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Sample records for bcr process

  1. Batch Covariance Relaxation (BCR) Adaptive Processing.

    Science.gov (United States)

    1981-08-01

    leads to the equivalent bandpass transfer function K Pk-8) Bpp (s) =17 - 22 where C2I is the radian IF frequency normalized by wc. Assuming, tacitly...transfer function in (2-3) is given by H +(f + fE) = H+ Bpp (I + 6 ) (2-13) provided that f and f, are understood to be normalized by fc = wc/2r. In...4..J - tj, 45I2 a I a N 1A CZ~ IJ~oa 1,1 2.0 X : Z 1-3 1 a * N -- e - -o 0 (A -1- 1U z 0 8 Or I W *IA O! IU fau a :at oc- -MZ a Iaaa a a m :wU I..- 1

  2. Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints

    International Nuclear Information System (INIS)

    Croce, C.M.; Huebner, K.; Isobe, M.; Fainstain, E.; Lifshitz, B.; Shtivelman, E.; Canaani, E.

    1987-01-01

    A probe derived from the 3' region of the BCR gene (breakpoint cluster region gene) detects four distinct loci in the human genome. One of the loci corresponds to the complete BCR gene, whereas the other contain a 3' segment of the gene. After HindIII cleavage of human DNA, these four loci are detected as 23-, 19-, 13-, and 9-kikobase-pair fragments, designated BCR4, BCR3, BCR2, and BCR1, respectively, with BCR1 deriving from the original complete BCR gene. All four BCR loci segregate 100% concordantly with human chromosome 22 in a rodent-human somatic cell hybrid panel and are located at chromosome region 22q11.2 by chromosomal in situ hybridization. The BCR2 and BCR4 loci are amplified in leukemia cell line K562 cells, indicating that they fall within the amplification unit that includes immunoglobulin λ light chain locus (IGL) and ABL locus on the K562 Philadelphia chromosome (Ph 1 ). Similarly, in mouse-human hybrids retaining a Ph 1 chromosome derived from an acute lymphoblastic leukemia-in the absence of the 9q + and 22, only BCR2 and BCR4 loci are retained. Thus, the order of loci on chromosome 22 is centromere → BCR2, BCR4, and IGL → BCR1 → BCR3 → SIS, possibly eliminating BCR2 and BCR4 loci as candidate targets for juxtaposition to the ABL gene in the acute lymphoblastic leukemia Ph 1 chromosome

  3. Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.

    LENUS (Irish Health Repository)

    Elzinga, Baukje M

    2013-06-01

    Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1\\/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl\\/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.

  4. Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface*

    Science.gov (United States)

    Wojcik, John; Lamontanara, Allan Joaquim; Grabe, Grzegorz; Koide, Akiko; Akin, Louesa; Gerig, Barbara; Hantschel, Oliver; Koide, Shohei

    2016-01-01

    Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl. PMID:26912659

  5. Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface.

    Science.gov (United States)

    Wojcik, John; Lamontanara, Allan Joaquim; Grabe, Grzegorz; Koide, Akiko; Akin, Louesa; Gerig, Barbara; Hantschel, Oliver; Koide, Shohei

    2016-04-15

    Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway.

    OpenAIRE

    Puil, L; Liu, J; Gish, G; Mbamalu, G; Bowtell, D; Pelicci, P G; Arlinghaus, R; Pawson, T

    1994-01-01

    The cytosolic 185 and 210 kDa Bcr-Abl protein tyrosine kinases play important roles in the development of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (Ph+ ALL). p185 and p210 Bcr-Abl contain identical abl-encoded sequences juxtaposed to a variable number of bcr-derived amino acids. As the mitogenic and transforming activities of tyrosine kinases involve stimulation of the Ras pathway, we analyzed Bcr-Abl oncoproteins for interacti...

  7. BCR/ABL downregulates DNA-PK(CS)-dependent and upregulates backup non-homologous end joining in leukemic cells.

    Science.gov (United States)

    Poplawski, Tomasz; Blasiak, Janusz

    2010-06-01

    Non-homologous end joining (NHEJ) and homologous recombination repair (HRR) are the main mechanisms involved in the processing of DNA double strand breaks (DSBs) in humans. We showed previously that the oncogenic tyrosine kinase BCR/ABL stimulated DSBs repair by HRR. To evaluate the role of BCR/ABL in DSBs repair by NHEJ we examined the ability of leukemic BCR/ABL-expressing cell line BV173 to repair DNA damage induced by two DNA topoisomerase II inhibitors: etoposide and sobuzoxane. DNA lesions induced by sobuzoxane are repaired by a NHEJ pathway which is dependent on the catalytic subunit of protein kinase dependent on DNA (DNA-PK(CS); D-NHEJ), whereas damage evoked by etoposide are repaired by two distinct NHEJ pathways, dependent on or independent of DNA-PK(CS) (backup NHEJ, B-NHEJ). Cells incubated with STI571, a highly specific inhibitor of BCR/ABL, displayed resistance to these agents associated with an accelerated kinetics of DSBs repair, as measured by the neutral comet assay and pulsed field gel electrophoresis. However, in a functional NHEJ assay, cells preincubated with STI571 repaired DSBs induced by a restriction enzyme with a lower efficacy than without the preincubation and addition of wortmannin, a specific inhibitor of DNA-PK(CS), did not change efficacy of the NHEJ reaction. We suggest that BCR/ABL switch on B-NHEJ which is more error-prone then D-NHEJ and in such manner contribute to the increase of the genomic instability of leukemic cells.

  8. Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation

    DEFF Research Database (Denmark)

    Satpathy, Shankha; Wagner, Sebastian A; Beli, Petra

    2015-01-01

    B-cell receptor (BCR) signaling is essential for the development and function of B cells; however, the spectrum of proteins involved in BCR signaling is not fully known. Here we used quantitative mass spectrometry-based proteomics to monitor the dynamics of BCR signaling complexes (signalosomes......) and to investigate the dynamics of downstream phosphorylation and ubiquitylation signaling. We identify most of the previously known components of BCR signaling, as well as many proteins that have not yet been implicated in this system. BCR activation leads to rapid tyrosine phosphorylation and ubiquitylation...... of the receptor-proximal signaling components, many of which are co-regulated by both the modifications. We illustrate the power of multilayered proteomic analyses for discovering novel BCR signaling components by demonstrating that BCR-induced phosphorylation of RAB7A at S72 prevents its association...

  9. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCR-JAK2 tyrosine-kinase.

    Directory of Open Access Journals (Sweden)

    Álvaro Cuesta-Domínguez

    Full Text Available Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2 in vivo. Together these findings suggest that adult and pediatric patients with BCR-ABL-negative leukemia and JAK2 overexpression may benefit from targeted therapies.

  10. Translocation of BCR to chromosome 9: A new cytogenetic variant detected by FISH in two Ph-negative, BCR-positive patients with chronic myeloid leukemia

    NARCIS (Netherlands)

    A. Hagemeijer (Anne); A. Buijs (Arjan); E.M.E. Smit (Elisabeth); L.A.J. Janssen (Bart); G.J.M. Creemers (Geert-Jan); D. van der Plas (D.); G.C. Grosveld (Gerard)

    1993-01-01

    textabstractLeukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: I) Cytogenetics showed a normal 46.XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2

  11. BCR-ABL fusion genes are inducible by X-irradiation in vitro

    International Nuclear Information System (INIS)

    Ito, Takashi; Seyama, Toshio; Mizuno, Terumi; Hayashi, Tomonori; Nakamura, Nori; Akiyama, Mitoshi; Dohi, Kiyohiko.

    1992-01-01

    The Philadelphia chromosome consists of a reciprocal translocation between the ABL oncogene at chromosome 9q34 and the BCR gene at chromosome 22q resulting in the expression of chimeric BCR-ABL mRNAs specific to chronic myelogenous leukemia (CML). The presence of the fusion genes can be detected with high specificity and sensitivity by means of reverse transcription and polymerase chain reaction. Using this assay, it was possible to detect BCR-ABL fusion genes induced among HL60 cells after 100 Gy of X-irradiation in vitro. A total of five fusion gene transcripts were obtained. These fusion genes contained not only CML-specific BCR-ABL rearrangements, but also other forms of BCR-ABL fusions. These latter genes had junctions of BCR exon 4/ABL exon 2 intervened by a segment of DNA of unknown origin, BCR exon 5/ABL exon 2, and BCR exon 4/ABL exon 2. The results appear to be the first evidence for the induction of the BCR-ABL fusion gene by X-irradiation. In terms of leukemogenesis, it is suggested that only those cells bearing certain CML-related BCR-ABL fusion genes are positively selected by virtue of a growth advantage in vivo. (author)

  12. Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I

    Directory of Open Access Journals (Sweden)

    Mian Afsar

    2012-09-01

    Full Text Available Abstract Background Chronic myelogenous leukemia (CML and Philadelphia chromosome-positive (Ph+ acute lymphatic leukemia (Ph + ALL are caused by the t(9;22, which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase “escapes” the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the ‘gatekeeper’ mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia. Methods The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC from Ph + ALL-patients. Results Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner. Conclusions Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.

  13. Optimisation of beryllium-7 gamma analysis following BCR sequential extraction

    International Nuclear Information System (INIS)

    Taylor, A.; Blake, W.H.; Keith-Roach, M.J.

    2012-01-01

    Graphical abstract: Showing decrease in analytical uncertainty using the optimal (combined preconcentrated sample extract) method. nv (no value) where extract activities were 7 Be geochemical behaviour is required to support tracer studies. ► Sequential extraction with natural 7 Be returns high analytical uncertainties. ► Preconcentrating extracts from a large sample mass improved analytical uncertainty. ► This optimised method can be readily employed in studies using low activity samples. - Abstract: The application of cosmogenic 7 Be as a sediment tracer at the catchment-scale requires an understanding of its geochemical associations in soil to underpin the assumption of irreversible adsorption. Sequential extractions offer a readily accessible means of determining the associations of 7 Be with operationally defined soil phases. However, the subdivision of the low activity concentrations of fallout 7 Be in soils into geochemical fractions can introduce high gamma counting uncertainties. Extending analysis time significantly is not always an option for batches of samples, owing to the on-going decay of 7 Be (t 1/2 = 53.3 days). Here, three different methods of preparing and quantifying 7 Be extracted using the optimised BCR three-step scheme have been evaluated and compared with a focus on reducing analytical uncertainties. The optimal method involved carrying out the BCR extraction in triplicate, sub-sampling each set of triplicates for stable Be analysis before combining each set and coprecipitating the 7 Be with metal oxyhydroxides to produce a thin source for gamma analysis. This method was applied to BCR extractions of natural 7 Be in four agricultural soils. The approach gave good counting statistics from a 24 h analysis period (∼10% (2σ) where extract activity >40% of total activity) and generated statistically useful sequential extraction profiles. Total recoveries of 7 Be fell between 84 and 112%. The stable Be data demonstrated that the

  14. Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells

    NARCIS (Netherlands)

    Avalos, Ana M.; Bilate, Angelina M.; Witte, Martin D.; Tai, Albert K.; He, Jiang; Frushicheva, Maria P.; Thill, Peter D.; Meyer-Wentrup, Friederike; Theile, Christopher S.; Chakraborty, Arup K.; Zhuang, Xiaowei; Ploegh, Hidde L.

    2014-01-01

    Valency requirements for B cell activation upon antigen encounter are poorly understood. OB1 transnuclear B cells express an IgG1 B cell receptor (BCR) specific for ovalbumin (OVA), the epitope of which can be mimicked using short synthetic peptides to allow antigen-specific engagement of the BCR.

  15. Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

    Science.gov (United States)

    Boer, Judith M.; Steeghs, Elisabeth M.P.; Marchante, João R.M.; Boeree, Aurélie; Beaudoin, James J.; Berna Beverloo, H.; Kuiper, Roland P.; Escherich, Gabriele; van der Velden, Vincent H.J.; van der Schoot, C. Ellen; de Groot-Kruseman, Hester A.; Pieters, Rob; den Boer, Monique L.

    2017-01-01

    Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p<0.01), and also higher, albeit not statistically significant, compared with the fusion-negative BCR-ABL1-like group. The 8-year cumulative incidence of relapse in the fusion-positive BCR-ABL1-like group (35%) was comparable with that in the fusion-negative BCR-ABL1-like group (35%), and worse than in the non-BCR-ABL1-like B-other group (17%, p=0.07). IKZF1 deletions, predominantly other than the dominant-negative isoform and full deletion, co-occurred with tyrosine kinase fusions. This study shows that tyrosine kinase fusion-positive cases are a high-risk subtype of BCP-ALL, which warrants further studies with specific kinase inhibitors to improve outcome. PMID:27894077

  16. Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK.

    Science.gov (United States)

    Kim, Ekaterina; Hurtz, Christian; Koehrer, Stefan; Wang, Zhiqiang; Balasubramanian, Sriram; Chang, Betty Y; Müschen, Markus; Davis, R Eric; Burger, Jan A

    2017-03-02

    Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR + B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR + ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR + ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR + ALL. Consequently, in mouse xenograft models of pre-BCR + ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR + ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR + ALL and highlight the importance of ibrutinib effects on alternative kinase targets. © 2017 by The American Society of Hematology.

  17. Anaerobic Biochemical Reactor (BCR) Treatment Of Mining-Influenced Water (MIW) - Investigation Of Metal Removal Efficiency and Ecotoxicity

    Science.gov (United States)

    BCR have been successful at removing a high percentage of metals from MIW, while BCR effluent toxicity has not been examined previously in the field. This study examined 4 active pilot BCR systems for removal of metals and toxicity. Removal efficiency for Al, As, Cd, Cu, Ni, Pb...

  18. Optimisation of beryllium-7 gamma analysis following BCR sequential extraction

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, A. [Plymouth University, School of Geography, Earth and Environmental Sciences, 8 Kirkby Place, Plymouth PL4 8AA (United Kingdom); Blake, W.H., E-mail: wblake@plymouth.ac.uk [Plymouth University, School of Geography, Earth and Environmental Sciences, 8 Kirkby Place, Plymouth PL4 8AA (United Kingdom); Keith-Roach, M.J. [Plymouth University, School of Geography, Earth and Environmental Sciences, 8 Kirkby Place, Plymouth PL4 8AA (United Kingdom); Kemakta Konsult, Stockholm (Sweden)

    2012-03-30

    Graphical abstract: Showing decrease in analytical uncertainty using the optimal (combined preconcentrated sample extract) method. nv (no value) where extract activities were BCR three-step scheme have been evaluated and compared with a focus on reducing analytical uncertainties. The optimal method involved carrying out the BCR extraction in triplicate, sub-sampling each set of triplicates for stable Be analysis before combining each set and coprecipitating the {sup 7}Be with metal oxyhydroxides to produce a thin source for gamma analysis. This method was applied to BCR extractions of natural {sup 7}Be in four agricultural soils. The approach gave good counting statistics from a 24 h analysis period ({approx}10% (2

  19. Heterogeneity of BCR-ABL rearrangement in patients with chronic myeloid leukemia in Pakistan.

    Science.gov (United States)

    Tabassum, Najia; Saboor, Mohammad; Ghani, Rubina; Moinuddin, Moinuddin

    2014-07-01

    Breakpoint cluster region-Abelson (BCR-ABL) rearrangement or Philadelphia (Ph) chromosome in Chronic Myeloid Leukemia (CML) is derived from a reciprocal chromosomal translocation between ABL gene on chromosome 9 and BCR gene on chromosome 22. This chimeric protein has various sizes and therefore different clinical behaviour. The purpose of this study was to determine the heterogeneity of BCR-ABL rearrangement in patients with Ph(+)CML in Pakistan. The study was conducted at Civil Hospital and Baqai Institute of Hematology (BIH) Karachi. Blood samples from 25 patients with CML were collected. Multiplex reverse transcription polymerase chain reaction (RT-PCR) was performed to identify various BCR-ABL transcripts. All 25 samples showed BCR-ABL rearrangements. Out of these, 24 (96%) patients expressed p210 BCR-ABL rearrangements i.e. 60% (n=15) had b3a2 and 32% (n=8) had b2a2 rearrangements. Co-expression of b3a2 /b2a2 rearrangement and p190 (e1a3) rearrangement was also identified in two patients. It is apparent that majority of the patients had p210 BCR-ABL rearrangements. Frequency of co-expression and rare fusion transcripts was very low.

  20. Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

    International Nuclear Information System (INIS)

    Chai, Juin Hsien; Zhang, Yong; Tan, Wei Han; Chng, Wee Joo; Li, Baojie; Wang, Xueying

    2011-01-01

    The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells. Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels. Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients

  1. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias.

    Science.gov (United States)

    Kamitsuji, Y; Kuroda, J; Kimura, S; Toyokuni, S; Watanabe, K; Ashihara, E; Tanaka, H; Yui, Y; Watanabe, M; Matsubara, H; Mizushima, Y; Hiraumi, Y; Kawata, E; Yoshikawa, T; Maekawa, T; Nakahata, T; Adachi, S

    2008-11-01

    Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.

  2. Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission

    Directory of Open Access Journals (Sweden)

    Costa Juliana

    2010-11-01

    Full Text Available Abstract Background The monitoring of BCR-ABL transcript levels by real-time quantitative polymerase chain reaction (RT-qPCR has become important to assess minimal residual disease (MRD and standard of care in the treatment of chronic myeloid leukemia (CML. In this study, we performed a prospective, sequential analysis using RT-qPCR monitoring of BCR-ABL gene rearrangements in blood samples from 91 CML patients in chronic phase (CP who achieved complete cytogenetic remission (CCyR and major molecular remission (MMR throughout imatinib treatment. Methods The absolute level of BCR-ABL transcript from peripheral blood was serially measured every 4 to 12 weeks by RT-qPCR. Only level variations > 0.5%, according to the international scale, was considered positive. Sequential cytogenetic analysis was also performed in bone marrow samples from all patients using standard protocols. Results Based on sequential analysis of BCR-ABL transcripts, the 91 patients were divided into three categories: (A 57 (62.6% had no variation on sequential analysis; (B 30 (32.9% had a single positive variation result obtained in a single sample; and (C 4 (4.39% had variations of BCR-ABL transcripts in at least two consecutive samples. Of the 34 patients who had elevated levels of transcripts (group B and C, 19 (55.8% had a BCR-ABL/BCR ratio, 13 (38.2% patients had a 1% to 10% increase and 2 patients had a >10% increase of RT-qPCR. The last two patients had lost a CCyR, and none of them showed mutations in the ABL gene. Transient cytogenetic alterations in Ph-negative cells were observed in five (5.5% patients, and none of whom lost CCyR. Conclusions Despite an increase levels of BCR-ABL/BCR ratio variations by RT-qPCR, the majority of CML patients with MMR remained in CCyR. Thus, such single variations should neither be considered predictive of subsequent failure and nor an indication for altering imatinib dose or switching to second generation therapy. Changing of

  3. Lack of bcr and abr promotes hypoxia-induced pulmonary hypertension in mice.

    Directory of Open Access Journals (Sweden)

    Min Yu

    Full Text Available Bcr and Abr are GTPase activating proteins that specifically downregulate activity of the small GTPase Rac in restricted cell types in vivo. Rac1 is expressed in smooth muscle cells, a critical cell type involved in the pathogenesis of pulmonary hypertension. The molecular mechanisms that underlie hypoxia-associated pulmonary hypertension are not well-defined.Bcr and abr null mutant mice were compared to wild type controls for the development of pulmonary hypertension after exposure to hypoxia. Also, pulmonary arterial smooth muscle cells from those mice were cultured in hypoxia and examined for proliferation, p38 activation and IL-6 production. Mice lacking Bcr or Abr exposed to hypoxia developed increased right ventricular pressure, hypertrophy and pulmonary vascular remodeling. Perivascular leukocyte infiltration in the lungs was increased, and under hypoxia bcr-/- and abr-/- macrophages generated more reactive oxygen species. Consistent with a contribution of inflammation and oxidative stress in pulmonary hypertension-associated vascular damage, Bcr and Abr-deficient animals showed elevated endothelial leakage after hypoxia exposure. Hypoxia-treated pulmonary arterial smooth muscle cells from Bcr- or Abr-deficient mice also proliferated faster than those of wild type mice. Moreover, activated Rac1, phosphorylated p38 and interleukin 6 were increased in these cells in the absence of Bcr or Abr. Inhibition of Rac1 activation with Z62954982, a novel Rac inhibitor, decreased proliferation, p38 phosphorylation and IL-6 levels in pulmonary arterial smooth muscle cells exposed to hypoxia.Bcr and Abr play a critical role in down-regulating hypoxia-induced pulmonary hypertension by deactivating Rac1 and, through this, reducing both oxidative stress generated by leukocytes as well as p38 phosphorylation, IL-6 production and proliferation of pulmonary arterial smooth muscle cells.

  4. The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins.

    Science.gov (United States)

    You, Liangshun; Liu, Hui; Huang, Jian; Xie, Wanzhuo; Wei, Jueying; Ye, Xiujin; Qian, Wenbin

    2017-01-31

    Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant. The response to JNJ-26854165 is associated with the downregulation of BCR/ABL dependently of proteosome activation. Moreover, in all tested CML cells, with the exception of T315I mutation cells, combining JNJ-26854165 and tyrosine kinase inhibitor (TKI) Imatinib or PD180970 leads to a synergistic effect. In conclusion, our results suggest that JNJ-26854165, used either alone or in combination with TKIs, represents a promising novel targeted approach to overcome TKI resistance and improve patient outcome in CML.

  5. Clinical relevance of the breakpoint sites within the M-BCR in 50 patients from Argentina with chronic myeloid leukemia.

    Science.gov (United States)

    Giere, I A; Larripa, I B

    1996-08-01

    Fifty patients from Argentina with chronic myeloid leukemia (CML) were studied in order to characterize the breakpoint site within the major breakpoint cluster region (M-BCR) and its relationship with the duration of the chronic phase (CP). The DNA digestion with the restriction enzymes: Bgl II, BAM HI and Hind III and hybridization with the 1.2Kb Hind III-Bgl II bcr probe showed that 56% of cases had the breakpoint in 5'M-bcr region and the remaining 44% in 3'M-bcr region. The duration of chronic phase from diagnosis to the onset of the blast crisis (BC) was correlated with the location of the breakpoint within the M-bcr and no statistical differences were observed between the 5' and the 3' groups. These data indicate that the breakpoint site within the bcr gene is not a prognostic indicator of the duration of CP of the disease.

  6. Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis.

    Science.gov (United States)

    Grebien, Florian; Hantschel, Oliver; Wojcik, John; Kaupe, Ines; Kovacic, Boris; Wyrzucki, Arkadiusz M; Gish, Gerald D; Cerny-Reiterer, Sabine; Koide, Akiko; Beug, Hartmut; Pawson, Tony; Valent, Peter; Koide, Shohei; Superti-Furga, Giulio

    2011-10-14

    Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work validates the SH2-kinase interface as an allosteric target for therapeutic intervention. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. PCR detection of a Maell polymorphism in the human major breakpoint cluster region (BCR)

    Energy Technology Data Exchange (ETDEWEB)

    McClure, J.S.; Litz, C.E. (Medical School, Minneapolis, MN (United States))

    1991-09-25

    Nested primer pairs flanking the second intron of the breakpoint cluster region were constructed from the published cDNA sequence. The outer primer pair 5{prime}BCR Exon 2 (5{prime}-GTT TCA GAA GCT TCT CCC TG-3{prime}) and 3{prime}BCR Exon 3 (5{prime}-ACT CTG CTT AAA TCC AGT GG-3{prime}), amplified a fragment of genomic DNA approximately 810 bp in length. The inner primer pair, 3{prime}BCR Exon 2(5{prime}-CGC TGA CCA TCA ATA AGG AA-3{prime}) and 5{prime}BCR Exon 3 (5{prime}-AGA AAC CCA TAG AGC CCC GG-3{prime}), amplified a fragment approximately 730 bp in length. Double stranded DNA amplified with the outer primer pair was subjected to asymmetric PCR using the inner primer pair. Sequencing reactions were performed using the Sequenase dideoxy sequencing kit with S{sup 35}-dATP. Sequences in homozygotes revealed either an A or a G 85 bp 5{prime} of the BCR BamHI site. Heterozygotes demonstrated both bands at the corresponding position.

  8. Interphase FISH for BCR-ABL1 rearrangement on neutrophils: A decisive tool to discriminate a lymphoid blast crisis of chronic myeloid leukemia from a de novo BCR-ABL1 positive acute lymphoblastic leukemia.

    Science.gov (United States)

    Balducci, Estelle; Loosveld, Marie; Rahal, Ilhem; Boudjarane, John; Alazard, Emilie; Missirian, Chantal; Lafage-Pochitaloff, Marina; Michel, Gérard; Zattara, Hélène

    2018-02-01

    Discrimination between lymphoid blast crisis of chronic myeloid leukemia (CML) and de novo BCR-ABL1 positive acute lymphoblastic leukemia (ALL) represents a diagnostic challenge because this distinction has a major incidence on the management of patients. Here, we report an uncommon pediatric case of ALL with cryptic ins(22;9)(q11;q34q34) and p190-type BCR-ABL1 transcript. We performed interphase fluorescence in situ hybridization (FISH) for BCR-ABL1 rearrangement on blood neutrophils, which was positive consistent with the diagnosis of lymphoid blast crisis of CML. This case illustrates the major interest of interphase FISH for BCR-ABL1 rearrangement on blood neutrophils as a decisive method to discriminate a lymphoid blast crisis of CML from a de novo BCR-ABL1 positive ALL. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

    DEFF Research Database (Denmark)

    Nicolini, Franck Emmanuel; Basak, Grzegorz W; Soverini, Simona

    2011-01-01

    T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow......) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL(T315I) mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors....

  10. The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3' kinase pathway.

    Science.gov (United States)

    Sattler, M; Salgia, R; Okuda, K; Uemura, N; Durstin, M A; Pisick, E; Xu, G; Li, J L; Prasad, K V; Griffin, J D

    1996-02-15

    Chronic myelogenous leukemia (CML) and some acute lymphoblastic leukemias (ALL) are caused by the t(9;22) chromosome translocation, which produces the constitutively activated BCR/ABL tyrosine kinase. When introduced into factor dependent hematopoietic cell lines, BCR/ABL induces the tyrosine phosphorylation of many cellular proteins. One prominent BCR/ABL substrate is p120CBL, the cellular homolog of the v-Cbl oncoprotein. In an effort to understand the possible contribution of p120CBL to transformation by BCR/ABL, we looked for cellular proteins which associate with p120CBL in hematopoietic cell lines transformed by BCR/ABL. In addition to p210BCR/ABL and c-ABL, p120CBL coprecipitated with an 85 kDa phosphoprotein, which was identified as the p85 subunit of PI3K. Anti-p120CBL immunoprecipitates from BCR/ABL-transformed, but not from untransformed, cell lines contained PI3K lipid kinase activity. Interestingly, the adaptor proteins CRKL and c-CRK were also found in these complexes. In vitro binding studies indicated that the SH2 domains of CRKL and c-CRK bound directly to p120CBL, while the SH3 domains of c-CRK and CRKL bound to BCR/ABL and c-ABL. The N-terminal and the C-terminal SH2 and the SH3 domain of p85PI3K bound directly in vitro to p120CBL. The ABL-SH2, but not ABL-SH3, could also bind to p120CBL. These data suggest that BCR/ABL may induce the formation of multimeric complexes of signaling proteins which include p120CBL, PI3K, c-CRK or CRKL, c-ABL and BCR/ABL itself.

  11. Chronic myeloid leukemia may be associated with several bcr-abl transcripts including the acute lymphoid leukemia-type 7 kb transcript

    NARCIS (Netherlands)

    Selleri, L.; von Lindern, M.; Hermans, A.; Meijer, D.; Torelli, G.; Grosveld, G.

    1990-01-01

    In the majority of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) patients, the c-abl gene is fused to the bcr gene, resulting in the transcription of an 8.5 kb chimeric bcr-abl mRNA, which is translated into a p210bcr-abl fusion protein. In about 50% of the Ph-positive acute lymphoid

  12. bcr-abl oncogene activation in Philadelphia chromosome-positive acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Hermans, A.; Gow, J.; Selleri, L.; von Lindern, M.; Hagemeijer, A.; Wiedemann, L. M.; Grosveld, G.

    1988-01-01

    Tumor-specific alterations in oncogenes are thought to play a central role in the development of cancer. An example is the consistent fusion of the bcr gene to the c-abl oncogene on the Ph chromosome in CML. The Ph chromosome can also be observed in ALL. About 50% of Ph+ ALL cases, in contrast to

  13. Determination of cortisol in two BCR reference sera by isotope dilution gas chromatography-mass spectrometry

    NARCIS (Netherlands)

    Derks; H.J.G.M.; Freudenthal; J.; Heiningen; A.van; Gramberg; L.G.; Klaasen; R.

    1984-01-01

    In dit rapport wordt een analytische methode voor de juiste en preciese bepaling van cortisol in humaan serum en zijn toepassing bij de certificatie van twee gevriesdroogde referentiesera van de BCR beschreven. De methode is gebaseerd op isotoopverdunnings gaschromatografie-massaspectrometrie

  14. Effect of Thai saraphi flower extracts on WT1 and BCR/ABL protein ...

    African Journals Online (AJOL)

    In this study, the cytotoxic effects of crude ethanolic and fractional extracts including hexane, ethyl acetate, and methanol fractions from M. siamensis flowers were investigated in order to determine their effect on WT1 expression in Molt4 and K562 cells and Bcr/Abl expression in K562 cells. Materials and Methods: The ...

  15. Frequency and clinical impact of ETV6/RUNX1, AF4‑MLL, and BCR ...

    African Journals Online (AJOL)

    2015-05-12

    May 12, 2015 ... features of prognostic importance, which include total white blood cell count (P = 0.416) and FAB subtype (P = 0.576). Conclusion: Presence of fusion ... Frequency and clinical impact of ETV6/RUNX1, AF4‑MLL, and BCR/ABL fusion ... define distinct clinic‑pathological subgroups and have been used in risk ...

  16. Modulation of BCR Signaling by the Induced Dimerization of Receptor-Associated SYK

    Directory of Open Access Journals (Sweden)

    Mark L. Westbroek

    2017-12-01

    Full Text Available Clustering of the B cell antigen receptor (BCR by polyvalent antigens is transmitted through the SYK tyrosine kinase to the activation of multiple intracellular pathways that determine the physiological consequences of receptor engagement. To explore factors that modulate the quantity and quality of signals sent by the crosslinked BCR, we developed a novel chemical mediator of dimerization to induce clustering of receptor-associated SYK. To accomplish this, we fused SYK with E. coli dihydrofolate reductase (eDHFR, which binds the small molecule trimethoprim (TMP with high affinity and selectivity and synthesized a dimer of TMP with a flexible linker. The TMP dimer is able to induce the aggregation of eDHFR-linked SYK in live cells. The induced dimerization of SYK bound to the BCR differentially regulates the activation of downstream transcription factors, promoting the activation of Nuclear Factor of Activated T cells (NFAT without affecting the activation of NFκB. The dimerization of SYK enhances the duration but not the amplitude of calcium mobilization by enhancing the extent and duration of its interaction with the crosslinked BCR at the plasma membrane.

  17. Quantification of BCR-ABL transcripts in peripheral blood cells and ...

    African Journals Online (AJOL)

    Purpose: To investigate the feasibility of using peripheral blood plasma samples as surrogates for blood cell sampling for quantification of breakpoint cluster region-Abelson oncogene (BCR-ABL) transcript levels to monitor treatment responses in chronic myeloid leukemia (CML) patients. Methods: Peripheral blood samples ...

  18. Frequency of BCR-ABL Transcript Types in Syrian CML Patients

    Directory of Open Access Journals (Sweden)

    Sulaf Farhat-Maghribi

    2016-01-01

    Full Text Available Background. In Syria, CML patients are started on tyrosine kinase inhibitors (TKIs and monitored until complete molecular response is achieved. BCR-ABL mRNA transcript type is not routinely identified, contrary to the recommendations. In this study we aimed to identify the frequency of different BCR-ABL transcripts in Syrian CML patients and highlight their significance on monitoring and treatment protocols. Methods. CML patients positive for BCR-ABL transcripts by quantitative RT-PCR were enrolled. BCR-ABL transcript types were investigated using a home-made PCR method that was adapted from published protocols and optimized. The transcript types were then confirmed using a commercially available research kit. Results. Twenty-four transcripts were found in 21 patients. The most common was b2a2, followed by b3a2, b3a3, and e1a3 present solely in 12 (57.1%, 3 (14.3%, 2 (9.5%, and 1 (4.8%, respectively. Three samples (14.3% contained dual transcripts. While b3a2 transcript was apparently associated with warning molecular response to imatinib treatment, b2a2, b3a3, and e1a3 transcripts collectively proved otherwise (P=0.047. Conclusion. It might be advisable to identify the BCR-ABL transcript type in CML patients at diagnosis, using an empirically verified method, in order to link the detected transcript with the clinical findings, possible resistance to treatment, and appropriate monitoring methods.

  19. A BCR/ABL-hIL-2 DNA Vaccine Enhances the Immune Responses in BALB/c Mice

    Directory of Open Access Journals (Sweden)

    Yanan Qin

    2013-01-01

    Full Text Available The use of a DNA vaccine encoding the BCR/ABL fusion gene is thought to be a promising approach for patients with chronic myeloid leukemia (CML to eradicate minimal residual disease after treatment with chemotherapy or targeted therapy. In this study, our strategy employs genetic technology to create a DNA vaccine encoding the BCR/ABL fusion and human interleukin-2 (hIL-2 genes. The successfully constructed plasmids BCR/ABL-pIRES-hIL-2, BCR/ABL-pIRES, and pIRES-hIL-2 were delivered intramuscularly to BALB/c mice at 14-day intervals for three cycles. The transcription and expression of the BCR/ABL and hIL-2 genes were found in the injected muscle tissues. The interferon-γ (IFN-γ serum levels were increased, and the splenic CD4+/CD8+ T cell ratio was significantly decreased in the BCR/ABL-pIRES-hIL-2-injected mice. Furthermore, specific antibodies against K562 cells could be detected by indirect immunofluorescence. These results indicate that a DNA vaccine containing BCR/ABL and hIL-2 together may elicit increased in vivo humoral and cellular immune responses in BALB/c mice.

  20. Inhibitory effect of PTD-OD-HA fusion protein on Bcr-Abl in K562 cells

    Directory of Open Access Journals (Sweden)

    Miao GAO

    2012-10-01

    Full Text Available Objective To study the transduction dynamics, location of PTD-OD-HA fusion protein and its interaction with Bcr-Abl oncoprotein in K562 cell lines, and explore the influence of PTD-OD-HA fusion protein on oligomerization and tyrosine kinase activity of Bcr-Abl. Methods PTD-OD-HA fusion protein was labeled with FITC and co-cultured with K562 cells. The transduction efficiency of labeled PTD-OD-HA at different doses and time intervals was observed under fluorescence microscope. The location of labeled PTD-OD-HA fusion protein in K562 cells was detected by confocal microscopy. The interaction of PTD-OD-HA fusion protein with Bcr-Abl oncoprotein was confirmed by coimmunoprecipitation. The phosphorylation of Bcr-Abl oncoprotein was detected by Western blotting. Results PTD-OD-HA fusion protein labeled with FITC was transduced into K562 cells in a dose- and time-dependent manner. PTD-OD-HA fusion protein was located in the cytoplasm of K562 cells and was consistent with the location of Bcr-Abl oncoprotein. The interaction of PTD-OD-HA fusion protein with Bcr-Abl oncoprotein was proved in K562 cells. This interaction could interrupt the homologous oligomerization of Bcr-Abl oncoprotein and reduce the phosphorylation of Bcr-Abl oncoprotein. Conclusion PTD-OD-HA fusion protein could be transduced into K562 cells efficiently, inhibit the oligomerization and reduce the phosphorylation of Bcr-Abl oncoprotein.

  1. Ph1 chromosomes and bcr gene rearrangements in chronic myelocytic leukemia patients developed from atomic bomb survivors

    International Nuclear Information System (INIS)

    Tanaka, Kimio; Takechi, Miho; Shigeta, Chiharu; Sakatani, Keiko; Oguma, Nobuo; Kamada, Nanao; Takimoto, Yasuo; Kuramoto, Atsushi

    1989-01-01

    This study compared findings of chronic myelocytic leukemia (CML) in A-bomb survivors (n=8) developing CML within 10 years after the bombing and in non-exposed CML patients (n=14). Both Ph 1 chromosomes and bcr rearrangement were observed in all patients in both exposed and non-exposed groups. There was no significant difference in distribution sites of bcr rearrangement between the groups. These results suggest that bcr-abl chimera mRNA and chimera protein associated with Ph 1 chromosomes have an important role in the development of CML among A-bomb survivors, as well as among non-exposed patients. (N.K.)

  2. Expression of p190 BCR-ABL fusion gene in a patient with chronic myeloid leukemia Expressão do rearranjo gênico BCR-ABL com ponto de quebra na região menor do gene BCR em um paciente com leucemia mielóide crônica

    Directory of Open Access Journals (Sweden)

    P. V. B. Carvalho

    2003-01-01

    Full Text Available A minority of chronic myeloid leukemia cases have breakpoints in the minor cluster region (m-bcr of the BCR-ABL gene. We report on a patient with Ph-positive and m-bcr breakpoint at diagnosis. She was treated with hydroxyurea and interferon-alpha. Two years later, she developed a lymphoid blast crisis and died shortly after. We discuss herein the different forms of the BCR-ABL oncogene, its products, and the possible influence of them on the clinical outcome of patients with the disease.A leucemia mielóide crônica (LMC é uma doença mieloproliferativa clonal e caracteriza-se pela presença da translocação cromossômica entre os braços longos dos cromossomos 9 e 22, o denominado cromossomo Ph. Esta translocação determina a fusão dos genes BCR e ABL. Os diferentes pontos de quebra no gene BCR determinam a síntese de proteínas com diferentes pesos moleculares pelo gene BCR-ABL. Nós relatamos o caso de uma paciente portadora de LMC com ponto de quebra cromossômico na região menor do gene BCR. Foi tratada com hidroxiuréia e interferon alfa. Dois anos após o diagnóstico desenvolveu crise blástica linfóide e evoluiu rapidamente para o óbito. Nós discutimos nesta apresentação as diferentes formas do gene BCR-ABL e seus produtos e a possível influência dos mesmos na evolução clínica dos pacientes com a doença.

  3. ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

    National Research Council Canada - National Science Library

    Reddy, E. P

    2007-01-01

    Because it is now apparent that a significant proportion of patients chronically treated with imatinib develop resistance due to the acquisition of mutations in the kinase domain of BCR-ABL our aim...

  4. Long-term remission in BCR/ABL-positive AML-M6 patient treated with Imatinib Mesylate.

    Science.gov (United States)

    Pompetti, Franca; Spadano, Antonio; Sau, Antonella; Mennucci, Antonio; Russo, Rosa; Catinella, Virginia; Franchi, Paolo Guanciali; Calabrese, Giuseppe; Palka, Giandomenico; Fioritoni, Giuseppe; Iacone, Antonio

    2007-04-01

    BCR/ABL-positive acute myeloid leukemia (AML) is a rare disease, characterized by a poor prognosis, with resistance to induction chemotherapy and frequent relapses in responsive patients. Here we report a case of BCR/ABL-positive AML-M6 who, after relapse, was treated with Imatinib Mesylate (600 mg/die) and within 4 months achieved a cytogenetic and molecular complete response. After more than 4 years of continuous Imatinib therapy, nested RT-PCR for BCR/ABL is persistently negative. The case reported shows that the response obtained with Imatinib Mesylate in BCR/ABL-positive AML may be long lasting, offering a chance of successful treatment for this poor prognosis group of patients.

  5. FUSION TRANSCRIPTS OF BCR/ABL GENE IN PATIENTES WITH CHRONIC MYELOID LEUKEMIA

    OpenAIRE

    Artigas, Carmen Gloria; Melo, Angélica; Roa, Juan Carlos; Roa, Iván; Quijada, Ingrid; Vittini, Cecilia; Cabrera, María Elena; Risueño, Concepción

    2003-01-01

    La anormalidad citogenética más común en la leucemia mieloide crónica (LMC) es el cromosoma Philadelphia, producida por la t(9;22), cuya expresión molecular es el gen de fusión BCR-ABL, que codifica proteínas con actividad tirosinquinasa. Según el punto de ruptura de los genes BCR o ABL se produce una proteína de fusión de 210-kD(p210) o 190-kD(p190). La presencia de este gen de fusión en pacientes con LMC tiene implicancia diagnóstica. Con el propósito de detectar transcriptos de fusión del ...

  6. Susceptibility of Ph-positive all to TKI therapy associated with Bcr-Abl rearrangement patterns: a retrospective analysis.

    Directory of Open Access Journals (Sweden)

    Yu Jing

    Full Text Available BACKGROUND: Tyrosine kinase inhibitors (TKIs have demonstrated success in the treatment of acute lymphoblastic leukemia (ALL in patients that express BCR-ABL rearrangements (Philadelphia chromosome [Ph]. The current study aimed to assess the efficacy of TKIs and prognostic factors in the treatment of adults with Ph+-ALL. METHODS: In this multicenter retrospective study, the relationship between Ph+-ALL and treatment outcomes among Chinese patients receiving TKI-containing induction/consolidation chemotherapy was examined. A total of 86 Ph+-ALL patients were included and followed for 3.85 (0.43-9.30 years. Overall survival (OS and event-free survival (EFS were analyzed. RESULTS: A total of 86 Ph+-ALL patients (40 females and 46 males; median age: 34.0 years were enrolled, including those with BCR/ABL transcripts 190 (n = 52, 210 (n = 25, and 230 (n = 2; BCR/ABL isoform determination was not available for 7 patients. Mortality was influenced by variable BCR/ABL transcripts and TKI administration, and BCR/ABL transcripts, hematopoietic stem cell transplantation (HSCT, and TKI administration were associated with the occurrence of events. The OS rate in the TKI administration group during steady state was significantly higher compared with those patients who did not receive TKI administration (P = 0.008, the EFS rate in the TKI administration group during steady state was significantly higher compared with those patients who did not receive TKIs (P = 0.012, and also higher than those with TKI salvage administration (P = 0.004. BCR/ABL transcripts 210 showed preferable OS and EFS compared with BCR/ABL transcripts 190 and 230 (P<0.05 for each. CONCLUSIONS: The susceptibility of Ph+-ALL to TKI associated with the patterns of BCR-ABL rearrangement is demonstrated for the first time, thus adding another risk-stratifying molecular prognostic tool for the management of patients with Ph+-ALL.

  7. Detection of BCR-ABL Fusion mRNA Using Reverse Transcriptase Loop-mediated Isothermal Amplification

    Energy Technology Data Exchange (ETDEWEB)

    Dugan, L C; Hall, S; Kohlgruber, A; Urbin, S; Torres, C; Wilson, P

    2011-12-08

    RT-PCR is commonly used for the detection of Bcr-Abl fusion transcripts in patients diagnosed with chronic myelogenous leukemia, CML. Two fusion transcripts predominate in CML, Br-Abl e13a2 and e14a2. They have developed reverse transcriptase isothermal loop-mediated amplification (RT-LAMP) assays to detect these two fusion transcripts along with the normal Bcr transcript.

  8. A critical role of CDKN3 in Bcr-Abl-mediated tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Qinghuang Chen

    Full Text Available CDKN3 (cyclin-dependent kinase inhibitor 3, a dual specificity protein phosphatase, dephosphorylates cyclin-dependent kinases (CDKs and thus functions as a key negative regulator of cell cycle progression. Deregulation or mutations of CDNK3 have been implicated in various cancers. However, the role of CDKN3 in Bcr-Abl-mediated chronic myelogenous leukemia (CML remains unknown. Here we found that CDKN3 acts as a tumor suppressor in Bcr-Abl-mediated leukemogenesis. Overexpression of CDKN3 sensitized the K562 leukemic cells to imanitib-induced apoptosis and dramatically inhibited K562 xenografted tumor growth in nude mouse model. Ectopic expression of CDKN3 significantly reduced the efficiency of Bcr-Abl-mediated transformation of FDCP1 cells to growth factor independence. In contrast, depletion of CDKN3 expression conferred resistance to imatinib-induced apoptosis in the leukemic cells and accelerated the growth of xenograph leukemia in mice. In addition, we found that CDKN3 mutant (CDKN3-C140S devoid of the phosphatase activity failed to affect the K562 leukemic cell survival and xenografted tumor growth, suggesting that the phosphatase of CDKN3 was required for its tumor suppressor function. Furthermore, we observed that overexpression of CDKN3 reduced the leukemic cell survival by dephosphorylating CDK2, thereby inhibiting CDK2-dependent XIAP expression. Moreover, overexpression of CDKN3 delayed G1/S transition in K562 leukemic cells. Our results highlight the importance of CDKN3 in Bcr-Abl-mediated leukemogenesis, and provide new insights into diagnostics and therapeutics of the leukemia.

  9. Hypoxia-Like Signatures Induced by BCR-ABL Potentially Alter the Glutamine Uptake for Maintaining Oxidative Phosphorylation.

    Directory of Open Access Journals (Sweden)

    Pallavi Sontakke

    Full Text Available The Warburg effect is probably the most prominent metabolic feature of cancer cells, although little is known about the underlying mechanisms and consequences. Here, we set out to study these features in detail in a number of leukemia backgrounds. The transcriptomes of human CB CD34+ cells transduced with various oncogenes, including BCR-ABL, MLL-AF9, FLT3-ITD, NUP98-HOXA9, STAT5A and KRASG12V were analyzed in detail. Our data indicate that in particular BCR-ABL, KRASG12V and STAT5 could impose hypoxic signaling under normoxic conditions. This coincided with an upregulation of glucose importers SLC2A1/3, hexokinases and HIF1 and 2. NMR-based metabolic profiling was performed in CB CD34+ cells transduced with BCR-ABL versus controls, both cultured under normoxia and hypoxia. Lactate and pyruvate levels were increased in BCR-ABL-expressing cells even under normoxia, coinciding with enhanced glutaminolysis which occurred in an HIF1/2-dependent manner. Expression of the glutamine importer SLC1A5 was increased in BCR-ABL+ cells, coinciding with an increased susceptibility to the glutaminase inhibitor BPTES. Oxygen consumption rates also decreased upon BPTES treatment, indicating a glutamine dependency for oxidative phosphorylation. The current study suggests that BCR-ABL-positive cancer cells make use of enhanced glutamine metabolism to maintain TCA cell cycle activity in glycolytic cells.

  10. Autophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment.

    LENUS (Irish Health Repository)

    Crowley, Lisa C

    2012-01-31

    Although Imatinib has transformed the treatment of chronic myeloid leukemia (CML), it is not curative due to the persistence of resistant cells that can regenerate the disease. We have examined how Bcr-Abl-expressing cells respond to two mechanistically different therapeutic agents, etoposide and Imatinib. We also examined Bcr-Abl expression at low and high levels as elevated expression has been associated with treatment failure. Cells expressing low levels of Bcr-Abl undergo apoptosis in response to the DNA-targeting agent (etoposide), whereas high-Bcr-Abl-expressing cells primarily induce autophagy. Autophagic populations engage a delayed nonapoptotic death; however, sufficient cells evade this and repopulate following the withdrawal of the drug. Non-Bcr-Abl-expressing 32D or Ba\\/F3 cells induce both apoptosis and autophagy in response to etoposide and can recover. Imatinib treatment induces both apoptosis and autophagy in all Bcr-Abl-expressing cells and populations rapidly recover. Inhibition of autophagy with ATG7 and Beclin1 siRNA significantly reduced the recovery of Imatinib-treated K562 cells, indicating the importance of autophagy for the recovery of treated cells. Combination regimes incorporating agents that disrupt Imatinib-induced autophagy would remain primarily targeted and may improve response to the treatment in CML.

  11. CD40 signaling synergizes with TLR-2 in the BCR independent activation of resting B cells.

    Directory of Open Access Journals (Sweden)

    Shweta Jain

    Full Text Available Conventionally, signaling through BCR initiates sequence of events necessary for activation and differentiation of B cells. We report an alternative approach, independent of BCR, for stimulating resting B (RB cells, by involving TLR-2 and CD40--molecules crucial for innate and adaptive immunity. CD40 triggering of TLR-2 stimulated RB cells significantly augments their activation, proliferation and differentiation. It also substantially ameliorates the calcium flux, antigen uptake capacity and ability of B cells to activate T cells. The survival of RB cells was improved and it increases the number of cells expressing activation induced deaminase (AID, signifying class switch recombination (CSR. Further, we also observed increased activation rate and decreased threshold period required for optimum stimulation of RB cells. These results corroborate well with microarray gene expression data. This study provides novel insights into coordination between the molecules of innate and adaptive immunity in activating B cells, in a BCR independent manner. This strategy can be exploited to design vaccines to bolster B cell activation and antigen presenting efficiency, leading to faster and better immune response.

  12. CD40 signaling synergizes with TLR-2 in the BCR independent activation of resting B cells.

    Science.gov (United States)

    Jain, Shweta; Chodisetti, Sathi Babu; Agrewala, Javed N

    2011-01-01

    Conventionally, signaling through BCR initiates sequence of events necessary for activation and differentiation of B cells. We report an alternative approach, independent of BCR, for stimulating resting B (RB) cells, by involving TLR-2 and CD40--molecules crucial for innate and adaptive immunity. CD40 triggering of TLR-2 stimulated RB cells significantly augments their activation, proliferation and differentiation. It also substantially ameliorates the calcium flux, antigen uptake capacity and ability of B cells to activate T cells. The survival of RB cells was improved and it increases the number of cells expressing activation induced deaminase (AID), signifying class switch recombination (CSR). Further, we also observed increased activation rate and decreased threshold period required for optimum stimulation of RB cells. These results corroborate well with microarray gene expression data. This study provides novel insights into coordination between the molecules of innate and adaptive immunity in activating B cells, in a BCR independent manner. This strategy can be exploited to design vaccines to bolster B cell activation and antigen presenting efficiency, leading to faster and better immune response.

  13. Heterogeneity of genomic fusion of BCR and ABL in Philadelphia chromosome-positive acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Rubin, C.M.; Carrino, J.J.; Dickler, M.N.; Leibowitz, D.; Smith, S.D.; Westbrook, C.A.

    1988-01-01

    Philadelphia chromosome-positive acute lymphoblastic leukemia occurs in two molecular forms, those with and those without rearrangement of the breakpoint cluster region on chromosome 22. The molecular abnormality in the former group is similar to that found in chronic myelogenous leukemia. To characterize the abnormality in the breakpoint cluster region-unrearranged form, the authors have mapped a 9; 22 translocation from the Philadelphia chromosome-positive acute lymphoblastic leukemia cell line SUP-B13 by using pulsed-field gel electrophoresis and have cloned the DNA at the translocation junctions. They demonstrate a BCR-ABL fusion gene on the Philadelphia chromosome. The exons from ABL are the same. Analysis of leukemic cells from four other patients with breakpoint cluster region-unrearranged Philadelphia chromosome-positive acute lymphoblastic leukemia revealed a rearrangement on chromosome 22 close to the breakpoint in SUP-B13 in only one patient. These data indicate that breakpoints do not cluster tightly in this region but are scattered, possibly in a large intron. Given the large size of BCR and the heterogeneity in breakpoint location, detection of BCR rearrangement by standard Southern blot analysis is difficult. Pulsed-field gel electrophoresis should allow detection at the DNA level in every patient and thus will permit clinical correlation of the breakpoint location with prognosis

  14. Regulatory effects of sestrin 3 (SESN3 in BCR-ABL expressing cells.

    Directory of Open Access Journals (Sweden)

    Eliza Vakana

    Full Text Available Chronic myeloid leukemia (CML and Ph+ acute lymphoblastic leukemia (ALL are characterized by the presence of the BCR-ABL oncoprotein, which leads to activation of a plethora of pro-mitogenic and pro-survival pathways, including the mTOR signaling cascade. We provide evidence that in BCR-ABL expressing cells, treatment with tyrosine kinase inhibitors (TKIs results in upregulation of mRNA levels and protein expression of sestrin3 (SESN3, a unique cellular inhibitor of mTOR complex 1 (mTORC1. Such upregulation appears to be mediated by regulatory effects on mTOR, as catalytic inhibition of the mTOR kinase also induces SESN3. Catalytic mTOR inhibition also results in upregulation of SESN3 expression in cells harboring the TKI-insensitive T315I-BCR-ABL mutant, which is resistant to imatinib mesylate. Overexpression of SESN3 results in inhibitory effects on different Ph+ leukemic cell lines including KT-1-derived leukemic precursors, indicating that SESN3 mediates anti-leukemic responses in Ph+ cells. Altogether, our findings suggest the existence of a novel mechanism for the generation of antileukemic responses in CML cells, involving upregulation of SESN3 expression.

  15. BCR-701: A review of 10-years of sequential extraction analyses

    International Nuclear Information System (INIS)

    Sutherland, Ross A.

