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Sample records for bcr process

  1. BCR-ABL1: Test

    Science.gov (United States)

    ... Thompson, E. (Revised 2009 July). Modalities of Cancer Therapy. Merck Manual for Healthcare Professionals [On-line information]. Available online at http://www.merck.com/mmpe/sec11/ch149/ch149b.html?qt=bcr-abl&alt=sh through ... 15). Current Status of Therapy for Chronic Myeloid Leukemia: A Review of Drug ...

  2. Molecular detection of BCR/ABL fusion gene in Saudi acute lymphoblastic leukemia patients.

    Science.gov (United States)

    El-Sissy, Azza; El-Mashari, May; Bassuni, Wafaa; El-Swaayed, Aziza

    2006-06-01

    Molecular cytogenetics is becoming one of the most useful tools targeting some genes which are generally considered to lead to leukemic transformation (as well as for numerical abnormalities). A fraction of acute lymphoblastic leukemia (ALL) cases carry the translocation t(9;22) (q34;q11.2) which juxtaposes the ABL proto-oncogene to the BCR gene generating a chimeric gene, BCR/ABL. This aberration is more frequent in adult ALL (20%-40%) than in pediatric ALL (<5%), and predicts poor clinical outcome. AIM OF OUR WORK: Is to study BCR/ABL fusion gene in ALL cases using fluorescent in situ hybridization. Twenty newly diagnosed ALL patients, 16 adult and 4 paediatric cases, were included in the study, 11 cases (55%) were of precursor B phenotype, 8 cases (40%) belonged to T lineage, while one case was biphenotypic expressing mainly precursor B cell markers tether with CD13, CD33, CD117, Detection of BCR/ABL fusion gene was done using interphase FISH technique and was confirmed molecularly using the RT-PCR technique. BCR/ABL fusion gene was negative in all the examined cases, yet abnormality involving 9q34, ABL gene, either by addition or deletion was detected in three cases (15%). Two of these cases were associated with BCR gene extra copies (three and four copies, respectively). This may reflect the frequency of association of ABL gene and BCR gene abnormality in our cases, and that absence of fusion gene BCR/ABL does not exclude their role in the leukomogenic process, yet a larger study is required to confirm and detect the prevalence of these gene disturbances in ALL and their association.

  3. An asymptomatic 61-year-old man with BCR-ABL-positive bone marrow following autologous transplantation for multiple myeloma

    Science.gov (United States)

    Roper, Nitin; Deangelo, Daniel; Kuo, Frank; Cin, Paola dal; Ghobrial, Irene; Aster, Jon C.

    2010-01-01

    A 61-year-old man treated with an autologous transplant for multiple myeloma was incidentally found to have a high level of BCR-ABL fusion gene-positive cells in his bone marrow. We describe the clinical decision-making process that led us to initiate therapy with imatinib, despite the absence of any clinical evidence of chronic myelogenous leukemia or other BCR-ABL associated hematologic malignancy. PMID:20730794

  4. Disruption of Bcr-Abl coiled coil oligomerization by design.

    Science.gov (United States)

    Dixon, Andrew S; Pendley, Scott S; Bruno, Benjamin J; Woessner, David W; Shimpi, Adrian A; Cheatham, Thomas E; Lim, Carol S

    2011-08-05

    Oligomerization is an important regulatory mechanism for many proteins, including oncoproteins and other pathogenic proteins. The oncoprotein Bcr-Abl relies on oligomerization via its coiled coil domain for its kinase activity, suggesting that a designed coiled coil domain with enhanced binding to Bcr-Abl and reduced self-oligomerization would be therapeutically useful. Key mutations in the coiled coil domain of Bcr-Abl were identified that reduce homo-oligomerization through intermolecular charge-charge repulsion yet increase interaction with the Bcr-Abl coiled coil through additional salt bridges, resulting in an enhanced ability to disrupt the oligomeric state of Bcr-Abl. The mutations were modeled computationally to optimize the design. Assays performed in vitro confirmed the validity and functionality of the optimal mutations, which were found to exhibit reduced homo-oligomerization and increased binding to the Bcr-Abl coiled coil domain. Introduction of the mutant coiled coil into K562 cells resulted in decreased phosphorylation of Bcr-Abl, reduced cell proliferation, and increased caspase-3/7 activity and DNA segmentation. Importantly, the mutant coiled coil domain was more efficacious than the wild type in all experiments performed. The improved inhibition of Bcr-Abl through oligomeric disruption resulting from this modified coiled coil domain represents a viable alternative to small molecule inhibitors for therapeutic intervention.

  5. 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.

  6. 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

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-10-01

    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 lambda light chain locus (IGL) and ABL locus on the K562 Philadelphia chromosome (Ph/sup 1/). Similarly, in mouse-human hybrids retaining a Ph/sup 1/ chromosome derived from an acute lymphoblastic leukemia-in the absence of the 9q/sup +/ 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/sup 1/ chromosome.

  7. 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...

  8. BCR and its mutants, the reciprocal t(9;22-associated ABL/BCR fusion proteins, differentially regulate the cytoskeleton and cell motility

    Directory of Open Access Journals (Sweden)

    Puccetti Elena

    2006-11-01

    Full Text Available Abstract Background The reciprocal (9;22 translocation fuses the bcr (breakpoint cluster region gene on chromosome 22 to the abl (Abelson-leukemia-virus gene on chromosome 9. Depending on the breakpoint on chromosome 22 (the Philadelphia chromosome – Ph+ the derivative 9+ encodes either the p40(ABL/BCR fusion transcript, detectable in about 65% patients suffering from chronic myeloid leukemia, or the p96(ABL/BCR fusion transcript, detectable in 100% of Ph+ acute lymphatic leukemia patients. The ABL/BCRs are N-terminally truncated BCR mutants. The fact that BCR contains Rho-GEF and Rac-GAP functions strongly suggest an important role in cytoskeleton modeling by regulating the activity of Rho-like GTPases, such as Rho, Rac and cdc42. We, therefore, compared the function of the ABL/BCR proteins with that of wild-type BCR. Methods We investigated the effects of BCR and ABL/BCRs i. on the activation status of Rho, Rac and cdc42 in GTPase-activation assays; ii. on the actin cytoskeleton by direct immunofluorescence; and iii on cell motility by studying migration into a three-dimensional stroma spheroid model, adhesion on an endothelial cell layer under shear stress in a flow chamber model, and chemotaxis and endothelial transmigration in a transwell model with an SDF-1α gradient. Results Here we show that both ABL/BCRs lost fundamental functional features of BCR regarding the regulation of small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells. Conclusion Our data presented here describe for the first time an analysis of the biological function of the reciprocal t(9;22 ABL/BCR fusion proteins in comparison to their physiological counterpart BCR.

  9. BCR and its mutants, the reciprocal t(9;22)-associated ABL/BCR fusion proteins, differentially regulate the cytoskeleton and cell motility

    International Nuclear Information System (INIS)

    Zheng, Xiaomin; Güller, Saskia; Beissert, Tim; Puccetti, Elena; Ruthardt, Martin

    2006-01-01

    The reciprocal (9;22) translocation fuses the bcr (breakpoint cluster region) gene on chromosome 22 to the abl (Abelson-leukemia-virus) gene on chromosome 9. Depending on the breakpoint on chromosome 22 (the Philadelphia chromosome – Ph+) the derivative 9+ encodes either the p40 (ABL/BCR) fusion transcript, detectable in about 65% patients suffering from chronic myeloid leukemia, or the p96 (ABL/BCR) fusion transcript, detectable in 100% of Ph+ acute lymphatic leukemia patients. The ABL/BCRs are N-terminally truncated BCR mutants. The fact that BCR contains Rho-GEF and Rac-GAP functions strongly suggest an important role in cytoskeleton modeling by regulating the activity of Rho-like GTPases, such as Rho, Rac and cdc42. We, therefore, compared the function of the ABL/BCR proteins with that of wild-type BCR. We investigated the effects of BCR and ABL/BCRs i.) on the activation status of Rho, Rac and cdc42 in GTPase-activation assays; ii.) on the actin cytoskeleton by direct immunofluorescence; and iii) on cell motility by studying migration into a three-dimensional stroma spheroid model, adhesion on an endothelial cell layer under shear stress in a flow chamber model, and chemotaxis and endothelial transmigration in a transwell model with an SDF-1α gradient. Here we show that both ABL/BCRs lost fundamental functional features of BCR regarding the regulation of small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells. Our data presented here describe for the first time an analysis of the biological function of the reciprocal t(9;22) ABL/BCR fusion proteins in comparison to their physiological counterpart BCR

  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. Protein Kinase CK2: A Targetable BCR-ABL Partner in Philadelphia Positive Leukemias

    Directory of Open Access Journals (Sweden)

    Alessandro Morotti

    2015-01-01

    Full Text Available BCR-ABL-mediated leukemias, either Chronic Myeloid Leukemia (CML or Philadelphia positive Acute Lymphoblastic Leukemia (ALL, are the paradigm of targeted molecular therapy of cancer due to the impressive clinical responses obtained with BCR-ABL specific tyrosine kinase inhibitors (TKIs. However, BCR-ABL TKIs do not allow completely eradicating both CML and ALL. Furthermore, ALL therapy is associated with much worse responses to TKIs than those observed in CML. The identification of additional pathways that mediate BCR-ABL leukemogenesis is indeed mandatory to achieve synthetic lethality together with TKI. Here, we review the role of BCR-ABL/protein kinase CK2 interaction in BCR-ABL leukemias, with potentially relevant implications for therapy.

  14. MYC protein dysregulation is driven by BCR-PI3K signalling in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Wang, Wei-Ge; Liu, Ze-Bing; Jiang, Xiang-Nan; Lee, Jimmy; Zhou, Xiao-Yan; Li, Xiao-Qiu

    2017-11-01

    MYC overexpression is a common feature of diffuse large B-cell lymphoma (DLBCL) and is associated with poor prognosis in patients with this neoplasm. We aimed to investigate the underlying mechanisms of MYC dysregulation, as they have not been fully determined. We immunohistochemically evaluated the correlation between B-cell receptor (BCR)-phosphoinositide 3-kinase (PI3K) pathway activity and MYC level in 108 cases of de-novo DLBCL, 25 of which featured loss of BCR, and investigated the effects of BCR-PI3K signalling on MYC level and phosphorylation in DLBCL cell lines. The expression levels of phospho-SYK and phospho-AKT correlated with MYC expression in BCR-positive DLBCL. MYC expression was significantly lower in BCR-negative tumour tissues than in BCR-positive tumour tissues. Upon BCR stimulation, the BCR-positive cell lines showed active BCR-PI3K signalling and decreased MYC phosphorylation at T58, leading to an increased overall level of MYC. Conversely, inhibition of BCR-PI3K signalling increased MYC phosphorylation and thus resulted in a decreased overall level of MYC. No effects were observed in the BCR-negative cell lines. Overexpression of MYC in DLBCL can be driven by the BCR-PI3K signalling pathway via dephosphorylation at T58, and BCR inhibitors may exert their functions by down-regulation of MYC. © 2017 John Wiley & Sons Ltd.

  15. 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.

  16. 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; Beverloo, H Berna; 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

    2017-01-17

    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 (pfusion-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.

  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. BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features.

    Science.gov (United States)

    Neuendorff, Nina Rosa; Burmeister, Thomas; Dörken, Bernd; Westermann, Jörg

    2016-08-01

    BCR-ABL-positive acute myeloid leukemia (AML) is a rare subtype of AML that is now included as a provisional entity in the 2016 revised WHO classification of myeloid malignancies. Since a clear distinction between de novo BCR-ABL+ AML and chronic myeloid leukemia (CML) blast crisis is challenging in many cases, the existence of de novo BCR-ABL+ AML has been a matter of debate for a long time. However, there is increasing evidence suggesting that BCR-ABL+ AML is in fact a distinct subgroup of AML. In this study, we analyzed all published cases since 1975 as well as cases from our institution in order to present common clinical and molecular features of this rare disease. Our analysis shows that BCR-ABL predominantly occurs in AML-NOS, CBF leukemia, and AML with myelodysplasia-related changes. The most common BCR-ABL transcripts (p190 and p210) are nearly equally distributed. Based on the analysis of published data, we provide a clinical algorithm for the initial differential diagnosis of BCR-ABL+ AML. The prognosis of BCR-ABL+ AML seems to depend on the cytogenetic and/or molecular background rather than on BCR-ABL itself. A therapy with tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinib is reasonable, but-due to a lack of systematic clinical data-their use cannot be routinely recommended in first-line therapy. Beyond first-line treatment of AML, the use of TKI remains an individual decision, both in combination with intensive chemotherapy and/or as a bridge to allogeneic stem cell transplantation. In each single case, potential benefits have to be weighed against potential risks.

  19. 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

  20. 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.

  1. Inhibition of BCR/ABL protein expression by miR-203 sensitizes for imatinib mesylate.

    Directory of Open Access Journals (Sweden)

    Yajuan Li

    Full Text Available Selective inhibition of BCR/ABL expression by RNA interference has been demonstrated as an effective strategy in CML treatment and a reversal to imatinib resistance. microRNAs (miRNAs are small regulatory RNAs involved in post-transcriptional gene regulation. miR-203 is supposed to directly regulate ABL and BCR/ABL expression, however, the role of miR-203 in imatinib-resistant cells is not clear. Here, we report that overexpression of miR-203 in BaF3-BCR/ABL cells with T315I mutant inhibited cell growth and colony formation ability. Furthermore, miR-203 increased sensitivity to imatinib in BaF3-BCR/ABL(T315I cells, thereby antagonizing the main mechanism of resistance to imatinib.

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

    National Research Council Canada - National Science Library

    Li, Shaoguang

    2008-01-01

    .... We identified Src kinases as key molecules in this BCR- ABL kinase activity-independent pathway and they are essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis...

  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. BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair

    Science.gov (United States)

    Fernandes, Margret S.; Reddy, Mamatha M.; Gonneville, Jeffrey R.; DeRoo, Scott C.; Podar, Klaus; Griffin, James D.; Weinstock, David M.

