4th week of therapy. Primary gross tumour volumes were visually delineated on CT images (GTV{sub CT}). PVs were visually determined on all PET scans (PV{sub VIS}). The following semiautomatic segmentation methods were applied to sequential PET scans: background-subtracted relative-threshold level (PV{sub RTL}), a gradient-based method using the watershed transform algorithm and hierarchical clustering analysis (PV{sub W} and {sub C}), and a fuzzy locally adaptive Bayesian algorithm (PV{sub FLAB}). Pretreatment PV{sub VIS} correlated best with PV{sub FLAB} and GTV{sub CT}. Correlations with PV{sub RTL} and PV{sub W} and {sub C} were weaker although statistically significant. During treatment, the PV{sub VIS}, PV{sub W} and {sub C} and PV{sub FLAB} significant decreased over time with the steepest decline over time for PV{sub FLAB}. Among these advanced segmentation methods, PV{sub FLAB} was the most robust in segmenting volumes in the third scan (67 % of tumours as compared to 40 % for PV{sub W} and {sub C} and 27 % for PV{sub RTL}). A decrease in PV{sub FLAB} above the median between the pretreatment scan and the scan obtained in the 4th week was associated with better disease-free survival (4 years 90 % versus 53 %). In patients with head and neck cancer, FLAB proved to be the best performing method for segmentation of the PV on repeat FLT PET/CT scans during (chemo)radiotherapy. This may

  6. Prediction of severe pre-eclampsia/HELLP syndrome by combination of sFlt-1, CT-pro-ET-1 and blood pressure: exploratory study.

    Science.gov (United States)

    Lind Malte, A; Uldbjerg, N; Wright, D; Tørring, N

    2018-06-01

    To evaluate the performance of a combination of angiogenic and vasoactive biomarkers to predict the development of severe pre-eclampsia (PE)/HELLP syndrome in the third trimester. Included were 215 women referred in the third trimester to an obstetric outpatient clinic with suspected PE (mean gestational age, 35 + 4 weeks), and 94 with normal pregnancy attending a midwife clinic. Cases were categorized as having subclinical PE, essential hypertension, gestational hypertension, moderate PE, and severe PE/HELLP syndrome. Blood samples were analyzed by immunoassay and groups were compared with respect to potential clinical and biochemical biomarkers, with the primary outcome being development of severe PE/HELLP syndrome within 1 week and within 2 weeks of analysis. The most promising markers were also assessed in combination. In the patients presenting with mild to moderate symptoms of PE, the individual markers which performed best for the prediction of progression to severe PE/HELLP syndrome within 1 week and within 2 weeks of biomarker evaluation were C-terminal pro-endothelin-1 (CT-pro-ET-1) (area under the receiver-operating characteristics curve (AUC), 0.82 and 0.78, respectively), soluble fms-like tyrosine kinase-1 (sFlt-1) (AUC, 0.81 and 0.76), systolic blood pressure (AUC, 0.80 and 0.68) and midregional pro-atrial natriuretic peptide (AUC, 0.79 and 0.77). The combination of biomarkers with the best performance was CT-pro-ET-1, sFlt-1 and systolic blood pressure, achieving an AUC of 0.94 for prediction of development of severe PE/HELLP syndrome within 1 week and an AUC of 0.83 for prediction of their development within 2 weeks of biomarker evaluation. The performance of CT-pro-ET-1 for prediction of the development of PE/HELLP syndrome in the third trimester was promising, especially in combination with sFlt-1 and systolic blood pressure. This was an exploratory study and our findings should be confirmed in further studies. Copyright © 2017

  7. A plasmodesmata-associated beta-1,3-glucanase in Arabidopsis.

    Science.gov (United States)

    Levy, Amit; Erlanger, Michael; Rosenthal, Michal; Epel, Bernard L

    2007-02-01

    Plasmodesmal conductivity is regulated in part by callose turnover, which is hypothesized to be determined by beta-1,3-glucan synthase versus glucanase activities. A proteomic analysis of an Arabidopsis thaliana plasmodesmata (Pd)-rich fraction identified a beta-1,3-glucanase as present in this fraction. The protein encoded by the putative plasmodesmal associated protein (ppap) gene, termed AtBG_ppap, had previously been found to be a post-translationally modified glycosylphosphatidylinositol (GPI) lipid-anchored protein. When fused to green fluorescent protein (GFP) and expressed in tobacco (Nicotiana tabacum) or Nicotiana benthamiana epidermal cells, this protein displays fluorescence patterns in the endoplasmic reticulum (ER) membrane system, along the cell periphery and in a punctate pattern that co-localizes with aniline blue-stained callose present around the Pd. Plasma membrane localization was verified by co-localization of AtBG_ppap:GFP together with a plasma membrane marker N-[3-triethylammoniumpropyl]-4-[p-diethylaminophenylhexatrienyl] pyridinium dibromide (FM4-64) in plasmolysed cells. In Arabidopsis T-DNA insertion mutants that do not transcribe AtBG_ppap, functional studies showed that GFP cell-to-cell movement between epidermal cells is reduced, and the conductivity coefficient of Pd is lower. Measurements of callose levels around Pd after wounding revealed that callose accumulation in the mutant plants was higher. Taken together, we suggest that AtBG_ppap is a Pd-associated membrane protein involved in plasmodesmal callose degradation, and functions in the gating of Pd.

  8. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) (Public Comment Draft)

    Science.gov (United States)

    EPA is developing an Integrated Risk Information System (IRIS) assessment of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and has released the draft assessment for public comment. When final, the assessment will appear on the IRIS database.

  9. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) (External Review Draft)

    Science.gov (United States)

    The IRIS Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) was released for external peer review in September 2016. The EPA’s Science Advisory Board’s (SAB) Chemical Assessment Advisory Committee (CAAC) will conduct a peer review of the scientific basis suppor...

  10. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) (Interagency Science Consultation Draft)

    Science.gov (United States)

    On March 10, 2016, the public comment draft Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine and the draft charge to external peer reviewers were released for public review and comment. The Toxicological Review and charge were reviewed internally by EPA and by othe...

  11. Thermochemistry of 1,3-diethylbarbituric and 1,3-diethyl-2-thiobarbituric acids: Experimental and computational study

    International Nuclear Information System (INIS)

    Notario, Rafael; Roux, María Victoria; Ros, Francisco; Emel’yanenko, Vladimir N.; Zaitsau, Dzmitry H.; Verevkin, Sergey P.

    2014-01-01

    Highlights: • Enthalpies of formation in condensed phase have been obtained. • Enthalpy of vaporization of 1,3-diethylbarbituric acid has been determined. • Enthalpy of sublimation of 1,3-diethyl-2-thiobarbituric acid has been determined. • Gas-phase enthalpies of formation have been obtained. • Gas-phase enthalpies of formation have been calculated at G3 and G4 levels. - Abstract: This paper reports an experimental and computational thermochemical study on two barbituric acid derivatives, viz. 1,3-diethylbarbituric acid and 1,3-diethyl-2-thiobarbituric acid. Values of standard molar enthalpies of formation in the gas phase at T = 298.15 K have been derived from experiment. Energies of combustion were measured by the static bomb combustion calorimetry in the case of 1,3-diethylbarbituric acid, and the rotating-bomb combustion calorimetry in the case of 1,3-diethyl-2-thiobarbituric acid. From the combustion energies, standard molar enthalpies of formation in the crystalline state at T = 298.15 K were calculated. The enthalpy of vaporization of 1,3-diethylbarbituric acid and enthalpy of sublimation of 1,3-diethyl-2-thiobarbituric acid were determined using the transpiration method. Combining calorimetric and transpiration results, values of −(611.9 ± 2.0) kJ · mol −1 and −(343.8 ± 2.2) kJ · mol −1 for the gas-phase enthalpies of formation at T = 298.15 K of 1,3-diethylbarbituric and 1,3-diethyl-2-thiobarbituric acids, respectively, were derived. Theoretical calculations at the G3 and G4 levels were performed, and a study of the molecular structure of the compounds has been carried out. Calculated enthalpies of formation were in very good agreement with the experimental values

  12. SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation.

    Science.gov (United States)

    Cao, Jin; Yu, Yi; Zhang, Zhengmao; Chen, Xi; Hu, Zhaoyong; Tong, Qiang; Chang, Jiang; Feng, Xin-Hua; Lin, Xia

    2018-01-01

    FoxO1 and FoxO3a (collectively FoxO1/3a) proteins regulate a wide array of cellular processes, including hepatic gluconeogenesis. Phosphorylation of FoxO1/3a is a key event that determines its subcellular location and transcriptional activity. During glucose synthesis, the activity of FoxO1/3a is negatively regulated by Akt-mediated phosphorylation, which leads to the cytoplasmic retention of FoxO1/3a. However, the nuclear phosphatase that directly regulates FoxO1/3a remains to be identified. In this study, we discovered a nuclear phosphatase, SCP4/CTDSPL2 (SCP4), that dephosphorylated FoxO1/3a and promoted FoxO1/3a transcription activity. We found that SCP4 enhanced the transcription of FoxO1/3a target genes encoding PEPCK1 and G6PC, key enzymes in hepatic gluconeogenesis. Ectopic expression of SCP4 increased, while knockdown of SCP4 inhibited, glucose production. Moreover, we demonstrated that gene ablation of SCP4 led to hypoglycemia in neonatal mice. Consistent with the positive role of SCP4 in gluconeogenesis, expression of SCP4 was regulated under pathophysiological conditions. SCP4 expression was induced by glucose deprivation in vitro and in vivo and was elevated in obese mice caused by genetic (A vy ) and dietary (high-fat) changes. Thus, our findings provided experimental evidence that SCP4 regulates hepatic gluconeogenesis and could serve as a potential target for the prevention and treatment of diet-induced glucose intolerance and type 2 diabetes. © 2017 by the American Diabetes Association.

  13. Analysis of 3-MCPD and 1,3-DCP in Various Foodstuffs Using GC-MS

    Science.gov (United States)

    Kim, Wooseok; Jeong, Yun A; On, Jiwon; Choi, Ari; Lee, Jee-yeon; Lee, Joon Goo; Lee, Kwang-Geun

    2015-01-01

    3-Monochloro-1,2-propanediol (3-MCPD) and 1,3-dichloro-2-propanol (1,3-DCP) are not only produced in the manufacturing process of foodstuffs such as hydrolyzed vegetable proteins and soy sauce but are also formed by heat processing in the presence of fat and low water activity. 3-MCPD exists both in free and ester forms, and the ester form has been also detected in various foods. Free 3-MCPD and 1,3-DCP are classified as Group 2B by the International Agency for Research on Cancer. Although there is no data confirming the toxicity of either compound in humans, their toxicity was evidenced in animal experimentation or in vitro. Although few studies have been conducted, free 3-MCPD has been shown to have neurotoxicity, reproductive toxicity, and carcinogenicity. In contrast, 1,3-DCP only has mutagenic activity. The purpose of this study was to analyze 3-MCPD and 1,3-DCP in various foods using gas chromatography -mass spectrometry. 3-MCPD and 1,3-DCP were analyzed using phenyl boronic acid derivatization and the liquid–liquid extraction method, respectively. The analytical method for 3-MCPD and 1,3-DCP was validated in terms of linearity, limit of detection (LOD), limit of quantitation, accuracy and precision. Consequently, the LODs of 3-MCPD and 1,3-DCP in various matrices were identified to be in the ranges of 4.18~10.56 ng/g and 1.06~3.15 ng/g, respectively. PMID:26483891

  14. Early Death in Two Patients with Acute Promyelocytic Leukemia Presenting the bcr3 Isoform, FLT3-ITD Mutation, and Elevated WT1 Level

    Directory of Open Access Journals (Sweden)

    Marianna Greco

    2013-01-01

    Full Text Available Despite major advances in the treatment of acute promyelocytic leukemia (APL, the problem of early death (ED remains unsolved. Alongside the currently known clinical and hematological risk factors, prognostic significance has been attributed to internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD, hypogranular variant morphology, and the bcr-3 isoform of PML-RARα. We describe premature death of two patients with the hypogranular variant of APL who presented remarkably high expression levels of Wilms' tumor gene (WT1. Our results point to WT1 as an important prognostic factor of ED that needs to be promptly evaluated in all newly diagnosed cases of APL.

  15. Searching for ?_1_3 at Daya Bay

    International Nuclear Information System (INIS)

    Giedt, Joel; Napolitano, James

    2015-01-01

    An experiment has been carried out by the Daya Bay Collaboration to measure the neutrino mixing angle θ_1_3. In addition, the grant has supported research into lattice field theory beyond the standard model.

  16. 1.3 GHz superconducting RF cavity program at Fermilab

    Energy Technology Data Exchange (ETDEWEB)

    Ginsburg, C.M.; Arkan, T.; Barbanotti, S.; Carter, H.; Champion, M.; Cooley, L.; Cooper, C.; Foley, M.; Ge, M.; Grimm, C.; Harms, E.; /Fermilab

    2011-03-01

    At Fermilab, 9-cell 1.3 GHz superconducting RF (SRF) cavities are prepared, qualified, and assembled into cryomodules (CMs) for Project X, an International Linear Collider (ILC), or other future projects. The 1.3 GHz SRF cavity program includes targeted R&D on 1-cell 1.3 GHz cavities for cavity performance improvement. Production cavity qualification includes cavity inspection, surface processing, clean assembly, and one or more cryogenic low-power CW qualification tests which typically include performance diagnostics. Qualified cavities are welded into helium vessels and are cryogenically tested with pulsed high-power. Well performing cavities are assembled into cryomodules for pulsed high-power testing in a cryomodule test facility, and possible installation into a beamline. The overall goals of the 1.3 GHz SRF cavity program, supporting facilities, and accomplishments are described.

  17. HANSF 1.3 user's manual

    Energy Technology Data Exchange (ETDEWEB)

    PLYS, M.G.

    1999-05-21

    The HANSF analysis tool is an integrated model considering phenomena inside a multi-canister overpack (MCO) spent nuclear fuel container such as fuel oxidation, convective and radiative heat transfer, and the potential for fission product release. It may be used for all phases of spent fuel disposition including cold vacuum drying, transportation, and storage. This manual reflects HANSF version 1.3, a revised version of version 1.2a. HANSF 1.3 was written to add new models for axial nodalization, add new features for ease of usage, and correct errors. HANSF 1.3 is intended for use on personal computers such as IBM-compatible machines with Intel processors running under a DOS-type operating system. HANSF 1.3 is known to compile under Lahey TI and Digital Visual FORTRAN, Version 6.0, but this does not preclude operation in other environments.

  18. Eesti Post investeerib Kasahstani 1,3 miljonit / Hindrek Riikoja

    Index Scriptorium Estoniae

    Riikoja, Hindrek

    2005-01-01

    Eesti Post investeerib tütarettevõtte Eesti Elektronpost vahendusel Kasahstani postiturule 1,3 miljonit krooni, et pakkuda koostöös sealse riikliku postifirmaga digitaalselt saadetud andmete printimise ning adressaatidele saatmise kompleksteenust

  19. Identification of a novel group of putative Arabidopsis thaliana beta-(1,3)-galactosyltransferases

    DEFF Research Database (Denmark)

    Qu, Yongmei; Egelund, Jack; Gilson, Paul R

    2008-01-01

    To begin biochemical and molecular studies on the biosynthesis of the type II arabinogalactan chains on arabinogalactan-proteins (AGPs), we adopted a bioinformatic approach to identify and systematically characterise the putative galactosyltransferases (GalTs) responsible for synthesizing the beta......-(1,3)-Gal linkage from CAZy GT-family-31 from Arabidopsis thaliana. These analyses confirmed that 20 members of the GT-31 family contained domains/motifs typical of biochemically characterised beta-(1,3)-GTs from mammalian systems. Microarray data confirm that members of this family are expressed......,3)-GalT activity. This bioinformatic/molecular study of CAZy GT-family-31 was validated by the recent report of Strasser et al. (Plant Cell 19:2278-2292, 2007) that another member of this family (At1g26810; GALT1) encodes a beta-(1,3)-GalT involved in the biosynthesis of the Lewis a epitope of N...

  20. High radiochemical yield synthesis of [18F]FLT from 3'-O-nosylated thymidine and its 3-N-BOC-protected analogue

    International Nuclear Information System (INIS)

    Yoon, M. K.; Oh, S. J.; Ryu, J. S.; Moon, D. H.

    2002-01-01

    We synthesized 3'-O-nosylate and its 3-N-BOC-protected thymidine derivatives as two precursors for high radiochemical yield synthesis of [ 18 F]FLT and optimized [ 18 F]fluorination conditions. (5'-O-DMTr-2'-deoxy-3'-O-nosyl-β-D-threo-pentofuranosyl)thymidine and its s 3-N-BOD-protected analogue were prepared with 54% and 28% yield, respectively. After drying of [ 18 F]F-, 3'-O-nosylate(10-30 mg) or its 3-N-BOC-protected(11-34 mg) precursor was added to 500 μl of CH3CN, respectively. The mixtures were heated at 100-130 .deg. C for 5-30 min. For hydrolysis, 250-500 μl 1N HCl at 50 .deg. C for 5 min condition was used and 1.5ml of 2M sodium acetate was used for neutralization. Reaction mixture was purified by HPLC. The optimal [ 18 F]fluorination yield of 3'-O-nosylate precursor was 85±5.4% with 34 mg of precursor and a reaction time of 5 min at 130 .deg. C. For 3-N-BOC-protected analogue, [ 18 F]fluorination yield was 82±5.4% with 34 mg of precursor and a reaction time of 5 min at 110. deg. C. After HPLC purification, overall radiochemical yield using each precursors were 40±5.2% and 42±5.4% and radiochemical purity were 98±0.5% and 97±2.1% for two precursors, respectively. Preparation time was 60±10.5 min including HPLC purification for two precursors. From these two precursors, [ 18 F]FLT can be easily prepared with high radiochemical yield. 3-N-BOC-protected precursor required milder [ 18 F]fluorination conditions than 3'-O-nosylate precursor

  1. 1-(3-Iodopropyl-4-methylquinolin-1-ium Iodide

    Directory of Open Access Journals (Sweden)

    Todor Deligeorgiev

    2015-11-01

    Full Text Available A solvent-free “one-pot” synthetic approach to 1-(3-iodopropyl-4-methylquinolin-1-ium iodide is reported in the present work. The title compound is derived from N-alkylation of 4-methylquinoline with 1,3-diiodopropane proceeded at room temperature. The target quinolinium salt is obtained in a highly pure form. It’s structure was evaluated by 1H-NMR, 13C-NMR, and DEPT135 spectra.

  2. Spin glass transition in the rhombohedral LiNi1/3Mn1/3Co1/3O2

    International Nuclear Information System (INIS)

    Bie, Xiaofei; Yang, Xu; Han, Bing; Chen, Nan; Liu, Lina; Wei, Yingjin; Wang, Chunzhong; Chen, Hong; Du, Fei; Chen, Gang

    2013-01-01

    Highlights: •The Rietveld analysis of XRD data reveals a single phase with rhombohedral structure. •Dc susceptibility data suggest a spin glass behavior at low T in the 333 compound. •The ac susceptibility measurements have been observed in the typical SG system. •Three models have been employed to study the behavior of the spin glass state. •Both geometrical frustration and disorder play important role in the formation of SG. -- Abstract: Layered LiNi 1/3 Mn 1/3 Co 1/3 O 2 has been synthesized by co-precipitation method, and the magnetic properties were comprehensively studied by dc and ac susceptibilities. The dc magnetization curves show the irreversibility and spin freezing behavior at 109 K and 9 K. The evolution of real and imaginary part of ac susceptibility under different frequencies indicates a spin glass transition at low temperature. Three models (the Néel–Arrhenius law, the Vogel–Fulcher law, and the power law) have been employed to study the relaxation behavior of the spin glass state. Both frustration and disorder play important role in the formation of spin glass

  3. Impact of morphological changes of LiNi1/3Mn1/3Co1/3O2 on lithium-ion cathode performances

    Science.gov (United States)

    Pierre-Etienne, Cabelguen; David, Peralta; Mikael, Cugnet; Pascal, Maillet

    2017-04-01

    Major advances in Li-ion battery technology rely on the nanostructuration of active materials to overcome the severe kinetics limitations of new - cheaper and safer - chemistries. However, opening porosities results in the decrease of volumetric performances, closing the door to significant applications such as portable electronics, electromobility, and grid storage. In this study, we analyze the link between morphologies and performances of model LiNi1/3Mn1/3Co1/3O2 materials. By quantifying exhaustively their microstructures using nitrogen adsorption, mercury intrusion porosimetry, and helium pycnometry, we can discuss how porosities and surface areas are linked to the electrochemical behavior. There is no geometrical parameters that can predict the performances of all our materials. The shape of agglomeration dictates the electrochemical behavior. A huge drop in volumetric performances is measured when microstructure is considered. We show that gravimetric and volumetric power performances are contrary to each other. Highly dense materials exhibit, by far, the best power performances in terms of volumetric figures, so that opening porosities might not be the best strategy, even in non-nanosized materials, for Li-ion battery technology.

  4. Recombinant β-1,3-1,4-glucanase from Theobroma cacao impairs Moniliophthora perniciosa mycelial growth.

    Science.gov (United States)

    Britto, Dahyana Santos; Pirovani, Carlos Priminho; Andrade, Bruno Silva; Dos Santos, Tassiara Pereira; Pungartnik, Cristina; Cascardo, Júlio Cezar M; Micheli, Fabienne; Gesteira, Abelmon S

    2013-09-01

    In this work, we identified a gene from Theobroma cacao L. genome and cDNA libraries, named TcGlu2, that encodes a β-1,3-1,4-glucanase. The TcGlu2 ORF was 720 bp in length and encoded a polypeptide of 239 amino acids with a molecular mass of 25.58 kDa. TcGlu2 contains a conserved domain characteristic of β-1,3-1,4-glucanases and presented high protein identity with β-1,3-1,4-glucanases from other plant species. Molecular modeling of TcGlu2 showed an active site of 13 amino acids typical of glucanase with β-1,3 and 1,4 action mode. The recombinant cDNA TcGlu2 obtained by heterologous expression in Escherichia coli and whose sequence was confirmed by mass spectrometry, has a molecular mass of about 22 kDa (with His-Tag) and showed antifungal activity against the fungus Moniliophthora perniciosa, causal agent of the witches' broom disease in cacao. The integrity of the hyphae membranes of M. perniciosa, incubated with protein TcGlu2, was analyzed with propidium iodide. After 1 h of incubation, a strong fluorescence emitted by the hyphae indicating the hydrolysis of the membrane by TcGlu2, was observed. To our knowledge, this is the first study of a cacao β-1,3-1,4-glucanase expression in heterologous system and the first analysis showing the antifungal activity of a β-1,3-1,4-glucanase, in particular against M. perniciosa.

  5. Lewis base catalyzed 1,3-dithiane addition to carbonyl and imino compounds using 2-trimethylsilyl-1,3-dithiane.

    Science.gov (United States)

    Michida, Makoto; Mukaiyama, Teruaki

    2008-09-01

    Lewis base-catalyzed 1,3-dithiane addition to electrophiles such as carbonyl compounds and N-substituted aldimines with 2-trimethylsilyl-1,3-dithiane (TMS-dithiane) is described. By the activation of the carbon-silicon bond in the presence of a Lewis base catalyst such as tetrabutylammonium phenoxide (PhONnBu(4)), a 1,3-dithiane addition reaction proceeded smoothly to afford the corresponding adducts in good to high yields under mild conditions. This synthesis is also applied to the reactions of ketones having alpha-protons, and of N-substituted aldimines.

  6. Solvent Induced Disulfide Bond Formation in 2,5-dimercapto-1,3,4-thiadiazole

    OpenAIRE

    Palanisamy Kalimuthu; Palraj Kalimuthu; S. Abraham John

    2007-01-01

    Disulfide bond formation is the decisive event in the protein folding to determine the conformation and stability of protein. To achieve this disulfide bond formation in vitro, we took 2,5-dimercapto-1,3,4-thiadiazole (DMcT) as a model compound. We found that disulfide bond formation takes place between two sulfhydryl groups of DMcT molecules in methanol. UV-Vis, FT-IR and mass spectroscopic as well as cyclic voltammetry were used to monitor the course of reaction. We proposed a mechanism for...

  7. β-1,3-glucan in developing cotton fibers

    International Nuclear Information System (INIS)

    Maltby, D.; Carpita, N.C.; Montezinos, D.; Kulow, C.; Delmer, D.P.

    1979-01-01

    Evidence is presented for the existence of a noncellulosic β-1,3-glucan in cotton fibers. The glucan can be isolated as distinct fractions of varying solubility. When fibers are homogenized rigorously in aqueous buffer, part of the total β-1,3-glucan is found as a soluble polymer in homogenates freed of cell walls. The proportion of total β-1,3-glucan which is found as the soluble polymer varies somewhat as a function of fiber age. The insoluble fraction of the BETA-1,3-glucan remains associated with the cell wall fraction. The glucan fraction which can be isolated as a soluble polymer in homogenates freed of cell walls is not associated with membranous material, and we propose that it represents glucan which is also extracellular but not tightly associated with the cell wall. Enzyme digestion studies indicate that all of the cotton fiber glucan is β-linked, and methylation analyses and enzyme studies both show that the predominant linkage in the glucan is 1 → 3. The possibility of some minor branching at C-6 can also be deduced from the methylation analyses. The timing of deposition of the β-1,3-glucan during fiber development coincides closely with the onset of secondary wall cellulose synthesis. Kinetic studies performed with ovules and fibers cultured in vitro show that incorporation of radioactivity from [ 14 C/glucose into β-1,3-glucan is linear with respect to time almost from the start of the labeling period; however, a lag is observed before incorporation into cellulose becomes linear with time, suggesting that these two different glucans are not polymerized directly from the same substrate pool. Pulse-chase experiments indicate that neither the β-1,3-glucan nor cellulose exhibits significant turnover after synthesis

  8. Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1-3) in colon cancer serum and tumours: a biomarker study

    International Nuclear Information System (INIS)

    Albrethsen, Jakob; Bøgebo, Rikke; Gammeltoft, Steen; Olsen, Jesper; Winther, Benny; Raskov, Hans

    2005-01-01

    Molecular markers for localized colon tumours and for prognosis following therapy are needed. Proteomics research is currently producing numerous biomarker studies with clinical potential. We investigate the protein composition of plasma and of tumour extracts with the aim of identifying biomarkers for colon cancer. By Surface Enhanced Laser Desorption/Ionisation – Time Of Flight / Mass spectrometry (SELDI-TOF/MS) we compare the protein profiles of colon cancer serum with serum from healthy individuals and the protein profiles of colon tumours with normal colon tissue. By size exclusion chromatography, we investigate the binding of HNP 1-3 to high mass plasma proteins. By microflow we investigate the effect of HNP 1-3 on mammalian cells. Human Neutrophil Peptides -1, -2 and -3 (HNP 1-3), also known as alfa-defensin-1, -2 and -3, are present in elevated concentrations in serum from colon cancer patients and in protein extracts from colon tumours. A fraction of HNP 1-3 in serum is bound to unidentified high mass plasma proteins. HNP 1-3 purified from colon tumours are lethal to mammalian cells. HNP 1-3 may serve as blood markers for colon cancer in combination with other diagnostic tools. We propose that HNP 1-3 are carried into the bloodstream by attaching to high mass plasma proteins in the tumour microenvironment. We discuss the effect of HNP 1-3 on tumour progression

  9. Protein profiling of preeclampsia placental tissues.

    Science.gov (United States)

    Shu, Chang; Liu, Zitao; Cui, Lifeng; Wei, Chengguo; Wang, Shuwen; Tang, Jian Jenny; Cui, Miao; Lian, Guodong; Li, Wei; Liu, Xiufen; Xu, Hongmei; Jiang, Jing; Lee, Peng; Zhang, David Y; He, Jin; Ye, Fei

    2014-01-01

    Preeclampsia is a multi-system disorder involved in pregnancy without an effective treatment except delivery. The precise pathogenesis of this complicated disorder is still not completely understood. The objective of this study is to evaluate the alterations of protein expression and phosphorylations that are important in regulating placental cell function in preterm and term preeclampsia. Using the Protein Pathway Array, 38 proteins in placental tissues were found to be differentially expressed between preterm preeclampsia and gestational age matched control, while 25 proteins were found to be expressed differentially between term preeclampsia and matched controls. Among these proteins, 16 proteins and their associated signaling pathways overlapped between preterm and term preeclampsia, suggesting the common pathogenesis of two subsets of disease. On the other hand, many proteins are uniquely altered in either preterm or term preeclampsia and correlated with severity of clinical symptoms and outcomes, therefore, providing molecular basis for these two subsets of preeclampsia. Furthermore, the expression levels of some of these proteins correlated with neonatal small for gestational age (PAI-1 and PAPP-A) and adverse outcomes (Flt-1) in women with preterm preeclampsia. These proteins could potentially be used as candidate biomarkers for predicting outcomes of preeclampsia.

  10. Protein profiling of preeclampsia placental tissues.

    Directory of Open Access Journals (Sweden)

    Chang Shu

    Full Text Available Preeclampsia is a multi-system disorder involved in pregnancy without an effective treatment except delivery. The precise pathogenesis of this complicated disorder is still not completely understood. The objective of this study is to evaluate the alterations of protein expression and phosphorylations that are important in regulating placental cell function in preterm and term preeclampsia. Using the Protein Pathway Array, 38 proteins in placental tissues were found to be differentially expressed between preterm preeclampsia and gestational age matched control, while 25 proteins were found to be expressed differentially between term preeclampsia and matched controls. Among these proteins, 16 proteins and their associated signaling pathways overlapped between preterm and term preeclampsia, suggesting the common pathogenesis of two subsets of disease. On the other hand, many proteins are uniquely altered in either preterm or term preeclampsia and correlated with severity of clinical symptoms and outcomes, therefore, providing molecular basis for these two subsets of preeclampsia. Furthermore, the expression levels of some of these proteins correlated with neonatal small for gestational age (PAI-1 and PAPP-A and adverse outcomes (Flt-1 in women with preterm preeclampsia. These proteins could potentially be used as candidate biomarkers for predicting outcomes of preeclampsia.

  11. Protein Profiling of Preeclampsia Placental Tissues

    Science.gov (United States)

    Shu, Chang; Liu, Zitao; Cui, Lifeng; Wei, Chengguo; Wang, Shuwen; Tang, Jian Jenny; Cui, Miao; Lian, Guodong; Li, Wei; Liu, Xiufen; Xu, Hongmei; Jiang, Jing; Lee, Peng; Zhang, David Y.

    2014-01-01

    Preeclampsia is a multi-system disorder involved in pregnancy without an effective treatment except delivery. The precise pathogenesis of this complicated disorder is still not completely understood. The objective of this study is to evaluate the alterations of protein expression and phosphorylations that are important in regulating placental cell function in preterm and term preeclampsia. Using the Protein Pathway Array, 38 proteins in placental tissues were found to be differentially expressed between preterm preeclampsia and gestational age matched control, while 25 proteins were found to be expressed differentially between term preeclampsia and matched controls. Among these proteins, 16 proteins and their associated signaling pathways overlapped between preterm and term preeclampsia, suggesting the common pathogenesis of two subsets of disease. On the other hand, many proteins are uniquely altered in either preterm or term preeclampsia and correlated with severity of clinical symptoms and outcomes, therefore, providing molecular basis for these two subsets of preeclampsia. Furthermore, the expression levels of some of these proteins correlated with neonatal small for gestational age (PAI-1 and PAPP-A) and adverse outcomes (Flt-1) in women with preterm preeclampsia. These proteins could potentially be used as candidate biomarkers for predicting outcomes of preeclampsia. PMID:25392996

  12. 1,3-Diphenylisobenzofuran: a Model Chromophore for Singlet Fission

    Czech Academy of Sciences Publication Activity Database

    Johnson, J. C.; Michl, Josef

    2017-01-01

    Roč. 375, č. 5 (2017), č. článku 80. ISSN 2365-0869 R&D Projects: GA ČR GA15-19143S Institutional support: RVO:61388963 Keywords : 1,3-diphenylisobenzofuran * photophysics * solar energy * singlet fission * covalent dimers Subject RIV: CF - Physical ; Theoretical Chemistry OBOR OECD: Physical chemistry Impact factor: 4.033, year: 2016

  13. 1,3-Butadiene: Biomarkers and application to risk assessment

    Czech Academy of Sciences Publication Activity Database

    Swenberg, J. A.; Bordeerat, N. K.; Boysen, G.; Carro, S.; Georgieva, N. I.; Troutman, J. M.; Upton, P. B.; Albertini, R. J.; Vacek, P. M.; Walker, V. E.; Šrám, Radim; Goggin, M.; Tretyakova, N.