    2010-01-01

    A detailed quantitative analysis was performed on data presented in the literature that focused on the sequential extraction of cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), lead (Pb) and zinc (Zn) from the certified reference material BCR-701 (lake sediment) using the three-step harmonized BCR procedure. The accuracy of data reported in the literature, including precision and different measures of trueness, was assessed relative to the certified values for BCR-701. Forty data sets were accepted following extreme outlier removal, and statistically summarized with measures of central tendency, dispersion, and distribution form. In general, literature data were similar in their measurement precision to the expert laboratories used to certify the trace element contents in BCR-701. The overall median precision for literature reported data was 10% (range 6-19%), compared to certifying laboratories of 9% (range 4-33%). One measure of literature data trueness was assessed via a confirmatory approach using a robust bootstrap method. Only 22% of the comparisons indicated significantly different (all were lower) concentrations reported in the literature compared to certified values. The question of whether the differences are practically significant for environmental studies is raised. Bias was computed as a measure of trueness, and literature data were more frequently negatively biased, indicating lower concentrations reported in the literature for the six trace elements for the three-step sequential procedure compared to the certified values. However, 95% confidence intervals about the average bias for the 18 comparisons indicated only four instances when a mean bias of 0 (i.e., measured = certified) was not incorporated-suggesting statistical difference. Finally, Z-scores incorporating a Horwitz-type function were used to assess the general trueness of laboratory data. Of the 468 laboratory Z-score values computed, 92% were considered to be satisfactory, 5% were

  16. AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance

    Science.gov (United States)

    O’Hare, Thomas; Shakespeare, William C.; Zhu, Xiaotian; Eide, Christopher A.; Rivera, Victor M.; Wang, Frank; Adrian, Lauren T.; Zhou, Tianjun; Huang, Wei-Sheng; Xu, Qihong; Metcalf, Chester A.; Tyner, Jeffrey W.; Loriaux, Marc M.; Corbin, Amie S.; Wardwell, Scott; Ning, Yaoyu; Keats, Jeffrey A.; Wang, Yihan; Sundaramoorthi, Raji; Thomas, Mathew; Zhou, Dong; Snodgrass, Joseph; Commodore, Lois; Sawyer, Tomi K.; Dalgarno, David C.; Deininger, Michael W.N.; Druker, Brian J.; Clackson, Tim

    2009-01-01

    SUMMARY Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABLT315I mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and pre-clinical evaluation of AP24534, a potent, orally available multi-targeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABLT315I-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML. PMID:19878872

  17. AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance

    Energy Technology Data Exchange (ETDEWEB)

    O’Hare, Thomas; Shakespeare, William C.; Zhu, Xiaotian; Eide, Christopher A.; Rivera, Victor M.; Wang, Frank; Adrian, Lauren T.; Zhou, Tianjun; Huang, Wei-Sheng; Xu, Qihong; Metcalf, III, Chester A.; Tyner, Jeffrey W.; Loriaux, Marc M.; Corbin, Amie S.; Wardwell, Scott; Ning, Yaoyu; Keats, Jeffrey A.; Wang, Yihan; Sundaramoorthi, Raji; Thomas, Mathew; Zhou, Dong; Snodgrass, Joseph; Commodore, Lois; Sawyer, Tomi K.; Dalgarno, David C.; Deininger, Michael W.N.; Druker, Brian J.; Clackson, Tim; (OHSU- Cancer Instit.); (ARIAD)

    2010-09-07

    Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL{sup T315I} mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL{sup T315I}-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.

  18. Interaction of the B cell-specific transcriptional coactivator OCA-B and galectin-1 and a possible role in regulating BCR-mediated B cell proliferation.

    Science.gov (United States)

    Yu, Xin; Siegel, Rachael; Roeder, Robert G

    2006-06-02

    OCA-B is a B cell-specific transcriptional coactivator for OCT factors during the activation of immunoglobulin genes. In addition, OCA-B is crucial for B cell activation and germinal center formation. However, the molecular mechanisms for OCA-B function in these processes are not clear. Our previous studies documented two OCA-B isoforms and suggested a novel mechanism for the function of the myristoylated, membrane-bound form of OCA-B/p35 as a signaling molecule. Here, we report the identification of galectin-1, and related galectins, as a novel OCA-B-interacting protein. The interaction of OCA-B and galectin-1 can be detected both in vivo and in vitro. The galectin-1 binding domain in OCA-B has been localized to the N terminus of OCA-B. In B cells lacking OCA-B expression, increased galectin-1 expression, secretion, and cell surface association are observed. Consistent with these observations, and a reported inhibitory interaction of galectin-1 with CD45, the phosphatase activity of CD45 is reduced modestly, but significantly, in OCA-B-deficient B cells. Finally, galectin-1 is shown to negatively regulate B cell proliferation and tyrosine phosphorylation upon BCR stimulation. Together, these results raise the possibility that OCA-B may regulate BCR signaling through an association with galectin-1.

  19. Characterization of the CDR3 structure of the Vβ21 T cell clone in patients with P210(BCR-ABL)-positive chronic myeloid leukemia and B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Zha, Xianfeng; Chen, Shaohua; Yang, Lijian; Li, Bo; Chen, Yu; Yan, Xiaojuan; Li, Yangqiu

    2011-10-01

    The clonally expanded T cells identified in most cancer patients that respond to tumor-associated antigen such as P210(BCR-ABL) protein have definite, specific antitumor cytotoxicity. T cell receptor (TCR) Vβ CDR3 repertoire diversity was analyzed in patients with chronic myeloid leukemia (CML) and BCR-ABL(+) B-cell acute lymphoblastic leukemia (B-ALL) by GeneScan. A high frequency of oligoclonal expansion of the TCR Vβ21 subfamily was observed in the peripheral blood of CML and B-ALL patients. These clonally expanded Vβ21 T cells were correlated with the pathophysiologic process of CML. A conserved amino acid motif (SLxxV) was observed within the CDR3 region in only 3 patients with CML. Preferential usage of the Jβ segments was also observed in a minority of patients. The 3-dimensional structures of the CDR3 region containing the same motif or using the same Jβ segment displayed low similarity; on the contrary, the conformation of the CDR3 region containing no conserved motif in some T cell clones was highly similar. In conclusion, our findings indicate a high frequency of TCR Vβ21 subfamily expansion in p210(BCR-ABL)-positive CML and B-ALL patients. The characterization of the CDR3 structure was complex. Regrettably, at this time it was not possible to confirm that the Vβ21 T cell clones were derived from the stimulation of p210(BCR-ABL) protein. Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  20. Guidelines for molecular monitoring of BCR-ABL1 in chronic myeloid leukemia patients by RT-qPCR

    Directory of Open Access Journals (Sweden)

    Irene Larripa

    2017-02-01

    Full Text Available Current clinical guidelines for managing chronic myeloid leukemia include molecular monitoring of BCR-ABL1 transcript quantitative reverse-transcription PCR. Despite the proven prognostic significance of molecular response, it is not widely appreciated that quantitative reverse-transcription PCR potentially produces highly variable data, which may affect the validity of results, making comparability between different laboratories difficult. Therefore, standardized reporting of BCR-ABL1 measurements is needed for optimal clinical management. An approach to achieve comparable BCR-ABL1 values is the use of an international reporting scale. Conversion to the international scale is achieved by the application of laboratory specific conversion factor that is obtained by using validated secondary reference calibrators. Moreover, with the aim to mitigate the interlaboratory imprecision of quantitative BCR-ABL1 measurements and to facilitate local laboratory results interpretation and reporting, we decide to prepare laboratory guidelines that will further facilitate interlaboratory comparative studies and independent quality-assessment programs, which are of paramount importance for worldwide standardization of BCR-ABL1 monitoring results, in particular for those most isolated laboratories, with not easy access to commercial kits or sample interchange programs

  1. The BTK Inhibitor Ibrutinib (PCI-32765) Blocks Hairy Cell Leukaemia Survival, Proliferation and BCR Signalling: A New Therapeutic Approach

    Science.gov (United States)

    Sivina, Mariela; Kreitman, Robert J.; Arons, Evgeny; Ravandi, Farhad; Burger, Jan A.

    2014-01-01

    B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins (A, G, and M) and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL. PMID:24697238

  2. Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity

    International Nuclear Information System (INIS)

    Pannucci, N L; Li, D; Sahay, S; Thomas, E K; Chen, R; Tala, I; Hu, T; Ciccarelli, B T; Megjugorac, N J; Adams III, H C; Rodriguez, P L; Fitzpatrick, E R; Lagunoff, D; Williams, D A; Whitehead, I P

    2013-01-01

    Previous studies have demonstrated that p210 BCR/ABL1 interacts directly with the xeroderma pigmentosum group B (XPB) protein, and that XPB is phosphorylated on tyrosine in cells that express p210 BCR/ABL1. In the current study, we have constructed a p210 BCR/ABL1 mutant that can no longer bind to XPB. The mutant has normal kinase activity and interacts with GRB2, but can no longer phosphorylate XPB. Loss of XPB binding is associated with reduced expression of c-MYC and reduced transforming potential in ex-vivo clonogenicity assays, but does not affect nucleotide excision repair in lymphoid or myeloid cells. When examined in a bone marrow transplantation (BMT) model for chronic myelogenous leukemia, mice that express the mutant exhibit attenuated myeloproliferation and lymphoproliferation when compared with mice that express unmodified p210 BCR/ABL1. Thus, the mutant-transplanted mice show predominantly neutrophilic expansion and altered progenitor expansion, and have significantly extended lifespans. This was confirmed in a BMT model for B-cell acute lymphoblastic leukemia, wherein the majority of the mutant-transplanted mice remain disease free. These results suggest that the interaction between p210 BCR/ABL1 and XPB can contribute to disease progression by influencing the lineage commitment of lymphoid and myeloid progenitors

  3. The Dictyostelium Bcr/Abr-related protein DRG regulates both Rac- and Rab-dependent pathways

    OpenAIRE

    Knetsch, Menno L.W.; Schäfers, Nicole; Horstmann, Heinz; Manstein, Dietmar J.

    2001-01-01

    Dictyostelium discoideum DdRacGap1 (DRG) contains both Rho-GEF and Rho-GAP domains, a feature it shares with mammalian Bcr and Abr. To elucidate the physiological role of this multifunctional protein, we characterized the enzymatic activity of recombinant DRG fragments in vitro, created DRG-null cells, and studied the function of the protein in vivo by analysing the phenotypic changes displayed by DRG-depleted cells and DRG-null cells complemented with DRG or DRG fragments. Our results show t...

  4. Determination of persistent organohalogenated pollutants in human hair reference material (BCR 397): an interlaboratory study

    Energy Technology Data Exchange (ETDEWEB)

    Gill, Udai [Health Canada, Product Safety Laboratory, Ottawa, Ontario (Canada); Covaci, Adrian [University of Antwerp, Toxicological Center, Wilrijk (Belgium); Ryan, John Jake [Health Canada, Bureau of Chemical Safety, Health Products and Food Branch, Ottawa, Ontario (Canada); Emond, Andre [Health Canada, Environmental Research Division, First Nations and Inuit Health Branch, Ottawa, Ontario K1A0L2 (Canada)

    2004-12-01

    A human powdered hair material (BCR 397) was tested for its content in persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs). Using different methods, three laboratories (two from Canada and one from Belgium) analysed a powdered hair sample to evaluate some methodologies and to obtain consensus values for selected POPs. Measured values for all PCB congeners and p,p'-DDE were within a relative standard deviation (RSD) of 15%. These first results contribute to the accuracy and precision for POPs quantification in hair and render test results more comparable among different laboratories. (orig.)

  5. [Early monitoring of BCR-ABL transcript levels and cytogenetic in assessing the prognosis of chronic myeloid leukemia].

    Science.gov (United States)

    Huang, Qin; Zhang, Xiao-yan; Li, Yan; Wang, Xiao-min

    2013-10-15

    To explore the prognostic significance of early monitoring of BCR-ABL transcript levels and cytogenetic evaluations for chronic myeloid leukemia in chronic phase (CML-CP). From July 2007 to May 2012, 56 CML-CP patients received oral imatinib 400 mg/d. The BCR-ABL transcript levels were monitored and cytogenetic examinations performed after 3 and 6 months respectively. The median follow-up time was 48 months. The 3-month BCR-ABL transcript levels ≤ 10% of patients 5-year overall survival (OS) and progression-free survival (PFS) were better than BCR-ABL transcript levels >10% of patients (OS: 100% vs 84.6%, P = 0.011; PFS: 94.6% vs 67.7%, P = 0.045); cytogenetics: Ph(+) ≤ 35 % of patients 5-year OS and PFS better than Ph(+) > 35% of patients (OS: 100% vs 76.2%, P = 0.001; PFS: 95.2% vs 38.1%, P = 0.001); the 6-month BCR-ABL transcripts level ≤ 1% of patients 5-year OS and PFS also better than BCR-ABL transcript levels> 1% of patients (OS: 100% vs 71.4%, P = 0.000; PFS: 95.2% vs 47.6%, P = 0.001); Ph(+) = 0% and Ph(+)> 0% patients, 5-year OS and PFS were significantly different (OS: 100% vs 68.6%, P = 0.000; PFS: 95.3% vs 45.7%, P = 0.000). Early molecular biology and cytogenetics monitoring have some significance in the prognostic assessment of CML-CP. And individualized treatment strategies should be based upon the monitoring results in conjunctions with comprehensive judgments.

  6. BCR translocation to derivative chromosome 2, a new case of chronic myeloid leukemia with complex variant translocation and Philadelphia chromosome

    International Nuclear Information System (INIS)

    Al-Achkar, W.; Wafa, A.; Al-Medani, S.

    2011-01-01

    The well-known typical fusion gene BCR/ABL can be observed in connection with a complex translocation event in only 5-8% of cases with chronic myeloid leukemia (CML). Herein we report an exceptional CML case with complex chromosomal aberrations not observed before, translocated BCR to the derivative chromosome 2 [der(2)], additional to involving a four chromosomes translocation implying chromosomal regions such as 1p32 and 2q21 besides 9q34 and 22q11.2. Which were characterized by molecular cytogenetics. (author)

  7. Association of HLA Class I and Class II genes with bcr-abl transcripts in leukemia patients with t(9;22 (q34;q11

    Directory of Open Access Journals (Sweden)

    Cano Pedro

    2004-06-01

    Full Text Available Abstract Background Based on the site of breakpoint in t(9;22 (q34;q11, bcr-abl fusion in leukemia patients is associated with different types of transcript proteins. In this study we have seen the association of HLA genes with different types of bcr-abl transcripts. The association could predict the bcr-abl peptide presentation by particular HLA molecules. Methods The study included a total of 189 patients of mixed ethnicity with chronic myelogenous leukemia and acute lymphocytic leukemia who were being considered for bone marrow transplantation. Typing of bcr-abl transcripts was done by reverse transcriptase PCR method. HLA typing was performed by molecular methods. The bcr-abl and HLA association was studied by calculating the relative risks and chi-square test. Results Significant negative associations (p Conclusions The negative associations of a particular bcr-abl transcript with specific HLA alleles suggests that these alleles play a critical role in presenting peptides derived from the chimeric proteins and eliciting a successful T-cell cytotoxic response. Knowledge of differential associations between HLA phenotypes and bcr-abl fusion transcript types would help in developing better strategies for immunization with the bcr-abl peptides against t(9;22 (q34;q11-positive leukemia.

  8. DMPD: Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin-1during B-cell development. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14962188 Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokin...ng) (.svg) (.html) (.csml) Show Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin...-1during B-cell development. PubmedID 14962188 Title Mechanisms of selection medi

  9. Unexpected heterogeneity of BCR-ABL fusion mRNA detected by polymerase chain reaction in Philadelphia chromosome-positive acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Hooberman, A.L.; Carrino, J.J.; Leibowitz, D.; Rowley, J.D.; Le Beau, M.M.; Arlin, Z.A.; Westbrook, C.A.

    1989-01-01

    The Philadelphia (Ph 1 ) chromosome results in a fusion of portions of the BCR gene from chromosome 22 and the ABL gene from chromosome 9, producing a chimeric BCR-ABL mRNA and protein. In lymphoblastic leukemias, there are two molecular subtypes of the Ph 1 chromosome, one with a rearrangement of the breakpoint cluster region (bcr) of the BCR gene, producing the same 8.5-kilobase BCR-ABL fusion mRNA seen in chronic myelogenous leukemia (CML), and the other, without a bcr rearrangement, producing a 7.0-kilobase BCR-ABL fusion mRNA that is seen only in acute lymphoblastic leukemia (ALL). The authors studied the molecular subtype of the Ph 1 chromosome in 11 cases of Ph 1 -positive ALL, including 2 with a previous diagnosis of CML, using a sensitive method to analyze the mRNA species based on the polymerase chain reaction (PCR). They observed unexpected heterogeneity in BCR-ABL mRNA in this population. They conclude that the PCR gives additional information about the Ph 1 chromosome gene products that cannot be obtained by genomic analysis, but that it cannot be used as the sole means of detection of this chromosomal abnormality in ALL because of the high incidence of false negative results

  10. Growth of chronic myeloid leukemia cells is inhibited by infection with Ad-SH2-HA adenovirus that disrupts Grb2-Bcr-Abl complexes.

    Science.gov (United States)

    Peng, Zhi; Luo, Hong-Wei; Yuan, Ying; Shi, Jing; Huang, Shi-Feng; Li, Chun-Li; Cao, Wei-Xi; Huang, Zong-Gan; Feng, Wen-Li

    2011-05-01

    The persistence of Bcr-Abl-positive cells in patients on imatinib therapy indicates that inhibition of the Bcr-Abl kinase activity alone might not be sufficient to eradicate the leukemia cells. Many downstream effectors of Bcr-Abl have been described, including activation of both the Grb2-SoS-Ras-MAPK and Grb2-Gab2-PI3K-Akt pathways. The Bcr-Abl-Grb2 interaction, which is mediated by the direct interaction of the Grb2 SH2 domain with the phospho-Bcr-Abl Y177, is required for activation of these signaling pathways. Therefore, disrupting their interaction represents a potential therapeutic strategy for inhibiting the oncogenic downstream signals of Bcr-Abl. Adenovirus Ad-SH2-HA expressing the Grb2 SH2 domain was constructed and applied in this study. As expected, Ad-SH2-HA efficiently infected CML cells and functioned by binding to the phospho-Bcr-Abl Y177 site, competitively disrupting the Grb2 SH2-phospho-Bcr-Abl Y177 complex. They induced potent anti-proliferation and apoptosis-inducing effects in CML cell lines. Moreover, the Ras, MAPK and Akt activities were significantly reduced in the Ad-SH2-HA treated cells. These were not observed with the point-mutated control adenovirus Ad-Sm-HA with abolished phospho-Bcr-Abl Y177 binding sites. These data indicate that, in addition to the direct targeting of Bcr-Abl, selective inhibition of its downstream signaling pathways may be a therapeutic option for CML, and the Ad-SH2-HA-mediated killing strategy could be explored as a promising anti-leukemia agent in CML.

  11. Expression of p210 BCR/ABl increases hematopoietic progenitor cell radiosensitivity

    International Nuclear Information System (INIS)

    Santucci, M.A.; Anklesaria, P.; Das, I.J.; Sakakeeny, M.A.; FitzGerald, T.J.; Greenberger, J.S.; Laneuville, P.

    1993-01-01

    The cytogenetic finding of the Ph1+ chromosome and its molecular biologic marker bcr/abl gene rearrangement in cells from patients with chronic myeloid leukemia are associated with a proliferative advantage of the Ph1+ clone in vivo. Although the transition to the acute terminal phase or blastic crisis is often associated with additional cytogenetic abnormalities, the molecular events which correlate the initial cytogenetic lesion with the terminal phase are poorly understood. Defective cellular DNA repair capacity is often associated with chromosomal instability, increased mutation frequency, and biologic alterations. The authors tested whether the protein product of the bcr/abl translocation (p210) could alter DNA repair after gamma-irradiation of murine cell lines expressing the bcr/abl cDNA. The 32D cl 3 parent, 32D cl 3 pYN (containing the control vector plasmid) and each of two sources of 32D cl 3 cells expressing p210 cDNA (32D-PC1 cell line and 32D-LG7 subclone) showed a D 0 of 1.62, 1.57, 1.16, and 1.27 Gy, respectively. Thus, expression of the p210 product induced a significant increase in radiosensitivity at the clinically relevant radiation therapy dose-rate. The increased radiosensitivity of p210-expressing cells persisted if cells were held before plating in a density-inhibited state for 8 hr after gamma-irradiation, indicating little effect on the repair of potentially lethal gamma-irradiation damage. The IL-3 dependent parent 32D cl 3 cells demonstrated programmed cell death in the absence of growth factor or following gamma-irradiation to 200 cGy. Expression of p210 cDNA in the 32D-PC1 and 32D-LG7 subclones abrogated IL-3 requirement of these cell lines and inhibited gamma-irradiation induced programmed cell death. These data suggest a role for p210 in amplifying gamma-irradiation DNA damage or broadly inhibiting DNA repair, conditions that may stimulate further cytogenetic alterations in hematopoietic cells. 43 refs., 3 figs., 1 tab

  12. Cytoprotective effect of imatinib mesylate in non-BCR-ABL-expressing cells along with autophagosome formation

    International Nuclear Information System (INIS)

    Ohtomo, Tadashi; Miyazawa, Keisuke; Naito, Munekazu; Moriya, Shota; Kuroda, Masahiko; Itoh, Masahiro; Tomoda, Akio

    2010-01-01

    Treatment with imatinib mesylate (IM) results in an increased viable cell number of non-BCR-ABL-expressing cell lines by inhibiting spontaneous apoptosis. Electron microscopy revealed an increase of autophagosomes in response to IM. IM attenuated the cytotoxic effect of cytosine arabinoside, as well as inhibiting cell death with serum-deprived culture. Cytoprotection with autophagosome formation by IM was observed in various leukemia and cancer cell lines as well as normal murine embryonic fibroblasts (MEFs). Complete inhibition of autophagy by knockdown of atg5 in the Tet-off atg5 -/- MEF system attenuated the cytoprotective effect of IM, indicating that the effect is partially dependent on autophagy. However, cytoprotection by IM was not mediated through suppression of ROS production via mitophagy, ER stress via ribophagy, or proapoptotic function of ABL kinase. Although the target tyrosine kinase(s) of IM remains unclear, our data provide novel therapeutic possibilities of using IM for cytoprotection.

  13. Effects of austenitization temperature on the microstructure of 15BCr30 and PL22 boron steels

    Directory of Open Access Journals (Sweden)

    C. A. Suski

    2013-01-01

    Full Text Available This paper studies boron precipitation and segregation at austenitic grain boundaries for low carbon boron steels types: PL22 and 15BCr30. The following parameters were evaluated: percentage of martensite/bainite, size and nucleation sites of austenitic grains and precipitates sizes. Three austenitization temperatures were studied (870, 1050 and 1200 °C. The highest martensite percentage occurred for 1050 °C. Iron-borocarbides were detected at grain boundaries for all tested temperatures. At 870 °C the coarse iron-borocarbides are due to non-solubility and coalescence. The highest martensite percentage at 1050 °C is caused by the discrete precipitation of iron-borocarbides at austenitic grains boundaries. The discrete precipitation was due to the low non-equilibrium segregation of boron at grain boundaries. The low non-equilibrium segregation and the small grain size at 1050 °C reduce the total boron concentration at grain boundaries.

  14. BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia.

    Science.gov (United States)

    Cuellar, Sandra; Vozniak, Michael; Rhodes, Jill; Forcello, Nicholas; Olszta, Daniel

    2017-01-01

    The management of chronic myeloid leukemia with BCR-ABL1 tyrosine kinase inhibitors has evolved chronic myeloid leukemia into a chronic, manageable disease. A patient-centered approach is important for the appropriate management of chronic myeloid leukemia and optimization of long-term treatment outcomes. The pharmacist plays a key role in treatment selection, monitoring drug-drug interactions, identification and management of adverse events, and educating patients on adherence. The combination of tyrosine kinase inhibitors with unique safety profiles and individual patients with unique medical histories can make managing treatment difficult. This review will provide up-to-date information regarding tyrosine kinase inhibitor-based treatment of patients with chronic myeloid leukemia. Management strategies for adverse events and considerations for drug-drug interactions will not only vary among patients but also across tyrosine kinase inhibitors. Drug-drug interactions can be mild to severe. In instances where co-administration of concomitant medications cannot be avoided, it is critical to understand how drug levels are impacted and how subsequent dose modifications ensure therapeutic drug levels are maintained. An important component of patient-centered management of chronic myeloid leukemia also includes educating patients on the significance of early and regular monitoring of therapeutic milestones, emphasizing the importance of adhering to treatment in achieving these targets, and appropriately modifying treatment if these clinical goals are not being met. Overall, staying apprised of current research, utilizing the close pharmacist-patient relationship, and having regular interactions with patients, will help achieve successful long-term treatment of chronic myeloid leukemia in the age of BCR-ABL1 tyrosine kinase inhibitors.

  15. Dual Drug Targeting of Mutant Bcr-Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance.

    Science.gov (United States)

    El Rashedy, Ahmed A; Olotu, Fisayo A; Soliman, Mahmoud E S

    2018-03-01

    Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and ABL-001 induced a 'bent' conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr-Abl by dual targeting. Our findings revealed that unlike in the Bcr-Abl-Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C-terminal helix that varied with time. This was coupled with significant alteration in Bcr-Abl stability, flexibility, and compactness and an overall structural re-orientation inwards towards the hydrophobic core, which reduced the solvent-exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

  16. Pristimerin induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation by blocking NF-κB signaling and depleting Bcr-Abl

    Science.gov (United States)

    2010-01-01

    Background Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. Bcr-Abl-T315I is the notorious point mutation that causes resistance to imatinib and the second generation tyrosine kinase inhibitors, leading to poor prognosis. CML blasts have constitutive p65 (RelA NF-κB) transcriptional activity, and NF-κB may be a potential target for molecular therapies in CML that may also be effective against CML cells with Bcr-Abl-T315I. Results In this report, we discovered that pristimerin, a quinonemethide triterpenoid isolated from Celastraceae and Hippocrateaceae, inhibited growth and induced apoptosis in CML cells, including the cells harboring Bcr-Abl-T315I mutation. Additionally, pristimerin inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Pristimerin blocked the TNFα-induced IκBα phosphorylation, translocation of p65, and expression of NF-κB-regulated genes. Pristimerin inhibited two steps in NF-κB signaling: TAK1→IKK and IKK→IκBα. Pristimerin potently inhibited two pairs of CML cell lines (KBM5 versus KBM5-T315I, 32D-Bcr-Abl versus 32D-Bcr-Abl-T315I) and primary cells from a CML patient with acquired resistance to imatinib. The mRNA and protein levels of Bcr-Abl in imatinib-sensitive (KBM5) or imatinib-resistant (KBM5-T315I) CML cells were reduced after pristimerin treatment. Further, inactivation of Bcr-Abl by imatinib pretreatment did not abrogate the TNFα-induced NF-κB activation while silencing p65 by siRNA did not affect the levels of Bcr-Abl, both results together indicating that NF-κB inactivation and Bcr-Abl inhibition may be parallel independent pathways. Conclusion To our knowledge, this is the first report to show that pristimerin is effective in vitro and in vivo against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-κB and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to

  17. Transformation of an Unclassified Myeloproliferative Neoplasm with a Rare BCR-JAK2 Fusion Transcript Resulting from the Translocation (9;22)(p24;q11)

    OpenAIRE

    A. N. Chamseddine; P. Etancelin; D. Penther; F. Parmentier; C. Kuadjovi; V. Camus; N. Contentin; P. Lenain; C. Bastard; H. Tilly; F. Jardin

    2015-01-01

    BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most...

  18. Expression of P190 and P210 BCR/ABL1 in normal human CD34(+) cells induces similar gene expression profiles and results in a STAT5-dependent expansion of the erythroid lineage

    DEFF Research Database (Denmark)

    Järås, Marcus; Johnels, Petra; Agerstam, Helena

    2009-01-01

    OBJECTIVE: The P190 and P210 BCR/ABL1 fusion genes are mainly associated with different types of hematologic malignancies, but it is presently unclear whether they are functionally different following expression in primitive human hematopoietic cells. MATERIALS AND METHODS: We investigated...... and systematically compared the effects of retroviral P190 BCR/ABL1 and P210 BCR/ABL1 expression on cell proliferation, differentiation, and global gene expression in human CD34(+) cells from cord blood. RESULTS: Expression of either P190 BCR/ABL1 or P210 BCR/ABL1 resulted in expansion of erythroid cells...... and stimulated erythropoietin-independent burst-forming unit-erythroid colony formation. By using a lentiviral anti-signal transducer and activator of transcription 5 (STAT5) short-hairpin RNA, we found that both P190 BCR/ABL1- and P210 BCR/ABL1-induced erythroid cell expansion were STAT5-dependent. Under...

  19. Prolonged treatment with imatinib mesylate in patients with advanced chronic myeloid leukemia causes a reduction of bcr/abl mRNA levels independent of cytogenetic response.

    Science.gov (United States)

    Cariani, E; Capucci, M; Micheletti, M; Spalenza, F; Zanella, I; Albertini, A; Rossi, G

    2003-06-01

    Bcr/abl mRNA levels were monitored in 13 patients with chronic myeloid leukemia receiving imatinib mesylate over a period of 78 weeks. During treatment median bcr/abl mRNA levels progressively declined from 77.2 normalized dose (nD) at baseline to 11.28 nD after 13 weeks ( P<0.05) and to 1.28 nD after 78 weeks ( P<0.05). After 13 weeks, bcr/abl mRNA levels were significantly lower in cytogenetic responders compared to nonresponders ( P<0.05), but subsequent decrease in the transcript levels caused the loss of any correlation to the cytogenetic status. These results suggest that bcr/abl mRNA levels may reflect cytogenetic response only during the early phases of imatinib therapy.

  20. BCR: a service to quality assurance in analytical chemistry - some experiences and achievements with regard to reference material preparation

    Energy Technology Data Exchange (ETDEWEB)

    Griepink, B. (Commission of the European Communities, Measurements and Testing Programme (BCR), Brussels (Belgium)); Quevauviller, P. (Commission of the European Communities, Measurements and Testing Programme (BCR), Brussels (Belgium)); Maier, E.A. (Commission of the European Communities, Measurements and Testing Programme (BCR), Brussels (Belgium)); Vandendriessche, S. (Commission of the European Communities, Measurements and Testing Programme (BCR), Brussels (Belgium))

    Despite all efforts to improve the quality of results of measurements, intercomparisons demonstrate a considerable discrepancy. This fact was also shown by many of the round robins organised by the BCR (Commission of the European Communities) on inorganic, speciation, and organic determinations in various environmental matrices. It is clear that further efforts have to be made to improve the state of the art of a wide variety of analyses. This means that the demand for certified reference materials (CRMs) is and will be in constant increase. RMs are required for the validation of methods, for proficiency testing or for training purposes. The production of RMs and CRMs resembling the composition of real matrices poses difficult problems for some compounds and is a challenge for the producers. This paper presents some recent experiences and achievements of the BCR in special cases. (orig.)

  1. Association of HLA Class I and Class II genes with bcr-abl transcripts in leukemia patients with t(9;22) (q34;q11)

    International Nuclear Information System (INIS)

    Mundhada, Shailendra; Luthra, Rajyalakshmi; Cano, Pedro

    2004-01-01

    Based on the site of breakpoint in t(9;22) (q34;q11), bcr-abl fusion in leukemia patients is associated with different types of transcript proteins. In this study we have seen the association of HLA genes with different types of bcr-abl transcripts. The association could predict the bcr-abl peptide presentation by particular HLA molecules. The study included a total of 189 patients of mixed ethnicity with chronic myelogenous leukemia and acute lymphocytic leukemia who were being considered for bone marrow transplantation. Typing of bcr-abl transcripts was done by reverse transcriptase PCR method. HLA typing was performed by molecular methods. The bcr-abl and HLA association was studied by calculating the relative risks and chi-square test. Significant negative associations (p < 0.05) were observed with HLA-A*02 (b2a2, e1a2), -A*68 (b2a2, b3a2, e1a2), -B*14 (b2a2, b3a2, e1a2), -B*15 (b2a2, b3a2), -B*40 (b2a2), -DQB1*0303 (b2a2, b3a2), -DQB1*0603 (b2a2), -DRB1*0401 (e1a2), -DRB1*0701 (b3a2), and -DRB1*1101 (b2a2). The negative associations of a particular bcr-abl transcript with specific HLA alleles suggests that these alleles play a critical role in presenting peptides derived from the chimeric proteins and eliciting a successful T-cell cytotoxic response. Knowledge of differential associations between HLA phenotypes and bcr-abl fusion transcript types would help in developing better strategies for immunization with the bcr-abl peptides against t(9;22) (q34;q11)-positive leukemia

  2. Disrupting BCR-ABL in Combination with Secondary Leukemia-Specific Pathways in CML Cells Leads to Enhanced Apoptosis and Decreased Proliferation

    OpenAIRE

    Woessner, David W.; Lim, Carol S.

    2012-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by expression of the fusion gene BCR-ABL following a chromosomal translocation in the hematopoietic stem cell.1 Therapeutic management of CML uses tyrosine kinase inhibitors (TKIs), which blocks ABL-signaling and effectively kill peripheral cells with BCR-ABL. However, TKIs are not curative, and chronic use of is required in order to treat CML. The primary failure for TKIs is through development of a resistant population d...

  3. c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells.

    Science.gov (United States)

    Waldron, T; De Dominici, M; Soliera, A R; Audia, A; Iacobucci, I; Lonetti, A; Martinelli, G; Zhang, Y; Martinez, R; Hyslop, T; Bender, T P; Calabretta, B

    2012-04-01

    Expression of c-Myb is required for normal hematopoiesis and for proliferation of myeloid leukemia blasts and a subset of T-cell leukemia, but its role in B-cell leukemogenesis is unknown. We tested the role of c-Myb in p190(BCR/ABL)-dependent B-cell leukemia in mice transplanted with p190(BCR/ABL)-transduced marrow cells with a c-Myb allele (Myb(f/d)) and in double transgenic p190(BCR/ABL)/Myb(w/d) mice. In both models, loss of a c-Myb allele caused a less aggressive B-cell leukemia. In p190(BCR/ABL)-expressing human B-cell leukemia lines, knockdown of c-Myb expression suppressed proliferation and colony formation. Compared with c-Myb(w/f) cells, expression of Bmi1, a regulator of stem cell proliferation and maintenance, was decreased in pre-B cells from Myb(w/d) p190(BCR/ABL) transgenic mice. Ectopic expression of a mutant c-Myb or Bmi1 enhanced the proliferation and colony formation of Myb(w/d) p190(BCR/ABL) B-cells; by contrast, Bmi1 downregulation inhibited colony formation of p190(BCR/ABL)-expressing murine B cells and human B-cell leukemia lines. Moreover, c-Myb interacted with a segment of the human Bmi1 promoter and enhanced its activity. In blasts from 19 Ph(1) adult acute lymphoblastic leukemia patients, levels of c-Myb and Bmi1 showed a positive correlation. Together, these findings support the existence of a c-Myb-Bmi1 transcription-regulatory pathway required for p190(BCR/ABL) leukemogenesis.

  4. Flow Cytometric Immunobead Assay for Detection of BCR-ABL1 Fusion Proteins in Chronic Myleoid Leukemia: Comparison with FISH and PCR Techniques

    Science.gov (United States)

    Recchia, Anna Grazia; Caruso, Nadia; Bossio, Sabrina; Pellicanò, Mariavaleria; De Stefano, Laura; Franzese, Stefania; Palummo, Angela; Abbadessa, Vincenzo; Lucia, Eugenio; Gentile, Massimo; Vigna, Ernesto; Caracciolo, Clementina; Agostino, Antolino; Galimberti, Sara; Levato, Luciano; Stagno, Fabio; Molica, Stefano; Martino, Bruno; Vigneri, Paolo; Di Raimondo, Francesco; Morabito, Fortunato

    2015-01-01

    Chronic Myeloid Leukemia (CML) is characterized by a balanced translocation juxtaposing the Abelson (ABL) and breakpoint cluster region (BCR) genes. The resulting BCR-ABL1 oncogene leads to increased proliferation and survival of leukemic cells. Successful treatment of CML has been accompanied by steady improvements in our capacity to accurately and sensitively monitor therapy response. Currently, measurement of BCR-ABL1 mRNA transcript levels by real-time quantitative PCR (RQ-PCR) defines critical response endpoints. An antibody-based technique for BCR-ABL1 protein recognition could be an attractive alternative to RQ-PCR. To date, there have been no studies evaluating whether flow-cytometry based assays could be of clinical utility in evaluating residual disease in CML patients. Here we describe a flow-cytometry assay that detects the presence of BCR-ABL1 fusion proteins in CML lysates to determine the applicability, reliability, and specificity of this method for both diagnosis and monitoring of CML patients for initial response to therapy. We show that: i) CML can be properly diagnosed at onset, (ii) follow-up assessments show detectable fusion protein (i.e. relative mean fluorescent intensity, rMFI%>1) when BCR-ABL1IS transcripts are between 1–10%, and (iii) rMFI% levels predict CCyR as defined by FISH analysis. Overall, the FCBA assay is a rapid technique, fully translatable to the routine management of CML patients. PMID:26111048

  5. Flow Cytometric Immunobead Assay for Detection of BCR-ABL1 Fusion Proteins in Chronic Myleoid Leukemia: Comparison with FISH and PCR Techniques.

    Directory of Open Access Journals (Sweden)

    Anna Grazia Recchia

    Full Text Available Chronic Myeloid Leukemia (CML is characterized by a balanced translocation juxtaposing the Abelson (ABL and breakpoint cluster region (BCR genes. The resulting BCR-ABL1 oncogene leads to increased proliferation and survival of leukemic cells. Successful treatment of CML has been accompanied by steady improvements in our capacity to accurately and sensitively monitor therapy response. Currently, measurement of BCR-ABL1 mRNA transcript levels by real-time quantitative PCR (RQ-PCR defines critical response endpoints. An antibody-based technique for BCR-ABL1 protein recognition could be an attractive alternative to RQ-PCR. To date, there have been no studies evaluating whether flow-cytometry based assays could be of clinical utility in evaluating residual disease in CML patients. Here we describe a flow-cytometry assay that detects the presence of BCR-ABL1 fusion proteins in CML lysates to determine the applicability, reliability, and specificity of this method for both diagnosis and monitoring of CML patients for initial response to therapy. We show that: i CML can be properly diagnosed at onset, (ii follow-up assessments show detectable fusion protein (i.e. relative mean fluorescent intensity, rMFI%>1 when BCR-ABL1IS transcripts are between 1-10%, and (iii rMFI% levels predict CCyR as defined by FISH analysis. Overall, the FCBA assay is a rapid technique, fully translatable to the routine management of CML patients.

  6. Computational dissection of allosteric inhibition of the SH2 domain of Bcr-Abl kinase by the monobody inhibitor AS25.

    Science.gov (United States)

    Ji, Mingfei; Zheng, Guodong; Li, Xiaolong; Zhang, Zhongqin; Jv, Guanqun; Wang, Xiaowei; Wang, Jialin

    2017-06-01

    The deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein represents an attractive pharmacological target for the treatment of chronic myeloid leukemia (CML). The high affinity of monobody AS25 was designed to target the Src homology 2 (SH2) domain of Bcr-Abl, leading to allosteric inhibition of Bcr-Abl through formation of protein-protein interactions. An I164E mutation in the SH2 domain disrupts AS25 binding to the SH2 domain of Bcr-Abl. The detailed mechanisms, however, remain to be unresolved. Here, molecular dynamics (MD) simulations and binding free energy calculations were performed to explore the conformational and energetic differences between the wild-type (WT) complexes of Bcr-Abl SH2 domain and AS25 (SH2 WT -AS25) as well as the mutated complexes (SH2 I164E -AS25). The results revealed that I164E mutation not only caused an increase in the conformational flexibility of SH2-AS25 complexes, but also weakened the binding affinity of AS25 to SH2. The comparative binding modes of SH2-AS25 complexes between WT and the I164E mutant were comprehensively analyzed to unravel the disruption of hydrophobic and hydrogen bonding interactions in the interface of the SH2-AS25 complex triggered by the I164E mutation. The results obtained may help to design the next generation of higher affinity Bcr-Abl SH2-specific peptide inhibitors.

  7. CALR, JAK2 and MPL mutation status in Argentinean patients with BCR-ABL1- negative myeloproliferative neoplasms.

    Science.gov (United States)

    Ojeda, Mara Jorgelina; Bragós, Irma Margarita; Calvo, Karina Lucrecia; Williams, Gladis Marcela; Carbonell, María Magdalena; Pratti, Arianna Flavia

    2018-05-01

    To establish the frequency of JAK2, MPL and CALR mutations in Argentinean patients with BCR-ABL1-negative  myeloproliferative neoplasms (MPN) and to compare their clinical and haematological features. Mutations of JAK2V617F, JAK2 exon 12, MPL W515L/K and CALR were analysed in 439 Argentinean patients with BCR-ABL1-negative MPN, including 176 polycythemia vera (PV), 214 essential thrombocythemia (ET) and 49 primary myelofibrosis (PMF). In 94.9% of PV, 85.5% ET and 85.2% PMF, we found mutations in JAK2, MPL or CALR. 74.9% carried JAK2V617F, 12.3% CALR mutations, 2.1% MPL mutations and 10.7% were triple negative. In ET, nine types of CALR mutations were identified, four of which were novel. PMF patients were limited to types 1 and 2, type 2 being more frequent. In ET, patients with CALR mutation were younger and had higher platelet counts than those with JAK2V617F and triple negative. In addition, JAK2V617F patients had high leucocyte and haemoglobin values compared with CALR-mutated and triple-negative patients. In PMF, patients with mutant CALR were associated with higher platelet counts. Our study underscores the importance of JAK2, MPL and CALR genotyping for accurate diagnosis of patients with BCR-ABL1-negative MPN.

  8. Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Tianjun; Commodore, Lois; Huang, Wei-Sheng; Wang, Yihan; Thomas, Mathew; Keats, Jeff; Xu, Qihong; Rivera, Victor M.; Shakespeare, William C.; Clackson, Tim; Dalgarno, David C.; Zhu, Xiaotian (ARIAD)

    2012-01-20

    The BCR-ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation-resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR-ABL, including T315I, acting as a pan-BCR-ABL inhibitor. Here, we undertook a combined crystallographic and structure-activity relationship analysis on ponatinib to understand this unique profile. While the ethynyl linker is a key inhibitor functionality that interacts with the gatekeeper, virtually all other components of ponatinib play an essential role in its T315I inhibitory activity. The extensive network of optimized molecular contacts found in the DFG-out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations. The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues.

  9. Combined Targeting of BCL-2 and BCR-ABL Tyrosine Kinase Eradicates Chronic Myeloid Leukemia Stem Cells

    Science.gov (United States)

    Mak, Po Yee; Mu, Hong; Zhou, Hongsheng; Mak, Duncan H.; Schober, Wendy; Leverson, Joel D.; Zhang, Bin; Bhatia, Ravi; Huang, Xuelin; Cortes, Jorge; Kantarjian, Hagop; Konopleva, Marina

    2016-01-01

    BCR-ABL tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML), but they rarely eliminate CML stem cells. Disease relapse is common upon therapy cessation, even in patients with complete molecular responses. Furthermore, once CML progresses to blast crisis (BC), treatment outcomes are dismal. We hypothesized that concomitant targeting of BCL-2 and BCR-ABL tyrosine kinase could overcome these limitations. We demonstrate increased BCL-2 expression at the protein level in bone marrow cells, particularly in Lin−Sca-1+cKit+ cells of inducible CML in mice as determined by CyTOF mass cytometry. Further, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly decreased leukemic Lin−Sca-1+cKit+ cell numbers and long-term stem cell frequency, and prolonged survival in a murine CML model. Additionally, this combination effectively eradicated CD34+CD38−, CD34+CD38+, and quiescent stem/progenitor CD34+ cells from BC CML patient samples. Our results suggest that BCL-2 is a key survival factor for CML stem/progenitor cells and that combined inhibition of BCL-2 and BCR-ABL tyrosine kinase has the potential to significantly improve depth of response and cure rates of chronic phase and BC CML. PMID:27605552

  10. Localization of preferential sites of rearrangement within the BCR gene in Philadelphia chromosome-positive acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Denny, C.T.; Shah, N.P.; Ogden, S.; Willman, C.; McConnell, T.; Crist, W.; Carroll, A.; Witte, O.N.

    1989-01-01

    The Philadelphia chromosome associated with acute lymphoblastic leukemia (ALL) has been linked to a hybrid BCR/ABL protein product that differs from that found in chronic myelogenous leukemia. This implies that the molecular structures of the two chromosomal translocations also differ. Localization of translocation breakpoints in Philadelphia chromosome-positive ALL has been impeded due to the only partial characterization of the BCR locus. The authors have isolated the entire 130-kilobase BCR genomic locus from a human cosmid library. They have demonstrated that these breakpoints are all located at the 3' end of the intron around an unusual restriction fragment length polymorphism caused by deletion of a 1-kilobase fragment containing Alu family reiterated sequences. This clustering is unexpected in light of previous theories of rearrangement in Philadelphia chromosome-positive chronic myelogenous leukemia that would have predicted a random dispersion of breakpoints in the first intron in Philadelphia chromosome-positive ALL. The proximity of the translocation breakpoints to this constitutive deletion may indicate shared mechanisms of rearrangement or that such polymorphisms mark areas of the genome prone to recombination

  11. Arsenic Mobility and Availability in Sediments by Application of BCR Sequential Extractions Method

    International Nuclear Information System (INIS)

    Larios, R.; Fernandez, R.; Rucandio, M. I.

    2011-01-01

    Arsenic is a metalloid found in nature, both naturally and due to anthropogenic activities. Among them, mining works are an important source of arsenic release to the environment. Asturias is a region where important mercury mines were exploited, and in them arsenic occurs in para genesis with mercury minerals. The toxicity and mobility of this element depends on the chemical species it is found. Fractionation studies are required to analyze the mobility of this metalloid in soils and sediments. Among them, the proposed by the Bureau Community of Reference (BCR) is one of the most employed. This method attempts to divide up, by operationally defined stages, the amount of this element associated with carbonates (fraction 1), iron and manganese oxy hydroxides (fraction 2), organic matter and sulphides (fraction 3), and finally as the amount associated residual fraction to primary and secondary minerals, that is, from the most labile fractions to the most refractory ones. Fractionation of arsenic in sediments from two mines in Asturias were studied, La Soterrana and Los Rueldos. Sediments from La Soterrana showed high levels of arsenic in the non-residual phases, indicating that the majority of arsenic has an anthropogenic origin. By contrast, in sediments from Los Rueldos most of the arsenic is concentrated in the residual phase, indicating that this element remains bound to very refractory primary minerals, as is also demonstrated by the strong correlation of arsenic fractionation and the fractionation of elements present in refractory minerals, such as iron, aluminum and titanium. (Author) 51 refs.

  12. Overcoming Bcr-Abl T315I mutation by combination of GNF-2 and ATP competitors in an Abl-independent mechanism

    International Nuclear Information System (INIS)

    Khateb, Mamduh; Ruimi, Nili; Khamisie, Hazem; Najajreh, Yousef; Mian, Afsar; Metodieva, Anna; Ruthardt, Martin; Mahajna, Jamal

    2012-01-01

    Philadelphia positive leukemias are characterized by the presence of Bcr-Abl fusion protein which exhibits an abnormal kinase activity. Selective Abl kinase inhibitors have been successfully established for the treatment of Ph (+) leukemias. Despite high rates of clinical response, Ph (+) patients can develop resistance against these kinase inhibitors mainly due to point mutations within the Abl protein. Of special interest is the ‘gatekeeper’ T315I mutation, which confers complete resistance to Abl kinase inhibitors. Recently, GNF-2, Abl allosteric kinase inhibitor, was demonstrated to possess cellular activity against Bcr-Abl transformed cells. Similarly to Abl kinase inhibitors (AKIs), GNF-2 failed to inhibit activity of mutated Bcr-Abl carrying the T315I mutation. Ba/F3 cells harboring native or T315I mutated Bcr-Abl constructs were treated with GNF-2 and AKIs. We monitored the effect of GNF-2 with AKIs on the proliferation and clonigenicity of the different Ba/F3 cells. In addition, we monitored the auto-phosphorylation activity of Bcr-Abl and JAK2 in cells treated with GNF-2 and AKIs. In this study, we report a cooperation between AKIs and GNF-2 in inhibiting proliferation and clonigenicity of Ba/F3 cells carrying T315I mutated Bcr-Abl. Interestingly, cooperation was most evident between Dasatinib and GNF-2. Furthermore, we showed that GNF-2 was moderately active in inhibiting the activity of JAK2 kinase, and presence of AKIs augmented GNF-2 activity. Our data illustrated the ability of allosteric inhibitors such as GNF-2 to cooperate with AKIs to overcome T315I mutation by Bcr-Abl-independent mechanisms, providing a possibility of enhancing AKIs efficacy and overcoming resistance in Ph+ leukemia cells

  13. Bach2 regulates aberrant activation of B cell in systemic lupus erythematosus and can be negatively regulated by BCR-ABL/PI3K.

    Science.gov (United States)

    Zhu, Zhengwei; Yang, Chao; Wen, Leilei; Liu, Lu; Zuo, Xianbo; Zhou, Fusheng; Gao, Jinping; Zheng, Xiaodong; Shi, Yinjuan; Zhu, Caihong; Liang, Bo; Yin, Xianyong; Wang, Wenjun; Cheng, Hui; Shen, Songke; Tang, Xianfa; Tang, Huayang; Sun, Liangdan; Zhang, Anping; Yang, Sen; Cui, Yong; Zhang, Xuejun; Sheng, Yujun

    2018-04-01

    This study was aimed to explore the effect of Bach2 on B cells in systemic lupus erythematosus (SLE), as well as the underlying mechanisms. Expression of Bach2, phosphorylated-Bach2 (p-Bach2), Akt, p-Akt and BCR-ABL (p210) in B cells isolated from SLE patients and the healthy persons were assessed by Western blot. Immunofluorescence staining was performed to assess the localization of Bach2 in B cells. Enzyme-linked immunosorbent assay (ELISA) was employed to detect IgG produced by B cells. Cell counting kit-8 (CCK-8) and Annexin-V FITC/PI double staining assay were adopted to evaluate cell proliferation and apoptosis in B cells, respectively. Compared to the healthy controls, Bach2, p-Akt and p210 were significantly decreased, while nuclear translocation of Bach2, IgG, CD40 and CD86 obviously up-regulated in B cells from SLE patients. Bach2 significantly inhibited the proliferation, promoted apoptosis of B cells from SLE patients, whereas BCR-ABL dramatically reversed cell changes induced by Bach2. Besides, BCR-ABL also inhibited nuclear translocation of Bach2 in B cells from SLE patients. Further, LY294002 treatment had no effect on decreased expression of Bach2 induced by BCR-ABL, but significantly eliminated BCR-ABL-induced phosphorylation of Bach2 and restored reduced nuclear translocation of Bach2 induced by BCR-ABL in B cells from SLE. Bach2 may play a suppressive role in B cells from SLE, and BCR-ABL may inhibit the nuclear translocation of Bach2 via serine phosphorylation through the PI3K pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Modeling of molecular interaction between apoptin, BCR-Abl and CrkL--an alternative approach to conventional rational drug design.

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    Soumya Panigrahi

    Full Text Available In this study we have calculated a 3D structure of apoptin and through modeling and docking approaches, we show its interaction with Bcr-Abl oncoprotein and its downstream signaling components, following which we confirm some of the newly-found interactions by biochemical methods. Bcr-Abl oncoprotein is aberrantly expressed in chronic myelogenous leukaemia (CML. It has several distinct functional domains in addition to the Abl kinase domain. The SH3 and SH2 domains cooperatively play important roles in autoinhibiting its kinase activity. Adapter molecules such as Grb2 and CrkL interact with proline-rich region and activate multiple Bcr-Abl downstream signaling pathways that contribute to growth and survival. Therefore, the oncogenic effect of Bcr-Abl could be inhibited by the interaction of small molecules with these domains. Apoptin is a viral protein with well-documented cancer-selective cytotoxicity. Apoptin attributes such as SH2-like sequence similarity with CrkL SH2 domain, unique SH3 domain binding sequence, presence of proline-rich segments, and its nuclear affinity render the molecule capable of interaction with Bcr-Abl. Despite almost two decades of research, the mode of apoptin's action remains elusive because 3D structure of apoptin is unavailable. We performed in silico three-dimensional modeling of apoptin, molecular docking experiments between apoptin model and the known structure of Bcr-Abl, and the 3D structures of SH2 domains of CrkL and Bcr-Abl. We also biochemically validated some of the interactions that were first predicted in silico. This structure-property relationship of apoptin may help in unlocking its cancer-selective toxic properties. Moreover, such models will guide us in developing of a new class of potent apoptin-like molecules with greater selectivity and potency.

  15. Differential regulation of the Rac1 GTPase-activating protein (GAP) BCR during oxygen/glucose deprivation in hippocampal and cortical neurons.