    2009-01-01

    Intracellular oxidative stress in cells transformed by the BCR-ABL oncogene is associated with increased DNA double-strand breaks. Imprecise repair of these breaks can result in the accumulation of mutations, leading to therapy-related drug resistance and disease progression. Using several BCR-ABL model systems, we found that BCR-ABL specifically promotes the repair of double-strand breaks through single-strand annealing (SSA), a mutagenic pathway that involves sequence repeats. Moreover, our results suggest that mutagenic SSA repair can be regulated through the interplay between BCR-ABL and extrinsic growth factors. Increased SSA activity required Y177 in BCR-ABL, as well as a functional PI3K and Ras pathway downstream of this site. Furthermore, our data hint at a common pathway for DSB repair whereby BCR-ABL, Tel-ABL, Tel-PDGFR, FLT3-ITD, and Jak2V617F all increase mutagenic repair. This increase in SSA may not be sufficiently suppressed by tyrosine kinase inhibitors in the stromal microenvironment. Therefore, drugs that target growth factor receptor signaling represent potential therapeutic agents to combat tyrosine kinase-induced genomic instability. PMID:19571320

  5. The bcr1 DNA repeat element is specific to the Bacillus cereus group and exhibits mobile element characteristics.

    Science.gov (United States)

    Økstad, Ole Andreas; Tourasse, Nicolas J; Stabell, Fredrik B; Sundfaer, Cathrine K; Egge-Jacobsen, Wolfgang; Risøen, Per Arne; Read, Timothy D; Kolstø, Anne-Brit

    2004-11-01

    Bacillus cereus strains ATCC 10987 and ATCC 14579 harbor an approximately 155-bp repeated element, bcr1, which is conserved in B. cereus, B. anthracis, B. thuringiensis, and B. mycoides but not in B. subtilis and B. licheniformis. In this study, we show by Southern blot hybridizations that bcr1 is present in all 54 B. cereus group strains tested but absent in 11 Bacillus strains outside the group, suggesting that bcr1 may be specific and ubiquitous to the B. cereus group. By comparative analysis of the complete genome sequences of B. cereus ATCC 10987, B. cereus ATCC 14579, and B. anthracis Ames, we show that bcr1 is exclusively present in the chromosome but absent from large plasmids carried by these strains and that the numbers of full-length bcr1 repeats for these strains are 79, 54, and 12, respectively. Numerous copies of partial bcr1 elements are also present in the three genomes (91, 128, and 53, respectively). Furthermore, the genomic localization of bcr1 is not conserved between strains with respect to chromosomal position or organization of gene neighbors, as only six full-length bcr1 loci are common to at least two of the three strains. However, the intergenic sequence surrounding a specific bcr1 repeat in one of the three strains is generally strongly conserved in the other two, even in loci where bcr1 is found exclusively in one strain. This finding indicates that bcr1 either has evolved by differential deletion from a very high number of repeats in a common ancestor to the B. cereus group or is moving around the chromosome. The identification of bcr1 repeats interrupting genes in B. cereus ATCC 10987 and ATCC 14579 and the presence of a flanking TTTAT motif in each end show that bcr1 exhibits features characteristic of a mobile element.

  6. BCR-ABL1 transcript types showed distinct laboratory characteristics in patients with chronic myeloid leukemia.

    Science.gov (United States)

    Vasconcelos, A P; Azevedo, I F; Melo, F C B C; Neves, W B; Azevedo, A C A C; Melo, R A M

    2017-04-20

    In chronic myeloid leukemia (CML) two main types of messenger RNA (e14a2 and e13a2) can be produced by BCR-ABL1 gene rearrangement. Due to conflicting results, the clinical value of these transcripts remains controversial. The aim of this study was to identify associations of e14a2 and e13a2 transcripts with laboratory variables and also the response to treatment. This study included 203 adult patients with CML treated with Imatinib as first-line drug in a reference hematology center in Northeast Brazil. Clinical and laboratory data were obtained after informed consent. Samples were collected for RNA extraction and analyzed by reverse transcription-polymerase chain reaction (PCR), according to the international protocol BIOMED-1. The LeukemiaNet 2013 criteria were used to establish the molecular response. The frequency distribution of the BCR-ABL1 transcripts was e14a2 (64%), e13a2 (34%), and double positives (2%). The results showed a statistically significant association of the e14a2 transcript type with thrombocytosis (P = 0.0005) and the e13a2 with higher leukocyte count (P = 0.0491). In a subgroup of 44 patients, the molecular response to treatment with Imatinib was assessed by quantitative PCR at 3 months (BCR-ABL1 ≤ 10%), 6 months (BCR-ABL1 ≤ 1%), or 12 months (BCR-ABL1 ≤ 0.1%). Although patients with the transcript e14a2 showed higher frequency of good responses than patients with the transcript e13a2, this difference was not statistically significant. In agreement with published data, our results showed association of the BCR-ABL1 transcript e14a2 with thrombocytosis and the BCR-ABL1 transcript e13a2 with higher leukocytosis in patients with chronic myeloid leukemia.

  7. [TEC promoter mediates P210(bcr/abl) gene expression in BaF3 cells].

    Science.gov (United States)

    Zhu, Yu-Feng; Wang, Yuan-Zhan; Meng, Fan-Yi

    2012-06-01

    P210(bcr/abl) transgene mouse is a good model to research the chronic myelogenous leukemia (CML), but the P210(bcr/abl) gene has a lethal effect on embryogenesis if driven by the constitutive promoter. So, the use of promoter which induces the special expression in hematopoietic tissue is the key to construct CML transgenic mice. This study was purposed to investigate the TEC promoter mediated P210(bcr/abl) gene expression in BaF3 cells. The CMVie promotes of IRES2-eGFP vector was replaced with the -364-+22 domain of TEC promoter cloned from mouse genome, and the P210(bcr/abl) gene was inserted into the EcoR I site of TEC-IRES2-eGFP vector. Then, the constructed vector was transfected into the BaF3 cells and 293 cells respectively. The expression levels of eGFP gene and P210(bcr/abl) gene in BaF3 and 293 cells were detected. The results showed that with fluorescent microscopy and flow cytometry, the eGFP gene was found to be expressed in the BaF3 cells, the expression rate was 7.10%, 23.35%, 64.61% at 6, 24, 72 h respectively after transfection, but the fluorescence was not seen in 293 cells. A 372 bp fragment of BCR/ABL mRNA was amplified by RT-PCR in BaF3 cells, but not in 293 cells. It is concluded that the -364-+22 domain of TEC promoter can mediate high-effective and specific expression of related genes in hematopoietic tissue, which can be used to construct P210(bcr/abl) transgene mice model.

  8. Unique amplification of BCR-ABL1 gene fusion in a case of T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Koka, Rima; Bade, Najeebah A; Sausville, Edward A; Ning, Yi; Zou, Ying

    2017-01-01

    ABL1 gene translocations can be seen in precursor T-acute lymphoblastic leukemia (T-ALL). The typical translocation partner is the NUP214 gene. BCR-ABL translocations are relatively rare in this entity. Furthermore, while there have been unique patterns of amplification noted among the NUP214-ABL fusion genes, there have been few such reports among cases with BCR-ABL fusion genes. Here we report a unique case of a 44-year old patient with T-ALL in which the blasts demonstrated a derivative chromosome 9 involving a 9;22 translocation and a dicentric Philadelphia chromosome 22 with a homogeneously staining region at the interface of the 9;22 translocation, leading to BCR-ABL1 gene amplification. Fluorescence in-situ hybridization (FISH) showed abnormal BCR/ABL1 fusions with the BCR-ABL1 gene amplification in 48% of the interphase cells analyzed. The translocation was confirmed by SNP array. We present a novel derivative chromosome 9 that shows BCR-ABL gene fusion along with a dicentric Philadelphia chromosome 22 with BCR-ABL1 gene amplification. This is a unique pattern of BCR-ABL fusion which has never been described in T-ALL. It is significant that the patient responded to standard treatment with the CALGB 10403 protocol and supplementation with a tyrosine kinase inhibitor. Identification of additional patients with this pattern of BCR-ABL fusion will allow for enhanced risk assessment and prognostication.

  9. Measurement of BCR-ABL1 by RT-qPCR in chronic myeloid leukaemia: findings from an International EQA Programme.

    Science.gov (United States)

    Scott, Stuart; Travis, Debbie; Whitby, Liam; Bainbridge, John; Cross, Nicholas C P; Barnett, David

    2017-05-01

    Sequential measurement of BCR-ABL1 mRNA levels by reverse transcription quantitative polymerase chain reaction (RT-qPCR) is embedded in the management of patients with chronic myeloid leukaemia (CML), and has played an important role in the remarkable improvement in patient outcomes seen in this disease. As a provider of external quality assessment (EQA) in this area, UK NEQAS for Leucocyte Immunophenotyping (UKNEQAS LI) has a unique perspective on the changing face of BCR-ABL1 testing in CML. To assess the impact of technical standardisation and the development of the International Scale (IS) upon the accuracy of BCR-ABL1 testing, we reviewed EQA trial data from 2007 to 2015. Comparison of participant results identified considerable variability at both high and low levels of disease, including therapeutically important decision points; however, results converted to the IS showed less variability compared to unconverted data sets. We also found that different methods of converting to the IS produce consistently different median results within UKNEQAS LI IS data sets. This data suggests that whilst the development of the IS has improved the comparability of results between centres, there is still the need for further improvement in the processes of converting raw results to the IS in order to fully realise the benefits of molecular monitoring of CML. © 2017 John Wiley & Sons Ltd.

  10. Biofilm formation and genetic variability of BCR1 gene in the Candida parapsilosis complex.

    Science.gov (United States)

    Treviño-Rangel, Rogelio de J; Rodríguez-Sánchez, Irám P; Rosas-Taraco, Adrián G; Hernández-Bello, Romel; González, José G; González, Gloria M

    2015-01-01

    Candida parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis are cryptic species that belong to the C. parapsilosis complex, which has been increasingly associated to fungemia in various geographic regions, principally due to the capability of these yeasts to form biofilms on indwelling medical devices. BCR1 is one of the most studied genes related to Candida spp. biofilms. To evaluate the biofilm forming capability of a subset of 65 clinical isolates of the C. parapsilosis complex using two conventional approaches, and to look for an association between the biofilm forming phenotype and genetic variants of a fragment of BCR1. The biofilm determination was carried out by crystal violet staining and tetrazolium reduction assay. On the other hand, a segment of BCR1 gene was sequenced by Sanger methodology. C. parapsilosis sensu stricto was statistically associated with a low biofilm production phenotype, while C. orthopsilosis was significantly associated with both phenotypes (high and low biofilm producers). According to the BCR1 sequence analysis, genetic variability was detected in C. orthopsilosis and C. metapsilosis without a particular biofilm formation phenotype association. Under the adopted experimental design, C. parapsilosis sensu stricto was associated with the low biofilm phenotype and C. orthopsilosis with both phenotypes (high and low biofilm producers). On the other hand, an association between a biofilm forming phenotype and a particular genetic variant of the analyzed BCR1 fragment was not found. Copyright © 2014 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

  11. [Generation and identification of P210(T315I-BCR/ABL) transgenic mice].

    Science.gov (United States)

    Zhu, Yufeng; Wang, Yuanzhan; Meng, Fanyi

    2015-03-01

    To construct the P210(T315I-BCR/ABL) transgenic mice model. The transgenic vector in which the P210(T315I-BCR/ABL) gene and eGFP gene was derived by APN/CD13 promoter was constructed and microinjected into the single-cell fertilized eggs of C57 mice. Transgene integration was conformed by PCR genotyping and P210(T315I-BCR/ABL) expression levels was evaluated by RT-PCR. The CML phenotype was confirmed by blood routine examination, Wright's staining for peripheral blood and bone marrow smears, HE staining for organs of transgenic mice. Three transgenic mice lines with high expression of P210(T315I-BCR/ABL) gene and eGFP gene was selected. Compared with the wild type mice, the levels of WBC, platelet and neutrophil granulocyte of transgenic mice began to increase gradually at 2 months, and increase to 23.9×10⁹/L, 4 136×10⁹/L, and 74.6% respectively at 6 months. The remarkable hyperplasia of granulocytes was seen in the peripheral blood and bone marrow smears with splenomegaly infiltrated by leukemic cells. The P210(T315I-BCR/ABL) transgenic mice was constructed and provided a model to explore the mechanism of T315I CML and screen out the drug for T315 CML patient.

  12. Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis

    Energy Technology Data Exchange (ETDEWEB)

    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 (AAS); (Mount Sinai Hospital); (Med U. Vienna); (UC); (IMP-CNRS)

    2012-10-25

    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.

  13. Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Groffen John

    2007-10-01

    Full Text Available Abstract Background Ph-positive leukemias are caused by the aberrant fusion of the BCR and ABL genes. Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor related to imatinib, which is widely used to treat chronic myelogenous leukemia. Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl. Results After transplant of 10,000 highly malignant leukemic cells into compatible recipients, untreated mice succumbed to leukemia within 21 days, whereas mice treated with 75 mg/kg nilotinib survived significantly longer. We examined cells from mice that developed leukemia while under treatment for Bcr/Abl kinase domain point mutations but these were not detected. In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out. Nilotinib also exhibited impressive anti-leukemia activity in P190 Bcr/Abl transgenic mice that had developed overt leukemia/lymphoma masses and that otherwise would have been expected to die within 7 days. Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced. Treated mice survived more than 30 days. Conclusion These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.

  14. 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.

  15. 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....

  16. 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

  17. Conserved and divergent roles of Bcr1 and CFEM proteins in Candida parapsilosis and Candida albicans.

    Directory of Open Access Journals (Sweden)

    Chen Ding

    Full Text Available Candida parapsilosis is a pathogenic fungus that is major cause of hospital-acquired infection, predominantly due to growth as biofilms on indwelling medical devices. It is related to Candida albicans, which remains the most common cause of candidiasis disease in humans. The transcription factor Bcr1 is an important regulator of biofilm formation in vitro in both C. parapsilosis and C. albicans. We show here that C. parapsilosis Bcr1 is required for in vivo biofilm development in a rat catheter model, like C. albicans. By comparing the transcription profiles of a bcr1 deletion in both species we found that regulation of expression of the CFEM family is conserved. In C. albicans, three of the five CFEM cell wall proteins (Rbt5, Pga7 and Csa1 are associated with both biofilm formation and acquisition of iron from heme, which is an important virulence characteristic. In C. parapsilosis, the CFEM family has undergone an expansion to 7 members. Expression of three genes (CFEM2, CFEM3, and CFEM6 is dependent on Bcr1, and is induced in low iron conditions. All three are involved in the acquisition of iron from heme. However, deletion of the three CFEM genes has no effect on biofilm formation in C. parapsilosis. Our data suggest that the role of the CFEM family in iron acquisition is conserved between C. albicans and C. parapsilosis, but their role in biofilm formation is not.

  18. 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

  19. 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

  20. 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 ...

  1. 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 ...

  2. Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors.

    Science.gov (United States)

    Pietarinen, Paavo O; Eide, Christopher A; Ayuda-Durán, Pilar; Potdar, Swapnil; Kuusanmäki, Heikki; Andersson, Emma I; Mpindi, John P; Pemovska, Tea; Kontro, Mika; Heckman, Caroline A; Kallioniemi, Olli; Wennerberg, Krister; Hjorth-Hansen, Henrik; Druker, Brian J; Enserink, Jorrit M; Tyner, Jeffrey W; Mustjoki, Satu; Porkka, Kimmo

    2017-04-04

    Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1-positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34-negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.

  3. 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.