    2011-01-01

    Roč. 192, 1-2 (2011), s. 150-154 ISSN 0009-2797 Institutional research plan: CEZ:AV0Z50390512 Keywords : risk assessment * 1,3-butadiene * occupational exposure Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.865, year: 2011

  14. Environmentally benign synthesis of sydnone containing 1,3,4 ...

    Indian Academy of Sciences (India)

    TECS

    lop benign synthetic methods for sydnone deriva- tives,. 9 we report here a new series of sydnone containing 1,3,4-thiadiazines by microwave irradia- tion under solvent-free conditions. 2. Experimental. 2.1 General remarks. Melting points were determined by open capillary method and are uncorrected. All compounds were.

  15. 48 CFR 970.2201-1-3 - Contract clause.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clause. 970.2201... SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Application of Labor Policies 970.2201-1-3 Contract clause. In addition to the clause at 48 CFR 52.222-1, Notice to the Government of Labor Disputes...

  16. 48 CFR 970.0407-1-3 - Contract clause.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract clause. 970.0407... SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Administrative Matters 970.0407-1-3 Contract clause. The contracting officer shall insert the clause at 970.5204-3, Access to and Ownership of Records...

  17. Variation of β-1,3-Glucanase, Chitinase and Polyphenoloxidase

    African Journals Online (AJOL)

    Cacao (Theobroma cacao L.) clones that differ in susceptibility to black pod disease were analysed for response to stress induced by pod inoculation with the fungus Phytophthora megakarya Braz. Et Griff. Fungal inoculation significantly stimulated β-1,3-glucanase activity in both soluble and ionically-bound fractions of the ...

  18. Irony and Aequabilitas : Horace, Satires 1.3

    Directory of Open Access Journals (Sweden)

    Jerome Kemp

    2010-11-01

    Full Text Available In Satire 1.3 Horace upholds ‘Stoic’ aequabilitas, ironically aligning it with Epicurean moderation to attack Stoic inflexibility. His connection between friendship and justice shows an awareness of this link in Hellenistic thought. His ironic use of philosophical material serves a serious, anti-Stoic purpose (pace some recent scholarship.

  19. Functionalization of Graphene via 1,3-Dipolar Cycloaddition

    NARCIS (Netherlands)

    Quintana, Mildred; Spyrou, Konstantinos; Grzelczak, Marek; Browne, Wesley R.; Rudolf, Petra; Prato, Maurizio

    Few-layer graphenes (FLG) produced by dispersion and exfoliation of graphite in N-methylpyrrolidone were successfully functionalized using the 1,3-dipolar cycloaddition of azomethine ylides. The amino functional groups attached to graphene sheets were quantified by the Kaiser test. These amino

  20. O interactions in 1,3-diphenyl-urea

    Indian Academy of Sciences (India)

    The synthesis, X-ray structure and role of intermolecular interactions have been studied in case of 1,3-diphenyl-urea, owing to its medicinal importance. The compound crystallizes in orthorhombic crystal system (space group, 21) with unit cell parameters, = 9.118(3), = 10.558(2), = 11.780(3) Å and = 4.

  1. Vapor-liquid equilibria of the water + 1,3-propanediol and water + 1,3-propanediol + lithium bromide systems

    Energy Technology Data Exchange (ETDEWEB)

    Mun, S Y; Lee, H

    1999-12-01

    Vapor-liquid equilibrium data of the water + 1,3-propanediol and water + 1,3-propanediol + lithium bromide systems were measured at 60, 160, 300, and 760 mmHg at temperatures ranging from 315 to 488 K. The apparatus used in this work is a modified still especially designed for the measurement of low-pressure VLE, in which both liquid and vapor are continuously recirculated. For the analysis of salt-containing solutions, a method incorporating refractometry and gravimetry was used. From the experimental measurements, the effect of lithium bromide on the VLE behavior of water + 1,3-propanediol was investigated. The experimental data of the salt-free system were successfully correlated using the Wilson, NRTL, and UNIQUAC models. In addition, the extended UNIQUAC model of Sander et al. was applied to the VLE calculation of salt-containing mixtures.

  2. Problem Definition Study on 1,3-Dinitrobenzene, 1,3,5-Trinitrobenzene and Di-n-Propyl Adipate

    Science.gov (United States)

    1979-11-01

    are significantly higher than the levels observed for * 1,3,5-tr it~be-zeve. 9Both corounds hav teen sh...r to exhibit c e-re:,onse mutagenicity in the...returned to work. However, cyanosis, general malaise and anorexia *0 appeared within two days after returning to work and she was admitted to the hospital...secondary anemia, anorexia , weight loss, insomnia, moderate cvanosis and yellow-brown discoloration of the skin. After removal from 1,3-dinitro- benzene

  3. Allogeneic stem cell transplantation benefits for patients ≥ 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

    Science.gov (United States)

    Poiré, Xavier; Labopin, Myriam; Polge, Emmanuelle; Passweg, Jakob; Craddock, Charles; Blaise, Didier; Cornelissen, Jan J; Volin, Liisa; Russell, Nigel H; Socié, Gérard; Michallet, Mauricette; Fegueux, Nathalie; Chevallier, Patrice; Brecht, Arne; Hunault-Berger, Mathilde; Mohty, Mohamad; Esteve, Jordi; Nagler, Arnon

    2018-02-01

    Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 ( FLT3 -ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3 -ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively ( P <0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft- versus -host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients ≥ 60 with FLT3 -ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients. Copyright© 2018 Ferrata Storti Foundation.

  4. Short-term, serum-free, static culture of cord blood-derived CD34+ cells: effects of FLT3-L and MIP-1alpha on in vitro expansion of hematopoietic progenitor cells.

    Science.gov (United States)

    Capmany, G; Querol, S; Cancelas, J A; García, J

    1999-08-01

    The use of ex vivo expanded cells has been suggested as a possible means to accelerate the speed of engraftment in cord blood (CB) transplantation. The aim of this study was to fix the optimal condition for the generation of committed progenitors without affecting the stem cell compartment. Analysis of the effects of FLT3-L and MIP-1alpha when combined with SCF, IL-3 and IL-6, in short-term (6 days), serum-free expansion cultures of CB-selected CD34+ cells. An important expansion was obtained that ranged between 8-15 times for CFU-GM, 21-51 times for the BFU-E/CFU-Mix population and 11 to 30 times for CD34+ cells assessed by flow cytometry. From the combinations tested, those in which FLT3-L was present had a significant increase in the expansion of committed progenitors, while the presence of MIP-1alpha had a detrimental effect on the generation of more differentiated cells. However, stem cell candidates assessed by week 5 CAFC assay could be maintained in culture when both MIP-1a and FLT3-L were present (up to 91% recovery). This culture system was also able to expand megakaryocytic precursors as determined by the co-expression of CD34 and CD61 antigens (45-70 times), in spite of the use of cytokines non-specific for the megakaryocytic lineage. The results obtained point to the combination of SCF, IL-3, IL-6, FLT3-L and MIP-1alpha as the best suited for a pre-clinical short-term serum-free static ex vivo expansion protocol of CB CD34+ cells, since it can generate large numbers of committed progenitor cells as well as maintaining week 5 CAFC.

  5. Purification and characterization of pathogenesis-related antifungal beta 1,3 glucanase from basrai banana fruit

    International Nuclear Information System (INIS)

    Yasmin, N.; Saleem, M.; Chaudhry, Z.I.

    2012-01-01

    Pathogenesis-related proteins have been described as proteins that are encoded by the plant genome and that are induced specifically in response to infections by pathogens. These represent a collection of unrelated protein families which function as part of the plant defense system. Pathogenesis-related antifungal protein has been isolated from the pulp of ripe Basrai bananas and purified through ammonium sulphate precipitation, Sephadex G- 75 gel filtration chromatography and electro-elution. The purified protein with acidic character (pI 6.81). has molecular weight of 34.5kDa, as determined by MALOI- TOF mass spectrometry. Mascot score obtained was 473 greater than 82, indicate extensive homology at a significant level (p.0.05) and the protein was identified as beta 1,3-glucanase with antifungal activity. It inhibited the growth of Fusarium oxysporum demonstrating the potential role of Basrai banana antifungal protein to control fungal diseases in plants, animals and human. (author)

  6. Synthesis of Spiroisoxazolines by 1,3-Dipolar Cycloaddition

    Directory of Open Access Journals (Sweden)

    Peter Ertl

    1997-04-01

    Full Text Available The cycloaddition of the chiral nitrile oxide 1 to 1-R-substituted 3,3-methylene-5,5-dimethyl-2-pyrrolidinones 2 (where R is H, n-butyl-, 1,1-dimethylethoxycarbonyl-, 1-methylethenyl- and acetyl- proceeds regioselectively under the formation of spiroisoxazolines, namely 7-R-substituted-6-oxo-8,8-dimethyl-1-oxa-2,7-diazaspiro[4,4]non-2-enes 5 and 6. The asymmetric induction expected by the a-chiral centre of the nitrile oxide 1 was not very effective, diastereoisomers 5 and 6 were formed in an approximate 50:50 ratio. The stereoselectivity of the 1,3-dipolar cycloaddition of the arylnitrile oxide 7 with the chiral lactam 3 and the achiral lactone 4 are investigated. The attack of the 1,3-dipole occurred from the less hindered face of the dipolarophile 3 and 4, giving the major isomer 8 and 10, respectively.

  7. Spin texture and magnetoroton excitations at nu=1/3.

    Science.gov (United States)

    Groshaus, Javier G; Dujovne, Irene; Gallais, Yann; Hirjibehedin, Cyrus F; Pinczuk, Aron; Tan, Yan-Wen; Stormer, Horst; Dennis, Brian S; Pfeiffer, Loren N; West, Ken W

    2008-02-01

    Neutral spin texture (ST) excitations at nu=1/3 are directly observed for the first time by resonant inelastic light scattering. They are determined to involve two simultaneous spin flips. At low magnetic fields, the ST energy is below that of the magnetoroton minimum. With increasing in-plane magnetic field these mode energies cross at a critical ratio of the Zeeman and Coulomb energies of eta(c)=0.020+/-0.001. Surprisingly, the intensity of the ST mode grows with temperature in the range in which the magnetoroton modes collapse. The temperature dependence is interpreted in terms of a competition between coexisting phases supporting different excitations. We consider the role of the ST excitations in activated transport at nu=1/3.

  8. FDG and FLT-PET for Early measurement of response to 37.5 mg daily sunitinib therapy in metastatic renal cell carcinoma.

    Science.gov (United States)

    Horn, Kevin P; Yap, Jeffrey T; Agarwal, Neeraj; Morton, Kathryn A; Kadrmas, Dan J; Beardmore, Britney; Butterfield, Regan I; Boucher, Kenneth; Hoffman, John M

    2015-09-03

    Metastatic renal cell carcinoma has a poor prognosis and an intrinsic resistance to standard treatment. Sunitinib is an oral receptor tyrosine kinase inhibitor that has been used as a first-line targeted therapy in metastatic renal cell carcinoma. While computed tomography (CT) is currently the gold standard for response assessment in oncological trials, numerous studies have shown that positron emission tomography (PET) imaging can provide information predictive of tumor response to treatment earlier than the typical interval for standard of care follow-up CT imaging. In this exploratory study we sought to characterize early tumor response in patients with metastatic renal cell carcinoma treated with continuous daily 37.5 mg sunitinib therapy. Twenty patients underwent dynamic acquisition positron emission tomography (PET) imaging using (18) F-fluorodeoxyglucose (FDG) and (18) F-fluorothymidine (FLT) at baseline and early in treatment (after 1, 2, 3 or 4 weeks) with 37.5 mg continuous daily dosing of sunitinib. Semi-quantitative analyses were performed to characterize the tumor metabolic (FDG) and proliferative (FLT) responses to treatment. Proliferative responses were observed in 9/19 patients and occurred in 2 patients at one week (the earliest interval evaluated) after the initiation of therapy. A metabolic response was observed in 5/19 patients, however this was not observed until after two weeks of therapy were completed. Metabolic progression was observed in 2/19 patients and proliferative progression was observed in 1/19 patients. Baseline FDG-PET tumor maximum standardized uptake values correlated inversely with overall survival (p = 0.0036). Conversely, baseline (18) F-fluorothymidine PET imaging did not have prognostic value (p = 0.56) but showed a greater early response rate at 1-2 weeks after initiating therapy. While preliminary in nature, these results show an immediate and sustained proliferative response followed by a delayed

  9. TU-G-BRA-07: Characterization of Tumor Proliferation During Successive Cycles of Anti-Angiogenic Therapy Using [F-18]FLT PET/CT

    International Nuclear Information System (INIS)

    Scarpelli, M; Perlman, S; Harmon, S; Perk, T; Scully, P; Bruce, J; Liu, G; Jeraj, R

    2015-01-01

    Purpose: Studies have shown cessation of anti-angiogenic treatment during the first cycle of therapy resulted in rebound of tumor proliferation (flare). This study characterized proliferation dynamics during the first and third cycle of anti-angiogenic treatment using [F-18]FLT PET. Methods: Thirteen patients with various solid cancers were treated with Axitinib (Pfizer, Inc) at a dose of 5mg orally, twice daily, on contiguous three-week cycles with intermittent dosing (two-weeks-on/one-week-off). All patients received three FLT PET/CT scans during cycle 1 (C1): at baseline (C1D0), peak Axitinib concentration (C1D14), and the end of washout (C1D21). Ten patients received up to an additional three scans at corresponding time points during cycle 3 (C3). Lesions were identified by a nuclear medicine physician and manually contoured. Tumor burden was quantified using standard SUV metrics. Correlations between imaging metrics across C1 and C3 were calculated using the Spearman correlation. Results: At C1 peak drug concentration 11/13 patients had decreases in SUVtotal, with median decrease of 50% (change from C1D0 to C1D14). At C3 peak drug concentration 7/7 patients had decreases in SUVtotal, with median decrease of 20% (C3D0 to C3D14). Proliferative flare during C1 washout (>20% increase from C1D14 to C1D21) occurred in 9/13 patients, with median SUVtotal increase of 190%. Flare was also seen in C3 for 5/5 patients, with median SUVtotal increase of 70% (change from C3D14 to C3D21). Correlations were found between changes in imaging metrics across C1 and C3, notably the change in SUVtotal from C1D0 to C1D21 and the change in SUVtotal from C1D0 to C3D0 (ρ = 0.80). Conclusion: Measurements of SUVtotal showed that both patient response to treatment and flare were evident in both cycles of treatment. Correlation between changes in SUVtotal across C1 and C3 suggest early time points could be used to characterize patient response in later cycles. Research funded in part by

  10. 2-Phenylimidazolium hemi(benzene-1,3-dicarboxylate monohydrate

    Directory of Open Access Journals (Sweden)

    Wen-Yu Zhang

    2011-08-01

    Full Text Available The asymmetric unit of the title compound, C9H9N2+·0.5C8H4O4−·H2O, contains one 2-phenylimidazolium cation, half a benzene-1,3-dicarboxylate anion and one water molecule. In the crystal, components are connected by N—H...O and O—H...O hydrogen-bonding interactions into a three-dimensional network.

  11. Alpha-defensins 1-3 release by dendritic cells is reduced by estrogen

    Directory of Open Access Journals (Sweden)

    Sperling Rhoda

    2011-08-01

    Full Text Available Abstract Background During pregnancy the immune system of the mother must protect any activation that may negatively affect the fetus. Changes in susceptibility to infection as well as resolution of some autoimmune disorders represent empirical evidence for pregnancy related alterations in immunity. Sex hormones reach extremely high levels during pregnancy and have been shown to have direct effects on many immune functions including the antiviral response of dendritic cells. Among the immunologically active proteins secreted by monocyte derived DCs (MDDC are the alpha-defensins 1-3. This family of cationic antimicrobial peptides has a broad spectrum of microbicidal activity and has also been shown to link innate to adaptive immunity by attracting T cells and immature DCs, which are essential for initiating and polarizing the immune response. Methods We compare culture-generated monocyte derived DCs (MDDCs with directly isolated myeloid dendritic cells (mDCs and plasmacytoid dendritic cells (pDCs and measure their alpha-defensins 1-3 secretion by ELISA both, in basal situations and after hormone (E2 or PG treatments. Moreover, using a cohort of pregnant women we isolated mDCs from blood and also measure the levels of these anti-microbial peptides along pregnancy. Results We show that mDCs and pDCs constitutively produce alpha-defensins 1-3 and at much higher levels than MDDCs. Alpha-defensins 1-3 production from mDCs and MDDCs but not pDCs is inhibited by E2. PG does not affect alpha-defensins 1-3 in any of the populations. Moreover, alpha-defensins 1-3 production by mDCs was reduced in the later stages of pregnancy in 40% of the patients. Conclusions Here, we demonstrate that mDCs and pDCs secrete alpha-defensins 1-3 and present a novel effect of E2 on the secretion of alpha-defensins 1-3 by dendritic cells.

  12. Increased plasma levels of soluble vascular endothelial growth factor receptor 1 (sFlt-1) in women by moderate exercise and increased plasma levels of vascular endothelial growth factor in overweight/obese women.

    Science.gov (United States)

    Makey, Kristina L; Patterson, Sharla G; Robinson, James; Loftin, Mark; Waddell, Dwight E; Miele, Lucio; Chinchar, Edmund; Huang, Min; Smith, Andrew D; Weber, Mark; Gu, Jian-Wei

    2013-01-01

    The incidence of breast cancer is increasing worldwide, and this seems to be related to an increase in lifestyle risk factors, including physical inactivity and overweight/obesity. We have reported previously that exercise induced a circulating angiostatic phenotype characterized by increased soluble fms-like tyrosine kinase-1 (sFlt-1) and endostatin and decreased unbound vascular endothelial growth factor (VEGF) in men. However, there are no data on women. The present study determines the following: (a) whether moderate exercise increased sFlt-1 and endostatin and decreased unbound VEGF in the circulation of adult female volunteers and (b) whether overweight/obese women have a higher plasma level of unbound VEGF than lean women. A total of 72 African American and White adult women volunteers ranging in age from 18 to 44 years were enrolled in the exercise study. All the participants walked on a treadmill for 30 min at a moderate intensity (55-59% heart rate reserve), and oxygen consumption (VO(2)) was quantified utilizing a metabolic cart. We obtained blood samples before and immediately after exercise from 63 participants. ELISA assays showed that the plasma levels of sFlt-1 were 67.8±3.7 pg/ml immediately after exercise (30 min), significantly higher than the basal levels, 54.5±3.3 pg/ml, before exercise (P<0.01; n=63). There was no significant difference in the % increase in the sFlt-1 levels after exercise between African American and White (P=0.533) women or between lean and overweight/obese women (P=0.892). There was no significant difference in the plasma levels of unbound VEGF (35.28±5.47 vs. 35.23±4.96 pg/ml; P=0.99) or endostatin (111.12±5.48 vs. 115.45±7.15 ng/ml; P=0.63) before and after exercise. The basal plasma levels of unbound VEGF in overweight/obese women were 52.26±9.6 pg/ml, significantly higher than the basal levels of unbound VEGF in lean women, 27.34±4.99 pg/ml (P<0.05). The results support our hypothesis that exercise

  13. Increased plasma levels of soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1) in women by moderate exercise and increased plasma levels of VEGF in overweight/obese women

    Science.gov (United States)

    Makey, Kristina L.; Patterson, Sharla G.; Robinson, James; Loftin, Mark; Waddell, Dwight E.; Miele, Lucio; Chinchar, Edmund; Huang, Min; Smith, Andrew D.; Weber, Mark; Gu, Jian-Wei

    2012-01-01

    The incidence of breast cancer is increasing worldwide, and this seems to be related to an increase in lifestyle risk factors, including physical inactivity, and overweight/obesity. We previously reported that exercise induced a circulating angiostatic phenotype characterized by increased sFlt-1 and endostatin and decreased unbound-VEGF in men. However, there is no data on women. The present study determines the following: 1) whether moderate exercise increased sFlt-1 and endostatin and decreased unbound-VEGF in the circulation of adult female volunteers; 2) whether overweight/obese women have a higher plasma level of unbound-VEGF than lean women. 72 African American and Caucasian adult women volunteers aged from 18–44 were enrolled into the exercise study. All the participants walked on a treadmill for 30 minutes at a moderate intensity (55–59% heart rate reserve), and oxygen consumption (VO2) was quantified by utilizing a metabolic cart. We had the blood samples before and immediately after exercise from 63 participants. ELISA assays (R&D Systems) showed that plasma levels of sFlt-1 were 67.8±3.7 pg/ml immediately after exercise (30 minutes), significantly higher than basal levels, 54.5±3.3 pg/ml, before exercise (P < 0.01; n=63). There was no significant difference in the % increase of sFlt-1 levels after exercise between African American and Caucasian (P=0.533) or between lean and overweight/obese women (P=0.892). There was no significant difference in plasma levels of unbound VEGF (35.28±5.47 vs. 35.23±4.96 pg/ml; P=0.99) or endostatin (111.12±5.48 vs. 115.45±7.15 ng/ml; P=0.63) before and after exercise. Basal plasma levels of unbound-VEGF in overweight/obese women were 52.26±9.6 pg/ml, significantly higher than basal levels of unbound-VEGF in lean women, 27.34±4.99 pg/ml (P < 0.05). The results support our hypothesis that exercise-induced plasma levels of sFlt-1 could be an important clinical biomarker to explore the mechanisms of exercise

  14. Improved cycling and high rate performance of core-shell LiFe1/3Mn1/3Co1/3PO4/carbon nanocomposites for lithium-ion batteries: Effect of the carbon source

    International Nuclear Information System (INIS)

    Li, Huanhuan; Chen, Yi; Chen, Long; Jiang, Haobin; Wang, Yaping; Wang, Hongbo; Li, Guochun; Li, Yunxing; Yuan, Yuan

    2014-01-01

    Highlights: • We report a fast microwave heating way to prepare LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /C. • The effects of different carbon sources were discussed in detail. • LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /BP2000 shows a discharge capacity of 160 mA h g −1 at 0.1 C. • LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /BP2000 elucidates excellent cyclic stability. • LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /BP2000 exhibits attractive rate capability. - Abstract: Core-shell type olivine solid solutions, LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /C, are synthesized via a very simple and rapid microwave heating route with different carbon sources. The obatined LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /C materials are characterized thoroughly by various analytical techniques such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy and energy-dispersive spectroscopy instrument. The particle sizes and distribution of the carbon layer of BP2000 carbon black coated LiFe 1/3 Mn 1/3 Co 1/3 PO 4 (LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /BP) are more uniform than that obtained from acetylene black (LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /AB) and Super P (LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /SP). Moreover, the LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /BP nanocomposite shows superior electrochemical properties such as high discharge capacity of 160 mA h g −1 at 0.1 C, excellent cyclic stability (143 mA h g −1 at 0.1 C after 30 cycles) and rate capability (76 mAh g −1 at 20 C), which are better than other two samples. Cyclic voltammetric and electrical tests disclose that the Li-ion diffusion, the reversibility of lithium extraction/insertion and electrical conductivity are significantly improved in LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /BP composite. Electrochemical impedance spectroscopy illustrates that LiFe 1/3 Mn 1/3 Co 1/3 PO 4 /BP composite electrode possesses low contact and charge-transfer impedances, which can lead to rapid electron transport during the electrochemical lithium insertion/extraction reaction. It is believed that olivine solid

  15. Apoptosis induced by 1,3,6,7-tetrahydroxyxanthone in Hepatocellular carcinoma and proteomic analysis.

    Science.gov (United States)

    Fu, Wei-ming; Zhang, Jin-fang; Wang, Hua; Tan, Hong-sheng; Wang, Wei-mao; Chen, Shih-Chi; Zhu, Xiao; Chan, Tak-ming; Tse, Ching-man; Leung, Kwong-sak; Lu, Gang; Xu, Hong-xi; Kung, Hsiang-fu

    2012-08-01

    Gamboge is a traditional Chinese medicine and our previous study showed that gambogic acid and gambogenic acid suppress the proliferation of HCC cells. In the present study, another active component, 1,3,6,7-tetrahydroxyxanthone (TTA), was identified to effectively suppress HCC cell growth. In addition, our Hoechst-PI staining and flow cytometry analyses indicated that TTA induced apoptosis in HCC cells. In order to identify the targets of TTA in HCC cells, a two-dimensional gel electrophoresis was performed, and proteins in different expressions were identified by MALDA-TOF MS and MS/MS analyses. In summary, eighteen proteins with different expressions were identified in which twelve were up-regulated and six were down-regulated. Among them, the four most distinctively expressed proteins were further studied and validated by western blotting. The β-tubulin and translationally controlled tumor protein were decreased while the 14-3-3σ and P16 protein expressions were up-regulated. In addition, TTA suppressed tumorigenesis partially through P16-pRb signaling. 14-3-3σ silence reversed the suppressive effect of cell growth and apoptosis induced by introducing TTA. In conclusion, TTA effectively suppressed cell growth through, at least partially, up-regulation of P16 and 14-3-3σ.

  16. 1,3Do and 1,3Pe states of two electron atoms under Debye plasma screening

    International Nuclear Information System (INIS)

    Saha, Jayanta K.; Bhattacharyya, S.; Mukherjee, T.K.; Mukherjee, P.K.

    2010-01-01

    Extensive non-relativistic variational calculations for estimating the energy values of 2pnd( 1,3 D o ) states [n=3-6] of two electron atoms (He, Li + ,Be 2+ ) and 2pnp( 1 P e )[n=3-8] and 2pnp( 3 P e ) states [n=2-7] of Be 2+ under weakly coupled plasma screening have been performed using explicitly correlated Hylleraas type basis. The modified energy eigenvalues of 1,3 P e states arising from two p electrons of Be 2+ ion and 1,3 D o states due to 2pnd configuration of Li + and Be 2+ ion in the Debye plasma environment are being reported for the first time. The effect of plasma has been incorporated through the Debye screening model. The system tends towards gradual instability and the number of bound states reduces with increasing plasma coupling strength. The wavelengths for 2pn ' p( 1 P e )[n ' =3-8]→2pnd( 1 D o )[n=3-6] and 2pn ' p( 3 P e )[n ' =2-8]→2pnd( 3 D o )[n=3-6] transitions in plasma embedded two electron atoms have also been reported.

  17. The Effect of Maternal Soluble FMS-like Tyrosine Kinase 1 during Pregnancy on Risk of Preterm Delivery

    Science.gov (United States)

    Straughen, Jennifer K.; Kumar, Pawan; Misra, Vinod K.

    2013-01-01

    Objective Soluble fms-like tyrosine kinase 1 (sFlt1) is an antiangiogenic protein that is associated with a number of disorders of placental angiogenesis. It has been hypothesized that disruption of placental angiogenesis may contribute to the pathophysiology of preterm delivery (PTD). However, the relationship of PTD risk to variation in sFlt1 levels is not well known. We investigate the relationship between longitudinal variation in maternal serum concentrations of sFlt1 and risk of PTD. Methods Data were collected in a longitudinal cohort study involving 278 pregnant women. Maternal serum sFlt1 concentrations were measured at 6–10, 10–14, 16–20, 22–26, and 32–36 weeks gestation. Data analyses used longitudinal regression models using repeated measures that allow robust inferences from our modest sample size. The outcome was birth prior to 37 weeks gestation. Results sFlt1 concentrations were higher in first trimester for preterm compared to term deliveries. This relationship reversed in second trimester because sFlt1 concentrations increased more rapidly across gestation for term deliveries. In Cox proportional hazards analyses, a 2 ng higher sFlt1 concentration across gestation was associated with a hazard ratio of 1.3 (95% CI: 1.1, 1.5) for PTD suggesting the importance of levels in early pregnancy. Conclusion Elevated maternal serum sFlt1 concentration during pregnancy is associated with increased risk of PTD. PMID:22348624

  18. Spatially resolved regression analysis of pre-treatment FDG, FLT and Cu-ATSM PET from post-treatment FDG PET: an exploratory study

    Science.gov (United States)

    Bowen, Stephen R; Chappell, Richard J; Bentzen, Søren M; Deveau, Michael A; Forrest, Lisa J; Jeraj, Robert

    2012-01-01

    Purpose To quantify associations between pre-radiotherapy and post-radiotherapy PET parameters via spatially resolved regression. Materials and methods Ten canine sinonasal cancer patients underwent PET/CT scans of [18F]FDG (FDGpre), [18F]FLT (FLTpre), and [61Cu]Cu-ATSM (Cu-ATSMpre). Following radiotherapy regimens of 50 Gy in 10 fractions, veterinary patients underwent FDG PET/CT scans at three months (FDGpost). Regression of standardized uptake values in baseline FDGpre, FLTpre and Cu-ATSMpre tumour voxels to those in FDGpost images was performed for linear, log-linear, generalized-linear and mixed-fit linear models. Goodness-of-fit in regression coefficients was assessed by R2. Hypothesis testing of coefficients over the patient population was performed. Results Multivariate linear model fits of FDGpre to FDGpost were significantly positive over the population (FDGpost~0.17 FDGpre, p=0.03), and classified slopes of RECIST non-responders and responders to be different (0.37 vs. 0.07, p=0.01). Generalized-linear model fits related FDGpre to FDGpost by a linear power law (FDGpost~FDGpre0.93, pregression analysis indicates that pre-treatment FDG PET uptake is most strongly associated with three-month post-treatment FDG PET uptake in this patient population, though associations are histopathology-dependent. PMID:22682748

  19. Acute WT1-positive promyelocytic leukemia with hypogranular variant morphology, bcr-3 isoform of PML-RARα and Flt3-ITD mutation: a rare case report

    Directory of Open Access Journals (Sweden)

    Xi Zhang

    Full Text Available ABSTRACT CONTEXT: Acute promyelocytic leukemia (APL accounts for 8% to 10% of cases of acute myeloid leukemia (AML. Remission in cases of high-risk APL is still difficult to achieve, and relapses occur readily. CASE REPORT: Here, we describe a case of APL with high white blood cell counts in blood tests and hypogranular variant morphology in bone marrow, together with fms-like tyrosine kinase-3 with internal tandem duplication mutations (FLT3-ITD, and bcr-3 isoform of PML-RARα. Most importantly, we detected high level of Wilms’ tumor gene (WT1 in marrow blasts, through the reverse transcription polymerase chain reaction (RT-PCR. To date, no clear conclusions about an association between WT1 expression levels and APL have been reached. This patient successively received a combined treatment regimen consisting of hydroxycarbamide, arsenic trioxide and idarubicin plus cytarabine, which ultimately enabled complete remission. Unfortunately, he subsequently died of sudden massive hemoptysis because of pulmonary infection. CONCLUSION: Based on our findings and a review of the literature, abnormal functioning of WT1 may be a high-risk factor in cases of APL. Further studies aimed towards evaluating the impact of WT1 expression on the prognosis for APL patients are of interest.

  20. Synthesis of [1,3 - 15 N2] uracil

    International Nuclear Information System (INIS)

    Chiriac, M.; Axente, D.

    2001-01-01

    The synthesis of 15 N labelled uracil, using CO( 15 NH 2 ) 2 as starting material, is presented. The experimental procedure is an adaptation of the synthesis methods for the corresponding unlabelled compounds. Urea- 15 N 2 used as starting material was obtained from H 15 NO 3 (99 at.% 15 N) produced at National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca.The uracil structure was determined using the mass spectrometry method and the isotopic labelling was determined by the same method on the molecular compound. The synthesis scheme of (1,3- 15 N 2 ) uracil is presented. (authors)

  1. Polymers Containing 1, 3, 4-Oxadiazole Rings for Advanced Materials

    Directory of Open Access Journals (Sweden)

    Mariana-Dana Damaceanu

    2011-10-01

    Full Text Available This paper presents the synthesis, properties and potential applications of new polymers containing 1, 3, 4-oxadiazole rings, tacking into account the requirements of the modern technologies. Two classes of polymers containing oxadiazole rings were approached: polyamides and polyimides. All the polymers were characterized with respect to the identification of their chemical structure, solubility, molecular weights, film forming ability, thermal, dielectric and optical properties, and the behaviour of polyoxadiazole films upon irradiation with pulsed KrF laser. All the properties were discussed in correlation with their chemical structure and compared with those of related polymers.

  2. 5-Methylbenzo[d][2,1,3]selenadiazole

    Directory of Open Access Journals (Sweden)

    Halima Ouahine

    2017-02-01

    Full Text Available In the crystal of the title compound, C7H6N2Se, the molecules are arranged in rods along the b-axis direction and form dimeric units due to intermolecular Se...N contacts of 2.982 (2 Å. The molecules are further linked by weak π–π stacking interactions between the 2,1,3-selenadiazole and six-membered aromatic rings [centroid–centroid distance = 3.8509 (11 Å and ring slippage = 1.539 (3 Å].

  3. Solid Waste Projection Model: Database (Version 1.3)

    International Nuclear Information System (INIS)

    Blackburn, C.L.