    Science.gov (United States)

    Smith, Katharine R; Rajgor, Dipen; Hanley, Jonathan G

    2017-12-08

    Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate. Excessive activation of glutamate receptors causes excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts, but the mechanisms that underlie this difference are unclear. Signaling via Rho-family small GTPases, their upstream guanine nucleotide exchange factors, and GTPase-activating proteins (GAPs) is differentially dysregulated in response to OGD/ischemia in hippocampal and cortical neurons. Increased Rac1 activity caused by OGD/ischemia contributes to neuronal death in hippocampal neurons via diverse effects on NADPH oxidase activity and dendritic spine morphology. The Rac1 guanine nucleotide exchange factor Tiam1 mediates an OGD-induced increase in Rac1 activity in hippocampal neurons; however, the identity of an antagonistic GAP remains elusive. Here we show that the Rac1 GAP breakpoint cluster region (BCR) associates with NMDA receptors (NMDARs) along with Tiam1 and that this protein complex is more abundant in hippocampal compared with cortical neurons. Although total BCR is similar in the two neuronal types, BCR is more active in hippocampal compared with cortical neurons. OGD causes an NMDAR- and Ca 2+ -permeable AMPAR-dependent deactivation of BCR in hippocampal but not cortical neurons. BCR knockdown occludes OGD-induced Rac1 activation in hippocampal neurons. Furthermore, disrupting the Tiam1-NMDAR interaction with a fragment of Tiam1 blocks OGD-induced Tiam1 activation but has no effect on the deactivation of BCR. This work identifies BCR as a critical player in Rac1 regulation during OGD in hippocampal neurons. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway.

    Science.gov (United States)

    Tauchi, T; Boswell, H S; Leibowitz, D; Broxmeyer, H E

    1994-01-01

    Enforced expression of p210bcr-abl transforms interleukin 3 (IL-3)-dependent hematopoietic cell lines to growth factor-independent proliferation. It has been demonstrated that nonreceptor tyrosine kinase oncogenes may couple to the p21ras pathway to exert their transforming effect. In particular, p210bcr-abl was recently found to effect p21ras activation in hematopoietic cells. In this context, experiments were performed to evaluate a protein signaling pathway by which p210bcr-abl might regulate p21ras. It was asked whether Shc p46/p52, a protein containing a src-homology region 2 (SH2) domain, and known to function upstream from p21ras, might form specific complexes with p210bcr-abl and thus, possibly alter p21ras activity by coupling to the guanine nucleotide exchange factor (Sos/CDC25) through the Grb2 protein-Sos complex. This latter complex has been previously demonstrated to occur ubiquitously. We found that p210bcr-abl formed a specific complex with Shc and with Grb2 in three different murine cell lines transfected with a p210bcr-abl expression vector. There appeared to be a higher order complex containing Shc, Grb2, and bcr-abl proteins. In contrast to p210bcr-abl transformed cells, in which there was constitutive tight association between Grb2 and Shc, binding between Grb2 and Shc was Steel factor (SLF)-dependent in a SLF-responsive, nontransformed parental cell line. The SLF-dependent association between Grb2 and Shc in nontransformed cells involved formation of a complex of Grb2 with c-kit receptor after SLF treatment. Thus, p210bcr-abl appears to function in a hematopoietic p21ras activation pathway to allow growth factor-independent coupling between Grb2, which exists in a complex with the guanine nucleotide exchange factor (Sos), and p21ras. Shc may not be required for Grb2-c-kit interaction, because it fails to bind strongly to c-kit.

  17. Frequency of p190 and p210 BCR-ABL rearrangements and survival in Brazilian adult patients with acute lymphoblastic leukemia

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    Ilana de França Azevedo

    2014-10-01

    Full Text Available Objective: This study investigated the occurrence of the p190 and p210 break point clusterregion-Abelson (BCR-ABL rearrangements in adults with acute lymphoblastic leukemia and possible associations with clinical and laboratory characteristics and survival. Methods: Forty-one over 18-year-old patients with acute lymphoblastic leukemia of both genders followed-up between January 2008 and May 2012 were included in this study. Clinical and laboratory data were obtained from the medical charts of the patients. Reverse transcription polymerase chain reaction (RT-PCR using specific primers was employed to identify molecular rearrangements. Results: At diagnosis, the median age was 33 years, and there was a predominance of males (61%. The most common immunophenotype was B lineage (76%. BCR-ABL rearrangements was detected in 14 (34% patients with the following distribution: p190 (28%, p210 (50% and double positive (22%. Overall survival of patients with a mean/median of 331/246 days of follow up was 39%, respectively, negative BCR-ABL (44% and positive BCR-ABL (28%. Conclusion: These results confirm the high frequency of BCR-ABL rearrangements and the low survival rate of adult Brazilian patients with acute lymphoblastic leukemia.

  18. Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

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    P. Balsas

    2017-03-01

    Full Text Available Abstract Background Pharmacological inhibition of B cell receptor (BCR signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk and spleen tyrosine kinase (Syk inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. Methods We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn, in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma. Results IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest. Conclusions These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.

  19. The Prevalence of JAK2, MPL, and CALR Mutations in Chinese Patients With BCR-ABL1-Negative Myeloproliferative Neoplasms.

    Science.gov (United States)

    Lin, Yani; Liu, Enbin; Sun, Qi; Ma, Jiao; Li, QingHua; Cao, Zeng; Wang, Jun; Jia, Yujiao; Zhang, Hongju; Song, Zhen; Ai, Xiaofei; Shi, Lihui; Feng, Xiaofang; Li, Chenwei; Wang, Jianxiang; Ru, Kun

    2015-07-01

    To evaluate the mutation frequency of JAK2 V617F, JAK2 exon 12, MPL exon 10, and CALR exon 9 and the value of the combined tests in the diagnosis of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). In the current study, mutations of JAK2 V617F, JAK2 exon 12, MPL exon 10, and CALR exon 9 were analyzed in 929 Chinese patients with BCR-ABL1-negative MPN, including 234 cases of polycythemia vera (PV), 428 ETs, 187 PMFs, and 80 unclassifiable MPNs (MPN-Us). Our result showed that the positive rate of any of four mutations in patients with PV, ET, PMF, and MPN-U was 89.3%, 83.4%, 87.2%, and 77.5%, respectively, which significantly improved the diagnostic rate, especially in ET and PMF. Meanwhile, we also found that the patients without any of four mutations were younger than those with one or more mutations. Unexpectedly, the coexistence of JAK2 V617F and CALR exon 9 was identified in six (0.6%) patients, and JAK2 V617F and MPL exon 10 were present simultaneously in two (0.2%) patients. In addition, we also identified several novel mutation types in CALR exon 9. The combined genetic tests of JAK2 V617F, JAK2 exon 12, MPL exon 10, and CALR exon 9 help improve the diagnostic rate for BCR-ABL1-negative MPN. Copyright© by the American Society for Clinical Pathology.

  20. Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains.

    Science.gov (United States)

    Sha, Fern; Gencer, Emel Basak; Georgeon, Sandrine; Koide, Akiko; Yasui, Norihisa; Koide, Shohei; Hantschel, Oliver

    2013-09-10

    The dysregulated tyrosine kinase BCR-ABL causes chronic myelogenous leukemia in humans and forms a large multiprotein complex that includes the Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2). The expression of SHP2 is necessary for BCR-ABL-dependent oncogenic transformation, but the precise signaling mechanisms of SHP2 are not well understood. We have developed binding proteins, termed monobodies, for the N- and C-terminal SH2 domains of SHP2. Intracellular expression followed by interactome analysis showed that the monobodies are essentially monospecific to SHP2. Two crystal structures revealed that the monobodies occupy the phosphopeptide-binding sites of the SH2 domains and thus can serve as competitors of SH2-phosphotyrosine interactions. Surprisingly, the segments of both monobodies that bind to the peptide-binding grooves run in the opposite direction to that of canonical phosphotyrosine peptides, which may contribute to their exquisite specificity. When expressed in cells, monobodies targeting the N-SH2 domain disrupted the interaction of SHP2 with its upstream activator, the Grb2-associated binder 2 adaptor protein, suggesting decoupling of SHP2 from the BCR-ABL protein complex. Inhibition of either N-SH2 or C-SH2 was sufficient to inhibit two tyrosine phosphorylation events that are critical for SHP2 catalytic activity and to block ERK activation. In contrast, targeting the N-SH2 or C-SH2 revealed distinct roles of the two SH2 domains in downstream signaling, such as the phosphorylation of paxillin and signal transducer and activator of transcription 5. Our results delineate a hierarchy of function for the SH2 domains of SHP2 and validate monobodies as potent and specific antagonists of protein-protein interactions in cancer cells.

  1. Screening und Charakterisierung von Peptidliganden für den BCR-ABL mRNA Translokationsbereich

    OpenAIRE

    Bäumler, Jörg

    2006-01-01

    Die reziproke Translokation t(9;22) ist in 95% der chronischen myeloischen Leukämie vorhanden. Bei der Translokation entsteht ein Fusionsprotein BCR-ABL, welches ausreichend für die Entstehung von Leukämien ist. 30% aller akuten lymphatischen Leukämien sind ebenfalls positiv für diese Translokation. Durch die Translokation entsteht am Translokationsbruchpunkt eine einzigartige RNA-Sequenz, welche als Ziel für eine RNA-Liganden Suche dienen kann. Ziel dieser Arbeit war es, Peptidliganden zu fi...

  2. ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

    Science.gov (United States)

    2010-05-01

    imatinib resistance with a novel ABL kinase inhibitor. Science. 2004; 305(5682):399-401 3. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob... Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid...araldehyde (5) (10 mmol), glacial acetic acid (5 mL), and a catalytic amount (100 lL ) of benzyl amine was re- fluxed for 5–8 h. After completion of

  3. The certification of the surface density (kg/m sub 2 ) of BCR CRM 038 ('fly ash from pulverised coal') comprised in methyl cellulose films simulating dust charged filters. BCR 128

    Energy Technology Data Exchange (ETDEWEB)

    Griepink, B; Marchandise, H; Colinet, E; Dams, R

    1988-01-01

    BCR CRM 38 ('Fly Ash') has been embedded in a stable methylcellulose foil of about 10{mu}m thickness. This has been done by making a slurry of fly ash and methylcellulose in water and spiking it with {sup 42}K as a radioactive tracer. The slurry was spread over glass plates and allowed to dry. 'Filters' of uniform size were punched out of the foil. The surface density (e.g. {mu}g/cm{sup 2}) of the fly ash was calculated for each individual 'filter' by comparing the {sup 42}K-activity of the filter with that of the initial suspension. The uncertainties in the so obtained surface density of random and of systematic origin have been estimated. The total relative uncertainty in the surface density of every element certified in BCR 38 is 4-6%. Studies of stability and homogeneity have revealed that this material is well suited for the verification of the results of non-destructive analytical techniques for dust components.

  4. The Role of Mitochondrial DNA Damage and Repair in the Resistance of BCR/ABL-Expressing Cells to Tyrosine Kinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Janusz Blasiak

    2013-08-01

    Full Text Available Chronic myeloid leukemia (CML is a hematological malignancy that arises from the transformation of stem hematopoietic cells by the fusion oncogene BCR/ABL and subsequent clonal expansion of BCR/ABL-positive progenitor leukemic cells. The BCR/ABL protein displays a constitutively increased tyrosine kinase activity that alters many regulatory pathways, leading to uncontrolled growth, impaired differentiation and increased resistance to apoptosis featured by leukemic cells. Current CML therapy is based on tyrosine kinase inhibitors (TKIs, primarily imatinib, which induce apoptosis in leukemic cells. However, some patients show primary resistance to TKIs while others develop it in the course of therapy. In both cases, resistance may be underlined by perturbations in apoptotic signaling in leukemic cells. As mitochondria may play an important role in such signaling, alteration in mitochondrial metabolism may change resistance to pro-apoptotic action of TKIs in BCR/ABL-positive cells. Because BCR/ABL may induce reactive oxygen species and unfaithful DNA repair, it may affect the stability of mitochondrial DNA, influencing mitochondrial apoptotic signaling and in this way change the sensitivity of CML cells to TKIs. Moreover, cancer cells, including BCR/ABL-positive cells, show an increased level of glucose metabolism, resulting from the shift from oxidative phosphorylation to glycolysis to supply ATP for extensive proliferation. Enhanced level of glycolysis may be associated with TKI resistance and requires change in the expression of several genes regulated mostly by hypoxia-inducible factor-1α, HIF-1α. Such regulation may be associated with the impaired mitochondrial respiratory system in CML cells. In summary, mitochondria and mitochondria-associated molecules and pathways may be attractive targets to overcome TKI resistance in CML.

  5. Disrupting BCR-ABL in combination with secondary leukemia-specific pathways in CML cells leads to enhanced apoptosis and decreased proliferation.

    Science.gov (United States)

    Woessner, David W; Lim, Carol S

    2013-01-07

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by expression of the fusion gene BCR-ABL following a chromosomal translocation in the hematopoietic stem cell. Therapeutic management of CML uses tyrosine kinase inhibitors (TKIs), which block ABL-signaling and effectively kill peripheral cells with BCR-ABL. However, TKIs are not curative, and chronic use is required in order to treat CML. The primary failure for TKIs is through the development of a resistant population due to mutations in the TKI binding regions. This led us to develop the mutant coiled-coil, CC(mut2), an alternative method for BCR-ABL signaling inhibition by targeting the N-terminal oligomerization domain of BCR, necessary for ABL activation. In this article, we explore additional pathways that are important for leukemic stem cell survival in K562 cells. Using a candidate-based approach, we test the combination of CC(mut2) and inhibitors of unique secondary pathways in leukemic cells. Transformative potential was reduced following silencing of the leukemic stem cell factor Alox5 by RNA interference. Furthermore, blockade of the oncogenic protein MUC-1 by the novel peptide GO-201 yielded reductions in proliferation and increased cell death. Finally, we found that inhibiting macroautophagy using chloroquine in addition to blocking BCR-ABL signaling with the CC(mut2) was most effective in limiting cell survival and proliferation. This study has elucidated possible combination therapies for CML using novel blockade of BCR-ABL and secondary leukemia-specific pathways.

  6. Early BCR-ABL1 Transcript Decline after 1 Month of Tyrosine Kinase Inhibitor Therapy as an Indicator for Treatment Response in Chronic Myeloid Leukemia.

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    Mohamed El Missiry

    Full Text Available In chronic myeloid leukemia (CML, early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5, and BCR-ABL1 transcript levels were measured at diagnosis (dg and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response. In our cohort, 21% of patients had no decrease in BCR-ABL1 transcript levels after 1 month and were classified as poor responders. Surprisingly, these patients had lower BCR-ABL1 transcript levels at dg compared to responders (31% vs. 48%, p = 0.0083. Poor responders also significantly more often had enlarged spleen (55% vs. 15%; p<0.01 and a higher percentage of Ph+ CD34+CD38- cells in the bone marrow (91% vs. 75%, p<0.05. The major molecular response rates were inferior in the poor responders (at 12m 18% vs. 64%, p<0.01; 18m 27% vs. 75%, p<0.01; 24m 55% vs. 87%, p<0.01. In conclusion, early treatment response analysis defines a biologically distinct patient subgroup with inferior long-term outcomes.

  7. Detection of a rare BCR-ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS).

    Science.gov (United States)

    Breitkopf, Susanne B; Yuan, Min; Pihan, German A; Asara, John M

    2012-10-02

    Hypothesis directed proteomics offers higher throughput over global analyses. We show that immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) in H929 multiple myeloma (MM) cancer cells led to the discovery of a rare and unexpected BCR-ABL fusion, informing a therapeutic intervention using imatinib (Gleevec). BCR-ABL is the driving mutation in chronic myeloid leukemia (CML) and is uncommon to other cancers. Three different IP-MS experiments central to cell signaling pathways were sufficient to discover a BCR-ABL fusion in H929 cells: phosphotyrosine (pY) peptide IP, p85 regulatory subunit of phosphoinositide-3-kinase (PI3K) IP, and the GRB2 adaptor IP. The pY peptides inform tyrosine kinase activity, p85 IP informs the activating adaptors and receptor tyrosine kinases (RTKs) involved in AKT activation and GRB2 IP identifies RTKs and adaptors leading to ERK activation. Integration of the bait-prey data from the three separate experiments identified the BCR-ABL protein complex, which was confirmed by biochemistry, cytogenetic methods, and DNA sequencing revealed the e14a2 fusion transcript. The tyrosine phosphatase SHP2 and the GAB2 adaptor protein, important for MAPK signaling, were common to all three IP-MS experiments. The comparative treatment of tyrosine kinase inhibitor (TKI) drugs revealed only imatinib, the standard of care in CML, was inhibitory to BCR-ABL leading to down-regulation of pERK and pS6K and inhibiting cell proliferation. These data suggest a model for directed proteomics from patient tumor samples for selecting the appropriate TKI drug(s) based on IP and LC-MS/MS. The data also suggest that MM patients, in addition to CML patients, may benefit from BCR-ABL diagnostic screening.

  8. Combining the ABL1 kinase inhibitor ponatinib and the histone deacetylase inhibitor vorinostat: a potential treatment for BCR-ABL-positive leukemia.

    Science.gov (United States)

    Okabe, Seiichi; Tauchi, Tetsuzo; Kimura, Shinya; Maekawa, Taira; Kitahara, Toshihiko; Tanaka, Yoko; Ohyashiki, Kazuma

    2014-01-01

    Resistance to imatinib (Gleevec®) in cancer cells is frequently because of acquired point mutations in the kinase domain of BCR-ABL. Ponatinib, also known as AP24534, is an oral multi-targeted tyrosine kinase inhibitor (TKI), and it has been investigated in a pivotal phase 2 clinical trial. The histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) has been evaluated for its significant clinical activity in hematological malignancies. Thus, treatments combining ABL TKIs with additional drugs may be a promising strategy in the treatment of leukemia. In the current study, we analyzed the efficacy of ponatinib and vorinostat treatment by using BCR-ABL-positive cell lines. Treatment with ponatinib for 72 h inhibited cell growth and induced apoptosis in K562 cells in a dose-dependent manner. We found that ponatinib potently inhibited the growth of Ba/F3 cells ectopically expressing BCR-ABL T315I mutation. Upon BCR-ABL phosphorylation, Crk-L was decreased, and poly (ADP-ribose) polymerase (PARP) was activated in a dose-dependent manner. Combined treatment of Ba/F3 T315I mutant cells with vorinostat and ponatinib resulted in significantly increased cytotoxicity. Additionally, the intracellular signaling of ponatinib and vorinostat was examined. Caspase 3 and PARP activation increased after combination treatment with ponatinib and vorinostat. Moreover, an increase in the phosphorylation levels of γH2A.X was observed. Previously established ponatinib-resistant Ba/F3 cells were also resistant to imatinib, nilotinib, and dasatinib. We investigated the difference in the efficacy of ponatinib and vorinostat by using ponatinib-resistant Ba/F3 cells. Combined treatment of ponatinib-resistant cells with ponatinib and vorinostat caused a significant increase in cytotoxicity. Thus, combined administration of ponatinib and vorinostat may be a powerful strategy against BCR-ABL mutant cells and could enhance the cytotoxic effects of ponatinib in those BCR

  9. BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Falchi, Lorenzo; Baron, Jessica M.; Orlikowski, Carrie Anne; Ferrajoli, Alessandra

    2016-01-01

    The B-cell receptor (BCR) signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology and clinical experience with the use of BCR signaling inhibitors for the treatment of patients with CLL. We next focus on both the most common and the most clinically significant toxicities associated with these drugs. PMID:26977270

  10. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance

    Science.gov (United States)

    Azam, Mohammad; Nardi, Valentina; Shakespeare, William C.; Metcalf, Chester A.; Bohacek, Regine S.; Wang, Yihan; Sundaramoorthi, Raji; Sliz, Piotr; Veach, Darren R.; Bornmann, William G.; Clarkson, Bayard; Dalgarno, David C.; Sawyer, Tomi K.; Daley, George Q.

    2006-01-01

    Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IMR) BCR/ABL kinase variants. Both compounds potently inhibit most IMR variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IMR-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance. PMID:16754879

  11. Bcr-aBL1 kinase domain mutation analysis in chronic myeloid leukaemia patients with suboptimal response to tyrosine kinase inhibitors

    Directory of Open Access Journals (Sweden)

    Tadej Pajič

    2012-12-01

    Conclusions: It seems that the BCR-ABl1 mutations are rare in patients who do not achieve a MMR by 18 months or more or who have lost MMR. The T315I mutation detected in one patient in our cohort of CML patients indicates that the BCR-ABL1 mutation analysis could be recommended in these cases. The silent mutation detected did not lead to amino acid change, however, it is listed in major single nucleotide polymorphisms databases (SNP, rs2227985. The role of the SNP in the resistance to TKIs is not clear.

  12. BCR CDR3 length distributions differ between blood and spleen and between old and young patients, and TCR distributions can be used to detect myelodysplastic syndrome

    International Nuclear Information System (INIS)

    Pickman, Yishai; Mehr, Ramit; Dunn-Walters, Deborah

    2013-01-01

    Complementarity-determining region 3 (CDR3) is the most hyper-variable region in B cell receptor (BCR) and T cell receptor (TCR) genes, and the most critical structure in antigen recognition and thereby in determining the fates of developing and responding lymphocytes. There are millions of different TCR Vβ chain or BCR heavy chain CDR3 sequences in human blood. Even now, when high-throughput sequencing becomes widely used, CDR3 length distributions (also called spectratypes) are still a much quicker and cheaper method of assessing repertoire diversity. However, distribution complexity and the large amount of information per sample (e.g. 32 distributions of the TCRα chain, and 24 of TCRβ) calls for the use of machine learning tools for full exploration. We have examined the ability of supervised machine learning, which uses computational models to find hidden patterns in predefined biological groups, to analyze CDR3 length distributions from various sources, and distinguish between experimental groups. We found that (a) splenic BCR CDR3 length distributions are characterized by low standard deviations and few local maxima, compared to peripheral blood distributions; (b) healthy elderly people's BCR CDR3 length distributions can be distinguished from those of the young; and (c) a machine learning model based on TCR CDR3 distribution features can detect myelodysplastic syndrome with approximately 93% accuracy. Overall, we demonstrate that using supervised machine learning methods can contribute to our understanding of lymphocyte repertoire diversity. (paper)

  13. Evolution of BCR/ABL gene mutation in CML is time dependent and dependent on the pressure exerted by tyrosine kinase inhibitor.

    Directory of Open Access Journals (Sweden)

    Shantashri Vaidya

    Full Text Available BACKGROUND: Mutations in the ABL kinase domain and SH3-SH2 domain of the BCR/ABL gene and amplification of the Philadelphia chromosome are the two important BCR/ABL dependent mechanisms of imatinib resistance. Here, we intended to study the role played by TKI, imatinib, in selection of gene mutations and development of chromosomal abnormalities in Indian CML patients. METHODS: Direct sequencing methodology was employed to detect mutations and conventional cytogenetics was done to identify Philadelphia duplication. RESULTS: Among the different mechanisms of imatinib resistance, kinase domain mutations (39% of the BCR/ABL gene were seen to be more prevalent, followed by mutations in the SH3-SH2 domain (4% and then BCR/ABL amplification with the least frequency (1%. The median duration of occurrence of mutation was significantly shorter for patients with front line imatinib than those pre-treated with hydroxyurea. Patients with high Sokal score (p = 0.003 showed significantly higher incidence of mutations, as compared to patients with low/intermediate score. Impact of mutations on the clinical outcome in AP and BC was observed to be insignificant. Of the 94 imatinib resistant patients, only 1 patient exhibited duplication of Philadelphia chromosome, suggesting a less frequent occurrence of this abnormality in Indian CML patients. CONCLUSION: Close monitoring at regular intervals and proper analysis of the disease resistance would facilitate early detection of resistance and thus aid in the selection of the most appropriate therapy.

  14. Rapid Evolution to Blast Crisis Associated with a Q252H ABL1 Kinase Domain Mutation in e19a2 BCR-ABL1 Chronic Myeloid Leukaemia

    Directory of Open Access Journals (Sweden)

    Sarah L. McCarron

    2013-01-01

    Full Text Available A minority of chronic myeloid leukaemia (CML patients express variant transcripts of which the e19a2 BCR-ABL1 fusion is the most common. Instances of tyrosine kinase inhibitor (TKI resistance in e19a2 BCR-ABL1 CML patients have rarely been reported. A case of e19a2 BCR-ABL1 CML is described in whom imatinib resistance, associated with a Q252H ABL1 kinase domain mutation, became apparent soon after initiation of TKI therapy. The patient rapidly transformed to myeloid blast crisis (BC with considerable bone marrow fibrosis and no significant molecular response to a second generation TKI. The clinical course was complicated by comorbidities with the patient rapidly succumbing to advanced disease. This scenario of Q252H-associated TKI resistance with rapid BC transformation has not been previously documented in e19a2 BCR-ABL1 CML. This case highlights the considerable challenges remaining in the management of TKI-resistant BC CML, particularly in the elderly patient.

  15. Photodynamic treatment (ALA-PDT) suppresses the expression of the oncogenic Bcr-Abl kinase and affects the cytoskeleton organization in K562 cells

    Czech Academy of Sciences Publication Activity Database

    Pluskalová, M.; Pešlová, G.; Grebeňová, D.; Halada, Petr; Hrkal, Z.

    2006-01-01

    Roč. 83, - (2006), s. 205-212 ISSN 1011-1344 R&D Projects: GA MZd NL7681 Institutional research plan: CEZ:AV0Z50200510 Keywords : k562 * bcr -abl * photodynamic treatment Subject RIV: EE - Microbiology, Virology Impact factor: 1.909, year: 2006

  16. BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells.

    Science.gov (United States)

    Guarini, Anna; Chiaretti, Sabina; Tavolaro, Simona; Maggio, Roberta; Peragine, Nadia; Citarella, Franca; Ricciardi, Maria Rosaria; Santangelo, Simona; Marinelli, Marilisa; De Propris, Maria Stefania; Messina, Monica; Mauro, Francesca Romana; Del Giudice, Ilaria; Foà, Robert

    2008-08-01

    Chronic lymphocytic leukemia (CLL) patients exhibit a variable clinical course. To investigate the association between clinicobiologic features and responsiveness of CLL cells to anti-IgM stimulation, we evaluated gene expression changes and modifications in cell-cycle distribution, proliferation, and apoptosis of IgV(H) mutated (M) and unmutated (UM) samples upon BCR cross-linking. Unsupervised analysis highlighted a different response profile to BCR stimulation between UM and M samples. Supervised analysis identified several genes modulated exclusively in the UM cases upon BCR cross-linking. Functional gene groups, including signal transduction, transcription, cell-cycle regulation, and cytoskeleton organization, were up-regulated upon stimulation in UM cases. Cell-cycle and proliferation analyses confirmed that IgM cross-linking induced a significant progression into the G(1) phase and a moderate increase of proliferative activity exclusively in UM patients. Moreover, we observed only a small reduction in the percentage of subG(0/1) cells, without changes in apoptosis, in UM cases; contrariwise, a significant increase of apoptotic levels was observed in stimulated cells from M cases. These results document that a differential genotypic and functional response to BCR ligation between IgV(H) M and UM cases is operational in CLL, indicating that response to antigenic stimulation plays a pivotal role in disease progression.

  17. BCR CDR3 length distributions differ between blood and spleen and between old and young patients, and TCR distributions can be used to detect myelodysplastic syndrome

    Science.gov (United States)

    Pickman, Yishai; Dunn-Walters, Deborah; Mehr, Ramit

    2013-10-01

    Complementarity-determining region 3 (CDR3) is the most hyper-variable region in B cell receptor (BCR) and T cell receptor (TCR) genes, and the most critical structure in antigen recognition and thereby in determining the fates of developing and responding lymphocytes. There are millions of different TCR Vβ chain or BCR heavy chain CDR3 sequences in human blood. Even now, when high-throughput sequencing becomes widely used, CDR3 length distributions (also called spectratypes) are still a much quicker and cheaper method of assessing repertoire diversity. However, distribution complexity and the large amount of information per sample (e.g. 32 distributions of the TCRα chain, and 24 of TCRβ) calls for the use of machine learning tools for full exploration. We have examined the ability of supervised machine learning, which uses computational models to find hidden patterns in predefined biological groups, to analyze CDR3 length distributions from various sources, and distinguish between experimental groups. We found that (a) splenic BCR CDR3 length distributions are characterized by low standard deviations and few local maxima, compared to peripheral blood distributions; (b) healthy elderly people's BCR CDR3 length distributions can be distinguished from those of the young; and (c) a machine learning model based on TCR CDR3 distribution features can detect myelodysplastic syndrome with approximately 93% accuracy. Overall, we demonstrate that using supervised machine learning methods can contribute to our understanding of lymphocyte repertoire diversity.

  18. Successful treatment with allogeneic stem cell transplantation followed by DLI and TKIs for e6a2 BCR-ABL-positive acute myeloid leukaemia

    Science.gov (United States)

    Harada, Yasuhiko; Nishiwaki, Satoshi; Sugimoto, Takumi; Onodera, Koichi; Goto, Tatsunori; Sato, Takahiko; Kamoshita, Sonoko; Kawashima, Naomi; Seto, Aika; Okuno, Shingo; Yamamoto, Satomi; Iwasaki, Toshihiro; Ozawa, Yukiyasu; Miyamura, Koichi; Akatsuka, Yoshiki; Sugiura, Isamu

    2017-01-01

    Abstract Rationale: Patients with the e6a2 BCR-ABL transcript, 1 of the atypical transcripts, have been reported to have a poor prognosis, and allogeneic stem cell transplantation (ASCT) can be considered as additional therapy. However, long-term survival after ASCT for this disease is rare. Patient concerns: This report concerns a 55-year-old female patient with e6a2 BCR-ABL-positive acute myeloid leukemia including the outcome of ASCT followed by donor lymphocyte infusion (DLI). Diagnoses: The breakpoint was confirmed by direct sequencing. Her minimal residual disease could be detected by nested reverse-transcription polymerase chain reaction using primers for the minor BCR-ABL (e1a2) transcript. Interventions: Treatment with tyrosine kinase inhibitors (TKIs) and ASCT followed by DLI. Outcomes: Despite multiple cytogenetic and molecular relapses after ASCT, she remains in molecular remission at 46 months after ASCT. Lessons: This case indicates the efficacy of the combination of the graft-versus-leukemia effect and TKIs for e6a2 BCR-ABL-positive acute leukemia. When the Philadelphia chromosome with an unusual chromosomal breakpoint is suggested, we should clarify the breakpoint because that information can aid molecular assessments and decisions to provide an additional or alternative therapy. PMID:29390324

  19. Sr and Pb isotopic composition of five USGS glasses (BHVO-2G, BIR-1G, BCR-2G, TB-1G, NKT-1G)

    NARCIS (Netherlands)

    Elburg, M.A.; Vroon, P.Z.; van der Wagt, R.A.C.A.; Tchalikian, A.

    2005-01-01

    Sr isotopic compositions and Rb/Sr ratios of three USGS glasses (BHVO-2G, BIR-1G, BCR-2G) are identical to those of the original USGS reference materials. NKT-1G and TB-1G give values of 0.70351 and 0.70558, respectively. Pb isotopic ratios were measured by the standard-sample bracketing technique

  20. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

    Directory of Open Access Journals (Sweden)

    Zafar Iqbal

    Full Text Available BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48, all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid

  1. Participation in BCR - certifications by the Laboratory of Analytical Chemistry, Institute for Nuclear Sciences, University of Gent, Belgium

    International Nuclear Information System (INIS)

    Cornelis, R.; Dyg, S.; Dams, R.; Griepink, B.

    1990-01-01

    During the last decade the Laboratory of Analytical Chemistry assisted in the certification of 31 environmental and food reference materials issued by the BCR (Bureau of Reference Materials of the European Communities). The efforts spent can be translated into the following statistics: the 10 most frequently certified elements assisted by the Gent Laboratory are As, Cd, Co, Cu, Fe, Hg, Mn, Pb, Se and Zn. They cover 70% of the certification work. The Gent Laboratory cooperated in 74% of the latter. There are 21 more major and trace elements certified, some in a single product only. Activation analysis was the main analytical technique applied by the Gent Laboratory. In many instances radiochemical separations were involved. (orig.)

  2. Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells.

    Science.gov (United States)

    Li, Qianyin; Huang, Zhenglan; Gao, Miao; Cao, Weixi; Xiao, Qin; Luo, Hongwei; Feng, Wenli

    2017-03-02

    The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance.

  3. Identification of Genes Upregulated by the Transcription Factor Bcr1 That Are Involved in Impermeability, Impenetrability, and Drug Resistance of Candida albicans a/α Biofilms

    Science.gov (United States)

    Srikantha, Thyagarajan; Daniels, Karla J.; Pujol, Claude; Kim, Elena

    2013-01-01

    Candida albicans forms two types of biofilm, depending upon the configuration of the mating type locus. Although architecturally similar, a/α biofilms are impermeable, impenetrable, and drug resistant, whereas a/a and α/α biofilms lack these traits. The difference appears to be the result of an alternative matrix. Overexpression in a/a cells of BCR1, a master regulator of the a/α matrix, conferred impermeability, impenetrability, and drug resistance to a/a biofilms. Deletion of BCR1 in a/α cells resulted in the loss of these a/α-specific biofilm traits. Using BCR1 overexpression in a/a cells, we screened 107 genes of interest and identified 8 that were upregulated by Bcr1. When each was overexpressed in a/a biofilms, the three a/α traits were partially conferred, and when each was deleted in a/α cells, the traits were partially lost. Five of the eight genes have been implicated in iron homeostasis, and six encode proteins that are either in the wall or plasma membrane or secreted. All six possess sites for O-linked and N-linked glycosylation that, like glycosylphosphatidylinositol (GPI) anchors, can cross-link to the wall and matrix, suggesting that they may exert a structural role in conferring impermeability, impenetrability, and drug resistance, in addition to their physiological functions. The fact that in a screen of 107 genes, all 8 of the Bcr1-upregulated genes identified play a role in impermeability, impenetrability, and drug resistance suggests that the formation of the a/α matrix is highly complex and involves a larger number of genes than the initial ones identified here. PMID:23563485

  4. Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Qianyin Li

    2017-03-01

    Full Text Available The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML. The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag, HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK and signal transducer and activator of transcription 5 (STAT5 pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI-resistance.

  5. Fractionation of metals by sequential extraction procedures (BCR and Tessier) in soil exposed to fire of wide temperature range

    Science.gov (United States)

    Fajkovic, Hana; Rončević, Sanda; Nemet, Ivan; Prohić, Esad; Leontić-Vazdar, Dana

    2017-04-01

    Forest fire presents serious problem, especially in Mediterranean Region. Effects of fire are numerous, from climate change and deforestation to loss of soil organic matter and changes in soil properties. One of the effects, not well documented, is possible redistribution and/or remobilisation of pollutants previously deposited in the soil, due to the new physical and chemical soil properties and changes in equilibrium conditions. For understanding and predicting possible redistribution and/or remobilisation of potential pollutants from soil, affected by fire different in temperature, several laboratory investigations were carried out. To evaluate the influence of organic matter on soil under fire, three soil samples were analysed and compared: (a) the one with added coniferous organic matter; (b) deciduous organic matter (b) and (c) soil without additional organic matter. Type of organic matter is closely related to pH of soil, as pH is influencing the mobility of some pollutants, e.g. metals. For that reason pH was also measured through all experimental steps. Each of mentioned soil samples (a, b and c) were heated at 1+3 different temperatures (25°C, 200°C, 500°C and 850°C). After heating, whereby fire effect on soil was simulated, samples were analysed by BCR protocol with the addition of a first step of sequential extraction procedure by Tessier and analysis of residual by aqua regia. Element fractionation of heavy metals by this procedure was used to determine the amounts of selected elements (Al, Cd, Cr, Co, Cu, Fe, Mn, Ni, Pb and Zn). Selected metal concentrations were determined using inductively coupled plasma atomic emission spectrometer. Further on, loss of organic matter was calculated after each heating procedure as well as the mineral composition. The mineral composition was determined using an X-ray diffraction. From obtained results, it can be concluded that temperature has an influence on concentration of elements in specific step of

  6. Genetic polymorphisms of hemostatic factors and thrombotic risk in non BCR-ABL myeloproliferative neoplasms: A pilot study

    Directory of Open Access Journals (Sweden)

    Dambrauskienė R

    2017-06-01

    Full Text Available The most important complications of Philadelphianegagive (non BCR-ABL myeloproliferative neoplasms (MPNs are vascular events. Our aim was to evaluate the effects of single nucleotide polymorphisms (SNPs, platelet glycoproteins (GPs (Ia/IIa, Ibα, IIb/IIIa and VI, von Willebrand factor (vWF, coagulation factor VII (FVII, β-fibrinogen, and the risk of thrombosis in patients with non BCR-ABL MPNs at the Lithuanian University of Health Sciences. Kaunas, Lithuania. Genotyping was done for 108 patients. The TT genotype of the GP Ia/IIa c.807C>T polymorphism was more frequently found in the group of MPN patients with arterial thrombosis compared to MPN patients who were thrombosis-free [26.5 vs. 11.5%, p = 0.049; odds ratio (OR 2.68; 95% confidence interval (95% CI 1.01-7.38]. The CT genotype of the β-fibrinogen c.-148C>T polymorphism occurred more frequently in MPN patients with arterial, and total thrombosis compared to the wild or homozygous genotype (57.7 vs. 40.0 vs. 12.5%; p = 0.027, (64.7 vs. 44.4 vs. 25%; p = 0.032, respectively. The carrier state for the c.-323P10 variant of FVII SNP (summation of P10/10 and P0/10 was more frequent in MPN patients with thrombosis compared to the wild-type genotype carriers (71.4 vs. 43.4%; p = 0.049; OR 3.26; 95% CI 1.01-11.31. The coexistence of heterozygous β-fibrinogen c.-148C>T and FVII c.-323P0/10 SNP, increased the risk of arterial thrombosis (21.1 vs. 3.7%, p = 0.008; OR 6.93; 95% CI 1.38-34.80. The TT genotype of GP Ia/IIa c.807C>T, the CT genotype of β-fibrinogen c.-148C>T and FVII c.-323P0/10 SNP could be associated with risk of thrombosis in MPN patients.

  7. Concomitant BCR-ABL1 positive chronic myelogenous leukemia emerging in a patient with MPL W515L associated primary myelofibrosis

    Directory of Open Access Journals (Sweden)

    Juan C. Gomez-Gelvez, MD

    2016-03-01

    Full Text Available Myeloproliferative neoplasms (MPNs are clonal hematopoietic stem cell disorders characterized by proliferation of one or more cell lineages in the bone marrow. At present, the main criterion in the 2008 World Health Organization classification of MPNs is the presence of an underlying genetic abnormality. These mutations are generally mutually exclusive except for rare reports in the literature. We report for the first time a detailed analysis of the clinical, histologic and cytogenetic/molecular features of a patient who initially presented with MPL W515L positive primary myelofibrosis and over the course of five years developed an MPN associated with both BCR-ABL1 and MPL W515L mutation. We discuss the diagnostic challenges and therapeutic implications of concomitant BCR-ABL1 translocation with MPL W515L mutation. Multiple genetic alterations may simultaneously coexist in patients exhibiting features of myeloproliferative disorders.

  8. Conventional and fluorescence in situ hybridization analysis of three-way complex BCR-ABL rearrangement in a chronic myeloid leukemia patient

    Directory of Open Access Journals (Sweden)

    Ganguly Bani

    2007-01-01

    Full Text Available Chromosomal analysis was carried out in bone marrow sample of an 11-year-old girl suspected of myeloproliferative disorder. Conventional G-banding study detected a complex three-way translocation involving 7, 9 and 22, which has resulted in the formation of a variant Philadelphia chromosome causing rearrangement of abl and bcr genes in 87% cells. Fluorescence in situ hybridization (FISH confirmed the fusion of bcr-abl oncogene. Thus the bone marrow karyotype was observed as 46,XX (13% / 46,XX,t(7;9;22(q11;q34;q11 (87%. Hyperdiploidy was present in two cells. In this study, both conventional cytogenetic and FISH diagnosis proved to be significant to identify the variant nature of the Philadelphia chromosome and hyperdiploid condition for introduction of a suitable treatment regimen and estimation of life expectancy of the young girl.

  9. Arsenic Mobility and Availability in Sediments by Application of BCR Sequential Extractions Method; Movilidad y Disponibilidad de Arsenico en Sedimentos Mediante la Aplicacion del Metodo de Extracciones Secuenciales BCR

    Energy Technology Data Exchange (ETDEWEB)

    Larios, R.; Fernandez, R.; Rucandio, M. I.

    2011-05-13

    Arsenic is a metalloid found in nature, both naturally and due to anthropogenic activities. Among them, mining works are an important source of arsenic release to the environment. Asturias is a region where important mercury mines were exploited, and in them arsenic occurs in para genesis with mercury minerals. The toxicity and mobility of this element depends on the chemical species it is found. Fractionation studies are required to analyze the mobility of this metalloid in soils and sediments. Among them, the proposed by the Bureau Community of Reference (BCR) is one of the most employed. This method attempts to divide up, by operationally defined stages, the amount of this element associated with carbonates (fraction 1), iron and manganese oxy hydroxides (fraction 2), organic matter and sulphides (fraction 3), and finally as the amount associated residual fraction to primary and secondary minerals, that is, from the most labile fractions to the most refractory ones. Fractionation of arsenic in sediments from two mines in Asturias were studied, La Soterrana and Los Rueldos. Sediments from La Soterrana showed high levels of arsenic in the non-residual phases, indicating that the majority of arsenic has an anthropogenic origin. By contrast, in sediments from Los Rueldos most of the arsenic is concentrated in the residual phase, indicating that this element remains bound to very refractory primary minerals, as is also demonstrated by the strong correlation of arsenic fractionation and the fractionation of elements present in refractory minerals, such as iron, aluminum and titanium. (Author) 51 refs.

  10. The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL.

    Science.gov (United States)

    Ru, Yi; Wang, Qinhao; Liu, Xiping; Zhang, Mei; Zhong, Daixing; Ye, Mingxiang; Li, Yuanchun; Han, Hua; Yao, Libo; Li, Xia

    2016-06-22

    Chronic myeloid leukemia (CML) is characterized by constitutively active fusion protein tyrosine kinase BCR-ABL. Although the tyrosine kinase inhibitor (TKI) against BCR-ABL, imatinib, is the first-line therapy for CML, acquired resistance almost inevitably emerges. The underlying mechanism are point mutations within the BCR-ABL gene, among which T315I is notorious because it resists to almost all currently available inhibitors. Here we took use of a previously generated chimeric ubiquitin ligase, SH2-U-box, in which SH2 from the adaptor protein Grb2 acts as a binding domain for activated BCR-ABL, while U-box from CHIP functions as an E3 ubiquitin ligase domain, so as to target the ubiquitination and degradation of both native and T315I-mutant BCR-ABL. As such, SH2-U-box significantly inhibited proliferation and induced apoptosis in CML cells harboring either the wild-type or T315I-mutant BCR-ABL (K562 or K562R), with BCR-ABL-dependent signaling pathways being repressed. Moreover, SH2-U-box worked in concert with imatinib in K562 cells. Importantly, SH2-U-box-carrying lentivirus could markedly suppress the growth of K562-xenografts in nude mice or K562R-xenografts in SCID mice, as well as that of primary CML cells. Collectively, by degrading the native and T315I-mutant BCR-ABL, the chimeric ubiquitin ligase SH2-U-box may serve as a potential therapy for both imatinib-sensitive and resistant CML.

  11. Voltammetric behaviour at gold electrodes immersed in the BCR sequential extraction scheme media Application of underpotential deposition-stripping voltammetry to determination of copper in soil extracts

    Energy Technology Data Exchange (ETDEWEB)

    Beni, Valerio; Newton, Hazel V.; Arrigan, Damien W.M.; Hill, Martin; Lane, William A.; Mathewson, Alan

    2004-01-30

    The development of mercury-free electroanalytical systems for in-field analysis of pollutants requires a foundation on the electrochemical behaviour of the chosen electrode material in the target sample matrices. In this work, the behaviour of gold working electrodes in the media employed in the BCR sequential extraction protocol, for the fractionation of metals in solid environmental matrices, is reported. All three of the BCR sequential extraction media are redox active, on the basis of acidity and oxygen content as well as the inherent reducing or oxidising nature of some of the reagents employed: 0.11 M acetic acid, 0.1 M hydroxylammonium chloride (adjusted to pH 2) and 1 M ammonium acetate (adjusted to pH 2) with added trace hydrogen peroxide. The available potential ranges together with the demonstrated detection of target metals in these media are presented. Stripping voltammetry of copper or lead in the BCR extract media solutions reveal a multi-peak behaviour due to the stripping of both bulk metal and underpotential metal deposits. A procedure based on underpotential deposition-stripping voltammetry (UPD-SV) was evaluated for application to determination of copper in 0.11 M acetic acid soil extracts. A preliminary screening step in which different deposition times are applied to the sample enables a deposition time commensurate with UPD-SV to be selected so that no bulk deposition or stripping occurs thus simplifying the shape and features of the resulting voltammograms. Choice of the suitable deposition time is then followed by standards addition calibration. The method was validated by the analysis of a number of BCR 0.11 M acetic acid soil extracts. Good agreement was obtained been the UPD-SV method and atomic spectroscopic results.

  12. Voltammetric behaviour at gold electrodes immersed in the BCR sequential extraction scheme media Application of underpotential deposition-stripping voltammetry to determination of copper in soil extracts

    International Nuclear Information System (INIS)

    Beni, Valerio; Newton, Hazel V.; Arrigan, Damien W.M.; Hill, Martin; Lane, William A.; Mathewson, Alan

    2004-01-01

    The development of mercury-free electroanalytical systems for in-field analysis of pollutants requires a foundation on the electrochemical behaviour of the chosen electrode material in the target sample matrices. In this work, the behaviour of gold working electrodes in the media employed in the BCR sequential extraction protocol, for the fractionation of metals in solid environmental matrices, is reported. All three of the BCR sequential extraction media are redox active, on the basis of acidity and oxygen content as well as the inherent reducing or oxidising nature of some of the reagents employed: 0.11 M acetic acid, 0.1 M hydroxylammonium chloride (adjusted to pH 2) and 1 M ammonium acetate (adjusted to pH 2) with added trace hydrogen peroxide. The available potential ranges together with the demonstrated detection of target metals in these media are presented. Stripping voltammetry of copper or lead in the BCR extract media solutions reveal a multi-peak behaviour due to the stripping of both bulk metal and underpotential metal deposits. A procedure based on underpotential deposition-stripping voltammetry (UPD-SV) was evaluated for application to determination of copper in 0.11 M acetic acid soil extracts. A preliminary screening step in which different deposition times are applied to the sample enables a deposition time commensurate with UPD-SV to be selected so that no bulk deposition or stripping occurs thus simplifying the shape and features of the resulting voltammograms. Choice of the suitable deposition time is then followed by standards addition calibration. The method was validated by the analysis of a number of BCR 0.11 M acetic acid soil extracts. Good agreement was obtained been the UPD-SV method and atomic spectroscopic results

  13. Contribution of nuclear analysis methods to the certification of BCR reference materials for non-metals in non-ferrous metals

    International Nuclear Information System (INIS)

    Pauwels, J.

    1979-01-01

    A number of reference materials for oxygen in different non-ferrous metals have been certified by BCR in the frame of a multidisciplinary Community project. The contribution of nuclear analysis methods is illustrated by several examples concerning the optimization of sample preparation techniques, the analysis of low and high oxygen non-ferrous metals and the extension of the program to other non-metals, especially nitrogen and carbon. (author)

  14. Fractionation of metals in street sediment samples by using the BCR sequential extraction procedure and multivariate statistical elucidation of the data

    International Nuclear Information System (INIS)

    Kartal, Senol; Aydin, Zeki; Tokalioglu, Serife

    2006-01-01

    The concentrations of metals (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, and Zn) in street sediment samples were determined by flame atomic absorption spectrometry (FAAS) using the modified BCR (the European Community Bureau of Reference) sequential extraction procedure. According to the BCR protocol for extracting the metals from the relevant target phases, 1.0 g of specimen of the sample was treated with 0.11 M acetic acid (exchangeable and bound to carbonates), 0.5 M hydroxylamine hydrochloride (bound to iron- and manganese-oxides), and 8.8 M hydrogen peroxide plus 1 M ammonium acetate (bound to sulphides and organics), sequentially. The residue was treated with aqua regia solution for recovery studies, although this step is not part of the BCR procedure. The mobility sequence based on the sum of the BCR sequential extraction stages was: Cd ∼ Zn (∼90%) > Pb (∼84%) > Cu (∼75%) > Mn (∼70%) > Co (∼57%) > Ni (∼43%) > Cr (∼40%) > Fe (∼17%). Enrichment factors as the criteria for examining the impact of the anthropogenic emission sources of heavy metals were calculated, and it was observed that the highest enriched elements were Cd, Pb, and Zn in the dust samples, average 190, 111, and 20, respectively. Correlation analysis (CA) and principal component analysis (PCA) were applied to the data matrix to evaluate the analytical results and to identify the possible pollution sources of metals. PCA revealed that the sampling area was mainly influenced from three pollution sources, namely; traffic, industrial, and natural sources. The results show that chemical sequential extraction is a precious operational tool. Validation of the analytical results was checked by both recovery studies and analysis of the standard reference material (NIST SRM 2711 Montana Soil)

  15. Low expression of miR-196b enhances the expression of BCR-ABL1 and HOXA9 oncogenes in chronic myeloid leukemogenesis.

    Directory of Open Access Journals (Sweden)

    Yue Liu

    Full Text Available MicroRNAs (miRNAs can function as tumor suppressors or oncogene promoters during tumor development. In this study, low levels of expression of miR-196b were detected in patients with chronic myeloid leukemia. Bisulfite genomic sequencing PCR and methylation-specific PCR were used to examine the methylation status of the CpG islands in the miR-196b promoter in K562 cells, patients with leukemia and healthy individuals. The CpG islands showed more methylation in patients with chronic myeloid leukemia compared with healthy individuals (P<0.05, which indicated that low expression of miR-196b may be associated with an increase in the methylation of CpG islands. The dual-luciferase reporter assay system demonstrated that BCR-ABL1 and HOXA9 are the target genes of miR-196b, which was consistent with predictions from bioinformatics software analyses. Further examination of cell function indicated that miR-196b acts to reduce BCR-ABL1 and HOXA9 protein levels, decrease cell proliferation rate and retard the cell cycle. A low level of expression of miR-196b can cause up-regulation of BCR-ABL1 and HOXA9 expression, which leads to the development of chronic myeloid leukemia. MiR-196b may represent an effective target for chronic myeloid leukemia therapy.

  16. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells.

    Science.gov (United States)

    Rix, U; Remsing Rix, L L; Terker, A S; Fernbach, N V; Hantschel, O; Planyavsky, M; Breitwieser, F P; Herrmann, H; Colinge, J; Bennett, K L; Augustin, M; Till, J H; Heinrich, M C; Valent, P; Superti-Furga, G

    2010-01-01

    Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.

  17. β-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia.

    Science.gov (United States)

    Eiring, A M; Khorashad, J S; Anderson, D J; Yu, F; Redwine, H M; Mason, C C; Reynolds, K R; Clair, P M; Gantz, K C; Zhang, T Y; Pomicter, A D; Kraft, I L; Bowler, A D; Johnson, K; Partlin, M Mac; O'Hare, T; Deininger, M W

    2015-12-01

    Activation of nuclear β-catenin and expression of its transcriptional targets promotes chronic myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and leukemic stem cell self-renewal. We report that nuclear β-catenin has a role in leukemia cell-intrinsic but not -extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib inhibition of BCR-ABL1 kinase activity, β-catenin expression was maintained in intrinsically resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) with bone marrow (BM) stromal cells. Thus, TKI resistance uncouples β-catenin expression from BCR-ABL1 kinase activity. In β-catenin reporter assays, intrinsically resistant cells showed increased transcriptional activity versus parental TKI-sensitive controls, and this was associated with restored expression of β-catenin target genes. In contrast, DC with BM stromal cells promoted TKI resistance, but had little effects on Lef/Tcf reporter activity and no consistent effects on cytoplasmic β-catenin levels, arguing against a role for β-catenin in extrinsic TKI resistance. N-cadherin or H-cadherin blocking antibodies abrogated DC-based resistance despite increasing Lef/Tcf reporter activity, suggesting that factors other than β-catenin contribute to extrinsic, BM-derived TKI resistance. Our data indicate that, while nuclear β-catenin enhances survival of intrinsically TKI-resistant CML progenitors, it is not required for extrinsic resistance mediated by the BM microenvironment.