  4. BCL6 modulates tonic BCR signaling in diffuse large B-cell lymphomas by repressing the SYK phosphatase, PTPROt.

    Science.gov (United States)

    Juszczynski, Przemyslaw; Chen, Linfeng; O'Donnell, Evan; Polo, Jose M; Ranuncolo, Stella M; Dalla-Favera, Riccardo; Melnick, Ari; Shipp, Margaret A

    2009-12-17

    Tonic B-cell receptor (BCR) signaling is a key survival pathway during normal B-cell ontogenesis and in a subset of diffuse large B-cell lymphomas (DLBCLs). We previously demonstrated that BCR-dependent DLBCL cell lines and primary tumors underwent apoptosis after treatment with an ATP-competitive inhibitor of the BCR-associated spleen tyrosine kinase (SYK). These "BCR-type" tumors also have more abundant expression of the transcriptional repressor, BCL6, and increased sensitivity to BCL6 inhibition. Herein, we evaluated potential connections between BCL6-mediated transcriptional repression and SYK-dependent BCR signaling. In transcriptionally profiled normal B-cell subsets (naive, germinal center, and memory B cells) and in primary DLBCLs, there were reciprocal patterns of expression of BCL6 and the SYK tyrosine phosphatase PTPROt. BCL6 repressed PTPROt transcription via a direct interaction with functional BCL6 binding sites in the PTPROt promoter. Enforced expression of BCL6 in normal naive B cells and RNAi-mediated depletion of BCL6 in germinal center B cells directly modulated PTPROt expression. In "BCR-type" DLBCLs, BCL6 depletion increased PTPROt expression and decreased phosphorylation of SYK and the downstream adaptor protein BLNK. Because BCL6 augments BCR signaling and BCL6 and SYK are both promising therapeutic targets in many DLBCLs, combined inhibition of these functionally related pathways warrants further study.

  5. Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma.

    Science.gov (United States)

    Bernard, Sophie; Danglade, Damien; Gardano, Laura; Laguillier, Christelle; Lazarian, Gregory; Roger, Claudine; Thieblemont, Catherine; Marzec, Jacek; Gribben, John; Cymbalista, Florence; Varin-Blank, Nadine; Ledoux, Dominique; Baran-Marszak, Fanny

    2015-06-15

    Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B-cell receptor (BCR)-mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR-associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL-1β, IL-6, IL-8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL-1β, IL-6, IL-8, CCL5, IL-10, TNFα and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR-induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR-induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short- and long-term co-culture. We demonstrated that BCR-induced survival relies on autocrine secretion of IL-1β, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis. © 2014 UICC.

  6. 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.)

  7. 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.

  8. Chronic Myeloid Leukemia 2011: Successes, challenges, and strategies – Proceedings of the 5th Annual BCR-ABL1 positive and BCR-ABL1 negative myeloproliferative neoplasms workshop

    Science.gov (United States)

    Mughal, Tariq I; Radich, Jerald P; Van Etten, Richard A.; Quintás-Cardama, Alfonso; Skorski, Tomasz; Ravandi, Farhad; DeAngelo, Daniel J.; Gambacorti-Passerini, Carlo; Martinelli, Giovanni; Tefferi, Ayalew

    2012-01-01

    This report is based on the presentations and discussions at the 5th annual BCR-ABL1 positive and BCR-ABL1 negative myeloproliferative neoplasms (MPN) workshop, which took place immediately following the 52nd American Society of Hematology (ASH) meeting in Orlando, Florida on December 7th-8th, 2011. Relevant data which was presented at the ASH meeting as well as all other recent publications were presented and discussed at the workshop. This report covers front-line therapies of BCR-ABL1-positive leukemias, in addition to addressing some topical biological, pre-clinical and clinical issues, such as new insights into genomic instability and resistance to tyrosine kinase inhibitors (TKIs), risk stratification and optimizing molecular monitoring. A report pertaining to the new therapies and other pertinent preclinical and clinical issues in the BCR-ABL1 negative MPNs is published separately. PMID:21850662

  9. Attomolar electrochemical detection of the BCR/ABL fusion gene based on an amplifying self-signal metal nanoparticle-conducting polymer hybrid composite.

    Science.gov (United States)

    Avelino, Karen Y P S; Frias, Isaac A M; Lucena-Silva, Norma; Gomes, Renan G; de Melo, Celso P; Oliveira, Maria D L; Andrade, César A S

    2016-12-01

    In the last ten years, conjugated polymers started to be used in the immobilization of nucleic acids via non-covalent interactions. In the present study, we describe the construction and use of an electrochemical DNA biosensor based on a nanostructured polyaniline-gold composite, specifically developed for the detection of the BCR/ABL chimeric oncogene. This chromosome translocation is used as a biomarker to confirm the clinical diagnosis of both chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). The working principle of the biosensor rests on measuring the conductivity resulting from the non-covalent interactions between the hybrid nanocomposite and the DNA probe. The nanostructured platform exhibits a large surface area that enhances the conductivity. Positive cases, which result from the hybridization between DNA probe and targeted gene, induce changes in the amperometric current and in the charge transfer resistance (R CT ) responses. Atomic force microscopy (AFM) images showed changes in the genosensor surface after exposure to cDNA sample of patient with leukemia, evidencing the hybridization process. This new hybrid sensing-platform displayed high specificity and selectivity, and its detection limit is estimated to be as low as 69.4 aM. The biosensor showed excellent analytical performance for the detection of the BCR/ABL oncogene in clinical samples of patients with leukemia. Hence, this electrochemical sensor appears as a simple and attractive tool for the molecular diagnosis of the BCR/ABL oncogene even in early-stage cases of leukemia and for the monitoring of minimum levels of residual disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. 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...

  11. Unleashing the Guardian: The Targetable BCR-ABL/HAUSP/PML/PTEN Network in Chronic Myeloid Leukemia.

    Science.gov (United States)

    Morotti, Alessandro; Torti, Davide; Carra, Giovanna; Panuzzo, Cristina; Crivellaro, Sabrina; Taulli, Riccardo; Fava, Carmen; Guerrasio, Angelo; Saglio, Giuseppe

    2017-01-01

    The complete eradication of Chronic Myeloid Leukemia is still challenging even in the era of highly selective and potent BCR-ABL tyrosine kinase inhibitors (TKIs). The 'Achilles heel' of TKI-based CML therapy is the inability of TKI to effectively target CML stem cells. Several pathways have been described to induce TKI insensitiveness in quiescent CML stem cells. In this review, we will describe the BCR-ABL/HAUSP/PML/PTEN network, whose signaling mediators converge to regulate the function of the tumor suppressor PTEN. We will also highlight the pharmacological strategies to modulate PTEN functions in order to sustain CML stem cell eradication. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. Disruption of Survivin in K562 cells elevates telomerase activity and protects cells against apoptosis induced by the Bcr-abl kinase inhibitor STI571

    OpenAIRE

    Wang, Zhanxiang; Pelus, Louis M.

    2008-01-01

    The Bcr-abl kinase inhibitor STI571 produces clinical responses in most patients with Chronic Myeloid Leukemia (CML); however, development of resistance limits utility. One strategy to overcome STI571 resistance is to decrease the level/activity of Bcr-abl. We reported that disruption of the anti-apoptotic protein Survivin promoted STI571-induced apoptosis in Bcr-abl+ K562 cells, through caspase-dependent Bcr-abl degradation. To investigate the utility of Survivin disruption in drug-resistant...

  1. SGX393 inhibits the CML mutant Bcr-Abl[superscript T315I] and preempts in vitro resistance when combined with nilotinib or dasatinib

    Energy Technology Data Exchange (ETDEWEB)

    O' Hare, Thomas; Eide, Christopher A.; Tyner, Jeffrey W.; Corbin, Amie S.; Wong, Matthew J.; Buchanan, Sean; Holme, Kevin; Jessen, Katayoun A.; Tang, Crystal; Lewis, Hal A.; Romero, Richard D.; Burley, Stephen K.; Deininger, Michael W. (OHSU- Cancer Instit.); (SGX)

    2010-01-12

    Imatinib inhibits Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The second-line inhibitors nilotinib and dasatinib are effective in patients with imatinib resistance resulting from Bcr-Abl kinase domain mutations. Bcr-Abl{sup T315I}, however, is resistant to all Abl kinase inhibitors in clinical use and is emerging as the most frequent cause of salvage therapy failure. SGX393 is a potent inhibitor of native and T315I-mutant Bcr-Abl kinase that blocks the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-Abl{sup T315I}, with minimal toxicity against Bcr-Abl-negative cell lines or normal bone marrow. A screen for Bcr-Abl mutants emerging in the presence of SGX393 revealed concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted emergence of resistant subclones, including Bcr-Abl{sup T315I}. These findings suggest that combination of a T315I inhibitor with the current clinically used inhibitors may be useful for reduction of Bcr-Abl mutants in Philadelphia chromosome-positive leukemia.

  2. 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.

  3. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib

    Science.gov (United States)

    Yeung, David T. O.; Yeoman, Alexandra L.; Altamura, Haley K.; Jamison, Bronte A.; Field, Chani R.; Hodgson, J. Graeme; Lustgarten, Stephanie; Rivera, Victor M.; Hughes, Timothy P.; Branford, Susan

    2016-01-01

    The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass-spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph+ Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance

  4. 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

  5. Transferred BCR/ABL DNA from K562 extracellular vesicles causes chronic myeloid leukemia in immunodeficient mice.

    Directory of Open Access Journals (Sweden)

    Jin Cai

    Full Text Available Our previous study showed that besides mRNAs and microRNAs, there are DNA fragments within extracellular vesicles (EVs. The BCR/ABL hybrid gene, involved in the pathogenesis of chronic myeloid leukemia (CML, could be transferred from K562 EVs to neutrophils and decrease their phagocytic activity in vitro. Our present study provides evidence that BCR/ABL DNAs transferred from EVs have pathophysiological significance in vivo. Two months after injection of K562 EVs into the tail vein of Sprague-Dawley (SD rats, they showed some characteristics of CML, e.g., feeble, febrile, and thin, with splenomegaly and neutrophilia but with reduced neutrophil phagocytic activity. These findings were also observed in immunodeficient NOD/SCID mice treated with K562 EVs; BCR/ABL mRNA and protein were found in their neutrophils. The administration of actinomycin D, an inhibitor of de novo mRNA synthesis, prevented the abnormalities caused by K562 EVs in NOD/SCID mice related to CML, including neutrophilia and bone marrow hyperplasia. As a specific inhibitor of tyrosine kinases, imatinib blocked the activity of tyrosine kinases and the expression of phospho-Crkl, induced by the de novo BCR/ABL protein caused by K562 EVs bearing BCR/ABL DNA. Our current study shows the pathophysiological significance of transferred tumor gene from EVs in vivo, which may represent an important mechanism for tumorigenesis, tumor progression, and metastasis.

  6. 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

  7. [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.

  8. Improved FRET Biosensor for the Measurement of BCR-ABL Activity in Chronic Myeloid Leukemia Cells.

    Science.gov (United States)

    Horiguchi, Mika; Fujioka, Mari; Kondo, Takeshi; Fujioka, Yoichiro; Li, Xinxin; Horiuchi, Kosui; O Satoh, Aya; Nepal, Prabha; Nishide, Shinya; Nanbo, Asuka; Teshima, Takanori; Ohba, Yusuke

    2017-02-02

    Although the co-development of companion diagnostics with molecular targeted drugs is desirable, truly efficient diagnostics are limited to diseases in which chromosomal translocations or overt mutations are clearly correlated with drug efficacy. Moreover, even for such diseases, few methods are available to predict whether drug administration is effective for each individual patient whose disease is expected to respond to the drug(s). We have previously developed a biosensor based on the principle of Förster resonance energy transfer to measure the activity of the tyrosine kinase BCR-ABL and its response to drug treatment in patient-derived chronic myeloid leukemia cells. The biosensor harbors CrkL, one of the major substrates of BCR-ABL, and is therefore named Pickles after phosphorylation indicator of CrkL en substrate. The efficacy of this technique as a clinical test has been demonstrated, but the number of cells available for analysis is limited in a case-dependent manner, owing to the cleavage of the biosensor in patient-derived leukemia cells. Here, we describe an improved biosensor with an amino acid substitution and a nuclear export signal being introduced. Of the two predicted cleavage positions in CrkL, the mutations inhibited one cleavage completely and the other cleavage partially, thus collectively increasing the number of cells available for drug evaluation. This improved version of the biosensor holds promise in the future development of companion diagnostics to predict responses to tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

  9. 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

  10. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

    NARCIS (Netherlands)

    Essafi, A.; Mattos, S.F. de; Hassen, Y.A.M.; Soeiro, I.; Mufti, G.J.; Thomas, N.S.B.; Medema, R.H.; Lam, E.W.-F.

    2005-01-01

    In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. FoxO3a lies downstream of Bcr-Abl signalling and is constitutively

  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. 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.

  13. 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......-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie......, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic...

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

    Energy Technology Data Exchange (ETDEWEB)

    Ohtomo, Tadashi [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan); Miyazawa, Keisuke, E-mail: miyazawa@tokyo-med.ac.jp [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan); Naito, Munekazu [Department of Anatomy, Tokyo Medical University, Tokyo (Japan); Moriya, Shota [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan); Kuroda, Masahiko [Department of Molecular Pathology, Tokyo Medical University, Tokyo (Japan); Itoh, Masahiro [Department of Anatomy, Tokyo Medical University, Tokyo (Japan); Tomoda, Akio [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan)

    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{sup -/-} 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.

  15. 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.

  16. Deregulated expression of Cdc6 as BCR/ABL-dependent survival factor in chronic myeloid leukemia cells.

    Science.gov (United States)

    Zhang, Jia-Hua; He, Yan-Li; Zhu, Rui; Du, Wen; Xiao, Jun-Hua

    2017-06-01

    Chronic myeloid leukemia is characterized by the presence of the reciprocal translocation t(9;22) and the BCR/ABL oncogene. The BCR/ABL oncogene activates multiple signaling pathways and involves the dysregulation of oncogenes during the progression of chronic myeloid leukemia. The cell division cycle protein 6, an essential regulator of DNA replication, is elevated in some human cancer cells. However, the expression of cell division cycle protein 6 in chronic myeloid leukemia and the underlying regulatory mechanism remain to be elucidated. In this study, our data showed that cell division cycle protein 6 expression was significantly upregulated in primary chronic myeloid leukemia cells and the chronic myeloid leukemia cell line K562 cells, as compared to the normal bone marrow mononuclear cells. BCR/ABL kinase inhibitor STI571 or BCR/ABL small interfering RNA could significantly downregulate cell division cycle protein 6 messenger RNA expression in K562 cells. Moreover, phosphoinositide 3-kinase/AKT pathway inhibitor LY294002 and Janus kinase/signal transducer and activator of transcription pathway inhibitor AG490 could downregulate cell division cycle protein 6 expression in K562 cells, but not RAS/mitogen-activated protein kinase pathway inhibitor PD98059 had such effect. Cell division cycle protein 6 gene silencing by small interfering RNA effectively resulted in decrease of proliferation, increase of apoptosis, and arrest of cell cycle in K562 cells. These findings have demonstrated that cell division cycle protein 6 overexpression may contribute to the high proliferation and low apoptosis in chronic myeloid leukemia cells and can be regulated by BCR/ABL signal transduction through downstream phosphoinositide 3-kinase/Akt and Janus kinase/signal transducer and activator of transcription pathways, suggesting cell division cycle protein 6 as a potential therapeutic target in chronic myeloid leukemia.