    1991-11-01

    The Solid Waste Projection Model (SWPM) system is an analytical tool developed by Pacific Northwest Laboratory (PNL) for Westinghouse Hanford Company (WHC). The SWPM system provides a modeling and analysis environment that supports decisions in the process of evaluating various solid waste management alternatives. This document, one of a series describing the SWPM system, contains detailed information regarding the software and data structures utilized in developing the SWPM Version 1.3 Database. This document is intended for use by experienced database specialists and supports database maintenance, utility development, and database enhancement

  4. APS beamline standard components handbook, Version 1.3

    International Nuclear Information System (INIS)

    Hahn, U.; Shu, D.; Kuzay, T.M.

    1993-02-01

    This Handbook in its current version (1.3) contains descriptions, specifications, and preliminary engineering design drawings for many of the standard components. The design status and schedules have been provided wherever possible. In the near future, the APS plans to update engineering drawings of identified standard beamline components and complete the Handbook. The completed version of this Handbook will become available to both the CATs and potential vendors. Use of standard components should result in major cost reductions for CATs in the areas of beamline design and construction

  5. l-2-Nitrimino-1,3-diazepane-4-carboxylic acid

    Directory of Open Access Journals (Sweden)

    Harutyun A. Karapetyan

    2008-05-01

    Full Text Available The cyclic form of l-nitroarginine, C6H10N4O4, crystallizes with two independent molecules in the asymmetric unit. According to the geometrical parameters, similar in both molecules, the structure corresponds to that of l-2-nitrimino-1,3-diazepane-4-carboxylic acid; there are, however, conformational differences between the independent molecules, one of them being close to a twisted chair while the other might be described as a rather flattened boat. All six active H atoms in the two molecules are involved in hydrogen bonds, two of which are intramolecular and four intermolecular, forming an infinite chain of molecules along the b axis.

  6. Spin Caloritronic Transport of 1,3,5-Triphenylverdazyl Radical

    International Nuclear Information System (INIS)

    Wu Qiu-Hua; Zhao Peng; Liu De-Sheng

    2016-01-01

    We investigate theoretically the spin caloritronic transport properties of a stable 1,3,5-triphenylverdazyl (TPV) radical sandwiched between Au electrodes through different connection fashions. Obvious spin Seebeck effect can be observed in the para-connection fashion. Furthermore, a pure spin current and a completely spin-polarized current can be realized by tuning the gate voltage. Furthermore, a 100% spin polarization without the need of gate voltage can be obtained in the meta-connection fashion. These results demonstrate that TPV radical is a promising material for spin caloritronic and spintronic applications. (paper)

  7. Study of [18F]FLT and [123I]IaraU for cellular imaging in HSV1 tk-transfected murine fibrosarcoma cells: evaluation of the tracer uptake using 5-fluoro, 5-iodo and 5-iodovinyl arabinosyl uridines as competitive probes

    International Nuclear Information System (INIS)

    Huang, Ho-Lien; Chiang, Li-Wu; Chen, Jia-Rong; Yang, Wen K.; Jeng, Kee-Ching; Chen, Jenn-Tzong; Duh, Ting-Shien; Lin, Wuu-Jyh; Farn, Shiou-Shiow; Chiang, Chi-Shiun; Huang, Chia-Wen; Lin, Kun-I; Yu, Chung-Shan

    2012-01-01

    As one of the most intensively studied probes for imaging of the cellular proliferation, [ 18 F]FLT was investigated whether the targeting specificity of thymidine kinase 1 (TK1) dependency could be enhanced through a synergistic effect mediated by herpes simplex type 1 virus (HSV1) tk gene in terms of the TK1 or TK2 expression. 5-[ 123 I]Iodo arabinosyl uridine ([ 123 I]IaraU) was prepared in a radiochemical yield of 8% and specific activity of 21 GBq/μmol, respectively. Inhibition of the cellular uptake of these two tracers was compared by using the arabinosyl uridine analogs such as 5-iodo, 5-fluoro and 5-(E)-iodovinyl arabinosyl uridine along with 2′-fluoro-5-iodo arabinosyl uridine (FIAU). Due to potential instability of the iodo group, accumulation index of 1.6 for [ 123 I]IaraU by HSV1-TK vs. control cells could virtually be achieved at 1.5 h, but dropped to 0.2 compared to 2.0 for [ 18 F]FLT at 5 h. The results from competitive inhibition by these nucleosides against the accumulation of [ 18 F]FLT implied that FLT exerted a mixed TK1- and TK2-dependent inhibition with HSV1-tk gene transfection because of the shifting of thymidine kinase status. Taken together, the combination of [ 18 F]FLT and HSV1-TK provides a synergistic imaging potency.

  8. Study of [18F]FLT and [123I]IaraU for cellular imaging in HSV1 tk-transfected murine fibrosarcoma cells: evaluation of the tracer uptake using 5-fluoro, 5-iodo and 5-iodovinyl arabinosyl uridines as competitive probes.

    Science.gov (United States)

    Huang, Ho-Lien; Chiang, Li-Wu; Chen, Jia-Rong; Yang, Wen K; Jeng, Kee-Ching; Chen, Jenn-Tzong; Duh, Ting-Shien; Lin, Wuu-Jyh; Farn, Shiou-Shiow; Chiang, Chi-Shiun; Huang, Chia-Wen; Lin, Kun-I; Yu, Chung-Shan

    2012-04-01

    As one of the most intensively studied probes for imaging of the cellular proliferation, [(18)F]FLT was investigated whether the targeting specificity of thymidine kinase 1 (TK1) dependency could be enhanced through a synergistic effect mediated by herpes simplex type 1 virus (HSV1) tk gene in terms of the TK1 or TK2 expression. 5-[(123)I]Iodo arabinosyl uridine ([(123)I]IaraU) was prepared in a radiochemical yield of 8% and specific activity of 21 GBq/μmol, respectively. Inhibition of the cellular uptake of these two tracers was compared by using the arabinosyl uridine analogs such as 5-iodo, 5-fluoro and 5-(E)-iodovinyl arabinosyl uridine along with 2'-fluoro-5-iodo arabinosyl uridine (FIAU). Due to potential instability of the iodo group, accumulation index of 1.6 for [(123)I]IaraU by HSV1-TK vs. control cells could virtually be achieved at 1.5 h, but dropped to 0.2 compared to 2.0 for [(18)F]FLT at 5 h. The results from competitive inhibition by these nucleosides against the accumulation of [(18)F]FLT implied that FLT exerted a mixed TK1- and TK2-dependent inhibition with HSV1-tk gene transfection because of the shifting of thymidine kinase status. Taken together, the combination of [(18)F]FLT and HSV1-TK provides a synergistic imaging potency. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Structural Analysis of a Family 81 Glycoside Hydrolase Implicates Its Recognition of β-1,3-Glucan Quaternary Structure.

    Science.gov (United States)

    Pluvinage, Benjamin; Fillo, Alexander; Massel, Patricia; Boraston, Alisdair B

    2017-09-05

    Family 81 glycoside hydrolases (GHs), which are known to cleave β-1,3-glucans, are found in archaea, bacteria, eukaryotes, and viruses. Here we examine the structural and functional features of the GH81 catalytic module, BhGH81, from the Bacillus halodurans protein BH0236 to probe the molecular basis of β-1,3-glucan recognition and cleavage. BhGH81 displayed activity on laminarin, curdlan, and pachyman, but not scleroglucan; the enzyme also cleaved β-1,3-glucooligosaccharides as small as β-1,3-glucotriose. The crystal structures of BhGH81 in complex with various β-1,3-glucooligosaccharides revealed distorted sugars in the -1 catalytic subsite and an arrangement consistent with an inverting catalytic mechanism having a proposed conformational itinerary of 2 S 0 → 2,5 B ‡ → 5 S 1 . Notably, the architecture of the catalytic site, location of an adjacent ancillary β-1,3-glucan binding site, and the surface properties of the enzyme indicate the likely ability to recognize the double and/or triple-helical quaternary structures adopted by β-1,3-glucans. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Oxidation of 1,3,7-trimethylxanthine by hypochlorite ion

    Science.gov (United States)

    Kheidorov, V. P.; Ershov, Yu. A.; Chalyi, G. Yu.; Titorovich, O. V.

    2011-08-01

    The kinetics of the oxidative conversion of 1,3,7-trimethylxanthine upon treatment with hypochlorite ions (OCl-) in aqueous medium at 283-298 K and pH 8.2 was studied. The reaction order with respect to each component was determined and proved to be 1. It was established that the temperature dependence of the reaction rate follows the Arrhenius equation. The activation parameters of the reaction were measured: E a = 33.58 kJ/mol, Δ H ≠ = 31.12 kJ/mol, Δ S ≠ = -170.02 J/(K mol), Δ G ≠ = 81.45 kJ/mol. The stoichiometry of the reaction was studied, and the chemistry of the oxidative conversion of caffeine treated with OCl- is discussed.

  11. 2-Ureido-1,3-thiazol-3-ium dihydrogen phosphate

    Directory of Open Access Journals (Sweden)

    Kateryna Gubina

    2011-07-01

    Full Text Available The title compound, C4H6N3OS+·H2PO4−, (I, was obtained as a result of hydrolysis of [(1,3-thiazol-2-ylaminocarbonyl]phosphoramidic acid, (II, in water. X-ray analysis has shown that the N—P bond in (II breaks, leading to the formation of the substituted carbamide (I. This compound exists as an internal salt. The unit cell consists of a urea cation and an anion of H2PO4−. Protonation of the N atom of the heterocyclic ring was confirmed by the location of the H atom in a difference Fourier map. The molecules of substituted urea are connected by O...O hydrogen bonds into unlimited planes. In turn, those planes are connected to each other via N—H...O hydrogen bonds with molecules of phosphoric acid, forming a three-dimensional polymer.

  12. Toxicity of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) in three vertebrate species.

    Science.gov (United States)

    Johnson, Mark S; McFarland, Craig A; Bazar, Matthew A; Quinn, Michael J; LaFiandra, Emily May; Talent, Larry G

    2010-04-01

    The explosive, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine or high-melting explosive (HMX), has been found in soils in areas used for testing and training by the military. Many of these areas contain habitat for valued wildlife species. In an effort to better understand the environmental consequences from exposure, a reptilian (western fence lizard [Sceloporus occidentalis]), an amphibian (red-backed salamander [Plethodon cinereus]), and a mammalian species (rabbit [Oryctolagus cuniculus]) were exposed to HMX under controlled laboratory conditions. Lizards and rabbits were exposed to HMX by way of corn oil through gavage, and salamanders were exposed to HMX in soil. Two deaths occurred from acute oral exposures to lizards to 5000 mg HMX/kg BW. Histological and gross pathologic assessment suggested gut impaction as a possible cause of death. Salamanders exposed to concentrations of HMX in soil 24 h after oral exposures. An LD(50) for rabbits was calculated as 93 mg/kg (95% confidence interval 76-117). A subacute 14-day testing regime found a lowest observed effect level of 10 mg/kg-d and a no observed adverse effect level of 5 mg/kg-d based on hyperkinesia and seizure incidence, although changes suggesting functional hepatic alterations were also found. These data suggest that physiologic differences between species, particularly in gastrointestinal structure and function, can affect the absorption of HMX and hence lead to marked differences in toxicity from exposure to the same compound.

  13. LINAG phase I. A technical report, Version: 1.3

    International Nuclear Information System (INIS)

    Mittig, Wolfgang

    2002-01-01

    . General remarks; II.2. Production of accelerated ISOL - RIBs from fission and comparison with photoinduced fission; III. High intensity multi-charge ion sources for LINAG I; III.1. Constraints; III.2. Multi-charged ion sources; IV. The linear accelerator; IV.1. General layout of the linear accelerator; IV.2. Source and low energy beam transport line; IV.3. The RFQ injector; IV.4. The superconducting linear accelerator; IV.5. Layout of the driver; IV.6. Review of the driver cost evaluation; V. The target and ion source; V.1. The production and fission fragments; V.1.1. The rotating target/converter; V.1.2. The target and ion source production system; V.1.3. Production rates; V.2. Radioprotection and target handling; VI. Security and radioprotection; VI.1.1. Ion source; VI.1.2.The RFQ; VI.1.3. The liner accelerator; VI.2.1. Ion source; VI.2.2. RFQ; VI.2.3. LINAC; VI.2.4. The high energy beam transport line; VI.2.5. Beam accidents; VI.2.6. Shielding for the target/ion - source; VI.2.7. The authorization procedures; VII. Siting, post-acceleration and coupling to experimental areas; VII.1. Post acceleration option; VII.1.1. Post acceleration in using the CIME cyclotron; VII.1.2. Re-injection of the CIME beams into CSS2; VII.1.3. Post acceleration with C0 + CSS1 + CSS2; VIII. Possible links between LINAG and EURISOL; VIII.1. Background to EURISOL; VIII.2. Synergies; IX. Summary of costs and general schedule; X. Conclusion

  14. Crystal structure of 4,4-dibromo-1-(3,4-dimethoxyphenyl-2-azabuta-1,3-diene-1-carbonitrile

    Directory of Open Access Journals (Sweden)

    Marwa Chaabene

    2016-08-01

    Full Text Available The title compound, C12H10Br2N2O2, represents an example of a planar π-conjugated 2-azabutadiene molecule, which is both an interesting starting material for further organic transformations and a potential ligand in organometallic coordination chemistry. Its metric molecular parameters are typical for the family of 2-azabuta-1,3-dienes not substituted at the (CH 3-position. In the crystal, the almost planar (r.m.s. deviation = 0.0658 Å azadiene molecules form one-dimensional double-wide ribbons through intermolecular halogen bonds (C—Br...O and C—Br...Br—C, which then stack in a slipped manner through weak C—H...Br and π–π interactions to generate a three-dimensional network.

  15. 2-(1,3-Dithiolan-2-ylidene)-5-(1,3-dithian-2-ylidene)-1,3,4,6- tetrathiapentalene(DHDA-TTP), a hybrid of BDH-TTP and BDA-TTP, and its metallic cation-radical salts.

    Science.gov (United States)

    Yamada, Jun-ichi; Watanabe, Maki; Toita, Takashi; Akutsu, Hiroki; Nakatsuji, Shin'ichi; Nishikawa, Hiroyuki; Ikemoto, Isao; Kikuchi, Koichi

    2002-05-21

    The synthesis and electrochemical properties of the DHDA-TTP donor, a hybrid of 2,5-bis(1,3-dithiolan-2-ylidene)-1,3,4,6-tetrathiapentalene (BDH-TTP) and 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP), has been investigated, and its ability to form metallic cation-radical salts is elucidated.

  16. Toxicity of hexahydro-1,3,5-trinitro-1,3,5-triazine to larval zebrafish (Danio rerio)

    Science.gov (United States)

    Mukhi, S.; Pan, X.; Cobb, G.P.; Patino, R.

    2005-01-01

    Hexahydro-1,3,5-trinitro-1,3,5-triazine, a cyclonitramine commonly known as RDX, is used in the production of military munitions. Contamination of soil, sediment, and ground and surface waters with RDX has been reported in different places around the world. Acute and subacute toxicities of RDX have been relatively well documented in terrestrial vertebrates, but among aquatic vertebrates the information available is limited. The objective of this study was to characterize the acute toxicity of RDX to larval zebrafish. Mortality (LC50) and incidence of vertebral column deformities (EC50) were two of the end points measured in this study. The 96-h LC50 was estimated at 22.98 and 25.64 mg l-1 in two different tests. The estimated no-observed-effective- concentration (NOEC) values of RDX on lethality were 13.27 ?? 0.05 and 15.32 ?? 0.30 mg l-1; and the lowest-observed-effective- concentration (LOEC) values were 16.52 ?? 0.05 and 19.09 ?? 0.23 mg l-1 in these two tests, respectively. The 96-h EC50 for vertebral deformities on survivors from one of the acute lethality tests was estimated at 20.84 mg l-1, with NOEC and LOEC of 9.75 ?? 0.34 and 12.84 ?? 0.34 mg l-1, respectively. Behavioral aberrations were also noted in this acute toxicity study, including the occurrence of whirling movement and lethargic behavior. The acute effects of RDX on survival, incidence of deformities, and behavior of larval zebrafish occurred at the high end of the most frequently reported concentrations of RDX in aquatic environments. The chronic effects of RDX in aquatic vertebrates need to be determined for an adequate assessment of the ecological risk of environmental RDX. ?? 2005 Elsevier Ltd. All rights reserved.

  17. An electron spin resonance study on the gamma-irradiation of urea, urea- d4, 1-3-dimethylurea, 1-3-diethylurea and 1,1',3,3'-tetramthylurea

    International Nuclear Information System (INIS)

    Kang, Y.S.; McManus, H.J.D.; Kevan, L.

    1994-01-01

    Urea, urea-d 4 , 1,3-dimethylurea, 1,3-diethylurea powder and 1,1',3,3'-tetramethylurea, and their solutions in D 2 O were γ-irradiated with 0.0882 kGy both at room temperature and at 77 K. The product radicals were identified with X-band electron spin resonance, based on the g-factor and hyperfine coupling constants. The radicals formed from urea and urea-d 4 were identified as nitrogen-centered and resulted from N-H bond dissociation. The radicals produced from 1,3-dimethylurea, 1,3-diethylurea and 1,1',3,3'-tetramethylurea were identified as carbon-centered and resulted from C-H bond cleavage. The electron spin resonance signals of 1,3-dimethylurea, 1,3-diethylurea and 1,1',3,3'-tetramethylurea are similar in both the powder and D 2 O solution. The radicals observed from 1,3-dimethylurea, 1,3-diethylurea and 1,1',3,3'-tetramethylurea were identified as . NH-CH 2 , . NH-CHCH 3 and . (CH 3 )(CH 2 ), respectively. (author)

  18. Technical advance: Generation of human pDC equivalents from primary monocytes using Flt3-L and their functional validation under hypoxia.

    Science.gov (United States)

    Sekar, Divya; Brüne, Bernhard; Weigert, Andreas

    2010-08-01

    The division of labor between DC subsets is evolutionarily well-defined. mDC are efficient in antigen presentation, whereas pDC act as rheostats of the immune system. They activate NK cells, cause bystander activation of mDC, and interact with T cells to induce tolerance. This ambiguity positions pDC at the center of inflammatory diseases, such as cancer, arthritis, and autoimmune diseases. The ability to generate human mDC ex vivo made it possible to engineer them to suit therapy needs. Unfortunately, a similar, easily accessible system to generate human pDC is not available. We describe a method to generate human pDC equivalents ex vivo, termed mo-pDC from peripheral blood monocytes using Flt3-L. mo-pDC showed a characteristic pDC profile, such as high CD123 and BDCA4, but low CD86 and TLR4 surface expression and a low capacity to induce autologous lymphocyte proliferation and to phagocytose apoptotic debris in comparison with mDC. Interestingly, mo-pDC up-regulated the pDC lineage-determining transcription factor E2-2 as well as expression of BDCA2, which is under the transcriptional control of E2-2 but not its inhibitor ID2, during differentiation. mo-pDC produced high levels of IFN-alpha when pretreated overnight with TNF-alpha. Under hypoxia, E2-2 was down-regulated, and ID2 was induced in mo-pDC, whereas surface expression of MHCI, CD86, and BDCA2 was decreased. Furthermore, mo-pDC produced high levels of inflammatory cytokines when differentiated under hypoxia compared with normoxia. Hence, mo-pDC can be used to study differentiation and functions of human pDC under microenvironmental stimuli.

  19. Photoluminescence of 1,3-dimethyl pyrazoloquinoline derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Koscien, E. [1st Liceum, Sobieskiego 22, 42-700 Lubliniec (Poland); Gondek, E.; Pokladko, M. [Institute of Physics, Technical University of Krakow, Podhorazych 1, 30-084 Krakow (Poland); Jarosz, B. [Department of Chemistry, Hugon Kollotaj Agricultural University, Al. Mickiewicza 24/28, 30-059 Krakow (Poland); Vlokh, R.O. [Institute of Physical Optics, Dragomanova 23, 79005 Lviv (Ukraine); Kityk, A.V. [Department of Electrical Engineering, Czestochowa University of Technology, Al. Armii Krajowej 17, 42-200 Czestochowa (Poland)], E-mail: kityk@ap.univie.ac.at

    2009-04-15

    This paper presents absorption and photoluminescence of 6-F, 6-Br, 6-Cl, 7-TFM and 6-COOEt derivatives of 1,3-dimethyl-1H-Pyrazolo[3,4-b]quinoline (DMPQ). The measured absorption and emission spectra are compared with the quantum chemical calculations performed by means of the semi-empirical methods (AM1 or PM3) that are applied either to the equilibrium conformations in vacuo (T = 0 K) or combined with the molecular dynamics simulations (T = 300 K). The spectra calculated by the AM1 method appear to be for all dyes in practically excellent agreement with the measured ones. In particular, the position of the first absorption band is obtained with the accuracy up to a few nanometers, whereas the calculated photoluminescence spectra predict the positions of the emission maxima for a gas phase with the accuracy up to 10-18 nm. The photoemission spectra of DMPQ dyes are considerably less solvatochromic comparing to phenyl-containing pyrazoloquinoline derivatives. According to the quantum chemical analysis the reason for such behaviour lies in a local character of the electronic transitions of DMPQ dyes which are characterized by a relatively small difference between the excited state and ground state dipole moments. Importantly that the rotational dynamics of both methyl subunits does not change this situation.

  20. Human postprandial gastric emptying of 1-3-millimeter spheres

    International Nuclear Information System (INIS)

    Meyer, J.H.; Elashoff, J.; Porter-Fink, V.; Dressman, J.; Amidon, G.L.

    1988-01-01

    Microspheres of pancreatin should empty from the stomachs of patients with pancreatic insufficiency as fast as food. The present study was undertaken in 26 healthy subjects to identify the size of spheres that would empty from the stomach with food and to determine whether different meals alter this size. Spheres of predefined sizes were labeled with /sup 113m/In or /sup 99m/Tc. Using a gamma-camera, we studied the concurrent gastric emptying of spheres labeled with /sup 113m/In and of chicken liver labeled with /sup 99m/Tc in 100-g, 154-kcal or 420-g, 919-kcal meals, or the concurrent emptying of 1-mm vs. larger spheres. One-millimeter spheres emptied consistently (p less than 0.01, paired t-test) faster than 2.4- or 3.2-mm spheres when ingested together with either the 420- or 100-g meals. Thus, in the 1-3-mm range of diameters, sphere size was a more important determinant of sphere emptying than meal size. Statistical analyses indicated that spheres 1.4 +/- 0.3 mm in diameter with a density of 1 empty at the same rate as /sup 99m/Tc-liver. Our data indicate some commercially marketed microspheres of pancreatin will empty too slowly to be effective in digestion of food

  1. Human postprandial gastric emptying of 1-3-millimeter spheres

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, J.H.; Elashoff, J.; Porter-Fink, V.; Dressman, J.; Amidon, G.L.

    1988-06-01

    Microspheres of pancreatin should empty from the stomachs of patients with pancreatic insufficiency as fast as food. The present study was undertaken in 26 healthy subjects to identify the size of spheres that would empty from the stomach with food and to determine whether different meals alter this size. Spheres of predefined sizes were labeled with /sup 113m/In or /sup 99m/Tc. Using a gamma-camera, we studied the concurrent gastric emptying of spheres labeled with /sup 113m/In and of chicken liver labeled with /sup 99m/Tc in 100-g, 154-kcal or 420-g, 919-kcal meals, or the concurrent emptying of 1-mm vs. larger spheres. One-millimeter spheres emptied consistently (p less than 0.01, paired t-test) faster than 2.4- or 3.2-mm spheres when ingested together with either the 420- or 100-g meals. Thus, in the 1-3-mm range of diameters, sphere size was a more important determinant of sphere emptying than meal size. Statistical analyses indicated that spheres 1.4 +/- 0.3 mm in diameter with a density of 1 empty at the same rate as /sup 99m/Tc-liver. Our data indicate some commercially marketed microspheres of pancreatin will empty too slowly to be effective in digestion of food.

  2. FLT3 ligand preserves the uncommitted CD34+CD38- progenitor cells during cytokine prestimulation for retroviral transduction

    DEFF Research Database (Denmark)

    Nielsen, S D; Husemoen, L L; Sørensen, T U

    2000-01-01

    for transduction of CD34+ cells. The effect of cytokine prestimulation on transduction efficiency and the population of uncommitted CD34+CD38- cells was determined. CD34+ cells harvested from umbilical cord blood were kept in suspension cultures and stimulated with combinations of the cytokines stem cell factor......Before stem cell gene therapy can be considered for clinical applications, problems regarding cytokine prestimulation remain to be solved. In this study, a retroviral vector carrying the genes for the enhanced version of green fluorescent protein (EGFP) and neomycin resistance (neo(r)) was used...... in a higher percentage of cells than the EGFP gene, but there seemed to be a positive correlation between expression of the two genes. The effect of cytokine prestimulation was therefore monitored using EGFP as marker for transduction. When SCF was compared to SCF in combination with more potent cytokines...

  3. {sup 18}F-FLT PET/CT as an imaging tool for early prediction of pathological response in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy: a pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Crippa, Flavio; Padovano, Barbara; Alessi, Alessandra; Bombardieri, Emilio; Pascali, Claudio; Bogni, Anna [Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy). Nuclear Medicine Unit; Agresti, Roberto; Maugeri, Ilaria; Rampa, Mario; Martelli, Gabriele [Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy). Breast Surgery Unit; Sandri, Marco [Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy). Molecular Targeting Unit; Mariani, Gabriella; Bianchi, Giulia; De Braud, Filippo [Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy). Medical Oncology Unit; Carcangiu, Maria Luisa [Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy). Pathology Unit; Trecate, Giovanna [Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy). Radiology-RMI Unit

    2015-05-01

    We evaluated whether {sup 18}F-3'-deoxy-3'-fluorothymidine positron emission tomography (FLT PET) can predict the final postoperative histopathological response in primary breast cancer after the first cycle of neoadjuvant chemotherapy (NCT). In this prospective cohort study of 15 patients with locally advanced operable breast cancer, FLT PET evaluations were performed before NCT, after the first cycle of NCT, and at the end of NCT. All patients subsequently underwent surgery. Variables from FLT PET examinations were correlated with postoperative histopathological results. At baseline, median of maximum standardized uptake values (SUV{sub max}) in the groups showing a complete pathological response (pCR) + residual cancer burden (RCB) I, RCB II or RCB III did not differ significantly for the primary tumour (5.0 vs. 2.9 vs. 8.9, p = 0.293) or for axillary nodes (7.9 vs. 1.6 vs. 7.0, p = 0.363), whereas the Spearman correlation between SUV{sub max} and Ki67 proliferation rate index was significant (r = 0.69, p < 0.001). Analysis of the relative percentage change of SUV{sub max}in the primary tumour (∇SUVT{sub max}(t{sub 1})) and axillary nodes (∇SUVN{sub max}(t{sub 1})) after the first NCT cycle showed that the power of ∇SUVT{sub max}(t{sub 1}) to predict pCR + RCB I responses (AUC = 0.91, p < 0.001) was statistically significant, whereas ∇SUVN{sub max}(t{sub 1}) had a moderate ability (AUC = 0.77, p = 0.119) to separate subjects with ΔSUVT{sub max}(t{sub 1}) > -52.9 % into two groups: RCB III patients and a heterogeneous group that included RCB I and RCB II patients. A predictive score μ based on ΔSUVT{sub max}(t{sub 1}) and ΔSUVN{sub max}(t{sub 1}) parameters is proposed. The preliminary findings of the present study suggest the potential utility of FLT PET scans for early monitoring of response to NCT and to formulate a therapeutic strategy consistent with the estimated efficacy of NCT. However, these results in a small patient population

  4. PU.1 is essential for CD11c expression in CD8(+/CD8(- lymphoid and monocyte-derived dendritic cells during GM-CSF or FLT3L-induced differentiation.

    Directory of Open Access Journals (Sweden)

    Xue-Jun Zhu

    Full Text Available Dendritic cells (DCs regulate innate and acquired immunity through their roles as antigen-presenting cells. Specific subsets of mature DCs, including monocyte-derived and lymphoid-derived DCs, can be distinguished based on distinct immunophenotypes and functional properties. The leukocyte integrin, CD11c, is considered a specific marker for DCs and it is expressed by all DC subsets. We created a strain of mice in which DCs and their progenitors could be lineage traced based on activity of the CD11c proximal promoter. Surprisingly, we observed levels of CD11c promoter activity that were similar in DCs and in other mature leukocytes, including monocytes, granulocytes, and lymphocytes. We sought to identify DNA elements and transcription factors that regulate DC-associated expression of CD11c. The ets transcription factor, PU.1, is a key regulator of DC development, and expression of PU.1 varies in different DC subsets. GM-CSF increased monocyte-derived DCs in mice and from mouse bone marrow cultured in vitro, but it did not increase CD8(+ lymphoid-derived DCs or B220(+ plasmacytoid DCs. FLT3L increased both monocyte-derived DCs and lymphoid-derived DCs from mouse bone marrow cultured in vitro. GM-CSF increased the 5.3 Kb CD11c proximal promoter activity in monocyte-derived DCs and CD8(+ lymphoid-derived DCs, but not in B220(+ plasmacytoid DCs. In contrast, FLT3L increased the CD11c proximal promoter activity in both monocyte-derived DCs and B220(+ plasmacytoid DCs. We used shRNA gene knockdown and chromatin immunoprecipitation to demonstrate that PU.1 is required for the effects of GM-CSF or FLT3L on monocyte-derived DCs. We conclude that both GM-CSF and FLT3L act through PU.1 to activate the 5.3 Kb CD11c proximal promoter in DCs and to induce differentiation of monocyte-derived DCs. We also confirm that the CD11c proximal promoter is not sufficient to direct lineage specificity of CD11c expression, and that additional DNA elements are required

  5. In vitro antioxidant activity of thiazolidinone derivatives of 1,3-thiazole and 1,3,4-thiadiazole.

    Science.gov (United States)

    Djukic, Mirjana; Fesatidou, Mara; Xenikakis, Iakovos; Geronikaki, Athina; Angelova, Violina T; Savic, Vladimir; Pasic, Marta; Krilovic, Branislav; Djukic, Dusan; Gobeljic, Borko; Pavlica, Marina; Djuric, Ana; Stanojevic, Ivan; Vojvodic, Danilo; Saso, Luciano

    2018-04-25

    The initial steps in preclinical drug developing research concern the synthesis of new compounds for specific therapeutic use which needs to be confirmed by in vitro and then in vivo testing. Nine thiazolidinone derivatives (numerically labeled 1-9) classified as follows: 1,3-thiazole-based compounds (1 and 2); 1,3,4-thiadiazole based compounds (3 and 4); substituted 5-benzylideno-2-adamantylthiazol[3,2-b][1,2,4]triazol-6(5H)ones (5-8); and an ethylaminothiazole-based chalcone (9), were tested for antioxidant activity (AOA) by using three in vitro assays: DPPH (1,1-diphenyl-2-picrylhydrazyl scavenging capacity test); FRAP (ferric reducing antioxidant power test); and TBARS (thiobarbituric acid reactive substances test). Compounds 1-4 and 9 in particular are newly synthesized compounds. Also, traditional antioxidants Vitamins E and C and α-lipoic acid (α-LA) were tested. The results of DPPH testing: Vitamin C 94.35%, Vitamin E 2.99% and α-LA 1.57%; compounds: 4 33.98%; 2 18.73%; 1 15.62%; 5 6.59%; 3 4.99%; 6-9 demonstrated almost no AOA. The results of TBARS testing (% of LPO inhibition): Vitamin C 62.32%; Vitamin E 36.29%; α-LA 51.36%; compounds: 1 62.11%; 5 66.71%; 9 60.93%; 4, 6 and 7 demonstrated ∼50%; 3 and 8 displayed ∼38%; 2 23.51%. By FRAP method, Vitamins E and C showed equal AOA, ∼100%, unlike α-LA (no AOA), and AOA of the tested compounds (expressed as a fraction of the AOA of Vitamin C) were: 2 and 4-75%; 8, 3 and 1-45%; 5-7 and 9-27%. Different red-ox reaction principles between these assays dictate different AOA outcomes for a single compound. Vitamin C appeared to be the superior antioxidant out of the traditional antioxidants; and compound 4 was superior to other tested thiazolidinone derivatives. Vitamin C appeared to be the superior antioxidant out of the traditional antioxidants; and compound 4 was superior to other tested thiazolidinone derivatives. Phenyl-functionalized benzylidene, amino-carbonyl functional domains and chelating

  6. Zn-Doped LiNi1/3Co1/3Mn1/3O2 Composite as Cathode Material for Lithium Ion Battery: Preparation, Characterization, and Electrochemical Properties

    Directory of Open Access Journals (Sweden)

    Han Du

    2015-01-01

    Full Text Available Zn-doped LiNi1/3Co1/3Mn1/3O2 composite, Li(Ni1/3Co1/3Mn1/31–xZnxO2 (x = 0.02; 0.05; 0.08, is synthesized by the sol-gel method. The crystal structure, morphology, and electrochemical performance are investigated via X-ray diffraction (XRD, scanning electron microscope (SEM, cyclic voltammetry (CV, and constant current charge/discharge experiment. The result reveals that Zn-doping cathode material can reach the initial charge/discharge capacity of 188.8/162.9 mAh·g−1 for Li(Ni1/3Co1/3Mn1/30.98Zn0.02O2 and 179.0/154.1 mAh·g−1 for Li(Ni1/3Co1/3Mn1/30.95Zn0.05O2 with the high voltage of 4.4 V at 0.1 C. Furthermore, the capacity retention of Li(Ni1/3Co1/3Mn1/30.98Zn0.02O2 is 95.1% at 0.5 C after 50 cycles at room temperature. The improved electrochemical properties of Zn-doped LiNi1/3Co1/3Mn1/3O2 are attributed to reduced electrode polarization, enhanced capacity reversibility, and excellent cyclic performance.