  18. Coupling a universal DNA circuit with graphene sheets/polyaniline/AuNPs nanocomposites for the detection of BCR/ABL fusion gene

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xueping [Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016 (China); Wang, Li [Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016 (China); Department of Medical Laboratory, Chongqing Emergency Medical Center (Chongqing The Fourth Hospital), Chongqing, 400016 (China); Sheng, Shangchun [The No.2 Peoples' Hospital of Yibin, Sichuan, 644000 (China); Wang, Teng; Yang, Juan [Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016 (China); Xie, Guoming, E-mail: guomingxie@cqmu.edu.cn [Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016 (China); Feng, Wenli, E-mail: fengwlcqmu@sina.com [Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016 (China)

    2015-08-19

    This article described a novel method by coupling a universal DNA circuit with graphene sheets/polyaniline/AuNPs nanocomposites (GS/PANI/AuNPs) for highly sensitive and specific detection of BCR/ABL fusion gene (bcr/abl) in chronic myeloid leukemia (CML). DNA circuit known as catalyzed hairpin assembly (CHA) is enzyme-free and can be simply operated to achieve exponential amplification, which has been widely employed in biosensing. However, application of CHA has been hindered by the need of specially redesigned sequences for each single-stranded DNA input. Herein, a transducer hairpin (HP) was designed to obtain a universal DNA circuit with favorable signal-to-background ratio. To further improve signal amplification, GS/PANI/AuNPs with excellent conductivity and enlarged effective area were introduced into this DNA circuit. Consequently, by combining the advantages of CHA and GS/PANI/AuNPs, bcr/abl could be detected in a linear range from 10 pM to 20 nM with a detection limit of 1.05 pM. Moreover, this protocol showed excellent specificity, good stability and was successfully applied for the detection of real sample, which demonstrated its great potential in clinical application. - Highlights: • A transducer hairpin was designed to improve the versatility of DNA circuit. • GS/PANI/AuNPs were introduced to the DNA circuit for further signal amplification. • The established biosensor displayed high sensitivity and good specificity.

  19. Use of the modified BCR three-step sequential extraction procedure for the study of trace element dynamics in contaminated soils

    International Nuclear Information System (INIS)

    Pueyo, M.; Mateu, J.; Rigol, A.; Vidal, M.; Lopez-Sanchez, J.F.; Rauret, G.

    2008-01-01

    The modified BCR three-step sequential extraction procedure was used to examine the temporal dynamics of trace elements in soils contaminated by an accidental spill from an opencast mine in south-west Spain. Soils were mainly contaminated with pyritic sludge and acidic wastewater, whereas some soils were affected only by acidic wastewater. The distributions obtained for both some major (Ca, Fe and Mn) and trace elements (As, Cd, Cu, Pb and Zn) in the sludge and soil samples taken at different times after the accident, 1-3 months and 21 months, were compared. Sequential extractions were useful in identifying different sources of contamination, and in obtaining additional information on the solubility of secondary minerals formed by pyrite oxidation. Thus, the effectiveness of the BCR procedure has proved to be a useful tool for predicting short- and long-term mobility of trace elements, even in complex environmental scenarios. - The modified BCR three-step sequential extraction procedure has proved a useful prediction tool for short- and long-term mobility of trace elements in contaminated soils

  20. BCR-crosslinking induces a transcription of protein phosphatase component G5PR that is required for mature B-cell survival

    International Nuclear Information System (INIS)

    Huq Ronny, Faisal Mahmudul; Igarashi, Hideya; Sakaguchi, Nobuo

    2006-01-01

    BCR-crosslinking triggers activation-induced cell death (AICD) selectively in the restricted stage of B-cell differentiation. We examined the transcription of a protein phosphatase subunit G5PR in immature and mature B-cells, because absence of this factor augmented cell sensitivity to AICD, associated with increased activation of JNK and Bim. BCR-crosslinking-induced G5pr transcription in AICD-resistant mature splenic IgM lo IgD hi B-cells but not in AICD susceptible immature IgM hi IgD lo B-cells. Thus, G5pr induction correlated with the prevention of AICD; High in mature splenic CD23 hi B-cells but low in immature B-cells of neonatal mice, sub-lethally irradiated mice, or xid mice. Lack of G5pr upregulation was associated with the prolonged activation of JNK. The G5pr cDNA transfection protected an immature B-cell line WEHI-231 from BCR-mediated AICD. The differential expression of G5PR might be responsible for the antigen-dependent selection of B-cells

  1. Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors in a single-center cohort.

    Science.gov (United States)

    Kander, Elizabeth M; Raza, Sania; Zhou, Zheng; Gao, Juehua; Zakarija, Anaadriana; McMahon, Brandon J; Stein, Brady L

    2015-11-01

    The BCR-ABL1-negative myeloproliferative neoplasms (MPN) share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhage are less well defined than those for thrombosis. Because patients with CALR mutations have higher platelet counts compared to JAK2 V617F-mutated patients, bleeding rates may be increased in this group. Our aim was to retrospectively evaluate whether acquired von Willebrand disease (AvWD), thrombocytosis, mutational status, or treatment history are associated with bleeding in a cohort of MPN patients. Using an electronic database, MPN patients seen between 2005 and 2013 were retrospectively identified using ICD-9 codes and billing records. A bleeding event was defined as one that was identified in the medical record and graded based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0. Among 351 MPN patients, 15.6 % experienced 64 bleeding event types. There was no association of bleeding with mutational status, gender, MPN subtype, aspirin use, prior thrombosis, or platelet count at presentation. There was an association between bleeding and older age at diagnosis. aVWD was identified in six patients. In this single-center retrospective study, bleeding events were identified in 15 % of patients, and associated with older age at diagnosis. aVWD was rarely tested for in this cohort.

  2. Assessing of distribution, mobility and bioavailability of exogenous Pb in agricultural soils using isotopic labeling method coupled with BCR approach.

    Science.gov (United States)

    Huang, Zhi-Yong; Xie, Hong; Cao, Ying-Lan; Cai, Chao; Zhang, Zhi

    2014-02-15

    The contamination of Pb in agricultural soils is one of the most important ecological problems, which potentially results in serious health risk on human health through food chain. Hence, the fate of exogenous Pb contaminated in agricultural soils is needed to be deeply explored. By spiking soils with the stable enriched isotopes of (206)Pb, the contamination of exogenous Pb(2+) ions in three agricultural soils sampled from the estuary areas of Jiulong River, China was simulated in the present study, and the distribution, mobility and bioavailability of exogenous Pb in the soils were investigated using the isotopic labeling method coupled with a four-stage BCR (European Community Bureau of Reference) sequential extraction procedure. Results showed that about 60-85% of exogenous Pb was found to distribute in reducible fractions, while the exogenous Pb in acid-extractable fractions was less than 1.0%. After planting, the amounts of exogenous Pb presenting in acid-extractable, reducible and oxidizable fractions in rhizospheric soils decreased by 60-66%, in which partial exogenous Pb was assimilated by plants while most of the metal might transfer downward due to daily watering and applying fertilizer. The results show that the isotopic labeling technique coupled with sequential extraction procedures enables us to explore the distribution, mobility and bioavailability of exogenous Pb contaminated in soils, which may be useful for the further soil remediation. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Evaluation of Mobility, Bioavailability and Toxicity of Pb and Cd in Contaminated Soil Using TCLP, BCR and Earthworms

    Science.gov (United States)

    Kede, Maria Luiza F. M.; Correia, Fabio V.; Conceição, Paulo F.; Salles Junior, Sidney F.; Marques, Marcia; Moreira, Josino C.; Pérez, Daniel V.

    2014-01-01

    The objective of the present study was to investigate the reduction of mobility, availability and toxicity found in soil contaminated with lead (Pb) and cadmium (Cd) from Santo Amaro Municipality, Bahia, Brazil using two combined methods, commonly tested separately according to the literature: metal mobilization with phosphates and phytoextraction. The strategy applied was the treatment with two sources of phosphates (separately and mixed) followed by phytoremediation with vetiver grass (Vetiveria zizanioides (L.)). The treatments applied (in triplicates) were: T1—potassium dihydrogen phosphate (KH2PO4); T2—reactive natural phosphate fertilizer (NRP) and; T3—a mixture 1:1 of KH2PO4 and NRP. After this step, untreated and treated soils were planted with vetiver grass. The extraction procedures and assays applied to contaminated soil before and after the treatments included metal mobility test (TCLP); sequential extraction with BCR method; toxicity assays with Eisenia andrei. The soil-to-plant transfer factors (TF) for Pb and Cd were estimated in all cases. All treatments with phosphates followed by phytoremediation reduced the mobility and availability of Pb and Cd, being KH2PO4 (T1) plus phytoremediation the most effective one. Soil toxicity however, remained high after all treatments. PMID:25386955

  4. Evaluation of Mobility, Bioavailability and Toxicity of Pb and Cd in Contaminated Soil Using TCLP, BCR and Earthworms

    Directory of Open Access Journals (Sweden)

    Maria Luiza F. M. Kede

    2014-11-01

    Full Text Available The objective of the present study was to investigate the reduction of mobility, availability and toxicity found in soil contaminated with lead (Pb and cadmium (Cd from Santo Amaro Municipality, Bahia, Brazil using two combined methods, commonly tested separately according to the literature: metal mobilization with phosphates and phytoextraction. The strategy applied was the treatment with two sources of phosphates (separately and mixed followed by phytoremediation with vetiver grass (Vetiveria zizanioides (L.. The treatments applied (in triplicates were: T1—potassium dihydrogen phosphate (KH2PO4; T2—reactive natural phosphate fertilizer (NRP and; T3—a mixture 1:1 of KH2PO4 and NRP. After this step, untreated and treated soils were planted with vetiver grass. The extraction procedures and assays applied to contaminated soil before and after the treatments included metal mobility test (TCLP; sequential extraction with BCR method; toxicity assays with Eisenia andrei. The soil-to-plant transfer factors (TF for Pb and Cd were estimated in all cases. All treatments with phosphates followed by phytoremediation reduced the mobility and availability of Pb and Cd, being KH2PO4 (T1 plus phytoremediation the most effective one. Soil toxicity however, remained high after all treatments.

  5. Frequency of janus associated kinase 2 (jak2) mutation in patients of bcr-abl negative myeloproliferative neoplasms

    International Nuclear Information System (INIS)

    Sadiq, M.A.; Ahmed, S.; Ali, N.

    2013-01-01

    To determine the frequency of Janus associated kinase 2 mutation in the patients of BCR-ABL negative classical myeloproliferative neoplasms. Study Design: Cross-sectional descriptive study Place and Duration of Study: Molecular Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi from Jul 2011 to Jul 2012. Patients and Methods: Ninety three consecutive patients of Polycythaemia vera (PV), Essential thrombocythaemia (ET) and Idiopathic myelofibrosis (IMF) diagnosed by the conventional haematological criteria were included in the study. All patients were screened for G-T point mutation (V617F) in the JAK2 gene on chromosome 9 by an allele specific PCR. Results: Out of the 93 myeloproliferative neoplasm (MPN) patients, 33(35%) had polycythaemia vera, 36(39%) had essential thrombocythaemia and 24(26%) had idiopathic myelofibrosis. JAK2 mutation was seen in 64/93 (69%) patients including 33/33(100%) in PV, 19/36(52.6%) in ET and 12/24(50%) in IMF. Conclusion: Classical myeloproliferative neoplasms are an important group of heamatological disorder in our country. JAK2 gene mutation is seen in significant proportion of these disorders (69%). JAK2 mutation analysis can be used to differentiate between polycythemia vera and secondary polycythemia in most cases with near certainty, where it was found in 100% of the cases. (author)

  6. [JAK2 V617F and exon 12 genetic variations in Korean patients with BCR/ABL1-negative myeloproliferative neoplasms].

    Science.gov (United States)

    Kim, Jeong Tae; Cho, Yong Gon; Choi, Sam Im; Lee, Young Jin; Kim, Hye Ran; Jang, Sook Jin; Moon, Dae Soo; Park, Young Jin; Park, Geon

    2010-12-01

    JAK2 genetic variations have been described in a high proportion of patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN). This study was designed to analyze the frequencies of JAK2 V617F and exon 12 variations, and their correlations with clinical characteristics of Korean patients with BCR/ABL1-negative MPN. We examined a total of 154 patients with BCR/ABL1-negative MPN that included 24, 26, 89, and 15 patients with polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), and unclassified myeloproliferative neoplasms (MPNU), respectively. We performed allele-specific PCR to detect V617F in all BCR/ABL1-negative patients, and performed direct sequencing to detect exon 12 variations in 47 V617F-negative MPN patients. JAK2 c.1641+179_183del5 variation was detected by restriction fragment length polymorphism assay in 176 healthy subjects. JAK2 V617F was detected in 91 patients (59.1%): PV (91.6%), PMF (46.2%), ET (52.8%), and MPNU (66.7%). In V617F-negative MPN patients, no mutations were found in exon 12. The c.1641+179_183del5 was detected in 68.1% of V617F-negative MPN patients and 45.4% of healthy subjects (P=0.008). JAK2 V617F was closely correlated with age and leukocytosis in BCR/ABL1-negative MPN patients (P<0.05). However, c.1641+179_183del5 was not related to age, sex, or complete blood cell count parameters in V617F-negative MPN patients and healthy subjects. The c.1641+179_183del5 was associated with an increased odds ratio for MPN (odds ratio, 2.6; 95% confidences interval, 1.3-5.1; P=0.007). Frequencies of V617F are similar to reported results. JAK2 exon 12 mutations may be rare and c.1641+179_183del5 may influence the occurrence of MPN in Korean patients with V6 17F-negative MPN.

  7. Fifth symposium on surface mining and reclamation. NCA/BCR coal conference and Expo IV

    Energy Technology Data Exchange (ETDEWEB)

    None

    1977-01-01

    The Fifth Symposium on Surface Mining and Reclamation, sponsored by the National Coal Association and Bituminous Coal Research, Inc., was held at the Kentucky Fair and Exposition Center, Louisville, Kentucky, October 18-20, 1977. Twenty-six papers from the proceedings have been entered individually into EDB and ERA. Topics covered include spoil bank revegetation, use of aerial photography, reclamation for row crop production, hydrology, computer programs related to this work, subirrigated alluvial valley floors, reclamation on steep slopes, mountain top removal, surface mine road design, successional processes involved in reclamation, land use planning, etc. (LTN)

  8. Assessing of distribution, mobility and bioavailability of exogenous Pb in agricultural soils using isotopic labeling method coupled with BCR approach

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Zhi-Yong, E-mail: zhyhuang@jmu.edu.cn [College of Bioengineering, Jimei University, Xiamen 361021 (China); Xie, Hong [College of Bioengineering, Jimei University, Xiamen 361021 (China); Shandong Vocational Animal Science and Veterinary College, Weifang 261061 (China); Cao, Ying-Lan [College of Bioengineering, Jimei University, Xiamen 361021 (China); Cai, Chao [Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Zhang, Zhi [College of Bioengineering, Jimei University, Xiamen 361021 (China)

    2014-02-15

    Highlights: • Large amounts of exogenous Pb were found to distribute in reducible fractions. • Very few of exogenous Pb were found to distribute in acid-extractable fractions. • More than 60% of exogenous Pb in rhizosphere soils lost after planting. • Isotopic labeling method and SEP enable to explore Pb bioavailability in soil. -- Abstract: The contamination of Pb in agricultural soils is one of the most important ecological problems, which potentially results in serious health risk on human health through food chain. Hence, the fate of exogenous Pb contaminated in agricultural soils is needed to be deeply explored. By spiking soils with the stable enriched isotopes of {sup 206}Pb, the contamination of exogenous Pb{sup 2+} ions in three agricultural soils sampled from the estuary areas of Jiulong River, China was simulated in the present study, and the distribution, mobility and bioavailability of exogenous Pb in the soils were investigated using the isotopic labeling method coupled with a four-stage BCR (European Community Bureau of Reference) sequential extraction procedure. Results showed that about 60–85% of exogenous Pb was found to distribute in reducible fractions, while the exogenous Pb in acid-extractable fractions was less than 1.0%. After planting, the amounts of exogenous Pb presenting in acid-extractable, reducible and oxidizable fractions in rhizospheric soils decreased by 60–66%, in which partial exogenous Pb was assimilated by plants while most of the metal might transfer downward due to daily watering and applying fertilizer. The results show that the isotopic labeling technique coupled with sequential extraction procedures enables us to explore the distribution, mobility and bioavailability of exogenous Pb contaminated in soils, which may be useful for the further soil remediation.

  9. Assessing of distribution, mobility and bioavailability of exogenous Pb in agricultural soils using isotopic labeling method coupled with BCR approach

    International Nuclear Information System (INIS)

    Huang, Zhi-Yong; Xie, Hong; Cao, Ying-Lan; Cai, Chao; Zhang, Zhi

    2014-01-01

    Highlights: • Large amounts of exogenous Pb were found to distribute in reducible fractions. • Very few of exogenous Pb were found to distribute in acid-extractable fractions. • More than 60% of exogenous Pb in rhizosphere soils lost after planting. • Isotopic labeling method and SEP enable to explore Pb bioavailability in soil. -- Abstract: The contamination of Pb in agricultural soils is one of the most important ecological problems, which potentially results in serious health risk on human health through food chain. Hence, the fate of exogenous Pb contaminated in agricultural soils is needed to be deeply explored. By spiking soils with the stable enriched isotopes of 206 Pb, the contamination of exogenous Pb 2+ ions in three agricultural soils sampled from the estuary areas of Jiulong River, China was simulated in the present study, and the distribution, mobility and bioavailability of exogenous Pb in the soils were investigated using the isotopic labeling method coupled with a four-stage BCR (European Community Bureau of Reference) sequential extraction procedure. Results showed that about 60–85% of exogenous Pb was found to distribute in reducible fractions, while the exogenous Pb in acid-extractable fractions was less than 1.0%. After planting, the amounts of exogenous Pb presenting in acid-extractable, reducible and oxidizable fractions in rhizospheric soils decreased by 60–66%, in which partial exogenous Pb was assimilated by plants while most of the metal might transfer downward due to daily watering and applying fertilizer. The results show that the isotopic labeling technique coupled with sequential extraction procedures enables us to explore the distribution, mobility and bioavailability of exogenous Pb contaminated in soils, which may be useful for the further soil remediation

  10. A longitudinal evaluation of performance of automated BCR-ABL1 quantitation using cartridge-based detection system.

    Science.gov (United States)

    Enjeti, Anoop; Granter, Neil; Ashraf, Asma; Fletcher, Linda; Branford, Susan; Rowlings, Philip; Dooley, Susan

    2015-10-01

    An automated cartridge-based detection system (GeneXpert; Cepheid) is being widely adopted in low throughput laboratories for monitoring BCR-ABL1 transcript in chronic myelogenous leukaemia. This Australian study evaluated the longitudinal performance specific characteristics of the automated system.The automated cartridge-based system was compared prospectively with the manual qRT-PCR-based reference method at SA Pathology, Adelaide, over a period of 2.5 years. A conversion factor determination was followed by four re-validations. Peripheral blood samples (n = 129) with international scale (IS) values within detectable range were selected for assessment. The mean bias, proportion of results within specified fold difference (2-, 3- and 5-fold), the concordance rate of major molecular remission (MMR) and concordance across a range of IS values on paired samples were evaluated.The initial conversion factor for the automated system was determined as 0.43. Except for the second re-validation, where a negative bias of 1.9-fold was detected, all other biases fell within desirable limits. A cartridge-specific conversion factor and efficiency value was introduced and the conversion factor was confirmed to be stable in subsequent re-validation cycles. Concordance with the reference method/laboratory at >0.1-≤10 IS was 78.2% and at ≤0.001 was 80%, compared to 86.8% in the >0.01-≤0.1 IS range. The overall and MMR concordance were 85.7% and 94% respectively, for samples that fell within ± 5-fold of the reference laboratory value over the entire period of study.Conversion factor and performance specific characteristics for the automated system were longitudinally stable in the clinically relevant range, following introduction by the manufacturer of lot specific efficiency values.

  11. Otimização das condições de pré-redução do As(V em extratos do método BCR para quantificação de arsênio por HG-AAS Optimization of pre-reduction conditions of as(V in BCR extracts to quantify arsenic by HG-AAS

    Directory of Open Access Journals (Sweden)

    Eduardo Vinícius Vieira Varejão

    2009-08-01

    Full Text Available A determinação de As por espectrometria de absorção atômica com geração de hidretos (HG-AAS constitui um método simples, sensível, preciso e de baixo custo. Entretanto, essa técnica requer a pré-redução das espécies de As(V, o que se obtém através do uso de agentes redutores como o KI. Em extratos contendo agentes oxidantes, a pré-redução do As é comprometida, como acontece em extratos obtidos pela aplicação do método BCR (acrônimo francês para Community Bureau of Reference para a extração sequencial de As em sedimentos. O objetivo deste trabalho foi avaliar as condições de redução do As(V a As(III, de modo a permitir o uso da HG-AAS para a quantificação do arsênio em extratos obtidos a partir do método BCR. Foram avaliadas condições reacionais utilizando KI, L-cisteína e ácido ascórbico. Para cada uma das etapas de extração do método BCR, diferentes condições de pré-redução possibilitaram a detecção quantitativa do As presente. O uso do método BCR para a extração de arsênio em amostras de sedimentos contaminadas e a aplicação das condições de pré-redução do As(V selecionadas, seguida pela detecção por HG-AAS, forneceram percentagens de recuperação entre 91 e 99 %.The determination of As by hydride generation atomic absorption spectroscopy (HG-AAS is a simple, sensitive, precise and low-cost method. However, this technique requires the pre-reduction of the existing As(V species, which is obtained by the use of reducing agents such as KI. In extracts containing oxidizing agents, the pre-reduction of As is impaired, as it occurs in extracts obtained by the BCR (French acronym for Community Bureau of Reference method for the sequential extraction of As in sediments. The objective of this study was to evaluate the conditions for the reduction of As(V to As(III in a way that allows the use of HG-AAS for the quantification of arsenic in extracts obtained using the BCR method. Reaction

  12. Droplet Digital PCR for BCR/ABL(P210) Detecting of CML: A High Sensitive Method of the Minimal Residual Disease& Disease Progression.

    Science.gov (United States)

    Wang, Wen-Jun; Zheng, Chao-Feng; Liu, Zhuang; Tan, Yan-Hong; Chen, Xiu-Hua; Zhao, Bin-Liang; Li, Guo-Xia; Xu, Zhi-Fang; Ren, Fang-Gang; Zhang, Yao-Fang; Chang, Jian-Mei; Wang, Hong-Wei

    2018-04-25

    The present study intended to establish a droplet digital PCR (dd-PCR) for monitoring minimal residual disease (MRD) in patients with BCR/ABL (P210)-positive CML, thereby achieving deep-level monitoring of tumor load and determining the efficacy for guided clinically individualized treatment. Using dd-PCR and RT-qPCR, two cell suspensions were obtained from K562 cells and normal peripheral blood mononuclear cells by gradient dilution and were measured at the cellular level. At peripheral blood(PB) level, 61 cases with CML-chronic phase (CML-CP) were obtained after tyrosine kinase inhibitors (TKIs) treatment and regular follow-ups. By RT-qPCR, BCR/ABL (P210) fusion gene was undetectable in PB after three successive analyses, which were performed once every three months. At the same time, dd-PCR was performed simultaneously with the last equal amount of cDNA. Ten CML patients with MR4.5 were followed up by the two methods. At the cellular level, consistency of results of dd-PCR and RT-qPCR reached R 2 ≥0.99, with conversion equation of Y=33.148X 1.222 (Y: dd-PCR results; X: RT-qPCR results). In the dd-PCR test, 11 of the 61 CML patients (18.03%) tested positive and showed statistically significant difference (PPCR 3 months earlier than by RT-qPCR. In contrast with RT-qPCR, dd-PCR is more sensitive, thus enabling accurate conversion of dd-PCR results into internationally standard RT-qPCR results by conversion equation, to achieve a deeper molecular biology-based stratification of BCR/ABL(P210) MRD. It has some reference value to monitor disease progression in clinic. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

    DEFF Research Database (Denmark)

    Nicolini, Franck E; Mauro, Michael J; Martinelli, Giovanni

    2009-01-01

    The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP......), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation...

  14. Nuclear topography and expression of the BCR/ABL fusion gene and its protein level influenced by cell differentiation and RNA interference

    Czech Academy of Sciences Publication Activity Database

    Bártová, Eva; Harničarová, Andrea; Pacherník, Jiří; Kozubek, Stanislav

    2005-01-01

    Roč. 29, č. 8 (2005), s. 901-913 ISSN 0145-2126 R&D Projects: GA AV ČR(CZ) 1QS500040508; GA ČR(CZ) GA202/04/0907; GA MZd NC6987; GA AV ČR(CZ) IAA5004306; GA MŠk(CZ) LC535 Institutional research plan: CEZ:AV0Z50040507 Keywords : BCR /ABL fusion gene * chromatin arrangement * gene expression Subject RIV: BO - Biophysics Impact factor: 2.372, year: 2005

  15. Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl+ K562 and Jak2(V617F)+ HEL Leukemia Cells

    International Nuclear Information System (INIS)

    Weber, Axel; Borghouts, Corina; Brendel, Christian; Moriggl, Richard; Delis, Natalia; Brill, Boris; Vafaizadeh, Vida; Groner, Bernd

    2015-01-01

    Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl + K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5

  16. Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice.

    Directory of Open Access Journals (Sweden)

    Kiyoko Yamamoto

    Full Text Available Patients in the chronic phase (CP of chronic myelogenous leukemia (CML have been treated successfully following the advent of ABL kinase inhibitors, but once they progress to the blast crisis (BC phase the prognosis becomes dismal. Although mechanisms underlying the progression are largely unknown, recent studies revealed the presence of alterations of key molecules for hematopoiesis, such as AML1/RUNX1. Our analysis of 13 BC cases revealed that three cases had AML1 mutations and the transcript levels of wild-type (wt. AML1 were elevated in BC compared with CP. Functional analysis of representative AML1 mutants using mouse hematopoietic cells revealed the possible contribution of some, but not all, mutants for the BC-phenotype. Specifically, K83Q and R139G, but neither R80C nor D171N mutants, conferred upon BCR-ABL-expressing cells a growth advantage over BCR-ABL-alone control cells in cytokine-free culture, and the cells thus grown killed mice upon intravenous transfer. Unexpectedly, wt.AML1 behaved similarly to K83Q and R139G mutants. In a bone marrow transplantation assay, K83Q and wt.AML1s induced the emergence of blast-like cells. The overall findings suggest the roles of altered functions of AML1 imposed by some, but not all, mutants, and the elevated expression of wt.AML1 for the disease progression of CML.

  17. Determination of cDNA encoding BCR/ABL fusion gene in patients with chronic myelogenous leukemia using a novel FRET-based quantum dots-DNA nanosensor.

    Science.gov (United States)

    Shamsipur, Mojtaba; Nasirian, Vahid; Barati, Ali; Mansouri, Kamran; Vaisi-Raygani, Asad; Kashanian, Soheila

    2017-05-08

    In the present study, we developed a sensitive method based on fluorescence resonance energy transfer (FRET) for the determination of the BCR/ABL fusion gene, which is used as a biomarker to confirm the clinical diagnosis of both chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). For this purpose, CdTe quantum dots (QDs) were conjugated to amino-modified 18-mer oligonucleotide ((N)DNA) to form the QDs-(N)DNA nanosensor. In the presence of methylene blue (MB) as an intercalator, the hybridization of QDs-(N)DNA with the target BCR/ABL fusion gene (complementary DNA), brings the MB (acceptor) at close proximity of the QDs (donor), leading to FRET upon photoexcitation of the QDs. The enhancement in the emission intensity of MB was used to follow up the hybridization, which was linearly proportional to concentration of the target complementary DNA in a range from 1.0 × 10 -9 to 1.25 × 10 -7  M. The detection limit of the proposed method was obtained to be 1.5 × 10 -10  M. Finally, the feasibility and selectivity of the proposed nanosensor was evaluated by the analysis of derived nucleotides from both mismatched sequences and clinical samples of patients with leukemia as real samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Silencing of BCR/ABL Chimeric Gene in Human Chronic Myelogenous Leukemia Cell Line K562 by siRNA-Nuclear Export Signal Peptide Conjugates.

    Science.gov (United States)

    Shinkai, Yasuhiro; Kashihara, Shinichi; Minematsu, Go; Fujii, Hirofumi; Naemura, Madoka; Kotake, Yojiro; Morita, Yasutaka; Ohnuki, Koichiro; Fokina, Alesya A; Stetsenko, Dmitry A; Filichev, Vyacheslav V; Fujii, Masayuki

    2017-06-01

    Herein we described the synthesis of siRNA-NES (nuclear export signal) peptide conjugates by solid phase fragment coupling and the application of them to silencing of bcr/abl chimeric gene in human chronic myelogenous leukemia cell line K562. Two types of siRNA-NES conjugates were prepared, and both sense strands at 5' ends were covalently linked to a NES peptide derived from TFIIIA and HIV-1 REV, respectively. Significant enhancement of silencing efficiency was observed for both of them. siRNA-TFIIIA NES conjugate suppressed the expression of BCR/ABL gene to 8.3% at 200 nM and 11.6% at 50 nM, and siRNA-HIV-1REV NES conjugate suppressed to 4.0% at 200 nM and 6.3% at 50 nM, whereas native siRNA suppressed to 36.3% at 200 nM and 30.2% at 50 nM. We could also show complex of siRNA-NES conjugate and designed amphiphilic peptide peptideβ7 could be taken up into cells with no cytotoxicity and showed excellent silencing efficiency. We believe that the complex siRNA-NES conjugate and peptideβ7 is a promising candidate for in vivo use and therapeutic applications.

  19. Accurate determination of arsenic in arsenobetaine standard solutions of BCR-626 and NMIJ CRM 7901-a by neutron activation analysis coupled with internal standard method.

    Science.gov (United States)

    Miura, Tsutomu; Chiba, Koichi; Kuroiwa, Takayoshi; Narukawa, Tomohiro; Hioki, Akiharu; Matsue, Hideaki

    2010-09-15

    Neutron activation analysis (NAA) coupled with an internal standard method was applied for the determination of As in the certified reference material (CRM) of arsenobetaine (AB) standard solutions to verify their certified values. Gold was used as an internal standard to compensate for the difference of the neutron exposure in an irradiation capsule and to improve the sample-to-sample repeatability. Application of the internal standard method significantly improved linearity of the calibration curve up to 1 microg of As, too. The analytical reliability of the proposed method was evaluated by k(0)-standardization NAA. The analytical results of As in AB standard solutions of BCR-626 and NMIJ CRM 7901-a were (499+/-55)mgkg(-1) (k=2) and (10.16+/-0.15)mgkg(-1) (k=2), respectively. These values were found to be 15-20% higher than the certified values. The between-bottle variation of BCR-626 was much larger than the expanded uncertainty of the certified value, although that of NMIJ CRM 7901-a was almost negligible. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  20. SÍNTESES E PROPRIEDADES DE FÁRMACOS INIBIDORES DA TIROSINA QUINASE BCR-ABL, UTILIZADOS NO TRATAMENTO DA LEUCEMIA MIELOIDE CRÔNICA

    Directory of Open Access Journals (Sweden)

    Liviane D. de Azevedo

    Full Text Available The chronic myeloid leukemia (CML is characterized by presence of the Philadelphia chromosome (Ph, originated from the translocation between chromosomes 9 and 22. This chromosome generates an abnormal protein tyrosine kinase which is responsible for tumor cell proliferation. The emergence of tyrosine kinase inhibitors (TKIs has transformed the treatment of CML and imatinib being the first representative of this class. Although treatment with imatinib has reached surprising results, approximately 30% of patients exhibited resistance, especially in later stages of the disease. This fact stimulated the development of novel BCR-ABL enzyme inhibitors drugs classified as tyrosine kinase inhibitors (TKIs of second and third generations. The TKIs have different chemical functions in their structure, and the knowledge of synthetic methods for preparation of these compounds can be a powerful tool for the development of new derivatives. The five approved BCR-ABL Tyrosine Kinase inhibitors (TKI used in Chronic Myeloid Leukemia (CML are reviewed aiming the main synthetic routes, highlighting the advantages and disadvantages associated with them.

  1. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase.

    Science.gov (United States)

    Hughes, T P; Saglio, G; Quintás-Cardama, A; Mauro, M J; Kim, D-W; Lipton, J H; Bradley-Garelik, M B; Ukropec, J; Hochhaus, A

    2015-09-01

    BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

  2. Estandarización de la TR-PCR para la detección de las fusiones génicas BCR-ABL en pacientes con leucemia Mieloide Crónica (LMC y Linfoide Aguda (LLA provenientes de HUSVP y Clíncia León XIII

    Directory of Open Access Journals (Sweden)

    Gonzálo Vásquez Palacio

    2006-04-01

    Full Text Available La translocación recíproca t(9:22(q34;q11 involucra el proto-oncogen ABL y el gen BCR, originando un gen de fusión BCR-ABL, que codifica una proteína con elevada actividad tirosina quinasa, implicada en la leucemogénesis.

  3. Determination of lactate dehydrogenase (LDH and Bcr-Abl transcript in the follow-up of patients with chronic myeloid leukemia = Determinação da lactate desidrogenase (LDH e do transcrito Bcr-Abl em pacientes com leucemia mielóide crônica

    Directory of Open Access Journals (Sweden)

    Roberto Iemitsu Tatakihara

    2010-07-01

    Full Text Available Chronic myeloid leukemia (CML is a malignant myeloproliferative disorder that originates from a pluripotent stem cell characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow into the bloodstream. The vast majority of patients with CML present Bcr-Abl transcripts. Lactate dehydrogenase (LDH is considered a biochemical marker common for tumor growth, anaerobic glycolysis and has been considered a poor prognostic factor for acute myeloid leukemia. Therefore, this study aimed to evaluate the concentration of LDH in plasma and the detection of the Bcr-Abl transcripts in patients with CML and healthy donors. We analyzed 22 patients demonstrably diagnosed with CML and 56 healthy donors. LDH concentration in plasma was higher in patients with CML. All patients with CML in this study were under treatment, but even so four patients had the Bcr-Abl (b3a2 transcript in peripheral blood. Two out of the four patients with b3a2 showed higher LDH (486 U L-1 and 589 U L-1. Thus, although the study was conducted with small numbers of samples, it is possible to suggest therapy alteration for two patients who presented transcript b3a2 in the peripheral blood samples and whose LDH concentration was high, in order to improve the disease. Leucemia mieloide crônica (LMC é uma desordem mieloproliferativa maligna que é originada de célula-tronco pluripotente caracterizada por expansão anormal, maligna de clones de células tronco da medula óssea na circulação. A grande maioria dos pacientes com LMC apresentam transcritos Bcr-Abl. Lactato desidrogenase (LDH,considerado um marcador bioquímico para crescimento tumoral, glicólise anaeróbica, e tem sido considerado um fator de pior prognóstico da LMC. Portanto, este estudo visa avaliar a concentraçãode LDH no plasma e a detecção do transcrito Bcr-Abl em 22 pacientes com LMC e 56 indivíduos saudáveis. Foram avaliados 22 pacientes com LMC e 56 doadores saudáveis. A

  4. 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.

  5. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis

    DEFF Research Database (Denmark)

    Nicolini, Franck E; Ibrahim, Amr R; Soverini, Simona

    2013-01-01

    The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64...... patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according...... to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315...

  6. Combined inhibition of β-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo.

    Science.gov (United States)

    Zhou, H; Mak, P Y; Mu, H; Mak, D H; Zeng, Z; Cortes, J; Liu, Q; Andreeff, M; Carter, B Z

    2017-10-01

    Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), both related to persistent β-catenin activation, remain formidable challenges for chronic myeloid leukemia (CML). We observed overexpression of β-catenin in BC-CML stem/progenitor cells, particularly in granulocyte-macrophage progenitors, and highest among a novel CD34 + CD38 + CD123 hi Tim-3 hi subset as determined by CyTOF analysis. Co-culture with mesenchymal stromal cells (MSCs) induced the expression of β-catenin and its target CD44 in CML cells. A novel Wnt/β-catenin signaling modulator, C82, and nilotinib synergistically killed KBM5 T315I and TKI-resistant primary BC-CML cells with or without BCR-ABL kinase mutations even under leukemia/MSC co-culture conditions. Silencing of β-catenin by short interfering RNA restored sensitivity of primary BCR-ABL T315I/E255V BC-CML cells to nilotinib. Combining the C82 pro-drug, PRI-724, with nilotinib significantly prolonged the survival of NOD/SCID/IL2Rγ null mice injected with primary BCR-ABL T315I/E255V BC-CML cells. The combined treatment selectively targeted CML progenitors and inhibited CD44, c-Myc, survivin, p-CRKL and p-STAT5 expression. In addition, pretreating primary BC-CML cells with C82, or the combination, but not with nilotinib alone, significantly impaired their engraftment potential in NOD/SCID/IL2Rγ-null-3/GM/SF mice and significantly prolonged survival. Our data suggest potential benefit of concomitant β-catenin and Bcr-Abl inhibition to prevent or overcome Bcr-Abl kinase-dependent or -independent TKI resistance in BC-CML.

  7. In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants.

    Science.gov (United States)

    Soverini, Simona; De Benedittis, Caterina; Castagnetti, Fausto; Gugliotta, Gabriele; Mancini, Manuela; Bavaro, Luana; Machova Polakova, Katerina; Linhartova, Jana; Iurlo, Alessandra; Russo, Domenico; Pane, Fabrizio; Saglio, Giuseppe; Rosti, Gianantonio; Cavo, Michele; Baccarani, Michele; Martinelli, Giovanni

    2016-08-02

    Imatinib-resistant chronic myeloid leukemia (CML) patients receiving second-line tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib have a higher risk of disease relapse and progression and not infrequently BCR-ABL1 kinase domain (KD) mutations are implicated in therapeutic failure. In this setting, earlier detection of emerging BCR-ABL1 KD mutations would offer greater chances of efficacy for subsequent salvage therapy and limit the biological consequences of full BCR-ABL1 kinase reactivation. Taking advantage of an already set up and validated next-generation deep amplicon sequencing (DS) assay, we aimed to assess whether DS may allow a larger window of detection of emerging BCR-ABL1 KD mutants predicting for an impending relapse. a total of 125 longitudinal samples from 51 CML patients who had acquired dasatinib- or nilotinib-resistant mutations during second-line therapy were analyzed by DS from the time of failure and mutation detection by conventional sequencing backwards. BCR-ABL1/ABL1%(IS) transcript levels were used to define whether the patient had 'optimal response', 'warning' or 'failure' at the time of first mutation detection by DS. DS was able to backtrack dasatinib- or nilotinib-resistant mutations to the previous sample(s) in 23/51 (45 %) pts. Median mutation burden at the time of first detection by DS was 5.5 % (range, 1.5-17.5 %); median interval between detection by DS and detection by conventional sequencing was 3 months (range, 1-9 months). In 5 cases, the mutations were detectable at baseline. In the remaining cases, response level at the time mutations were first detected by DS could be defined as 'Warning' (according to the 2013 ELN definitions of response to 2nd-line therapy) in 13 cases, as 'Optimal response' in one case, as 'Failure' in 4 cases. No dasatinib- or nilotinib-resistant mutations were detected by DS in 15 randomly selected patients with 'warning' at various timepoints, that later turned into optimal

  8. Biodegradable charged polyester-based vectors (BCPVs) as an efficient non-viral transfection nanoagent for gene knockdown of the BCR-ABL hybrid oncogene in a human chronic myeloid leukemia cell line

    Science.gov (United States)

    Yang, Chengbin; Panwar, Nishtha; Wang, Yucheng; Zhang, Butian; Liu, Maixian; Toh, Huiting; Yoon, Ho Sup; Tjin, Swee Chuan; Chong, Peter Han Joo; Law, Wing-Cheung; Chen, Chih-Kuang; Yong, Ken-Tye

    2016-04-01

    First-line therapy of chronic myelogenous leukemia (CML) has always involved the use of BCR-ABL tyrosine-kinase inhibitors which is associated with an abnormal chromosome called Philadelphia chromosome. Although the overall survival rate has been improved by the current therapeutic regime, the presence of resistance has resulted in limited efficacy. In this study, an RNA interference (RNAi)-based therapeutic regime is proposed with the aim to knockdown the BCR-ABL hybrid oncogene using small interfering RNA (siRNA). The siRNA transfection rates have usually been limited due to the declining contact probability among polyplexes and the non-adherent nature of leukemic cells. Our work aims at addressing this limitation by using a biodegradable charged polyester-based vector (BCPV) as a nanocarrier for the delivery of BCR-ABL-specific siRNA to the suspension culture of a K562 CML cell line. BCR-ABL siRNAs were encapsulated in the BCPVs by electrostatic force. Cell internalization was facilitated by the BCPV and assessed by confocal microscopy and flow cytometry. The regulation of the BCR-ABL level in K562 cells as a result of RNAi was analyzed by real-time polymerase chain reaction (RT-PCR). We observed that BCPV was able to form stable nanoplexes with siRNA molecules, even in the presence of fetal bovine serum (FBS), and successfully assisted in vitro siRNA transfection in the non-adherent K562 cells. As a consequence of downregulation of BCR-ABL, BCPV-siRNA nanoplexes inhibited cell proliferation and promoted cell apoptosis. All results were compared with a commercial transfection reagent, Lipofectamine2000™, which served as a positive control. More importantly, this class of non-viral vector exhibits biodegradable features and negligible cytotoxicity, thus providing a versatile platform to deliver siRNA to non-adherent leukemia cells with high transfection efficiency by effectively overcoming extra- and intra-cellular barriers. Due to the excellent in vitro

  9. Determination of lactate dehydrogenase (LDH and Bcr-Abl transcript in the follow-up of patients with chronic myeloid leukemia - doi: 10.4025/actascihealthsci.v32i2.6408 Determination of lactate dehydrogenase (LDH and Bcr-Abl transcript in the follow-up of patients with chronic myeloid leukemia - doi: 10.4025/actascihealthsci.v32i2.6408

    Directory of Open Access Journals (Sweden)

    Thiago Cezar Fujita

    2010-09-01

    Full Text Available Chronic myeloid leukemia (CML is a malignant myeloproliferative disorder that originates from a pluripotent stem cell characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow into the bloodstream. The vast majority of patients with CML present Bcr-Abl transcripts. Lactate dehydrogenase (LDH is considered a biochemical marker common for tumor growth, anaerobic glycolysis and has been considered a poor prognostic factor for acute myeloid leukemia. Therefore, this study aimed to evaluate the concentration of LDH in plasma and the detection of the Bcr-Abl transcripts in patients with CML and healthy donors. We analyzed 22 patients demonstrably diagnosed with CML and 56 healthy donors. LDH concentration in plasma was higher in patients with CML. All patients with CML in this study were under treatment, but even so four patients had the Bcr-Abl (b3a2 transcript in peripheral blood. Two out of the four patients with b3a2 showed higher LDH (486 U L-1 and 589 U L-1. Thus, although the study was conducted with small numbers of samples, it is possible to suggest therapy alteration for two patients who presented transcript b3a2 in the peripheral blood samples and whose LDH concentration was high, in order to improve the disease.Chronic myeloid leukemia (CML is a malignant myeloproliferative disorder that originates from a pluripotent stem cell characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow into the bloodstream. The vast majority of patients with CML present Bcr-Abl transcripts. Lactate dehydrogenase (LDH is considered a biochemical marker common for tumor growth, anaerobic glycolysis and has been considered a poor prognostic factor for acute myeloid leukemia. Therefore, this study aimed to evaluate the concentration of LDH in plasma and the detection of the Bcr-Abl transcripts in patients with CML and healthy donors. We analyzed 22 patients demonstrably diagnosed

  10. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification.

    Science.gov (United States)

    Morinaga, Koji; Yamauchi, Takahiro; Kimura, Shinya; Maekawa, Taira; Ueda, Takanori

    2008-06-01

    Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-establishment of Abl kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-Abl, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the Abl kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new Abl kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual Abl/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients' leukemia. (c) 2008 Wiley-Liss, Inc.

  11. Ascorbate/menadione-induced oxidative stress kills cancer cells that express normal or mutated forms of the oncogenic protein Bcr-Abl. An in vitro and in vivo mechanistic study.

    Science.gov (United States)

    Beck, Raphaël; Pedrosa, Rozangela Curi; Dejeans, Nicolas; Glorieux, Christophe; Levêque, Philippe; Gallez, Bernard; Taper, Henryk; Eeckhoudt, Stéphane; Knoops, Laurent; Calderon, Pedro Buc; Verrax, Julien

    2011-10-01

    Numerous studies suggest that generation of oxidative stress could be useful in cancer treatment. In this study, we evaluated, in vitro and in vivo, the antitumor potential of oxidative stress induced by ascorbate/menadione (asc/men). This combination of a reducing agent (ascorbate) and a redox active quinone (menadione) generates redox cycling leading to formation of reactive oxygen species (ROS). Asc/men was tested in several cell types including K562 cells (a stable human-derived leukemia cell line), freshly isolated leukocytes from patients with chronic myeloid leukemia, BaF3 cells (a murine pro-B cell line) transfected with Bcr-Abl and peripheral blood leukocytes derived from healthy donors. Although these latter cells were resistant to asc/men, survival of all the other cell lines was markedly reduced, including the BaF3 cells expressing either wild-type or mutated Bcr-Abl. In a standard in vivo model of subcutaneous tumor transplantation, asc/men provoked a significant delay in the proliferation of K562 and BaF3 cells expressing the T315I mutated form of Bcr-Abl. No effect of asc/men was observed when these latter cells were injected into blood of mice most probably because of the high antioxidant potential of red blood cells, as shown by in vitro experiments. We postulate that cancer cells are more sensitive to asc/men than healthy cells because of their lack of antioxidant enzymes, mainly catalase. The mechanism underlying this cytotoxicity involves the oxidative cleavage of Hsp90 with a subsequent loss of its chaperone function thus leading to degradation of wild-type and mutated Bcr-Abl protein.

  12. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity.

    Science.gov (United States)

    Yokota, Asumi; Kimura, Shinya; Masuda, Satohiro; Ashihara, Eishi; Kuroda, Junya; Sato, Kiyoshi; Kamitsuji, Yuri; Kawata, Eri; Deguchi, Yasuyuki; Urasaki, Yoshimasa; Terui, Yasuhito; Ruthardt, Martin; Ueda, Takanori; Hatake, Kiyohiko; Inui, Ken-ichi; Maekawa, Taira

    2007-01-01

    Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

  13. [Development of Ph negative acute myeloid leukemia in a patient with minor-BCR/ABL positive chronic myeloid leukemia achieving a partial cytogenetic response during tyrosine kinase inhibitor treatment].

    Science.gov (United States)

    Fujii, Soichiro; Miura, Ikuo; Tanaka, Hideo

    2015-06-01

    A 78-year-old male, who had CKD and chronic heart failure, was referred to our hospital for evaluation of leukocytosis. His bone marrow contained 12% blast cells and chromosome analysis showed the Ph chromosome as well as other changes. The patient was diagnosed with the accelerated-phase CML because FISH and RT-PCR disclosed BCR/ABL fusion signals and minor BCR/ABL, respectively. Imatinib was administered, but the CML was resistant to this treatment. We gave him nilotinib employing a reduced and intermittent administration protocol because of the progression of anemia and heart failure. The patient achieved PCyR in 8 months, but, 12 months later, his WBC count increased and 83% of the cells were blasts. Because the probable diagnosis was the blast crisis of CML, we switched from nilotinib to dasatinib. However, leukocytosis worsened and he died of pneumonia. It was later revealed that he had a normal karyotype and both FISH and RT-PCR analysis of BCR/ABL were negative. His final diagnosis was Ph negative AML developing from Ph positive CML in PCyR. Since there were no dysplastic changes indicative of MDS, it was assumed that the AML was not secondary leukemia caused by the tyrosine kinase inhibitor but, rather, de novo AML.

  14. Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome–positive or BCR-ABL–positive acute lymphoblastic leukemia: a Canadian consensus

    Science.gov (United States)

    Couban, S.; Savoie, L.; Mourad, Y. Abou; Leber, B.; Minden, M.; Turner, R.; Palada, V.; Shehata, N.; Christofides, A.; Lachance, S.

    2014-01-01

    Adult Philadelphia chromosome–positive (Ph+) or BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (all) is an acute leukemia previously associated with a high relapse rate, short disease-free survival, and poor overall survival. In adults, allogeneic hematopoietic cell transplant in first remission remains the only proven curative strategy for transplant-eligible patients. The introduction of tyrosine kinase inhibitors (tkis) in the treatment of patients with Ph+ or BCR-ABL+ all has significantly improved the depth and duration of complete remission, allowing more patients to proceed to transplantation. Although tkis are now considered a standard of care in this setting, few randomized trials have examined the optimal use of tkis in patients with Ph+ all. Questions of major importance remain, including the best way to administer these medications, the choice of tki to administer, and the schedule and the duration to use. We present the results of a systematic review of the literature with consensus recommendations based on the available evidence. PMID:24764712

  15. Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy.

    Science.gov (United States)

    Liu, Sheng-Hung; Lin, Chao-Hsiung; Liang, Fong-Ping; Chen, Pei-Fen; Kuo, Cheng-Deng; Alam, Mohd Mujahid; Maiti, Barnali; Hung, Shih-Kai; Chi, Chin-Wen; Sun, Chung-Ming; Fu, Shu-Ling

    2014-01-15

    Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Four-channel asymmetric Real-Time PCR hybridization probe assay: a rapid pre-screening method for critical BCR-ABL kinase domain mutations.

    Science.gov (United States)

    Martinez-Serra, Jordi; Gutiérrez, Antonio; Marcús, Toni F; Soverini, Simona; Amat, Juan Carlos; Navarro-Palou, María; Ros, Teresa; Bex, Teresa; Ballester, Carmen; Bauça, Josep Miquel; SanFelix, Sara; Novo, Andrés; Vidal, Carmen; Santos, Carmen; Besalduch, Joan

    2012-03-01

    Within the laboratory protocols, used for the study of BCR-ABL resistance mutations in chronic myeloid leukemia patients treated with Imatinib, direct sequencing remains the reference method. Since the incidence of patients with a mutation-related loss of response is not very high, it is very useful in the routine laboratory to perform a fast pre-screening method. With this in mind, we have designed a new technique, based on a single Real-Time FRET-based PCR, followed by a study of melting peaks. This new tool, developed in a LightCycler 2.0, combines four different fluorescence channels for the simultaneous detection, in a single close tube, of critical mutations within the ABL kinase domain. Assay evaluation performed on 33 samples, previously genotyped by sequentiation, resulted in full concordance of results. This new methodology detects in a few steps the presence of critical mutations associated to Imatinib resistance. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. 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.

  18. Speciation of heavy metals Cu, Ni and Zn by modified BCR sequential extraction procedure in sediments from Banten Bay, Banten Province, Indonesia

    Science.gov (United States)

    Lestari; Budiyanto, F.; Hindarti, D.

    2018-02-01

    Banten Bay is categorized as a marine area that is busy with marine tourism activities, settlements and also industries. One potential impact of the condition is the occurrence of pollution from both industrial and domestic sources, erosion and sedimentation in the coastal environment. Samples were collected from 25 representative stations in April 2016. Chemical speciation of three heavy metals (Cu, Ni, and Zn) was studied using a modified sequential extraction procedure proposed by the European Standard, Measurements and Testing (SM&T) program, formerly the Community Bureau of Reference (BCR). The aims of this study are to determine geochemical speciation of 4 bounds of metal: acid-soluble, reducible, oxidizable and residual, and to assess their impacts in the sediments of Banten Bay, Indonesia. The result shows that the percentage of Copper (45.90-83.75%), Nickel (18.28-65.66%), and Zinc (30.45-79.51%) were mostly accumulated in residual fraction of the total concentrations. The Risk Assessment Code (RAC) reveals that about 0-7.07% of Copper and 1.11-24.35 % of Zinc at sites exist in exchangeable fraction and therefore, they are in low risk category. While 7.34-34.90 of Ni at sites exists in exchangeable fraction and therefore, it is in medium risk category to aquatic environment.