  17. Detection of BCR-ABL and E2A-PBX1 fusion genes by RT-PCR in acute lymphoblastic leukaemia with failed or normal cytogenetics.

    Science.gov (United States)

    Devaraj, P E; Foroni, L; Kitra-Roussos, V; Secker-Walker, L M

    1995-02-01

    To evaluate the use of molecular analysis as a complement to karyotypic analysis in the detection of specific chromosomal abnormalities, the occurrence of t(1;19)(q23;p13) and t(9;22)(q34;q11) was investigated by RT-PCR in 43 diagnostic acute lymphoblastic leukaemia cases in whom cytogenetic investigations had failed (32 cases) or showed only a normal karyotype (> or = 20 normal metaphases, 11 cases). One child (aged 14 years) and five adults (aged 18-60 years) were BCR-ABL positive on first round for M-BCR-ABL (one case) or m-BCR-ABL (one case), or on nested PCR for m-BCR-ABL (three cases). Co-expression of M-BCR-ABL (first-round PCR) and m-BCR-ABL (nested PCR was seen in one case. One m-BCR-ABL-positive case also expressed the E2A-PBX1 fusion transcript. Patients positive for the transcript(s) were older, had higher white blood cell counts and a significantly poorer event-free survival (P < 0.001) than those negative for the transcript.

  18. 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

  19. 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...

  20. Coexistence of p190 BCR/ABL Transcript and CALR 52-bp Deletion in Chronic Myeloid Leukemia Blast Crisis: A Case Report.

    Science.gov (United States)

    Seghatoleslami, Mohammad; Ketabchi, Neda; Ordo, Alireza; Asl, Javad Mohammadi; Golchin, Neda; Saki, Najmaldin

    2016-01-01

    We introduce a 78-year-old woman presented with thrombocytosis and high blast count who had a history of splenectomy. Her cytogenetic analysis revealed aberrant chromosomal rearrangements in different clonal populations harboring 46XX karyotype with t(9;22) (q34;q11). RT-PCR assay detected the e1a2 BCR-ABL translocation resulting from rearrangement of the minor breakpoint cluster region (m-bcr) in BCR gene. Subsequent evaluation of the disease showed calreticulin (CALR) 52-bp deletion as well as the absence of JAK2 (V617F) heterozygous mutation in granulocyte population of peripheral blood using allele-specific PCR and bi-directional DNA sequencing. To our knowledge, this is the first case of a patient initially diagnosed as p190 BCR-ABL transcript positive CML in blast crisis characterized by a 52-bp deletion in CALR gene.

  1. Coexistence of P190 BCR/ABL transcript and CALR 52-bp deletion in chronic myeloid leukemia blast crisis: a case report

    Directory of Open Access Journals (Sweden)

    najmaldin saki

    2016-01-01

    Full Text Available We present a case of a 78-year-old woman presented with thrombocytosis and high blast count, who had a history of splenectomy. Her cytogenetic analysis revealed aberrant chromosomal rearrangements in different clonal populations harboring 46XX karyotype with t(9;22(q34;q11. RT-PCR assay detected the e1a2 BCR-ABL translocation resulting from a rearrangement of the minor breakpoint cluster region (m-bcr in the BCR gene. Subsequent evaluations of the disease showed calreticulin (CALR 52-bp deletion as well as the absence of JAK2V617F heterozygous mutation in granulocyte population of peripheral blood using allele-specific PCR and bi-directional DNA sequencing. To our knowledge, this is the first case of a patient initially diagnosed as p190 BCR-ABL transcript positive CML in blastic crisis characterized with a 52-bp deletion in CALR gene.

  2. Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase: ENEST1st sub-analysis.

    Science.gov (United States)

    Hochhaus, Andreas; Mahon, Franҫois-Xavier; le Coutre, Philipp; Petrov, Ljubomir; Janssen, Jeroen J W M; Cross, Nicholas C P; Rea, Delphine; Castagnetti, Fausto; Hellmann, Andrzej; Rosti, Gianantonio; Gattermann, Norbert; Coronel, Maria Liz Paciello; Gutierrez, Maria Asuncion Echeveste; Garcia-Gutierrez, Valentin; Vincenzi, Beatrice; Dezzani, Luca; Giles, Francis J

    2017-07-01

    The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph-/BCR-ABL1 + chronic myeloid leukemia. Patients received nilotinib 300 mg twice daily, up to 24 months. At screening, 983 patients were identified as Ph+ and 30 patients as Ph-/BCR-ABL + based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph-/BCR-ABL1 + subgroup, no additional chromosomal aberrations were reported. In the Ph+ subgroup, 952 patients had safety and molecular assessments. In the Ph-/BCR-ABL1 + subgroup, 30 patients had safety assessments and 28 were followed up for molecular assessments. At 18 months, the molecular response (MR) 4 rate [MR 4 ; BCR-ABL1 ≤0.01% on International Scale (IS)] was similar in the Ph-/BCR-ABL1+ (39.3%) and Ph+ subgroups (38.1%). By 24 months, the cumulative rates of major molecular response (BCR-ABL1 IS ≤0.1%;), MR 4 , and MR 4.5 (BCR-ABL1 IS ≤0.0032%) were 85.7, 60.7, and 50.0%, respectively, in the Ph-/BCR-ABL1 + subgroup, and 80.3, 54.7, and 38.3%, respectively, in the Ph+ subgroup. In both Ph-/BCR-ABL1 + and Ph+ subgroups, rash (20 and 22%), pruritus (16.7 and 16.7%), nasopharyngitis (13.3 and 10.4%), fatigue (10 and 14.2%), headache (10 and 15.8%), and nausea (6.7 vs 11.4%) were frequent non-hematologic adverse events, whereas hypophosphatemia (23.3 and 6.8%), anemia (10 and 6.5%), and thrombocytopenia (3.3 and 10.2%) were the common hematologic/biochemical laboratory events. Based on similar molecular response and safety results in both subgroups, we conclude that Ph-/BCR-ABL1 + patients benefit from nilotinib in the same way as Ph+ patients.

  3. 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

  4. 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.

  5. Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges.

    Science.gov (United States)

    Noens, Lucien; Hensen, Marja; Kucmin-Bemelmans, Izabela; Lofgren, Christina; Gilloteau, Isabelle; Vrijens, Bernard

    2014-03-01

    BCR-ABL inhibitors for treating chronic myeloid leukemia in chronic phase have transformed a previously incurable malignancy into a manageable condition. However, suboptimal medication adherence has been observed with these agents affecting clinical outcomes and healthcare costs. In order to raise awareness of the problem of adherence, and before developing pragmatic strategies to enhance medication adherence, a deep understanding of the best approaches for measuring adherence in chronic myeloid leukemia patients and identifying non-adherence is required. A systematic literature review on the prevalence, measurement methods, consequences and risk factors for non-adherence to BCR-ABL inhibitors and adherence-enhancing interventions was performed and critically appraised. Of the 19 included articles, 9 were retrospective. Average adherence varied from 19% to almost 100% of the proportion of prescribed drug taken, but it was measured through various different methods and within different study groups. Suboptimal adherence was associated with a negative impact on both clinical and economic outcomes. There is a lack of supportive evidence demonstrating a difference in adherence across BCR-ABL inhibitors and even contradictory results between the 2(nd) generation inhibitors. Drug-related adverse events and forgetfulness were common reasons for intentional and unintentional non-adherence, respectively, but further research is required to identify additional reasons behind non-adherence or patients at risk of non-adherence. Non-adherence in chronic myeloid leukemia patients treated with BCR-ABL inhibitors is common and associated with critical outcomes. However, this review highlights important existing gaps, reveals inconsistent definitions, and a lack of standardized methods for measuring adherence in chronic myeloid leukemia. All require further investigation.

  6. 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.

  7. 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

  8. Characterization of a novel variant BCR-ABL1 fusion transcript in a patient with chronic myeloid leukemia: Implications for molecular monitoring.

    Science.gov (United States)

    Crampe, Mireille; Haslam, Karl; Kelly, Johanna; Conneally, Eibhlin; Langabeer, Stephen E

    2017-06-01

    Molecular monitoring of BCR-ABL1 transcript levels using quantitative polymerase chain reaction is an essential part of the modern management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Establishing the diagnostic BCR-ABL1 fusion transcript is necessary in order to select appropriate primers and probes for such monitoring. A case is described in which quantitative polymerase chain reaction failed to detect the presence of BCR-ABL1 fusion transcript in a Philadelphia chromosome-positive chronic myeloid leukemia patient. Further investigation demonstrated a novel in-frame BCR-ABL1 fusion transcript with a breakpoint in BCR exon 13 and insertion of a sequence of ABL1 intron 1, therefore enabling subsequent molecular monitoring. This case highlights the requirement for characterization of the BCR-ABL1 transcript type at chronic myeloid leukemia diagnosis. Issues concerning standardized methodological approaches and interpretation of transcript levels in such rare cases are discussed. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

  9. 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.

  10. 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.

  11. A novelBCR-ABL1fusion gene with genetic heterogeneity indicates a good prognosis in a chronic myeloid leukemia case.

    Science.gov (United States)

    Zhou, Fen; Jin, Runming; Hu, Yu; Mei, Heng

    2017-01-01

    Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder caused by the fusion of the BCR and ABL1 genes. Quantitative RT-PCR (qRT-PCR) is a routinely performed screening technique to identify BCR-ABL1 fusion genes, but a limitation of this method is its inability to recognize novel fusions that have not been previously characterized. Next-generation sequencing (NGS) is an effective and sensitive detection method for the determination of novel BCR-ABL1 fusion genes as well as previously characterized ones. The oncoprotein tyrosine kinase BCR-ABL1 is a constitutively active kinase involved in the activation of a number of signaling pathways, and it has been the therapeutic target for tyrosine kinase inhibitors (TKIs) such as imatinib. Reports have presented opposing viewpoints about the effect of the disrupted Src homology 3 (SH3) domain on TKI efficacy. We here report that using NGS we identified a novel BCR-ABL1 fusion gene with breakpoints in the BCR intron 14 and the ABL1 intron 2, leading to partial deletion of its SH3 domain. In the present case, the patient received targeted therapy with the TKI imatinib at 400 mg/day and no adverse reaction was reported. The patient eventually entered remission with decreased proliferation of karyocytes and granulocytes. We also identified mutations in genes, including TP53 , FLT3 , ASXL1 , SETBP1 , CEBPA and CBL, that seemed to have an influence on the outcome of TKI therapy targeting the BCR-ABL1 protein. Together with previously reported results, it is clear that the genetic heterogeneity of CML patients significantly affects the presentation of the disease and its progression and therefore should inform the design of the therapeutic strategy.

  12. CD-200 induces apoptosis and inhibits Bcr-Abl signaling in imatinib-resistant chronic myeloid leukemia with T315I mutation.

    Science.gov (United States)

    Fang, Zhenghuan; Jung, Kyung Hee; Yan, Hong Hua; Kim, Soo Jung; Son, Mi Kwon; Rumman, Marufa; Lee, Hyunseung; Kim, Ki Woon; Yoo, Hye-Dong; Hong, Soon-Sun

    2015-07-01

    Chronic myeloid leukemia (CML) is characterized by a constitutively active Bcr-Abl tyrosine kinase. Although Imatinib has been proven to be an effective drug against CML, its resistance has been observed with disease relapse due to T315I predominant point mutation. Liriodendron tulipifera L., one of the fastest growing hardwood tree species, exerts antioxidant activity and anti-inflammatory effects. However, its anticancer effect has been minimally reported. In this study, we extracted CD-200 from Liriodendron tulipifera L. and investigated its effect on cell survival or apoptosis in CML cells with Bcr-Abl/T315I (BaF3/T315I) as well as wild-type Bcr-Abl (BaF3/WT). CD-200 inhibited cell proliferation in the BaF3/WT cells, and also in the BaF3/T315I cells with Imatinib resistance. Moreover, it strongly inhibited Bcr-Abl signaling pathways in a dose-dependent manner. Also, it significantly increased the sub-G1 phase and the expression of cleaved PARP and caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we observed that CD-200 induced apoptosis with a loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin. Furthermore, CD-200 showed a significant inhibition in tumor growth, compared to Imatinib in BaF3/T315I mouse xenograft models. Taken together, our study demonstrates that CD-200 exhibits apoptosis induction and anti-proliferative effect by blocking the Bcr-Abl signaling pathways in the Bcr-Abl/T315I with resistance to Imatinib. We suggest that CD-200 may be a natural product to target Bcr-Abl and overcome Imatinib resistance in CML patients.

  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. Identification of novel tyrosine kinase inhibitors for drug resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study

    Science.gov (United States)

    Banavath, Hemanth Naick; Sharma, Om Prakash; Kumar, Muthuvel Suresh; Baskaran, R.

    2014-11-01

    BCR-ABL tyrosine kinase plays a major role in the pathogenesis of chronic myeloid leukemia (CML) and is a proven target for drug development. Currently available drugs in the market are effective against CML; however, side-effects and drug-resistant mutations in BCR-ABL limit their full potential. Using high throughput virtual screening approach, we have screened several small molecule databases and docked against wild-type and drug resistant T315I mutant BCR-ABL. Drugs that are currently available, such as imatinib and ponatinib, were also docked against BCR-ABL protein to set a cutoff value for our screening. Selected lead compounds were further evaluated for chemical reactivity employing density functional theory approach, all selected ligands shows HLG value > 0.09900 and the binding free energy between protein-ligand complex interactions obtained was rescored using MM-GBSA. The selected compounds showed least ΔG score -71.53 KJ/mol to maximum -126.71 KJ/mol in both wild type and drug resistant T315I mutant BCR-ABL. Following which, the stability of the docking complexes were evaluated by molecular dynamics simulation (MD) using GROMACS4.5.5. Results uncovered seven lead molecules, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Total uncertainty budget calculation for the determination of mercury in incineration ash (BCR 176R) by atomic fluorescence spectrometry.