  7. SRSF1-3 contributes to diversification of the immunoglobulin variable region gene by promoting accumulation of AID in the nucleus.

    Science.gov (United States)

    Kawaguchi, Yuka; Nariki, Hiroaki; Kawamoto, Naoko; Kanehiro, Yuichi; Miyazaki, Satoshi; Suzuki, Mari; Magari, Masaki; Tokumitsu, Hiroshi; Kanayama, Naoki

    2017-04-01

    Activation-induced cytidine deaminase (AID) is essential for diversification of the Ig variable region (IgV). AID is excluded from the nucleus, where it normally functions. However, the molecular mechanisms responsible for regulating AID localization remain to be elucidated. The SR-protein splicing factor SRSF1 is a nucleocytoplasmic shuttling protein, a splicing isoform of which called SRSF1-3, has previously been shown to contribute to IgV diversification in chicken DT40 cells. In this study, we examined whether SRSF1-3 functions in IgV diversification by promoting nuclear localization of AID. AID expressed alone was localized predominantly in the cytoplasm. In contrast, co-expression of AID with SRSF1-3 led to the nuclear accumulation of both AID and SRSF1-3 and the formation of a protein complex that contained them both, although SRSF1-3 was dispensable for nuclear import of AID. Expression of either SRSF1-3 or a C-terminally-truncated AID mutant increased IgV diversification in DT40 cells. However, overexpression of exogenous SRSF1-3 was unable to further enhance IgV diversification in DT40 cells expressing the truncated AID mutant, although SRSF1-3 was able to form a protein complex with the AID mutant. These results suggest that SRSF1-3 promotes nuclear localization of AID probably by forming a nuclear protein complex, which might stabilize nuclear AID and induce IgV diversification in an AID C-terminus-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Effect of Nb doping on electrochemical properties of LiNi{sub 1/3}Co{sub 1/3}Mn{sub 1/3}O{sub 2} at high cutoff voltage for lithium-ion battery

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Jiefan [School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130 (China); Liu, Hongguang, E-mail: hongguangliu_01@163.com [School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130 (China); CNOOC Tianjin Chemical Research & Design Institute, Tianjin 300131 (China); Ye, Xuehai; Xia, Jiping; Lu, Yang; Lin, Chaowang; Yu, Xiaowei [CNOOC Tianjin Chemical Research & Design Institute, Tianjin 300131 (China)

    2015-09-25

    Highlights: • Nb substituted LiNi{sub 1/3}Co{sub 1/3}Mn{sub 1/3−x}Nb{sub x}O{sub 2} (x = 0–0.03) was prepared by sol–gel method. • 2% Nb-substituted sample showed better cycle performance at high cutoff voltage. • Ex situ analysis was used to show the structure changes of Nb-doped samples. - Abstract: Nb doped cathode materials with the formula LiNi{sub 1/3}Co{sub 1/3}Mn{sub 1/3−x}Nb{sub x}O{sub 2} (x = 0, 0.01, 0.02, 0.03) have been prepared successfully by sol–gel method. The effect of Nb substitution on the crystal structure and electrochemical properties of LiNi{sub 1/3}Co{sub 1/3}Mn{sub 1/3}O{sub 2} were studied systematically by X-ray diffraction (XRD) and various electrochemical measurements. The results showed Nb substitution played an important role in the good cycling performance of LiNi{sub 1/3}Co{sub 1/3}Mn{sub 1/3}O{sub 2}. Charge/discharge tests revealed that LiNi{sub 1/3}Co{sub 1/3}Mn{sub 1/3–0.02}Nb{sub 0.02}O{sub 2} showed a capacity retention of 94.1% at 1 C after 50 cycles in a high cutoff voltage range (3.0–4.6 V), while discharge capacity of LiNi{sub 1/3}Co{sub 1/3}Mn{sub 1/3}O{sub 2} remains only 89.4% of that at 1 C. Ex-situ XRD analysis and EIS analysis indicated that the improved electrochemical properties of Nb-doped sample result from the more stable structure and lower resistance during the electrochemical cycling.

  9. Enhancement of electrochemical performance of LiNi_1_/_3Co_1_/_3Mn_1_/_3O_2 by surface modification with MnO_2

    International Nuclear Information System (INIS)

    Guo, Xin; Cong, Li-Na; Zhao, Qin; Tai, Ling-Hua; Wu, Xing-Long; Zhang, Jing-Ping; Wang, Rong-Shun; Xie, Hai-Ming; Sun, Li-Qun

    2015-01-01

    LiNi_1_/_3Co_1_/_3Mn_1_/_3O_2 is successfully coated with MnO_2 by a chemical deposition method. The X-ray diffraction (XRD), scanning electron microscope (SEM) and high resolution transmission electron microscope (HRTEM) results demonstrate that MnO_2 forms a thin layer on the surface of LiNi_1_/_3Co_1_/_3Mn_1_/_3O_2 without destroying the crystal structure of the core material. Compared with pristine LiNi_1_/_3Co_1_/_3Mn_1_/_3O_2, the MnO_2-coated sample shows enhanced electrochemical performance especially the rate capability. Even at a current density of 750 mA g"−"1, the discharge capacity of MnO_2-coated LiNi_1_/_3Co_1_/_3Mn_1_/_3O_2 is 155.15 mAh g"−"1, while that of the pristine electrode is only 132.84 mAh g"−"1 in the range of 2.5–4.5 V. The cyclic voltammetry (CV) and X-ray photoelectron spectroscopy (XPS) curves show that the MnO_2 coating layer reacts with Li"+ during cycling, which is responsible for the higher discharge capacity of MnO_2-coated LiNi_1_/_3Co_1_/_3Mn_1_/_3O_2. Electrochemical impedance spectroscopy (EIS) results confirmed that the MnO_2 coating layer plays an important role in reducing the charge transfer resistance on the electrolyte–electrode interfaces. - Highlights: • MnO_2 coated LiNi_1_/_3Co_1_/_3Mn_1_/_3O_2 cathode material is synthesized for the first time. • MnO_2 offers available sites for insertion of extracted lithium. • The preserved surface and crystal structures results in the improved kinetics.

  10. A facile synthesis of Li_2Fe_1_/_3Mn_1_/_3Ni_1_/_3SiO_4/C composites as cathode materials for lithium-ion batteries

    International Nuclear Information System (INIS)

    Yang, Rong; Wang, Liqing; Deng, Kunfa; Lv, Mengni; Xu, Yunhua

    2016-01-01

    The novel Li_2Fe_1_/_3Mn_1_/_3Ni_1_/_3SiO_4/C has been successfully synthesized by a feasible solution process in ternary system. The spherical carbon-coated composites are obtained using a heat treatment in the presence of sucrose. X-ray diffraction (XRD) diffractogram displays that the Li_2Fe_1_/_3Mn_1_/_3Ni_1_/_3SiO_4/C crystallized in an orthorhombic structure with a space group of Pmn21. The energy-dispersive X-ray spectroscopy mappings indicate that Fe, Mn and Ni elements are distributed homogenously in Li_2Fe_1_/_3Mn_1_/_3Ni_1_/_3SiO_4/C nano-spherical particle with size less than 50 nm. The lithium storage capacity and cycling performance of the Li_2Fe_1_/_3Mn_1_/_3Ni_1_/_3SiO_4/C presents good results when tested as cathode materials in lithium cells at room temperature. It delivers an initial discharge capacity of 181.4 mAh g"−"1 and a discharge capacity of 172.9 mAh g"−"1 after 20 cycles at 0.1C in the voltage range of 1.5–4.6V. Furthermore, it also exhibits an excellent rate capability with a capacity under different current densities of about 144.0 mAh g"−"1 (0.2 C), 117.9 mAh g"−"1 (0.5 C), 106.1 mAh g"−"1 (1 C), respectively and a good capacity cycling maintenance of 153.7 mAh g"−"1 after 60 cycles. Above results indicate that the spherical Li_2Fe_1_/_3Mn_1_/_3Ni_1_/_3SiO_4/C becomes a very promising candidate for cathode material in lithium-ion batteries. - Highlights: • Li_2Fe_1_/_3Mn_1_/_3Ni_1_/_3SiO_4/C was obtained by solution process in a ternary system. • The material was pure phase ternary solid solution with tetrahedral morphology. • The spherical particle size was less than 50 nm with graphitized carbon coating. • The nanocomposite revealed high discharge capacity and excellent rate capability.

  11. Red rot resistant transgenic sugarcane developed through expression of β-1,3-glucanase gene.

    Directory of Open Access Journals (Sweden)

    Shivani Nayyar

    Full Text Available Sugarcane (Saccharum spp. is a commercially important crop, vulnerable to fungal disease red rot caused by Colletotrichum falcatum Went. The pathogen attacks sucrose accumulating parenchyma cells of cane stalk leading to severe losses in cane yield and sugar recovery. We report development of red rot resistant transgenic sugarcane through expression of β-1,3-glucanase gene from Trichoderma spp. The transgene integration and its expression were confirmed by quantitative reverse transcription-PCR in first clonal generation raised from T0 plants revealing up to 4.4-fold higher expression, in comparison to non-transgenic sugarcane. Bioassay of transgenic plants with two virulent C. falcatum pathotypes, Cf 08 and Cf 09 causing red rot disease demonstrated that some plants were resistant to Cf 08 and moderately resistant to Cf 09. The electron micrographs of sucrose storing stalk parenchyma cells from these plants displayed characteristic sucrose-filled cells inhibiting Cf 08 hyphae and lysis of Cf 09 hyphae; in contrast, the cells of susceptible plants were sucrose depleted and prone to both the pathotypes. The transgene expression was up-regulated (up to 2.0-fold in leaves and 5.0-fold in roots after infection, as compared to before infection in resistant plants. The transgene was successfully transmitted to second clonal generation raised from resistant transgenic plants. β-1,3-glucanase protein structural model revealed that active sites Glutamate 628 and Aspartate 569 of the catalytic domain acted as proton donor and nucleophile having role in cleaving β-1,3-glycosidic bonds and pathogen hyphal lysis.

  12. β-1,3-1,4-glucanase gene from Bacillus velezensis ZJ20 exerts antifungal effect on plant pathogenic fungi.

    Science.gov (United States)

    Xu, Ting; Zhu, Tianhui; Li, Shujiang

    2016-02-01

    Bacillus velezensis is a known antifungal bacteria. To understand the role of β-1, 3-1, 4-glucanase played on B. velezensis about the mechanism which exerts effect on fungi, we isolated and cloned the β-1, 3-1, 4-glucanase gene (Bglu1) from B. velezensis ZJ20. The Bglu1 open reading frame was 732 bp that encoded a protein with 243 amino acids and a calculated molecular weight of 27.3 kDa. The same gene without the signal peptide, termed Bglu2, was also cloned and expressed in E. coli BL21. Among the two variants, only Bglu2 protein was expressed. Purified Bglu2 could be eluted with imidazole solution at concentrations ranging from 100 to 500 mM although the highest expression was observed at 150 and 200 mM and the purest was at 500 mM. In addition, activity of the crude enzyme was 1527 U ml(-1) and the highest activity of the purified enzyme was 1706 U ml(-1). The purified β-1, 3-1, 4-glucanase had activity on a wide range of pH and temperatures and displayed optimal activity at pH 5.0 and 35 °C. More importantly, the mycelial morphology of three pathogenic fungi was destroyed by the purified β-1, 3-1, 4-glucanase. In conclusion, β-1, 3-1, 4-glucanase from B. velezensis ZJ20 can be highly expressed in E. coli BL21 and the recombinant protein is pathogenic to fungi.

  13. Spin freezing phenomenon and transport properties in La{sub 1/3}Nd{sub 1/3}Ba{sub 1/3}MnO{sub 3}

    Energy Technology Data Exchange (ETDEWEB)

    Li Guoqing E-mail: gqli@mail.sy.ln.cn; Ze Xianyu; Kim, C.-O.; Kim, H.-J.; Lee, Y.-W

    2002-02-01

    The magnetic and transport properties of La{sub 1/3}Nd{sub 1/3}Ba{sub 1/3}MnO{sub 3} with the colossal magnetoresistant (CMR) effect were studied by using SQUID. The irreversible curve for magnetizing intensity vs. temperature in an applied magnetic field of 13 Oe indicates that the spins of electrons are frozen, and therefore spin-glass state is probably formed below the Curie temperature. This fact implied that La{sub 1/3}Nd{sub 1/3}Ba{sub 1/3}MnO{sub 3} is mictomagnetic, that is, ferromagnetism and antiferromagnetism co-exist in this kind of material.

  14. Chitinase, beta-1,3-glucanase, osmotin, and extensin are expressed in tobacco explants during flower formation

    DEFF Research Database (Denmark)

    Neale, A D; Wahleithner, J A; Lund, Marianne

    1990-01-01

    be considered a pathogenesis-related protein. These genes, which were highly expressed in explants during de novo flower formation but not in explants forming vegetative shoots [Meeks-Wagner et al. (1989). Plant Cell 1, 25-35], were also regulated developmentally in day-neutral and photoresponsive tobacco......Sequence analysis of five gene families that were isolated from tobacco thin cell layer explants initiating floral development [Meeks-Wagner et al. (1989). Plant Cell 1, 25-35] showed that two encode the pathogenesis-related proteins basic chitinase and basic beta-1,3-glucanase, while a third...... encodes the cell wall protein extensin, which also accumulates during pathogen attack. Another sequence family encodes the water stress-induced protein osmotin [Singh et al. (1989). Plant Physiol. 90, 1096-1101]. We found that osmotin was also induced by viral infection and wounding and, hence, could...

  15. Improved high-voltage performance of LiNi1/3Co1/3Mn1/3O2 cathode with Tris(2,2,2-trifluoroethyl) phosphite as electrolyte additive

    International Nuclear Information System (INIS)

    Wang, Long; Ma, Yulin; Li, Qin; Cui, Yingzhi; Wang, Panpan; Cheng, Xinqun; Zuo, Pengjian; Du, Chunyu; Gao, Yunzhi

    2017-01-01

    Tris(2,2,2-trifluoroethyl) phosphite (TTFEP) is investigated as an electrolyte additive to improve the electrochemical performance of LiNi 1/3 Co 1/3 Mn 1/3 O 2 cathode at high operating voltage (4.6 V). Charge/discharge measurements demonstrate that TTFEP is effective to improve the cycling stability and rate capability of LiNi 1/3 Co 1/3 Mn 1/3 O 2 cathode. The capacity retention of LiNi 1/3 Co 1/3 Mn 1/3 O 2 /Li cell with 1% TTFEP-containing electrolyte reaches up to 85.4% after 100 cycles at 0.5C (1C = 160 mA g −1 ), while that of the cell with the baseline electrolyte (1 M LiPF 6 in EC/DMC electrolyte) only remains 74.2%. Moreover, the discharge capacity of the cathode with 1% TTFEP-containing electrolyte could maintain around 112.0 mAh g −1 at 4C. Based on the characterization of electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), a protective interphase film formed on the cathode surface can be found due to the preferential oxidation of TTFEP, which inhibits the electrolyte decomposition and mitigates the cathode structural destruction, leading to the improved electrochemical performance of LiNi 1/3 Co 1/3 Mn 1/3 O 2 cathode at high voltage.

  16. The sFlt-1/PlGF ratio associates with prolongation and adverse outcome of pregnancy in women with (suspected) preeclampsia: analysis of a high-risk cohort.

    Science.gov (United States)

    Saleh, Langeza; Verdonk, Koen; Jan Danser, A H; Steegers, Eric A P; Russcher, Henk; van den Meiracker, Anton H; Visser, Willy

    2016-04-01

    To evaluate the additive value of the sFlt-1/PlGF ratio for diagnosing preeclampsia (PE) and predicting prolongation of pregnancy and adverse outcome in a cohort of women with PE or at high risk of PE. Patients with suspected or confirmed clinical PE were recruited. At time of inclusion blood for measurement of sFlt-1and PlGF was taken. Values were determined after delivery. A cut-off ratio of ≥85 was defined as a positive test. A total of 107 patients were included. Of the patients, 62 (58%) met the clinical criteria of PE at time of blood sampling. In 10% of these patients (n=6) the ratio was ratio was ≥85 (false positive), resulting in positive and negative predictive values of 95% and 88% respectively. One patient with false positive ratio developed superimposed PE and 2 developed gestational hypertension, and adverse outcome occurred in all three. An adverse pregnancy outcome was only encountered in 1 of the 6 patients with a false negative ratio. Using a binary regression model with adjustment for gestational age ratio (P=0.036). The additive value of an increased ratio for diagnosing PE is limited since most patients with clinical PE also have a positive ratio. However, an elevated ratio is superior to the clinical diagnosis of PE for predicting an adverse pregnancy outcome. Furthermore, irrespective of clinical PE, a low ratio is inversely correlated with prolongation of pregnancy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Influence of Temperature on the Performance of LiNi1/3Co1/3Mn1/3O2 Prepared by High-Temperature Ball-Milling Method

    Directory of Open Access Journals (Sweden)

    Ming Tian

    2018-01-01

    Full Text Available Aiming at the preparation of high electrochemical performance LiNi1/3Co1/3Mn1/3O2 cathode material for lithium-ion battery, LiNi1/3Co1/3Mn1/3O2 was prepared with lithium carbonate, nickel (II oxide, cobalt (II, III oxide, and manganese dioxide as raw materials by high-temperature ball-milling method. Influence of ball-milling temperature was investigated in this work. It was shown that the fine LiNi1/3Co1/3Mn1/3O2 powder with high electrochemical performance can be produced by the high-temperature ball-milling process, and the optimal ball-milling temperature obtained in the current study was 750°C. Its initial discharge capacity was 146.0 mAhg−1 at the rate of 0.1 C, and over 50 cycles its capacity retention rate was 90.2%.

  18. Uncovering a facile large-scale synthesis of LiNi1/3Co1/3Mn1/3O2 nanoflowers for high power lithium-ion batteries

    Science.gov (United States)

    Hua, Wei-Bo; Guo, Xiao-Dong; Zheng, Zhuo; Wang, Yan-Jie; Zhong, Ben-He; Fang, Baizeng; Wang, Jia-Zhao; Chou, Shu-Lei; Liu, Heng

    2015-02-01

    Developing advanced electrode materials that deliver high energy at ultra-fast charge and discharge rates are very crucial to meet an increasing large-scale market demand for high power lithium ion batteries (LIBs). A three-dimensional (3D) nanoflower structure is successfully developed in the large-scale synthesis of LiNi1/3Co1/3Mn1/3O2 material for the first time. The fast co-precipitation is the key technique to prepare the nanoflower structure in our method. After heat treatment, the obtained LiNi1/3Co1/3Mn1/3O2 nanoflowers (NL333) pronouncedly present a pristine flower-like nano-architecture and provide fast pathways for the transport of Li-ions and electrons. As a cathode material in a LIB, the prepared NL333 electrode demonstrates an outstanding high-rate capability. Particularly, in a narrow voltage range of 2.7-4.3 V, the discharge capacity at an ultra-fast charge-discharge rate (20C) is up to 126 mAh g-1, which reaches 78% of that at 0.2C, and is much higher than that (i.e., 44.17%) of the traditional bulk LiNi1/3Co1/3Mn1/3O2.

  19. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies

    Directory of Open Access Journals (Sweden)

    Srdan Verstovsek

    2016-12-01

    Full Text Available Abstract Background Pacritinib (SB1518 is a highly selective kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. This multicenter phase 1/2 study evaluated the maximum tolerated dose (MTD, safety, and clinical activity of pacritinib in patients with myelofibrosis (MF and other advanced myeloid malignancies. Methods In the phase 1 dose-escalation part of the study, 43 adults with advanced myeloid malignancies received pacritinib 100 to 600 mg once daily (QD. In the phase 2 part of the study, 31 adults with refractory or intermediate- or high-risk newly diagnosed MF and any degree of cytopenia received pacritinib 400 mg QD. The primary endpoint is a ≥35% reduction in spleen volume at week 24 as determined by magnetic resonance imaging. Results Five patients (11.6% experienced a dose-limiting toxicity during cycle 1 of phase 1. The clinical benefit rate was 86.0% (13 patients achieving clinical improvement and 24 patients having stable disease. The MTD was established at 500 mg QD, and the recommended phase 2 dose was 400 mg QD. In phase 2, the primary endpoint was achieved by 23.5% of evaluable patients (4/17, with 47.4% (9/19 achieving a ≥50% spleen length reduction at week 24 as measured by physical examination. At week 24, 38.9% of evaluable patients (7/18 achieved a ≥50% decrease in MF Quality of Life and Symptom Assessment total score. Gastrointestinal toxicities were the most common adverse events and were predominantly grade 1/2 in severity. Grade 3/4 anemia was reported in 5/31 patients and grade 3/4 thrombocytopenia was reported in 3/31 patients. The most frequent AEs considered to be treatment related were diarrhea (28/31, nausea (15/31, vomiting (9/31, and fatigue (4/31. Grade 3 treatment-related AEs were reported in seven patients (22.6%, four of whom had diarrhea. No grade 4/5 treatment-related AEs were reported. No leukopenia, neutropenia, or lymphopenia were reported. Conclusions Pacritinib was well

  20. A novel process for recycling and resynthesizing LiNi1/3Co1/3Mn1/3O2 from the cathode scraps intended for lithium-ion batteries

    International Nuclear Information System (INIS)

    Zhang, Xihua; Xie, Yongbing; Cao, Hongbin; Nawaz, Faheem; Zhang, Yi

    2014-01-01

    Highlights: • A simple process to recycle cathode scraps intended for lithium-ion batteries. • Complete separation of the cathode material from the aluminum foil is achieved. • The recovered aluminum foil is highly pure. • LiNi 1/3 Co 1/3 Mn 1/3 O 2 is directly resynthesized from the separated cathode material. - Abstract: To solve the recycling challenge for aqueous binder based lithium-ion batteries (LIBs), a novel process for recycling and resynthesizing LiNi 1/3 Co 1/3 Mn 1/3 O 2 from the cathode scraps generated during manufacturing process is proposed in this study. Trifluoroacetic acid (TFA) is employed to separate the cathode material from the aluminum foil. The effects of TFA concentration, liquid/solid (L/S) ratio, reaction temperature and time on the separation efficiencies of the cathode material and aluminum foil are investigated systematically. The cathode material can be separated completely under the optimal experimental condition of 15 vol.% TFA solution, L/S ratio of 8.0 mL g −1 , reacting at 40 °C for 180 min along with appropriate agitation. LiNi 1/3 Co 1/3 Mn 1/3 O 2 is successfully resynthesized from the separated cathode material by solid state reaction method. Several kinds of characterizations are performed to verify the typical properties of the resynthesized LiNi 1/3 Co 1/3 Mn 1/3 O 2 powder. Electrochemical tests show that the initial charge and discharge capacities of the resynthesized LiNi 1/3 Co 1/3 Mn 1/3 O 2 are 201 mAh g −1 and 155.4 mAh g −1 (2.8–4.5 V, 0.1 C), respectively. The discharge capacity remains at 129 mAh g −1 even after 30 cycles with a capacity retention ratio of 83.01%

  1. Extracellular cell wall β(1,3)glucan is required to couple septation to actomyosin ring contraction

    Science.gov (United States)

    Muñoz, Javier; Cortés, Juan Carlos G.; Sipiczki, Matthias; Ramos, Mariona; Clemente-Ramos, José Angel; Moreno, M. Belén; Martins, Ivone M.; Pérez, Pilar

    2013-01-01

    Cytokinesis has been extensively studied in different models, but the role of the extracellular cell wall is less understood. Here we studied this process in fission yeast. The essential protein Bgs4 synthesizes the main cell wall β(1,3)glucan. We show that Bgs4-derived β(1,3)glucan is required for correct and stable actomyosin ring positioning in the cell middle, before the start of septum formation and anchorage to the cell wall. Consequently, β(1,3)glucan loss generated ring sliding, oblique positioned rings and septa, misdirected septum synthesis indicative of relaxed rings, and uncoupling between a fast ring and membrane ingression and slow septum synthesis, suggesting that cytokinesis can progress with defective septum pushing and/or ring pulling forces. Moreover, Bgs4-derived β(1,3)glucan is essential for secondary septum formation and correct primary septum completion. Therefore, our results show that extracellular β(1,3)glucan is required for cytokinesis to connect the cell wall with the plasma membrane and for contractile ring function, as proposed for the equivalent extracellular matrix in animal cells. PMID:24165938

  2. 21 CFR 177.1345 - Ethylene/1,3-phenylene oxyethylene isophthalate/ terephthalate copolymer.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Ethylene/1,3-phenylene oxyethylene isophthalate... Ethylene/1,3-phenylene oxyethylene isophthalate/ terephthalate copolymer. Ethylene/1, 3-phenylene... polymers complying with § 177.1630. (a) Identity. For the purpose of this section, ethylene/1,3-phenylene...

  3. Cooperative assembly of Co-Smad4 MH1 with R-Smad1/3 MH1 on DNA: a molecular dynamics simulation study.

    Directory of Open Access Journals (Sweden)

    Guihong Wang

    Full Text Available Smads, the homologs of Sma and MAD proteins, play a key role in gene expression regulation in the transforming growth factor-β (TGF-β signaling pathway. Recent experimental studies have revealed that Smad4/R-Smad heterodimers bound on DNA are energetically more favorable than homodimeric R-Smad/R-Smad complexes bound on DNA, which indicates that Smad4 might act as binding vehicle to cooperatively assemble with activated R-Smads on DNA in the nucleus. However, the details of interaction mechanism for cooperative recruitment of Smad4 protein to R-Smad proteins on DNA, and allosteric communication between the Smad4-DNA and R-Smad-DNA interfaces via DNA mediating are not yet clear so far.In the present work, we have constructed a series of Smadn+DNA+Smadn (n = 1, 3, 4 models and carried out molecular dynamics simulations, free energy calculations and DNA dynamics analysis for them to study the interaction properties of Smadn (n = 1, 3, 4 with DNA molecule.The results revealed that the binding of Smad4 protein to DNA molecule facilitates energetically the formation of the heteromeric Smad4+DNA+Smad1/3 complex by increasing the affinity of Smad1/3 with DNA molecule. Further investigations through the residue/base motion correlation and DNA dynamics analyses predicted that the binding of Smad4 protein to DNA molecule in the heteromeric Smad4+DNA+Smad1/3 model induces an allosteric communication from the Smad4-DNA interface to Smad1/Smad3-DNA interface via DNA base-pair helical motions, surface conformation changes and new hydrogen bond formations. The present work theoretically explains the mechanism of cooperative recruitment of Smad4 protein to Smad1/3 protein via DNA-mediated indirect readout mode in the nucleus.

  4. Tandem Rh-Catalyzed Oxidative C-H Olefination and Cyclization of Enantiomerically Enriched Benzo-1,3-Sulfamidates: Stereoselective Synthesis of trans-1,3-Disubstituted Isoindolines.

    Science.gov (United States)

    Achary, Raghavendra; Jung, In-A; Lee, Hyeon-Kyu

    2018-04-06

    A tandem process, involving Rh(III)-catalyzed oxidative C-H olefination of enantiomerically enriched 4-aryl-benzo-1,3-sulfamidates and subsequent intramolecular aza-Michael cyclization has been developed. The reaction produces trans-benzosulfamidate-fused-1,3-disubstituted isoindolines as major products, in which the configurational integrity of the stereogenic center in the starting material is preserved. Further transformations of the benzosulfamidate-fused-1,3-disubstituted isoindolines are described.

  5. Leaching process for recovering valuable metals from the LiNi1/3Co1/3Mn1/3O2 cathode of lithium-ion batteries.

    Science.gov (United States)

    He, Li-Po; Sun, Shu-Ying; Song, Xing-Fu; Yu, Jian-Guo

    2017-06-01

    In view of the importance of environmental protection and resource recovery, recycling of spent lithium-ion batteries (LIBs) and electrode scraps generated during manufacturing processes is quite necessary. An environmentally sound leaching process for the recovery of Li, Ni, Co, and Mn from spent LiNi 1/3 Co 1/3 Mn 1/3 O 2 -based LIBs and cathode scraps was investigated in this study. Eh-pH diagrams were used to determine suitable leaching conditions. Operating variables affecting the leaching efficiencies for Li, Ni, Co, and Mn from LiNi 1/3 Co 1/3 Mn 1/3 O 2 , such as the H 2 SO 4 concentration, temperature, H 2 O 2 concentration, stirring speed, and pulp density, were investigated to determine the most efficient conditions for leaching. The leaching efficiencies for Li, Ni, Co, and Mn reached 99.7% under the optimized conditions of 1M H 2 SO 4 , 1vol% H 2 O 2 , 400rpm stirring speed, 40g/L pulp density, and 60min leaching time at 40°C. The leaching kinetics of LiNi 1/3 Co 1/3 Mn 1/3 O 2 were found to be significantly faster than those of LiCoO 2 . Based on the variation in the weight fraction of the metal in the residue, the "cubic rate law" was revised as follows: θ(1-f) 1/3 =(1-kt/r 0 ρ), which could characterize the leaching kinetics optimally. The activation energies were determined to be 64.98, 65.16, 66.12, and 66.04kJ/mol for Li, Ni, Co, and Mn, respectively, indicating that the leaching process was controlled by the rate of surface chemical reactions. Finally, a simple process was proposed for the recovery of valuable metals from spent LiNi 1/3 Co 1/3 Mn 1/3 O 2 -based LIBs and cathode scraps. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Influence of water management and fertilizer application on "1"3"7Cs and "1"3"3Cs uptake in paddy rice fields

    International Nuclear Information System (INIS)

    Wakabayashi, Shokichi; Itoh, Sumio; Kihou, Nobuharu; Matsunami, Hisaya; Hachinohe, Mayumi; Hamamatsu, Shioka; Takahashi, Shigeru

    2016-01-01

    Cesium-137 derived from the Tokyo Electric Power Company's Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident contaminated large areas of agricultural land in Eastern Japan. Previous studies before the accident have indicated that flooding enhances radiocesium uptake in rice fields. We investigated the influence of water management in combination with fertilizers on "1"3"7Cs concentrations in rice plants at two fields in southern Ibaraki Prefecture. Stable Cs ("1"3"3Cs) in the plants was also determined as an analogue for predicting "1"3"7Cs behavior after long-term aging of soil "1"3"7Cs. The experimental periods comprised 3 y starting from 2012 in one field, and 2 y from 2013 in another field. These fields were divided into three water management sections: a long-flooding section without midsummer drainage, and medial-flooding, and short-flooding sections with one- or two-week midsummer drainage and earlier end of flooding than the long-flooding section. Six or four types of fertilizer subsections (most differing only in potassium application) were nested in each water management section. Generally, the long-flooding treatment led to higher "1"3"7Cs and "1"3"3Cs concentrations in both straw and brown rice than medial- and short-flooding treatments, although there were some notable exceptions in the first experimental year at each site. Effects of differing potassium fertilizer treatments were cumulative; the effects on "1"3"7Cs and "1"3"3Cs concentrations in rice plants were not obvious in 2012 and 2013, but in 2014, these concentrations were highest where potassium fertilizer had been absent and lowest where basal dressings of K had been tripled. The relationship between "1"3"7Cs and "1"3"3Cs in rice plants was not correlative in the first experimental year at each site, but correlation became evident in the subsequent year(s). This study demonstrates a novel finding that omitting midsummer drainage and/or delaying drainage during the grain-filling period

  7. Growth mechanisms for spherical mixed hydroxide agglomerates prepared by co-precipitation method: A case of Ni{sub 1/3}Co{sub 1/3}Mn{sub 1/3}(OH){sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Yue [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing 100084 (China); Xu, Shengming, E-mail: smxu@stinghua.edu.cn [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing 100084 (China); Xie, Ming [The State Key Laboratory of Advanced Technologies for Comprehensive Utilization of Precious Metals, Kunming 650106 (China); He, Yinghe, E-mail: yinghe.he@jcu.edu.au [School of Engineering and Physical Sciences, James Cook University, Douglas, Queensland 4811 (Australia); Huang, Guoyong [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing 100084 (China); Yang, Youcai [The State Key Laboratory of Advanced Technologies for Comprehensive Utilization of Precious Metals, Kunming 650106 (China)

    2015-01-15

    Highlights: • Anisotropic growth of Ni{sub 1/3}Co{sub 1/3}Mn{sub 1/3}(OH){sub 2} along the [0 0 1] direction was revealed. • DFT calculation results show crystal surface energies of (0 0 1) plane is highest. • A new model was proposed to explain the formation of spherical agglomerates. - Abstract: Spherical Ni{sub 1/3}Co{sub 1/3}Mn{sub 1/3}(OH){sub 2} agglomerates were synthesized by the co-precipitation method in the presence of ammonia. The results show that the growth mechanism of spherical agglomerates follows three-stages, i.e. nucleation and anisotropic growth of single crystals; agglomeration of polycrystalline crystallites agglomerated by single crystal grains as primary particles to form embryonic agglomerates; formation, growth and consolidation of spherical agglomerates or particles by agglomeration of embryonic agglomerates, continued growth of individual crystals in the agglomerates and further attachment of primary particles. The first two stages are very fast while the last stage takes almost the entire process to complete. The main reason for the anisotropic growth of Ni{sub 1/3}Co{sub 1/3}Mn{sub 1/3}(OH){sub 2} crystal is that crystal surface energy of E{sub (001)}, E{sub (100)}, E{sub (101)} and E{sub (102)} is different with E{sub (001)} being the highest. The morphology of the final spherical agglomerates is explained by partial re-crystallization of contacting primary particles. The growth process of spherical agglomerates was examined by X-ray diffraction, scanning electron microscope, transmission electron microscope and calculation of crystal surface energy using density function theory.