  19. Multivariate Analyses and Evaluation of Heavy Metals by Chemometric BCR Sequential Extraction Method in Surface Sediments from Lingdingyang Bay, South China

    Directory of Open Access Journals (Sweden)

    Linglong Cao

    2015-04-01

    Full Text Available Sediments in estuary areas are recognized as the ultimate reservoirs for numerous contaminants, e.g., toxic metals. Multivariate analyses by chemometric evaluation were performed to classify metal ions (Cu, Zn, As, Cr, Pb, Ni and Cd in superficial sediments from Lingdingyang Bay and to determine whether or not there were potential contamination risks based on the BCR sequential extraction scheme. The results revealed that Cd was mainly in acid-soluble form with an average of 75.99% of its total contents and thus of high potential availability, indicating significant anthropogenic sources, while Cr, As, Ni were enriched in the residual fraction which could be considered as the safest ingredients to the environment. According to the proportion of secondary to primary phases (KRSP, Cd had the highest bioavailable fraction and represented high or very high risk, followed by Pb and Cu with medium risks in most of samples. The combined evaluation of the Pollution Load Index (PLI and the mean Effect Range Median Quotient (mERM-Q highlighted that the greatest potential environmental risk area was in the northwest of Lingdingyang Bay. Almost all of the sediments had a 21% probability of toxicity. Additionally, Principal Component Analysis (PCA revealed that the survey region was significantly affected by two main sources of anthropogenic contributions: PC1 showed increased loadings of variables in acid-soluble and reducible fractions that were consistent with the input from industrial wastes (such as manufacturing, metallurgy, chemical industry and domestic sewages; PC2 was characterized by increased loadings of variables in residual fraction that could be attributed to leaching and weathering of parent rocks. The results obtained demonstrated the need for appropriate remediation measures to alleviate soil pollution problem due to the more aggregation of potentially risky metals. Therefore, it is of crucial significance to implement the targeted

  20. Comparative study of different methodologies to detect the JAK2 V617F mutation in chronic BCR-ABL1 negative myeloproliferative neoplasms

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    Alline Didone

    2016-04-01

    Full Text Available Objectives: A mutation in the JAK2 gene, V617F, has been identified in several BCR-ABL1 negative myeloproliferative neoplasms (MPN: polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF. Defining the presence or absence of this mutation is an essential part of clinical diagnostic algorithms and patient management. Here, we aimed to evaluate the performance of three PCR-based assays: Amplification Refractory Mutation System (ARMS, High-Resolution Melting analysis (HRM, and Sanger direct sequencing, and compare their results with those obtained by a PCR restriction fragment polymorphism assay (PCR-RFLP. Design and methods: We used blood samples from 136 patients (PV=20; PMF=20; ET=28, and other MPN suspected cases=68. Results: Comparable results were observed among the four assays in patients with PV, PMF, and MPN suspected cases. In patients with a diagnosis of ET, the JAK2 V617F mutation was detected in 67.8% of them by the PCR-ARMS and PCR-HRM assay and in 64% of them by the conventional Sanger sequence approach. The PCR-ARMS and PCR-HRM assays were 100% concordant. With these tests, only one of the 20 patients with ET and one of the three patients with clinically suspected MPN gave different results compared with those obtained by the PCR-RFLP. Conclusions: Our results have demonstrated that the PCR-ARMS and PCR-HRM assays could detect the JAK2 V617F mutation effectively in MPN patients, but PCR-HRM assays are rapid and the most cost-effective procedures. Keywords: Myeloproliferative, JAK2 V617F, Mutation, Wild type, Screening

  1. SH2 Domain-Based FRET Biosensor for Measuring BCR-ABL Activity in Living CML Cells.

    Science.gov (United States)

    Fujioka, Mari; Asano, Yumi; Nakada, Shigeyuki; Ohba, Yusuke

    2017-01-01

    Fluorescent proteins (FPs) displaying distinct spectra have shed their light on a wide range of biological functions. Moreover, sophisticated biosensors engineered to contain single or multiple FPs, including Förster resonance energy transfer (FRET)-based biosensors, spatiotemporally reveal the molecular mechanisms underlying a variety of pathophysiological processes. However, their usefulness for applied life sciences has yet to be fully explored. Recently, our research group has begun to expand the potential of FPs from basic biological research to the clinic. Here, we describe a method to evaluate the responsiveness of leukemia cells from patients to tyrosine kinase inhibitors using a biosensor based on FP technology and the principle of FRET. Upon phosphorylation of the tyrosine residue of the biosensor, binding of the SH2 domain to phosphotyrosine induces conformational change of the biosensor and brings the donor and acceptor FPs into close proximity. Therefore, kinase activity and response to kinase inhibitors can be monitored by an increase and a decrease in FRET efficiency, respectively. As in basic research, this biosensor resolves hitherto arduous tasks and may provide innovative technological advances in clinical laboratory examinations. State-of-the-art detection devices that enable such innovation are also introduced.

  2. MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells.

    Directory of Open Access Journals (Sweden)

    Shuit-Mun Wong

    Full Text Available Chronic myeloid leukemia (CML is a clonal disorder of hematopoietic stem/progenitor cells that is caused by the Bcr-Abl oncoprotein. Clinical resistance to the Bcr-Abl inhibitor imatinib is a critical problem in treating CML. This study investigated the antitumor effect and mechanism of MPT0B169, a new antitubulin agent, in K562 CML cells and their derived imatinib-resistant cells, IMR2 and IMR3. IMR2 and IMR3 cells showed complete resistance to imatinib-induced growth inhibition and apoptosis. Resistance involved ERK1/2 overactivation and MDR1 overexpression. MPT0B169 inhibited the growth of K562, IMR2, and IMR3 cells in a dose- and time-dependent manner. MPT0B169 substantially inhibited the mRNA and protein levels of Bcr-Abl, followed by its downstream pathways including Akt, ERK1/2, and STAT3 in these cells. MPT0B169 treatment resulted in a decrease in the polymer form of tubulin according to Western blot analysis. It triggered cell cycle arrest at the G2/M phase before apoptosis, which was related to the upregulation of the mitotic marker MPM2 and the cyclin B1 level, and a change in the phosphorylation of Cdk1. MPT0B169 induced apoptosis in nonresistant and imatinib-resistant cells via a mitochondrion-mediated caspase pathway. Further study showed that the agent led to a decrease in the antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and an increase in the apoptotic protein Bax. Taken together, our results suggest that MPT0B169 might be a promising agent for overcoming imatinib resistance in CML cells.

  3. Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy.

    Science.gov (United States)

    Shiseki, Masayuki; Yoshida, Chikashi; Takezako, Naoki; Ohwada, Akira; Kumagai, Takashi; Nishiwaki, Kaichi; Horikoshi, Akira; Fukuda, Tetsuya; Takano, Hina; Kouzai, Yasuji; Tanaka, Junji; Morita, Satoshi; Sakamoto, Junichi; Sakamaki, Hisashi; Inokuchi, Koiti

    2017-10-01

    With the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI) to inhibit BCR-ABL1 kinase, the outcome of chronic-phase chronic myeloid leukemia (CP-CML) has improved dramatically. However, only a small proportion of CP-CML patients subsequently achieve a deep molecular response (DMR) with imatinib. Dasatinib, a second-generation TKI, is more potent than imatinib in the inhibition of BCR-ABL1 tyrosine kinase in vitro and more effective in CP-CML patients who do not achieve an optimal response with imatinib treatment. In the present study, we attempted to investigate whether switching the treatment from imatinib to dasatinib can induce DMR in 16 CP-CML patients treated with imatinib for at least two years who achieved a major molecular response (MMR) with detectable levels of BCR-ABL1 transcripts. The rates of achievement of DMR at 1, 3, 6 and 12 months after switching to dasatinib treatment in the 16 patients were 44% (7/16), 56% (9/16), 63% (10/16) and 75% (12/16), respectively. The cumulative rate of achieving DMR at 12 months from initiation of dasatinib therapy was 93.8% (15/16). The proportion of natural killer cells and cytotoxic T cells in peripheral lymphocytes increased after switching to dasatinib. In contrast, the proportion of regulatory T cells decreased during treatment. The safety profile of dasatinib was consistent with previous studies. Switching to dasatinib would be a therapeutic option for CP-CML patients who achieved MMR but not DMR by imatinib, especially for patients who wish to discontinue TKI therapy.

  4. Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec alters different oncogenes, apoptotic/antiapoptotic genes and cell proliferation factors (microarray study).

    Science.gov (United States)

    Zhelev, Zhivko; Bakalova, Rumiana; Ohba, Hideki; Ewis, Ashraf; Ishikawa, Mitsuru; Shinohara, Yasuo; Baba, Yoshinobu

    2004-07-16

    Short 21-mer double-stranded/small-interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia. The ds/siRNAs were transfected into bcr-abl-positive K-562 (derived from blast crisis chronic myelogenous leukemia), using lipofectamine. Penetrating of ds/siRNAs into the cells was detected by fluorescent confocal microscopy, using fluorescein-labeled ds/siRNAs. The cells were treated with mix of three siRNA sequences (3 x 60 nM) during 6 days with three repetitive transfections. The siRNA-treatment was accompanied with significant reduction of bcr-abl mRNA, p210, protein tyrosine kinase activity and cell proliferation index. Treatment of cells with Glivec (during 8 days with four repetitive doses, 180 nM single dose) resulted in analogous reduction of cell proliferation activity, stronger suppression of protein tyrosine kinase activity, and very low reduction of p210. siRNA-mix and Glivec did not affect significantly the viability of normal lymphocytes. Microarray analysis of siRNA- and Glivec-treated K-562 cells demonstrated that both pathways of bcr-abl suppression were accompanied with overexpression and suppression of many different oncogenes, apoptotic/antiapoptotic and cell proliferation factors. The following genes of interest were found to decrease in relatively equal degree in both siRNA- and Glivec-treated cells: Bcd orf1 and orf2 proto-oncogene, chromatin-specific transcription elongation factor FACT 140-kDa subunit mRNA, gene encoding splicing factor SF1, and mRNA for Tec protein tyrosine kinase. siRNA-mix and Glivec provoked overexpression of the following common genes: c-jun proto-oncogene, protein kinase C-alpha, pvt-1 oncogene homologue (myc activator), interleukin-6, 1-8D gene from interferon-inducible gene family, tumor necrosis factor receptor superfamily (10b), and STAT-induced STAT inhibitor.

  5. Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl{sup +} K562 and Jak2(V617F){sup +} HEL Leukemia Cells

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Axel [Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main 60596 (Germany); Borghouts, Corina [Ganymed Pharmaceuticals AG, Mainz 55131 (Germany); Brendel, Christian [Boston Children’s Hospital, Division of Hematology/Oncology, Boston, MA 02115 (United States); Moriggl, Richard [Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090 (Austria); Delis, Natalia; Brill, Boris; Vafaizadeh, Vida; Groner, Bernd, E-mail: Groner@em.uni-frankfurt.de [Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main 60596 (Germany)

    2015-03-19

    Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl{sup +} K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells

  6. BCR-ABL1: Test

    Science.gov (United States)

    ... Gregory J. Tsongalis, PhD, HCLD, CC. Professor of Pathology, Director, Molecular Pathology, Dartmouth Hitchcock Medical Center and Geisel School of ... Reviews Besa, E. and Woermann, U. (Updated 2010 March 16). Chronic Myelogenous Leukemia. eMedicine [On-line information]. ...

  7. Stepwise effects of the BCR sequential chemical extraction procedure on dissolution and metal release from common ferromagnesian clay minerals: A combined solution chemistry and X-ray powder diffraction study

    Energy Technology Data Exchange (ETDEWEB)

    Ryan, P.C. [Geology Department, Middlebury College, Middlebury, Vermont 05753 (United States)], E-mail: pryan@middlebury.edu; Hillier, S. [Macaulay Institute, Aberdeen, AB15 8QH UK (United Kingdom); Wall, A.J. [Department of Geosciences, Penn State University, University Park, Pennsylvania, 16802 (United States)

    2008-12-15

    Sequential extraction procedures (SEPs) are commonly used to determine speciation of trace metals in soils and sediments. However, the non-selectivity of reagents for targeted phases has remained a lingering concern. Furthermore, potentially reactive phases such as phyllosilicate clay minerals often contain trace metals in structural sites, and their reactivity has not been quantified. Accordingly, the objective of this study is to analyze the behavior of trace metal-bearing clay minerals exposed to the revised BCR 3-step plus aqua regia SEP. Mineral quantification based on stoichiometric analysis and quantitative powder X-ray diffraction (XRD) documents progressive dissolution of chlorite (CCa-2 ripidolite) and two varieties of smectite (SapCa-2 saponite and SWa-1 nontronite) during steps 1-3 of the BCR procedure. In total, 8 ({+-} 1) % of ripidolite, 19 ({+-} 1) % of saponite, and 19 ({+-} 3) % of nontronite (% mineral mass) dissolved during extractions assumed by many researchers to release trace metals from exchange sites, carbonates, hydroxides, sulfides and organic matter. For all three reference clays, release of Ni into solution is correlated with clay dissolution. Hydrolysis of relatively weak Mg-O bonds (362 kJ/mol) during all stages, reduction of Fe(III) during hydroxylamine hydrochloride extraction and oxidation of Fe(II) during hydrogen peroxide extraction are the main reasons for clay mineral dissolution. These findings underscore the need for precise mineral quantification when using SEPs to understand the origin/partitioning of trace metals with solid phases.

  8. Molecular genetic tests for JAK2V617F, Exon12_JAK2 and MPLW515K/L are highly informative in the evaluation of patients suspected to have BCR-ABL1-negative myeloproliferative neoplasms.

    Science.gov (United States)

    dos Santos, Marcos Tadeu; Mitne-Neto, Miguel; Miyashiro, Kozue; Chauffaille, Maria de Lourdes L Ferrari; Rizzatti, Edgar Gil

    2014-02-01

    Polycythaemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF), are the most common myeloproliferative neoplasms (MPN) in patients without the BCR-ABL1 gene rearrangement. They are caused by clonal expansion of haematopoietic stem cells and share, as a diagnostic criterion, the identification of JAK2V617F mutation. Classically, when other clinical criteria are present, a JAK2V617F negative case requires the analysis of Exon12_JAK2 for the diagnosis of PV, and of MPL515K/L mutations for the diagnosis of ET and MF. Here, we evaluated 78 samples from Brazilian patients suspected to have MPN, without stratification for PV, ET or MF. We found that 28 (35.9%) are JAK2V617F carriers; from the 50 remaining samples, one (2%) showed an Exon12_JAK2 mutation, and another (2%) was positive for MPLW515L mutation. In summary, the investigation of JAK2V617F, Exon12_JAK2 and MPLW515K/L was relevant for the diagnosis of 38.4% of patients suspected to have BCR-ABL1-negative MPN, suggesting that molecular genetic tests are useful for a quick and unequivocal diagnosis of MPN.

  9. Process Debottlenecking and Retrofit of Palm Oil Milling Process via Inoperability Input-Output Modelling

    Directory of Open Access Journals (Sweden)

    May Tan May

    2018-01-01

    Full Text Available In recent years, there has been an increase in crude palm oil (CPO demand, resulting in palm oil mills (POMs seizing the opportunity to increase CPO production to make more profits. A series of equipment are designed to operate in their optimum capacities in the current existing POMs. Some equipment may be limited by their maximum design capacities when there is a need to increase CPO production, resulting in process bottlenecks. In this research, a framework is developed to provide stepwise procedures on identifying bottlenecks and retrofitting a POM process to cater for the increase in production capacity. This framework adapts an algebraic approach known as Inoperability Input-Output Modelling (IIM. To illustrate the application of the framework, an industrial POM case study was solved using LINGO software in this work, by maximising its production capacity. Benefit-to-Cost Ratio (BCR analysis was also performed to assess the economic feasibility. As results, the Screw Press was identified as the bottleneck. The retrofitting recommendation was to purchase an additional Screw Press to cater for the new throughput with BCR of 54.57. It was found the POM to be able to achieve the maximum targeted production capacity of 8,139.65 kg/hr of CPO without any bottlenecks.

  10. Synthesis, magnetic properties and Moessbauer spectroscopy for the pyrochlore family Bi{sub 2}BB Prime O{sub 7} with B=Cr and Fe and B Prime =Nb, Ta and Sb

    Energy Technology Data Exchange (ETDEWEB)

    Blanco, Maria C. [INFIQC (CONICET), Dpto. de Fisicoquimica, Fac. de Ciencias Quimicas, U.N.C., Cordoba (X5000HUA) (Argentina); Franco, Diego G. [INFIQC (CONICET), Dpto. de Fisicoquimica, Fac. de Ciencias Quimicas, U.N.C., Cordoba (X5000HUA) (Argentina); Centro Atomico Bariloche - CNEA, Av. E. Bustillo 9500, S.C. de Bariloche (8500), R.N. (Argentina); Jalit, Yamile; Pannunzio Miner, Elisa V. [INFIQC (CONICET), Dpto. de Fisicoquimica, Fac. de Ciencias Quimicas, U.N.C., Cordoba (X5000HUA) (Argentina); Berndt, Graciele; Paesano, Andrea [Departamento de Fisica, Universidade Estadual de Maringa, Parana (Brazil); Nieva, Gladys [Centro Atomico Bariloche - CNEA, Av. E. Bustillo 9500, S.C. de Bariloche (8500), R.N. (Argentina); Carbonio, Raul E., E-mail: carbonio@mail.fcq.unc.edu.ar [INFIQC (CONICET), Dpto. de Fisicoquimica, Fac. de Ciencias Quimicas, U.N.C., Cordoba (X5000HUA) (Argentina)

    2012-08-15

    The samples Bi{sub 2}BB Prime O{sub 7}, with B=Cr and Fe and B Prime =Nb, Ta and Sb were prepared by solid state method. The crystallographic structure was investigated on the basis of X-ray powder diffraction data. Rietveld refinements show that the crystal structure is cubic, space group Fd-3m. The Bi{sup 3+} cation on the eight-coordinate pyrochlore A-site shows displacive disorder, as a consequence of its lone pair electron configuration. There is also a considerable A-site disorder shown by Rietveld Analysis and confirmed in the case of the iron containing samples with Moessbauer spectroscopy. The magnetic measurements show paramagnetic behavior at all temperatures for the Cr oxides. The Fe pyrochlores show antiferromagnetic order around 10 K.

  11. Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl.

    Science.gov (United States)

    Odai, H; Sasaki, K; Iwamatsu, A; Nakamoto, T; Ueno, H; Yamagata, T; Mitani, K; Yazaki, Y; Hirai, H

    1997-04-15

    -phosphorylated and associated with Shc and Bcr-Abl. These facts suggest that pp135 is a signaling molecule that has a unique enzymatic activity and should play an important role in the signaling pathway triggered by GM-CSF and in the transformation of hematopoietic cells caused by Bcr-Abl.

  12. Application of a modified BCR sequential extraction (three-step) procedure for the determination of extractable trace metal contents in a sewage sludge amended soil reference material (CRM 483), complemented by a three-year stability study of acetic acid and EDTA extractable metal content.

    Science.gov (United States)

    Rauret, G; López-Sánchez, J F; Sahuquillo, A; Barahona, E; Lachica, M; Ure, A M; Davidson, C M; Gomez, A; Lück, D; Bacon, J; Yli-Halla, M; Muntau, H; Quevauviller, P

    2000-06-01

    This paper provides additional data on a sewage sludge amended soil certified reference material, CRM 483, which was certified in 1997 for its EDTA and acetic acid extractable contents of some trace metals, following standardised extraction procedures. The additional work aimed to test the long-term stability of the material and the applicability of an improved version of the BCR three-step sequential extraction procedure on the sewage sludge amended soil (CRM 483). The paper demonstrates the CRM 483 long-term stability for EDTA and acetic acid extractable contents of Cd, Cr, Cu, Ni, Pb and Zn and gives the results (obtained in the framework of an interlaboratory study) for the extractable contents of the same elements in the CRM 483, following the BCR three-step sequential extraction scheme. The aqua regia extractable contents following the ISO 11466 Standard are also given. The data are given as indicative (not certified) values.

  13. Clinical Efficacy and Safety of First-Line Dasatinib Therapy and the Relevance of Velocity of BCR-ABL1 Transcript Decline for Achievement of Molecular Responses in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Report from the Juntendo Yamanashi Cooperative Study Group.

    Science.gov (United States)

    Takaku, Tomoiku; Iriyama, Noriyoshi; Mitsumori, Toru; Sato, Eriko; Gotoh, Akihiko; Kirito, Keita; Noguchi, Masaaki; Koike, Michiaki; Sakamoto, Junichi; Oba, Koji; Komatsu, Norio

    2018-01-01

    The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels. Thirty-two patients with chronic-phase CML (CML-CP) were enrolled and 30 received 100 mg dasatinib once daily. At 24 months of follow-up, 21 (72%) and 24 (83%) patients achieved an MMR by 12 and 24 months, respectively; the rates of a deep molecular response (DMR) by 12 and 24 months were 48 and 59%, respectively. A shorter halving time of BCR-ABL1 transcripts (≤10.6 days) accurately predicted both an MMR and a DMR. The incidence of pleural effusion was 50%. Our study reconfirmed the efficacy and safety of dasatinib treatment in Japanese patients with newly diagnosed CML-CP. In addition, the usefulness of the halving time of BCR-ABL1 transcripts was validated. These data emphasize the significance of an early treatment response in achieving a DMR during dasatinib therapy. © 2017 S. Karger AG, Basel.

  14. A novel dic (17;18 (p13.1;q11.2 with loss of TP53 and BCR/ABL rearrangement in an Imatinib resistant chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Al-achkar Walid

    2012-08-01

    Full Text Available Abstract Background The so-called Philadelphia (Ph chromosome is present in more than 90% of chronic myeloid leukemia (CML cases. It results in juxtaposition of the 5′ part of the BCR gene on chromosome 22 to the 3′ part of the ABL gene on chromosome 9. Since the majority of CML cases are currently treated with Imatinib, variant rearrangements in general have no specific prognostic significance, although the mechanisms involved in resistance to therapy have yet to be investigated. The T315I mutation within the abl-gene is the most frequent one associated with resistance to tyrosine kinase inhibitors. Results This study evaluated a Ph chromosome positive CML case resistant to imatinib mesylate. A dic(17;18, loss of TP53 gene, co-expression of b2a2 and b3a2 fusions transcript and a T315I mutation were found. Conclusions We reported here a novel case of a Ph chromosome positive CML with a secondary abnormality [dic(17;18], resulting to Glivec resistance but good response to nilotinib. The dic(17;18 might be a marker for poor prognosis in CML. Our finding indicated for an aggressive progression of the disease. The patient died under the treatment due to unknown reasons.

  15. Expression of p89c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells

    International Nuclear Information System (INIS)

    Manzotti, G; Mariani, S A; Corradini, F; Bussolari, R; Cesi, V; Vergalli, J; Ferrari-Amorotti, G; Fragliasso, V; Soliera, A R; Cattelani, S; Raschellà, G; Holyoake, T L; Calabretta, B

    2012-01-01

    The c-Myb gene encodes the p75 c-Myb isoform and less-abundant proteins generated by alternatively spliced transcripts. Among these, the best known is p c-Mybex9b , which contains 121 additional amino acids between exon 9 and 10, in a domain involved in protein–protein interactions and negative regulation. In hematopoietic cells, expression of p c-Mybex9b accounts for 10–15% of total c-Myb; these levels may be biologically relevant because modest changes in c-Myb expression affects proliferation and survival of leukemic cells and lineage choice and frequency of normal hematopoietic progenitors. In this study, we assessed biochemical activities of p c-Mybex9b and the consequences of perturbing its expression in K562 and primary chronic myeloid leukemia (CML) progenitor cells. Compared with p75 c-Myb , p c-Mybex9b is more stable and more effective in transactivating Myb-regulated promoters. Ectopic expression of p c-Mybex9b enhanced proliferation and colony formation and reduced imatinib (IM) sensitivity of K562 cells; conversely, specific downregulation of p c-Mybex9b reduced proliferation and colony formation, enhanced IM sensitivity of K562 cells and markedly suppressed colony formation of CML CD34 + cells, without affecting the levels of p75 c-Myb . Together, these studies indicate that expression of the low-abundance p c-Mybex9b isoform has an important role for the overall biological effects of c-Myb in BCR/ABL-transformed cells

  16. Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs).

    Science.gov (United States)

    Kalle, Arunasree M; Sachchidanand, Sachchidanand; Pallu, Reddanna

    2010-09-01

    Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE(2) to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE(2)-cAMP-PKC-mediated pathway. Copyright 2010 Elsevier Ltd. All rights reserved.

  17. Effect of Mechanical Stresses and Annealing on the Magnetic Structure and the Magnetic Impedance of Amorphous CoFeSiBCr Microwires

    Science.gov (United States)

    Nematov, M. G.; Salem, M. M.; Azim, U.; Akhmat, M.; Morchenko, A. T.; Yudanov, N. A.; Panina, L. V.

    2018-02-01

    The structural and magnetic properties of amorphous ferromagnetic microwires can undergo significant measurements under the action of external mechanical stresses and heat treatment. The study of transformations occurring in this case is important for designing various sensors of mechanical stresses, loading, and temperature and also for inducing in the wires a certain type of magnetic anisotropy that plays a significant role in the realization of various effects in them. In this work, the influence of external stresses and annealing on the processes of the magnetization and the magnetic impedance of Co71Fe5B11Si10Cr3 microwires having a low positive magnetostriction ( 10-8) in amorphous state has been studied. The influence of external stresses leads to a sharp change in the character of the magnetization reversal curve, which was due to the change in the sign of the magnetostriction and the type of magnetic anisotropy. The amplitude of higher harmonics and the value of the magnetic impedance, respectively, are sensitive to mechanical stresses. Elastic stresses in the wires with a partial crystallization do not lead to a marked change in the magnetic properties; however, annealing can lead to a substantial increase in the axial magnetic anisotropy of the wires existing in the stressed state. The experimental results are analyzed in the framework of a magnetostriction model of induced magnetic anisotropy.

  18. Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies

    Science.gov (United States)

    Cazzaniga, Giovanni; De Lorenzo, Paola; Alten, Julia; Röttgers, Silja; Hancock, Jeremy; Saha, Vaskar; Castor, Anders; Madsen, Hans O.; Gandemer, Virginie; Cavé, Hélène; Leoni, Veronica; Köhler, Rolf; Ferrari, Giulia M.; Bleckmann, Kirsten; Pieters, Rob; van der Velden, Vincent; Stary, Jan; Zuna, Jan; Escherich, Gabriele; zur Stadt, Udo; Aricò, Maurizio; Conter, Valentino; Schrappe, Martin; Valsecchi, Maria Grazia; Biondi, Andrea

    2018-01-01

    The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10−4 and 70 with MRD≥5×10−4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis. PMID

  19. Mechanical characterization of Cu-Zn wire electrode base used in EDM and study of influence of the process of machining on its properties

    Energy Technology Data Exchange (ETDEWEB)

    Sedjal, H., E-mail: hasedjal@yahoo.fr; Amirat, B. [Département of Mechanical engineering, University of M.MAMMERI, Tizi Ouzou (Algeria); Aichour, M.; Marouf, T.; Chitroub, M. [Engineering and Material Sciences Laboratory, Department of Metallurgy, Polytechnic national school, Algiers (Algeria)

    2015-03-30

    This work is part of a Research National project (PNR) carried out by the group of research of the engineering and material sciences laboratory of the polytechnic national school at Algiers in collaboration with company BCR, which relates to “the characterization of the wire intended for the EDM of matrices metal. The goal of this work is to bring metallographic explanations on the wire electrode used by the machine ROBOFIL 290P, mechanically characterized this wire as of knowing of advantage about the process of its manufacturing (wiredrawing, .) The methods of studies used are it micro Vickers pyramid hardness, the tensile test, optical microscopy and scan electronic microscopy SEM.

  20. Application of the Fenton's process in a bubble column reactor for hydroquinone degradation.

    Science.gov (United States)

    Lima, Vanessa N; Rodrigues, Carmen S D; Madeira, Luis M

    2017-11-27

    The aim of this study was to assess the degradation and mineralization of hydroquinone (HQ) by the Fenton's process in a bubble column reactor (BCR). The effect of the main operating variables, namely, air flow rate, effluent volume, hydrogen peroxide (H 2 O 2 ) concentration, catalyst (Fe 2+ ) dose, initial pH, and temperature, were assessed. For all air flow rates tested, no concentration gradients along the column were noticed, evidencing that a good mixing was reached in the BCR. For the best conditions tested ([H 2 O 2 ] = 500 mg/L, [Fe 2+ ] = 45 mg/L, T = 24 °C, Q air  = 2.5 mL/min, pH = 3.0, and V = 5 L), complete HQ degradation was reached, with ~ 39% of total organic carbon (TOC) removal, and an efficiency of the oxidant use-η H2O2 -of 0.39 (ratio between TOC removed per H 2 O 2 consumed normalized by the theoretical stoichiometric value); moreover, a non-toxic effluent was generated. Under these conditions, the intermediates and final oxidation compounds identified and quantified were a few carboxylic acids, namely, maleic, pyruvic, and oxalic. As a strategy to improve the TOC removal, a gradual dosage of the optimal H 2 O 2 concentration was implemented, being obtained ~ 55% of mineralization (with complete HQ degradation). Finally, the matrix effect was evaluated, for which a real wastewater was spiked with 100 mg/L of HQ; no reduction in terms of HQ degradation and mineralization was observed compared to the solution in distilled water.

  1. Fuel processing. Wastes processing

    International Nuclear Information System (INIS)

    Bourgeois, M.

    2000-01-01

    The gaseous, liquid and solid radioactive effluents generated by the fuel reprocessing, can't be release in the environment. They have to be treated in order to respect the limits of the pollution regulations. These processing are detailed and discussed in this technical paper. A second part is devoted to the SPIN research program relative to the separation of the long life radionuclides in order to reduce the radioactive wastes storage volume. (A.L.B.)

  2. Process Accounting

    OpenAIRE

    Gilbertson, Keith

    2002-01-01

    Standard utilities can help you collect and interpret your Linux system's process accounting data. Describes the uses of process accounting, standard process accounting commands, and example code that makes use of process accounting utilities.

  3. Targeting the BCR signalosome in B cell malignancies

    NARCIS (Netherlands)

    de Rooij, M.F.M.

    2017-01-01

    Chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM) are B-cell malignancies which are still incurable. In these lymphomas, the cells proliferate in specialized niches in lymph nodes and bone marrow, in which they are provided by stromal-derived

  4. 75 FR 5069 - BCR Holdings, Inc.; Notice of Application

    Science.gov (United States)

    2010-02-01

    ...) 208-3676 or TTY, (202) 502-8659. Any questions regarding this application should be directed to Thomas W. Cook, 805 East Union Street, Broken Arrow, OK 74011, via telephone at (918) 449-0333, or e-mail...

  5. Meat Processing.

    Science.gov (United States)

    Legacy, Jim; And Others

    This publication provides an introduction to meat processing for adult students in vocational and technical education programs. Organized in four chapters, the booklet provides a brief overview of the meat processing industry and the techniques of meat processing and butchering. The first chapter introduces the meat processing industry and…

  6. Process development

    Energy Technology Data Exchange (ETDEWEB)

    Schuegerl, K

    1984-01-01

    The item 'process development' comprises the production of acetonic/butonal with C. acetobylicum and the yeasting of potato waste. The target is to increase productivity by taking the following measures - optimation of media, on-line process analysis, analysis of reaction, mathematic modelling and identification of parameters, process simulation, development of a state estimator with the help of the on-line process analysis and the model, optimization and adaptive control.

  7. Poisson processes

    NARCIS (Netherlands)

    Boxma, O.J.; Yechiali, U.; Ruggeri, F.; Kenett, R.S.; Faltin, F.W.

    2007-01-01

    The Poisson process is a stochastic counting process that arises naturally in a large variety of daily life situations. We present a few definitions of the Poisson process and discuss several properties as well as relations to some well-known probability distributions. We further briefly discuss the

  8. Data processing

    CERN Document Server

    Fry, T F

    2013-01-01

    Data Processing discusses the principles, practices, and associated tools in data processing. The book is comprised of 17 chapters that are organized into three parts. The first part covers the characteristics, systems, and methods of data processing. Part 2 deals with the data processing practice; this part discusses the data input, output, and storage. The last part discusses topics related to systems and software in data processing, which include checks and controls, computer language and programs, and program elements and structures. The text will be useful to practitioners of computer-rel

  9. IL-4Rα-associated antigen processing by B cells promotes immunity in Nippostrongylus brasiliensis infection.

    Directory of Open Access Journals (Sweden)

    William G C Horsnell

    2013-10-01

    Full Text Available In this study, B cell function in protective T(H2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Rα and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Rα⁻/⁻ mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Rα expressing B cells into naïve BALB/c mice, but not IL-4Rα or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4⁺ T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88⁻/⁻ B cells. These data suggest TLR dependent antigen processing by IL-4Rα-responsive B cells producing IL-13 contribute significantly to CD4⁺ T cell-mediated protective immunity against N. brasiliensis infection.

  10. Stochastic processes

    CERN Document Server

    Parzen, Emanuel

    1962-01-01

    Well-written and accessible, this classic introduction to stochastic processes and related mathematics is appropriate for advanced undergraduate students of mathematics with a knowledge of calculus and continuous probability theory. The treatment offers examples of the wide variety of empirical phenomena for which stochastic processes provide mathematical models, and it develops the methods of probability model-building.Chapter 1 presents precise definitions of the notions of a random variable and a stochastic process and introduces the Wiener and Poisson processes. Subsequent chapters examine

  11. Magnetics Processing

    Data.gov (United States)

    Federal Laboratory Consortium — The Magnetics Processing Lab equipped to perform testing of magnetometers, integrate them into aircraft systems, and perform data analysis, including noise reduction...

  12. Data processing

    International Nuclear Information System (INIS)

    Cousot, P.

    1988-01-01

    The 1988 progress report of the Data Processing laboratory (Polytechnic School, France), is presented. The laboratory research fields are: the semantics, the tests and the semantic analysis of the codes, the formal calculus, the software applications, the algorithms, the neuron networks and VLSI (Very Large Scale Integration). The investigations concerning the polynomial rings are performed by means of the standard basis approach. Among the research topics, the Pascal codes, the parallel processing, the combinatorial, statistical and asymptotic properties of the fundamental data processing tools, the signal processing and the pattern recognition. The published papers, the congress communications and the thesis are also included [fr

  13. Suppurative processes

    International Nuclear Information System (INIS)

    Vinner, M.G.

    1983-01-01

    Suppurative process in the case of bronchiectatic disease, abscess and gang rene of lungs, has been described. Characteristic signs of roentgenologic pictu re of the above-mentioned diseases are considered. It is shown,that in most cas es roentgenologic studies give a possibility to make a high-quality diagnosis of suppurative processes

  14. Design Processes

    DEFF Research Database (Denmark)

    Ovesen, Nis

    2009-01-01

    Inspiration for most research and optimisations on design processes still seem to focus within the narrow field of the traditional design practise. The focus in this study turns to associated businesses of the design professions in order to learn from their development processes. Through interviews...... and emerging production methods....

  15. Process development

    International Nuclear Information System (INIS)

    Zapata G, G.

    1989-01-01

    Process development: The paper describes the organization and laboratory facilities of the group working on radioactive ore processing studies. Contains a review of the carried research and the plans for the next future. A list of the published reports is also presented

  16. Sustainable processing

    DEFF Research Database (Denmark)

    Kristensen, Niels Heine

    2004-01-01

    Kristensen_NH and_Beck A: Sustainable processing. In Otto Schmid, Alexander Beck and Ursula Kretzschmar (Editors) (2004): Underlying Principles in Organic and "Low-Input Food" Processing - Literature Survey. Research Institute of Organic Agriculture FiBL, CH-5070 Frick, Switzerland. ISBN 3-906081-58-3...

  17. Food processing

    NARCIS (Netherlands)

    Teodorowicz, Malgorzata; Neerven, Van Joost; Savelkoul, Huub

    2017-01-01

    The majority of foods that are consumed in our developed society have been processed. Processing promotes a non-enzymatic reaction between proteins and sugars, the Maillard reaction (MR). Maillard reaction products (MRPs) contribute to the taste, smell and color of many food products, and thus

  18. Membrane processes

    Science.gov (United States)

    Staszak, Katarzyna

    2017-11-01

    The membrane processes have played important role in the industrial separation process. These technologies can be found in all industrial areas such as food, beverages, metallurgy, pulp and paper, textile, pharmaceutical, automotive, biotechnology and chemical industry, as well as in water treatment for domestic and industrial application. Although these processes are known since twentieth century, there are still many studies that focus on the testing of new membranes' materials and determining of conditions for optimal selectivity, i. e. the optimum transmembrane pressure (TMP) or permeate flux to minimize fouling. Moreover the researchers proposed some calculation methods to predict the membrane processes properties. In this article, the laboratory scale experiments of membrane separation techniques, as well their validation by calculation methods are presented. Because membrane is the "heart" of the process, experimental and computational methods for its characterization are also described.

  19. Process mining

    DEFF Research Database (Denmark)

    van der Aalst, W.M.P.; Rubin, V.; Verbeek, H.M.W.

    2010-01-01

    Process mining includes the automated discovery of processes from event logs. Based on observed events (e.g., activities being executed or messages being exchanged) a process model is constructed. One of the essential problems in process mining is that one cannot assume to have seen all possible...... behavior. At best, one has seen a representative subset. Therefore, classical synthesis techniques are not suitable as they aim at finding a model that is able to exactly reproduce the log. Existing process mining techniques try to avoid such “overfitting” by generalizing the model to allow for more...... support for it). None of the existing techniques enables the user to control the balance between “overfitting” and “underfitting”. To address this, we propose a two-step approach. First, using a configurable approach, a transition system is constructed. Then, using the “theory of regions”, the model...

  20. Partial processing

    International Nuclear Information System (INIS)

    1978-11-01

    This discussion paper considers the possibility of applying to the recycle of plutonium in thermal reactors a particular method of partial processing based on the PUREX process but named CIVEX to emphasise the differences. The CIVEX process is based primarily on the retention of short-lived fission products. The paper suggests: (1) the recycle of fission products with uranium and plutonium in thermal reactor fuel would be technically feasible; (2) it would, however, take ten years or more to develop the CIVEX process to the point where it could be launched on a commercial scale; (3) since the majority of spent fuel to be reprocessed this century will have been in storage for ten years or more, the recycling of short-lived fission products with the U-Pu would not provide an effective means of making refabrication fuel ''inaccessible'' because the radioactivity associated with the fission products would have decayed. There would therefore be no advantage in partial processing

  1. Process monitoring

    International Nuclear Information System (INIS)

    Anon.

    1981-01-01

    Many of the measurements and observations made in a nuclear processing facility to monitor processes and product quality can also be used to monitor the location and movements of nuclear materials. In this session information is presented on how to use process monitoring data to enhance nuclear material control and accounting (MC and A). It will be seen that SNM losses can generally be detected with greater sensitivity and timeliness and point of loss localized more closely than by conventional MC and A systems if process monitoring data are applied. The purpose of this session is to enable the participants to: (1) identify process unit operations that could improve control units for monitoring SNM losses; (2) choose key measurement points and formulate a loss indicator for each control unit; and (3) describe how the sensitivities and timeliness of loss detection could be determined for each loss indicator

  2. Process automation

    International Nuclear Information System (INIS)

    Moser, D.R.

    1986-01-01

    Process automation technology has been pursued in the chemical processing industries and to a very limited extent in nuclear fuel reprocessing. Its effective use has been restricted in the past by the lack of diverse and reliable process instrumentation and the unavailability of sophisticated software designed for process control. The Integrated Equipment Test (IET) facility was developed by the Consolidated Fuel Reprocessing Program (CFRP) in part to demonstrate new concepts for control of advanced nuclear fuel reprocessing plants. A demonstration of fuel reprocessing equipment automation using advanced instrumentation and a modern, microprocessor-based control system is nearing completion in the facility. This facility provides for the synergistic testing of all chemical process features of a prototypical fuel reprocessing plant that can be attained with unirradiated uranium-bearing feed materials. The unique equipment and mission of the IET facility make it an ideal test bed for automation studies. This effort will provide for the demonstration of the plant automation concept and for the development of techniques for similar applications in a full-scale plant. A set of preliminary recommendations for implementing process automation has been compiled. Some of these concepts are not generally recognized or accepted. The automation work now under way in the IET facility should be useful to others in helping avoid costly mistakes because of the underutilization or misapplication of process automation. 6 figs

  3. Perceptual Processing Affects Conceptual Processing

    Science.gov (United States)

    van Dantzig, Saskia; Pecher, Diane; Zeelenberg, Rene; Barsalou, Lawrence W.

    2008-01-01

    According to the Perceptual Symbols Theory of cognition (Barsalou, 1999), modality-specific simulations underlie the representation of concepts. A strong prediction of this view is that perceptual processing affects conceptual processing. In this study, participants performed a perceptual detection task and a conceptual property-verification task…

  4. Sewer Processes

    DEFF Research Database (Denmark)

    Hvitved-Jacobsen, Thorkild; Vollertsen, Jes; Nielsen, Asbjørn Haaning

    Since the first edition was published over a decade ago, advancements have been made in the design, operation, and maintenance of sewer systems, and new problems have emerged. For example, sewer processes are now integrated in computer models, and simultaneously, odor and corrosion problems caused...... by hydrogen sulfide and other volatile organic compounds, as well as other potential health issues, have caused environmental concerns to rise. Reflecting the most current developments, Sewer Processes: Microbial and Chemical Process Engineering of Sewer Networks, Second Edition, offers the reader updated...... and valuable information on the sewer as a chemical and biological reactor. It focuses on how to predict critical impacts and control adverse effects. It also provides an integrated description of sewer processes in modeling terms. This second edition is full of illustrative examples and figures, includes...

  5. Electrochemical Processes

    DEFF Research Database (Denmark)

    Bech-Nielsen, Gregers

    1997-01-01

    The notes describe in detail primary and secondary galvanic cells, fuel cells, electrochemical synthesis and electroplating processes, corrosion: measurments, inhibitors, cathodic and anodic protection, details of metal dissolution reactions, Pourbaix diagrams and purification of waste water from...

  6. Dissolution processes

    International Nuclear Information System (INIS)

    Silver, G.L.

    1976-01-01

    This review contains more than 100 observations and 224 references on the dissolution phenomenon. The dissolution processes are grouped into three categories: methods of aqueous attack, fusion methods, and miscellaneous observations on phenomena related to dissolution problems

  7. Renewal processes

    CERN Document Server

    Mitov, Kosto V

    2014-01-01

    This monograph serves as an introductory text to classical renewal theory and some of its applications for graduate students and researchers in mathematics and probability theory. Renewal processes play an important part in modeling many phenomena in insurance, finance, queuing systems, inventory control and other areas. In this book, an overview of univariate renewal theory is given and renewal processes in the non-lattice and lattice case are discussed. A pre-requisite is a basic knowledge of probability theory.

  8. Fuel processing

    International Nuclear Information System (INIS)

    Allardice, R.H.

    1990-01-01

    The technical and economic viability of the fast breeder reactor as an electricity generating system depends not only upon the reactor performance but also on a capability to recycle plutonium efficiently, reliably and economically through the reactor and fuel cycle facilities. Thus the fuel cycle is an integral and essential part of the system. Fuel cycle research and development has focused on demonstrating that the challenging technical requirements of processing plutonium fuel could be met and that the sometimes conflicting requirements of the fuel developer, fuel fabricator and fuel reprocessor could be reconciled. Pilot plant operation and development and design studies have established both the technical and economic feasibility of the fuel cycle but scope for further improvement exists through process intensification and flowsheet optimization. These objectives and the increasing processing demands made by the continuing improvement to fuel design and irradiation performance provide an incentive for continuing fuel cycle development work. (author)

  9. Organizing Process

    DEFF Research Database (Denmark)

    Hull Kristensen, Peer; Bojesen, Anders

    This paper invites to discuss the processes of individualization and organizing being carried out under what we might see as an emerging regime of change. The underlying argumentation is that in certain processes of change, competence becomes questionable at all times. The hazy characteristics...... of this regime of change are pursued through a discussion of competencies as opposed to qualifications illustrated by distinct cases from the Danish public sector in the search for repetitive mechanisms. The cases are put into a general perspective by drawing upon experiences from similar change processes...... in MNCs. The paper concludes by asking whether we can escape from a regime of competence in a world defined by a rhetoric of change and create a more promising world in which doubt and search serve as a strategy for gaining knowledge and professionalism that improve on our capability for mutualism....

  10. Welding process

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    For the final chapter of this book, there is basic introduction on welding process. The good radiography must know somehow on welding process so that they can know what kind of welding that must rejected or not. All of the exposure technique that mention in earlier chapter almost applicable in this field because welding process is critical problem if there is no inspection will be done. So, for this chapter, all the discontinuity that usually appeared will be discussed and there is another discontinuity maybe not to important and do not give big impact if found it, do not described here. On top of that, the decision to accept or reject based on code, standard and specification that agreed by both to make sure that decision that agreed is corrected and more meaningful.

  11. Adaptive Immunity to Leukemia Is Inhibited by Cross-Reactive Induced Regulatory T Cells.

    Science.gov (United States)

    Manlove, Luke S; Berquam-Vrieze, Katherine E; Pauken, Kristen E; Williams, Richard T; Jenkins, Marc K; Farrar, Michael A

    2015-10-15

    BCR-ABL(+) acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific Ag that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL(+) leukemia progression although ultimately this immune response fails. To address how BCR-ABL(+) leukemia escapes immune surveillance, we developed a peptide: MHC class II tetramer that labels endogenous BCR-ABL-specific CD4(+) T cells. Naive mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. The small number of naive BCR-ABL-specific T cells was due to negative selection in the thymus, which depleted BCR-ABL-specific T cells. Consistent with this observation, we saw that BCR-ABL-specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL(+) leukemia, BCR-ABL-specific T cells proliferated and converted into regulatory T (Treg) cells, a process that was dependent on cross-reactivity with self-antigen, TGF-β1, and MHC class II Ag presentation by leukemic cells. Treg cells were critical for leukemia progression in C57BL/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. Thus, BCR-ABL(+) leukemia actively suppresses antileukemia immune responses by converting cross-reactive leukemia-specific T cells into Treg cells. Copyright © 2015 by The American Association of Immunologists, Inc.

  12. Markov Processes in Image Processing

    Science.gov (United States)

    Petrov, E. P.; Kharina, N. L.

    2018-05-01

    Digital images are used as an information carrier in different sciences and technologies. The aspiration to increase the number of bits in the image pixels for the purpose of obtaining more information is observed. In the paper, some methods of compression and contour detection on the basis of two-dimensional Markov chain are offered. Increasing the number of bits on the image pixels will allow one to allocate fine object details more precisely, but it significantly complicates image processing. The methods of image processing do not concede by the efficiency to well-known analogues, but surpass them in processing speed. An image is separated into binary images, and processing is carried out in parallel with each without an increase in speed, when increasing the number of bits on the image pixels. One more advantage of methods is the low consumption of energy resources. Only logical procedures are used and there are no computing operations. The methods can be useful in processing images of any class and assignment in processing systems with a limited time and energy resources.

  13. Film processing

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    The processing was made not only to show what are in the film but also to produce radiograph with high quality where the information gathered really presented level of the quality of the object inspected. Besides that, good procedure will make the film with good quality can keep the film in long time for reference. Here, more detailed on how the dark room functioned and its design. So, the good procedure while processed the film will be discussed detailed in this chapter from entering the dark room to exit from there.

  14. Extraction process

    International Nuclear Information System (INIS)

    Rendall, J.S.; Cahalan, M.J.

    1979-01-01

    A process is described for extracting at least two desired constituents from a mineral, using a liquid reagent which produces the constituents, or compounds thereof, in separable form and independently extracting those constituents, or compounds. The process is especially valuable for the extraction of phosphoric acid and metal values from acidulated phosphate rock, the slurry being contacted with selective extractants for phosphoric acid and metal (e.g. uranium) values. In an example, uranium values are oxidized to uranyl form and extracted using an ion exchange resin. (U.K.)

  15. Process simulation

    International Nuclear Information System (INIS)

    Cao, E.G.; Suarez, P.S.; Pantaleon, J.C.

    1984-01-01

    The search for an optimal design of a heavy water plant is done by means of a simulation model for the mass and enthalpy balances of the SH 2 -H 2 O exchange process. A symplified model for the simulation diagram where the entire plant is represented by a sole tray tower with recicles, and heat and mass feeds/extractions was used. The tower is simulated by the method developed by Tomich with the convergence part given by the algorithm of Broyden. The concluding part of the work is centered in setting the design parameters (flowrates, heat exchange rates, number of plates) wich give the desired process operating conditions. (author) [es

  16. Processing Proteases

    DEFF Research Database (Denmark)

    Ødum, Anders Sebastian Rosenkrans

    -terminal of the scissile bond, leaving C-terminal fusions to have non-native C-termini after processing. A solution yielding native C-termini would allow novel expression and purification systems for therapeutic proteins and peptides.The peptidyl-Lys metallopeptidase (LysN) of the fungus Armillaria mellea (Am) is one...... of few known proteases to have substrate specificity for the C-terminal side of the scissile bond. LysN exhibits specificity for lysine, and has primarily been used to complement trypsin in to proteomic studies. A working hypothesis during this study was the potential of LysN as a processing protease...

  17. Processing Branches

    DEFF Research Database (Denmark)

    Schindler, Christoph; Tamke, Martin; Tabatabai, Ali

    2014-01-01

    Angled and forked wood – a desired material until 19th century, was swept away by industrialization and its standardization of processes and materials. Contemporary information technology has the potential for the capturing and recognition of individual geometries through laser scanning...

  18. BENTONITE PROCESSING

    Directory of Open Access Journals (Sweden)

    Anamarija Kutlić

    2012-07-01

    Full Text Available Bentonite has vide variety of uses. Special use of bentonite, where its absorbing properties are employed to provide water-tight sealing is for an underground repository in granites In this paper, bentonite processing and beneficiation are described.

  19. Purex process

    International Nuclear Information System (INIS)

    Starks, J.B.

    1977-01-01

    The following aspects of the Purex Process are discussed: head end dissolution, first solvent extraction cycle, second plutonium solvent extraction cycle, second uranium solvent extraction cycle, solvent recovery systems, primary recovery column for high activity waste, low activity waste, laboratory waste evaporation, vessel vent system, airflow and filtration, acid recovery unit, fume recovery, and discharges to seepage basin

  20. Innovation process

    DEFF Research Database (Denmark)

    Kolodovski, A.

    2006-01-01

    Purpose of this report: This report was prepared for RISO team involved in design of the innovation system Report provides innovation methodology to establish common understanding of the process concepts and related terminology The report does not includeRISO- or Denmark-specific cultural, econom...

  1. Processing Determinism

    Science.gov (United States)

    O'Grady, William

    2015-01-01

    I propose that the course of development in first and second language acquisition is shaped by two types of processing pressures--internal efficiency-related factors relevant to easing the burden on working memory and external input-related factors such as frequency of occurrence. In an attempt to document the role of internal factors, I consider…

  2. Shale processing

    Energy Technology Data Exchange (ETDEWEB)

    Hampton, W H

    1928-05-29

    The process of treating bituminiferous solid materials such as shale or the like to obtain valuable products therefrom, which comprises digesting a mixture of such material in comminuted condition with a suitable digestion liquid, such as an oil, recovering products vaporized in the digestion, and separating residual solid matter from the digestion liquid by centrifuging.

  3. Radiation processing

    International Nuclear Information System (INIS)

    Noriah Mod Ali

    2005-01-01

    This chapter covers the basic principle and application of radiation technology. The topic titled specific application discussed briefly the following subtopics: 1) Polymer modification - crosslinking, polymerisation, degradation, grafting; 2) Medical sterilisation; 3) Food irradiation; 4) Environmental protection - waste processing, pollutants treatment

  4. Leaching process

    International Nuclear Information System (INIS)

    Heinen, H.J.; McClelland, G.E.; Lindstrom, R.E.

    1982-01-01

    A gold and uranium ore is heap leached in accordance with the process comprising initial agglomeration of fines in the feed by means of a binding agent and cyanide solution. The lixiviant comprises a compatible mixture of sodium cyanide and sodium bicarbonate

  5. Leaching process

    Energy Technology Data Exchange (ETDEWEB)

    Heinen, H J; McClelland, G E; Lindstrom, R E

    1982-10-18

    A gold and uranium ore is heap leached in accordance with the process comprising initial agglomeration of fines in the feed by means of a binding agent and cyanide solution. The lixiviant comprises a compatible mixture of sodium cyanide and sodium bicarbonate.

  6. Signal Processing

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    Signal processing techniques, extensively used nowadays to maximize the performance of audio and video equipment, have been a key part in the design of hardware and software for high energy physics detectors since pioneering applications in the UA1 experiment at CERN in 1979

  7. Process validation for radiation processing

    International Nuclear Information System (INIS)

    Miller, A.

    1999-01-01

    Process validation concerns the establishment of the irradiation conditions that will lead to the desired changes of the irradiated product. Process validation therefore establishes the link between absorbed dose and the characteristics of the product, such as degree of crosslinking in a polyethylene tube, prolongation of shelf life of a food product, or degree of sterility of the medical device. Detailed international standards are written for the documentation of radiation sterilization, such as EN 552 and ISO 11137, and the steps of process validation that are described in these standards are discussed in this paper. They include material testing for the documentation of the correct functioning of the product, microbiological testing for selection of the minimum required dose and dose mapping for documentation of attainment of the required dose in all parts of the product. The process validation must be maintained by reviews and repeated measurements as necessary. This paper presents recommendations and guidance for the execution of these components of process validation. (author)

  8. Stochastic processes

    CERN Document Server

    Borodin, Andrei N

    2017-01-01

    This book provides a rigorous yet accessible introduction to the theory of stochastic processes. A significant part of the book is devoted to the classic theory of stochastic processes. In turn, it also presents proofs of well-known results, sometimes together with new approaches. Moreover, the book explores topics not previously covered elsewhere, such as distributions of functionals of diffusions stopped at different random times, the Brownian local time, diffusions with jumps, and an invariance principle for random walks and local times. Supported by carefully selected material, the book showcases a wealth of examples that demonstrate how to solve concrete problems by applying theoretical results. It addresses a broad range of applications, focusing on concrete computational techniques rather than on abstract theory. The content presented here is largely self-contained, making it suitable for researchers and graduate students alike.