    Science.gov (United States)

    Tirez, Kristof; Beutels, Filip; Brusten, Wilfried; Noten, Bart; De Brucker, Nicole

    2002-11-01

    The mercury mass fraction has been determined by atomic fluorescence spectrometry (AFS) in the framework of the project "Certification of a reference material (trace elements in fly ash) in replacement of BCR CRM 176". Calculation of the uncertainty budget, as described in this manuscript, emphasizes a practical and realistic approach to estimation of uncertainty components on the basis of statistical assumptions. GUM Workbench software was used, and resulted in a mercury mass fraction of 1.58+/-0.11 mg kg(-1) (with coverage factor k=2.2, 95% probability) related to dry mass, submitted in the certification exercise. The calculated total uncertainty budget applies to analogous samples analyzed by this procedure.

  17. Fluorescence in situ hybridization patterns of BCR/ABL1 fusion in chronic myelogenous leukemia at diagnosis

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    Poonam P Jain

    2012-01-01

    Full Text Available Background : Chronic myelogenous leukemia (CML is characterised by the t(9;22(q34;q11.2 which results in the formation of the BCR/ABL1 fusion gene. Occasionally, the t(9;22 may be associated with submicroscopic deletions of chromosomes 9 and/or 22 which appear to be associated with a worse prognosis. Three or four-way variant t(9;22 may also occur. All these changes as well as gain of the Philadelphia chromosome which represents disease progression can be detected by fluorescence in situ hybridization (FISH analysis. FISH analysis at presentation is used to determine the number of cells with BCR/ABL1 fusion and establish whether the patterns are typical or atypical. Response to therapy can then be monitored by serial testing. Patients and Methods : The study group consisted of all patients diagnosed or suspected to have CML who had interphase FISH analysis at presentation on peripheral blood/bone marrow using a commercially available BCR/ABL1 dual colour, dual fusion probe. The study was performed at a tertiary hospital in India between 2004 and 2010. Results: There were 1076 diagnostic samples which were positive for BCR/ABL1 fusion. Typical dual fusion signals (two fusions, one red and one green, 2F1R1G were seen in 801 cases (74 %. Atypical signal patterns were seen in 275 cases (26%. These were: 1F1R2G (4%, 1F2R1G (2.5% and 1F1R1G (11% representing deletions of the derivative 9 involving chromosome 9 sequences, chromosome 22 sequences, or both respectively; 3F1R1G (6.5% usually representing gain of an additional Philadelphia chromosome and 1F2R2G (1% representing a three- or four-way variant translocation. More than one signal pattern was seen in 1%. Conclusions: Our findings were similar to the literature with respect to the distribution of signal patterns except that we had a lower number of patients with variant translocations. While each signal pattern is typically associated with a particular abnormality, there can be more than one

  18. 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...

  19. 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.

  20. The role of mitochondrial DNA damage and repair in the resistance of BCR/ABL-expressing cells to tyrosine kinase inhibitors.

    Science.gov (United States)

    Glowacki, Sylwester; Synowiec, Ewelina; Blasiak, Janusz

    2013-08-07

    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.

  1. 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.

  2. 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

  3. Biosensing of BCR/ABL fusion gene using an intensity-interrogation surface plasmon resonance imaging system

    Science.gov (United States)

    Wu, Jiangling; Huang, Yu; Bian, Xintong; Li, DanDan; Cheng, Quan; Ding, Shijia

    2016-10-01

    In this work, a custom-made intensity-interrogation surface plasmon resonance imaging (SPRi) system has been developed to directly detect a specific sequence of BCR/ABL fusion gene in chronic myelogenous leukemia (CML). The variation in the reflected light intensity detected from the sensor chip composed of gold islands array is proportional to the change of refractive index due to the selective hybridization of surface-bound DNA probes with target ssDNA. SPRi measurements were performed with different concentrations of synthetic target DNA sequence. The calibration curve of synthetic target sequence shows a good relationship between the concentration of synthetic target and the change of reflected light intensity. The detection limit of this SPRi measurement could approach 10.29 nM. By comparing SPRi images, the target ssDNA and non-complementary DNA sequence are able to be distinguished. This SPRi system has been applied for assay of BCR/ABL fusion gene extracted from real samples. This nucleic acid-based SPRi biosensor therefore offers an alternative high-effective, high-throughput label-free tool for DNA detection in biomedical research and molecular diagnosis.

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

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    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.

  5. A case of acute myeloid leukemia with e6a2 BCR-ABL fusion transcript acquired after progressing from chronic myelomonocytic leukemia

    OpenAIRE

    Jinjuan Yao; Dan Douer; Lu Wang; Maria E. Arcila; Khedoudja Nafa; April Chiu

    2017-01-01

    Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myeloid leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while a small subset of the cases expresses e1a2 or e19a2 transcripts. We report a patient with chronic myelomonocytic leukemia (CMML), initially Ph chromosome negative at presentation, with rapid disease progression to acute myeloid leukemia (AML) and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion trans...

  6. MEK inhibition potentiates the antitumor effect of Arsenic Trioxide in Bcr-Abl+ Imatinib-resistant Chronic Myeloid Leukemia cells: preclinical in vitro and in vivo study

    OpenAIRE

    Mazzera, Laura

    2014-01-01

    La Leucemia Mieloide Cronica (LMC) è una malattia caratterizzata dalla presenza di una specifica anormalità cromosomica, il cromosoma Philadelphia, codificante per una proteina di fusione di peso molecolare 210 Kd (p210) chiamata Bcr-Abl, che è una tirosin-chinasi sempre attiva. Il farmaco d’elezione per il trattamento di questa patologia è il tirosin-chinasi inibitore (TKI) Imatinib (Gleevec) che riduce l'attività di Bcr-Abl. L’utilizzo dell’Imatinib in clinica è però limitato dall’insorgenz...

  7. Coexistence of p210BCR-ABLand CBFβ-MYH11 fusion genes in myeloid leukemia: A report of 4 cases.

    Science.gov (United States)

    Wang, Yuan-Yuan; Ding, Wen-Jing; Jiang, Feng; Chen, Zi-Xing; Cen, Jian-Nong; Qi, Xiao-Fei; Liang, Jian-Ying; Liu, Dan-Dan; Pan, Jin-Lan; Chen, Su-Ning

    2017-11-01

    Numerous acquired molecular and cytogenetic abnormalities are strongly associated with hematological malignancies. The breakpoint cluster region-ABL proto-oncogene 1 ( BCR-ABL ) rearrangement leads to a p210 chimeric protein in typical chronic myeloid leukemia (CML), whereas 17-25% of patients with acute lymphocytic leukemia and 0.9-3% patients with de novo acute myeloid leukemia (AML) carry a p190 BCR-ABL fusion protein. Cases of patients with AML/CML carrying two specific primary molecular changes, BCR-ABL and core binding factor-β-myosin heavy chain 11 ( CBFβ-MYH11 ) fusion genes have been rarely reported. The present study aimed to understand the nature and mechanism of this particular type of leukemia through case reports and literature review. A total of four patients who were diagnosed as AML/CML with BCR-ABL and CBFβ-MYH11 fusion genes in the First Affiliated Hospital of Soochow University (Suzhou, China) between January 2004 and December 2012 were examined. Morphological analysis of bone marrow cells, flow cytometry, quantitative polymerase chain reaction of p 210BCR-ABL and CBFβ-MYH11 transcripts as well as cytogenetic and fluorescence in situ hybridization analyses were performed. A total of 4 patients who exhibited fusion of p 210BCR-ABL and CBFβ-MYH11 were identified. A single patient (case 1) was first diagnosed CML-acute phase (AP), which progressed rapidly to CML-blast crisis (BC), and three patients (cases 2, 3 and 4) were diagnosed with AML with bone marrow eosinophilia at first presentation with no evidence of previous onset of CML. All cases achieved remission following conventional chemotherapy/hematological stem cell transplantation combined with the inhibitor of tyrosine kinase (TKI) maintenance therapy. The patients with CML carrying and expressing BCR-ABL and CBFβ-MYH11 fusion genes appeared more likely to rapidly progress to AP or BC. Therefore, the product of the CBFβ-MYH11 fusion gene may serve an important role in the

  8. Speciation of heavy metals in street dust samples from Sakarya I. Organized industrial district using the BCR sequential extraction procedure by ICP-OES

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    N. Ozcan

    2013-05-01

    Full Text Available This paper focuses on the concentrations of heavy metals (Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn in 20 dust samples collected from the streets of the Organized Industrial District in Sakarya, Turkey using sequential extraction procedure were determined by ICP-OES. The three-step BCR sequential extraction procedure was used in order to evaluate mobility, availability and persistence of heavy elements in street dust samples. Three operationally defined fractions isolated using the BCR procedure was: acid extractable, reducible, and oxidizable. The mobility sequence based on the sum of the BCR sequential extraction stages: Cd (82.3% > Mn (80.0% > Zn (78.8% > Cu (70.2% > Ni (65.9% > Pb (63.8% > Cr (47.3% > Co (32.6%. Validation of the analytical results was checked by analysis of the BCR-701 certified reference material. The concentrations of metals in the street dust samples have been shown a decrease after the each extraction stage.

  9. Frequency of the minor BCR-ABL (e1;a2 transcript oncogene in a Mexican population with adult acute lymphoblastic leukaemia

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    I. Olarte-Carrillo

    2015-07-01

    Conclusion: Prevalence of BCR-ABL expression by RT-PCR has not previously been reported in Mexico. Our laboratory found a higher prevalence than that reported in Latin-American series, but lower than that reported for the European population.

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

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    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.

  11. 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...

  12. 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...

  13. 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

  14. 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)

  15. BCR-ABL transcripts are early predictors for hematological relapse in chronic myeloid leukemia after hematopoietic cell transplantation with reduced intensity conditioning

    NARCIS (Netherlands)

    Lange, T; Deininger, M; Brand, R; Hegenbart, U; Al-Ali, H; Krahl, R; Poenisch, W; Uharek, L; Leiblein, S; Gentilini, C; Petersdorf, E; Storb, RF; Niederwieser, D

    Kinetics of BCR-ABL transcript elimination and its prognostic implications on relapse were analyzed in patients with chronic myeloid leukemia (CML) after reduced intensity hematopoietic cell transplantation (HCT). In all, 19 CML patients were conditioned with 2Gy total-body irradiation in

  16. 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

  17. [Construction of Eukaryotic Expression Vector of siRNA Specific for BCR/ABL Fusion Gene and Its Effects on K562 Cells].

    Science.gov (United States)

    Li, Ming; Wang, Bao-Lin; Wang, Li-Na; Xi, Ya-Ming

    2016-12-01

    To construct eukaryotic expression vector of siRNA specific for BCR/ABL and to investigate the effect of recombinant plasmid on BCR/ABL and P210 protein expression in K562 cells. siRNA(small interfering RNA)was designed according to the Tuschl's principle of Ai-based medicine, and was converted into cDNA coding expression of shRNA(small hairpin RNAs)of siRNA for BCR/ABL fusion gene. The cDNA was synthesized and inserted into plasmid pTER. The pTER117 and pTER363 of recombinant plasmid being eukaryotic expression vector was controlled by the H1 promoter of RNA polymerase III, and identified by the restriction map and the sequence analysis. The recombinant plasmid did not only have the screening resisting antibiotics, its expression but also are induced by tetracycline (tet). After steadily transfection into K562 cells by Lipofectamine, their positive mono-cell clones being resistant to Zeocin were isolated. TaqMan real-time quantitative RT-PCR (RQ-PCR) and Western blot respectively detected expression of BCR/ABL mRNA and P210 protein. Trypaum blue dying was used to analyze the proliferation of K562 cells. Cell apoptosis was observed by flow cytometer. the recombinant plasmid was steadily transfected into K562 cells by Lipofectamine 2000, Their positive mono-cell clones being resistant to Zeocin were isolated. The proliferation of K562 cells were remarkably inhibited by the recombinant plasmid induced gene expression by tetracycline. Tetracycline induced its expression for 48 h and 72 h. pTER117, pTER363 decreased the mRNA level of BCR/ABL 90%, 82% and 91.5%, 84%, respectively, P210 protein were almost measured in K562 cells. FCM analysis showed that the recombinant plasmid induced apoptosis in K562 cells, the apoptosis rate were respectively 34.4%, 58.1% in K562 cells treated by pTER117 for 48 h and 72 h, apoptosis rate were 31.8%, 54.6% by pTER363, but the control groups did not show these effects on K562 cells. The siRNA eukaryotic expression vector against BCR

  18. 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

  19. 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

  20. [Construction of genetically modified dendritic cell vaccine expressing bcr/abl fusion gene and inducing specific cytotoxic T lymphocytes to kill K562 cells in vitro].

    Science.gov (United States)

    Wang, Wen-Wen; Huang, Ren-Wei; Hu, Yuan; Li, Xu-Dong; Wang, Dong-Ning; He, Yi; Liu, Jia-Jun

    2009-06-01

    Specific immunological effect mediated by T lymphocytes plays an important role in treating chronic myelocytic leukemia (CML). Dendritic cells (DCs)-based immunotherapy has become popular in treating tumors. This study was to construct DC vaccines by transducing with replication-defective recombinant adenoviruses expressing bcr/abl fusion gene of CML, observe the lethal effects of specific cytotoxic T lymphocytes (CTLs) triggered by genetically modified DC vaccines expressing bcr/abl fusion gene against K562 cells in vitro. DNA fragment of bcr/abl fusion gene was amplified by reverse transcription-polymerase chain reaction (RT-PCR) to construct a recombinant adenovirus vector and produce recombinant adenoviruses. DCs were induced from peripheral blood monocytes in vitro, and transfected with recombinant adenoviruses or pulsed with peptide to induce specific CTLs. The lethal effect of CTLs against leukemic K562 cells in vitro was observed. We successfully constructed the replication-defective recombinant adenoviral vector expressing bcr/abl fusion gene. The recombinant adenoviruses we produced had a high virus titer of 2.0 x 10(10) pfu/mL. Transfection efficiency of DCs in vitro was 50%-60%. DC vaccines expressing bcr/abl fusion gene were successfully prepared and used to induce specific CTLs. With effector:target cell ratios of 40:1 and 20:1, the killing rates of K562 cells by CTLs were (47.6+/-4.7)% and (47.5+/-1.6)% in genetically modified DCs group, (25.8+/-4.4)% and (24.6+/-6.3)% in peptide-pulsed DCs group, and were (5.7+/-1.3)% and (4.5+/-1.6)% in control DCs group. The differences between every two groups were significant (all Pfusion gene has a stronger contribution than peptide-pulsed DCs in triggering specific CTLs against K562 cells.

  1. Chemometric evaluation for the relation of BCR sequential extraction method and in vitro gastro-intestinal method for the assessment of metal bioavailability in contaminated soils in Turkey.