  8. Growth mechanisms for spherical mixed hydroxide agglomerates prepared by co-precipitation method: A case of Ni1/3Co1/3Mn1/3(OH)2

    International Nuclear Information System (INIS)

    Yang, Yue; Xu, Shengming; Xie, Ming; He, Yinghe; Huang, Guoyong; Yang, Youcai

    2015-01-01

    Highlights: • Anisotropic growth of Ni 1/3 Co 1/3 Mn 1/3 (OH) 2 along the [0 0 1] direction was revealed. • DFT calculation results show crystal surface energies of (0 0 1) plane is highest. • A new model was proposed to explain the formation of spherical agglomerates. - Abstract: Spherical Ni 1/3 Co 1/3 Mn 1/3 (OH) 2 agglomerates were synthesized by the co-precipitation method in the presence of ammonia. The results show that the growth mechanism of spherical agglomerates follows three-stages, i.e. nucleation and anisotropic growth of single crystals; agglomeration of polycrystalline crystallites agglomerated by single crystal grains as primary particles to form embryonic agglomerates; formation, growth and consolidation of spherical agglomerates or particles by agglomeration of embryonic agglomerates, continued growth of individual crystals in the agglomerates and further attachment of primary particles. The first two stages are very fast while the last stage takes almost the entire process to complete. The main reason for the anisotropic growth of Ni 1/3 Co 1/3 Mn 1/3 (OH) 2 crystal is that crystal surface energy of E (001) , E (100) , E (101) and E (102) is different with E (001) being the highest. The morphology of the final spherical agglomerates is explained by partial re-crystallization of contacting primary particles. The growth process of spherical agglomerates was examined by X-ray diffraction, scanning electron microscope, transmission electron microscope and calculation of crystal surface energy using density function theory

  9. Composites Li2MnO3·LiMn1/3Ni1/3Co1/3O2: Optimized synthesis and applications as advanced high-voltage cathode for batteries working at elevated temperatures

    International Nuclear Information System (INIS)

    Yu Chuang; Li Guangshe; Guan Xiangfeng; Zheng Jing; Li Liping; Chen Tianwen

    2012-01-01

    Highlights: ► Composites xLi 2 MnO 3 ·(1 − x)LiMn 1/3 Ni 1/3 Co 1/3 O 2 (x = 0.1–0.4) were prepared by a novel two-step molten-salt route. ► Structure and chemical compositions of the composites were optimized to show an optimum electrochemical property. ► Composite electrode 0.3Li 2 MnO 3 ·0.7LiMn 1/3 Ni 1/3 Co 1/3 O 2 exhibited an excellent electrochemical performance at elevated temperature of 45.4 °C. ► Electrode kinetics of composites was uncovered for the excellent electrochemical performance at elevated temperature. - Abstract: This work reports on the optimized preparation of a series of composites xLi 2 MnO 3 ·(1 − x)LiMn 1/3 Ni 1/3 Co 1/3 O 2 (x = 0.1–0.4) with an aim to find an advanced high-voltage cathode for lithium-ion batteries that can work at elevated temperatures. Developing a two-step molten-salt method leads to composites with a layered-type structure, showing a particle size distribution ranging from 350 to 450 nm. The composites are featured by oxidation states stabilized as Mn 4+ , Ni 2+ , and Co 3+ , and by lattice occupation of Li + in both transition-metal layers and lithium layer of LiMn 1/3 Ni 1/3 Co 1/3 O 2 . When acting as a cathode of lithium-ion batteries, the composite at x = 0.3 shows an optimum electrochemical performance as characterized by a discharge capacity of 120 mAh g −1 at a high current density of 500 mA g −1 and a capacity retention of 64% after 20 cycles. Surprisingly, this electrochemical performance is significantly improved at elevated temperatures. Namely, discharge capacity is increased to 140.4 mAh g −1 at a high current density of 500 mA g −1 , while average capacity decay rate becomes very small to 0.76%. These excellent performance is explained in terms of the dramatically improved lithium-ion diffusions in both electrode and surface films at elevated temperatures.

  10. Two galactose-α-1,3-galactose carrying peptidases from pork kidney mediate anaphylactogenic responses in delayed meat allergy

    DEFF Research Database (Denmark)

    Hilger, Christiane; Fischer, Jörg; Swiontek, Kyra

    2016-01-01

    BACKGROUND: Serum IgE-antibodies directed at galactose-α-1,3-galactose (α-Gal) are associated with a novel form of delayed anaphylaxis occuring upon consumption of red meat or innards. Pork kidney is known as the most potent trigger of this syndrome, but the culprit allergens have not yet been...... resistent to heat denaturation. Pork kidney extract, isolated ACE I and AP-N were able to activate patient basophils and elicit positive responses in skin prick tests. CONCLUSION: Two cell-membrane proteins carrying α-Gal epitopes were identified in pork kidney. For the first time, isolated meat proteins...... were shown to induce basophil activation in patients with delayed anaphylaxis to red meat providing further confirmation for the clinical relevance of these α-Gal-carrying proteins. This article is protected by copyright. All rights reserved....

  11. β(1,3-glucanosyl-transferase activity is essential for cell wall integrity and viability of Schizosaccharomyces pombe.

    Directory of Open Access Journals (Sweden)

    María de Medina-Redondo

    Full Text Available BACKGROUND: The formation of the cell wall in Schizosaccharomyces pombe requires the coordinated activity of enzymes involved in the biosynthesis and modification of β-glucans. The β(1,3-glucan synthase complex synthesizes linear β(1,3-glucans, which remain unorganized until they are cross-linked to other β(1,3-glucans and other cell wall components. Transferases of the GH72 family play important roles in cell wall assembly and its rearrangement in Saccharomyces cerevisiae and Aspergillus fumigatus. Four genes encoding β(1,3-glucanosyl-transferases -gas1(+, gas2(+, gas4(+ and gas5(+- are present in S. pombe, although their function has not been analyzed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the characterization of the catalytic activity of gas1p, gas2p and gas5p together with studies directed to understand their function during vegetative growth. From the functional point of view, gas1p is essential for cell integrity and viability during vegetative growth, since gas1Δ mutants can only grow in osmotically supported media, while gas2p and gas5p play a minor role in cell wall construction. From the biochemical point of view, all of them display β(1,3-glucanosyl-transferase activity, although they differ in their specificity for substrate length, cleavage point and product size. In light of all the above, together with the differences in expression profiles during the life cycle, the S. pombe GH72 proteins may accomplish complementary, non-overlapping functions in fission yeast. CONCLUSIONS/SIGNIFICANCE: We conclude that β(1,3-glucanosyl-transferase activity is essential for viability in fission yeast, being required to maintain cell integrity during vegetative growth.

  12. Isoxazolium N-ylides and 1-oxa-5-azahexa-1,3,5-trienes on the way from isoxazoles to 2H-1,3-oxazines

    Directory of Open Access Journals (Sweden)

    Alexander F. Khlebnikov

    2014-08-01

    Full Text Available Theoretical and experimental studies of the reaction of isoxazoles with diazo compounds show that the formation of 2H-1,3-oxazines proceeds via the formation of (3Z-1-oxa-5-azahexa-1,3,5-trienes which undergo a 6π-cyclization. The stationary points corresponding to the probable reaction intermediates, isoxazolium N-ylides, were located by DFT calculations at the B3LYP/6-31G(d level only for derivatives without a substituent in position 3 of the isoxazole ring. These isoxazolium N-ylides are thermodynamically and kinetically very unstable. According to the calculations and experimental results 2H-1,3-oxazines are usually more thermodynamically stable than the corresponding open-chain isomers, (3Z-1-oxa-5-azahexa-1,3,5-trienes. The exception are oxaazahexatrienes derived from 5-alkoxyisoxazoles, which are thermodynamically more stable than the corresponding 2H-1,3-oxazines. Therefore, the reaction of diazo esters with 5-alkoxyisoxazoles is a good approach to 1,4-di(alkoxycarbonyl-2-azabuta-1,3-dienes. The reaction conditions for the preparation of aryl- and halogen-substituted 2H-1,3-oxazines and 1,4-di(alkoxycarbonyl-2-azabuta-1,3-dienes from isoxazoles were investigated.

  13. GENE EXPRESSION CHANGES IN ARABIDOPSIS THALIANA SEEDLING ROOTS EXPOSED TO THE MUNITION HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE

    Science.gov (United States)

    Arabidopsis thaliana root transcriptome responses to the munition, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), were assessed using serial analysis of gene expression (SAGE). Comparison of the transcriptional profile for the RDX response to a profile previously described for Ar...

  14. General Approach to Prepare 0.33Li₂MnO₃ · 0.67LiNi1/3Co1/3Mn1/3O₂ Hollow Microspheres for High Performance Lithium Ion Batteries.

    Science.gov (United States)

    Li, Jingfa; Xu, Wenjin; Zhang, Lei; Li, Min

    2018-06-01

    Li-excess manganese-based oxide layered structures, have drawn increasing interests as the promising cathodes to succeed the conventional LiCoO2 in lithium ion batteries (LIBs). It could deliver a higher energy density and output potential, as well as the nature of environment benign and low cost. Pristine Li-excess manganese-based oxides however suffer from poor rate capacity and voltage fading after cycling, and their inherent capacity limits of bulk size in performance. Micro-/Nanostructured electrode materials are considered to hold the key to overcome these thresholds. This paper reports a general approach to prepare 0.33Li2MnO3 · 0.67LiNi1/3Co1/3Mn1/3O2 microspheres with pores and void space, which benefits improving both the capacity and cyclability. The electrode made of hollow 0.33Li2MnO3 · 0.67LiNi1/3Co1/3Mn1/3O2 microspheres exhibits a 224 mAh g-1 discharge capacity over 200 cycles at 0.25 C rate, and 195 mAh g-1 at 5.0 C rate. These results indicated good perspective of hollow microspheres for practical battery applications.

  15. High rate performance of novel cathode material Li1.33Ni1/3Co1/3Mn1/3O2 for lithium ion batteries

    International Nuclear Information System (INIS)

    Liu Haowen; Tan Long

    2011-01-01

    Highlights: → A novel cathode material with highly ordered structure has been prepared for the first time. → The charge and discharge current is 1000 mA g -1 and 2000 mA g -1 , respectively. → The results indicate better discharge capacity and cyclability. - Abstract: Li 1.33 Ni 1/3 Co 1/3 Mn 1/3 O 2 with highly ordered structure has been successfully synthesized via a simple co-precipitation process. Charge-discharge tests showed that the initial discharge capacities are 153.0 mAh g -1 and 128.9 mAh g -1 at 5 C (1000 mA g -1 ) and 10 C (2000 mA g -1 ) between 2.5 and 4.5 V, respectively. The average full-charge time of this material is less than 12 min at 5 C and 6 min at 10 C. The electrode material composed of the prepared showed a better cyclability. The excellent high rate performance is attributed to the improved ordered layered structure and the electrical conductivity. The excess Li shorten Li + diffusion distance between these submicron and nano-scaled particles. The results show that Li 1.33 Ni 1/3 Co 1/3 Mn 1/3 O 2 cathode material has potential application in lithium ion batteries.

  16. Effects of Residual Lithium in the precursors of Li[Ni1/3Co1/3Mn1/3]O2 on their lithium-ion battery performance

    Science.gov (United States)

    Jo, Minsang; Ku, Heesuk; Park, Sanghyuk; Song, Junho; Kwon, Kyungjung

    2018-07-01

    Li[Ni1/3Co1/3Mn1/3]O2 cathode active materials are synthesized from co-precipitated hydroxide precursors Lix[Ni1/3Co1/3Mn1/3]1-x(OH)2, and the effect of residual Li in the precursors on the lithium-ion battery (LIB) performance of their corresponding cathode active materials is investigated. Three kinds of precursors that contain different amounts of Li are selected depending on different conditions of the solution composition for the co-precipitation and washing process. It is confirmed that the introduction of Li to the precursors reduces the degree of structural perfection by X-ray diffraction analysis. Undesirable cation mixing occurs with the increasing Li content of the precursors, which is inferred from a decline in lattice parameters and the calculated intensity ratio of (003) and (104) peaks. In the voltage range of 3.0-4.3 V, the initial charge/discharge capacities and the rate capability of the cathode active materials are aggravated when Li exists in the precursors. Therefore, it could be concluded that the strict control of Li in a solution for co-precipitation of precursors is necessary in the resynthesis of cathode active materials from spent LIBs.

  17. Tissue-specific and pathogen-induced regulation of a Nicotiana plumbaginifolia beta-1,3-glucanase gene.

    Science.gov (United States)

    Castresana, C; de Carvalho, F; Gheysen, G; Habets, M; Inzé, D; Van Montagu, M

    1990-01-01

    The Nicotiana plumbaginifolia gn1 gene encoding a beta-1,3-glucanase isoform has been characterized. The gn1 product represents an isoform distinct from the previously identified tobacco beta-1,3-glucanases. By expressing gn1 in Escherichia coli, we have determined directly that the encoded protein does, indeed, correspond to a beta-1,3-glucanase. In N. plumbaginifolia, gn1 was found to be expressed in roots and older leaves. Transgenic tobacco plants containing the 5'-noncoding region of gn1 fused to the beta-glucuronidase (GUS) reporter gene also showed maximum levels of GUS activity in roots and older leaves. No detectable activity was present in the upper part of the transgenic plants with the exception of stem cells at the bases of emerging shoots. The expression conferred by the gn1 promoter was differentially induced in response to specific plant stress treatments. Studies of three plant-bacteria interactions showed high levels of GUS activity when infection resulted in a hypersensitive reaction. Increased gene expression was confined to cells surrounding the necrotic lesions. The observed expression pattern suggests that the characterized beta-1,3-glucanase plays a role both in plant development and in the defense response against pathogen infection. PMID:2152158

  18. Estimate of dietary intake of chloropropanols (3-MCPD and 1,3-DCP and health risk assessment

    Directory of Open Access Journals (Sweden)

    Adriana Pavesi Arisseto

    2013-02-01

    Full Text Available Chloropropanols, including 3-monochloropropane-1,2-diol (3-MCPD and 1,3-dichloropropan-2-ol (1,3-DCP, comprise a group of chemical contaminants with carcinogenic and genotoxic properties. They have been found in a variety of processed foods and food ingredients, such as hydrolyzed vegetable protein, soy sauce, cereal-based products, malt-derived ingredients, and smoked foods. This study aimed to assess the dietary exposure to 3-MCPD and 1,3-DCP in Brazil and verify whether the presence of these substances in foods could represent health risks. The intake was calculated by combining data on food consumption, provided by the Consumer Expenditure Survey 2008-2009, with the levels of contaminant occurrence determined by gas chromatography-mass spectrometry. The exposure to 3-MCPD ranged from 0.06 to 0.51 µg.kg bw-1.day-1 considering average and high consumers, while the intake of 1,3-DCP was estimated to be 0.0036 µg.kg bw-1.day-1 in the worst case scenario evaluated. Based on these results, it was verified that the Brazilians' exposure to chloropropanols does not present a significant health risk. However, the consumption of specific foods containing high levels of 3-MCPD could exceed the provisional maximum tolerable daily intake of 2 µg.kg bw-1 established for this compound and, therefore, represent a potential concern.

  19. 1,3,5-Triethylbenzene Transformation Reactions Compared to Its Transalkylation Reaction with Ethylbenzene

    KAUST Repository

    Akhtar, M. Naseem

    2009-08-20

    The transalkylation of 1,3,5-triethylbenzene (1,3,5-TEB) with ethylbenzene (EB) has been studied over USYtype catalysts using a riser simulator that mimics the operation of a fluidized-bed reactor. The reaction mixture EB and 1,3,5-TEB was used at a molar ratio of 1:1, which is equivalent to 40:60 wt % of EB/1,3,5-TEB, respectively. The reaction temperature was varied from 350 to 500 °C with a time on stream ranging from 3-15 s. The effect of reaction conditions on 1,3,5-TEB conversion, DEB selectivity, and isomerization of 1,3,5-TEB is reported. The transalkylation of 1,3,5-TEB with EB has been compared to the transformation reaction of pure 1,3,5-TEB and EB. The experimental results have revealed that reactivity of 1,3,5-TEB and selectivity of DEB is increased during the transalkylation reaction (EB + 1,3,5-TEB) as compared to the transformation reaction of pure EB or 1,3,5-TEB. The 1,3,5-TEB undergoes isomerization and a cracking reaction to produce DEB and EB but does not undergo any appreciable disproportionation reaction. The isomerization of 1,3,5-TEB is more active at low temperatures, while cracking is more active at high temperatures. © 2009 American Chemical Society.

  20. 1,3,5-Triethylbenzene Transformation Reactions Compared to Its Transalkylation Reaction with Ethylbenzene

    KAUST Repository

    Akhtar, M. Naseem; Sulaiman, Al Khattaf

    2009-01-01

    The transalkylation of 1,3,5-triethylbenzene (1,3,5-TEB) with ethylbenzene (EB) has been studied over USYtype catalysts using a riser simulator that mimics the operation of a fluidized-bed reactor. The reaction mixture EB and 1,3,5-TEB was used at a molar ratio of 1:1, which is equivalent to 40:60 wt % of EB/1,3,5-TEB, respectively. The reaction temperature was varied from 350 to 500 °C with a time on stream ranging from 3-15 s. The effect of reaction conditions on 1,3,5-TEB conversion, DEB selectivity, and isomerization of 1,3,5-TEB is reported. The transalkylation of 1,3,5-TEB with EB has been compared to the transformation reaction of pure 1,3,5-TEB and EB. The experimental results have revealed that reactivity of 1,3,5-TEB and selectivity of DEB is increased during the transalkylation reaction (EB + 1,3,5-TEB) as compared to the transformation reaction of pure EB or 1,3,5-TEB. The 1,3,5-TEB undergoes isomerization and a cracking reaction to produce DEB and EB but does not undergo any appreciable disproportionation reaction. The isomerization of 1,3,5-TEB is more active at low temperatures, while cracking is more active at high temperatures. © 2009 American Chemical Society.

  1. Kailua-Kona, Hawaii 1/3 arc-second DEM

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 1/3-second Kailua-Kona Hawaii Elevation Grid provides bathymetric data in ASCII raster format of 1/3-second resolution in geographic coordinates. This grid is...

  2. The C-terminal HRET sequence of Kv1.3 regulates gating rather than targeting of Kv1.3 to the plasma membrane.

    Science.gov (United States)

    Voros, Orsolya; Szilagyi, Orsolya; Balajthy, András; Somodi, Sándor; Panyi, Gyorgy; Hajdu, Péter

    2018-04-12

    Kv1.3 channels are expressed in several cell types including immune cells, such as T lymphocytes. The targeting of Kv1.3 to the plasma membrane is essential for T cell clonal expansion and assumed to be guided by the C-terminus of the channel. Using two point mutants of Kv1.3 with remarkably different features compared to the wild-type Kv1.3 (A413V and H399K having fast inactivation kinetics and tetraethylammonium-insensitivity, respectively) we showed that both Kv1.3 channel variants target to the membrane when the C-terminus was truncated right after the conserved HRET sequence and produce currents identical to those with a full-length C-terminus. The truncation before the HRET sequence (NOHRET channels) resulted in reduced membrane-targeting but non-functional phenotypes. NOHRET channels did not display gating currents, and coexpression with wild-type Kv1.3 did not rescue the NOHRET-A413V phenotype, no heteromeric current was observed. Interestingly, mutants of wild-type Kv1.3 lacking HRET(E) (deletion) or substituted with five alanines for the HRET(E) motif expressed current indistinguishable from the wild-type. These results demonstrate that the C-terminal region of Kv1.3 immediately proximal to the S6 helix is required for the activation gating and conduction, whereas the presence of the distal region of the C-terminus is not exclusively required for trafficking of Kv1.3 to the plasma membrane.

  3. Auto-SCT induces a phenotypic shift from CMP to GMP progenitors, reduces clonogenic potential and enhances in vitro and in vivo cycling activity defined by (18)F-FLT PET scanning.

    Science.gov (United States)

    Woolthuis, C; Agool, A; Olthof, S; Slart, R H J A; Huls, G; Smid, W M; Schuringa, J J; Vellenga, E

    2011-01-01

    Autologous SCT (auto-SCT) introduces a reduced tolerance to chemotherapy even in patients with adequate engraftment, suggesting long-term effects of the transplantation procedure on the BM capacity. To study the hematopoietic cell compartment after auto-SCT, CD34(+) BM cells (n = 16) from patients at 6-9 months after auto-SCT were studied with regard to the progenitor subsets, colony frequency and cell cycle status. The BM compartments were studied in vivo using PET tracer 3-fluoro-3-deoxy-L-thymidine (¹⁸F-FLT PET). BM CD34(+) cells after auto-SCT were compared with normal CD34(+) cells and showed a phenotypic shift from common myeloid progenitor (CMP mean percentage 3.7 vs 19.4%, P=0.001) to granulocyte-macrophage progenitor (GMP mean percentage 51.8 vs 27.6%, P=0.01). In addition, a reduced clonogenic potential and higher cycling activity especially of the GMP fraction (41% ± 4 in G2/S phase vs 19% ± 2, P = 0.03) were observed in BM after auto-SCT compared with normal. The enhanced cycling activity was confirmed in vivo by showing a significantly higher uptake of the ¹⁸F-FLT PET tracer by the BM compartment. This study shows that auto-SCT results in defects of the hematopoietic compartment at least 6 months after auto-SCT, characterized by changes in the composition of progenitor subsets and enhanced in vitro and in vivo cycling activity.

  4. Electrochemical Study of Bromide in the Presence of 1,3-Indandione. Application to the Electrochemical Synthesis of Bromo Derivatives of 1,3-Indandione

    Directory of Open Access Journals (Sweden)

    N. Akaberi

    2001-06-01

    Full Text Available The electrochemical oxidation of bromide in the presence of 1,3-indandione (1 in water/acetic acid and methanol/acetic acid mixtures has been studied by cyclic voltammetry and controlled-potential coulometry. The results indicate the participation of 1,3-indandione in the bromination reaction. On the basis of the electroanalytical and preparative results a reaction mechanism including electron transfer, chemical reaction and regeneration of bromide was discussed. The electrochemical synthesis of bromo derivatives of 1,3-indandione (2-3 has been successfully performed at constant current, in an undivided cell, in good yield and purity.

  5. 48 CFR 970.1504-1-3 - Special considerations: Laboratory management and operation.

    Science.gov (United States)

    2010-10-01

    ...: Laboratory management and operation. 970.1504-1-3 Section 970.1504-1-3 Federal Acquisition Regulations System DEPARTMENT OF ENERGY AGENCY SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Contracting by Negotiation 970.1504-1-3 Special considerations: Laboratory management and operation. (a) For the management...

  6. 41 CFR 301-1.3 - Who is eligible for TDY allowances?

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 4 2010-07-01 2010-07-01 false Who is eligible for TDY allowances? 301-1.3 Section 301-1.3 Public Contracts and Property Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES INTRODUCTION 1-APPLICABILITY § 301-1.3 Who is eligible for TDY...

  7. 37 CFR 1.3 - Business to be conducted with decorum and courtesy.

    Science.gov (United States)

    2010-07-01

    ... decorum and courtesy. 1.3 Section 1.3 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE GENERAL RULES OF PRACTICE IN PATENT CASES General Provisions General Information and Correspondence § 1.3 Business to be conducted with decorum and courtesy...

  8. 30 CFR 1.3 - Use of letters and acronym MSHA.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Use of letters and acronym MSHA. 1.3 Section 1.3 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR OFFICIAL EMBLEM AND...; ESTABLISHMENT AND USE OF OFFICIAL EMBLEM § 1.3 Use of letters and acronym MSHA. The letters and acronym MSHA may...

  9. High rate performances of the cathode material LiNi1/3Co1/3Mn1/3O2 synthesized using low temperature hydroxide precipitation

    International Nuclear Information System (INIS)

    Cheng, Cuixia; Tan, Long; Liu, Haowen; Huang, Xintang

    2011-01-01

    Graphical abstract: A low-temperature reaction route is introduced based on hydroxide precipitation method to synthesize a cathode material LiNi 1/3 Co 1/3 Mn 1/3 O 2 . The charge-discharge tests were performed at 1000 mA g -1 between 2.5 and 4.5 V and the discharge capacity is about 160 mAh g -1 . The discharge capacity of the material is strongly impacted by the reaction temperature. The powders sintered at 850 o C show the best electrochemical performance. Highlights: → A low-temperature reaction route is introduced based on hydroxide precipitation method to synthesize a novel cathode material LiNi 1/3 Co 1/3 Mn 1/3 O 2 . → The charge-discharge tests were performed at higher current as 5 C between 2.5 and 4.5 V. → The discharge capacity of the material is strongly impacted by the reaction temperature. The powders sintered at 850 o C show the best electrochemical performance. -- Abstract: A low-temperature reaction route is introduced based on hydroxide precipitation method to synthesize the cathode material LiNi 1/3 Co 1/3 Mn 1/3 O 2 . The crystal structure and morphology of the prepared powder have been characterized by X-ray diffraction and Scan electron microscope, respectively. The charge-discharge tests were performed between 2.5 and 4.5 V. The discharge capacity of the material is strongly impacted by the reaction temperature. The powders sintered at 850 o C show the best electrochemical performance and the initial discharge capacity is about 160 mAh g -1 at 5 C. Powder X-ray diffraction and Scan electron microscope results reveal that the excellent electrochemical performances should be ascribed to the lower precursor reaction temperature, the lower degree of cation mixing and analogous spherical small particles, which can improve the transfer of Li ions and electrons. All these results indicate that this material has potential application in lithium-ion batteries.

  10. Synchrotron radiation-based 61Ni Mössbauer spectroscopic study of Li(Ni1/3Mn1/3Co1/3)O2 cathode materials of lithium ion rechargeable battery

    Science.gov (United States)

    Segi, Takashi; Masuda, Ryo; Kobayashi, Yasuhiro; Tsubota, Takayuki; Yoda, Yoshitaka; Seto, Makoto

    2016-12-01

    Layered rocksalt type oxides, such as Li(Ni1/3Mn1/3Co1/3)O2, are widely used as the cathode active materials of lithium-ion rechargeable batteries. Because the nickel ions are associated with the role of the charge compensation at discharge and charge, the 61Ni Mössbauer measurements at 6 K using synchrotron radiation were performed to reveal the role of Ni. The Ni ions of the active materials play two roles for the redox process between the charge and discharge states of lithium-ion batteries. Half of the total Ni ions change to the low-spin Ni3+ with Jahn-Teller distortion from the Ni2+ ions of the discharge state. The remainder exhibit low-spin state divalent Ni ions.

  11. Three-dimensional evaluation of compositional and structural changes in cycled LiNi1/3Co1/3Mn1/3O2 by atom probe tomography

    Science.gov (United States)

    Lee, Ji Yeong; Kim, Ji Yoon; Cho, Hae In; Lee, Chi Ho; Kim, Han Sung; Lee, Sang Uck; Prosa, Ty J.; Larson, David J.; Yu, Tae Hwan; Ahn, Jae-Pyoung

    2018-03-01

    Accelerated capacity fading of LiNi1/3Co1/3Mn1/3O2 (NCM111) electrode by the chemical migration of lithium (Li) or transition metals (TMs), and surface reconstruction in the surface during electrochemical cycling were evaluated by correlative analysis of atom probe tomography (APT) and transmission electron microscopy (TEM). The cycled NCM111 showed a lack of Li at surface which provides the driving force for long-range Ni migration toward surface. A schematic model for phase transformation and the kinetics of TM migration within the layered structure by density functional theory (DFT) calculations was proposed. This study provides insights into capacity loss and voltage fade upon electrochemical charge-discharge process of NCM111 by measuring the variation of Li composition away from the surface.

  12. When Ethyl Isocyanoacetate Meets Isatins: A 1,3-Dipolar/Inverse 1,3-Dipolar/Olefination Reaction for Access to 3-Ylideneoxindoles.

    Science.gov (United States)

    Yuan, Wen-Kui; Cui, Tao; Liu, Wei; Wen, Li-Rong; Li, Ming

    2018-03-16

    A new CuI/1,10-phen-catalyzed reaction for the synthesis of 3-ylideneoxindoles from readily available isatins and ethyl isocyanoacetate, in which ethyl isocyanoacetate acts as a latent two-carbon donor like the Wittig reagent, is reported. A tandem procedure including 1,3-dipolar cycloaddition/inverse 1,3-dipolar ring opening/olefination allows the preparation of 3-ylideneoxindoles with broad functional group tolerance.

  13. Ion radical rupture of the carbon-carbon bond in oxidation of 1,3,1',3'-tetramethyl-2,3,2',3'- tetrahydro-2,2'-diperimidinyl

    International Nuclear Information System (INIS)

    Sabanov, V.Kh.; Kibizova, A.Yu.; Klimov, E.S.; Berberova, N.T.; Okhlobystin, O.Yu.

    1987-01-01

    Electrochemical and chemical oxidation of 1,3,1',3'-tetramethyl-2,3,2',3'-tetrahydro-2,2'-dipyriminyl takes place with rupture of the C-C bond in the initially formed cation radical. In the oxidation of the compound with aluminum chloride in nitrobenzene, ESR revealed a cation radical with an unresolved hyperfine structure. Oxidation of the dihydrodimer with nitrosonium perchlorate in nitrobenzene or nitromethane resulted in the same spectra. Cyclic volt-ampere diagrams are included

  14. Electrochemical Study of Bromide in the Presence of 1,3-Indandione. Application to the Electrochemical Synthesis of Bromo Derivatives of 1,3-Indandione

    OpenAIRE

    Nematollahi, D.; Akaberi, N.

    2001-01-01

    The electrochemical oxidation of bromide in the presence of 1,3-indandione (1) in water/acetic acid and methanol/acetic acid mixtures has been studied by cyclic voltammetry and controlled-potential coulometry. The results indicate the participation of 1,3-indandione in the bromination reaction. On the basis of the electroanalytical and preparative results a reaction mechanism including electron transfer, chemical reaction and regeneration of bromide was discussed. The electrochemical synthesi...

  15. Enantioselective preparation of 1,3-dithiane 1-oxides by asymmetric oxidation of 1,3-dithianes bearing a chiral auxiliary

    OpenAIRE

    Yoshihiko, Watanabe; Yojiro, Ono; Shigefumi, Hayashi; Yoshio, Ueno; Takeshi, Toru

    1996-01-01

    Oxidation of 1,3-dithianes bearing a chiral auxiliary derived from (+) or (-)-camphor or diacetone D-(+)-glucose by the Sharpless reagent [Ti(OPi)4-diethyl L-(+)- or D-(-)-tartrate-ButOOH] affords, with high stereoselectivity, the monosulfoxides in good to excellent yields. Removal of the chiral auxiliary by base-catalysed hydrolysis yields (R)- and (S)-1,3-dithiane 1-oxides in high yields.