  9. Offshoring Process

    DEFF Research Database (Denmark)

    Slepniov, Dmitrij; Sørensen, Brian Vejrum; Katayama, Hiroshi

    2011-01-01

    The purpose of this chapter is to contribute to the knowledge on how production offshoring and international operations management vary across cultural contexts. The chapter attempts to shed light on how companies approach the process of offshoring in different cultural contexts. In order...... of globalisation. Yet there are clear differences in how offshoring is conducted in Denmark and Japan. The main differences are outlined in a framework and explained employing cultural variables. The findings lead to a number of propositions suggesting that the process of offshoring is not simply a uniform...... technical-rational calculation of the most efficient organisation of activities across national borders, but it is rather specific to the parent companies’ national contexts....

  10. Photobiomodulation Process

    Directory of Open Access Journals (Sweden)

    Yang-Yi Xu

    2012-01-01

    Full Text Available Photobiomodulation (PBM is a modulation of laser irradiation or monochromatic light (LI on biosystems. There is little research on PBM dynamics although its phenomena and mechanism have been widely studied. The PBM was discussed from dynamic viewpoint in this paper. It was found that the primary process of cellular PBM might be the key process of cellular PBM so that the transition rate of cellular molecules can be extended to discuss the dose relationship of PBM. There may be a dose zone in which low intensity LI (LIL at different doses has biological effects similar to each other, so that biological information model of PBM might hold. LIL may self-adaptively modulate a chronic stress until it becomes successful.

  11. Multiphoton processes

    International Nuclear Information System (INIS)

    Manus, C.; Mainfray, G.

    1980-01-01

    The main features of multiphoton processes are described on a somewhat elementary basis. The emphasis is put on multiphoton ionization of atoms where the influence of resonance effects is given through typical examples. The important role played by the coherence of light is shown to produce a very dramatic influence on multiphoton absorption. Different observations concerning molecules, electrons, as well as solid surfaces illustrate the generality of these very non linear interaction between light and matter

  12. Process heat. Triggering the processes

    Energy Technology Data Exchange (ETDEWEB)

    Augsten, Eva

    2012-07-01

    If solar process heat is to find a market, then the decision makers in industrial companies need to be aware that it actually exists. This was one of the main goals of the So-Pro project, which officially drew to a close in April 2012. (orig.)

  13. Metagenomic Analysis of Subtidal Sediments from Polar and Subpolar Coastal Environments Highlights the Relevance of Anaerobic Hydrocarbon Degradation Processes

    Energy Technology Data Exchange (ETDEWEB)

    Espinola, Fernando J.; Dionisi, Hebe M.; Borglin, Sharon; Brislawn, Colin J.; Jansson, Janet K.; Mac Cormack, Walter P.; Carroll, Jolynn; Sjoling, Sara; Lozada , Mariana

    2018-01-02

    In this work, we analyzed the community structure and metabolic potential of sediment microbial communities in high-latitude coastal environments subjected to low to moderate levels of chronic pollution. Subtidal sediments from four low-energy inlets located in polar and subpolar regions from both Hemispheres were analyzed using large-scale 16S rRNA gene and metagenomic sequencing. Communities showed high diversity (Shannon’s index 6.8 to 10.2), with distinct phylogenetic structures (<40% shared taxa at the Phylum level among regions) but similar metabolic potential in terms of sequences assigned to KOs. Environmental factors (mainly salinity, temperature, and in less extent organic pollution) were drivers of both phylogenetic and functional traits. Bacterial taxa correlating with hydrocarbon pollution included families of anaerobic or facultative anaerobic lifestyle, such as Desulfuromonadaceae, Geobacteraceae, and Rhodocyclaceae. In accordance, biomarker genes for anaerobic hydrocarbon degradation (bamA, ebdA, bcrA, and bssA) were prevalent, only outnumbered by alkB, and their sequences were taxonomically binned to the same bacterial groups. BssA-assigned metagenomic sequences showed an extremely wide diversity distributed all along the phylogeny known for this gene, including bssA sensu stricto, nmsA, assA, and other clusters from poorly or not yet described variants. This work increases our understanding of microbial community patterns in cold coastal sediments, and highlights the relevance of anaerobic hydrocarbon degradation processes in subtidal environments.

  14. Speech Processing.

    Science.gov (United States)

    1983-05-01

    The VDE system developed had the capability of recognizing up to 248 separate words in syntactic structures. 4 The two systems described are isolated...AND SPEAKER RECOGNITION by M.J.Hunt 5 ASSESSMENT OF SPEECH SYSTEMS ’ ..- * . by R.K.Moore 6 A SURVEY OF CURRENT EQUIPMENT AND RESEARCH’ by J.S.Bridle...TECHNOLOGY IN NAVY TRAINING SYSTEMS by R.Breaux, M.Blind and R.Lynchard 10 9 I-I GENERAL REVIEW OF MILITARY APPLICATIONS OF VOICE PROCESSING DR. BRUNO

  15. Markov processes

    CERN Document Server

    Kirkwood, James R

    2015-01-01

    Review of ProbabilityShort HistoryReview of Basic Probability DefinitionsSome Common Probability DistributionsProperties of a Probability DistributionProperties of the Expected ValueExpected Value of a Random Variable with Common DistributionsGenerating FunctionsMoment Generating FunctionsExercisesDiscrete-Time, Finite-State Markov ChainsIntroductionNotationTransition MatricesDirected Graphs: Examples of Markov ChainsRandom Walk with Reflecting BoundariesGambler’s RuinEhrenfest ModelCentral Problem of Markov ChainsCondition to Ensure a Unique Equilibrium StateFinding the Equilibrium StateTransient and Recurrent StatesIndicator FunctionsPerron-Frobenius TheoremAbsorbing Markov ChainsMean First Passage TimeMean Recurrence Time and the Equilibrium StateFundamental Matrix for Regular Markov ChainsDividing a Markov Chain into Equivalence ClassesPeriodic Markov ChainsReducible Markov ChainsSummaryExercisesDiscrete-Time, Infinite-State Markov ChainsRenewal ProcessesDelayed Renewal ProcessesEquilibrium State f...

  16. Coking processes

    Energy Technology Data Exchange (ETDEWEB)

    Hiller, H K

    1917-11-20

    A gas suitable for use in containers or motor-vehicles, etc., and consisting mainly of methane, is obtained by distilling at a temperature not exceeding 500/sup 0/C bastard cannel coal, lignite, wood, peat, shale, etc., in an horizontal or vertical retort, through which the material is continuously fed in a thin layer or column by means of a screw conveyor or the like. Cracking or dissociation of the gaseous products is prevented by introducing into the retort part of the gas which is the result of the process and which is compressed to a pressure of at least 15 atmospheres and allowed to expand into the retort to cool and carry away the gaseous products produced. These are then passed through condensers for extracting liquid hydrocarbons, and other hydrocarbons are extracted by passage through washing-oils. The gas is then compressed by a water-cooled pump to a pressure of 15 atmospheres, whereby a spirit similar to petrol is formed, and a stable gas left which is mainly methane, part of the gas being used to carry out the process described above.

  17. Etherification process

    Science.gov (United States)

    Smith, L.A. Jr.; Hearn, D.; Jones, E.M. Jr.

    1990-08-21

    A liquid phase process is described for oligomerization of C[sub 4] and C[sub 5] isoolefins or the etherification thereof with C[sub 1] to C[sub 6] alcohols wherein the reactants are contacted in a reactor with a fixed bed acid cation exchange resin catalyst at an LHSV of 5 to 20, pressure of 0 to 400 psig and temperature of 120 to 300 F wherein the improvement is the operation of the reactor at a pressure to maintain the reaction mixture at its boiling point whereby at least a portion but less than all of the reaction mixture is vaporized. By operating at the boiling point and allowing a portion of the reaction mixture to vaporize, the exothermic heat of reaction is dissipated by the formation of more boil up and the temperature in the reactor is controlled. 2 figs.

  18. Oligomerization process

    Science.gov (United States)

    Smith, L.A. Jr.; Hearn, D.; Jones, E.M. Jr.

    1991-03-26

    A liquid phase process is described for oligomerization of C[sub 4] and C[sub 5] isoolefins or the etherification thereof with C[sub 1] to C[sub 6] alcohols wherein the reactants are contacted in a reactor with a fixed bed acid cation exchange resin catalyst at an LHSV of 5 to 20, pressure of 0 to 400 psig and temperature of 120 to 300 F wherein the improvement is the operation of the reactor at a pressure to maintain the reaction mixture at its boiling point whereby at least a portion but less than all of the reaction mixture is vaporized. By operating at the boiling point and allowing a portion of the reaction mixture to vaporize, the exothermic heat of reaction is dissipated by the formation of more boil up and the temperature in the reactor is controlled. 2 figures.

  19. Lithospheric processes

    Energy Technology Data Exchange (ETDEWEB)

    Baldridge, W. [and others

    2000-12-01

    The authors used geophysical, geochemical, and numerical modeling to study selected problems related to Earth's lithosphere. We interpreted seismic waves to better characterize the thickness and properties of the crust and lithosphere. In the southwestern US and Tien Shari, crust of high elevation is dynamically supported above buoyant mantle. In California, mineral fabric in the mantle correlate with regional strain history. Although plumes of buoyant mantle may explain surface deformation and magmatism, our geochemical work does not support this mechanism for Iberia. Generation and ascent of magmas remains puzzling. Our work in Hawaii constrains the residence of magma beneath Hualalai to be a few hundred to about 1000 years. In the crust, heat drives fluid and mass transport. Numerical modeling yielded robust and accurate predictions of these processes. This work is important fundamental science, and applies to mitigation of volcanic and earthquake hazards, Test Ban Treaties, nuclear waste storage, environmental remediation, and hydrothermal energy.

  20. Lithospheric processes

    International Nuclear Information System (INIS)

    Baldridge, W.S.

    2000-01-01

    The authors used geophysical, geochemical, and numerical modeling to study selected problems related to Earth's lithosphere. We interpreted seismic waves to better characterize the thickness and properties of the crust and lithosphere. In the southwestern US and Tien Shari, crust of high elevation is dynamically supported above buoyant mantle. In California, mineral fabric in the mantle correlate with regional strain history. Although plumes of buoyant mantle may explain surface deformation and magmatism, our geochemical work does not support this mechanism for Iberia. Generation and ascent of magmas remains puzzling. Our work in Hawaii constrains the residence of magma beneath Hualalai to be a few hundred to about 1000 years. In the crust, heat drives fluid and mass transport. Numerical modeling yielded robust and accurate predictions of these processes. This work is important fundamental science, and applies to mitigation of volcanic and earthquake hazards, Test Ban Treaties, nuclear waste storage, environmental remediation, and hydrothermal energy

  1. Carbonizing process

    Energy Technology Data Exchange (ETDEWEB)

    1923-11-22

    In the downward distillation of coal, shale, lignite, or the like, the heat is generated by the combustion of liquid or gaseous fuel above the charge the zone of carbonization thus initiated travelling downwards through the charge. The combustible gases employed are preferably those resulting from the process but gases such as natural gas may be employed. The charge is in a moistened and pervious state the lower parts being maintained at a temperature not above 212/sup 0/F until influenced by contact with the carbonization zone and steam may be admitted to increase the yield of ammonia. The combustible gases may be supplied with insufficient air so as to impart to them a reducing effect.

  2. WELDING PROCESS

    Science.gov (United States)

    Zambrow, J.; Hausner, H.

    1957-09-24

    A method of joining metal parts for the preparation of relatively long, thin fuel element cores of uranium or alloys thereof for nuclear reactors is described. The process includes the steps of cleaning the surfaces to be jointed, placing the sunfaces together, and providing between and in contact with them, a layer of a compound in finely divided form that is decomposable to metal by heat. The fuel element members are then heated at the contact zone and maintained under pressure during the heating to decompose the compound to metal and sinter the members and reduced metal together producing a weld. The preferred class of decomposable compounds are the metal hydrides such as uranium hydride, which release hydrogen thus providing a reducing atmosphere in the vicinity of the welding operation.

  3. Processing Disability.

    Science.gov (United States)

    Harris, Jasmine

    2015-01-01

    This Article argues that the practice of holding so many adjudicative proceedings related to disability in private settings (e.g., guardianship, special education due process, civil commitment, and social security) relative to our strong normative presumption of public access to adjudication may cultivate and perpetuate stigma in contravention of the goals of inclusion and enhanced agency set forth in antidiscrimination laws. Descriptively, the law has a complicated history with disability--initially rendering disability invisible; later, underwriting particular narratives of disability synonymous with incapacity; and, in recent history, promoting the full socio-economic visibility of people with disabilities. The Americans with Disabilities Act (ADA), the marquee civil rights legislation for people with disabilities (about to enter its twenty-fifth year), expresses a national approach to disability that recognizes the role of society in its construction, maintenance, and potential remedy. However, the ADA’s mission is incomplete. It has not generated the types of interactions between people with disabilities and nondisabled people empirically shown to deconstruct deeply entrenched social stigma. Prescriptively, procedural design can act as an "ntistigma agent"to resist and mitigate disability stigma. This Article focuses on one element of institutional design--public access to adjudication--as a potential tool to construct and disseminate counter-narratives of disability. The unique substantive focus in disability adjudication on questions of agency provides a potential public space for the negotiation of nuanced definitions of disability and capacity more reflective of the human condition.

  4. Detailed conformation dynamics and activation process of wild type c-Abl and T315I mutant

    Science.gov (United States)

    Yang, Li-Jun; Zhao, Wen-Hua; Liu, Qian

    2014-10-01

    Bcr-Abl is an important target for therapy against chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). The synergistic effect between myristyl pocket and the ATP pocket has been found. But its detailed information based on molecular level still has not been achieved. In this study, conventional molecular dynamics (CMD) and target molecular dynamics (TMD) simulations were performed to explore the effect of T315I mutation on dynamics and activation process of Abl containing the N-terminal cap (Ncap). The CMD simulation results reveal the increasing flexibility of ATP pocket in kinase domain (KD) after T315I mutation which confirms the disability of ATP-pocket inhibitors to the Abl-T315I mutant. On the contrary, the T315I mutation decreased the flexibility of remote helix αI which suggests the synergistic effect between them. The mobility of farther regions containing Ncap, SH3, SH2 and SH2-KD linker were not affected by T315I mutation. The TMD simulation results show that the activation process of wild type Abl and Abl-T315I mutant experienced global conformation change. Their differences were elucidated by the activation motion of subsegments including A-loop, P-loop and Ncap. Besides, the T315I mutation caused decreasing energy barrier and increasing intermediate number in activation process, which results easier activation process. The TMD and CMD results indicate that a drug targeting only the ATP pocket is not enough to inhibit the Abl-T315I mutant. An effective way to inhibit the abnormal activity of Abl-T315I mutant is to combine the ATP-pocket inhibitors with inhibitors binding at non-ATP pockets mainly related to Ncap, SH2-KD linker and myristyl pocket.

  5. [In process.

    Science.gov (United States)

    Kaasch, Michael; Kaasch, Joachim

    -increasing competitiveness which came to a head as an embroiled dispute resulting from differences in scientific and scientific policy views. In the process a battle was fought over research resources so that, what was at first an apparently personal quarrel, affected the course of research promotion at an institutional level in the area of life sciences in the GDR. Despite several attempts at mediation, old age finally forced the adversaries to put aside their differences.

  6. Data Processing

    Science.gov (United States)

    Grangeat, P.

    A new area of biology has been opened up by nanoscale exploration of the living world. This has been made possible by technological progress, which has provided the tools needed to make devices that can measure things on such length and time scales. In a sense, this is a new window upon the living world, so rich and so diverse. Many of the investigative methods described in this book seek to obtain complementary physical, chemical, and biological data to understand the way it works and the way it is organised. At these length and time scales, only dedicated instrumentation could apprehend the relevant phenomena. There is no way for our senses to observe these things directly. One important field of application is molecular medicine, which aims to explain the mechanisms of life and disease by the presence and quantification of specific molecular entities. This involves combining information about genes, proteins, cells, and organs. This in turn requires the association of instruments for molecular diagnosis, either in vitro, e.g., the microarray or the lab-on-a-chip, or in vivo, e.g., probes for molecular biopsy, and tools for molecular imaging, used to localise molecular information in living organisms in a non-invasive way. These considerations concern both preclinical research for drug design and human medical applications. With the development of DNA and RNA chips [1], genomics has revolutionised investigative methods for cells and cell processes [2,3]. By sequencing the human genome, new ways have been found for understanding the fundamental mechanisms of life [4]. A revolution is currently under way with the analysis of the proteome [5-8], i.e., the complete set of proteins that can be found in some given biological medium, such as the blood plasma. The goal is to characterise certain diseases by recognisable signatures in the proteomic profile, as determined from a blood sample or a biopsy, for example [9-13]. What is at stake is the early detection of

  7. Hydrothermal Processes

    Science.gov (United States)

    German, C. R.; von Damm, K. L.

    2003-12-01

    What is Hydrothermal Circulation?Hydrothermal circulation occurs when seawater percolates downward through fractured ocean crust along the volcanic mid-ocean ridge (MOR) system. The seawater is first heated and then undergoes chemical modification through reaction with the host rock as it continues downward, reaching maximum temperatures that can exceed 400 °C. At these temperatures the fluids become extremely buoyant and rise rapidly back to the seafloor where they are expelled into the overlying water column. Seafloor hydrothermal circulation plays a significant role in the cycling of energy and mass between the solid earth and the oceans; the first identification of submarine hydrothermal venting and their accompanying chemosynthetically based communities in the late 1970s remains one of the most exciting discoveries in modern science. The existence of some form of hydrothermal circulation had been predicted almost as soon as the significance of ridges themselves was first recognized, with the emergence of plate tectonic theory. Magma wells up from the Earth's interior along "spreading centers" or "MORs" to produce fresh ocean crust at a rate of ˜20 km3 yr-1, forming new seafloor at a rate of ˜3.3 km2 yr-1 (Parsons, 1981; White et al., 1992). The young oceanic lithosphere formed in this way cools as it moves away from the ridge crest. Although much of this cooling occurs by upward conduction of heat through the lithosphere, early heat-flow studies quickly established that a significant proportion of the total heat flux must also occur via some additional convective process (Figure 1), i.e., through circulation of cold seawater within the upper ocean crust (Anderson and Silbeck, 1981). (2K)Figure 1. Oceanic heat flow versus age of ocean crust. Data from the Pacific, Atlantic, and Indian oceans, averaged over 2 Ma intervals (circles) depart from the theoretical cooling curve (solid line) indicating convective cooling of young ocean crust by circulating seawater

  8. Multidimensional process discovery

    NARCIS (Netherlands)

    Ribeiro, J.T.S.

    2013-01-01

    Typically represented in event logs, business process data describe the execution of process events over time. Business process intelligence (BPI) techniques such as process mining can be applied to get strategic insight into business processes. Process discovery, conformance checking and

  9. PC image processing

    International Nuclear Information System (INIS)

    Hwa, Mok Jin Il; Am, Ha Jeng Ung

    1995-04-01

    This book starts summary of digital image processing and personal computer, and classification of personal computer image processing system, digital image processing, development of personal computer and image processing, image processing system, basic method of image processing such as color image processing and video processing, software and interface, computer graphics, video image and video processing application cases on image processing like satellite image processing, color transformation of image processing in high speed and portrait work system.

  10. AN ADVANCED OXIDATION PROCESS : FENTON PROCESS

    Directory of Open Access Journals (Sweden)

    Engin GÜRTEKİN

    2008-03-01

    Full Text Available Biological wastewater treatment is not effective treatment method if raw wastewater contains toxic and refractory organics. Advanced oxidation processes are applied before or after biological treatment for the detoxification and reclamation of this kind of wastewaters. The advanced oxidation processes are based on the formation of powerful hydroxyl radicals. Among advanced oxidation processes Fenton process is one of the most promising methods. Because application of Fenton process is simple and cost effective and also reaction occurs in a short time period. Fenton process is applied for many different proposes. In this study, Fenton process was evaluated as an advanced oxidation process in wastewater treatment.

  11. Management of processes of electrochemical dimensional processing

    Science.gov (United States)

    Akhmetov, I. D.; Zakirova, A. R.; Sadykov, Z. B.

    2017-09-01

    In different industries a lot high-precision parts are produced from hard-processed scarce materials. Forming such details can only be acting during non-contact processing, or a minimum of effort, and doable by the use, for example, of electro-chemical processing. At the present stage of development of metal working processes are important management issues electrochemical machining and its automation. This article provides some indicators and factors of electrochemical machining process.

  12. Extensible packet processing architecture

    Science.gov (United States)

    Robertson, Perry J.; Hamlet, Jason R.; Pierson, Lyndon G.; Olsberg, Ronald R.; Chun, Guy D.

    2013-08-20

    A technique for distributed packet processing includes sequentially passing packets associated with packet flows between a plurality of processing engines along a flow through data bus linking the plurality of processing engines in series. At least one packet within a given packet flow is marked by a given processing engine to signify by the given processing engine to the other processing engines that the given processing engine has claimed the given packet flow for processing. A processing function is applied to each of the packet flows within the processing engines and the processed packets are output on a time-shared, arbitered data bus coupled to the plurality of processing engines.

  13. BPMN process views construction

    NARCIS (Netherlands)

    Yongchareon, S.; Liu, Chengfei; Zhao, X.; Kowalkiewicz, M.; Kitagawa, H.; Ishikawa, Y.

    2010-01-01

    Process view technology is catching more attentions in modern business process management, as it enables the customisation of business process representation. This capability helps improve the privacy protection, authority control, flexible display, etc., in business process modelling. One of

  14. Silicon integrated circuit process

    International Nuclear Information System (INIS)

    Lee, Jong Duck

    1985-12-01

    This book introduces the process of silicon integrated circuit. It is composed of seven parts, which are oxidation process, diffusion process, ion implantation process such as ion implantation equipment, damage, annealing and influence on manufacture of integrated circuit and device, chemical vapor deposition process like silicon Epitaxy LPCVD and PECVD, photolithography process, including a sensitizer, spin, harden bake, reflection of light and problems related process, infrared light bake, wet-etch, dry etch, special etch and problems of etching, metal process like metal process like metal-silicon connection, aluminum process, credibility of aluminum and test process.

  15. Silicon integrated circuit process

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Duck

    1985-12-15

    This book introduces the process of silicon integrated circuit. It is composed of seven parts, which are oxidation process, diffusion process, ion implantation process such as ion implantation equipment, damage, annealing and influence on manufacture of integrated circuit and device, chemical vapor deposition process like silicon Epitaxy LPCVD and PECVD, photolithography process, including a sensitizer, spin, harden bake, reflection of light and problems related process, infrared light bake, wet-etch, dry etch, special etch and problems of etching, metal process like metal process like metal-silicon connection, aluminum process, credibility of aluminum and test process.

  16. Calmodulin protects cells from death under normal growth conditions and mitogenic starvation but plays a mediating role in cell death upon B-cell receptor stimulation

    DEFF Research Database (Denmark)

    Schmalzigaug, R; Ye, Q; Berchtold, M W

    2001-01-01

    stimulation of the B-cell receptor (BCR), the resting Ca2+ levels remain elevated after the initial transient in CaMII-/- cells. Despite higher Ca2+ resting levels, the CaMII-/- cells are partially protected from BCR induced apoptosis indicating that CaM plays a dual role in apoptotic processes....

  17. MicroRNAs regulate B-cell receptor signaling-induced apoptosis

    NARCIS (Netherlands)

    Kluiver, J. L.; Chen, C-Z

    Apoptosis induced by B-cell receptor (BCR) signaling is critical for antigen-driven selection, a process critical to tolerance and immunity. Here, we examined the roles of microRNAs (miRNAs) in BCR signaling-induced apoptosis using the widely applied WEHI-231 model. Comparison of miRNA levels in

  18. The Newest Laser Processing

    International Nuclear Information System (INIS)

    Lee, Baek Yeon

    2007-01-01

    This book mentions laser processing with laser principle, laser history, laser beam property, laser kinds, foundation of laser processing such as laser oscillation, characteristic of laser processing, laser for processing and its characteristic, processing of laser hole including conception of processing of laser hole and each material, and hole processing of metal material, cut of laser, reality of cut, laser welding, laser surface hardening, application case of special processing and safety measurement of laser.

  19. Minimal and careful processing

    OpenAIRE

    Nielsen, Thorkild

    2004-01-01

    In several standards, guidelines and publications, organic food processing is strongly associated with "minimal processing" and "careful processing". The term "minimal processing" is nowadays often used in the general food processing industry and described in literature. The term "careful processing" is used more specifically within organic food processing but is not yet clearly defined. The concept of carefulness seems to fit very well with the processing of organic foods, especially if it i...

  20. Thinning spatial point processes into Poisson processes

    DEFF Research Database (Denmark)

    Møller, Jesper; Schoenberg, Frederic Paik

    2010-01-01

    are identified, and where we simulate backwards and forwards in order to obtain the thinned process. In the case of a Cox process, a simple independent thinning technique is proposed. In both cases, the thinning results in a Poisson process if and only if the true Papangelou conditional intensity is used, and......In this paper we describe methods for randomly thinning certain classes of spatial point processes. In the case of a Markov point process, the proposed method involves a dependent thinning of a spatial birth-and-death process, where clans of ancestors associated with the original points......, thus, can be used as a graphical exploratory tool for inspecting the goodness-of-fit of a spatial point process model. Several examples, including clustered and inhibitive point processes, are considered....

  1. Thinning spatial point processes into Poisson processes

    DEFF Research Database (Denmark)

    Møller, Jesper; Schoenberg, Frederic Paik

    , and where one simulates backwards and forwards in order to obtain the thinned process. In the case of a Cox process, a simple independent thinning technique is proposed. In both cases, the thinning results in a Poisson process if and only if the true Papangelou conditional intensity is used, and thus can......This paper describes methods for randomly thinning certain classes of spatial point processes. In the case of a Markov point process, the proposed method involves a dependent thinning of a spatial birth-and-death process, where clans of ancestors associated with the original points are identified...... be used as a diagnostic for assessing the goodness-of-fit of a spatial point process model. Several examples, including clustered and inhibitive point processes, are considered....

  2. A process insight repository supporting process optimization

    OpenAIRE

    Vetlugin, Andrey

    2012-01-01

    Existing solutions for analysis and optimization of manufacturing processes, such as online analysis processing or statistical calculations, have shortcomings that limit continuous process improvements. In particular, they lack means of storing and integrating the results of analysis. This makes the valuable information that can be used for process optimizations used only once and then disposed. The goal of the Advanced Manufacturing Analytics (AdMA) research project is to design an integrate...

  3. Process mining: making knowledge discovery process centric

    NARCIS (Netherlands)

    Aalst, van der W.M.P.

    2011-01-01

    Recently, the Task Force on Process Mining released the Process Mining Manifesto. The manifesto is supported by 53 organizations and 77 process mining experts contributed to it. The active contributions from end-users, tool vendors, consultants, analysts, and researchers illustrate the growing

  4. Business process model repositories : efficient process retrieval

    NARCIS (Netherlands)

    Yan, Z.

    2012-01-01

    As organizations increasingly work in process-oriented manner, the number of business process models that they develop and have to maintain increases. As a consequence, it has become common for organizations to have collections of hundreds or even thousands of business process models. When a

  5. Combinations of Novel Histone Deacetylase and Bcr-Abl Inhibitors in the Therapy of Imatinib Mesylate-Sensitive and -Refractory Bcr-Abl Expressing Leukemia

    Science.gov (United States)

    2008-12-01

    Balasis,1Purva Bali,1Veronica Estrella ,1Sandhya Kumaraswamy,1 Rekha Rao,1Kathy Rocha,1Bryan Herger,1Francis Lee,2 Victoria Richon,3 and Kapil Bhalla1...Balasis M, Bali P, Estrella V, Kumaraswamy S, et al. Histone deacetylase inhibitors deplete EZH2 and associated Polycomb Repressive Complex 2 proteins

  6. Test and evaluate the tri-gas low-Btu coal-gasification process. Final report, October 21, 1977-October 31, 1980

    Energy Technology Data Exchange (ETDEWEB)

    Zabetakis, M.G.

    1980-12-01

    This report describes the continuation of work done to develop the BCR TRI-GAS multiple fluidized-bed gasification process. The objective is the gasification of all ranks of coals with the only product being a clean, low-Btu fuel gas. Design and construction of a 100 lb/h process and equipment development unit (PEDU) was completed on the previous contract. The process consists of three fluid-bed reactors in series, each having a specific function: Stage 1 - pretreatment; Stage 2- - gasification; Stage 3 - maximization of carbon utilization. Under the present contract, 59 PEDU tests have been conducted. A number of these were single-stage tests, mostly in Stage 1; however, integrated PEDU tests were conducted with a western coal (Rosebud) and two eastern coals (Illinois No. 6 and Pittsburgh seam). Both Rosebud and Pittsburgh seam coals were gasified with the PEDU operating in the design mode. Operation with Illinois No. 6 seam coal was also very promising; however, time limitations precluded further testing with this coal. One of the crucial tasks was to operate the Stage 1 reactor to pretreat and devolatilize caking coals. By adding a small amount of air to the fluidizing gas, the caking properties of the coal can be eliminated. However, it was also desirable to release a high percentage of the volatile matter from the coal in this vessel. To accomplish this, the reactor had to be operated above the agglomerating temperature of caking coals. By maintaining a low ratio of fresh to treated coal, this objective was achieved. Both Illinois No. 6 and Pittsburgh seam coals were treated at temperatures of 800 to 900 F without agglomerating in the vessel.

  7. Uranium enrichment. Enrichment processes

    International Nuclear Information System (INIS)

    Alexandre, M.; Quaegebeur, J.P.

    2009-01-01

    Despite the remarkable progresses made in the diversity and the efficiency of the different uranium enrichment processes, only two industrial processes remain today which satisfy all of enriched uranium needs: the gaseous diffusion and the centrifugation. This article describes both processes and some others still at the demonstration or at the laboratory stage of development: 1 - general considerations; 2 - gaseous diffusion: physical principles, implementation, utilisation in the world; 3 - centrifugation: principles, elementary separation factor, flows inside a centrifuge, modeling of separation efficiencies, mechanical design, types of industrial centrifuges, realisation of cascades, main characteristics of the centrifugation process; 4 - aerodynamic processes: vortex process, nozzle process; 5 - chemical exchange separation processes: Japanese ASAHI process, French CHEMEX process; 6 - laser-based processes: SILVA process, SILMO process; 7 - electromagnetic and ionic processes: mass spectrometer and calutron, ion cyclotron resonance, rotating plasmas; 8 - thermal diffusion; 9 - conclusion. (J.S.)

  8. The permanental process

    DEFF Research Database (Denmark)

    McCullagh, Peter; Møller, Jesper

    2006-01-01

    We extend the boson process first to a large class of Cox processes and second to an even larger class of infinitely divisible point processes. Density and moment results are studied in detail. These results are obtained in closed form as weighted permanents, so the extension i called a permanental...... process. Temporal extensions and a particularly tractable case of the permanental process are also studied. Extensions of the fermion process along similar lines, leading to so-called determinantal processes, are discussed....

  9. The permanent process

    DEFF Research Database (Denmark)

    Møller, Jesper; McCullagh, Peter

    We extend the boson process first to a large class of Cox processes and second an even larger class of infinitely divisible point processes. Density and moment results are studied in detail. These results are obtained in closed form as weighted permanents, so the extension is called a permanent...... process. Temporal extensions and a particularly tractable case of the permanent process are also studied. Extensions of the ferminon process along similar lines, leading to so-called determinant processes, are discussed at the end. While the permanent process is attractive, the determinant process...

  10. Explosive processes in nucleosynthesis

    International Nuclear Information System (INIS)

    Boyd, R.N.

    2002-01-01

    There are many explosive processes in nucleosynthesis: big bang nucleosynthesis, the rp-process, the γ-process, the ν-process, and the r-process. However, I will discuss just the rp-process and the r-process in detail, primarily because both seem to have been very active research areas of late, and because they have great potential for studies with radioactive nuclear beams. I will also discuss briefly the γ-process because of its inevitability in conjunction with the rp-process. (orig.)

  11. Process Intensification: A Perspective on Process Synthesis

    DEFF Research Database (Denmark)

    Lutze, Philip; Gani, Rafiqul; Woodley, John

    2010-01-01

    In recent years, process intensification (PI) has attracted considerable academic interest as a potential means for process improvement, to meet the increasing demands for sustainable production. A variety of intensified operations developed in academia and industry creates a large number...... of options to potentially improve the process but to identify the set of feasible solutions for PI in which the optimal can be found takes considerable resources. Hence, a process synthesis tool to achieve PI would potentially assist in the generation and evaluation of PI options. Currently, several process...... design tools with a clear focus on specific PI tasks exist. Therefore, in this paper, the concept of a general systematic framework for synthesis and design of PI options in hierarchical steps through analyzing an existing process, generating PI options in a superstructure and evaluating intensified...

  12. Mining processes in dentistry

    NARCIS (Netherlands)

    Mans, R.S.; Reijers, H.A.; van Genuchten, M.; Wismeijer, D.

    2012-01-01

    Business processes in dentistry are quickly evolving towards "digital dentistry". This means that many steps in the dental process will increasingly deal with computerized information or computerized half products. A complicating factor in the improvement of process performance in dentistry,

  13. Realtime Color Stereovision Processing

    National Research Council Canada - National Science Library

    Formwalt, Bryon

    2000-01-01

    .... This research takes a step forward in real time machine vision processing. It investigates techniques for implementing a real time stereovision processing system using two miniature color cameras...

  14. Business Process Customization using Process Merging Techniques

    NARCIS (Netherlands)

    Bulanov, Pavel; Lazovik, Alexander; Aiello, Marco

    2012-01-01

    One of the important application of service composition techniques lies in the field of business process management. Essentially a business process can be considered as a composition of services, which is usually prepared by domain experts, and many tasks still have to be performed manually. These

  15. From Process Understanding to Process Control

    NARCIS (Netherlands)

    Streefland, M.

    2010-01-01

    A licensed pharmaceutical process is required to be executed within the validated ranges throughout the lifetime of product manufacturing. Changes to the process usually require the manufacturer to demonstrate that the safety and efficacy of the product remains unchanged. Recent changes in the

  16. Idaho Chemical Processing Plant Process Efficiency improvements

    International Nuclear Information System (INIS)

    Griebenow, B.

    1996-03-01

    In response to decreasing funding levels available to support activities at the Idaho Chemical Processing Plant (ICPP) and a desire to be cost competitive, the Department of Energy Idaho Operations Office (DOE-ID) and Lockheed Idaho Technologies Company have increased their emphasis on cost-saving measures. The ICPP Effectiveness Improvement Initiative involves many activities to improve cost effectiveness and competitiveness. This report documents the methodology and results of one of those cost cutting measures, the Process Efficiency Improvement Activity. The Process Efficiency Improvement Activity performed a systematic review of major work processes at the ICPP to increase productivity and to identify nonvalue-added requirements. A two-phase approach was selected for the activity to allow for near-term implementation of relatively easy process modifications in the first phase while obtaining long-term continuous improvement in the second phase and beyond. Phase I of the initiative included a concentrated review of processes that had a high potential for cost savings with the intent of realizing savings in Fiscal Year 1996 (FY-96.) Phase II consists of implementing long-term strategies too complex for Phase I implementation and evaluation of processes not targeted for Phase I review. The Phase II effort is targeted for realizing cost savings in FY-97 and beyond

  17. Making process improvement 'stick'.

    Science.gov (United States)

    Studer, Quint

    2014-06-01

    To sustain gains from a process improvement initiative, healthcare organizations should: Explain to staff why a process improvement initiative is needed. Encourage leaders within the organization to champion the process improvement, and tie their evaluations to its outcomes. Ensure that both leaders and employees have the skills to help sustain the sought-after process improvements.

  18. Fractional Poisson process (II)

    International Nuclear Information System (INIS)

    Wang Xiaotian; Wen Zhixiong; Zhang Shiying

    2006-01-01

    In this paper, we propose a stochastic process W H (t)(H-bar (12,1)) which we call fractional Poisson process. The process W H (t) is self-similar in wide sense, displays long range dependence, and has more fatter tail than Gaussian process. In addition, it converges to fractional Brownian motion in distribution

  19. Genetic process mining

    NARCIS (Netherlands)

    Aalst, van der W.M.P.; Alves De Medeiros, A.K.; Weijters, A.J.M.M.; Ciardo, G.; Darondeau, P.

    2005-01-01

    The topic of process mining has attracted the attention of both researchers and tool vendors in the Business Process Management (BPM) space. The goal of process mining is to discover process models from event logs, i.e., events logged by some information system are used to extract information about

  20. Business process quality management

    NARCIS (Netherlands)

    Reijers, H.A.; Mendling, J.; Recker, J.; Brocke, vom J.; Rosemann, M.

    2010-01-01

    Abstract Process modeling is a central element in any approach to Business Process Management (BPM). However, what hinders both practitioners and aca demics is the lack of support for assessing the quality of process models — let alone realizing high quality process models. Existing frameworks are

  1. Shell coal gasification process

    Energy Technology Data Exchange (ETDEWEB)

    Hennekes, B. [Shell Global Solutions (US) Inc. (United States). Technology Marketing

    2002-07-01

    The presentation, on which 17 slides/overheads are included in the papers, explained the principles of the Shell coal gasification process and the methods incorporated for control of sulfur dioxide, nitrogen oxides, particulates and mercury. The economics of the process were discussed. The differences between gasification and burning, and the differences between the Shell process and other processes were discussed.

  2. Exploring processes and deviations

    NARCIS (Netherlands)

    Leemans, S.J.J.; Fahland, D.; Aalst, van der W.M.P.; Fournier, F.; Mendling, J.

    2015-01-01

    In process mining, one of the main challenges is to discover a process model, while balancing several quality criteria. This often requires repeatedly setting parameters, discovering a map and evaluating it, which we refer to as process exploration. Commercial process mining tools like Disco,

  3. Distributed genetic process mining

    NARCIS (Netherlands)

    Bratosin, C.C.; Sidorova, N.; Aalst, van der W.M.P.

    2010-01-01

    Process mining aims at discovering process models from data logs in order to offer insight into the real use of information systems. Most of the existing process mining algorithms fail to discover complex constructs or have problems dealing with noise and infrequent behavior. The genetic process

  4. Dosimetry and process control for radiation processing

    International Nuclear Information System (INIS)

    Mod Ali, N.

    2002-01-01

    Complete text of publication follows. Accurate radiation dosimetry can provide quality assurance in radiation processing. Considerable relevant experiences in dosimetry by the SSDL-MINT has necessitate the development of methods making measurement at gamma plant traceable to the national standard. It involves the establishment of proper calibration procedure and selection of appropriate transfer system/technique to assure adequate traceability to a primary radiation standard. The effort forms the basis for irradiation process control, the legal approval of the process by the public health authorities (medical product sterilization and food preservation) and the safety and acceptance of the product

  5. Thin film processes

    CERN Document Server

    Vossen, John L

    1978-01-01

    Remarkable advances have been made in recent years in the science and technology of thin film processes for deposition and etching. It is the purpose of this book to bring together tutorial reviews of selected filmdeposition and etching processes from a process viewpoint. Emphasis is placed on the practical use of the processes to provide working guidelines for their implementation, a guide to the literature, and an overview of each process.

  6. A Campbell random process

    International Nuclear Information System (INIS)

    Reuss, J.D.; Misguich, J.H.

    1993-02-01

    The Campbell process is a stationary random process which can have various correlation functions, according to the choice of an elementary response function. The statistical properties of this process are presented. A numerical algorithm and a subroutine for generating such a process is built up and tested, for the physically interesting case of a Campbell process with Gaussian correlations. The (non-Gaussian) probability distribution appears to be similar to the Gamma distribution

  7. Business process transformation the process tangram framework

    CERN Document Server

    Sharma, Chitra

    2015-01-01

    This book presents a framework through transformation and explains  how business goals can be translated into realistic plans that are tangible and yield real results in terms of the top line and the bottom line. Process Transformation is like a tangram puzzle, which has multiple solutions yet is essentially composed of seven 'tans' that hold it together. Based on practical experience and intensive research into existing material, 'Process Tangram' is a simple yet powerful framework that proposes Process Transformation as a program. The seven 'tans' are: the transformation program itself, triggers, goals, tools and techniques, culture, communication and success factors. With its segregation into tans and division into core elements, this framework makes it possible to use 'pick and choose' to quickly and easily map an organization's specific requirements. Change management and process modeling are covered in detail. In addition, the book approaches managed services as a model of service delivery, which it ex...

  8. Dry process potentials

    International Nuclear Information System (INIS)

    Faugeras, P.

    1997-01-01

    Various dry processes have been studied and more or less developed in order particularly to reduce the waste quantities but none of them had replaced the PUREX process, for reasons departing to policy errors, un-appropriate demonstration examples or too late development, although realistic and efficient dry processes such as a fluoride selective volatility based processes have been demonstrated in France (CLOVIS, ATILA) and would be ten times cheaper than the PUREX process. Dry processes could regain interest in case of a nuclear revival (following global warming fears) or thermal wastes over-production. In the near future, dry processes could be introduced in complement to the PUREX process, especially at the end of the process cycle, for a more efficient recycling and safer storage (inactivation)

  9. Honing process optimization algorithms

    Science.gov (United States)

    Kadyrov, Ramil R.; Charikov, Pavel N.; Pryanichnikova, Valeria V.

    2018-03-01

    This article considers the relevance of honing processes for creating high-quality mechanical engineering products. The features of the honing process are revealed and such important concepts as the task for optimization of honing operations, the optimal structure of the honing working cycles, stepped and stepless honing cycles, simulation of processing and its purpose are emphasized. It is noted that the reliability of the mathematical model determines the quality parameters of the honing process control. An algorithm for continuous control of the honing process is proposed. The process model reliably describes the machining of a workpiece in a sufficiently wide area and can be used to operate the CNC machine CC743.

  10. Defense waste processing facility precipitate hydrolysis process

    International Nuclear Information System (INIS)

    Doherty, J.P.; Eibling, R.E.; Marek, J.C.

    1986-03-01

    Sodium tetraphenylborate and sodium titanate are used to assist in the concentration of soluble radionuclide in the Savannah River Plant's high-level waste. In the Defense Waste Processing Facility, concentrated tetraphenylborate/sodium titanate slurry containing cesium-137, strontium-90 and traces of plutonium from the waste tank farm is hydrolyzed in the Salt Processing Cell forming organic and aqueous phases. The two phases are then separated and the organic phase is decontaminated for incineration outside the DWPF building. The aqueous phase, containing the radionuclides and less than 10% of the original organic, is blended with the insoluble radionuclides in the high-level waste sludge and is fed to the glass melter for vitrification into borosilicate glass. During the Savannah River Laboratory's development of this process, copper (II) was found to act as a catalyst during the hydrolysis reactions, which improved the organic removal and simplified the design of the reactor

  11. The Diazo Copying Process.

    Science.gov (United States)

    Osterby, Bruce

    1989-01-01

    Described is an activity which demonstrates an organic-based reprographic method that is used extensively for the duplication of microfilm and engineering drawings. Discussed are the chemistry of the process and how to demonstrate the process for students. (CW)

  12. Waste processing air cleaning

    International Nuclear Information System (INIS)

    Kriskovich, J.R.

    1998-01-01

    Waste processing and preparing waste to support waste processing relies heavily on ventilation. Ventilation is used at the Hanford Site on the waste storage tanks to provide confinement, cooling, and removal of flammable gases

  13. Radiochemical Processing Laboratory (RPL)

    Data.gov (United States)

    Federal Laboratory Consortium — The Radiochemical Processing Laboratory (RPL)�is a scientific facility funded by DOE to create and implement innovative processes for environmental clean-up and...

  14. Laser material processing

    CERN Document Server

    Steen, William

    2010-01-01

    This text moves from the basics of laser physics to detailed treatments of all major materials processing techniques for which lasers are now essential. New chapters cover laser physics, drilling, micro- and nanomanufacturing and biomedical laser processing.

  15. Business Process Inventory

    Data.gov (United States)

    Office of Personnel Management — Inventory of maps and descriptions of the business processes of the U.S. Office of Personnel Management (OPM), with an emphasis on the processes of the Office of the...

  16. Process evaluation distributed system

    Science.gov (United States)

    Moffatt, Christopher L. (Inventor)

    2006-01-01

    The distributed system includes a database server, an administration module, a process evaluation module, and a data display module. The administration module is in communication with the database server for providing observation criteria information to the database server. The process evaluation module is in communication with the database server for obtaining the observation criteria information from the database server and collecting process data based on the observation criteria information. The process evaluation module utilizes a personal digital assistant (PDA). A data display module in communication with the database server, including a website for viewing collected process data in a desired metrics form, the data display module also for providing desired editing and modification of the collected process data. The connectivity established by the database server to the administration module, the process evaluation module, and the data display module, minimizes the requirement for manual input of the collected process data.

  17. Group Decision Process Support

    DEFF Research Database (Denmark)

    Gøtze, John; Hijikata, Masao

    1997-01-01

    Introducing the notion of Group Decision Process Support Systems (GDPSS) to traditional decision-support theorists.......Introducing the notion of Group Decision Process Support Systems (GDPSS) to traditional decision-support theorists....

  18. Cognitive processes in CBT

    NARCIS (Netherlands)

    Becker, E.S.; Vrijsen, J.N.; Hofmann, S.G.; Asmundson, G.J.G.

    2017-01-01

    Automatic cognitive processing helps us navigate the world. However, if the emotional and cognitive interplay becomes skewed, those cognitive processes can become maladaptive and result in psychopathology. Although biases are present in most mental disorders, different disorders are characterized by

  19. Improving Healthcare Logistics Processes

    DEFF Research Database (Denmark)

    Feibert, Diana Cordes

    logistics processes in hospitals and aims to provide theoretically and empirically based evidence for improving these processes to both expand the knowledge base of healthcare logistics and provide a decision tool for hospital logistics managers to improve their processes. Case studies were conducted...... processes. Furthermore, a method for benchmarking healthcare logistics processes was developed. Finally, a theoretically and empirically founded framework was developed to support managers in making an informed decision on how to improve healthcare logistics processes. This study contributes to the limited...... literature concerned with the improvement of logistics processes in hospitals. Furthermore, the developed framework provides guidance for logistics managers in hospitals on how to improve their processes given the circumstances in which they operate....

  20. Flavor changing lepton processes

    International Nuclear Information System (INIS)

    Kuno, Yoshitaka

    2002-01-01

    The flavor changing lepton processes, or in another words the lepton flavor changing processes, are described with emphasis on the updated theoretical motivations and the on-going experimental progress on a new high-intense muon source. (author)

  1. Process innovation laboratory

    DEFF Research Database (Denmark)

    Møller, Charles

    2007-01-01

    to create a new methodology for developing and exploring process models and applications. The paper outlines the process innovation laboratory as a new approach to BPI. The process innovation laboratory is a comprehensive framework and a collaborative workspace for experimenting with process models....... The process innovation laboratory facilitates innovation by using an integrated action learning approach to process modelling in a controlled environment. The study is based on design science and the paper also discusses the implications to EIS research and practice......Most organizations today are required not only to operate effective business processes but also to allow for changing business conditions at an increasing rate. Today nearly every business relies on their enterprise information systems (EIS) for process integration and future generations of EIS...

  2. The Integrated Renovation Process

    DEFF Research Database (Denmark)

    Galiotto, Nicolas; Heiselberg, Per; Knudstrup, Mary-Ann

    The Integrated Renovation Process (IRP) is a user customized methodology based on judiciously selected constructivist and interactive multi-criteria decision making methods (Galiotto, Heiselberg, & Knudstrup, 2014 (expected)). When applied for home renovation, the Integrated Renovation Process...

  3. Wetland Groundwater Processes

    National Research Council Canada - National Science Library

    Williams, Greg

    1993-01-01

    This technical note summarizes hydrologic and hydraulic (H AND H) processes and the related terminology that will likely be encountered during an evaluation of the effect of ground-water processes on wetland function...

  4. Flue Gas Desulphurization Processes

    International Nuclear Information System (INIS)

    Aly, A.I.M.; Halhouli, K.A.; Abu-Ashur, B.M.

    1999-01-01

    Flue gas desulphurization process are discussed. These processes can be grouped into non-regenerable systems and regenerable systems. The non-regenerable systems produce a product which is either disposed of as waste or sold as a by-product e.g. lime/limestone process. While in the regenerable systems, e.g. Wellman-Lord process, the SO 2 is regenerated from the sorbent(sodium sulphite), which is returned to absorb more SO 2 . Also a newer technology for flue gas desulphurization is discussed. The Ispra process uses bromine as oxidant, producing HBr, from which bromine is regenerated by electrolysis. The only by-products of this process are sulphuric acid and hydrogen, which are both valuable products, and no waste products are produced. Suggested modifications on the process are made based on experimental investigations to improve the efficiency of the process and to reduce its costs

  5. Chemical radwaste solidification processes

    International Nuclear Information System (INIS)

    Malloy, C.W.

    1979-01-01

    Some of these processes and their problems are briefly reviewed: early cement systems; urea-formaldehyde; Dow solidification process; low-viscosity chemical agents (POLYPAC); and water-extensible polyester. 9 refs

  6. The plasma hearth process: Process residuals characterization

    International Nuclear Information System (INIS)

    Leatherman, G.L.; Geimer, R.; Batdorf, J.; Hassel, G.; Wolfe, P.; Carney, K.P.

    1994-01-01

    The Plasma Hearth Process (PHP) is a high-temperature waste treatment process being developed by Science Applications International Corporation (SAIC) for the Department of Energy (DOE) that destroys hazardous organics while stabilizing radionuclides and hazardous metals in a vitreous slag waste form. The PHP has potential application for the treatment of a wide range of mixed waste types in both the low-level and transuranic (TRU) mixed waste categories. DOE, through the Office of Technology Development's Mixed Waste Integrated Program (MWIP) is conducting a three phase development project to ready the PHP for implementation in the DOE complex

  7. Process and device for processing radioactive wastes

    International Nuclear Information System (INIS)

    1974-01-01

    A method is described for processing liquid radioactive wastes. It includes the heating of the liquid wastes so that the contained liquids are evaporated and a practically anhydrous mass of solid particles inferior in volume to that of the wastes introduced is formed, then the transformation of the solid particles into a monolithic structure. This transformation includes the compressing of the particles and sintering or fusion. The solidifying agent is a mixture of polyethylene and paraffin wax or a styrene copolymer and a polyester resin. The device used for processing the radioactive liquid wastes is also described [fr

  8. Grind hardening process

    CERN Document Server

    Salonitis, Konstantinos

    2015-01-01

    This book presents the grind-hardening process and the main studies published since it was introduced in 1990s.  The modelling of the various aspects of the process, such as the process forces, temperature profile developed, hardness profiles, residual stresses etc. are described in detail. The book is of interest to the research community working with mathematical modeling and optimization of manufacturing processes.

  9. Software Process Improvement Defined

    DEFF Research Database (Denmark)

    Aaen, Ivan

    2002-01-01

    This paper argues in favor of the development of explanatory theory on software process improvement. The last one or two decades commitment to prescriptive approaches in software process improvement theory may contribute to the emergence of a gulf dividing theorists and practitioners....... It is proposed that this divide be met by the development of theory evaluating prescriptive approaches and informing practice with a focus on the software process policymaking and process control aspects of improvement efforts...

  10. Modeling multiphase materials processes

    CERN Document Server

    Iguchi, Manabu

    2010-01-01

    ""Modeling Multiphase Materials Processes: Gas-Liquid Systems"" describes the methodology and application of physical and mathematical modeling to multi-phase flow phenomena in materials processing. The book focuses on systems involving gas-liquid interaction, the most prevalent in current metallurgical processes. The performance characteristics of these processes are largely dependent on transport phenomena. This volume covers the inherent characteristics that complicate the modeling of transport phenomena in such systems, including complex multiphase structure, intense turbulence, opacity of

  11. Dosimetry for radiation processing

    DEFF Research Database (Denmark)

    Miller, Arne

    1986-01-01

    During the past few years significant advances have taken place in the different areas of dosimetry for radiation processing, mainly stimulated by the increased interest in radiation for food preservation, plastic processing and sterilization of medical products. Reference services both...... and sterilization dosimetry, optichromic dosimeters in the shape of small tubes for food processing, and ESR spectroscopy of alanine for reference dosimetry. In this paper the special features of radiation processing dosimetry are discussed, several commonly used dosimeters are reviewed, and factors leading...

  12. Generating process model collections

    NARCIS (Netherlands)

    Yan, Z.; Dijkman, R.M.; Grefen, P.W.P.J.

    2017-01-01

    Business process management plays an important role in the management of organizations. More and more organizations describe their operations as business processes. It is common for organizations to have collections of thousands of business processes, but for reasons of confidentiality these

  13. Multiphoton processes: conference proceedings

    International Nuclear Information System (INIS)

    Lambropoulos, P.; Smith, S.J.