    Science.gov (United States)

    Karadaş, Cennet; Kara, Derya

    2012-05-01

    A chemometric evaluation has been done to classify metal ions in soils and to determine whether or not the gastric and intestinal phases of a physiologically based extraction test bear any relation to any of the phases of the four-stage Community Bureau of Reference (BCR) extraction protocol. Nine trace analytes (As, Ba, Cd, Cr, Cu, Mn, Ni, Pb and Zn) were determined in extracts obtained from the BCR sequential extraction procedure as well as from in vitro gastro-intestinal experiments. The results showed that high As, Pb, Zn and Cd concentrations were found in these soils. Principal component analysis (PCA) and linear discriminant analysis were used as classification techniques. Stepwise multiple linear regression analysis was applied to the data set to determine how the bioaccessibility of a metal is linked to the operationally defined fractions of metal speciation in soil. This analysis showed that the metal concentrations in the intestinal and gastric extracts are mainly dependent on the concentrations found in BCR phases 1 and 2 for each metal ion except for Cr, which was mainly dependent on the concentrations found in BCR phase 3. From the chemometric technique of correlation analysis, it was concluded that the metals extracted using BCR phases 1 and 2 are more likely to be bioaccessible, i.e. are also extracted by gastric and intestinal digestion solutions. When the correlation and PCA results were interpreted together, it indicated that the bioaccessiblity of Zn, Pb, Mn and Cd were higher than As, Ba, Cr, Ni and Cu for these soils.

  2. PLK1 inhibitors synergistically potentiate HDAC inhibitor lethality in imatinib mesylate-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo.

    Science.gov (United States)

    Dasmahapatra, Girija; Patel, Hiral; Nguyen, Tri; Attkisson, Elisa; Grant, Steven

    2013-01-15

    To determine whether Polo-like kinase 1 (PLK1) inhibitors (e.g., BI2536) and histone deacetylase (HDAC) inhibitors (e.g., vorinostat) interact synergistically in the BCR/ABL(+) leukemia cells sensitive or resistant to imatinib mesylate (IM) in vitro and in vivo. K562 and LAMA84 cells sensitive or resistant to imatinib mesylate and primary CML cells were exposed to BI2536 and vorinostat. Effects on cell viability and signaling pathways were determined using flow cytometry, Western blotting, and gene transfection. K562 and BV173/E255K animal models were used to test in vivo efficacy. Cotreatment with BI2536 and vorinostat synergistically induced cell death in parental or imatinib mesylate-resistant BCR/ABL(+) cells and primary CD34(+) bone marrow cells but was minimally toxic to normal cells. BI2536/vorinostat cotreatment triggered pronounced mitochondrial dysfunction, inhibition of p-BCR/ABL, caspase activation, PARP cleavage, reactive oxygen species (ROS) generation, and DNA damage (manifest by increased expression of γH2A.X, p-ATM, p-ATR), events attenuated by the antioxidant TBAP. PLK1 short hairpin RNA (shRNA) knockdown significantly increased HDACI lethality, whereas HDAC1-3 shRNA knockdown reciprocally increased BI2536-induced apoptosis. Genetic interruption of the DNA damage linker H1.2 partially but significantly reduced PLK1/HDAC inhibitor-mediated cell death, suggesting a functional role for DNA damage in lethality. Finally, BI2536/vorinostat cotreatment dramatically reduced tumor growth in both subcutaneous and systemic BCR/ABL(+) leukemia xenograft models and significantly enhanced animal survival. These findings suggest that concomitant PLK1 and HDAC inhibition is active against imatinib mesylate-sensitive or refractory CML and ALL cells both in vitro and in vivo and that this strategy warrants further evaluation in the setting of BCR/ABL(+) leukemias. ©2012 AACR.

  3. 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.

  4. 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.

  5. BCR-ABL1-positive chronic myeloid leukemia emerging in a patient with secondary myelofibrosis harboring the JAK2-V617F mutation.

    Science.gov (United States)

    Amemiya, Ayae; Ito, Yoshikazu; Ishibashi, Yasunori; Saito, Yuu; Katagiri, Seiichiro; Suguro, Tamiko; Asano, Michiyo; Yoshizawa, Seiichiro; Akahane, Daigo; Tanaka, Yuko; Fujimoto, Hiroaki; Okabe, Seiichi; Gotoh, Moritaka; Tauchi, Tetsuzo; Ohyashiki, Kazuma

    2017-01-01

    A 53-year-old woman with a 27-year history of myeloproliferative neoplasms came to our hospital because of a marked white blood cell count increase and progressive anemia. Clinical examination demonstrated positivity for BCR-ABL1 and JAK2-V617F mutations. She was given a diagnosis of chronic myeloid leukemia. Using the international scale, a molecular response (MR) 4.5 was achieved after treatment with dasatinib, despite the persistence of marked splenomegaly. The pathological findings of myelofibrosis were demonstrated by bone marrow biopsy. After stopping dasatinib administration for 4 years and 5 months, treatment with ruxolitinib was started. Five months later, the size of her spleen was reduced. We speculated that translocation of BCR-ABL1 might have occurred in a sub-clone of the JAK2-V617F mutated tumor clone.

  6. A novel BCR-ABL transcript e2a2 in a chronic myelogenous leukaemia patient with a duplicated Ph-chromosome and monosomy 7.

    Science.gov (United States)

    Leibundgut, E O; Jotterand, M; Rigamonti, V; Parlier, V; Mühlematter, D; Tobler, A; Solenthaler, M

    1999-09-01

    A novel BCR-ABL transcript was detected by multiplex RT-PCR in a patient with Philadelphia chromosome (Ph) positive chronic myelogenous leukaemia (CML) in accelerated phase. Sequencing of the aberrant transcript revealed an in-frame e2a2 fusion that included a 9 basepairs insertion. Cytogenetic analysis showed t(9;22), an additional Ph chromosome and monosomy 7. The clinical course was dismal: therapy was poorly tolerated, and the patient died in blast crisis 10 months after diagnosis. These data support the association of additional Ph and monosomy 7 with poor prognosis and suggest that the novel e2a2 BCR-ABL transcript may be related to an aggressive clinical course.

  7. Philadelphia-positive acute lymphoblastic leukemia patients already harbor BCR-ABL kinase domain mutations at low levels at the time of diagnosis

    Science.gov (United States)

    Soverini, Simona; Vitale, Antonella; Poerio, Angela; Gnani, Alessandra; Colarossi, Sabrina; Iacobucci, Ilaria; Cimino, Giuseppe; Elia, Loredana; Lonetti, Annalisa; Vignetti, Marco; Paolini, Stefania; Meloni, Giovanna; di Maio, Valeria; Papayannidis, Cristina; Amabile, Marilina; Guarini, Anna; Baccarani, Michele; Martinelli, Giovanni; Foà, Robin

    2011-01-01

    Background In patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point mutations in the BCR-ABL kinase domain. We aimed to assess: (i) in how many patients BCR-ABL kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy. Design and Methods We retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphia-positive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample. Results Mutations at relatively low levels (2–4 clones out of 200) could be detected in all patients – eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib. Conclusions Our results suggest that the BCR-ABL kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors. PMID:21193419

  8. A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Seymour, J F; Kim, D W; Rubin, E

    2014-01-01

    leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m(2)/h, 32 mg/m(2)/h or 24 mg/m(2)/h. Fifty...

  9. 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)

  10. 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.

  11. 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)

  12. UV Differentially Induces Oxidative Stress, DNA Damage and Apoptosis in BCR-ABL1-Positive Cells Sensitive and Resistant to Imatinib

    Science.gov (United States)

    Synowiec, Ewelina; Hoser, Grazyna; Wojcik, Katarzyna; Pawlowska, Elzbieta; Skorski, Tomasz; Błasiak, Janusz

    2015-01-01

    Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, we investigated the extent of oxidative stress, DNA damage, apoptosis and expression of apoptosis-related genes in BCR-ABL1 cells sensitive and resistant to imatinib. The resistance resulted either from the Y253H mutation in the BCR-ABL1 gene or incubation in increasing concentrations of imatinib (AR). UV irradiation at a dose rate of 0.12 J/(m2·s) induced more DNA damage detected by the T4 pyrimidine dimers glycosylase and hOGG1, recognizing oxidative modifications to DNA bases in imatinib-resistant than -sensitive cells. The resistant cells displayed also higher susceptibility to UV-induced apoptosis. These cells had lower native mitochondrial membrane potential than imatinib-sensitive cells, but UV-irradiation reversed that relationship. We observed a significant lowering of the expression of the succinate dehydrogenase (SDHB) gene, encoding a component of the complex II of the mitochondrial respiratory chain, which is involved in apoptosis sensing. Although detailed mechanism of imatinib resistance in AR cells in unknown, we detected the presence of the Y253H mutation in a fraction of these cells. In conclusion, imatinib-resistant cells may display a different extent of genome instability than their imatinib-sensitive counterparts, which may follow their different reactions to both endogenous and exogenous DNA-damaging factors, including DNA repair and apoptosis. PMID:26251899

  13. Frequency and clinical impact of ETV6/RUNX1, AF4-MLL, and BCR/ABL fusion genes on features of acute lymphoblastic leukemia at presentation.

    Science.gov (United States)

    Ajuba, I C; Madu, A J; Okocha, C; Ibegbulam, O G; Okpala, I; Nna, O E

    2016-01-01

    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 at assessing the relationship between these translocations and the presence of other indicators of disease severity (white cell count, hemoglobin concentration, platelet count, and hematocrit) in ALL. Forty chemotherapy naïve patients aged between 9 months and 54 years had their marrow samples analyzed for the prevalent mutations. Their clinical and laboratory details on presentation were also obtained. Abnormal genes detected were BCR/ABL1 major transcript in 5 (12.5%), ETV6/RUNX1 in 2 (5.0%), MLL/AF4 none and none of the patients had more than one fusion gene. There was no relationship between the presence of these fusion genes and the clinical and laboratory features of ALL. An association exists between the fusion genes and ethnic origin of the patients (P = 0.005). There is no significant association between the abnormal fusion genes detected and some laboratory features of prognostic importance, which include total white blood cell count (P = 0.416) and FAB subtype (P = 0.576). Presence of fusion the genes BCR/ABL1, ETV6/RUNX1, and MLL/AF4 does not have any impact on the clinical and laboratory features of ALL at presentation.

  14. 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

  15. 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.

  16. BCR-ABL, ETV6-RUNX1 and E2A-PBX1: prevalence of the most common acute lymphoblastic leukemia fusion genes in Mexican patients.

    Science.gov (United States)

    Jiménez-Morales, S; Miranda-Peralta, E; Saldaña-Alvarez, Y; Perez-Vera, P; Paredes-Aguilera, R; Rivera-Luna, R; Velázquez-Cruz, R; Ramírez-Bello, J; Carnevale, A; Orozco, L

    2008-10-01

    This study was conducted to determine the frequency of the most common fusion genes in Mexican pediatric patients with acute lymphoblastic leukemia (ALL). Molecular analysis using RT-PCR was carried out in 53-blood samples: 52 patients with de novo ALL and one with relapsed ALL. The ETV6-RUNX1 fusion was found in 7 cases (13.5%), BCR-ABL fusion was detected in 2 cases (3.8%), and 6 patients (11.5%) expressed the chimeric gene E2A-PBX1. The prevalence of E2A-PBX1 is one of the highest that has been described thus far in childhood ALL. Furthermore, we detected both the BCR-ABL, and E2A-PBX1 fusion in the relapsed patient. With regards to the immunophenotype, ETV6-RUNX1 was expressed in both pre-B and T-cell cases, while the presence of E2A-PBX1 and BCR-ABL was associated with the pre-B ALL phenotype. The prevalence of E2A-PBX1 in Mexican pediatric cases supports the existence of ethnic differences in the frequency of molecular markers of ALL.

  17. 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.

  18. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Pueyo, M.; Mateu, J.; Rigol, A.; Vidal, M. [Departament de Quimica Analitica, Universitat de Barcelona, Marti i Franques 1-11, E-08028 Barcelona (Spain); Lopez-Sanchez, J.F. [Departament de Quimica Analitica, Universitat de Barcelona, Marti i Franques 1-11, E-08028 Barcelona (Spain)], E-mail: fermin.lopez@ub.edu; Rauret, G. [Departament de Quimica Analitica, Universitat de Barcelona, Marti i Franques 1-11, E-08028 Barcelona (Spain)

    2008-03-15

    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. Design and analytic validation of BCR-ABL1 quantitative reverse transcription polymerase chain reaction assay for monitoring minimal residual disease.

    Science.gov (United States)

    Jennings, Lawrence J; Smith, Frederick A; Halling, Kevin C; Persons, Diane L; Kamel-Reid, Suzanne

    2012-01-01

    Monitoring minimal residual disease by quantitative reverse transcription polymerase chain reaction has proven clinically useful, but as yet there are no Food and Drug Administration-approved tests. Guidelines have been published that provide important information on validation of such tests; however, no practical examples have previously been published. To provide an example of the design and validation of a quantitative reverse transcription polymerase chain reaction test. To describe the approach used by an individual laboratory for development and validation of a laboratory-developed quantitative reverse transcription polymerase chain reaction test for BCR-ABL1 fusion transcripts. Elements of design and analytic validation of a laboratory-developed quantitative molecular test are discussed using quantitative detection of BCR-ABL1 fusion transcripts as an example. Validation of laboratory-developed quantitative molecular tests requires careful planning and execution to adequately address all required analytic performance parameters. How these are addressed depends on the potential for technical errors and confidence required for a given test result. We demonstrate how one laboratory validated and clinically implemented a quantitative BCR-ABL1 assay that can be used for the management of patients with chronic myelogenous leukemia.

  1. PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation.

    Science.gov (United States)

    Mian, A A; Rafiei, A; Haberbosch, I; Zeifman, A; Titov, I; Stroylov, V; Metodieva, A; Stroganov, O; Novikov, F; Brill, B; Chilov, G; Hoelzer, D; Ottmann, O G; Ruthardt, M

    2015-05-01

    Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.

  2. Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations.

    Science.gov (United States)

    Naqvi, Kiran; Cortes, Jorge E; Luthra, Raja; O'Brien, Susan; Wierda, William; Borthakur, Gautam; Kadia, Tapan; Garcia-Manero, Guillermo; Ravandi, Farhad; Rios, Mary Beth; Dellasala, Sara; Pierce, Sherry; Jabbour, Elias; Patel, Keyur; Kantarjian, Hagop

    2018-02-20

    Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR-ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP). 9/14 CP patients responded to treatment (best response complete hematologic response-CHR-4; complete cytogenetic response-CCyR-1; major molecular response-MMR-4); only 4/12 AP patients (CHR 3; MMR 1) and 7/22 BP patients responded (CCyR 2; MMR 2; partial cytogenetic response-PCyR-3). After a median follow-up of 65 months from mutation detection, 36 patients (75%) died: 9/14 (64%) in CP, 9/12 (75%) in AP, and 18/22 (82%) in BP (p = 0.003); median overall survival was 12 months. Patients with E255K/V mutation have a poor prognosis, regardless of the stage of the disease at detection.