  16. Changes of MODY signal pathway genes in the endoplasmic reticulum stress in INS-1-3 cells.

    Directory of Open Access Journals (Sweden)

    Yanan Dong

    Full Text Available Metabolic disturbances induce endoplasmic reticulum stress (ERS in pancreatic beta cells. This study aims to investigate whether a common pathway exists in the ERS induced by various chemicals, including high levels of glucose and palmitate in INS-1-3 cells.ERS in INS-1-3 cells was induced by exposure cells to thapsigargin (TG, tunicamycin (TM or palmitic acid (PA +high glucose (HG. Digital gene expression (DGE profiling technique was used to detect differentially expressed genes. The profile of gene expression was detected by gene oncology (GO function and pathway enrichment analysis. Nkx6.1 over-expression was established in INS-1-3 cell lines by lentivirus infection to revert the inhibition of Nkx6.1 expression found in the situation of ERS. Real time reverse transcription polymerase chain reaction (RT-PCR was used to verify the expression changes of key genes. Cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide (MTT assay. The apoptosis was determined by flow cytometry. INS-1-3 cell function was measured by glucose stimulated insulin secretion test(GSIS.As compared to control, DGE demonstrated that there were 135, 57 and 74 differentially expressed genes in TM, TG and HG+PA groups, respectively. Those differentially expressed genes were enriched to ERS, antigen processing and presentation, protein export pathways, and interestingly, the maturity onset diabetes of the young (MODY pathway. Nkx6.1 is one of common down-regulated gene in MODY signaling pathway among TM, TG and HG+PA groups. Over-expression of Nkx6.1 ameliorated glucolipotoxicity induced apoptosis rate by 45.4%, and increased proliferation by 40.9%. At the same time, GSIS increased by 1.82 folds.MODY pathway genes expression was changed in the state of ERS. Over-expression of Nkx6.1 protected the INS-1-3 cells from glucolipotoxicity.

  17. Voltage-Gated Potassium Channels Kv1.3--Potentially New Molecular Target in Cancer Diagnostics and Therapy.

    Science.gov (United States)

    Teisseyre, Andrzej; Gąsiorowska, Justyna; Michalak, Krystyna

    2015-01-01

    Voltage-gated potassium channels, Kv1.3, which were discovered in 1984, are integral membrane proteins which are activated ("open") upon change of the cell membrane potential, enabling a passive flux of potassium ions across the cell membrane. The channels are expressed in many different tissues, both normal and cancer. Since 2005 it has been known that the channels are expressed not only in the plasma membrane, but also in the inner mitochondrial membrane. The activity of Kv1.3 channels plays an important role, among others, in setting the cell resting membrane potential, cell proliferation, apoptosis and volume regulation. For some years, these channels have been considered a potentially new molecular target in both the diagnostics and therapy of some cancer diseases. This review article focuses on: 1) changes of expression of the channels in cancer disorders with special regard to correlations between the channels' expression and stage of the disease, 2) influence of inhibitors of Kv1.3 channels on proliferation and apoptosis of cancer cells, 3) possible future applications of Kv1.3 channels' inhibitors in therapy of some cancer diseases. In the last section, the results of studies performed in our Laboratory of Bioelectricity on the influence of selected biologically active plant-derived compounds from the groups of flavonoids and stilbenes and their natural and synthetic derivatives on the activity of Kv1.3 channels in normal and cancer cells are reviewed. A possible application of some compounds from these groups to support therapy of cancer diseases, such as breast, colon and lymph node cancer, and melanoma or chronic lymphocytic leukemia (B-CLL), is announced.

  18. Effect of Cu Doping on the Structural and Electrochemical Performance of LiNi1/3Co1/3Mn1/3O2 Cathode Materials

    Science.gov (United States)

    Yang, Li; Ren, Fengzhagn; Feng, Qigao; Xu, Guangri; Li, Xiaobo; Li, Yuanchao; Zhao, Erqing; Ma, Jignjign; Fan, Shumin

    2018-04-01

    The structural and electrochemical performance of Cu-doped, Li[Ni1/3-xCo1/3 Mn1/3Cux]O2 (x = 0-0.1) cathode materials obtained by means of the sol-gel method are discussed; we used critic acid as gels and spent mixed batteries as the raw materials. The effects of the sintering time, sintering temperature, and Cu doping ratio on the phase structure, morphology, and element composition and the behavior in a galvanostatical charge/discharge test have been systemically studied. The results show that the Cu-doped material exhibits better galvanostatic charge/discharge cycling performance. At 0.2 C, its original discharge specific capacity is 180.4 mAh g-1 and its Coulomb efficiency is 90.3%. The Cu-doped material demonstrate an outstanding specific capacity at 0.2 C, 0.5 C, and 2.0 C. In comparison with the original capacities of 178 mAh g-1, 159.5 mAh g-1, and 119.4 mAh g-1, the discharge capacity after 50 cycles is 160.8 mAh g-1, 143.4 mAh g-1, and 90.1 mAh g-1, respectively. This obvious improvement relative to bare Li[Ni1/3Co1/3Mn1/3]O2 cathode materials arises from an enlarged Li layer spacing and a reduced degree of cation mixing. Therefore, Cu-doped cathode materials have obvious advantages in the field of lithium-ion batteries and their applications.

  19. Identification of rice cornichon as a possible cargo receptor for the Golgi-localized sodium transporter OsHKT1;3

    Czech Academy of Sciences Publication Activity Database

    Rosas-Santiago, P.; Lagunas-Goméz, D.; Barkla, B. J.; Vera-Estrella, R.; Lalonde, S.; Jones, A.; Frommer, W. B.; Zimmermannová, Olga; Sychrová, Hana; Pantoja, O.

    2015-01-01

    Roč. 66, č. 9 (2015), s. 2733-2748 ISSN 0022-0957 R&D Projects: GA MŠk(CZ) LD13037 Institutional support: RVO:67985823 Keywords : Cornichon * endoplasmic reticulum * Golgi * OsHKT1-3 * protein–protein interaction Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.677, year: 2015

  20. Suppression of Retinal Neovascularization in vivo by Inhibition of Vascular Endothelial Growth Factor (VEGF) Using Soluble VEGF-Receptor Chimeric Proteins

    Science.gov (United States)

    Aiello, Lloyd Paul; Pierce, Eric A.; Foley, Eliot D.; Takagi, Hitoshi; Chen, Helen; Riddle, Lavon; Ferrara, Napoleone; King, George L.; Smith, Lois E. H.

    1995-11-01

    The majority of severe visual loss in the United States results from complications associated with retinal neovascularization in patients with ischemic ocular diseases such as diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. Intraocular expression of the angiogenic protein vascular endothelial growth factor (VEGF) is closely correlated with neovascularization in these human disorders and with ischemia-induced retinal neovascularization in mice. In this study, we evaluated whether in vivo inhibition of VEGF action could suppress retinal neovascularization in a murine model of ischemic retinopathy. VEGF-neutralizing chimeric proteins were constructed by joining the extracellular domain of either human (Flt) or mouse (Flk) high-affinity VEGF receptors with IgG. Control chimeric proteins that did not bind VEGF were also used. VEGF-receptor chimeric proteins eliminated in vitro retinal endothelial cell growth stimulation by either VEGF (P hypoxic conditioned medium (P < 0.005) without affecting growth under nonstimulated conditions. Control proteins had no effect. To assess in vivo response, animals with bilateral retinal ischemia received intravitreal injections of VEGF antagonist in one eye and control protein in the contralateral eye. Retinal neovascularization was quantitated histologically by a masked protocol. Retinal neovascularization in the eye injected with human Flt or murine Flk chimeric protein was reduced in 100% (25/25; P < 0.0001) and 95% (21/22; P < 0.0001) of animals, respectively, compared to the control treated eye. This response was evident after only a single intravitreal injection and was dose dependent with suppression of neovascularization noted after total delivery of 200 ng of protein (P < 0.002). Reduction of histologically evident neovascular nuclei per 6-um section averaged 47% ± 4% (P < 0.001) and 37% ± 2% (P < 0.001) for Flt and Flk chimeric proteins with maximal inhibitory effects of 77% and 66

  1. Effects of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) metabolites on cricket (Acheta domesticus) survival and reproductive success

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Baohong [Institute of Environmental and Human Health (TIEHH), and Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409-1163 (United States); Freitag, Christina M. [Institute of Environmental and Human Health (TIEHH), and Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409-1163 (United States); Canas, Jaclyn E. [Institute of Environmental and Human Health (TIEHH), and Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409-1163 (United States); Cheng Qiuqiong [Institute of Environmental and Human Health (TIEHH), and Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409-1163 (United States); Anderson, Todd A. [Institute of Environmental and Human Health (TIEHH), and Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock, TX 79409-1163 (United States)]. E-mail: todd.anderson@tiehh.ttu.edu

    2006-11-15

    The effect of two major hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) metabolites, hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX), on cricket (Acheta domesticus) survival and reproduction was studied. RDX metabolites did not have adverse effects on cricket survival, growth, and egg production. However, MNX and TNX did affect egg hatching. MNX and TNX were more toxic in spiked-sand than in topical tests. TNX was more toxic to egg than MNX. Developmental stage and exposure time affected hatching. After 30 days exposure to MNX or TNX, the EC{sub 2}, EC{sub 5}, and EC{sub 95} were 47, 128, and 247 {mu}g/g for TNX, and 65, 140, and 253 {mu}g/g for MNX in topical tests. The ECs for 20, 50, and 95 were 21, 52, and 99 {mu}g/g for MNX, and 12, 48, and 97 {mu}g/g for TNX in sand. No gross abnormalities in cricket nypmhs were observed in all experiments indicating that neither TNX or MNX is teratogenic in this assay. - RDX metabolites did not have adverse effects on cricket survival, growth, and egg production, but adversely affected egg hatching.

  2. Effect of two major N-nitroso hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) metabolites on earthworm reproductive success

    International Nuclear Information System (INIS)

    Zhang Baohong; Cox, Stephen B.; McMurry, Scott T.; Jackson, W. Andrew; Cobb, George P.; Anderson, Todd A.

    2008-01-01

    Soil and topical tests were employed to investigate the effect of two N-nitroso metabolites of RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) on earthworm reproduction. The lowest observed effect concentration (LOEC) for cocoon production and hatching was 50 mg/kg for both hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) in soil. MNX and TNX also significantly affected cocoon hatching in soil (p 20 values for MNX were 8.7 and 8.8 mg/kg for cocoon and juvenile production, respectively, compared to 9.2 and 9.1 mg/kg for TNX, respectively. The EC 20 values for the total number of cocoon hatchlings were 3.1 and 4.7 mg/kg for MNX and TNX, respectively, in soil and 4.5 and 3.1 mg/L in the topical test. Both MNX and TNX inhibited cocoon production and hatching, suggesting that they may have a negative affect on soil ecosystems at contaminated sites. - RDX metabolites affect earthworm cocoon production and hatching

  3. Effects of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) metabolites on cricket (Acheta domesticus) survival and reproductive success

    International Nuclear Information System (INIS)

    Zhang Baohong; Freitag, Christina M.; Canas, Jaclyn E.; Cheng Qiuqiong; Anderson, Todd A.

    2006-01-01

    The effect of two major hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) metabolites, hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX), on cricket (Acheta domesticus) survival and reproduction was studied. RDX metabolites did not have adverse effects on cricket survival, growth, and egg production. However, MNX and TNX did affect egg hatching. MNX and TNX were more toxic in spiked-sand than in topical tests. TNX was more toxic to egg than MNX. Developmental stage and exposure time affected hatching. After 30 days exposure to MNX or TNX, the EC 2 , EC 5 , and EC 95 were 47, 128, and 247 μg/g for TNX, and 65, 140, and 253 μg/g for MNX in topical tests. The ECs for 20, 50, and 95 were 21, 52, and 99 μg/g for MNX, and 12, 48, and 97 μg/g for TNX in sand. No gross abnormalities in cricket nypmhs were observed in all experiments indicating that neither TNX or MNX is teratogenic in this assay. - RDX metabolites did not have adverse effects on cricket survival, growth, and egg production, but adversely affected egg hatching

  4. Porcine Knock-in Fibroblasts Expressing hDAF on α-1,3-Galactosyltransferase (GGTA1) Gene Locus.

    Science.gov (United States)

    Kim, Ji Woo; Kim, Hye-Min; Lee, Sang Mi; Kang, Man-Jong

    2012-10-01

    The Galactose-α1,3-galactose (α1,3Gal) epitope is responsible for hyperacute rejection in pig-to-human xenotransplantation. Human decay-accelerating factor (hDAF) is a cell surface regulatory protein that serves as a complement inhibitor to protect self cells from complement attack. The generation of α1,3-galactosyltransferase (GGTA1) knock-out pigs expressing DAF is a necessary step for their use as organ donors for humans. In this study, we established GGTA1 knock-out cell lines expressing DAF from pig ear fibroblasts for somatic cell nuclear transfer. hDAF expression was detected in hDAF knock-in heterozygous cells, but not in normal pig cells. Expression of the GGTA1 gene was lower in the knock-in heterozygous cell line compared to the normal pig cell. Knock-in heterozygous cells afforded more effective protection against cytotoxicity with human serum than with GGTA1 knock-out heterozygous and control cells. These cell lines may be used in the production of GGTA1 knock-out and DAF expression pigs for xenotransplantation.

  5. Synthesis and preliminary ex vivo evaluation of the spasmolytic activity of 1,3-thiazolium- and 1,3,4-thiadiazolium-5-methylthio- and 5-thioacetate derivatives

    Directory of Open Access Journals (Sweden)

    Luis José A. S.

    2014-06-01

    Full Text Available Seven new compounds have been synthetized in satisfactory yields (51-78 % through the treatment of mesoionic 1,3-thiazolium-5-thiolate (4a-d and 1,3,4-thiadiazolium- 5-thiolate (10a,b with chloroacetic acid or methyl iodide: 1,3,4-thiadiazolium-5-methylthio- (11 and 5-thioacetate (12. The structure of the title compounds was elucidated by elemental analysis, IR, 1H and 13C NMR spectroscopy. The newly synthesized compounds 5a, 6a, 11 and 12 were evaluated for their ex vivo spasmolytic potential on four isolated smooth muscles (rat aorta and uterus, guinea pig ileum and trachea and compared with scopolamine. Some of the compounds exhibited potent spasmolytic activity equal to or stronger than scopolamine

  6. First-cycle defect evolution of Li1-xNi1/3Mn1/3Co1/3O2 lithium ion battery electrodes investigated by positron annihilation spectroscopy

    Science.gov (United States)

    Seidlmayer, Stefan; Buchberger, Irmgard; Reiner, Markus; Gigl, Thomas; Gilles, Ralph; Gasteiger, Hubert A.; Hugenschmidt, Christoph

    2016-12-01

    In this study the structure and evolution of vacancy type defects in lithium ion batteries are investigated in respect of crystallographic properties. The relation between positron annihilation and electronic structure is discussed in terms of structural dynamics during the lithiation process. Samples of Li1-xNi1/3Mn1/3Co1/3O2 (NMC-111) electrodes with decreasing lithium content (x = 0-0.7) covering the whole range of state of charge were electrochemically prepared for the non-destructive analysis using positron coincidence Doppler broadening spectroscopy (CDBS). The positron measurements allowed us to observe the evolution of the defect structure caused by the delithiation process in the NMC-111 electrodes. The combination of CDBS with X-ray diffraction for the characterization of the lattice structures enabled the analysis of the well-known kinetic-hindrance-effect in the first charge-discharge cycle and possible implications of vacancy ordering. In particular, CDBS revealed the highest degree of relithiation after discharge to 3.0 V at 55 °C. For the first time, we report on the successful application of CDBS on NMC-111 electrodes yielding new insights in the important role of defects caused by the delithiation process and the kinetic hindrance effect.

  7. Chemical-wet Synthesis and Electrochemistry of LiNi1/3Co1/3Mn1/3O2 Cathode Materials for Li-ion Batteries

    International Nuclear Information System (INIS)

    Hsieh, Chien-Te; Mo, Chung-Yu; Chen, Yu-Fu; Chung, Yi-Jou

    2013-01-01

    LiNi 1/3 Co 1/3 Mn 1/3 O 2 (LNCM) with a well-ordered layered structure, confirmed by X-ray diffraction, was synthesized by the chemical-wet synthesis incorporated with (i) a pulse microwave-assisted heating of LNCM precursors and (ii) a carbon coating technique. The microwave irradiation periods (i.e., 5–20 min) and amount of carbon additive (i.e., glucose content: 0.1–0.75%) served as key factors in modifying as-prepared LNCM powders. The electrochemical performance of as-prepared LNCM cathodes was well characterized by cyclic voltammetry and charge–discharge cycling at 0.1–5C. Both appropriate microwave heating and carbon coating significantly improve discharge capacity, rate capability, and cycling stability of LNCM cathodes. This improved performance can be attributed to the facts that an appropriate microwave heating of LNCM precursors induces low cation mixing of the layered lattices and the carbon coating enables the creation of outer circuit of charge-transfer pathway, preventing cathode corrosion from direct contact to the electrolyte. The C-coated LNCM cathode shows the increased capacity retention from 70.2 to 93.3% after 50 cycles at 1C. On the basis of the experimental results, both the microwave heating and the carbon coating provide a feasible potential way to improve the electrochemical performance of LNCM cathode, benefiting the development of Li-ion batteries

  8. Hydrogen peroxide assisted synthesis of LiNi1/3Co1/3Mn1/3O2 as high-performance cathode for lithium-ion batteries

    Science.gov (United States)

    Lin, Chaohong; Zhang, Yongzhi; Chen, Li; Lei, Ying; Ou, Junke; Guo, Yong; Yuan, Hongyan; Xiao, Dan

    2015-04-01

    LiNi1/3Co1/3Mn1/3O2 (NCM) is a promising cathode material for lithium-ion battery. In this research, a facile co-precipitation process is employed, during which the mixed solution of NH3·H2O, H2O2 (30% aqueous solution) and LiOH·H2O is added into the nitrate solution. Notably, H2O2 is introduced as the oxidant and dispersant during the co-precipitation process to oxidize the metal ions and decrease the agglomeration of the precursor by giving out O2, and then improves the specific capacity, stability and energy density of NCM. Additionally, O3 is employed to further oxidize NCM to enhance the stability during the calcination process. The obtained NCM material with single crystal structure exhibits a high initial discharge specific capacity of 208.9 mAh g-1 at 0.1 C (1 C = 280 mA g-1), an excellent cycle stability with high retained capacity of 176.3 mAh g-1 after 50 cycles, and a high initial discharge specific capacities of 150.6 mAh g-1 at 5 C even at a high cutoff potential (4.6 V).

  9. Countering the Segregation of Transition-Metal Ions in LiMn1/3 Co1/3 Ni1/3 O2 Cathode for Ultralong Life and High-Energy Li-Ion Batteries.

    Science.gov (United States)

    Luo, Dong; Fang, Shaohua; Tamiya, Yu; Yang, Li; Hirano, Shin-Ichi

    2016-08-01

    High-voltage layered lithium transition-metal oxides are very promising cathodes for high-energy Li-ion batteries. However, these materials often suffer from a fast degradation of cycling stability due to structural evolutions. It seriously impedes the large-scale application of layered lithium transition-metal oxides. In this work, an ultralong life LiMn1/3 Co1/3 Ni1/3 O2 microspherical cathode is prepared by constructing an Mn-rich surface. Its capacity retention ratio at 700 mA g(-1) is as large as 92.9% after 600 cycles. The energy dispersive X-ray maps of electrodes after numerous cycles demonstrate that the ultralong life of the as-prepared cathode is attributed to the mitigation of TM-ions segregation. Additionally, it is discovered that layered lithium transition-metal oxide cathodes with an Mn-rich surface can mitigate the segregation of TM ions and the corrosion of active materials. This study provides a new strategy to counter the segregation of TM ions in layered lithium transition-metal oxides and will help to the design and development of high-energy cathodes with ultralong life. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Interlaboratory study of the heat capacity of LiNi{sub 1/3}Mn{sub 1/3}Co{sub 1/3}O{sub 2} (NMC111) with layered structure

    Energy Technology Data Exchange (ETDEWEB)

    Cupid, Damian M.; Gotcu, Petronela [Karlsruhe Institute of Technology (KIT), Eggenstein-Leopoldshafen (Germany). Inst. for Applied Materials - Applied Materials Physics (IAM-AWP); Beutl, Alexander [Vienna Univ. (Austria). Inst. of Inorganic Chemistry - Functional Materials; and others

    2017-11-15

    An interlaboratory study was performed to determine the heat capacity of an active material for lithium-ion batteries with layered structure and nominal composition LiNi{sub 1/3} . Mn{sub 1/3}Co{sub 1/3}O{sub 2} (NMC111). The commercial sample, which was characterized using powder X-ray diffraction and inductively coupled plasma-optical emission spectroscopy, is single phase (α-NaFeO{sub 2} crystal structure) with a composition of Li{sub 1.02}Ni{sub 0.32}Mn{sub 0.31}Co{sub 0.30}O{sub 2}. Heat capacity measurements of the homogeneous sample were performed at five laboratories using different operators, methods, devices, temperature ranges, gas atmospheres and crucible materials. The experimental procedures from each laboratory are presented and the results of the individual laboratories are analyzed. Based on a comprehensive evaluation of the data from each laboratory, the heat capacity of the NMC111 sample from 315 K to 1 020 K is obtained with an expanded reproducibility uncertainty of less than 1.22 %.

  11. Catalytic degradation of the soil fumigant 1,3-dichloropropene in aqueous biochar slurry

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Jiaolong [School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (China); Cheng, Yuxiao; Sun, Mingxing [Shanghai Entry–Exit Inspection and Quarantine Bureau, Shanghai 200135 (China); Yan, Lili [School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (China); Shen, Guoqing, E-mail: gqsh@sjtu.edu.cn [School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (China)

    2016-11-01

    Biochar has been explored as a cost-effective sorbent of contaminants, such as soil fumigant. However, contaminant-loaded biochar probably becomes a source of secondary air pollution. In this study, biochars developed from cow manure and rice husk at 300 °C or 700 °C were used to investigate the catalytic degradation of the soil fumigant 1,3-dichloropropene (1,3-D) in aqueous biochar slurry. Results showed that the adsorption of 1,3-D on the biochars was influenced by Langmuir surface monolayer adsorption. The maximum adsorption capacity of cow manure was greater than that of rice husk at the same pyrolysis temperature. Batch experiments revealed that 1,3-D degradation was improved in aqueous biochar slurry. The most rapid 1,3-D degradation occurred on cow manure-derived biochar produced at 300 °C (C-300), with t{sub 1/2} = 3.47 days. The degradation efficiency of 1,3-D on C-300 was 95.52%. Environmentally persistent free radicals (EPFRs) in biochars were detected via electron paramagnetic resonance (EPR) techniques. Dissolved organic matter (DOM) and hydroxyl radical (·OH) in biochars were detected by using a fluorescence spectrophotometer coupled with a terephthalic acid trapping method. The improvement of 1,3-D degradation efficiency may be attributed to EPFRs and DOM in aqueous biochar slurry. Our results may pose implications in the development of effective reduction strategies for soil fumigant emission with biochar. - Highlights: • Hydrolysis of 1,3-D was accelerated in aqueous biochar slurry. • 1,3-D adsorption kinetics on biochars fitted well with Langmuir model. • Cow manure biochar showed higher catalytic degradation activity for 1,3-D than rice husk biochar did. • EPFRs and DOM have potential roles in 1,3-D degradation on biochar.

  12. Catalytic degradation of the soil fumigant 1,3-dichloropropene in aqueous biochar slurry

    International Nuclear Information System (INIS)

    Qin, Jiaolong; Cheng, Yuxiao; Sun, Mingxing; Yan, Lili; Shen, Guoqing

    2016-01-01

    Biochar has been explored as a cost-effective sorbent of contaminants, such as soil fumigant. However, contaminant-loaded biochar probably becomes a source of secondary air pollution. In this study, biochars developed from cow manure and rice husk at 300 °C or 700 °C were used to investigate the catalytic degradation of the soil fumigant 1,3-dichloropropene (1,3-D) in aqueous biochar slurry. Results showed that the adsorption of 1,3-D on the biochars was influenced by Langmuir surface monolayer adsorption. The maximum adsorption capacity of cow manure was greater than that of rice husk at the same pyrolysis temperature. Batch experiments revealed that 1,3-D degradation was improved in aqueous biochar slurry. The most rapid 1,3-D degradation occurred on cow manure-derived biochar produced at 300 °C (C-300), with t 1/2 = 3.47 days. The degradation efficiency of 1,3-D on C-300 was 95.52%. Environmentally persistent free radicals (EPFRs) in biochars were detected via electron paramagnetic resonance (EPR) techniques. Dissolved organic matter (DOM) and hydroxyl radical (·OH) in biochars were detected by using a fluorescence spectrophotometer coupled with a terephthalic acid trapping method. The improvement of 1,3-D degradation efficiency may be attributed to EPFRs and DOM in aqueous biochar slurry. Our results may pose implications in the development of effective reduction strategies for soil fumigant emission with biochar. - Highlights: • Hydrolysis of 1,3-D was accelerated in aqueous biochar slurry. • 1,3-D adsorption kinetics on biochars fitted well with Langmuir model. • Cow manure biochar showed higher catalytic degradation activity for 1,3-D than rice husk biochar did. • EPFRs and DOM have potential roles in 1,3-D degradation on biochar.

  13. The voltage-gated potassium channel subunit, Kv1.3, is expressed in epithelia

    DEFF Research Database (Denmark)

    Grunnet, Morten; Rasmussen, Hanne B; Hay-Schmidt, Anders

    2003-01-01

    The Shaker-type voltage-gated potassium channel, Kv1.3, is believed to be restricted in distribution to lymphocytes and neurons. In lymphocytes, this channel has gained intense attention since it has been proven that inhibition of Kv1.3 channels compromise T lymphocyte activation. To investigate...

  14. Production of 1,3-propanediol by Klebsiella pneumoniae using raw ...

    African Journals Online (AJOL)

    Yomi

    2012-01-16

    Jan 16, 2012 ... Available online at http://www.academicjournals.org/AJB ... The conversion of glycerol to 1,3-propanediol (1,3-PD) is an environmentally friendly biological process and has .... as carrier gas at flow rate of 40 ml min-1, detector.

  15. Function and Biosynthesis of Cell Wall α-1,3-Glucan in Fungi

    Directory of Open Access Journals (Sweden)

    Akira Yoshimi

    2017-11-01

    Full Text Available Although α-1,3-glucan is a major cell wall polysaccharide in filamentous fungi, its biological functions remain unclear, except that it acts as a virulence factor in animal and plant pathogenic fungi: it conceals cell wall β-glucan on the fungal cell surface to circumvent recognition by hosts. However, cell wall α-1,3-glucan is also present in many of non-pathogenic fungi. Recently, the universal function of α-1,3-glucan as an aggregation factor has been demonstrated. Applications of fungi with modified cell wall α-1,3-glucan in the fermentation industry and of in vitro enzymatically-synthesized α-1,3-glucan in bio-plastics have been developed. This review focuses on the recent progress in our understanding of the biological functions and biosynthetic mechanism of cell wall α-1,3-glucan in fungi. We briefly consider the history of studies on α-1,3-glucan, overview its biological functions and biosynthesis, and finally consider the industrial applications of fungi deficient in α-1,3-glucan.

  16. Chiral 1,3,2-oxazaborolidines in asymmetric synthesis: recent advances

    International Nuclear Information System (INIS)

    Glushkov, Vladimir A; Tolstikov, Alexander G

    2004-01-01

    The use of chiral 1,3,2-oxazaborolidines in asymmetric organic synthesis, particularly, in enantioselective reduction of ketones, imines and oxime ethers, asymmetric Diels-Alder reactions, aldol condensation and atroposelective reduction of lactones is reviewed. Reactions of immobilised 1,3,2-oxazaborolidines are also considered.

  17. Exploring strain-promoted 1,3-dipolar cycloadditions of end functionalized polymers

    NARCIS (Netherlands)

    Ledin, Petr A; Kolishetti, Nagesh; Hudlikar, Manish S; Boons, Geert-Jan

    2014-01-01

    Strain-promoted 1,3-dipolar cycloaddition of cyclooctynes with 1,3-dipoles such as azides, nitrones, and nitrile oxides, are of interest for the functionalization of polymers. In this study, we have explored the use of a 4-dibenzocyclooctynol (DIBO)-containing chain transfer agent in reversible

  18. Crystal structures and spectroscopic properties of 2¿3 phospha-1,3-dionates and 1,3-dionates of calcium ¿ comparative studies on the 1,3-diphenyl- and 1,3-Di(tert-butyl) derivatives¿

    NARCIS (Netherlands)

    Becker, Gerd; Niemeyer, Mark; Mundt, Otto; Schwarz, Wolfgang; Westerhausen, Matthias; Ossberger, Manfred W.; Mayer, Peter; Nöth, Heinrich; Zhong, Zhiyuan; Dijkstra, Pieter J.; Feijen, Jan

    2004-01-01

    Der Wasserstoff-Metall-Austausch zwischen Dibenzoylphosphan und Calciumcarbid in Tetrahydrofuran (THF) ergibt nach Zusatz des Liganden 1, 3, 5-Trimethyl-1, 3, 5-triazinan (TMTA) den als Kokristallisat mit Benzol isolierten zweikernigen Komplex Bis[(tmta-N, N, N)calcium-bis(dibenzoylphosphanid)

  19. 7 CFR 301.1-3 - Action on special need requests.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 5 2010-01-01 2010-01-01 false Action on special need requests. 301.1-3 Section 301.1... INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE DOMESTIC QUARANTINE NOTICES Preemption and Special Need Requests § 301.1-3 Action on special need requests. (a) Upon receipt of a complete special need request...

  20. Potential of Klebsiella oxytoca for 1,3-propanediol production from ...

    African Journals Online (AJOL)

    The increased rate of glycerol consumption and the formation of 1,3-propanediol coincides with formate degradation. This indicates that formate degradation likely works as an alternative means to generate part of the nicotine adenine dinucleotide (NADH) used by the 1,3-propanediol-dehydrogenase enzyme. Yield in mole ...

  1. Resonance Raman investigation of the radical cation of 1,3,5-hexatriene

    DEFF Research Database (Denmark)

    Keszhelyi, T.; Wilbrandt, R.; Cave, R.J.

    1994-01-01

    The resonance Raman spectrum of the 1,3,5-hexatriene radical cation generated by gamma-irradiation in a Freon glass is reported. The spectrum is excited at 395 nm in resonance with the second absorption band. Identical spectra are obtained from ionized (E)- and (Z)-1,3,5-hexatriene. The presence...

  2. Synthesis and inhibitory effect on photosynthetic electron transport of 1,3,5-triazinylcarboxylic acid derivatives

    NARCIS (Netherlands)

    Fujimori, A.; Ikeda, Y.; Okano, R.; Hiraki, M.; Rensen, van J.J.S.; Boger, P.; Kohno, H.; Wakabayashi, K.

    2005-01-01

    This study relates to the modification of 2-benzylamino-4-methyl-6-trifluoromethyl-1,3,5-triazine. New 1,3,5-triazine compounds with an electron-withdrawing carboxyl group, e.g. ester group, substituted for the trifluoromethyl group, were synthesized and assayed for activity to inhibit

  3. 40 CFR 80.55 - Measurement methods for benzene and 1,3-butadiene.

    Science.gov (United States)

    2010-07-01

    ... accomplished by bag sampling as used for total hydrocarbons determination. This procedure is detailed in 40 CFR 86.109. (b) Benzene and 1,3-butadiene must be analyzed by gas chromatography. Expected values for benzene and 1,3-butadiene in bag samples for the baseline fuel are 4.0 ppm and 0.30 ppm respectively. At...

  4. Electron–electron interactions in the chemical bond: “1/3” Effect in ...

    Indian Academy of Sciences (India)

    Unknown

    Abstract. The prominent “1/3” effect observed in the Hall effect plateaus of two- dimensional electron gas (2DEG) systems has been postulated to indicating 1/3 fractional charge quasiparticle excitations arising from electron–electron interactions. Tunneling shot-noise experiments on 2DEF exhibiting fractional quantum Hall ...

  5. Alternative Synthesis of 2,4-Substituted-1,3-thiazines and 2,5 ...

    African Journals Online (AJOL)

    To the best of our knowledge, this is the first report in which phenacetamidines have been utilized as precursors for thiazine synthesis. The syntheses of novel cyclic fused 1,3-diazabutadienes 13 and 2-aza-1,3-butadiene 17, and iodocyclization of 17 leading to the formation of thiazole 16a are also reported. In this paper a ...

  6. Protective Effects of Surfactant Protein D (SP-D) Treatment in 1,3-β-glucan-modulated Allergic Inflammation

    DEFF Research Database (Denmark)

    Fakih, Dalia; Pilecki, Bartosz; Schlosser, Anders

    2015-01-01

    SP-D is a pulmonary collectin important in lung immunity. SP-D-deficient mice (Sftpd(-/-)) are reported to be susceptible to ovalbumin (OVA)- and fungal allergen-induced pulmonary inflammation, while treatment with exogenous SP-D has therapeutic effects in such disease models. β-glucans are a div...