    1984-01-01

    The chapters of this volume represent the invited papers delivered at the conference. They are arranged according to thermatic proximity beginning with atoms and continuing with molecules and surfaces. Section headings include multiphoton processes in atoms, field fluctuations and collisions in multiphoton process, and multiphoton processes in molecules and surfaces. Abstracts of individual items from the conference were prepared separately for the data base

  14. Semisolid Metal Processing Consortium

    Energy Technology Data Exchange (ETDEWEB)

    Apelian,Diran

    2002-01-10

    Mathematical modeling and simulations of semisolid filling processes remains a critical issue in understanding and optimizing the process. Semisolid slurries are non-Newtonian materials that exhibit complex rheological behavior. There the way these slurries flow in cavities is very different from the way liquid in classical casting fills cavities. Actually filling in semisolid processing is often counter intuitive

  15. How yogurt is processed

    Science.gov (United States)

    This month’s Processing column on the theme of “How Is It Processed?” focuses on yogurt. Yogurt is known for its health-promoting properties. This column will provide a brief overview of the history of yogurt and the current market. It will also unveil both traditional and modern yogurt processing t...

  16. Clinical Process Intelligence

    DEFF Research Database (Denmark)

    Vilstrup Pedersen, Klaus

    2006-01-01

    .e. local guidelines. From a knowledge management point of view, this externalization of generalized processes, gives the opportunity to learn from, evaluate and optimize the processes. "Clinical Process Intelligence" (CPI), will denote the goal of getting generalized insight into patient centered health...

  17. Process research and development

    Science.gov (United States)

    Bickler, D. B.

    1986-01-01

    The following major processes involved in the production of crystalline-silicon solar cells were discussed: surface preparation, junction formation, metallization, and assembly. The status of each of these processes, and the sequence in which these processes are applied, were described as they were in 1975, as they were in 1985, and what they might be in the future.

  18. The Constitutional Amendment Process

    Science.gov (United States)

    Chism, Kahlil

    2005-01-01

    This article discusses the constitutional amendment process. Although the process is not described in great detail, Article V of the United States Constitution allows for and provides instruction on amending the Constitution. While the amendment process currently consists of six steps, the Constitution is nevertheless quite difficult to change.…

  19. Teaching Process Design through Integrated Process Synthesis

    Science.gov (United States)

    Metzger, Matthew J.; Glasser, Benjamin J.; Patel, Bilal; Hildebrandt, Diane; Glasser, David

    2012-01-01

    The design course is an integral part of chemical engineering education. A novel approach to the design course was recently introduced at the University of the Witwatersrand, Johannesburg, South Africa. The course aimed to introduce students to systematic tools and techniques for setting and evaluating performance targets for processes, as well as…

  20. Statistical Process Control for KSC Processing

    Science.gov (United States)

    Ford, Roger G.; Delgado, Hector; Tilley, Randy

    1996-01-01

    The 1996 Summer Faculty Fellowship Program and Kennedy Space Center (KSC) served as the basis for a research effort into statistical process control for KSC processing. The effort entailed several tasks and goals. The first was to develop a customized statistical process control (SPC) course for the Safety and Mission Assurance Trends Analysis Group. The actual teaching of this course took place over several weeks. In addition, an Internet version of the same course complete with animation and video excerpts from the course when it was taught at KSC was developed. The application of SPC to shuttle processing took up the rest of the summer research project. This effort entailed the evaluation of SPC use at KSC, both present and potential, due to the change in roles for NASA and the Single Flight Operations Contractor (SFOC). Individual consulting on SPC use was accomplished as well as an evaluation of SPC software for KSC use in the future. A final accomplishment of the orientation of the author to NASA changes, terminology, data format, and new NASA task definitions will allow future consultation when the needs arise.

  1. Process-based costing.

    Science.gov (United States)

    Lee, Robert H; Bott, Marjorie J; Forbes, Sarah; Redford, Linda; Swagerty, Daniel L; Taunton, Roma Lee

    2003-01-01

    Understanding how quality improvement affects costs is important. Unfortunately, low-cost, reliable ways of measuring direct costs are scarce. This article builds on the principles of process improvement to develop a costing strategy that meets both criteria. Process-based costing has 4 steps: developing a flowchart, estimating resource use, valuing resources, and calculating direct costs. To illustrate the technique, this article uses it to cost the care planning process in 3 long-term care facilities. We conclude that process-based costing is easy to implement; generates reliable, valid data; and allows nursing managers to assess the costs of new or modified processes.

  2. Colloid process engineering

    CERN Document Server

    Peukert, Wolfgang; Rehage, Heinz; Schuchmann, Heike

    2015-01-01

    This book deals with colloidal systems in technical processes and the influence of colloidal systems by technical processes. It explores how new measurement capabilities can offer the potential for a dynamic development of scientific and engineering, and examines the origin of colloidal systems and its use for new products. The future challenges to colloidal process engineering are the development of appropriate equipment and processes for the production and obtainment of multi-phase structures and energetic interactions in market-relevant quantities. The book explores the relevant processes and for controlled production and how they can be used across all scales.

  3. Nonaqueous processing methods

    International Nuclear Information System (INIS)

    Coops, M.S.; Bowersox, D.F.

    1984-09-01

    A high-temperature process utilizing molten salt extraction from molten metal alloys has been developed for purification of spent power reactor fuels. Experiments with laboratory-scale processing operations show that purification and throughput parameters comparable to the Barnwell Purex process can be achieved by pyrochemical processing in equipment one-tenth the size, with all wastes being discharged as stable metal alloys at greatly reduced volume and disposal cost. This basic technology can be developed for large-scale processing of spent reactor fuels. 13 references, 4 figures

  4. Data processing made simple

    CERN Document Server

    Wooldridge, Susan

    2013-01-01

    Data Processing: Made Simple, Second Edition presents discussions of a number of trends and developments in the world of commercial data processing. The book covers the rapid growth of micro- and mini-computers for both home and office use; word processing and the 'automated office'; the advent of distributed data processing; and the continued growth of database-oriented systems. The text also discusses modern digital computers; fundamental computer concepts; information and data processing requirements of commercial organizations; and the historical perspective of the computer industry. The

  5. Thin film processes II

    CERN Document Server

    Kern, Werner

    1991-01-01

    This sequel to the 1978 classic, Thin Film Processes, gives a clear, practical exposition of important thin film deposition and etching processes that have not yet been adequately reviewed. It discusses selected processes in tutorial overviews with implementation guide lines and an introduction to the literature. Though edited to stand alone, when taken together, Thin Film Processes II and its predecessor present a thorough grounding in modern thin film techniques.Key Features* Provides an all-new sequel to the 1978 classic, Thin Film Processes* Introduces new topics, and sever

  6. FFTF gas processing systems

    International Nuclear Information System (INIS)

    Halverson, T.G.

    1977-01-01

    The design and operation of the two radioactive gas processing systems at the Fast Flux Test Facility (FFTF) exemplifies the concept that will be used in the first generation of Liquid Metal Fast Breeder Reactors (LMFBR's). The two systems, the Radioactive Argon Processing System (RAPS) and the Cell Atmosphere Processing System (CAPS), process the argon and nitrogen used in the FFTF for cover gas on liquid metal systems and as inert atmospheres in steel lined cells housing sodium equipment. The RAPS specifically processes the argon cover gas from the reactor coolant system, providing for decontamination and eventual reuse. The CAPS processes radioactive gasses from inerted cells and other liquid metal cover gas systems, providing for decontamination and ultimate discharge to the atmosphere. The cryogenic processing of waste gas by both systems is described

  7. BCR-ABL V280G Mutation, Potential Role in Imatinib Resistance: First Case Report

    OpenAIRE

    Azevedo, Ana P; Reichert, Alice; Afonso, Celina; Alberca, Maria D; Tavares, Purifica??o; Lima, Fernando

    2017-01-01

    Export Date: 28 December 2017 Correspondence Address: Azevedo, A.P.; Department of Clinical Pathology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Estrada do Forte do Alto do Duque, Portugal; email: Chemicals/CAS: glycine, 56-40-6, 6000-43-7, 6000-44-8; hydroxyurea, 127-07-1; imatinib, 152459-95-5, 220127-57-1; nilotinib, 641571-10-0; valine, 7004-03-7, 72-18-4 References: Radich, J.P., Shah, N.P., Mauro, M.J., Integrating current treatment options ...

  8. Coexistance of JAK2V617F mutation and BCR/ABL translocation in one patient

    Directory of Open Access Journals (Sweden)

    Murat Albayrak

    2010-09-01

    Full Text Available Dear Editor,The myeloproliferative disorders (MPDs constitute a subcategory of chronic myeloid disorders and include chronic myeloid leukemia (CML, essential thrombocytemia (ET, polycythemia vera (PV and myelofibrosis (MF. In 1960, the discovery of the Philadelphia chromosome (Ph became a cornerstone in CML treatment and led to the development of moleculary targeted therapy. Recently, an acquired mutation in the Janus kinase 2 (JAK2 gene has been discovered in nearly all patents with PV and approximately half of the patients with primary MF and ET. Subsequently, the mutation has been demonstrated in atypical MPDs (chronic neutrophilic leukemia, unclassified, de novo myelodysplastic syndrome or acute myeloid leukemia.1 It has been hoped that targeted inhibition of JAK2V617F should achieve similar disease control as thyrosine kinases has produced in CML.

  9. Seventh symposium on coal mine drainage research. NCA/BCR coal conference and Expo IV

    Energy Technology Data Exchange (ETDEWEB)

    None

    1977-01-01

    The Seventh Symposium on Coal Mine Drainage Research, sponsored by the National Coal Association and Bituminous Coal Research, Inc., was held at the Kentucky Fair and Exposition Center, Louisville, Kentucky, October 18-20, 1977. Seventeen papers from the proceedings have been entered individually into EDB and ERA. Topics covered include chemical reactions of pyrite oxidation and acid formation in spoil banks, abandoned mines, etc., formation of small acid lakes from the drainage and their neutralization by natural and other neutralization measures, trace elements in acid mine drainage, ground water contamination, limnology, effects of surface mined ground reclamation and neutralization, water purification and treatment, mining and coal preparation plant waste disposal, ash and fly ash disposal (to minimize leaching from the wastes), runoff from large coal storage stockpiles during storms (prevention of environmental effects by collection and neutralization by passing through an ash pond). (LTN)

  10. High frequency dielectric reference materials BCR projekt 43. Final report of phase 1

    International Nuclear Information System (INIS)

    Chantry, G.

    1980-01-01

    The Group of High Frequency Specialists from Belgium, France, Germany, The Netherlands and the UK, was awarded contracts in 1975 to carry out a programme of measurements on the high frequency dielectric properties of materials. The object of this first phase of a projected three phase programme was to establish the reliability of existing methods of measurement and to examine the possibilities of specifying and producing some standard reference materials, both liquid and solid, which could be used for calibrating and checking the performance of industrial measurement equipment. The liquids chosen for the first phase were cyclohexane, cis and trans decalin, chlorobenzene and 0.1, 1, and 10% solutions of chlorobenzene in cyclohexane. Each group had a limited frequency range over which it could make meaningful measurements but there was sufficient overlap to ensure that all random and systematic errors could be quantitatively assayed. The real (epsilon') and imaginary (epsilon'') components of the complex permittivity for all the liquids were measured over the frequency range 10 - 3,000 GHz and for the two most lossy liquids (chlorobenzene and 10% chlorobenzene in cyclohexane) this range was extended downwards to one GHz. The programme established for the first time the possible experimental imprecisions to be expected in high frequency dielecric measurements and showed that the chosen liquids could be useful standard reference materials if sufficiently pure specimens could be obtained commercially at a reasonable price. The programme did however reveal an unexpected snag in that the liquids, especially cyclohexane, were found to be rather more liable to contamination than expected. Since cyclohexane is a very low-loss liquid, only a small amount of a lossy contaminant need be absorbed to make the observed loss increase dramatically. This report contains all the measured results in both tabular and graphical form and in addition full technical details are given of the measurement procedures

  11. Biologically based risk estimation for radiation-induced CML. Inferences from BCR and ABL geometric distributions

    Czech Academy of Sciences Publication Activity Database

    Radivoyevitch, T.; Kozubek, Stanislav; Sachs, R. K.

    2001-01-01

    Roč. 40, č. 1 (2001), s. 1-9 ISSN 0301-634X Institutional research plan: CEZ:AV0Z5004920 Keywords : chronic myeloid leukemia * chronic myelogenous leukemia Subject RIV: BO - Biophysics Impact factor: 1.776, year: 2001

  12. Frequency and clinical impact of ETV6/RUNX1, AF4‑MLL, and BCR ...

    African Journals Online (AJOL)

    Background: Variations in disease presentation and outcome of leukemia treatment has been associated with the presence of certain mutant genes. Three major translocations (ETV6‑RUNX1, BCR‑ABL, and AF4‑MLL) in acute lymphoblastic leukemia (ALL) have been shown to affect treatment outcome. This study is aimed ...

  13. Quantification of BCR-ABL transcripts in peripheral blood cells and ...

    African Journals Online (AJOL)

    Makmor-Bakry1 and Norazrina Azmi1*. 1Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Wilayah Persekutuan, 2Department of Hematology,. Ampang Hospital, Ampang, Selangor, 3Quality Use of Medicines Research Group, Faculty of Pharmacy, Universiti Kebangsaan. Malaysia, Kuala Lumpur ...

  14. Determination of selenium in BCR single cell protein via destructive neutron activation analysis

    International Nuclear Information System (INIS)

    Goeij, J.J.M. de; Zegers, C.

    1978-10-01

    The amount of selenium in single cell protein (SCP), a product of BP Research Centre at Sunbury-at-Thames, England, was determined by neutron activation analysis. The SCP-samples were irradiated in the reactor of the Interuniversity Reactor Institute at Delft, in a neutron flux of 1.0 x 10 13 n/cm 2 s for 24 hours. After chemical destruction of the samples the amount of selenium was determined by measuring the γ-peaks of selenium-75

  15. The certification of carbon and nitrogen in molybdenum (BCR No.23)

    International Nuclear Information System (INIS)

    Vandecasteele, C.

    1985-01-01

    The experimental procedures used for the certification of carbon and nitrogen in molybdenum (CRM 023), which has already been certified for oxygen, are presented. Samples were analysed by 5 different laboratories using photon and charged particle activation analysis. The analytical methods and the approach used to analyse the data are described. The carbon content is certified to be below 0.2 μg/g; the nitrogen content to be below 0.3 μg/g

  16. Mercury speciation in coastal sediments from the central east coast of India by modified BCR method.

    Digital Repository Service at National Institute of Oceanography (India)

    Chakraborty, P.; Babu, P.V.R.; Vudamala, K.; Ramteke, D.; Chennuri, K.

    pervasiveness and adverse effects on wildlife and human health (US EPA, 1997). The high biomagnifications rate of Hg in food chain, makes this metal of the most environmental concern (Fitzgerald et al., 2007; Morel et al., 1998). Global oceans, coastal zones... been reported that coastal sediments act both as a sink and source for toxic metals (Chakraborty et al., 2012b). Sediment contamination in the coastal areas is a major environmental issue because of its potential toxic effects on biological resources...

  17. Recent advances in the bcr-abl negative chronic myeloproliferative diseases

    Directory of Open Access Journals (Sweden)

    Stroncek David F

    2006-10-01

    Full Text Available Abstract The chronic myeloproliferative disorders are clonal hematopoietic stem cell disorders of unknown etiology. In one of these (chronic myeloid leukemia, there is an associated pathognomonic chromosomal abnormality known as the Philadelphia chromosome. This leads to constitutive tyrosine kinase activity which is responsible for the disease and is used as a target for effective therapy. This review concentrates on the search in the other conditions (polycythemia vera, essential thrombocythemia and idiopathic mylofibrosis for a similar biological marker with therapeutic potential. There is no obvious chromosomal marker in these conditions and yet evidence of clonality can be obtained in females by the use of X-inactivation patterns. PRV-1mRNA over expression, raised vitamin B12 levels and raised neutrophil alkaline phosphatase scores are evidence that cells in these conditions have received excessive signals for proliferation, maturation and reduced apoptosis. The ability of erythroid colonies to grow spontaneously without added external erythropoietin in some cases, provided a useful marker and a clue to this abnormal signaling. In the past year several important discoveries have been made which go a long way in elucidating the involved pathways. The recently discovered JAK2 V617F mutation which occurs in the majority of cases of polycythemia vera and in about half of the cases with the two other conditions, enables constitutive tyrosine kinase activity without the need for ligand binding to hematopoietic receptors. This mutation has become the biological marker for these conditions and has spurred the development of a specific therapy to neutralize its effects. The realization that inherited mutations in the thrombopoietin receptor (c-Mpl can cause a phenotype of thrombocytosis such as in Mpl Baltimore (K39N and in a Japanese family with S505A, has prompted the search for acquired mutations in this receptor in chronic myeloproliferative disease. Recently, two mutations have been found; W515L and W515K. These mutations have been evident in patients with essential thrombocythemia and idiopathic myelofibrosis but not in polycythemia vera. They presumably act by causing constitutional, activating conformational changes in the receptor. The discovery of JAK2 and Mpl mutations is leading to rapid advancements in understanding the pathophysiology and in the treatment of these diseases.

  18. The certification of boron in primary ingot aluminium. BCR No.25

    International Nuclear Information System (INIS)

    Vandecasteele, C.; Colinet, E.

    1984-01-01

    This report sets out the experimental procedures used for the certification of boron in primary ingot aluminium, which has already been certified for carbon and oxygen. Samples were analysed by seven different laboratories using the following methods: spectrophotometry, ICP-emission spectrometry, isotope dilution mass spectrometry, spark source mass spectrometry and charged particle activation analysis. The analytical methods and the statistical approach to analyse the data are described

  19. Assessment of the BCR sequential extraction procedure for thallium fractionation using synthetic mineral mixtures

    Czech Academy of Sciences Publication Activity Database

    Vaněk, A.; Grygar, Tomáš; Chrastný, V.; Tejnecký, V.; Drahota, Petr; Komárek, M.

    2010-01-01

    Roč. 176, 1-3 (2010), s. 913-918 ISSN 0304-3894 Institutional research plan: CEZ:AV0Z4032918; CEZ:AV0Z30130516 Keywords : Metal * Sequential extraction * Goethite * Ferrihydrite * Birnessite * Illite Subject RIV: DD - Geochemistry Impact factor: 3.723, year: 2010

  20. A BCR-ABL Kinase Activity-Independent Signaling Pathway in Chronic Myelogenous Leukemia

    Science.gov (United States)

    2008-02-01

    Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, et al. (2005) Cancer Cell 7:129–141. 10. Druker BJ...2532–9. 15. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J...HG, Mountford JC, Holyoake TL. Punish the parent not the progeny. Blood. 2005; 105: 1862–6. 63. Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg

  1. Specific Depletion of Myelin-Reactive B Cells via BCR-Targeting.

    Science.gov (United States)

    Stepanov, A V; Belogurov, A A; Kothapalli, P; Shamborant, O G; Knorre, V D; Telegin, G B; Ovsepyan, A A; Ponomarenko, N A; Deyev, S M; Kaveri, S V; Gabibov, A G

    2015-01-01

    B cells play a crucial role in the development and pathogenesis of systemic and organ-specific autoimmune diseases. Autoreactive B cells not only produce antibodies, but also secrete pro-inflammatory cytokines and present specific autoantigens to T cells. The treatment of autoimmune diseases via the elimination of the majority of B cells using the monoclonal anti-CD19/20 antibody (Rituximab) causes systemic side effects and, thus, requires a major revision. Therapeutic intervention directed towards selective elimination of pathogenic autoreactive B cells has the potential to become a universal approach to the treatment of various autoimmune abnormalities. Here, we developed a recombinant immunotoxin based on the immunodominant peptide of the myelin basic protein (MBP), fused to the antibody Fc domain. We showed that the obtained immunotoxin provides selective in vivo elimination of autoreactive B cells in mice with experimental autoimmune encephalomyelitis. The proposed conception may be further used for the development of new therapeutics for a targeted treatment of multiple sclerosis and other autoimmune disorders.

  2. Determination of trace elements in BCR single cell protein via destructive neutron activation analyses

    International Nuclear Information System (INIS)

    Tjioe, P.S.; Goeij, J.J.M. de; Nooijen, J.L.; Kroon, J.J.

    1978-10-01

    The amount of some trace elements in single cell protein (SCP), a product of BP Research Centre at Sunbury-at-Thames, England, was determined by neutron activation analysis. The SCP-samples were irradiated in the reactor of the Interuniversity Reactor Institute at Delft in a neutron flux of 1.0x10 13 n/cm 2 s for 12 hours. Samples of Bowen's Kale were used as reference material. After a decay of two or three days the samples were chemically destroyed, and the trace elements were separated. The quantity of the following elements was determined by measuring the γ-activity by means of a scintillation counter: antimony, cadmium, mercury, arsenic and selenium. The amounts of these elements in the SCP and in the reference material were tabled

  3. Oncogenic Kinase Bcr-Abl and Its Resistance to Pharmacological Inhibitors

    Czech Academy of Sciences Publication Activity Database

    Kryštof, Vladimír

    2008-01-01

    Roč. 102, č. 9 (2008), s. 795-800 E-ISSN 1213-7103 Institutional research plan: CEZ:AV0Z50380511 Keywords : imatinib * inhibitor * chronic myeloid leukaemia * kinase * cancer Subject RIV: CE - Biochemistry www.chemicke-listy.cz/docs/full/2008_09_795-800.pdf

  4. Imatinib-loaded polyelectrolyte microcapsules for sustained targeting of BCR-ABL+ leukemia stem cells.

    Science.gov (United States)

    Palamà, Ilaria E; Leporatti, Stefano; de Luca, Emanuela; Di Renzo, Nicola; Maffia, Michele; Gambacorti-Passerini, Carlo; Rinaldi, Ross; Gigli, Giuseppe; Cingolani, Roberto; Coluccia, Addolorata M L

    2010-04-01

    The lack of sensitivity of chronic myeloid leukemia (CML) stem cells to imatinib mesylate (IM) commonly leads to drug dose escalation or early disease relapses when therapy is stopped. Here, we report that packaging of IM into a biodegradable carrier based on polyelectrolyte microcapsules increases drug retention and antitumor activity in CML stem cells, also improving the ex vivo purging of malignant progenitors from patient autografts. Microparticles/capsules were obtained by layer-by-layer (LbL) self-assembly of oppositely charged polyelectrolyte multilayers on removable calcium carbonate (CaCO(3)) templates and loaded with or without IM. A leukemic cell line (KU812) and CD34(+) cells freshly isolated from healthy donors or CML patients were tested. Polyelectrolyte microcapsules (PMCs) with an average diameter of 3 microm, fluorescently labelled multilayers sensitive to the action of intracellular proteases and 95-99% encapsulation efficiency of IM, were prepared. Cell uptake efficiency of such biodegradable carriers was quantified in KU812, leukemic and normal CD34(+) stem cells (range: 70-85%), and empty PMCs did not impact cell viability. IM-loaded PMCs selectively targeted CML cells, by promoting apoptosis at doses that exert only cytostatic effects by IM alone. More importantly, residual CML cells from patient leukapheresis products were reduced or eliminated more efficiently by using IM-loaded PMCs compared with freely soluble IM, with a purging efficiency of several logs. No adverse effects on normal CD34(+) stem-cell survival and their clonogenic potential was noticed in long-term cultures of hematopoietic progenitors in vitro. This pilot study provides the proof-of-principle for the clinical application of biodegradable IM-loaded PMC as feasible, safe and effective ex vivo purging agents to target CML stem cells, in order to improve transplant outcome of resistant/relapsed patients or reduce IM dose escalation.

  5. Third symposium on coal preparation. NCA/BCR coal conference and Expo IV

    Energy Technology Data Exchange (ETDEWEB)

    None

    1977-01-01

    The third Symposium on Coal preparation, sponsored by the National Coal Association and Bituminous Coal Research, Inc., was held at the Kentucky Fair and Exposition Center, Louisville, Kentucky, October 18-20, 1977. Fourteen papers from the proceedings have been entered individually into EDB and ERA; five additional papers had been entered previously from other sources. Topics covered involved chemical comminution and chemical desulfurization of coal (aimed at reducing sulfur sufficiently with some coals to meet air quality standards without flue gas desulfurization), coal cleaning concepts, removing coal fines and recycling wash water, comparative evaluation of coal preparation methods, coal refuse disposal without polluting the environment, spoil bank reprocessing, noise control in coal preparation plants, etc. (LTN)

  6. Poisson branching point processes

    International Nuclear Information System (INIS)

    Matsuo, K.; Teich, M.C.; Saleh, B.E.A.

    1984-01-01

    We investigate the statistical properties of a special branching point process. The initial process is assumed to be a homogeneous Poisson point process (HPP). The initiating events at each branching stage are carried forward to the following stage. In addition, each initiating event independently contributes a nonstationary Poisson point process (whose rate is a specified function) located at that point. The additional contributions from all points of a given stage constitute a doubly stochastic Poisson point process (DSPP) whose rate is a filtered version of the initiating point process at that stage. The process studied is a generalization of a Poisson branching process in which random time delays are permitted in the generation of events. Particular attention is given to the limit in which the number of branching stages is infinite while the average number of added events per event of the previous stage is infinitesimal. In the special case when the branching is instantaneous this limit of continuous branching corresponds to the well-known Yule--Furry process with an initial Poisson population. The Poisson branching point process provides a useful description for many problems in various scientific disciplines, such as the behavior of electron multipliers, neutron chain reactions, and cosmic ray showers

  7. A secondary fuel removal process: plasma processing

    Energy Technology Data Exchange (ETDEWEB)

    Min, J Y; Kim, Y S [Hanyang Univ., Seoul (Korea, Republic of); Bae, K K; Yang, M S [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1997-07-01

    Plasma etching process of UO{sub 2} by using fluorine containing gas plasma is studied as a secondary fuel removal process for DUPIC (Direct Use of PWR spent fuel Into Candu) process which is taken into consideration for potential future fuel cycle in Korea. CF{sub 4}/O{sub 2} gas mixture is chosen for reactant gas and the etching rates of UO{sub 2} by the gas plasma are investigated as functions of CF{sub 4}/O{sub 2} ratio, plasma power, substrate temperature, and plasma gas pressure. It is found that the optimum CF{sub 4}/O{sub 2} ratio is around 4:1 at all temperatures up to 400 deg C and the etching rate increases with increasing r.f. power and substrate temperature. Under 150W r.f. power the etching rate reaches 1100 monolayers/min at 400 deg C, which is equivalent to about 0.5mm/min. (author).

  8. The SILVA atomic process

    International Nuclear Information System (INIS)

    Cazalet, J.

    1997-01-01

    The SILVA laser isotope separation process is based on the laser selective photo-ionization of uranium atomic vapour; the process is presently under development by CEA and COGEMA in France, with the aim to reduce by a factor three the cost of uranium enrichment. The two main components of a SILVA process plant are the lasers (copper vapour lasers and dye lasers) and the separator for the vaporization (with a high energy electron beam), ionization and separation operations. Researches on the SILVA process started in 1985 and the technical and economical feasibility is to be demonstrated in 1997. The progresses of similar rival processes and other processes are discussed and the remaining research stages and themes of the SILVA program are presented

  9. Technology or Process First?

    DEFF Research Database (Denmark)

    Siurdyban, Artur Henryk; Svejvig, Per; Møller, Charles

    Enterprise Systems Management (ESM) and Business Pro- cess Management (BPM), although highly correlated, have evolved as alternative and mutually exclusive approaches to corporate infrastruc- ture. As a result, companies struggle to nd the right balance between technology and process factors...... in infrastructure implementation projects. The purpose of this paper is articulate a need and a direction to medi- ate between the process-driven and the technology-driven approaches. Using a cross-case analysis, we gain insight into two examples of sys- tems and process implementation. We highlight the dierences...... between them using strategic alignment, Enterprise Systems and Business Process Management theories. We argue that the insights from these cases can lead to a better alignment between process and technology. Implications for practice include the direction towards a closer integration of process...

  10. Badge Office Process Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Haurykiewicz, John Paul [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dinehart, Timothy Grant [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Parker, Robert Young [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-05-12

    The purpose of this process analysis was to analyze the Badge Offices’ current processes from a systems perspective and consider ways of pursuing objectives set forth by SEC-PS, namely increased customer flow (throughput) and reduced customer wait times. Information for the analysis was gathered for the project primarily through Badge Office Subject Matter Experts (SMEs), and in-person observation of prevailing processes. Using the information gathered, a process simulation model was constructed to represent current operations and allow assessment of potential process changes relative to factors mentioned previously. The overall purpose of the analysis was to provide SEC-PS management with information and recommendations to serve as a basis for additional focused study and areas for potential process improvements in the future.

  11. Business process transformation

    CERN Document Server

    Grover, Varun

    2015-01-01

    Featuring contributions from prominent thinkers and researchers, this volume in the ""Advances in Management Information Systems"" series provides a rich set of conceptual, empirical, and introspective studies that epitomize fundamental knowledge in the area of Business Process Transformation. Processes are interpreted broadly to include operational and managerial processes within and between organizations, as well as those involved in knowledge generation. Transformation includes radical and incremental change, its conduct, management, and outcome. The editors and contributing authors pay clo

  12. Rational Unified Process

    OpenAIRE

    Kopal, Nils

    2016-01-01

    In this German seminar paper, which was written in the year 2011 at the University of Duisburg for a Bachelor Colloquium in Applied computer science, we show a brief overview of the Rational Unified Process (RUP). Thus, interested students or generally interested people in software development gain a first impression of RUP. The paper includes a survey and overview of the underlying process structure, the phases of the process, its workflows, and describes the always by the RUP developers pos...

  13. Deference and Due Process

    OpenAIRE

    Vermeule, Cornelius Adrian

    2015-01-01

    In the textbooks, procedural due process is a strictly judicial enterprise; although substantive entitlements are created by legislative and executive action, it is for courts to decide independently what process the Constitution requires. The notion that procedural due process might be committed primarily to the discretion of the agencies themselves is almost entirely absent from the academic literature. The facts on the ground are very different. Thanks to converging strands of caselaw ...

  14. Process Improvement Essentials

    CERN Document Server

    Persse, James R

    2006-01-01

    Process Improvement Essentials combines the foundation needed to understand process improvement theory with the best practices to help individuals implement process improvement initiatives in their organization. The three leading programs: ISO 9001:2000, CMMI, and Six Sigma--amidst the buzz and hype--tend to get lumped together under a common label. This book delivers a combined guide to all three programs, compares their applicability, and then sets the foundation for further exploration.

  15. Basic digital signal processing

    CERN Document Server

    Lockhart, Gordon B

    1985-01-01

    Basic Digital Signal Processing describes the principles of digital signal processing and experiments with BASIC programs involving the fast Fourier theorem (FFT). The book reviews the fundamentals of the BASIC program, continuous and discrete time signals including analog signals, Fourier analysis, discrete Fourier transform, signal energy, power. The text also explains digital signal processing involving digital filters, linear time-variant systems, discrete time unit impulse, discrete-time convolution, and the alternative structure for second order infinite impulse response (IIR) sections.

  16. Multiphoton processes: conference proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Lambropoulos, P.; Smith, S.J. (eds.)

    1984-01-01

    The chapters of this volume represent the invited papers delivered at the conference. They are arranged according to thermatic proximity beginning with atoms and continuing with molecules and surfaces. Section headings include multiphoton processes in atoms, field fluctuations and collisions in multiphoton process, and multiphoton processes in molecules and surfaces. Abstracts of individual items from the conference were prepared separately for the data base. (GHT)

  17. TEP process flow diagram

    Energy Technology Data Exchange (ETDEWEB)

    Wilms, R Scott [Los Alamos National Laboratory; Carlson, Bryan [Los Alamos National Laboratory; Coons, James [Los Alamos National Laboratory; Kubic, William [Los Alamos National Laboratory

    2008-01-01

    This presentation describes the development of the proposed Process Flow Diagram (PFD) for the Tokamak Exhaust Processing System (TEP) of ITER. A brief review of design efforts leading up to the PFD is followed by a description of the hydrogen-like, air-like, and waterlike processes. Two new design values are described; the mostcommon and most-demanding design values. The proposed PFD is shown to meet specifications under the most-common and mostdemanding design values.

  18. Standard Model processes

    CERN Document Server

    Mangano, M.L.; Aguilar-Saavedra, Juan Antonio; Alekhin, S.; Badger, S.; Bauer, C.W.; Becher, T.; Bertone, V.; Bonvini, M.; Boselli, S.; Bothmann, E.; Boughezal, R.; Cacciari, M.; Carloni Calame, C.M.; Caola, F.; Campbell, J.M.; Carrazza, S.; Chiesa, M.; Cieri, L.; Cimaglia, F.; Febres Cordero, F.; Ferrarese, P.; D'Enterria, D.; Ferrera, G.; Garcia i Tormo, X.; Garzelli, M.V.; Germann, E.; Hirschi, V.; Han, T.; Ita, H.; Jäger, B.; Kallweit, S.; Karlberg, A.; Kuttimalai, S.; Krauss, F.; Larkoski, A.J.; Lindert, J.; Luisoni, G.; Maierhöfer, P.; Mattelaer, O.; Martinez, H.; Moch, S.; Montagna, G.; Moretti, M.; Nason, P.; Nicrosini, O.; Oleari, C.; Pagani, D.; Papaefstathiou, A.; Petriello, F.; Piccinini, F.; Pierini, M.; Pierog, T.; Pozzorini, S.; Re, E.; Robens, T.; Rojo, J.; Ruiz, R.; Sakurai, K.; Salam, G.P.; Salfelder, L.; Schönherr, M.; Schulze, M.; Schumann, S.; Selvaggi, M.; Shivaji, A.; Siodmok, A.; Skands, P.; Torrielli, P.; Tramontano, F.; Tsinikos, I.; Tweedie, B.; Vicini, A.; Westhoff, S.; Zaro, M.; Zeppenfeld, D.; CERN. Geneva. ATS Department

    2017-06-22

    This report summarises the properties of Standard Model processes at the 100 TeV pp collider. We document the production rates and typical distributions for a number of benchmark Standard Model processes, and discuss new dynamical phenomena arising at the highest energies available at this collider. We discuss the intrinsic physics interest in the measurement of these Standard Model processes, as well as their role as backgrounds for New Physics searches.

  19. Scientific information processing procedures

    Directory of Open Access Journals (Sweden)

    García, Maylin

    2013-07-01

    Full Text Available The paper systematizes several theoretical view-points on scientific information processing skill. It decomposes the processing skills into sub-skills. Several methods such analysis, synthesis, induction, deduction, document analysis were used to build up a theoretical framework. Interviews and survey to professional being trained and a case study was carried out to evaluate the results. All professional in the sample improved their performance in scientific information processing.

  20. Integrated Renovation Process

    DEFF Research Database (Denmark)

    Galiotto, Nicolas; Heiselberg, Per; Knudstrup, Mary-Ann

    2016-01-01

    renovation to be overcome. The homeowners were better integrated and their preferences and immaterial values were better taken into account. To keep the decision-making process economically viable and timely, the process as known today still needs to be improved, and new tools need to be developed....... This paper presents a new scheme: the integrated renovation process. One successful case study is introduced, and recommendations for future developments needed in the field are provided....

  1. Transuranium processing plant

    International Nuclear Information System (INIS)

    King, L.J.

    1983-01-01

    The Transuranium Processing Plant (TRU) is a remotely operated, hot-cell, chemical processing facility of advanced design. The heart of TRU is a battery of nine heavily shielded process cells housed in a two-story building. Each cell, with its 54-inch-thick walls of a special high-density concrete, has enough shielding to stop the neutrons and gamma radiation from 1 gram of 252/sub Cf/ and associated fission products. Four cells contain chemical processing equipment, three contain equipment for the preparation and inspection of HFIR targets, and two cells are used for analytical chemistry operations. In addition, there are eight laboratories used for process development, for part of the process-control analyses, and for product finishing operations. Although the Transuranium Processing Plant was built for the purpose of recovering transuranium elements from targets irradiated in the High Flux Isotope Reactor (HFIR), it is also a highly versatile facility which has extensive provisions for changing and modifying equipment. Thus, it was a relatively simple matter to install a Solvent Extraction Test Facility (SETF) in one of the TRU chemical processing cells for use in the evaluation and demonstration of solvent extraction flowsheets for the recovery of fissile and fertile materials from irradiated reactor fuels. The equipment in the SETF has been designed for process development and demonstrations and the particular type of mixer-settler contactors was chosen because it is easy to observe and sample

  2. Linearity in Process Languages

    DEFF Research Database (Denmark)

    Nygaard, Mikkel; Winskel, Glynn

    2002-01-01

    The meaning and mathematical consequences of linearity (managing without a presumed ability to copy) are studied for a path-based model of processes which is also a model of affine-linear logic. This connection yields an affine-linear language for processes, automatically respecting open......-map bisimulation, in which a range of process operations can be expressed. An operational semantics is provided for the tensor fragment of the language. Different ways to make assemblies of processes lead to different choices of exponential, some of which respect bisimulation....

  3. Refractometry in process engineering

    Energy Technology Data Exchange (ETDEWEB)

    Roepscher, H

    1980-02-01

    Following a brief historical introduction into general refractometry, the limiting angle refractometer is dealt with in the first section and the differential refractometer in the second section, as well as process engineering information on this measuring method being given. An attempt is made with an extensive close-to-practice description to introduce the planner and technician to this physical measuring method in process engineering in order that they be able to use it themselves if necessary. When properly applied, it can be a valuable help to process control in compliance with process automization.

  4. Process modeling style

    CERN Document Server

    Long, John

    2014-01-01

    Process Modeling Style focuses on other aspects of process modeling beyond notation that are very important to practitioners. Many people who model processes focus on the specific notation used to create their drawings. While that is important, there are many other aspects to modeling, such as naming, creating identifiers, descriptions, interfaces, patterns, and creating useful process documentation. Experience author John Long focuses on those non-notational aspects of modeling, which practitioners will find invaluable. Gives solid advice for creating roles, work produ

  5. The Critical Design Process

    DEFF Research Database (Denmark)

    Brunsgaard, Camilla; Knudstrup, Mary-Ann; Heiselberg, Per

    2014-01-01

    within Danish tradition of architecture and construction. The objective of the research presented in this paper, is to compare the different design processes behind the making of passive houses in a Danish context. We evaluated the process with regard to the integrated and traditional design process....... Data analysis showed that the majority of the consortiums worked in an integrated manner; though there was room for improvment. Additionally, the paper discusses the challanges of implementing the integrated design process in practice and suggests ways of overcomming some of the barriers . In doing so...

  6. Multimodal Processes Rescheduling

    DEFF Research Database (Denmark)

    Bocewicz, Grzegorz; Banaszak, Zbigniew A.; Nielsen, Peter

    2013-01-01

    Cyclic scheduling problems concerning multimodal processes are usually observed in FMSs producing multi-type parts where the Automated Guided Vehicles System (AGVS) plays a role of a material handling system. Schedulability analysis of concurrently flowing cyclic processes (SCCP) exe-cuted in the......Cyclic scheduling problems concerning multimodal processes are usually observed in FMSs producing multi-type parts where the Automated Guided Vehicles System (AGVS) plays a role of a material handling system. Schedulability analysis of concurrently flowing cyclic processes (SCCP) exe...

  7. Fuels Processing Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — NETL’s Fuels Processing Laboratory in Morgantown, WV, provides researchers with the equipment they need to thoroughly explore the catalytic issues associated with...

  8. Quantum information processing

    National Research Council Canada - National Science Library

    Leuchs, Gerd; Beth, Thomas

    2003-01-01

    ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 SimulationofHamiltonians... References... 1 1 1 3 5 8 10 2 Quantum Information Processing and Error Correction with Jump Codes (G. Alber, M. Mussinger...

  9. Exhaust gas processing facility

    International Nuclear Information System (INIS)

    Terada, Shin-ichi.

    1995-01-01

    The facility of the present invention comprises a radioactive liquid storage vessel, an exhaust gas dehumidifying device for dehumidifying gases exhausted from the vessel and an exhaust gas processing device for reducing radioactive materials in the exhaust gases. A purified gas line is disposed to the radioactive liquid storage vessel for purging exhaust gases generated from the radioactive liquid, then dehumidified and condensed liquid is recovered, and exhaust gases are discharged through an exhaust gas pipe disposed downstream of the exhaust gas processing device. With such procedures, the scale of the exhaust gas processing facility can be reduced and exhaust gases can be processed efficiently. (T.M.)

  10. Chemical process hazards analysis

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-02-01

    The Office of Worker Health and Safety (EH-5) under the Assistant Secretary for the Environment, Safety and Health of the US Department (DOE) has published two handbooks for use by DOE contractors managing facilities and processes covered by the Occupational Safety and Health Administration (OSHA) Rule for Process Safety Management of Highly Hazardous Chemicals (29 CFR 1910.119), herein referred to as the PSM Rule. The PSM Rule contains an integrated set of chemical process safety management elements designed to prevent chemical releases that can lead to catastrophic fires, explosions, or toxic exposures. The purpose of the two handbooks, ``Process Safety Management for Highly Hazardous Chemicals`` and ``Chemical Process Hazards Analysis,`` is to facilitate implementation of the provisions of the PSM Rule within the DOE. The purpose of this handbook ``Chemical Process Hazards Analysis,`` is to facilitate, within the DOE, the performance of chemical process hazards analyses (PrHAs) as required under the PSM Rule. It provides basic information for the performance of PrHAs, and should not be considered a complete resource on PrHA methods. Likewise, to determine if a facility is covered by the PSM rule, the reader should refer to the handbook, ``Process Safety Management for Highly Hazardous Chemicals`` (DOE- HDBK-1101-96). Promulgation of the PSM Rule has heightened the awareness of chemical safety management issues within the DOE. This handbook is intended for use by DOE facilities and processes covered by the PSM rule to facilitate contractor implementation of the PrHA element of the PSM Rule. However, contractors whose facilities and processes not covered by the PSM Rule may also use this handbook as a basis for conducting process hazards analyses as part of their good management practices. This handbook explains the minimum requirements for PrHAs outlined in the PSM Rule. Nowhere have requirements been added beyond what is specifically required by the rule.

  11. Processer og procesledelse

    DEFF Research Database (Denmark)

    Madsen, Benedicte

    Bogen udfolder, nuancerer og konkretiserer procesledelse ift. mentale, relationelle og organisatoriske processer. Eksempler på kapitel-overskrifter: Procesbegrebet, Rammesætning, Kontraktredskabet, Mødeledelse, Samtaler, Reflekterende positioner og processer, Konflikthåndtering og teamudvikling......, Invitation til det dialogiske rum - om at arbejde over og under stregen, og Mentale omstruktureringer....

  12. The Player Engagement Process

    DEFF Research Database (Denmark)

    Schoenau-Fog, Henrik

    2011-01-01

    , categories and triggers involved in this process. By applying grounded theory to the analysis of the responses, a process-oriented player engagement framework was developed and four main components consisting of objectives, activities, accomplishments and affects as well as the corresponding categories...

  13. Mineral Processing Technology Roadmap

    Energy Technology Data Exchange (ETDEWEB)

    none,

    2000-09-01

    This document represents the roadmap for Processing Technology Research in the US Mining Industry. It was developed based on the results of a Processing Technology Roadmap Workshop sponsored by the National Mining Association in conjunction with the US Department of Energy, Office of Energy Efficiency and Renewable Energy, Office of Industrial Technologies. The Workshop was held January 24 - 25, 2000.

  14. Process control program development

    International Nuclear Information System (INIS)

    Dameron, H.J.

    1985-01-01

    This paper details the development and implementation of a ''Process Control Program'' at Duke Power's three nuclear stations - Oconee, McGuire, and Catawba. Each station is required by Technical Specification to have a ''Process Control Program'' (PCP) to control all dewatering and/or solidification activities for radioactive wastes

  15. Valuing the Accreditation Process

    Science.gov (United States)

    Bahr, Maria

    2018-01-01

    The value of the National Association for Developmental Education (NADE) accreditation process is far-reaching. Not only do students and programs benefit from the process, but also the entire institution. Through data collection of student performance, analysis, and resulting action plans, faculty and administrators can work cohesively towards…

  16. CMOS/SOS processing

    Science.gov (United States)

    Ramondetta, P.

    1980-01-01

    Report describes processes used in making complementary - metal - oxide - semiconductor/silicon-on-sapphire (CMOS/SOS) integrated circuits. Report lists processing steps ranging from initial preparation of sapphire wafers to final mapping of "good" and "bad" circuits on a wafer.

  17. Management oriented process

    International Nuclear Information System (INIS)

    2004-01-01

    ANAV decided to implement process-oriented management by adopting the U. S. NEI (Nuclear Electric Industry) model. The article describes the initial phases of the project, its current status and future prospects. The project has been considered as an improvement in the areas of organization and human factors. Recently, IAEA standard drafts are including processes as an accepted management model. (Author)

  18. Hybrid quantum information processing

    Energy Technology Data Exchange (ETDEWEB)

    Furusawa, Akira [Department of Applied Physics, School of Engineering, The University of Tokyo (Japan)

    2014-12-04

    I will briefly explain the definition and advantage of hybrid quantum information processing, which is hybridization of qubit and continuous-variable technologies. The final goal would be realization of universal gate sets both for qubit and continuous-variable quantum information processing with the hybrid technologies. For that purpose, qubit teleportation with a continuousvariable teleporter is one of the most important ingredients.

  19. Industrial separation processes : fundamentals

    NARCIS (Netherlands)

    Haan, de A.B.; Bosch, Hans

    2013-01-01

    Separation processes on an industrial scale comprise well over half of the capital and operating costs. They are basic knowledge in every chemical engineering and process engineering study. This book provides comprehensive and fundamental knowledge of university teaching in this discipline,

  20. METAL PLATING PROCESS

    Science.gov (United States)

    Walker, D.E.; Noland, R.A.

    1958-08-12

    A process ts described for obtaining a closely bonded coating of steel or iron on uranium. The process consists of providing, between the steel and uramium. a layer of silver. amd then pressure rolling tbe assembly at about 600 deg C until a reduction of from l0 to 50% has been obtained.

  1. The Analytical Hierarchy Process

    DEFF Research Database (Denmark)

    Barfod, Michael Bruhn

    2007-01-01

    The technical note gathers the theory behind the Analytical Hierarchy Process (AHP) and present its advantages and disadvantages in practical use.......The technical note gathers the theory behind the Analytical Hierarchy Process (AHP) and present its advantages and disadvantages in practical use....

  2. Semantic Business Process Modeling

    OpenAIRE

    Markovic, Ivan

    2010-01-01

    This book presents a process-oriented business modeling framework based on semantic technologies. The framework consists of modeling languages, methods, and tools that allow for semantic modeling of business motivation, business policies and rules, and business processes. Quality of the proposed modeling framework is evaluated based on the modeling content of SAP Solution Composer and several real-world business scenarios.

  3. Process energy analysis

    International Nuclear Information System (INIS)

    Kaiser, V.

    1993-01-01

    In Chapter 2 process energy cost analysis for chemical processing is treated in a general way, independent of the specific form of energy and power production. Especially, energy data collection and data treatment, energy accounting (metering, balance setting), specific energy input, and utility energy costs and prices are discussed. (R.P.) 14 refs., 4 figs., 16 tabs

  4. Continuous affine processes

    DEFF Research Database (Denmark)

    Buchardt, Kristian

    2016-01-01

    Affine processes possess the property that expectations of exponential affine transformations are given by a set of Riccati differential equations, which is the main feature of this popular class of processes. In this paper we generalise these results for expectations of more general transformati...

  5. Food-Processing Wastes.

    Science.gov (United States)

    Frenkel, Val S; Cummings, Gregg A; Maillacheruvu, K Y; Tang, Walter Z

    2017-10-01

    Literature published in 2016 and early 2017 related to food processing wastes treatment for industrial applications are reviewed. This review is a subsection of the Treatment Systems section of the annual Water Environment Federation literature review and covers the following food processing industries and applications: general, meat and poultry, fruits and vegetables, dairy and beverage, and miscellaneous treatment of food wastes.

  6. Food processing and allergenicity.

    Science.gov (United States)

    Verhoeckx, Kitty C M; Vissers, Yvonne M; Baumert, Joseph L; Faludi, Roland; Feys, Marcel; Flanagan, Simon; Herouet-Guicheney, Corinne; Holzhauser, Thomas; Shimojo, Ryo; van der Bolt, Nieke; Wichers, Harry; Kimber, Ian

    2015-06-01

    Food processing can have many beneficial effects. However, processing may also alter the allergenic properties of food proteins. A wide variety of processing methods is available and their use depends largely on the food to be processed. In this review the impact of processing (heat and non-heat treatment) on the allergenic potential of proteins, and on the antigenic (IgG-binding) and allergenic (IgE-binding) properties of proteins has been considered. A variety of allergenic foods (peanuts, tree nuts, cows' milk, hens' eggs, soy, wheat and mustard) have been reviewed. The overall conclusion drawn is that processing does not completely abolish the allergenic potential of allergens. Currently, only fermentation and hydrolysis may have potential to reduce allergenicity to such an extent that symptoms will not be elicited, while other methods might be promising but need more data. Literature on the effect of processing on allergenic potential and the ability to induce sensitisation is scarce. This is an important issue since processing may impact on the ability of proteins to cause the acquisition of allergic sensitisation, and the subject should be a focus of future research. Also, there remains a need to develop robust and integrated methods for the risk assessment of food allergenicity. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Business process intelligence

    NARCIS (Netherlands)

    Castellanos, M.; Alves De Medeiros, A.K.; Mendling, J.; Weber, B.; Weijters, A.J.M.M.; Cardoso, J.; Aalst, van der W.M.P.

    2009-01-01

    Business Process Intelligence (BPI,) is an emerging area that is getting increasingly popularfor enterprises. The need to improve business process efficiency, to react quickly to changes and to meet regulatory compliance is among the main drivers for BPI. BPI refers to the application of Business

  8. Correctness of concurrent processes

    NARCIS (Netherlands)

    E.R. Olderog (Ernst-Rüdiger)

    1989-01-01

    textabstractA new notion of correctness for concurrent processes is introduced and investigated. It is a relationship P sat S between process terms P built up from operators of CCS [Mi 80], CSP [Ho 85] and COSY [LTS 79] and logical formulas S specifying sets of finite communication sequences as in

  9. Uranium processing and properties

    CERN Document Server

    2013-01-01

    Covers a broad spectrum of topics and applications that deal with uranium processing and the properties of uranium Offers extensive coverage of both new and established practices for dealing with uranium supplies in nuclear engineering Promotes the documentation of the state-of-the-art processing techniques utilized for uranium and other specialty metals

  10. Relational Processing Following Stroke

    Science.gov (United States)

    Andrews, Glenda; Halford, Graeme S.; Shum, David; Maujean, Annick; Chappell, Mark; Birney, Damian

    2013-01-01

    The research examined relational processing following stroke. Stroke patients (14 with frontal, 30 with non-frontal lesions) and 41 matched controls completed four relational processing tasks: sentence comprehension, Latin square matrix completion, modified Dimensional Change Card Sorting, and n-back. Each task included items at two or three…

  11. Contaminated nickel scrap processing

    International Nuclear Information System (INIS)

    Compere, A.L.; Griffith, W.L.; Hayden, H.W.; Johnson, J.S. Jr.; Wilson, D.F.

    1994-12-01

    The DOE will soon choose between treating contaminated nickel scrap as a legacy waste and developing high-volume nickel decontamination processes. In addition to reducing the volume of legacy wastes, a decontamination process could make 200,000 tons of this strategic metal available for domestic use. Contaminants in DOE nickel scrap include 234 Th, 234 Pa, 137 Cs, 239 Pu (trace), 60 Co, U, 99 Tc, and 237 Np (trace). This report reviews several industrial-scale processes -- electrorefining, electrowinning, vapormetallurgy, and leaching -- used for the purification of nickel. Conventional nickel electrolysis processes are particularly attractive because they use side-stream purification of process solutions to improve the purity of nickel metal. Additionally, nickel purification by electrolysis is effective in a variety of electrolyte systems, including sulfate, chloride, and nitrate. Conventional electrorefining processes typically use a mixed electrolyte which includes sulfate, chloride, and borate. The use of an electrorefining or electrowinning system for scrap nickel recovery could be combined effectively with a variety of processes, including cementation, solvent extraction, ion exchange, complex-formation, and surface sorption, developed for uranium and transuranic purification. Selected processes were reviewed and evaluated for use in nickel side-stream purification. 80 refs

  12. Production process of VE

    International Nuclear Information System (INIS)

    1987-07-01

    This book tells of synopsis of production process of VE(value engineering), object selection method and establishment of target, collection of object information, design of function, write improvement suggestion, evaluation of improvement suggestion, all sorts of worksheets of production process of VE, explanation of IE, explanation of PERT.

  13. Perspectives on Innovation Processes

    NARCIS (Netherlands)

    Garud, R.; Tuertscher, P.R.; Van de Ven, A.H.

    2013-01-01

    Innovation is often thought of as an outcome. In this chapter, we review the literatures on innovation processes pertaining to the invention, development, and implementation of ideas. In particular, we explore how these processes unfold within firms, across multi-party networks, and within

  14. Hyperspectral image processing methods

    Science.gov (United States)

    Hyperspectral image processing refers to the use of computer algorithms to extract, store and manipulate both spatial and spectral information contained in hyperspectral images across the visible and near-infrared portion of the electromagnetic spectrum. A typical hyperspectral image processing work...