  3. Dehydrocostus Lactone Suppresses Proliferation of Human Chronic Myeloid Leukemia Cells Through Bcr/Abl-JAK/STAT Signaling Pathways.

    Science.gov (United States)

    Cai, Hong; Qin, Xiaosong; Yang, Chunhui

    2017-10-01

    This study evaluates the anticancer effects of dehydrocostus lactone, a plant-derived sesquiterpene lactone, on human chronic myeloid leukemia cells. Dehydrocostus lactone significantly inhibits cell proliferation by inducing cells to undergo cell cycle arrest, apoptosis, and differentiation. Dehydrocostus lactone suppresses the expression of cyclin B1, cyclin A, cyclin E, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 1 (CDK1) and increases p21 expression, resulting in S-G2/M phase arrest in K562 cells. Dehydrocostus lactone also induces apoptosis by increasing the generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (MMP), and modulating the protein levels of Bcl-2 family members. We also found that dehydrocostus lactone significantly inhibits the phosphorylation expression of Bcr/Abl, STAT5, JAK2, and STAT3 and downstream molecules including p-CrkL, Mcl-1, Bcl-XL, and Bcl-2 proteins in K562 cells. At a low concentration, dehydrocostus lactone significantly increased CD11b and CD14 expression on the surface of K562 cells, and induced cells to differentiate into monocytes or mature macrophages. Taken together, this study provides new insight into the molecular mechanisms of dehydrocostus lactone actions that may contribute to the chemoprevention of chronic myeloid leukemia. J. Cell. Biochem. 118: 3381-3390, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. 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

  5. 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)

  6. 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

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

    Directory of Open Access Journals (Sweden)

    Axel Weber

    2015-03-01

    Full Text Available 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Increased acetylation of lysine 317/320 of p53 caused by BCR-ABL protects from cytoplasmic translocation of p53 and mitochondria-dependent apoptosis in response to DNA damage

    NARCIS (Netherlands)

    Kusio-Kobialka, Monika; Wolanin, Kamila; Podszywalow-Bartnicka, Paulina; Sikora, Ewa; Skowronek, Krzysztof; McKenna, Sharon L.; Ghizzoni, Massimo; Dekker, Frank J.; Piwocka, Katarzyna

    Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells caused by the expression of BCR-ABL. Loss of p53 has not been implicated as important for the development of CML. Mutations in p53 protein are infrequent, however they correlate with the disease progression. The absence of p53

  14. 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.

  15. 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

  16. 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

  17. Which method better evaluates the molecular response in newly diagnosed chronic phase chronic myeloid leukemia patients with imatinib treatment, BCR-ABL(IS) or log reduction from the baseline level?

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    Qin, Ya-Zhen; Jiang, Qian; Jiang, Hao; Li, Jin-Lan; Li, Ling-Di; Zhu, Hong-Hu; Lai, Yue-Yun; Lu, Xi-Jing; Liu, Yan-Rong; Jiang, Bin; Huang, Xiao-Jun

    2013-09-01

    The molecular response of chronic myeloid leukemia (CML) patients to tyrosine kinase inhibitor treatment can be evaluated either by BCR-ABL mRNA levels on international scale (IS) or by log reduction from the baseline level of the laboratory. Both methods were compared in 248 newly diagnosed chronic phase CML patients treated with imatinib. The major molecular responses (MMR) obtained by both methods predict progression-free survival (PFS, all Plog reduction method, had the same PFS as MMR patients identified by both methods. The molecular responses of patients at 3 and 6 months, as evaluated by the two methods, have similar predictive values on their cytogenetic responses at 12 months and on their molecular responses at 18 months. Both ≤ 10%(IS) and ≥ 1 log reduction at 3 months and ≤ 1%(IS) at 6 months were significantly associated with PFS (P=0.0011, 0.0090, and 0.0064). The percentages of patients with BCR-ABL(IS) of ≤ 1%, >1-10%, and of >10% at 3 months and 6 months in the German CML Study IV were similar with those with corresponding BCR-ABL(IS) in our center, but was significantly different with those evaluated by the log reduction method. Therefore, the molecular response evaluated by BCR-ABL(IS) has similar trends in PFS and in response prediction, but can better differentiate patients than that by the log reduction method. Furthermore, the IS method allows comparison among molecular response results from different laboratories. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  18. 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.

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    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.

  19. 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.

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    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.

  20. Expression of BCR-ABL, E2A-PBX1, and MLL-AF4 fusion transcripts in newly diagnosed children with acute lymphoblastic leukemia: a Children's Cancer Group initiative.

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    Gaynon, P S; Crotty, M L; Sather, H N; Bostrom, B C; Nachman, J B; Steinherz, P G; Heerema, N A; Sarquis, M; Tuel-Ahlgren, L; Uckun, F M

    1997-06-01

    We used reverse transcriptase polymerase chain reaction (RT-PCR) assays to examine primary leukemic cells in on-study diagnostic bone marrow specimens from 642 children with newly diagnosed acute lymphoblastic leukemia (ALL) for the expression of MLL-AF4, E2A-PBX1, and BCR-ABL fusion transcripts. All PCR assays were performed centrally in the Children's Cancer Group ALL Biology Reference Laboratory. MLL-AF4 transcript was found in only 0.7% of the study population which excluded infants. E2A-PBX1 transcript was found in 2.5% of the study population and 3.3% of B-precursor cases. Expression was associated with massive hepatomegaly. BCR-ABL transcript was found in 2.3% of cases and correlated with older age, induction failure, and inferior event-free survival (EFS). RT-PCR assays allow rapid identification of patients with MLL-AF4 and BCR-ABL positive ALL. These patients have a poor outcome with contemporary therapy and rapid identification facilitates timely allocation to innovative treatment programs.

  1. Establishment and characterization of A novel Philadelphia-chromosome positive chronic myeloid leukemia cell line, TCC-S, expressing P210 and P190 BCR/ABL transcripts but missing normal ABL gene.

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    Van, Phan Nguyen Thanh; Xinh, Phan Thi; Kano, Yasuhiko; Tokunaga, Katsushi; Sato, Yuko

    2005-03-01

    A novel Philadelphia-chromosome positive (Ph+) cell line, TCC-S, has been established from a patient with Ph+ chronic myeloid leukemia (CML) in the blastic crisis. TCC-S cells were shown to express both P210 and P190 BCR/ABL transcripts by reverse transcriptase-polymerase chain reaction (PCR), although quantitative-PCR revealed that TCC-S cells mainly expressed P210 BCR/ABL transcript. Karyotype analysis revealed several triploid clones which constantly harbored two der(9)del(9) (p12)t(9;22) (q34;qll)s and two del(9) (q21)s. The der(9)del(9) (p12)t(9;22) (q34;q11) is rarely found in other CML cell lines. Moreover, to the best of our knowledge, del(9) (q21) resulting in missing of a restrict region including normal ABL gene has not been found among CML cell lines previously described. Thus, TCC-S cells with only BCR/ABL gene and no normal ABL gene may be a useful tool for functional study of ABL in Ph+ CML.

  2. Fractionation And Environmental Risk Of Trace Metals In Surface Sediment Of The East China Sea By Modified BCR Sequential Extraction Method

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    Roy Andreas

    2016-05-01

    Full Text Available Geochemical fractionation of Cadmium (Cd, Lead (Pb, Cobalt (Co, Zink (Zn, Iron (Fe and Manganese (Mn in sediment of the East China Sea were determined using four-stages of modified BCR sequential extraction method combination with ICP-MS. The total concentration of trace metals in sediment samples were in the following order: Fe >Mn>Pb> Zn > Co > Cd. Cd is present mainly in acid soluble fraction. Pb and Mn are in the group with presenting of easy reducible fraction and acid soluble fraction. Fe and Co were found in a group with mainly in residual fraction, while Zn was distributed in all four fractions. The highest contamination factors were found for Cd and Mn while the lowest were found for Fe and Co in almost station. The result showed low risk for Fe and Co in all station, Pb (except S2 and S3, Zn at S3,S6 and S7, and Mn at S1. A medium risk is indicated for Pb at S2 and S3, Zn at S1 and S5, and Mn at S2 and S6. A high risk showed for Zn at S2 and S4, and Mn at S4 and S5, while Cd at almost station (except S4 was very high risk.

  3. 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.

  4. Acute WT1-positive promyelocytic leukemia with hypogranular variant morphology, bcr-3 isoform of PML-RARα and Flt3-ITD mutation: a rare case report

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    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.

  5. Mouse embryonic stem cells that express a NUP98-HOXD13 fusion protein are impaired in their ability to differentiate and can be complemented by BCR-ABL.

    Science.gov (United States)

    Slape, Christopher; Chung, Yang Jo; Soloway, Paul D.; Tessarollo, Lino; Aplan, Peter D

    2007-01-01

    NUP98-HOXD13 (NHD13) fusions have been identified in patients with myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML) and chronic myeloid leukemia blast crisis (CML-BC). We generated “knock-in” mouse embryonic stem (ES) cells that express a NHD13 fusion gene from the endogenous murine NUP98 promoter, and used an in vitro differentiation system to differentiate the ES cells to haematopoietic colonies. Replating assays demonstrated that the partially differentiated NHD13 ES cells were immortal, and two of these cultures were transferred to liquid culture. These cell lines are partially differentiated immature haematopoietic cells, as determined by morphology, immunophenotype and gene expression profile. Despite these characteristics, they were unable to differentiate when exposed to high concentrations of Epo, G-CSF, or M-CSF. The cell lines are incompletely transformed, as evidenced by their dependence on IL3, and their failure to initiate tumours when injected into immunodeficient mice. We attempted genetic complementation of the NHD13 gene using IL3 independence and tumorigenicity in immunodeficient mice as markers of transformation, and found that BCR-ABL successfully transformed the cell lines. These findings support the hypothesis that expression of a NHD13 fusion gene impairs haematopoietic differentiation, and that these cell lines present a model system to study the nature of this impaired differentiation. PMID:17377591

  6. Treating Philadelphia chromosome/BCR-ABL1 positive patients with Glivec (Imatinib mesylate): 10 years' experience at Patan Hospital, Nepal.

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    Kayastha, Gyan K; Ranjitkar, Nora; Gurung, Radha; Kc, Raj K; Karki, Sanjit; Shrestha, Roshan; Thapa, Raj K; Rajbhandari, Piyush; Poudyal, Buddhi; Acharya, Paras; Roberts, David J; Hayes, Bruce; Zimmerman, Mark; Basnyat, Buddha; Mansfield, Aaron

    2017-06-01

    The Glivec International Patient Assistance Programme makes Glivec (Imatinib mesylate) available to Philadelphia chromosome/BCR-ABL1 positive patients with chronic myeloid leukaemia (CML) in Lower and Middle Income Countries (LMIC). We have established a large cohort of 211 CML patients who are eligible for Imatinib, in Kathmandu, Nepal. Thirty-one patients were lost to follow-up. We report on 180 CML patients with a median age of 38 years (range 9-81). Of these 180 patients, 162 underwent cytogenetic testing and 110 were investigated by reverse transcription polymerase chain reaction. One hundred and thirty-nine of the 180 patients (77·2%) had at least one optimal response. Taken together, our cohort has a 95% overall survival rate and 78% of the patients were still taking Glivec at a median time of 48·8 months (range 3-140 months). The number of patients who actually failed therapy, as defined by the LeukaemiaNet 2013 criteria, was 39 (21·7%). While our cohort has some differences with those in North America or Europe, we have shown Glivec is effective in inducing an optimal response in our patients in Nepal and that it is possible to deliver a clinical service for CML patients using tyrosine kinase inhibitors in resource-poor settings. © 2017 John Wiley & Sons Ltd.

  7. 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.

  8. [Clinical and laboratorial analysis for 15 adult cases of mixed phenotypic acute leukemia with Ph chromosome and/or positive BCR-ABL].

    Science.gov (United States)

    Yan, Ling-Zhi; Chen, Su-Ning; Ping, Na-Na; Wang, Qin-Rong; Liu, Hong; Ding, Zi-Xuan; Zhu, Ming-Qing; Liang, Jian-Ying; Liu, Dan-Dan; Cen, Jian-Nong; Pan, Jin-Lan; Qiu, Hui-Ying; Sun, Ai-Ning; Wu, De-Pei

    2013-10-01

    The purpose of this study was to summary the clinical and laboratorial features in 15 adult cases of mixed phenotypic acute leukemia with Ph chromosome and/or BCR-ABL fusion gene positive (Ph(+)MPAL), 15 adult patients with Ph(+)MPAL were defined by WHO-2008 classification. The clinical characteristics, results of morphology, immunology, cytogenetics and molecular genetic detections and results of follow-up in 15 adult patients with Ph(+)MPAL were analyzed retrospectively. The results showed that 15 patients among 87 cases of MPAL demonstrated Ph(+)MPAL (17.2%; 15/87) (7 males and 8 females), their median age was 51 (range 16-81) year old and median WBC count at diagnosis was 69 (12.7-921)×10(9)/L. Based on FAB criteria, these patients showed different morphologic types, including AML (13.3%; 2/15), ALL (40.0%; 6/15), HAL (46.7%; 7/15). Immunologic analysis indicated that 15 cases of Ph(-)MPAL were all classified as B-lymphoid +myeloid mixed immunophenotype. Except one patient, all expressed CD34 antigen on the surface of leukemia cells with 64.3% strong positive, only Ph (53.3%; 8/15), Ph with additional chromosomal abnormalities (33.3%; 5/15) and normal karyotype (13.3%; 2/15) were cytogenetically identified. BCR-ABL fusion gene transcript positive were detected by multiplex reverse transcription PCR in all cases, with e1a2 subtype (p190) (40.0%; 6/15) and b2a2 or b3a2 (p210) subtype (60.0%; 9/15). Four out of 7 (57.1%) patients were found to have IKZF1 gene deletion, without other common gene mutations. Seven out of 10 cases (70.0%) achieved complete remission (CR) after one cycle of induction chemotherapy. In the induction stage, CR rate seemed higher when tyrosine kinase inhibitors (TKI) were added to chemotherapy (83.3%:50.0%; P = 0.206). Overall survival (OS) in 4 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) was longer than that in 4 patients received chemotherapy alone (P = 0.004). It is concluded that Ph(+)MPAL mainly

  9. 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

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

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    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

  11. Distinct in vivo engraftment and growth patterns of t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL+ human leukemia cells in SCID mice.