  7. The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses

    Directory of Open Access Journals (Sweden)

    Liheng Shi

    2017-12-01

    Full Text Available L-type voltage-gated calcium channels (LTCCs regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Cav1.2, Cav1.3, and Cav1.4 expressed in the retina. While Cav1.2 is expressed in all retinal cells including the Müller glia and neurons, Cav1.3 and Cav1.4 are expressed in the retinal neurons with Cav1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Cav1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Cav1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Cav1.3 are not associated with severe vision impairment in humans or in Cav1.3-null (Cav1.3−/− mice. However, a failure to regulate Cav1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Cav1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Cav1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG recordings and immunohistochemical staining, we found that Cav1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Cav1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Cav1.3−/− mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT. Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Cav1.3−/− mice retinas. Hence, Cav1.3 plays a more prominent role in retinal physiology and function than previously reported.

  8. The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses.

    Science.gov (United States)

    Shi, Liheng; Chang, Janet Ya-An; Yu, Fei; Ko, Michael L; Ko, Gladys Y-P

    2017-01-01

    L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Ca v 1.2, Ca v 1.3, and Ca v 1.4) expressed in the retina. While Ca v 1.2 is expressed in all retinal cells including the Müller glia and neurons, Ca v 1.3 and Ca v 1.4 are expressed in the retinal neurons with Ca v 1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Ca v 1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Ca v 1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Ca v 1.3 are not associated with severe vision impairment in humans or in Ca v 1.3-null (Ca v 1.3 -/- ) mice. However, a failure to regulate Ca v 1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Ca v 1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Ca v 1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Ca v 1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Ca v 1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Ca v 1.3 -/- mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Ca v 1.3 -/- mice retinas. Hence, Ca v 1.3 plays a more prominent role in retinal physiology and function than previously reported.

  9. Effect of viscoelastic and dielectric relaxing matrix on ferroelastic behaviour of 1-3 piezocomposites

    Directory of Open Access Journals (Sweden)

    R. Jayendiran

    2015-02-01

    Full Text Available This work focuses on evaluating the time-dependent non-linear ferroelastic behaviour of 1-3 piezocomposites under pure uni-axial compressive stress loading condition. An experimental setup is developed to study the influence of high-stress levels on the stress-strain and stress-polarization behaviour of 1-3 piezocomposites. The electro-elastic effective properties of 1-3 piezocomposites are measured experimentally based on IEEE standard and compared with the proposed numerical model using finite-element software ABAQUS. The time-dependent effective properties are evaluated using viscoelastic model and it is incorporated into a 3D micromechanical model to predict the viscoelastic behaviour of 1-3 piezocomposites under mechanical loading. The simulated results are compared with the viscoelastic behaviour of 1-3 piezocomposites obtained from experiments.

  10. Pot-Economy Autooxidative Condensation of 2-Aryl-2-lithio-1,3-dithianes.

    Science.gov (United States)

    Vale, João R; Rimpiläinen, Tatu; Sievänen, Elina; Rissanen, Kari; Afonso, Carlos A M; Candeias, Nuno R

    2018-02-16

    The autoxidative condensation of 2-aryl-2-lithio-1,3-dithianes is here reported. Treatment of 2-aryl-1,3-dithianes with n-BuLi in the absence of any electrophile leads to condensation of three molecules of 1,3-dithianes and formation of highly functionalized α-thioether ketones orthothioesters in 51-89% yields upon air exposure. The method was further expanded to benzaldehyde dithioacetals, affording corresponding orthothioesters and α-thioether ketones in 48-97% yields. The experimental results combined with density functional theory studies support a mechanism triggered by the autoxidation of 2-aryl-2-lithio-1,3-dithianes to yield a highly reactive thioester that undergoes condensation with two other molecules of 2-aryl-2-lithio-1,3-dithiane.

  11. LiNi1/3Co1/3Mn1/3O2 nanoplates with {010} active planes exposing prepared in polyol medium as a high-performance cathode for Li-ion battery.

    Science.gov (United States)

    Li, Jili; Yao, Ruimin; Cao, Chuanbao

    2014-04-09

    As we know, Li(+)-ion transport in layered LiNi1/3Co1/3Mn1/3O2 (NCM) is through two-dimensional channels parallel to the Li(+)-ion layers that are indexed as {010} active planes. In this paper, NCM nanoplates with exposed {010} active facets are synthesized in a polyol medium (ethylene glycol) and characterized by XRD, XPS, SEM, and HR-TEM. In addition, the effects of reaction conditions on the morphologies, structures and electrochemical performances are also evaluated. The results show that more {010} facets can be exposed with the thickness of NCM nanoplates increasing which can lead to more channels for Li(+)-ion migration. However, when the annealing temperatures exceed 900 °C, many new crystal planes grow along the thickness direction covering the {010} facets. In all of the NCM nanoplates obtained at different conditions, the NCM nanoplates calcined at 850 °C for 12 h (NCM-850-12H) display a high initial discharge capacity of 207.6 mAh g(-1) at 0.1 C (1 C = 200 mA g(-1)) between 2.5 and 4.5 V higher than most of NCM materials as cathodes for lithium ion batteries. The discharge capacities of NCM-850-12H are 169.8, 160.5, and 149.3 mAh g(-1) at 2, 5, and 7 C, respectively, illustrating the excellent rate capability. The superior electrochemical performance of NCM-850-12H cathode can be attributed to more {010} active planes exposure.

  12. Identification of rice cornichon as a possible cargo receptor for the Golgi-localized sodium transporter OsHKT1;3.

    Science.gov (United States)

    Rosas-Santiago, Paul; Lagunas-Gómez, Daniel; Barkla, Bronwyn J; Vera-Estrella, Rosario; Lalonde, Sylvie; Jones, Alexander; Frommer, Wolf B; Zimmermannova, Olga; Sychrová, Hana; Pantoja, Omar

    2015-05-01

    Membrane proteins are synthesized and folded in the endoplasmic reticulum (ER), and continue their path to their site of residence along the secretory pathway. The COPII system has been identified as a key player for selecting and directing the fate of membrane and secretory cargo proteins. Selection of cargo proteins within the COPII vesicles is achieved by cargo receptors. The cornichon cargo receptor belongs to a conserved protein family found in eukaryotes that has been demonstrated to participate in the selection of integral membrane proteins as cargo for their correct targeting. Here it is demonstrated at the cellular level that rice cornichon OsCNIH1 interacts with OsHKT1;3 and, in yeast cells, enables the expression of the sodium transporter to the Golgi apparatus. Physical and functional HKT-cornichon interactions are confirmed by the mating-based split ubiquitin system, bimolecular fluorescence complementation, and Xenopus oocyte and yeast expression systems. The interaction between the two proteins occurs in the ER of plant cells and their co-expression in oocytes leads to the sequestration of the transporter in the ER. In the yeast cornichon mutant erv14, OsHKT1;3 is mistargeted, preventing the toxic effects of sodium transport in the cell observed in wild-type cells or in the erv14 mutant that co-expressed OsHKT1;3 with either OsCNIH1 or Erv14p. Identification and characterization of rice cornichon as a possible cargo receptor opens up the opportunity to improve our knowledge on membrane protein targeting in plant cells. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  13. Identification of rice cornichon as a possible cargo receptor for the Golgi-localized sodium transporter OsHKT1;3

    Science.gov (United States)

    Rosas-Santiago, Paul; Lagunas-Gómez, Daniel; Barkla, Bronwyn J.; Vera-Estrella, Rosario; Lalonde, Sylvie; Jones, Alexander; Frommer, Wolf B.; Zimmermannova, Olga; Sychrová, Hana; Pantoja, Omar

    2015-01-01

    Membrane proteins are synthesized and folded in the endoplasmic reticulum (ER), and continue their path to their site of residence along the secretory pathway. The COPII system has been identified as a key player for selecting and directing the fate of membrane and secretory cargo proteins. Selection of cargo proteins within the COPII vesicles is achieved by cargo receptors. The cornichon cargo receptor belongs to a conserved protein family found in eukaryotes that has been demonstrated to participate in the selection of integral membrane proteins as cargo for their correct targeting. Here it is demonstrated at the cellular level that rice cornichon OsCNIH1 interacts with OsHKT1;3 and, in yeast cells, enables the expression of the sodium transporter to the Golgi apparatus. Physical and functional HKT–cornichon interactions are confirmed by the mating-based split ubiquitin system, bimolecular fluorescence complementation, and Xenopus oocyte and yeast expression systems. The interaction between the two proteins occurs in the ER of plant cells and their co-expression in oocytes leads to the sequestration of the transporter in the ER. In the yeast cornichon mutant erv14, OsHKT1;3 is mistargeted, preventing the toxic effects of sodium transport in the cell observed in wild-type cells or in the erv14 mutant that co-expressed OsHKT1;3 with either OsCNIH1 or Erv14p. Identification and characterization of rice cornichon as a possible cargo receptor opens up the opportunity to improve our knowledge on membrane protein targeting in plant cells. PMID:25750424

  14. Bis[2-(1,3-benzothiazol-2-ylphenyl-κ2C1,N][1,3-bis(4-bromophenylpropane-1,3-dionato-κ2O,O′]iridium(III

    Directory of Open Access Journals (Sweden)

    Sung Kwon Kang

    2013-08-01

    Full Text Available The title complex, [Ir(C15H9Br2O2(C13H8NS2], lies about a crystallographic twofold rotation axis passing through the IrIII atom and the central C atom of the bis(bromophenylpropane-1,3-dionate ligand. The IrIII atom adopts a distorted octahedral geometry coordinated by two N atoms in the axial positions, and two C and two O atoms in the equatorial plane. The dihedral angle between the two thiazole ring systems in the complex is 77.45 (10°.

  15. Novel Reaction of N,N'-Bisarylmethanediamines with Formaldehyde. Synthesis of Some New 1,3,5-Triaryl-1,3,5-hexahydrotriazines

    Directory of Open Access Journals (Sweden)

    Abolfazl Olyaei

    2006-07-01

    Full Text Available The acid-catalyzed cyclocondensation of N,N'-bisaryl (aryl = 2-pyrimidinyl, 2- pyrazinyl and 4-nitrophenyl methanediamines 5a-c with aqueous formaldehyde in refluxing acetonitrile leads to the formation of the corresponding 1,3,5-triaryl-1,3,5-hexa- hydrotriazines 6a-c. The stoichiometric reactions of 2-aminopyrimidine and 2-amino- pyrazine with aqueous formaldehyde in acetonitrile under reflux conditions also afforded 6a and 6b, respectively. Treatment of 2-aminopyrimidine with aqueous formaldehyde in a 3:2 ratio yielded N,N',N"-tris(2-pyrimidinyldimethylenetriamine (7a as a sole product, which upon subsequent reaction with formaldehyde also afforded 6a. The reaction of N,N'-biphenylmethanediamine with formaldehyde was also investigated.

  16. Development of a calibration system for airborne "1"3"1I monitoring devices

    International Nuclear Information System (INIS)

    Zhao, C.; Tang, F.; He, L.; Xu, Y.; Lu, X.

    2016-01-01

    A prototype calibration system for airborne "1"3"1I monitoring devices was developed at the Shanghai Institute of Measurement and Testing Technology (SIMT). This system consists of a gaseous "1"3"1I_2 generator, an airborne storage chamber, an airborne iodine sampler, and an HPGe spectrometer. With this system, "1"3"1I reference samples in the form of charcoal filters and charcoal cartridges, with activities ranging from 100 to 10,000 Bq, were produced with overall relative standard uncertainties of 2.8% (for filter samples) and 3.5% (for cartridge samples); the activities range could be extended according to need. - Highlights: • Original calibration system for airborne "1"3"1I monitoring devices was developed. • Two types of "1"3"1I reference samples was prepared. • The activity of the produced "1"3"1I reference sample could be easily controlled. • The influence of uneven distribution of "1"3"1I in cartridge samples was considered.

  17. Energy profiles for ketene cyclizations. Interconversion of 1,3-oxazin-6-ones, mesoionic 1,3-oxazinium olates and acylketenes, imidoylketenes, oxoketenimines, and cyclization products.

    Science.gov (United States)

    Bornemann, Holger; Wentrup, Curt

    2005-07-22

    The energy surface connecting oxazinium olates 9, several possible conformers of ketenes 10 and 11, and the final cyclization products 12, 13 and 14, as well as the isomeric 1,3-oxazine-6-ones 15, ring opening of the latter to N-acylimidoylketenes 16, and subsequent rearrangement of 16 to oxoketenimines 17, azetinones 18, and the cyclization products 19 and 20 are evaluated computationally at the B3LYP/6-31G and B3LYP/6-311+G//B3LYP/6-31G levels. The cyclizations of ketenes to oxazinium olates 9 and oxazines 15 have the characteristics of pseudopericyclic reactions. Plots of the energy vs internal reaction coordinate for the cyclization of transoid acylketenes such as 10 to 9 (via TS1) and 16 to 15 (via TS7) feature two inflection points and indicate that the part of the energy surface above the lower inflection points describe internal rotation of the acyl function in the ketene moiety, and the part below this point describes the cyclization of the cisoid ketene to the planar mesoionic oxazinium olate 9 or oxazinone 15. The 1,3-shifts of the OR group that interconvert ketenes 16 and ketenimines 17 via four-membered cyclic transition states TS8 behave similarly, the first portion (from the ketenimine side) of the activation barrier being due largely to internal rotation of substituents, and the top part being due to the 1,3-shift proper.

  18. Synthesis and Characterization of Mono- and Bicycle Heterocyclic Derivatives Containing 1, 2,4-Triazole, 1,3,4-Thiadiazine and 1,3-Thiazole Rings

    Directory of Open Access Journals (Sweden)

    Navabeh Nami

    2012-01-01

    Full Text Available Reaction of tartaric acid with thiocarbohydrazide (2 and thiosemicarbazide (6 afforded 1,2-bis(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl-ethane-1,2-diol (3 and 1,2-bis(5-mercapto-4H-1,2,4-triazol-3-yl-ethane-1,2-diol (7. Reaction of compounds 3 and 7 with DMAD (dimethylacety lendi carboxylate and DEAD (diethylacetylendicarboxylate gave 1,2-bis(7-[(z-methoxycarbonylmethylen]-5,6-dihydro-5H-6-one-[1,2,4] riazolo[3,4-b] [1,3,4] thiadiazin-3-yl-ethan-1,2-diol (4, 1,2-bis(7-[(z-ethoxycarbonylmethylen] -5,6-dihydro -5H-6-one-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl-ethan-1,2- diol (5 and 1,2-bis(6-[(z-methoxycarbonylmethylen]-5-oxo-[1,3]thiazolo[2,3-c] [1,2,4]triazol-3-yl-ethan-1,2-diol (8 in good yields.

  19. 1,3 benzene dioxole derivates as radioprotective agents. Pt. 4

    International Nuclear Information System (INIS)

    Dallacker, F.; Holschbach, M.; Konings, A.W.T.

    1990-01-01

    We describe the acid-catalysed transformation of o-terpenyl-dioxolephenols into 1,3-dioxole[4,5-g]chromanes 1a-1f and their methoxyl derivatives 2a-2f. The 1,3-dioxole[4,5-g]chromens 4a-4d, 5a-5d and 6a-6g are produced by treatment of the 1,3-dioxole[4,5-g]chromanes with DDQ in benzene. Moreover the chromenes 4-6 be synthesized by cyclohydrogenation of the corresponding open-chain compounds in good yields with DDQ. (orig.) [de

  20. Proprotein convertase 1/3 inhibited macrophages: A novel therapeutic based on drone macrophages.

    Science.gov (United States)

    Duhamel, Marie; Rodet, Franck; Murgoci, Adriana; Wisztorski, Maxence; Day, Robert; Fournier, Isabelle; Salzet, Michel

    2016-06-01

    We demonstrated here thanks to proteomic, that proprotein convertase 1/3 knockdown macrophages present all the characteristic of activated pro-inflammatory macrophages. TLR4 and TLR9 signaling pathways can be enhanced leading to the secretion of pro-inflammatory factors and antitumor factors. We can control their activation by controlling one enzyme, PC1/3. In a tumor context, PC1/3 inhibition in macrophages may reactivate them and lead to a cytokine storm after stimulation "at distance" with a TLR ligand. Therefore, we name these proprotein convertase inhibited macrophages the "drone macrophages". They constitute an innovative cell therapy to treat efficiently tumors.

  1. 1,3-Dichloro-2-propanol inhibits progesterone production through the expression of steroidogenic enzymes and cAMP concentration in Leydig cells.

    Science.gov (United States)

    Sun, Jianxia; Bai, Shun; Bai, Weibin; Zou, Feiyan; Zhang, Lei; Li, Guoqiang; Hu, Yunfeng; Li, Mingwei; Yan, Rian; Su, Zhijian; Huang, Yadong

    2014-07-01

    1,3-Dichloro-2-propanol (1,3-DCP) is a well-known food processing contaminant that has been shown to impede male reproductive function. However, its mechanism of action remains elusive. In this study, the effects of 1,3-DCP on progesterone production were investigated using the R2C Leydig cell model. 1,3-DCP significantly reduced cell viability from 7.48% to 97.4% at doses comprised between 0.5 and 6mM. Single cell gel/comet assays and atomic force microscopy assays showed that 1,3-DCP induced early phase cell apoptosis. In addition, 1,3-DCP significantly reduced progesterone production detected by radioimmunoassay (RIA). The results from quantitative polymerase chain reaction and western blotting demonstrated that the mRNA expression levels of steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase were significantly down-regulated in R2C cells. Particularly, the change rhythm of Star expression was highly consistent with progesterone production. Furthermore, the cyclic adenosine monophosphate (cAMP) and the mitochondrial membrane potential mediated by ROS, which are involved in regulating progesterone synthesis were also decreased in response to the 1,3-DCP treatment. Overall, the data presented here suggested that 1,3-DCP interferes with the male steroidogenic capacity mainly by down-regulating the level of cAMP and the key enzymes involved in the androgen synthesis pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Tetrahydro-2,1,3-boraoxazines - a new group boron heterocyclics

    International Nuclear Information System (INIS)

    Piotrowska, H.; Serafin, B.; Urbanski, T.; Vasudeva, S.K.

    1977-01-01

    The synthesis of new group of compounds derivative of tetrahydro-2,1,3 boraoxazine(5) by condensation of aminoalcohols 3 with aryloboronic acids(4) was carried out. The properties of new compounds are presented. (B.C.)

  3. Human Decompression Trial With 1.3 ATA Oxygen in Helium

    National Research Council Canada - National Science Library

    1998-01-01

    The Naval Medical Research Institute (NMRI) was tasked to develop helium-oxygen decompression tables for a proposed closed circuit breathing apparatus which Will deliver a constant oxygen partial pressure of 1.3 atmospheres (ATA...

  4. Regio- and stereochemistry of 1,3-dipolar cycloaddition of nitrile oxides to alkenes

    International Nuclear Information System (INIS)

    Litvinovskaya, Raisa P; Khripach, Vladimir A

    2001-01-01

    The published data on the chemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to different types of alkene derivatives are systematised. Various aspects of stereo- and regiochemistry of this reaction are considered. The bibliography includes 182 references.

  5. Synthesis of novel N-, S-substituted-polyhalo-1, 3-butadienes and ...

    Indian Academy of Sciences (India)

    Polyhalogenated-2-nitro-1, 3-butadienes are important synthetic precursors for a variety of poly- functionalized ... biodegradation of morpholine with strains of Mycobac- terium or ...... pounds from very simple precursor in a one-pot ope- ration.

  6. A Comparative Study of the Inclusion Complexes of 2-[5'-benzylidene-2'-phenyl-4'-oxo-1', 3'-thiazolidine]-1, 3-benzothiazole and 2-[5'-(p-N,N-dimethylamino- benzylidene-2'-phenyl-4'-oxo-1', 3'-thiazolidine]-1, 3-benzothiazole withβ-Cyclodextrin

    Directory of Open Access Journals (Sweden)

    S. Panda

    2011-01-01

    Full Text Available The compounds 2-[5'-benzylidene-2'-phenyl-4'-oxo-1', 3'-thiazolidine]-1, 3-benzothiazole and 2-[5'-(p-N,N-dimethylamino- benzylidene-2'-phenyl-4'-oxo-1', 3'-thiazolidine]-1, 3-benzothiazole have been synthesized in their purest forms starting from 2-aminobenzothiazole. The inclusion complexes of the above compounds have been prepared with β-cyclodextrin to increase their solubility and bioaccessibility in polar medium. The formation of inclusion complexes have been ascertained by study of spectral characteristic before and after inclusion complex formation. The stability of inclusion complexes and nature of interaction between the host and guest are known from the determination of thermodynamic parameters. Further the antibacterial and antifungal activities of the compounds are determined which is found to increase significantly after inclusion complex formation

  7. Effect of methyl substitution on optoelectronic properties of 1,3,6,8-tetraphenyl pyrenes

    Directory of Open Access Journals (Sweden)

    LIU Yanling

    2014-06-01

    Full Text Available Geometric structures of the ground states and excited states,frontier molecular orbitals,ionization potentials,electron affinities,reorganization energies,and absorption and emission spectra of three novel methyl-substituted 1,3,6,8-tetra-phenylpyrenes were studied theoretically by quantum-chemical methods,such as density functional theory (DFT.The results show that the position of methyl substituent on benzene ring has much effect on the optoelectronic properties of methyl-substituted 1,3,6,8-tetra-phenylpyrenes.Interestingly,the geometric structures and optoelectronic properties of the designed compound 1,3,6,8-tetra-p-tolylpyrene (TPPy are similar to those of 1,3,6,8-tetrakis(3,5-dimethylphenylpyrene (TDMPPy,which is worthy of being further researched.

  8. 75 FR 51388 - 2-methyl-1,3-propanediol; Exemption from the Requirement of a Tolerance

    Science.gov (United States)

    2010-08-20

    ... dermal sensitization study in guinea pigs, 2- methyl-1,3-propanediol was determined to have mild... entities may include, but are not limited to: Crop production (NAICS code 111). Animal production (NAICS...

  9. Determination of "1"3"5Cs by accelerator mass spectrometry

    International Nuclear Information System (INIS)

    MacDonald, C.M.; Charles, C.R.J.; Zhao, X.-L.; Kieser, W.E.; Cornett, R.J.; Litherland, A.E.

    2015-01-01

    The ratio of anthropogenic "1"3"5Cs and "1"3"7Cs isotopes is characteristic of a uranium fission source. This research evaluates the technique of isotope dilution (yield tracing) for the purpose of quantifying "1"3"5Cs by accelerator mass spectrometry with on-line isobar separation. Interferences from Ba, Zn_2, and isotopes of equal mass to charge ratios were successfully suppressed. However, some sample crosstalk from source contamination remains. The transmission and di-fluoride ionization efficiencies of Cs isotopes were found to be 8 × 10"−"3 and 1.7 × 10"−"7 respectively. This quantification of "1"3"5Cs using yield tracing by accelerator mass spectrometry shows promise for future environmental sample analysis once the issues of sample crosstalk and low efficiency can be resolved.

  10. Detailed studies of a high-capacity electrode material for rechargeable batteries, Li2MnO3-LiCo(1/3)Ni(1/3)Mn(1/3)O2.

    Science.gov (United States)

    Yabuuchi, Naoaki; Yoshii, Kazuhiro; Myung, Seung-Taek; Nakai, Izumi; Komaba, Shinichi

    2011-03-30

    Lithium-excess manganese layered oxides, which are commonly described by the chemical formula zLi(2)MnO(3)-(1-z)LiMeO(2) (Me = Co, Ni, Mn, etc.), are of great importance as positive electrode materials for rechargeable lithium batteries. In this Article, Li(x)Co(0.13)Ni(0.13)Mn(0.54)O(2-δ) samples are prepared from Li(1.2)Ni(0.13)Co(0.13)Mn(0.54)O(2) (or 0.5Li(2)MnO(3)-0.5LiCo(1/3)Ni(1/3)Mn(1/3)O(2)) by an electrochemical oxidation/reduction process in an electrochemical cell to study a reaction mechanism in detail before and after charging across a voltage plateau at 4.5 V vs Li/Li(+). Changes of the bulk and surface structures are examined by synchrotron X-ray diffraction (SXRD), X-ray absorption spectroscopy (XAS), X-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectroscopy (SIMS). SXRD data show that simultaneous oxygen and lithium removal at the voltage plateau upon initial charge causes the structural rearrangement, including a cation migration process from metal to lithium layers, which is also supported by XAS. This is consistent with the mechanism proposed in the literature related to the Li-excess manganese layered oxides. Oxygen removal associated with the initial charge on the high voltage plateau causes oxygen molecule generation in the electrochemical cells. The oxygen molecules in the cell are electrochemically reduced in the subsequent discharge below 3.0 V, leading to the extra capacity. Surface analysis confirms the formation of the oxygen containing species, such as lithium carbonate, which accumulates on the electrode surface. The oxygen containing species are electrochemically decomposed upon second charge above 4.0 V. The results suggest that, in addition to the conventional transition metal redox reactions, at least some of the reversible capacity for the Li-excess manganese layered oxides originates from the electrochemical redox reaction of the oxygen molecules at the electrode surface.

  11. Delayed myelosuppression with acute exposure to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and environmental degradation product hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) in rats

    Energy Technology Data Exchange (ETDEWEB)

    Jaligama, Sridhar; Kale, Vijay M.; Wilbanks, Mitchell S. [Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209 (United States); Perkins, Edward J. [US Army Engineer Research and Development Center, Vicksburg, MS 39180 (United States); Meyer, Sharon A., E-mail: meyer@ulm.edu [Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209 (United States)

    2013-02-01

    Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX. Both RDX and MNX caused a modest decrease in blood hemoglobin and ∼ 50% loss of granulocytes (NOAELs = 47 mg/kg) in female Sprague–Dawley rats observed 14 days post-exposure. We explored the possibility that blood cell loss observed after 14 days was delayed in onset because of toxicity to bone marrow (BM) progenitors. RDX and MNX decreased granulocyte/macrophage-colony forming cells (GM-CFCs) at 14, but not 7, days (NOAELs = 24 mg/kg). The earliest observed time at which MNX decreased GM-CFCs was 10 days post-exposure. RDX and MNX likewise decreased BM burst-forming units-erythroid (BFU-Es) at 14, but not 7, days. Granulocyte–erythrocyte–monocyte–megakaryocyte (GEMM)-CFCs were unaffected by RDX and MNX at 7 days suggesting precursor depletion did not account for GM-CFC and BFU-E loss. MNX added to the culture media was without effect on GM-CFC formation indicating no direct inhibition. Flow cytometry showed no differential loss of BM multilineage progenitors (Thy1.1{sup +}) or erythroid (CD71{sup +}) precursors with MNX suggesting myeloid and erythroid lineages were comparably affected. Collectively, these data indicate that acute exposure to both RDX and MNX caused delayed suppression of myelo- and erythropoiesis with subsequent decrease of peripheral granulocytes and erythrocytes. Highlights: ► Acute oral exposure to munitions RDX causes myelosuppression. ► Environmental degradation product MNX is comparable in effect. ► RDX and MNX are cytotoxic to both myeloid and erythroid

  12. Water promoted allylic nucleophilic substitution reactions of (E)-1,3 diphenylallyl acetate

    KAUST Repository

    Ghorpade, Seema Arun; Sawant, Dinesh N; Makki, Arwa; Sekar, N; Eppinger, Jö rg

    2017-01-01

    Transition metal free, water based, greener protocol for allylic alkylation, allylic amination, O-allylation of (E)-1,3-diphenylallyl acetate is described. The developed methodology is applicable for a wide range of nucleophiles furnishing excellent yields of corresponding products up to 87% under mild reaction conditions. A Distinct effect of water and base is explored for allylic nucleophilic substitution reactions of (E)-1,3-diphenylallyl acetate.

  13. National Ignition Facility subsystem design requirements transportation and handling, SSDR 1.1.1.3.2

    International Nuclear Information System (INIS)

    Yakuma, S.; McNairy, R.

    1996-01-01

    This Subsystem Design Requirement document is a development specification that establishes the performance, design, development, and test requirements for the Transportation ampersand Material Handling Systems (WBS 1.1.1.3.2) of the NIF Laser System (WBS 1.3 and 1.4). The NIF is a multi-pass, 192-beam, high-power, neodymium-glass laser that meets requirements set forth in the NIF SDR 002 (Laser System). 5 figs

  14. Correlations of Rotylenchulus reniformis Population Densities with 1,3-Dichloropropene Dosage Rate and Pineapple Yields

    OpenAIRE

    Schenck, Susan

    1990-01-01

    The relationships between Rotylenchulus reniformis population densities and pineapple growth and yield were studied in a small-plot field experiment. Increasing rates of handgun-injected 1,3-dichloropropene (1,3-D) preplant fumigant from 0 to 337 liters/ha resulted in greater nematode control, faster plant growth, and larger pineapple fruits. Rotylenchulus reniformis population densities at 2, 4, 6, and 8 months postplant were correlated with plant size and yield. The shorter the time period ...

  15. The secret life of ion channels: Kv1.3 potassium channels and proliferation.

    Science.gov (United States)

    Pérez-García, M Teresa; Cidad, Pilar; López-López, José R

    2018-01-01

    Kv1.3 channels are involved in the switch to proliferation of normally quiescent cells, being implicated in the control of cell cycle in many different cell types and in many different ways. They modulate membrane potential controlling K + fluxes, sense changes in potential, and interact with many signaling molecules through their intracellular domains. From a mechanistic point of view, we can describe the role of Kv1.3 channels in proliferation with at least three different models. In the "membrane potential model," membrane hyperpolarization resulting from Kv1.3 activation provides the driving force for Ca 2+ influx required to activate Ca 2+ -dependent transcription. This model explains most of the data obtained from several cells from the immune system. In the "voltage sensor model," Kv1.3 channels serve mainly as sensors that transduce electrical signals into biochemical cascades, independently of their effect on membrane potential. Kv1.3-dependent proliferation of vascular smooth muscle cells (VSMCs) could fit this model. Finally, in the "channelosome balance model," the master switch determining proliferation may be related to the control of the Kv1.3 to Kv1.5 ratio, as described in glial cells and also in VSMCs. Since the three mechanisms cannot function independently, these models are obviously not exclusive. Nevertheless, they could be exploited differentially in different cells and tissues. This large functional flexibility of Kv1.3 channels surely gives a new perspective on their functions beyond their elementary role as ion channels, although a conclusive picture of the mechanisms involved in Kv1.3 signaling to proliferation is yet to be reached.

  16. ASUPAN SUPLEMEN BUKAN DETERMINAN KEJADIAN STUNTING ANAK BALITA (1-3 TAHUN

    Directory of Open Access Journals (Sweden)

    Didik Hariyadi

    2016-07-01

    Full Text Available Abstract: Supplement Intake Not Determinants Stunting Events Children (1-3 Years. This study aims relationship supplement intake with the incidence of stunting among Children aged 1-3 years who live in urban areas Kubu Raya. An observational study with the cross-sectional design. The research was conducted in Kubu Raya in August to November 2014. Measurement of nutritional status using indicators PB/U. Supplement intake asked to interview. Statistical analysis was performed using Chi-square test.The results showed the percentage of stunting in Children aged 1-3 years in the amount of 39.51%.The most consumed form of supplements which are of the type syrup as much as 34.6% of 82.7% respondents toddler supplements. No significant relationship exists between supplement intake with the incidence of stunting in Children aged 1-3 years in the urban area of Kubu Raya. Abstrak: Asupan Suplemen Bukan Determinan Kejadian Stunting Anak balita (1-3 Tahun. Penelitian ini bertujuan hubungan asupan suplemen dengan kejadian stunting pada anak balita usia 1-3 tahun yang tinggal di daerah urbanKubu Raya. Penelitian ini bersifat observasional dengan rancangan cross sectional. Penelitian dilaksanakan di Kabupaten Kubu Raya pada bulan Agustus sampai November 2014. Pengukuran status gizi menggunakan indikator PB/U. Asupan suplemen ditanyakan dengan wawancara. Analisis statistik dilakukan dengan menggunakan uji Chi square.Hasil penelitian menunjukan persentase kejadian stunting pada balita umur 1-3 tahun yaitu sebesar 39,51%. Sebanyak 82.7% balita responden mengonsumsi suplemen, dengan bentuk suplemen yang terbanyak dikonsumsi adalah dari jenis sirup sebanyak 34.6%.Tidak ada hubungan yang bemakna antara asupan suplemen dengan kejadian stunting pada balita umur 1-3 tahun di daerah urban Kubu Raya.

  17. The 1:1 adduct of caffeine and 2-(1,3-dioxoisoindolin-2-ylacetic acid

    Directory of Open Access Journals (Sweden)

    Moazzam H. Bhatti

    2011-09-01

    Full Text Available In the crystal structure of the title adduct [systematic name: 2-(1,3-dioxoisoindolin-2-ylacetic acid–1,3,7-trimethyl-1,2,3,6-tetrahydro-7H-purine-2,6-dione (1/1], C8H10N4O2·C10H7NO4, the components are linked by an O—H...N hydrogen-bond and no proton transfer occurs.