  15. Methods of information processing

    Energy Technology Data Exchange (ETDEWEB)

    Kosarev, Yu G; Gusev, V D

    1978-01-01

    Works are presented on automation systems for editing and publishing operations by methods of processing symbol information and information contained in training selection (ranking of objectives by promise, classification algorithm of tones and noise). The book will be of interest to specialists in the automation of processing textural information, programming, and pattern recognition.

  16. Process for preparing radiopharmaceuticals

    International Nuclear Information System (INIS)

    Barak, M.; Winchell, H.S.

    1977-01-01

    A process for the preparation of technetium-99m labeled pharmaceuticals is disclosed. The process comprises initially isolating technetium-99m pertechnetate by adsorption upon an adsorbent packing in a chromatographic column. The technetium-99m is then eluted from the packing with a biological compound to form a radiopharmaceutical

  17. Contaminated nickel scrap processing

    Energy Technology Data Exchange (ETDEWEB)

    Compere, A.L.; Griffith, W.L.; Hayden, H.W.; Johnson, J.S. Jr.; Wilson, D.F.

    1994-12-01

    The DOE will soon choose between treating contaminated nickel scrap as a legacy waste and developing high-volume nickel decontamination processes. In addition to reducing the volume of legacy wastes, a decontamination process could make 200,000 tons of this strategic metal available for domestic use. Contaminants in DOE nickel scrap include {sup 234}Th, {sup 234}Pa, {sup 137}Cs, {sup 239}Pu (trace), {sup 60}Co, U, {sup 99}Tc, and {sup 237}Np (trace). This report reviews several industrial-scale processes -- electrorefining, electrowinning, vapormetallurgy, and leaching -- used for the purification of nickel. Conventional nickel electrolysis processes are particularly attractive because they use side-stream purification of process solutions to improve the purity of nickel metal. Additionally, nickel purification by electrolysis is effective in a variety of electrolyte systems, including sulfate, chloride, and nitrate. Conventional electrorefining processes typically use a mixed electrolyte which includes sulfate, chloride, and borate. The use of an electrorefining or electrowinning system for scrap nickel recovery could be combined effectively with a variety of processes, including cementation, solvent extraction, ion exchange, complex-formation, and surface sorption, developed for uranium and transuranic purification. Selected processes were reviewed and evaluated for use in nickel side-stream purification. 80 refs.

  18. Microcontroller base process emulator

    OpenAIRE

    Jovrea Titus Claudiu

    2009-01-01

    This paper describes the design of a microcontroller base emulator for a conventional industrial process. The emulator is made with microcontroller and is used for testing and evaluating the performances of the industrial regulators. The parameters of the emulated process are fully customizable online and downloadable thru a serial communication from a personal computer.

  19. Cementation process study

    International Nuclear Information System (INIS)

    Park, H.H.; Han, K.W.; Ahn, S.J.; Choi, K.S.; Lee, M.W.; Ryu, Y.K.

    1985-01-01

    In the cementation process study, in 1984, design of the waste treatment simulator was finished for the first step. We can experience not only the operation of solidification system but the design and construction of comming large scale plant through the design of cementation process. (Author)

  20. Monitoring of operating processes

    International Nuclear Information System (INIS)

    Barry, R.F.

    1981-01-01

    Apparatus is described for monitoring the processes of a nuclear reactor to detect off-normal operation of any process and for testing the monitoring apparatus. The processes are evaluated by response to their paramters, such as temperature, pressure, etc. The apparatus includes a pair of monitoring paths or signal processing units. Each unit includes facilities for receiving on a time-sharing basis, a status binary word made up of digits each indicating the status of a process, whether normal or off-normal, and test-signal binary words simulating the status binary words. The status words and test words are processed in succession during successive cycles. During each cycle, the two units receive the same status word and the same test word. The test words simulate the status words both when they indicate normal operation and when they indicate off-normal operation. Each signal-processing unit includes a pair of memories. Each memory receives a status word or a test word, as the case may be, and converts the received word into a converted status word or a converted test word. The memories of each monitoring unit operate into a non-coincidence which signals non-coincidence of the converted word out of one memory of a signal-processing unit not identical to the converted word of the other memory of the same unit

  1. Teaching the Writing Process

    Science.gov (United States)

    Keen, John

    2017-01-01

    This article outlines some cognitive process models of writing composition. Possible reasons why students' writing capabilities do not match their abilities in some other school subjects are explored. Research findings on the efficacy of process approaches to teaching writing are presented and potential shortcomings are discussed. Product-based…

  2. Heavy oils processing materials requirements crude processing

    Energy Technology Data Exchange (ETDEWEB)

    Sloley, Andrew W. [CH2M Hill, Englewood, CO (United States)

    2012-07-01

    Over time, recommended best practices for crude unit materials selection have evolved to accommodate new operating requirements, feed qualities, and product qualities. The shift to heavier oil processing is one of the major changes in crude feed quality occurring over the last 20 years. The three major types of crude unit corrosion include sulfidation attack, naphthenic acid attack, and corrosion resulting from hydrolyzable chlorides. Heavy oils processing makes all three areas worse. Heavy oils have higher sulfur content; higher naphthenic acid content; and are more difficult to desalt, leading to higher chloride corrosion rates. Materials selection involves two major criteria, meeting required safety standards, and optimizing economics of the overall plant. Proper materials selection is only one component of a plant integrity approach. Materials selection cannot eliminate all corrosion. Proper materials selection requires appropriate support from other elements of an integrity protection program. The elements of integrity preservation include: materials selection (type and corrosion allowance); management limits on operating conditions allowed; feed quality control; chemical additives for corrosion reduction; and preventive maintenance and inspection (PMI). The following discussion must be taken in the context of the application of required supporting work in all the other areas. Within that context, specific materials recommendations are made to minimize corrosion due to the most common causes in the crude unit. (author)

  3. Nuclear process heat

    International Nuclear Information System (INIS)

    Barnert, H.; Hohn, H.; Schad, M.; Schwarz, D.; Singh, J.

    1993-01-01

    In a system for the application of high temperature heat from the HTR one must distinguish between the current generation and the use of process heat. In this respect it is important that the current can be generated by dual purpose power plants. The process heat is used as sensible heat, vaporisation heat and as chemical energy at the chemical conversion for the conversion of raw materials, the refinement of fossil primary energy carriers and finally circuit processes for the fission of water. These processes supply the market for heat, fuels, motor fuels and basic materials. Fifteen examples of HTR heat processes from various projects and programmes are presented in form of energy balances, however in a rather short way. (orig./DG) [de

  4. Nonhomogeneous fractional Poisson processes

    Energy Technology Data Exchange (ETDEWEB)

    Wang Xiaotian [School of Management, Tianjin University, Tianjin 300072 (China)]. E-mail: swa001@126.com; Zhang Shiying [School of Management, Tianjin University, Tianjin 300072 (China); Fan Shen [Computer and Information School, Zhejiang Wanli University, Ningbo 315100 (China)

    2007-01-15

    In this paper, we propose a class of non-Gaussian stationary increment processes, named nonhomogeneous fractional Poisson processes W{sub H}{sup (j)}(t), which permit the study of the effects of long-range dependance in a large number of fields including quantum physics and finance. The processes W{sub H}{sup (j)}(t) are self-similar in a wide sense, exhibit more fatter tail than Gaussian processes, and converge to the Gaussian processes in distribution in some cases. In addition, we also show that the intensity function {lambda}(t) strongly influences the existence of the highest finite moment of W{sub H}{sup (j)}(t) and the behaviour of the tail probability of W{sub H}{sup (j)}(t)

  5. Nonhomogeneous fractional Poisson processes

    International Nuclear Information System (INIS)

    Wang Xiaotian; Zhang Shiying; Fan Shen

    2007-01-01

    In this paper, we propose a class of non-Gaussian stationary increment processes, named nonhomogeneous fractional Poisson processes W H (j) (t), which permit the study of the effects of long-range dependance in a large number of fields including quantum physics and finance. The processes W H (j) (t) are self-similar in a wide sense, exhibit more fatter tail than Gaussian processes, and converge to the Gaussian processes in distribution in some cases. In addition, we also show that the intensity function λ(t) strongly influences the existence of the highest finite moment of W H (j) (t) and the behaviour of the tail probability of W H (j) (t)

  6. Identification of wastewater processes

    DEFF Research Database (Denmark)

    Carstensen, Niels Jacob

    The introduction of on-line sensors for monitoring of nutrient salts concentrations on wastewater treatment plants with nutrient removal, opens a wide new area of modelling wastewater processes. The subject of this thesis is the formulation of operational dynamic models based on time series...... of ammonia, nitrate, and phosphate concentrations, which are measured in the aeration tanks of the biological nutrient removal system. The alternatign operation modes of the BIO-DENITRO and BIO-DENIPHO processes are of particular interest. Time series models of the hydraulic and biological processes are very......-known theory of the processes with the significant effects found in data. These models are called grey box models, and they contain rate expressions for the processes of influent load of nutrients, transport of nutrients between the aeration tanks, hydrolysis and growth of biomass, nitrification...

  7. Quantum independent increment processes

    CERN Document Server

    Franz, Uwe

    2006-01-01

    This is the second of two volumes containing the revised and completed notes of lectures given at the school "Quantum Independent Increment Processes: Structure and Applications to Physics". This school was held at the Alfried-Krupp-Wissenschaftskolleg in Greifswald in March, 2003, and supported by the Volkswagen Foundation. The school gave an introduction to current research on quantum independent increment processes aimed at graduate students and non-specialists working in classical and quantum probability, operator algebras, and mathematical physics. The present second volume contains the following lectures: "Random Walks on Finite Quantum Groups" by Uwe Franz and Rolf Gohm, "Quantum Markov Processes and Applications in Physics" by Burkhard Kümmerer, Classical and Free Infinite Divisibility and Lévy Processes" by Ole E. Barndorff-Nielsen, Steen Thorbjornsen, and "Lévy Processes on Quantum Groups and Dual Groups" by Uwe Franz.

  8. Integrated biofuels process synthesis

    DEFF Research Database (Denmark)

    Torres-Ortega, Carlo Edgar; Rong, Ben-Guang

    2017-01-01

    Second and third generation bioethanol and biodiesel are more environmentally friendly fuels than gasoline and petrodiesel, andmore sustainable than first generation biofuels. However, their production processes are more complex and more expensive. In this chapter, we describe a two-stage synthesis......% used for bioethanol process), and steam and electricity from combustion (54%used as electricity) in the bioethanol and biodiesel processes. In the second stage, we saved about 5% in equipment costs and 12% in utility costs for bioethanol separation. This dual synthesis methodology, consisting of a top......-level screening task followed by a down-level intensification task, proved to be an efficient methodology for integrated biofuel process synthesis. The case study illustrates and provides important insights into the optimal synthesis and intensification of biofuel production processes with the proposed synthesis...

  9. Managing Software Process Evolution

    DEFF Research Database (Denmark)

    This book focuses on the design, development, management, governance and application of evolving software processes that are aligned with changing business objectives, such as expansion to new domains or shifting to global production. In the context of an evolving business world, it examines...... the complete software process lifecycle, from the initial definition of a product to its systematic improvement. In doing so, it addresses difficult problems, such as how to implement processes in highly regulated domains or where to find a suitable notation system for documenting processes, and provides...... essential insights and tips to help readers manage process evolutions. And last but not least, it provides a wealth of examples and cases on how to deal with software evolution in practice. Reflecting these topics, the book is divided into three parts. Part 1 focuses on software business transformation...

  10. Beryllium chemistry and processing

    CERN Document Server

    Walsh, Kenneth A

    2009-01-01

    This book introduces beryllium; its history, its chemical, mechanical, and physical properties including nuclear properties. The 29 chapters include the mineralogy of beryllium and the preferred global sources of ore bodies. The identification and specifics of the industrial metallurgical processes used to form oxide from the ore and then metal from the oxide are thoroughly described. The special features of beryllium chemistry are introduced, including analytical chemical practices. Beryllium compounds of industrial interest are identified and discussed. Alloying, casting, powder processing, forming, metal removal, joining and other manufacturing processes are covered. The effect of composition and process on the mechanical and physical properties of beryllium alloys assists the reader in material selection. The physical metallurgy chapter brings conformity between chemical and physical metallurgical processing of beryllium, metal, alloys, and compounds. The environmental degradation of beryllium and its all...

  11. Business process support

    Energy Technology Data Exchange (ETDEWEB)

    Carle, Adriana; Fiducia, Daniel [Transportadora de Gas del Sur S.A. (TGS), Buenos Aires (Argentina)

    2005-07-01

    This paper is about the own development of business support software. The developed applications are used to support two business processes: one of them is the process of gas transportation and the other is the natural gas processing. This software has interphases with the ERP SAP, software SCADA and on line gas transportation simulation software. The main functionalities of the applications are: entrance on line real time of clients transport nominations, transport programming, allocation of the clients transport nominations, transport control, measurements, balanced pipeline, allocation of gas volume to the gas processing plants, calculate of product tons processed in each plant and tons of product distributed to clients. All the developed software generates information to the internal staff, regulatory authorities and clients. (author)

  12. Branching processes in biology

    CERN Document Server

    Kimmel, Marek

    2015-01-01

    This book provides a theoretical background of branching processes and discusses their biological applications. Branching processes are a well-developed and powerful set of tools in the field of applied probability. The range of applications considered includes molecular biology, cellular biology, human evolution and medicine. The branching processes discussed include Galton-Watson, Markov, Bellman-Harris, Multitype, and General Processes. As an aid to understanding specific examples, two introductory chapters, and two glossaries are included that provide background material in mathematics and in biology. The book will be of interest to scientists who work in quantitative modeling of biological systems, particularly probabilists, mathematical biologists, biostatisticians, cell biologists, molecular biologists, and bioinformaticians. The authors are a mathematician and cell biologist who have collaborated for more than a decade in the field of branching processes in biology for this new edition. This second ex...

  13. EDITORIAL: Industrial Process Tomography

    Science.gov (United States)

    Anton Johansen, Geir; Wang, Mi

    2008-09-01

    There has been tremendous development within measurement science and technology over the past couple of decades. New sensor technologies and compact versatile signal recovery electronics are continuously expanding the limits of what can be measured and the accuracy with which this can be done. Miniaturization of sensors and the use of nanotechnology push these limits further. Also, thanks to powerful and cost-effective computer systems, sophisticated measurement and reconstruction algorithms previously only accessible in advanced laboratories are now available for in situ online measurement systems. The process industries increasingly require more process-related information, motivated by key issues such as improved process control, process utilization and process yields, ultimately driven by cost-effectiveness, quality assurance, environmental and safety demands. Industrial process tomography methods have taken advantage of the general progress in measurement science, and aim at providing more information, both quantitatively and qualitatively, on multiphase systems and their dynamics. The typical approach for such systems has been to carry out one local or bulk measurement and assume that this is representative of the whole system. In some cases, this is sufficient. However, there are many complex systems where the component distribution varies continuously and often unpredictably in space and time. The foundation of industrial tomography is to conduct several measurements around the periphery of a multiphase process, and use these measurements to unravel the cross-sectional distribution of the process components in time and space. This information is used in the design and optimization of industrial processes and process equipment, and also to improve the accuracy of multiphase system measurements in general. In this issue we are proud to present a selection of the 145 papers presented at the 5th World Congress on Industrial Process Tomography in Bergen

  14. States in Process Calculi

    Directory of Open Access Journals (Sweden)

    Christoph Wagner

    2014-08-01

    Full Text Available Formal reasoning about distributed algorithms (like Consensus typically requires to analyze global states in a traditional state-based style. This is in contrast to the traditional action-based reasoning of process calculi. Nevertheless, we use domain-specific variants of the latter, as they are convenient modeling languages in which the local code of processes can be programmed explicitly, with the local state information usually managed via parameter lists of process constants. However, domain-specific process calculi are often equipped with (unlabeled reduction semantics, building upon a rich and convenient notion of structural congruence. Unfortunately, the price for this convenience is that the analysis is cumbersome: the set of reachable states is modulo structural congruence, and the processes' state information is very hard to identify. We extract from congruence classes of reachable states individual state-informative representatives that we supply with a proper formal semantics. As a result, we can now freely switch between the process calculus terms and their representatives, and we can use the stateful representatives to perform assertional reasoning on process calculus models.

  15. Welding processes handbook

    CERN Document Server

    Weman, Klas

    2003-01-01

    Deals with the main commercially significant and commonly used welding processes. This title takes the student or novice welder through the individual steps involved in each process in an easily understood way. It covers many of the requirements referred to in European Standards including EN719, EN 729, EN 729 and EN 287.$bWelding processes handbook is a concise, explanatory guide to the main commercially significant and commonly-used welding processes. It takes the novice welder or student through the individual steps involved in each process in a clear and easily understood way. It is intended to provide an up-to-date reference to the major applications of welding as they are used in industry. The contents have been arranged so that it can be used as a textbook for European welding courses in accordance with guidelines from the European Welding Federation. Welding processes and equipment necessary for each process are described so that they can be applied to all instruction levels required by the EWF and th...

  16. Organic waste incineration processes

    Energy Technology Data Exchange (ETDEWEB)

    Lemort, F.; Charvillat, J.P.; Nabot, J.P. [CEA Valrho, Bagnols sur Ceze Cedex (France); Chateauvieux, H.; Thiebaut, C. [CEA Valduc, 21 - Is-sur-Tille (France)

    2001-07-01

    Nuclear activities produce organic waste compatible with thermal processes designed to obtain a significant weight and volume reduction as well as to stabilize the inorganic residue in a form suitable for various interim storage or disposal routes. Several processes may be implemented (e.g. excess air, plasma, fluidized bed or rotating furnace) depending on the nature of the waste and the desired objectives. The authors focus on the IRIS rotating-kiln process, which was used for the first time with radioactive materials during the first half of 1999. IRIS is capable of processing highly chlorinated and {alpha}-contaminated waste at a rate of several kilograms per hour, while limiting corrosion due to chlorine as well as mechanical entrainment of radioactive particles in the off-gas stream. Although operated industrially, the process is under continual development to improve its performance and adapt it to a wider range of industrial applications. The main focus of attention today is on adapting the pyrolytic processes to waste with highly variable compositions and to enhance the efficiency of the off-gas purification systems. These subjects are of considerable interest for a large number of heat treatment processes (including all off-gas treatment systems) for which extremely durable, high-performance and low-flow electrostatic precipitators are now being developed. (author)

  17. Organic waste incineration processes

    International Nuclear Information System (INIS)

    Lemort, F.; Charvillat, J.P.; Nabot, J.P.; Chateauvieux, H.; Thiebaut, C.

    2001-01-01

    Nuclear activities produce organic waste compatible with thermal processes designed to obtain a significant weight and volume reduction as well as to stabilize the inorganic residue in a form suitable for various interim storage or disposal routes. Several processes may be implemented (e.g. excess air, plasma, fluidized bed or rotating furnace) depending on the nature of the waste and the desired objectives. The authors focus on the IRIS rotating-kiln process, which was used for the first time with radioactive materials during the first half of 1999. IRIS is capable of processing highly chlorinated and α-contaminated waste at a rate of several kilograms per hour, while limiting corrosion due to chlorine as well as mechanical entrainment of radioactive particles in the off-gas stream. Although operated industrially, the process is under continual development to improve its performance and adapt it to a wider range of industrial applications. The main focus of attention today is on adapting the pyrolytic processes to waste with highly variable compositions and to enhance the efficiency of the off-gas purification systems. These subjects are of considerable interest for a large number of heat treatment processes (including all off-gas treatment systems) for which extremely durable, high-performance and low-flow electrostatic precipitators are now being developed. (author)

  18. IT Project Prioritization Process

    DEFF Research Database (Denmark)

    Shollo, Arisa; Constantiou, Ioanna

    2013-01-01

    In most of the large companies IT project prioritization process is designed based on principles of evidencebased management. We investigate a case of IT project prioritization in a financial institution, and in particular, how managers practice evidence-based management during this process. We use...... a rich dataset built from a longitudinal study of the prioritization process for the IT projects. Our findings indicate that managers reach a decision not only by using evidence but from the interplay between the evidence and the judgment devices that managers employ. The interplay between evidence...

  19. Revealing the programming process

    DEFF Research Database (Denmark)

    Bennedsen, Jens; Caspersen, Michael Edelgaard

    2005-01-01

    One of the most important goals of an introductory programming course is that the students learn a systematic approach to the development of computer programs. Revealing the programming process is an important part of this; however, textbooks do not address the issue -- probably because...... the textbook medium is static and therefore ill-suited to expose the process of programming. We have found that process recordings in the form of captured narrated programming sessions are a simple, cheap, and efficient way of providing the revelation.We identify seven different elements of the programming...

  20. Process of performance assessment

    International Nuclear Information System (INIS)

    King, C.M.; Halford, D.K.

    1987-01-01

    Performance assessment is the process used to evaluate the environmental consequences of disposal of radioactive waste in the biosphere. An introductory review of the subject is presented. Emphasis is placed on the process of performance assessment from the standpoint of defining the process. Performance assessment, from evolving experience at DOE sites, has short-term and long-term subprograms, the components of which are discussed. The role of mathematical modeling in performance assessment is addressed including the pros and cons of current approaches. Finally, the system/site/technology issues as the focal point of this symposium are reviewed

  1. Semi-Markov processes

    CERN Document Server

    Grabski

    2014-01-01

    Semi-Markov Processes: Applications in System Reliability and Maintenance is a modern view of discrete state space and continuous time semi-Markov processes and their applications in reliability and maintenance. The book explains how to construct semi-Markov models and discusses the different reliability parameters and characteristics that can be obtained from those models. The book is a useful resource for mathematicians, engineering practitioners, and PhD and MSc students who want to understand the basic concepts and results of semi-Markov process theory. Clearly defines the properties and

  2. Irreversible processes kinetic theory

    CERN Document Server

    Brush, Stephen G

    2013-01-01

    Kinetic Theory, Volume 2: Irreversible Processes deals with the kinetic theory of gases and the irreversible processes they undergo. It includes the two papers by James Clerk Maxwell and Ludwig Boltzmann in which the basic equations for transport processes in gases are formulated, together with the first derivation of Boltzmann's ""H-theorem"" and a discussion of this theorem, along with the problem of irreversibility.Comprised of 10 chapters, this volume begins with an introduction to the fundamental nature of heat and of gases, along with Boltzmann's work on the kinetic theory of gases and s

  3. Catalytic biomass pyrolysis process

    Science.gov (United States)

    Dayton, David C.; Gupta, Raghubir P.; Turk, Brian S.; Kataria, Atish; Shen, Jian-Ping

    2018-04-17

    Described herein are processes for converting a biomass starting material (such as lignocellulosic materials) into a low oxygen containing, stable liquid intermediate that can be refined to make liquid hydrocarbon fuels. More specifically, the process can be a catalytic biomass pyrolysis process wherein an oxygen removing catalyst is employed in the reactor while the biomass is subjected to pyrolysis conditions. The stream exiting the pyrolysis reactor comprises bio-oil having a low oxygen content, and such stream may be subjected to further steps, such as separation and/or condensation to isolate the bio-oil.

  4. DWPF process control

    International Nuclear Information System (INIS)

    Heckendoin, F.M. II

    1983-01-01

    The Defense Waste Processing Facility (DWPF) for waste vitrification at the Savannah River Plant (SRP) is in the final design stage. Instrumentation to provide the parameter sensing required to assure the quality of the two-foot-diameter, ten-foot-high waste canister is in the final stage of development. All step of the process and instrumentation are now operating as nearly full-scale prototypes at SRP. Quality will be maintained by assuring that only the intended material enters the canisters, and by sensing the resultant condition of the filled canisters. Primary emphasis will be on instrumentation of the process

  5. Advanced uranium enrichment processes

    International Nuclear Information System (INIS)

    Clerc, M.; Plurien, P.

    1986-01-01

    Three advanced Uranium enrichment processes are dealt with in the report: AVLIS (Atomic Vapour LASER Isotope Separation), MLIS (Molecular LASER Isotope Separation) and PSP (Plasma Separation Process). The description of the physical and technical features of the processes constitutes a major part of the report. If further presents comparisons with existing industrially used enrichment technologies, gives information on actual development programmes and budgets and ends with a chapter on perspectives and conclusions. An extensive bibliography of the relevant open literature is added to the different subjects discussed. The report was drawn up by the nuclear research Centre (CEA) Saclay on behalf of the Commission of the European Communities

  6. Plasma processing for VLSI

    CERN Document Server

    Einspruch, Norman G

    1984-01-01

    VLSI Electronics: Microstructure Science, Volume 8: Plasma Processing for VLSI (Very Large Scale Integration) discusses the utilization of plasmas for general semiconductor processing. It also includes expositions on advanced deposition of materials for metallization, lithographic methods that use plasmas as exposure sources and for multiple resist patterning, and device structures made possible by anisotropic etching.This volume is divided into four sections. It begins with the history of plasma processing, a discussion of some of the early developments and trends for VLSI. The second section

  7. Radioactive waste processing method

    International Nuclear Information System (INIS)

    Sakuramoto, Naohiko.

    1992-01-01

    When granular materials comprising radioactive wastes containing phosphorus are processed at first in a fluidized bed type furnace, if the granular materials are phosphorus-containing activated carbon, granular materials comprising alkali compound such as calcium hydroxide and barium hydroxide are used as fluidizing media. Even granular materials of slow burning speed can be burnt stably in a fluidizing state by high temperature heat of the fluidizing media, thereby enabling to take a long burning processing time. Accordingly, radioactive activated carbon wastes can be processed by burning treatment. (T.M.)

  8. Nano integrated circuit process

    International Nuclear Information System (INIS)

    Yoon, Yung Sup

    2004-02-01

    This book contains nine chapters, which are introduction of manufacture of semiconductor chip, oxidation such as Dry-oxidation, wet oxidation, oxidation model and oxide film, diffusion like diffusion process, diffusion equation, diffusion coefficient and diffusion system, ion implantation, including ion distribution, channeling, multiimplantation and masking and its system, sputtering such as CVD and PVD, lithography, wet etch and dry etch, interconnection and flattening like metal-silicon connection, silicide, multiple layer metal process and flattening, an integrated circuit process, including MOSFET and CMOS.

  9. Transnational Learning Processes

    DEFF Research Database (Denmark)

    Nedergaard, Peter

    This paper analyses and compares the transnational learning processes in the employment field in the European Union and among the Nordic countries. Based theoretically on a social constructivist model of learning and methodologically on a questionnaire distributed to the relevant participants......, a number of hypotheses concerning transnational learning processes are tested. The paper closes with a number of suggestions regarding an optimal institutional setting for facilitating transnational learning processes.Key words: Transnational learning, Open Method of Coordination, Learning, Employment......, European Employment Strategy, European Union, Nordic countries....

  10. Nano integrated circuit process

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Yung Sup

    2004-02-15

    This book contains nine chapters, which are introduction of manufacture of semiconductor chip, oxidation such as Dry-oxidation, wet oxidation, oxidation model and oxide film, diffusion like diffusion process, diffusion equation, diffusion coefficient and diffusion system, ion implantation, including ion distribution, channeling, multiimplantation and masking and its system, sputtering such as CVD and PVD, lithography, wet etch and dry etch, interconnection and flattening like metal-silicon connection, silicide, multiple layer metal process and flattening, an integrated circuit process, including MOSFET and CMOS.

  11. Getting Started with Processing

    CERN Document Server

    Reas, Casey

    2010-01-01

    Learn computer programming the easy way with Processing, a simple language that lets you use code to create drawings, animation, and interactive graphics. Programming courses usually start with theory, but this book lets you jump right into creative and fun projects. It's ideal for anyone who wants to learn basic programming, and serves as a simple introduction to graphics for people with some programming skills. Written by the founders of Processing, this book takes you through the learning process one step at a time to help you grasp core programming concepts. You'll learn how to sketch wi

  12. Quantum Information Processing

    CERN Document Server

    Leuchs, Gerd

    2005-01-01

    Quantum processing and communication is emerging as a challenging technique at the beginning of the new millennium. This is an up-to-date insight into the current research of quantum superposition, entanglement, and the quantum measurement process - the key ingredients of quantum information processing. The authors further address quantum protocols and algorithms. Complementary to similar programmes in other countries and at the European level, the German Research Foundation (DFG) started a focused research program on quantum information in 1999. The contributions - written by leading experts - bring together the latest results in quantum information as well as addressing all the relevant questions

  13. Robot welding process control

    Science.gov (United States)

    Romine, Peter L.

    1991-01-01

    This final report documents the development and installation of software and hardware for Robotic Welding Process Control. Primary emphasis is on serial communications between the CYRO 750 robotic welder, Heurikon minicomputer running Hunter & Ready VRTX, and an IBM PC/AT, for offline programming and control and closed-loop welding control. The requirements for completion of the implementation of the Rocketdyne weld tracking control are discussed. The procedure for downloading programs from the Intergraph, over the network, is discussed. Conclusions are made on the results of this task, and recommendations are made for efficient implementation of communications, weld process control development, and advanced process control procedures using the Heurikon.

  14. Lasers in chemical processing

    International Nuclear Information System (INIS)

    Davis, J.I.

    1982-01-01

    The high cost of laser energy is the crucial issue in any potential laser-processing application. It is expensive relative to other forms of energy and to most bulk chemicals. We show those factors that have previously frustrated attempts to find commercially viable laser-induced processes for the production of materials. Having identified the general criteria to be satisfied by an economically successful laser process and shown how these imply the laser-system requirements, we present a status report on the uranium laser isotope separation (LIS) program at the Lawrence Livermore National Laboratory

  15. Dosimetry for radiation processing

    International Nuclear Information System (INIS)

    Miller, Arne

    1986-01-01

    During the past few years significant advances have taken place in the different areas of dosimetry for radiation processing, mainly stimulated by the increased interest in radiation for food preservation, plastic processing and sterilization of medical products. Reference services both by international organizations (IAEA) and national laboratories have helped to improve the reliability of dose measurements. In this paper the special features of radiation processing dosimetry are discussed, several commonly used dosimeters are reviewed, and factors leading to traceable and reliable dosimetry are discussed. (author)

  16. The SILVA atomic process

    International Nuclear Information System (INIS)

    Cazalet, J.

    1996-01-01

    The SILVA isotopic laser separation process of atomic uranium vapor requires the use of specific high power visible light laser devices and systems for uranium evaporation and management (separation modules). The CEA, in collaboration with industrialists, has developed these components and built some demonstration plants. The scientific and technological challenges raised by this process are now surmounted. The principle of the SILVA process is the selective photo-ionization of uranium isotopes using laser photon beams tuned to the exact excitation frequency of the isotope electron layers. This paper describes the principle of the SILVA process (lasers and separator), the technical feasibility and actual progress of the program and its future steps, its economical stakes, and the results obtained so far. (J.S.). 2 figs., 2 photos

  17. Cognitive Processing Hardware Elements

    National Research Council Canada - National Science Library

    Widrow, Bernard; Eliashberg, Victor; Kamenetsky, Max

    2005-01-01

    The purpose of this research is to identify and develop cognitive information processing systems and algorithms that can be implemented with novel architectures and devices with the goal of achieving...

  18. Ferrous Metal Processing Plants

    Data.gov (United States)

    Department of Homeland Security — This map layer includes ferrous metal processing plants in the United States. The data represent commodities covered by the Minerals Information Team (MIT) of the...

  19. Nonferrous Metal Processing Plants

    Data.gov (United States)

    Department of Homeland Security — This map layer includes nonferrous metal processing plants in the United States. The data represent commodities covered by the Minerals Information Team (MIT) of the...

  20. Canada's hydrocarbon processing evolution

    International Nuclear Information System (INIS)

    Wise, T.H.; Horton, R.

    2000-01-01

    The development of petroleum refining, petrochemicals and natural gas industries in Canada are discussed together with future issues and prospects. Figures give data on (a) refined products trade 1998; (b) refining capacity; (c) product demand 1980-1999; (d) refinery crude runs and capacity; (e) refining and marketing, historical returns 1993-1999; (f) processing power index for Canada and USA; (g) ethylene capacity; (eye) Montreal petrochemical capacities; (j) Sarnia petrochemical capacities in 2000; (k) Alberta petrochemicals capacities 2001; (l) ethylene net equivalent trade; (m) ethylene costs 1999 for W. Canada and other countries. It was concluded that the hydrocarbon processing business continues to expand in Canada and natural gas processing is likely to increase. Petrochemicals may expand in W. Canada, possibly using feed stock from the Far North. Offshore developments may stimulate new processing on the E. Coast

  1. Essentials of stochastic processes

    CERN Document Server

    Durrett, Richard

    2016-01-01

    Building upon the previous editions, this textbook is a first course in stochastic processes taken by undergraduate and graduate students (MS and PhD students from math, statistics, economics, computer science, engineering, and finance departments) who have had a course in probability theory. It covers Markov chains in discrete and continuous time, Poisson processes, renewal processes, martingales, and option pricing. One can only learn a subject by seeing it in action, so there are a large number of examples and more than 300 carefully chosen exercises to deepen the reader’s understanding. Drawing from teaching experience and student feedback, there are many new examples and problems with solutions that use TI-83 to eliminate the tedious details of solving linear equations by hand, and the collection of exercises is much improved, with many more biological examples. Originally included in previous editions, material too advanced for this first course in stochastic processes has been eliminated while treatm...

  2. Product and Process Modelling

    DEFF Research Database (Denmark)

    Cameron, Ian T.; Gani, Rafiqul

    . These approaches are put into the context of life cycle modelling, where multiscale and multiform modelling is increasingly prevalent in the 21st century. The book commences with a discussion of modern product and process modelling theory and practice followed by a series of case studies drawn from a variety......This book covers the area of product and process modelling via a case study approach. It addresses a wide range of modelling applications with emphasis on modelling methodology and the subsequent in-depth analysis of mathematical models to gain insight via structural aspects of the models...... to biotechnology applications, food, polymer and human health application areas. The book highlights to important nature of modern product and process modelling in the decision making processes across the life cycle. As such it provides an important resource for students, researchers and industrial practitioners....

  3. HYDICE postflight data processing

    Science.gov (United States)

    Aldrich, William S.; Kappus, Mary E.; Resmini, Ronald G.; Mitchell, Peter A.

    1996-06-01

    The hyperspectral digital imagery collection experiment (HYDICE) sensor records instrument counts for scene data, in-flight spectral and radiometric calibration sequences, and dark current levels onto an AMPEX DCRsi data tape. Following flight, the HYDICE ground data processing subsystem (GDPS) transforms selected scene data from digital numbers (DN) to calibrated radiance levels at the sensor aperture. This processing includes: dark current correction, spectral and radiometric calibration, conversion to radiance, and replacement of bad detector elements. A description of the algorithms for post-flight data processing is presented. A brief analysis of the original radiometric calibration procedure is given, along with a description of the development of the modified procedure currently used. Example data collected during the 1995 flight season, but uncorrected and processed, are shown to demonstrate the removal of apparent sensor artifacts (e.g., non-uniformities in detector response over the array) as a result of this transformation.

  4. Reconfigurable network processing platforms

    NARCIS (Netherlands)

    Kachris, C.

    2007-01-01

    This dissertation presents our investigation on how to efficiently exploit reconfigurable hardware to design flexible, high performance, and power efficient network devices capable to adapt to varying processing requirements of network applications and traffic. The proposed reconfigurable network

  5. Towards processable Afrikaans

    CSIR Research Space (South Africa)

    Pretorius, L

    2009-06-01

    Full Text Available In this paper researchers discuss a number of structural problems that are faced with when designing a machine-oriented controlled natural language for Afrikaans taking the underlying principles of Attempto Controlled English (ACE) and Processable...

  6. Gas processing device

    International Nuclear Information System (INIS)

    Kobayashi, Yoshihiro; Seki, Eiji.

    1991-01-01

    State of electric discharge is detected based on a gas pressure in a sealed container and a discharging current flowing between both of electrodes. When electric arc discharges occur, introduction of gases to be processed is stopped and a voltage applied to both of the electrodes is interrupted. Then, when the gas pressure in the sealed container is lowered to a predetermined value, a power source voltage is applied again to both of the electrodes to recover glow discharges, and the introduction of the gas to be processed is started. With such steps, even if electric arc discharges occur, they are eliminated automatically and, accordingly, normal glow discharges can be recovered, to prevent failures of the device due to electric arc discharges. The glow discharges are recovered automatically without stopping the operation of the gas processing device, and gas injection and solidification processing can be conducted continuously and stably. (T.M.)

  7. Cooperative processing data bases

    Science.gov (United States)

    Hasta, Juzar

    1991-01-01

    Cooperative processing for the 1990's using client-server technology is addressed. The main theme is concepts of downsizing from mainframes and minicomputers to workstations on a local area network (LAN). This document is presented in view graph form.

  8. Radiation processing in Japan

    International Nuclear Information System (INIS)

    Makuuchi, Keizo

    2001-01-01

    Economic scale of radiation application in the field of industry, agriculture and medicine in Japan in 1997 was investigated to compare its economic impacts with that of nuclear energy industry. Total production value of radiation application accounted for 54% of nuclear industry including nuclear energy industry and radiation applications in three fields above. Industrial radiation applications were further divided into five groups, namely nondestructive test, RI instruments, radiation facilities, radiation processing and ion beam processing. More than 70% of the total production value was brought about by ion beam processing for use with IC and semiconductors. Future economic prospect of radiation processing of polymers, for example cross-linking, EB curing, graft polymerization and degradation, is reviewed. Particular attention was paid to radiation vulcanization of natural rubber latex and also to degradation of natural polymers. (S. Ohno)

  9. Logistics Innovation Process Revisited

    DEFF Research Database (Denmark)

    Gammelgaard, Britta; Su, Shong-Iee Ivan; Yang, Su-Lan

    2011-01-01

    Purpose – The purpose of this paper is to learn more about logistics innovation processes and their implications for the focal organization as well as the supply chain, especially suppliers. Design/methodology/approach – The empirical basis of the study is a longitudinal action research project...... that was triggered by the practical needs of new ways of handling material flows of a hospital. This approach made it possible to revisit theory on logistics innovation process. Findings – Apart from the tangible benefits reported to the case hospital, five findings can be extracted from this study: the logistics...... innovation process model may include not just customers but also suppliers; logistics innovation in buyer-supplier relations may serve as an alternative to outsourcing; logistics innovation processes are dynamic and may improve supplier partnerships; logistics innovations in the supply chain are as dependent...

  10. Negative ion detachment processes

    International Nuclear Information System (INIS)

    Champion, R.L.; Doverspike, L.D.

    1990-10-01

    This paper discusses the following topics: H - and D - collisions with atomic hydrogen; collisional decomposition of SF 6 - ; two-electron loss processes in negative ion collisions; associative electron detachment; and negative ion desorption from surfaces

  11. Acoustic MIMO signal processing

    CERN Document Server

    Huang, Yiteng; Chen, Jingdong

    2006-01-01

    A timely and important book addressing a variety of acoustic signal processing problems under multiple-input multiple-output (MIMO) scenarios. It uniquely investigates these problems within a unified framework offering a novel and penetrating analysis.

  12. Introduction to stochastic processes

    CERN Document Server

    Cinlar, Erhan

    2013-01-01

    Clear presentation employs methods that recognize computer-related aspects of theory. Topics include expectations and independence, Bernoulli processes and sums of independent random variables, Markov chains, renewal theory, more. 1975 edition.

  13. Dosimetry for radiation processing

    International Nuclear Information System (INIS)

    McLaughlin, W.L.; Boyd, A.W.; Chadwick, K.H.; McDonald, J.C.; Miller, A.

    1989-01-01

    Radiation processing is a relatively young industry with broad applications and considerable commercial success. Dosimetry provides an independent and effective way of developing and controlling many industrial processes. In the sterilization of medical devices and in food irradiation, where the radiation treatment impacts directly on public health, the measurements of dose provide the official means of regulating and approving its use. In this respect, dosimetry provides the operator with a means of characterizing the facility, of proving that products are treated within acceptable dose limits and of controlling the routine operation. This book presents an up-to-date review of the theory, data and measurement techniques for radiation processing dosimetry in a practical and useful way. It is hoped that this book will lead to improved measurement procedures, more accurate and precise dosimetry and a greater appreciation of the necessity of dosimetry for radiation processing. (author)

  14. SIMULATION OF LOGISTICS PROCESSES

    Directory of Open Access Journals (Sweden)

    Yu. Taranenko

    2016-08-01

    Full Text Available The article deals with the theoretical basis of the simulation. The study shows the simulation of logistic processes in industrial countries is an integral part of many economic projects aimed at the creation or improvement of logistics systems. The paper was used model Beer Game for management of logistics processes in the enterprise. The simulation model implements in AnyLogic package. AnyLogic product allows us to consider the logistics processes as an integrated system, which allows reaching better solutions. Logistics process management involves pooling the sales market, production and distribution to ensure the temporal level of customer service at the lowest cost overall. This made it possible to conduct experiments and to determine the optimal size of the warehouse at the lowest cost.

  15. Digital image processing

    National Research Council Canada - National Science Library

    Gonzalez, Rafael C; Woods, Richard E

    2008-01-01

    Completely self-contained-and heavily illustrated-this introduction to basic concepts and methodologies for digital image processing is written at a level that truly is suitable for seniors and first...

  16. Ultrahigh bandwidth signal processing

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo

    2016-01-01

    Optical time lenses have proven to be very versatile for advanced optical signal processing. Based on a controlled interplay between dispersion and phase-modulation by e.g. four-wave mixing, the processing is phase-preserving, an hence useful for all types of data signals including coherent multi......-level modulation founats. This has enabled processing of phase-modulated spectrally efficient data signals, such as orthogonal frequency division multiplexed (OFDM) signa In that case, a spectral telescope system was used, using two time lenses with different focal lengths (chirp rates), yielding a spectral...... regeneratio These operations require a broad bandwidth nonlinear platform, and novel photonic integrated nonlinear platform like aluminum gallium arsenide nano-waveguides used for 1.28 Tbaud optical signal processing will be described....

  17. Rubber compounding and processing

    CSIR Research Space (South Africa)

    John, MJ

    2014-06-01

    Full Text Available This chapter presents an overview on the compounding and processing techniques of natural rubber compounds. The introductory portion deals with different types of rubbers and principles of rubber compounding. The primary and secondary fillers used...

  18. Radiation processing in Japan

    Energy Technology Data Exchange (ETDEWEB)

    Makuuchi, Keizo [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    2001-03-01

    Economic scale of radiation application in the field of industry, agriculture and medicine in Japan in 1997 was investigated to compare its economic impacts with that of nuclear energy industry. Total production value of radiation application accounted for 54% of nuclear industry including nuclear energy industry and radiation applications in three fields above. Industrial radiation applications were further divided into five groups, namely nondestructive test, RI instruments, radiation facilities, radiation processing and ion beam processing. More than 70% of the total production value was brought about by ion beam processing for use with IC and semiconductors. Future economic prospect of radiation processing of polymers, for example cross-linking, EB curing, graft polymerization and degradation, is reviewed. Particular attention was paid to radiation vulcanization of natural rubber latex and also to degradation of natural polymers. (S. Ohno)

  19. Desalination processes and technologies

    International Nuclear Information System (INIS)

    Furukawa, D.H.

    1996-01-01

    Reasons of the development of desalination processes, the modern desalination technologies, such as multi-stage flash evaporation, multi-effect distillation, reverse osmosis, and the prospects of using nuclear power for desalination purposes are discussed. 9 refs

  20. Enrichment: centrifuge process

    International Nuclear Information System (INIS)

    Soubbaramayer.

    1989-01-01

    This short course is divided into three sections devoted respectively to the physics of the process, some practical problems raised by the design of a centrifuge and the present situation of centrifugation in the World. 31 figs., 18 refs

  1. Constitutional reform as process

    OpenAIRE

    Schultze, Rainer-Olaf (Prof.)

    2000-01-01

    Constitutional reform as process. - In: The politics of constitutional reform in North America / Rainer-Olaf Schultze ... (eds.). - Opladen : Leske + Budrich, 2000. - S. 11-31. - (Politikwissenschaftliche paperbacks ; 30)

  2. Paper 2: Process characterisation

    African Journals Online (AJOL)

    drinie

    A variety of names represent the prefermentation process, due to emphasis placed on ... monitoring and control instrumentation employed successfully at existing side-stream ..... MÜNCH E (1998) DSP-Prefermenter Technology Book. Science ...

  3. Project management process.

    Science.gov (United States)

    2007-03-01

    This course provides INDOT staff with foundational knowledge and skills in project management principles and methodologies. INDOTs project management processes provide the tools for interdisciplinary teams to efficiently and effectively deliver pr...

  4. Processed Products Database System

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection of annual data on processed seafood products. The Division provides authoritative advice, coordination and guidance on matters related to the collection,...

  5. Model Process Control Language

    Data.gov (United States)

    National Aeronautics and Space Administration — The MPC (Model Process Control) language enables the capture, communication and preservation of a simulation instance, with sufficient detail that it can be...

  6. Digital image processing

    National Research Council Canada - National Science Library

    Gonzalez, Rafael C; Woods, Richard E

    2008-01-01

    ...-year graduate students in almost any technical discipline. The leading textbook in its field for more than twenty years, it continues its cutting-edge focus on contemporary developments in all mainstream areas of image processing-e.g...

  7. CAPSULE REPORT: EVAPORATION PROCESS

    Science.gov (United States)

    Evaporation has been an established technology in the metal finishing industry for many years. In this process, wastewaters containing reusable materials, such as copper, nickel, or chromium compounds are heated, producing a water vapor that is continuously removed and condensed....

  8. Aerospace Materials Process Modelling

    Science.gov (United States)

    1988-08-01

    Cooling Transformation diagram ( CCT diagram ) When a IT diagram is used in the heat process modelling, we suppose that a sudden cooling (instantaneous...processes. CE, chooses instead to study thermo-mechanical properties referring to a CCT diagram . This is thinked to be more reliable to give a true...k , mm-_____sml l ml A I 1 III 12.4 This determination is however based on the following approximations: i) A CCT diagram is valid only for the

  9. Radiopharmaceutical drug review process

    International Nuclear Information System (INIS)

    Frankel, R.

    1985-01-01

    To ensure proper radioactive drug use (such as quality, diagnostic improvement, and minimal radioactive exposure), the Food and Drug Administration evaluates new drugs with respect to safety, effectiveness, and accuracy and adequacy of the labeling. The IND or NDA process is used for this purpose. A brief description of the process, including the Chemical Classification System and the therapeutic potential classification, is presented as it applies to radiopharmaceuticals. Also, the status of the IND or NDA review of radiopharmaceuticals is given

  10. Qualification of conditioning process

    International Nuclear Information System (INIS)

    Wolf, J.

    1989-01-01

    A conditioning process is qualified by the PTB if the execution of pre-treatment and conditioning occurs so that a safe and orderly final storage of the products and waste containers produced can be assumed. All the relevant operating conditions for the plant are laid down by the producer/conditioner of the waste in a handbook. The elements of product inspection by process qualification are shown in tabular form. (DG) [de

  11. Hydrogen recovery process

    Science.gov (United States)

    Baker, Richard W.; Lokhandwala, Kaaeid A.; He, Zhenjie; Pinnau, Ingo

    2000-01-01

    A treatment process for a hydrogen-containing off-gas stream from a refinery, petrochemical plant or the like. The process includes three separation steps: condensation, membrane separation and hydrocarbon fraction separation. The membrane separation step is characterized in that it is carried out under conditions at which the membrane exhibits a selectivity in favor of methane over hydrogen of at least about 2.5.

  12. Process through practice

    DEFF Research Database (Denmark)

    Burry, Jane; Burry, Mark; Tamke, Martin

    2012-01-01

    This paper describes the development of a design and prototype production system for novel structural use of networked small components of wood deploying elastic and plastic bending. The design process engaged with a significant number of different overlapping and interrelated design criteria...... simulation and feedback. The outcome was amplified through carrying out the research over a series of workshops with distinct foci and participation. Two full scale demonstrators have so far been constructed and exhibited as outputs of the process....

  13. Process for compound transformation

    KAUST Repository

    Basset, Jean-Marie

    2016-12-29

    Embodiments of the present disclosure provide for methods of using a catalytic system to chemically transform a compound (e.g., a hydrocarbon). In an embodiment, the method does not employ grafting the catalyst prior to catalysis. In particular, embodiments of the present disclosure provide for a process of hydrocarbon (e.g., C1 to C20 hydrocarbon) metathesis (e.g., alkane, olefin, or alkyne metathesis) transformation, where the process can be conducted without employing grafting prior to catalysis.

  14. Processes of Strategic Renewal,

    OpenAIRE

    Harald Aadne, John; Mahnke, Volker

    2010-01-01

    We discuss strategic renewal from a competence perspective. We argue that the management of speed and timing in this process is viewed distinctively when perceived through a cognitive lens. Managers need more firmly grounded process-understanding. The key idea of this paper is to dynamically conceptualize key activities of strategic renewal, and possible sources of break-down as they relate to the managment of speed and timing. Based on a case from the media industry, we identi...

  15. Hydrogen production processes

    International Nuclear Information System (INIS)

    2003-01-01

    The goals of this first Gedepeon workshop on hydrogen production processes are: to stimulate the information exchange about research programs and research advances in the domain of hydrogen production processes, to indicate the domains of interest of these processes and the potentialities linked with the coupling of a nuclear reactor, to establish the actions of common interest for the CEA, the CNRS, and eventually EDF, that can be funded in the framework of the Gedepeon research group. This document gathers the slides of the 17 presentations given at this workshop and dealing with: the H 2 question and the international research programs (Lucchese P.); the CEA's research program (Lucchese P., Anzieu P.); processes based on the iodine/sulfur cycle: efficiency of a facility - flow-sheets, efficiencies, hard points (Borgard J.M.), R and D about the I/S cycle: Bunsen reaction (Colette S.), R and D about the I/S cycle: the HI/I 2 /H 2 O system (Doizi D.), demonstration loop/chemical engineering (Duhamet J.), materials and corrosion (Terlain A.); other processes under study: the Westinghouse cycle (Eysseric C.), other processes under study at the CEA (UT3, plasma,...) (Lemort F.), database about thermochemical cycles (Abanades S.), Zn/ZnO cycle (Broust F.), H 2 production by cracking, high temperature reforming with carbon trapping (Flamant G.), membrane technology (De Lamare J.); high-temperature electrolysis: SOFC used as electrolyzers (Grastien R.); generic aspects linked with hydrogen production: technical-economical evaluation of processes (Werkoff F.), thermodynamic tools (Neveu P.), the reactor-process coupling (Aujollet P.). (J.S.)

  16. Qualitative Process Theory.

    Science.gov (United States)

    1984-07-01

    solving common sense reasoning mathematical reasoning naive physics aritificial intelligence * 20. ABSTRACT (Continue o,, reverse side Ift necessary and...AD-A148 987 QUALITATIVE PROCESS THEORY(U) MASSACHUSETTS INST OF 1/2 TEEH CAMBRIDGE ARTIFICIAL INTELLIGENCE LAB K D FORBUS JUL 84 RI-TR-789 N88814-80...NATIONAL BUREAU Of STAN ARDS IJ% A 4 I .7 Technical Report 789 Q[-----Qualitative• Process M° Theory . Kenneth Dale Forbus MIT Artificial Intelligence

  17. Electron-attachment processes

    International Nuclear Information System (INIS)

    Christophorou, L.G.; McCorkle, D.L.; Christodoulides, A.A.

    1982-01-01

    Topics covered include: (1) modes of production of negative ions, (2) techniques for the study of electron attachment processes, (3) dissociative electron attachment to ground-state molecules, (4) dissociative electron attachment to hot molecules (effects of temperature on dissociative electron attachment), (5) molecular parent negative ions, and (6) negative ions formed by ion-pair processes and by collisions of molecules with ground state and Rydberg atoms

  18. Process management practice

    International Nuclear Information System (INIS)

    Pyeon, In Beom

    1983-04-01

    This book gives descriptions of qualifying subject and test scope like production plan and control, economic feasibility, process management, quality management and operations research, industrial economics like materials and marketing management, production management such as meaning and goals of process management and production plan and control, basic economic concept, official interest and equivalence, and depreciation, and OR concept such as network analysis and PERT CPM and stimulation.

  19. Harmful Waste Process

    International Nuclear Information System (INIS)

    Ki, Mun Bong; Lee, Shi Jin; Park, Jun Seok; Yoon, Seok Pyo; Lee, Jae Hyo; Jo, Byeong Ryeol

    2008-08-01

    This book gives descriptions of processing harmful waste, including concerned law and definition of harmful waste, current conditions and generation of harmful waste in Korea, international condition of harmful waste, minimizing of generation of harmful waste, treatment and storage. It also tells of basic science for harmful waste disposal with physics, chemistry, combustion engineering, microbiology and technique of disposal such as physical, chemical, biological process, stabilizing and solidification, incineration and waste in landfill.

  20. Natural Information Processing Systems

    OpenAIRE

    John Sweller; Susan Sweller

    2006-01-01

    Natural information processing systems such as biological evolution and human cognition organize information used to govern the activities of natural entities. When dealing with biologically secondary information, these systems can be specified by five common principles that we propose underlie natural information processing systems. The principles equate: (1) human long-term memory with a genome; (2) learning from other humans with biological reproduction; (3) problem solving through random ...