  18. Water promoted allylic nucleophilic substitution reactions of (E)-1,3 diphenylallyl acetate

    KAUST Repository

    Ghorpade, Seema Arun

    2017-11-30

    Transition metal free, water based, greener protocol for allylic alkylation, allylic amination, O-allylation of (E)-1,3-diphenylallyl acetate is described. The developed methodology is applicable for a wide range of nucleophiles furnishing excellent yields of corresponding products up to 87% under mild reaction conditions. A Distinct effect of water and base is explored for allylic nucleophilic substitution reactions of (E)-1,3-diphenylallyl acetate.

  19. Reversible addition-fragmentation chain transfer polymerization of 2-chloro-1,3-butadiene

    OpenAIRE

    Pullan, Nikki; Liu, Max; Topham, Paul D.

    2013-01-01

    Controlled polymerization of 2-chloro-1,3-butadiene using reversible addition–fragmentation chain transfer (RAFT) polymerization has been demonstrated for the first time. 2-Chloro-1,3-butadiene, more commonly known as chloroprene, has significant industrial relevance as a crosslinked rubber, with uses ranging from adhesives to integral automotive components. However, problems surrounding the inherent toxicity of the lifecycle of the thiourea-vulcanized rubber have led to the need for control ...

  20. 1,3,5,8-tetrahydroxyxanthone regulates ANGPTL3-LPL pathway to lessen the ketosis in mice.

    Science.gov (United States)

    Xiao, Hong-Bo; Sun, Zhi-Liang; Zhou, Nan

    2012-05-12

    Ketosis is a metabolic disorder closely associated with both lipid and carbohydrate metabolism. Recent studies show that angiopoietin-like protein 3 (ANGPTL3) contributes to the development of metabolic disorder. The objective of this study was to explore the inhibitory effect of 1,3,5,8-tetrahydroxyxanthone (Xan), a naturally occurring flavonoid compound, on ketosis and the mechanisms involved in this regulation. After 4weeks, Xan (10 or 30mg/kg, intragastrically) treatment decreased plasma total ketone bodies, malondialdehyde, 8-isoprostane, triglyceride, total cholesterol levels, and hepatic ANGPTL3 expression concomitantly with increased plasma glucose concentration and adipose lipoprotein lipase (LPL) expression in ketosis murine. The present results suggest that Xan regulates ANGPTL3-LPL pathway to lessen the ketosis in mice. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Novel Aldo-Keto Reductases for the Biocatalytic Conversion of 3-Hydroxybutanal to 1,3-Butanediol: Structural and Biochemical Studies

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Taeho; Flick, Robert; Brunzelle, Joseph; Singer, Alex; Evdokimova, Elena; Brown, Greg; Joo, Jeong Chan; Minasov, George A.; Anderson, Wayne F.; Mahadevan, Radhakrishnan; Savchenko, Alexei; Yakunin, Alexander F. (KRICT); (Toronto); (NWU)

    2017-01-27

    The nonnatural alcohol 1,3-butanediol (1,3-BDO) is a valuable building block for the synthesis of various polymers. One of the potential pathways for the biosynthesis of 1,3-BDO includes the biotransformation of acetaldehyde to 1,3-BDO via 3-hydroxybutanal (3-HB) using aldolases and aldo-keto reductases (AKRs). This pathway requires an AKR selective for 3-HB, but inactive toward acetaldehyde, so it can be used for one-pot synthesis. In this work, we screened more than 20 purified uncharacterized AKRs for 3-HB reduction and identified 10 enzymes with significant activity and nine proteins with detectable activity. PA1127 fromPseudomonas aeruginosashowed the highest activity and was selected for comparative studies with STM2406 fromSalmonella entericaserovar Typhimurium, for which we have determined the crystal structure. Both AKRs used NADPH as a cofactor, reduced a broad range of aldehydes, and showed low activities toward acetaldehyde. The crystal structures of STM2406 in complex with cacodylate or NADPH revealed the active site with bound molecules of a substrate mimic or cofactor. Site-directed mutagenesis of STM2406 and PA1127 identified the key residues important for the activity against 3-HB and aromatic aldehydes, which include the residues of the substrate-binding pocket and C-terminal loop. Our results revealed that the replacement of the STM2406 Asn65 by Met enhanced the activity and the affinity of this protein toward 3-HB, resulting in a 7-fold increase inkcat/Km. Our work provides further insights into the molecular mechanisms of the substrate selectivity of AKRs and for the rational design of these enzymes toward new substrates.

    IMPORTANCEIn this study, we identified several aldo-keto reductases with significant activity in reducing 3

  2. Novel histone deacetylase 8-selective inhibitor 1,3,4-oxadiazole-alanine hybrid induces apoptosis in breast cancer cells.

    Science.gov (United States)

    Pidugu, Vijaya Rao; Yarla, Nagendra Sastry; Bishayee, Anupam; Kalle, Arunasree M; Satya, Alapati Krishna

    2017-11-01

    Identification of isoform-specific histone deacetylase inhibitors (HDACi) is a significant advantage to overcome the adverse side effects of pan-HDACi for the treatment of various diseases, including cancer. We have designed, and synthesized novel 1,3,4 oxadiazole with glycine/alanine hybrids as HDAC8-specific inhibitors and preliminary evaluation has indicated that 1,3,4 oxadiazole with alanine hybrid [(R)-2-amino-N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)propanamide (10b)] to be a potent HDAC8 inhibitor. In the present study, the in vitro efficacy of the molecule in inhibiting the cancer cell proliferation and the underlying molecular mechanism was studied. 10b inhibited the growth of MDA-MB-231 and MCF7 breast cancer cells, with a lower IC 50 of 230 and 1000 nM, respectively, compared to K562, COLO-205 and HepG2 cells and was not cytotoxic to normal breast epithelial cells, MCF10A. 10b was specific to HDAC8 and did not affect the expression of other class I HDACs. Further, a dose-dependent increase in H3K9 acetylation levels demonstrated the HDAC-inhibitory activity of 10b in MDA-MB-231 cells. Flow cytometric analysis indicated a dose-dependent increase and decrease in the percent apoptotic cells and mitochondrial membrane potential, respectively, when treated with 10b. Immunoblot analysis showed a modulation of Bax/Bcl2 ratio with a decrease in Bcl2 expression and no change in Bax expression. 10b treatment resulted in induction of p21 and inhibition of CDK1 proteins along with cytochrome c release from mitochondria, activation of caspases-3 and -9 and cleavage of poly ADP-ribose polymerase leading to apoptotic death of MDA-MB-231 and MCF7 cells. In conclusion, our results clearly demonstrated the efficacy of 10b as an anticancer agent against breast cancer.

  3. Hydroxyl radical and ozone initiated photochemical reactions of 1,3-butadiene

    Science.gov (United States)

    Liu, Xiaoyu; Jeffries, Harvey E.; Sexton, Kenneth G.

    1,3-Butadiene, classified as hazardous in the 1990 Clean Air Act Amendments, is an important ambient air pollutant. Understanding its atmospheric transformation is useful for its own sake, and is also helpful for eliciting isoprene's fate in the atmosphere (isoprene dominates the biogenic emissions in US). In this paper, samples from both hydroxyl- and ozone-initiated photooxidation of 1,3-butadiene were analyzed by derivatization with O- (2,3,4,5,6-pentafluorobenzyl)-hydroxylamine followed by separation and detection by gas chromatography/ion trap mass spectrometry to detect and identify carbonyl compounds. The following carbonyls were observed: formaldehyde, acrolein, glycolaldehyde, glycidaldehyde, 3-hydroxy-propanaldehyde, hydroxy acetone, and malonaldehyde, which can be classified into three categories: epoxy carbonyls, hydroxyl carbonyls, and di-carbonyls. Three non-carbonyls, furan, 1,3-buatdiene monoxide, and 1,3-butadiene diepoxide, were also found. To confirm their identities, both commercially available and synthesized standards were used. To investigate the mechanism of 1,3-butadiene, separate batch reactor experiments for acrolein and 1,3-butadiene monoxide were carried out. Time series samples for several products were also taken. When necessary, computational chemistry methods were also employed. Based on these results, various schemes for the reaction mechanism are proposed.

  4. The cell wall-localized atypical β-1,3 glucanase ZERZAUST controls tissue morphogenesis in Arabidopsis thaliana.

    Science.gov (United States)

    Vaddepalli, Prasad; Fulton, Lynette; Wieland, Jennifer; Wassmer, Katrin; Schaeffer, Milena; Ranf, Stefanie; Schneitz, Kay

    2017-06-15

    Orchestration of cellular behavior in plant organogenesis requires integration of intercellular communication and cell wall dynamics. The underlying signaling mechanisms are poorly understood. Tissue morphogenesis in Arabidopsis depends on the receptor-like kinase STRUBBELIG. Mutations in ZERZAUST were previously shown to result in a strubbelig -like mutant phenotype. Here, we report on the molecular identification and functional characterization of ZERZAUST We show that ZERZAUST encodes a putative GPI-anchored β-1,3 glucanase suggested to degrade the cell wall polymer callose. However, a combination of in vitro , cell biological and genetic experiments indicate that ZERZAUST is not involved in the regulation of callose accumulation. Nonetheless, Fourier-transformed infrared-spectroscopy revealed that zerzaust mutants show defects in cell wall composition. Furthermore, the results indicate that ZERZAUST represents a mobile apoplastic protein, and that its carbohydrate-binding module family 43 domain is required for proper subcellular localization and function whereas its GPI anchor is dispensable. Our collective data reveal that the atypical β-1,3 glucanase ZERZAUST acts in a non-cell-autonomous manner and is required for cell wall organization during tissue morphogenesis. © 2017. Published by The Company of Biologists Ltd.

  5. Novel 1,3,4-Oxadiazole Induces Anticancer Activity by Targeting NF-κB in Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Chakrabhavi Dhananjaya Mohan

    2018-03-01

    Full Text Available Aberrant activation of NF-κB is linked with the progression of human malignancies including hepatocellular carcinoma (HCC, and blockade of NF-κB signaling could be a potential target in the treatment of several cancers. Therefore, designing of novel small molecule inhibitors that target NF-κB activation is of prime importance in the treatment of several cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells, and identified 2-(3-chlorobenzo[b]thiophen-2-yl-5-(3-methoxyphenyl-1,3,4-oxadiazole (CMO as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry, apoptosis (annexin V-propidium iodide-FITC staining, and phosphorylation of NF-κB signaling pathway proteins (IκB and p65 in HCC cells. We found that CMO induced antiproliferative effect in dose- and time-dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IκB (Ser 32 in the cytoplasmic extract and p65 (Ser 536 in the nuclear extract of HCC cells. It also abrogated the DNA binding ability and transcriptional activity of NF-κB. CMO induced the cleavage of PARP and caspase-3 in a time-dependent manner. In addition, transfection with p65 small interfering RNA blocks CMO-induced caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with the hydrophobic region of p65 protein. Thus, we are reporting CMO as an inhibitor of NF-κB signaling pathway.

  6. Immune Enhancing Activity of β-(1,3)-Glucan Isolated from Genus Agrobacterium in Bone-Marrow Derived Macrophages and Mice Splenocytes.

    Science.gov (United States)

    Byun, Eui-Baek; Jang, Beom-Su; Byun, Eui-Hong; Sung, Nak-Yun

    2016-01-01

    An effective method for activating macrophages and deriving a Th1 immune response could be used to improve the defenses of hosts. In this study, we investigated the immunomodulation effect and the related signaling mechanism of [Formula: see text]-(1,3)-glucan, isolated from the Agrobacterium species. Here, we found that [Formula: see text]-(1,3)-glucan predominantly induced the tumor necrosis factor (TNF)-[Formula: see text], interleukin (IL)-1[Formula: see text], IL-6, IL-12p70, and nitric oxide, which was dependent on mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-[Formula: see text]B signaling. Additionally, [Formula: see text]-(1,3)-glucan treatment significantly up-regulated the expression of the co-stimulatory molecules CD80 and CD86, and also significantly increased the expression of iNOS and Dectin-1, which is a transmembrane protein that binds [Formula: see text]-glucan and associates with macrophage activation. Importantly, the splenic T cells co-cultured with [Formula: see text]-(1,3)-glucan-treated macrophages produced the a Th1 cytokine profile that includes high levels of IFN-[Formula: see text], but not IL-4 (Th2 cytokine), indicating that [Formula: see text]-(1,3)-glucan contributes to Th1 polarization of the immune response. Taken together, our results suggest that [Formula: see text]-(1,3)-glucan isolated from Agrobacterium species can induce macrophage activation through the MAPK and NF-[Formula: see text]B signaling pathway, as well as Th1 polarization.

  7. SRSF1-3 contributes to diversification of the immunoglobulin variable region gene by promoting accumulation of AID in the nucleus

    OpenAIRE

    Kawaguchi, Yuka; Nariki, Hiroaki; Kawamoto, Naoko; Kanehiro, Yuichi; Miyazaki, Satoshi; Suzuki, Mari; Magari, Masaki; Tokumitsu, Hiroshi; Kanayama, Naoki

    2017-01-01

     Activation-induced cytidine deaminase (AID) is essential for diversification of the Ig variable region (IgV). AID is excluded from the nucleus, where it normally functions. However, the molecular mechanisms responsible for regulating AID localization remain to be elucidated. The SR-protein splicing factor SRSF1 is a nucleocytoplasmic shuttling protein, a splicing isoform of which called SRSF1-3, has previously been shown to contribute to IgV diversification in chicken DT40 cells. In this stu...

  8. Trinuclear Lanthanoid Complexes of 1,3,5-Triamino-1,3,5-trideoxy-cis-inositol with a Unique, Sandwich-Type Cage Structure(1).

    Science.gov (United States)

    Hedinger, Roman; Ghisletta, Michele; Hegetschweiler, Kaspar; Tóth, Eva; Merbach, André E.; Sessoli, Roberta; Gatteschi, Dante; Gramlich, Volker

    1998-12-28

    A variety of trinuclear complexes [M(3)(H(-)(3)L)(2)](3+) [M = Y, La, Eu, Gd, Dy; L = 1,3,5-triamino-1,3,5-trideoxy-cis-inositol (taci) and 1,3,5-trideoxy-1,3,5-tris(dimethylamino)-cis-inositol (tdci)] was prepared as solid materials of the composition M(3)(H(-)(3)L)(2)X(3).pH(2)O.qEtOH (X = Cl, NO(3); 2.5

  9. Conversion of 1,3-Propylene Glycol on Rutile TiO2(110)

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Long; Li, Zhenjun; Smith, R. Scott; Kay, Bruce D.; Dohnalek, Zdenek

    2014-10-09

    The adsorption of 1,3-propylene glycol (1,3-PG) on partially reduced TiO2(110) and its conversion to products have been studied by a combination of molecular beam dosing and temperature programmed desorption (TPD). When the Ti surface sites are saturated by 1,3-PG, ~80% of the molecules undergo further reactions to yield products that are liberated during the TPD ramp. In contrast to ethylene glycol (EG) and 1,2- propylene glycol (1,2-PG) that yield only alkenes and water at very low coverages (< 0.05 ML), two additional products, HCHO and C2H4, along with propylene (CH3CHCH2) and water are observed for 1,3-PG. Identical TPD line shapes and desorption yields for HCHO and C2H4 suggest that these products result from C-C bond cleavage and are coupled. At higher 1,3-PG coverages (> 0.1 ML), propanal (CH3CH2CHO) and two additional products, 1-propanol (CH3CH2CH2OH) and acrolein (CH2CHCHO), are observed. The desorption of 1-propanol is found to be coupled with the desorption of acrolein, suggesting that these products are formed by the disproportionation of two 1,3-PG molecules. The coverage dependent TPD results further show that propylene formation dominates at low coverages (< 0.3 ML), while the decomposition and disproportionation channels increase rapidly at higher coverages and reach yields comparable to that of propylene at the 1,3-PG saturation coverage of 0.5 ML. The observed surface chemistry clearly shows how the molecular structure of glycols influences their reaction pathways on oxide surfaces.

  10. Improved 1,3-Propanediol Synthesis from Glycerol by the Robust Lactobacillus reuteri Strain DSM 20016.

    Science.gov (United States)

    Ricci, Maria Antonietta; Russo, Annamaria; Pisano, Isabella; Palmieri, Luigi; de Angelis, Maria; Agrimi, Gennaro

    2015-06-01

    Various Lactobacillus reuteri strains were screened for the ability to convert glycerol to 1,3- propanediol (1,3-PDO) in a glycerol-glucose co-fermentation. Only L. reuteri DSM 20016, a well-known probiotic, was able to efficiently carry out this bioconversion. Several process strategies were employed to improve this process. CO(2+) addition to the fermentation medium, led to a high product titer (46 g/l) of 1,3-PDO and to improved biomass synthesis. L. reuteri DSM 20016 produced also ca. 3 μg/g of cell dry weight of vitamin B12, conferring an economic value to the biomass produced in the process. Incidentally, we found that L. reuteri displays the highest resistance to CO(2+) ions ever reported for a microorganism. Two waste materials (crude glycerol from biodiesel industry and spruce hydrolysate from paper industry) alone or in combination were used as feedstocks for the production of 1,3-PDO by L. reuteri DSM 20016. Crude glycerol was efficiently converted into 1,3-PDO although with a lower titer than pure glycerol (-18%). Compared with the fermentation carried out with pure substrates, the 1,3- PDO produced was significantly lower (40.7 vs. 24.2 g/l) using cellulosic hydrolysate and crude glycerol, but strong increases of the maximal biomass produced (+27%) and of the glucose consumption rate (+46%) were found. The results of this study lay the foundation for further investigations to exploit the biotechnological potential of L. reuteri DSM 20016 to produce 1,3-PDO and vitamin B12 using industry byproducts.

  11. Is inositol (1,3,4,5)-tetrakisphosphate a new second messenger?

    International Nuclear Information System (INIS)

    Hansen, C.A.; Williamson, J.R.

    1986-01-01

    Hormone-stimulated hydrolysis of inositol (Ins) lipids results in the rapid formation of Ins(1,4,5)P 3 , the second messenger for intracellular Ca 2+ mobilization. Recently, a more polar inositol phosphate, Ins(1,3,4,5)P 4 as well as its probable hydrolysis product Ins(1,3,4)P 3 have been reported to accumulate in carbachol-stimulated brain slices. Vasopressin addition to hepatocytes prelabeled with [ 3 H]-Ins also showed a rapid increase of Ins(1,3,4,5)P 4 , which was similar to that of Ins(1,4,5)P 3 , while the accumulation of Ins(1,3,4)P 3 was slower. In order to examine whether Ins(1,3,4,5)P 4 has any functional effects on Ca 2+ homeostasis, it was synthesized enzymatically from [ 3 H]-Ins(1,4,5)P 3 using a partially purified phosphoinositol kinase activity from rat brain cortex. [ 3 H]-labeled inositol phosphates were separated by anion exchange chromatography and analyzed by HPLC using ammonium formate/phosphoric acid gradient elution. Preliminary experiments indicate that Ins(1,3,4,5)P 4 up to 10 μM does not release Ca 2+ from vesicular pools in saponin-permeabilized hepatocytes. It has a slight inhibitory effect on Ins(1,4,5)P 3 -induced Ca 2+ release. The effect of Ins(1,3,4,5)P 4 on plasma membrane Ca 2+ fluxes are presently being investigated

  12. Concentration of "1"3"4Cs + "1"3"7Cs bonded to the organic fraction of sediments offshore Fukushima, Japan

    International Nuclear Information System (INIS)

    Ono, Tsuneo; Ambe, Daisuke; Kaeriyama, Hideki

    2015-01-01

    We conducted a sequential chemical extraction experiment for radiocesium ("1"3"4Cs + "1"3"7Cs) using 21 surface sediment samples and two sets of size-fractionated surface sediment samples collected offshore Fukushima. Our results support earlier reports in this area that organic substances in marine sediments have an apparently higher preference for radiocesium than mineral substances. Observations suggest that mineral and organic substances in the marine sediments offshore Fukushima have the same order of preference for radiocesium, primarily because of the existence of ionic competitors in seawater. The apparent preference of radiocesium for organic material is greater because of the partial coverage of sediment mineral surfaces by organic substances. By using these relationships, we created a 2-D map of radiocesium concentration in sediment organic fraction in offshore-Fukushima region. Combining our results with existing monitoring data of marine benthos in offshore-Fukushima sediments, we estimated a transfer coefficient of radiocesium from sediment organic materials to benthic polychaetes as less than 0.03-0.008. (author)

  13. Platinum(0-1,3-divinyl-1,1,3,3-tetramethyldisiloxane Complex as a Pt Source for Pt/SnO2 Catalyst

    Directory of Open Access Journals (Sweden)

    Agnieszka Martyla

    2014-01-01

    Full Text Available This paper presents new preparation method of Pt/SnO2, an important catalytic system. Besides of its application as a heterogenic industrial catalyst, it is also used as a catalyst in electrochemical processes, especially in fuel cells. Platinum is commonly used as an anode catalyst in low temperature fuel cells, fuelled with alcohols of low molecular weight such as methanol. Platinum(0-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex was used as a precursor of metallic phase. The aim of the research was to obtain a highly active in electrochemical system Pt/SnO2 catalyst with low metal load. Considering small size of Pt crystallites, it should result in high activity of Pt/SnO2 system. The presented method of SnO2 synthesis allows for obtaining support consisting of nanoparticles. The effect of the thermal treatment on activity of Pt/SnO2 gel was demonstrated. The system properties were investigated using TEM, FTIR (ATR, and XRD techniques to describe its thermal structural evolution. The results showed two electrocatalytical activity peaks for drying at a temperature of 430 K and above 650 K.

  14. On the low pressure shock initiation of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine based plastic bonded explosives

    Science.gov (United States)

    Vandersall, Kevin S.; Tarver, Craig M.; Garcia, Frank; Chidester, Steven K.

    2010-05-01

    In large explosive and propellant charges, relatively low shock pressures on the order of 1-2 GPa impacting large volumes and lasting tens of microseconds can cause shock initiation of detonation. The pressure buildup process requires several centimeters of shock propagation before shock to detonation transition occurs. In this paper, experimentally measured run distances to detonation for lower input shock pressures are shown to be much longer than predicted by extrapolation of high shock pressure data. Run distance to detonation and embedded manganin gauge pressure histories are measured using large diameter charges of six octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) based plastic bonded explosives (PBX's): PBX 9404; LX-04; LX-07; LX-10; PBX 9501; and EDC37. The embedded gauge records show that the lower shock pressures create fewer and less energetic "hot spot" reaction sites, which consume the surrounding explosive particles at reduced reaction rates and cause longer distances to detonation. The experimental data is analyzed using the ignition and growth reactive flow model of shock initiation in solid explosives. Using minimum values of the degrees of compression required to ignite hot spot reactions, the previously determined high shock pressure ignition and growth model parameters for the six explosives accurately simulate the much longer run distances to detonation and much slower growths of pressure behind the shock fronts measured during the shock initiation of HMX PBX's at several low shock pressures.

  15. Monte Carlo calculations of the elastic moduli and pressure-volume-temperature equation of state for hexahydro-1,3,5-trinitro-1,3,5-triazine

    International Nuclear Information System (INIS)

    Sewell, Thomas D.; Bennett, Carl M.

    2000-01-01

    Isothermal-isobaric Monte Carlo calculations were used to obtain predictions of the elastic coefficients and derived engineering moduli and Poisson ratios for crystalline hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). The elastic coefficients were computed using the strain fluctuation formula due to Rahman and Parrinello [J. Chem. Phys. 76, 2662 (1982)]. Calculations were performed as a function of temperature (218 K≤T≤333 K) and hydrostatic pressure (0 GPa≤p≤4 GPa). The predicted values of the moduli and Poisson ratios under ambient conditions are in accord with general expectations for molecular crystals and with a very recent, unpublished determination for RDX. The moduli exhibit a sensitive pressure dependence whereas the Poisson ratios are relatively independent of pressure. The temperature dependence of the moduli is comparable to the precision of the results. However, the crystal does exhibit thermal softening for most pressures. An additional product of the calculations is information about the pressure-volume-temperature (pVT) equation of state. We obtain near-quantitative agreement with experiment for the case of hydrostatic compression and reasonable, but not quantitative, correspondence for thermal expansion. The results indicate a significant dependence of the thermal expansion coefficients on hydrostatic pressure. (c) 2000 American Institute of Physics

  16. Comparison of ASTEC 1.3 and ASTEC 1.3 R2 calculations in case of SBO for VVER-1000 reactor

    International Nuclear Information System (INIS)

    Atanasova, B.; Stefanova, A.; Grudev, P.

    2009-01-01

    The report presents the results from severe accident analyses performed with the both versions of ASTEC v1.3 and ASTEC v1.3R2 computer code for a VVER 1000 type of reactor. The purpose of this analysis is to assess the progress of ASTEC code modeling of main phenomena arising during hypothetical severe accidents. The final target of these analyses is to estimate the behaviour of the ASTEC code, its capability for simulation of severe accidents, including safety systems and Severe Accident Management (SAM) procedures. The analyses have been performed assuming a station blackout with simultaneous loss of HPIS, LPIS (ECCSs), EFWS and spray system due to failure of DGs. Hydro accumulators are not available. In the calculation it is assumed opening and stuck-open of PRZ relief valves. It has been organized the Fission Products path through the SEMPELL valve. It should be said that this investigation was limited to the 'in-vessel' phase of the sequence; therefore the effect of sprays on containment atmosphere has not been studied. (authors)

  17. Biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) by a prospective consortium and its most effective isolate Serratia marcescens

    Energy Technology Data Exchange (ETDEWEB)

    Young, D.M.; Ogden, K.L. [Univ. of Arizona, Tucson, AZ (United States). Dept. of Chemical and Environmental Engineering; Unkefer, P.J. [Los Alamos National Lab., NM (United States). Chemical Science and Technology Div.

    1997-03-05

    The biotransformation of hexahydro-1,3,5-trinitro-1,3,5 triazine (RDX) has been observed in liquid culture by a consortium of bacteria found in horse manure. Five types of bacteria were found to predominate in the consortium and were isolated. The most effective of these isolates at transforming RDX was Serratia marcescens. The biotransformation of RDX by all of these bacteria was found to occur only in the anoxic stationary phase. The process of bacterial growth and RDX biotransformation was quantified for the purpose of developing a predictive type model. Cell growth was assumed to follow Monod kinetics. All of the aerobic and anoxid growth parameters were determined: {mu}{sub max}, K{sub s}, and Y{sub x/s}. RDX was found to competitively inhibit cell growth in both atmospheres. Degradation of RDX by Serratia marcescens was found to proceed through the stepwise reduction of the three nitro groups to nitroso groups. Each of these reductions was found to be first order in both component and cell concentrations. The degradation rate constant for the first step in this reduction process by the consortium was 0.022 L/g cells {center_dot} h compared to 0.033 L/g cells {center_dot} h for the most efficient isolate.

  18. Electron shuttle-mediated biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine adsorbed to granular activated carbon.

    Science.gov (United States)

    Millerick, Kayleigh; Drew, Scott R; Finneran, Kevin T

    2013-08-06

    Granular activated carbon (GAC) effectively removes hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) from groundwater but generates RDX-laden GAC that must be disposed of or regenerated. Batch reactors containing GAC to which RDX was preadsorbed were used in experiments to test the potential for adsorbed RDX reduction and daughter product formation using (i) chemically reduced anthrahydroquinone-2,6-disulfonate (AH2QDS), (ii) resting Geobacter metallireducens strain GS-15, and (iii) a combined system containing AQDS and GS-15. Approximately 97.0% of the adsorbed RDX was transformed in each of these experimental systems by 90 h. Chemically reduced AQDS (AH2QDS) transformed 99.2% of adsorbed RDX; formaldehyde was produced rapidly and was stoichiometric (3 mol HCHO per mol RDX). Geobacter metallireducens also reduced RDX with and without AQDS present. This is the first study to demonstrate biological transformation of RDX adsorbed to GAC. Formaldehyde increased and then decreased in biological systems, suggesting a previously unreported capacity for G. metallireducens to oxidize formaldehyde, which was confirmed with resting cell suspensions. These data suggest the masses of GAC waste currently produced by activated carbon at RDX remediation sites can be minimized, decreasing the carbon footprint of the treatment technology. Alternatively, this strategy may be used to develop a Bio-GAC system for ex situ RDX treatment.

  19. Vicarious nucleophilic substitution to prepare 1,3-diamino-2,4,6-trinitrobenzene or 1,3,5-triamino-2,4,6-trinitrobenzene

    Science.gov (United States)

    Mitchell, Alexander R.; Pagoria, Philip F.; Schmidt, Robert D.

    1996-01-01

    The present invention relates to a process to produce 1,3-diamino-2,4,6-trinitrobenzene (DATB) or 1,3,5-triamino-2,4,6,-trinitrobenzene (TATB) by: (a) reacting at ambient pressure and a temperature of between about 0.degree. and 50.degree. C. for between about 0.1 and 24 hr, a trinitroaromatic compound of structure V: ##STR1## wherein X, Y, and Z are each independently selected from --H, or --NH.sub.2, with the proviso that at least 1 or 2 of X, Y, and Z are hydrogen, with an amount effective to produce DATB or TATB of 1,1,1-trialkylhydrazinium halide wherein alkyl is selected from methyl, ethyl, propyl or butyl and halide is selected from chloride, bromide or iodide. in the presence of a strong base selected from sodium butoxide, potassium butoxide, potassium propoxide, sodium propoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, and combinations thereof; in a solvent selected from the group consisting of methanol, ethanol, propanol, butanol, dimethylsulphoxide, N-methylpyrrolidone, hexamethylphosphoramide, dimethylformide, dimethylacetamide and mixtures thereof, provided that when alcohols are present primarily DATB and picramide is formed; and (b) isolating the DATB or TATB produced. DATB and TATB are useful specialty explosives. TATB is also used for the preparation of benzenehexamine, a starting material for the synthesis of novel materials (optical imaging devices, liquid crystals, ferromagnetic compounds).

  20. Characterization of polymorphic states in energetic samples of 1,3,5-trinitro-1,3,5-triazine (RDX) fabricated using drop-on-demand inkjet technology.

    Science.gov (United States)

    Emmons, Erik D; Farrell, Mikella E; Holthoff, Ellen L; Tripathi, Ashish; Green, Norman; Moon, Raphael P; Guicheteau, Jason A; Christesen, Steven D; Pellegrino, Paul M; Fountain, Augustus W

    2012-06-01

    The United States Army and the first responder community are evaluating optical detection systems for the trace detection of hazardous energetic materials. Fielded detection systems must be evaluated with the appropriate material concentrations to accurately identify the residue in theater. Trace levels of energetic materials have been observed in mutable polymorphic phases and, therefore, the systems being evaluated must be able to detect and accurately identify variant sample phases observed in spectral data. In this work, we report on the novel application of drop-on-demand technology for the fabrication of standardized trace 1,3,5-trinitro-1,3,5-triazine (RDX) samples. The drop-on-demand sample fabrication technique is compared both visually and spectrally to the more commonly used drop-and-dry technique. As the drop-on-demand technique allows for the fabrication of trace level hazard materials, concerted efforts focused on characterization of the polymorphic phase changes observed with low concentrations of RDX commonly used in drop-on-demand processing. This information is important when evaluating optical detection technologies using samples prepared with a drop-on-demand inkjet system, as the technology may be "trained" to detect the common bulk α phase of the explosive based on its spectral features but fall short in positively detecting a trace quantity of RDX (β-phase). We report the polymorphic shifts observed between α- and β-phases of this energetic material and discuss the conditions leading to the favoring of one phase over the other.

  1. Performance of mesophilic anaerobic granules for removal of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) from aqueous solution

    International Nuclear Information System (INIS)

    An Chunjiang; He Yanling; Huang Guohe; Liu Yonghong

    2010-01-01

    The performance of mesophilic anaerobic granules to degrade octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) was investigated under various conditions. The results of batch experiments showed that anaerobic granules were capable of removing HMX from aqueous solution with high efficiency. Both biotic and abiotic mechanisms contributed to the removal of HMX by anaerobic granules under mesophilic conditions. Adsorption appeared to play a significant role in the abiotic process. Furthermore, HMX could be biodegraded by anaerobic granules as the sole substrate. After 16 days of incubation, 99.04% and 96.42% of total HMX could be removed by 1 g VSS/L acclimated and unacclimated granules, respectively. Vancomycin, an inhibitor of acetogenic bacteria, caused a significant inhibition of HMX biotransformation, while 2-bromoethanesulfonic acid, an inhibitor of methanogenic bacteria, only resulted in a slight decrease of metabolic activity. The presence of the glucose, as a suitable electron donor and carbon source, was found to enhance the degradation of HMX by anaerobic granules. Our study showed that sulfate had little adve