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    Waurzyniak, B J; Heerema, N; Sensel, M G; Gaynon, P S; Kraft, P; Sather, H N; Chelstrom, L; Reaman, G H; Uckun, F M

    1998-12-01

    The SCID mouse represents a valuable tool for assessing growth characteristics and drug sensitivity of human leukemic cells. We have examined differences in the engraftment patterns in SCID mice of primary human leukemic cells isolated from children (E2A-PBX1+ or t(9;22)+/BCR-ABL+ acute lymphoblastic leukemia. Leukemic cells from 13/24 t(1;19)+/E2A-PBX1+ patients caused overt leukemia in SCID mice. Macroscopic lesions were evident in 6/13 cases, with multiple sites involved in some mice: hepatomegaly,(3) splenomegaly(4), thymic enlargement; liver tumors(1), kidney tumors(1), abdominal tumors(1). Microscopic lesions in SCID mouse organs were present in all 13 cases and involved the bone marrow, brain, heart, gut, liver, kidney, lung, ovary, pancreas, skeletal muscle, spleen, and thymus. Leukemic cells from 5/20 t(9;22)+/BCR-ABL+ patients caused overt leukemia in SCID mice. Notably, macroscopic lesions (splenomegaly; leukemic bones; hepatic tumors) were observed in only 1 case. In all 5 cases, microscopic lesions were found in the mouse bone marrow. Additional microscopic lesions were restricted to skeletal muscle, spleen, and mesentery (1 case) or thymus (1 case). These findings differ markedly from those of t(1;19)+/E2A-PBX1+ leukemic cells due to the lack of involvement of major organs such as liver, pancreas, kidney, skin, or brain. These data illustrate the biological heterogeneity of childhood ALL and suggest that the differential risks associated with t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL ALL might arise from unique engraftment and proliferation capabilities of the respective leukemic cell populations.

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

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    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.

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

    Science.gov (United States)

    Wong, Shuit-Mun; Liu, Fu-Hwa; Lee, Yueh-Lun; Huang, Huei-Mei

    2016-01-01

    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.

  14. New mutations detected by denaturing high performance liquid chromatography during screening of exon 6 bcr-abl mutations in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.

    Science.gov (United States)

    Mascarenhas, Cintia C; Cunha, Anderson F; Miranda, Eliana C; Zulli, Roberto; Silveira, Rosana A; Costa, Fernando F; Pagnano, Katia B B; De Souza, Carmino A

    2009-07-01

    Point mutations within the ABL kinase domain are the most frequent mechanism for reactivation of kinase activity of the BCR-ABL gene and have been associated with clinical resistance to tyrosine kinase (TK) inhibitors in patients with CML, conferring a poor prognosis. T315I (Treonine-->Isoleucine) is a mutation in the exon 6 of BCR-ABL gene that makes the protein resistant to kinase inhibitors currently used for treating CML. Denaturing High-performance liquid chromatography (D-HPLC) allows for high throughput mutation screening. In this study, we screened mutations in exon 6 of the BCR-ABL gene in patients presenting failure or sub optimal response according to Leukemia Net criteria and correlated the presence of mutations with clinical outcome. Genomic DNA was extracted from peripheral blood samples from 93 patients with CML (5 intolerant and 88 resistant). The PCR product was analysed by D-HPLC, and the patients samples with abnormal D-HLPC profiles were submitted to automated sequencing, using specific primers. Overall survival (OS) was calculated from the date of mutation analysis, for the whole group and for both groups (mutation versus no mutation). We screened mutations in exon 6 of the BCR-ABL gene in 93 CML TKI - resistant patients. Twenty-three out of 93 samples (25%) showed an abnormal elution profile. Automated sequencing confirmed the presence of a nucleotide change in 19 out of 23 cases: one polymorphism, T315T, seven known point mutations: T315I, F317L, V339L, M351T, E355G and F359V and three novel mutations: C305R, D325D and I360S. OS for the whole group was 80% in a median observation time of 30 months. OS for patients without the mutation was 87% and with the mutation was 56%, in a median observation time of 37 and 10 months, respectively (p < 0.0001, RR = 68). D-HPLC is a practical and sensitive method for routine clinical monitoring for emergence of kinase domain mutations and may be useful for optimising therapy in CML. The screening of

  15. 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

  16. Patients with Philadelphia-positive leukemia with BCR-ABL kinase mutations before allogeneic transplantation predominantly relapse with the same mutation.

    Science.gov (United States)

    Egan, Daniel N; Beppu, Lan; Radich, Jerald P

    2015-01-01

    Despite the successes of tyrosine kinase inhibitors (TKIs) in improving outcomes in patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), allogeneic hematopoietic stem cell transplantation (HSCT) continues to be an important and potentially curative option for selected patients with either disease. After HSCT, TKIs are increasingly being used to treat or prevent disease relapse, and practice patterns suggest that these TKIs are often chosen empirically without regard to pre-HSCT mutation status. We investigated whether ABL kinase domain mutations persist after transplantation and, thus, whether pre-HSCT mutation status should inform the selection of post-HSCT TKIs in these patients. We retrospectively analyzed adults who underwent allogeneic HSCT for CML and Ph + ALL at our institution between 2000 and 2010, and we identified subjects who had detectable BCR-ABL transcripts by polymerase chain reaction (PCR), as well as available RNA for Sanger sequencing of the ABL kinase domain, in both the pre- and post-HSCT settings. In total, 95 CML and 20 Ph + ALL patients with positive PCR transcripts were identified, of which 10 (10.5%) and 4 (20.0%), respectively, were found to have pre-HSCT ABL kinase mutations known to confer TKI resistance. In 9 (64.2%) of these 14 patients, the same kinase mutation was also detectable at an average time of 191 days after HSCT. Seven (50.0%) of the 14 harboring mutations had relapsed/refractory disease by last follow-up, of which, in retrospect, 6 had received a predictably ineffective TKI within the first 100 days after transplantation based on our mutation analysis. These data support the idea that pre-existing mutations in the ABL kinase domain, frequently associated with resistance to TKIs and prevalent in a transplantation population, are persistently detectable in the majority of patients after transplantation. We propose that such resistance patterns should be considered

  17. Frequency of the ETV6-RUNX1, BCR-ABL1, TCF3-PBX1, and MLL-AFF1 fusion genes in Guatemalan pediatric acute lymphoblastic leukemia patients and their ethnic associations.

    Science.gov (United States)

    Carranza, Claudia; Granados, Lilian; Morales, Oneida; Jo, Wendy; Villagran, Swuanny; Tinti, Damaris; Villegas, Mauricio; Antillón, Federico; Torselli, Silvana; Silva, Gabriel

    2013-06-01

    Fusion genes involved in acute lymphoblastic leukemia (ALL) occur mostly due to genetic and environmental factors, and only a limited number of studies have reported any ethnic influence. This study assesses whether an ethnic influence has an effect on the frequency of any of the four fusion genes: BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, and MLL-AFF1 found in ALL. To study this ethnic influence, mononuclear cells were obtained from bone marrow samples from 143 patients with ALL. We performed RNA extraction and reverse transcription, then assessed the quality of the cDNA by amplifying the ABL1 control gene, and finally evaluated the presence of the four transcripts by multiplex polymerase chain reaction. We found 10 patients who had the BCR-ABL1 fusion gene (7%); 3 patients (2%) were TCF3-PBX1 positive; and 6 patients (4.5%) were ETV6-RUNX1 positive. The incidence of this last fusion gene is quite low when compared to the values reported in most countries. The low incidence of the ETV6-RUNX1 fusion gene found in Guatemala matches the incidence rates that have been reported in Spain and Indian Romani. Since it is known that an ethnic resemblance exists among these three populations, as shown by ancestral marker studies, the ALL data suggests an ethnic influence on the occurrence and frequency of this particular fusion gene. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. RT-PCR ANALYSIS OF E2A-PBX1, TEL-AML1, BCR-ABL AND MLL-AF4 FUSION GENE TRANSCRIPTS IN B-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Iuliu-Cristian Ivanov

    2013-11-01

    Full Text Available Acute lymphoblastic leukemia represents a heterogeneous group of hematological malignancies, defined by clonal proliferation of lymphoid cells. Immunophenotyping by flow cytometry and molecular analysis for the detection of genetic anomalies are clinical standard procedures for diagnosis, sub-classification and post-therapeutic evaluation. Samples from 105 patients diagnosed with acute lymphoblastic leukemia were immunophenotyped at diagnosis and were investigated by molecular analysis in order to identify the occurrence of four fusion genes: MLL-AF4, TEL-AML-1, BCR-ABL-p190, E2A-PBX-1. There were no associations found between the immunophenotype and the presence of any fusion genes evaluated. Both methods in combination remain a prerequisite for an improved subclassification of hematological malignancies, therapeutic decision, and evaluation of treatment response.

  19. Three-way principal component analysis as a tool to evaluate the chemical stability of metal bearing residues from wastewater treatment by the ferrite process

    International Nuclear Information System (INIS)

    Pardo, Rafael; Vega, Marisol; Barrado, Enrique; Castrillejo, Yolanda; Sánchez, Isabel

    2013-01-01

    Highlights: • Metal fractionation of residues from the ferrite process was investigated by n-way PCA. • BCR sequential extraction procedure used for metal fractionation. • Tucker3 algorithm originated a coherent two-term trilinear model. • Metal fractionation patterns correlate with magnetic character of solids. -- Abstract: The chemical fractionation patterns of eight metals (Cd, Co, Cu, Cr, Mn, Ni, Pb and Zn) have been determined in 27 metal-bearing residues by using the BCR sequential extraction procedure. The residues were generated as by-products during the optimization of a semi-continuous reactor for metal removal from wastewater based on ferrite synthesis by co-precipitation. The three-dimensional X dataset (samples × metals × fractions) obtained by applying the BCR procedure has been analyzed by multivariate methods: matrix augmentation (MA-PCA) and three-way principal component analysis, 3-PCA (PARAFAC and Tucker3 models). MA-PCA and PARAFAC methods led to two-factor models giving a satisfactory but incomplete picture of the metal fractionation patterns, but the Tucker3 [2,1,2] model allowed to simultaneously describe both the ‘pseudo-total’ (acid-soluble) contents and the chemical fractionation by means of two non-null interactions g 111 and g 212 which explain 53.5% and 18.0% of the total variance, respectively. The A-mode loadings of the g 212 interaction showed the close relationship between the magnetic character of the solid residues, i.e. the crystalline structure, and the chemical fractionation patterns of the metals resulting from the application of the BCR sequential extraction procedure

  20. 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.

  1. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement.

    Science.gov (United States)

    Soverini, Simona; De Benedittis, Caterina; Papayannidis, Cristina; Paolini, Stefania; Venturi, Claudia; Iacobucci, Ilaria; Luppi, Mario; Bresciani, Paola; Salvucci, Marzia; Russo, Domenico; Sica, Simona; Orlandi, Ester; Intermesoli, Tamara; Gozzini, Antonella; Bonifacio, Massimiliano; Rigolin, Gian Matteo; Pane, Fabrizio; Baccarani, Michele; Cavo, Michele; Martinelli, Giovanni

    2014-04-01

    Patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR-ABL kinase domain (KD) mutations. To analyze the changes that second-generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR-ABL KD mutation analyses performed in the authors' laboratory from January 2004 to January 2013. Interrogation of the database retrieved 450 mutation analyses in 272 patients with Ph+ ALL. Prescreening of samples was performed with denaturing high-performance liquid chromatography (D-HPLC), followed by direct sequencing of D-HPLC-positive cases. BCR-ABL KD mutations were detected in 70% of imatinib-resistant patients, with T315I, E255K, and Y253H mutations accounting for 75% of cases. Seventy-eight percent of the patients reported to be resistant to second-generation TKIs after imatinib failure were positive for mutations, and 58% of them had multiple mutations. Analysis of patients relapsing on dasatinib revealed a newly acquired T315I mutation in almost two-thirds of the cases. Direct sequencing detected no mutations at diagnosis, even in patients who relapsed after a few months. Second-generation TKIs ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long-term disease control remains a problem, and the T315I mutation is revealed to be an even more frequent enemy. BCR-ABL KD mutation screening of patients with Ph+ ALL who are receiving imatinib or second-generation TKIs would be a precious ally for timely treatment optimization. In contrast, the clinical usefulness of conventional direct sequencing at diagnosis seems to be very low. American Cancer Society. © 2013 American Cancer Society.

  2. 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.

  3. Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).

    Science.gov (United States)

    Barosi, G; Tefferi, A; Besses, C; Birgegard, G; Cervantes, F; Finazzi, G; Gisslinger, H; Griesshammer, M; Harrison, C; Hehlmann, R; Hermouet, S; Kiladjian, J-J; Kröger, N; Mesa, R; Mc Mullin, M F; Pardanani, A; Passamonti, F; Samuelsson, J; Vannucchi, A M; Reiter, A; Silver, R T; Verstovsek, S; Tognoni, G; Barbui, T

    2015-01-01

    The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

  4. A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Xia, D.Y.; Liu, L.; Hao, M.W.; Liu, Q.; Chen, R.A.; Liang, Y.M.

    2014-01-01

    p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML

  5. A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Xia, D.Y.; Liu, L.; Hao, M.W.; Liu, Q.; Chen, R.A.; Liang, Y.M. [Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi' an (China)

    2014-10-14

    p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.

  6. First Case of Biphenotypic/bilineal (B/myeloid, B/monocytic) Mixed Phenotype Acute Leukemia with t(9;22)(q34;q11.2);BCR-ABL1.

    Science.gov (United States)

    Kim, Hyeong Nyeon; Hur, Mina; Kim, Hanah; Ji, Misuk; Moon, Hee-Won; Yun, Yeo-Min; Lee, Mark Hong

    2016-07-01

    Mixed phenotype acute leukemia (MPAL) includes biphenotypic leukemia, bilineal leukemia, or its combination by the 2008 WHO classification. A few cases of combined biphenotypic/bilineal MPAL have been reported so far; they all had biphenotypic expressions in only one of the two distinct leukemic populations. A 43-year-old female presented with leukocytosis and bicytopenia. Her complete blood counts were: hemoglobin, 6.9 g/dL; white blood cells, 62.8×10(9)/L; and platelets, 83×10(9)/L. Neither lymphadenopathy nor organomegaly was observed. Blasts and promonocytes/monoblasts were increased in her peripheral blood (42%) and bone marrow (60.1%). Flow cytometric analysis revealed two distinct populations of leukemic cells, which expressed CD11c, CD19, and cytoplasmic CD79a in common. Additionally, the first population expressed CD10 and CD117 (B/myeloid), and the second one expressed CD14 and CD20 (B/monocytic). She had a karyotype of 46,XX,inv(9)(p12q13),t(9;22)(q34;q11.2)[20] and BCR/ABL1 rearrangement. To the best of our knowledge, this is the first reported case of biphenotypic/bilineal MPAL with B/myeloid and B/monocytic expressions. © 2016 by the Association of Clinical Scientists, Inc.

  7. Allium Roseum L. Extract Exerts Potent Suppressive Activities on Chronic Myeloid Leukemia K562 Cell Viability Through the Inhibition of BCR-ABL, PI3K/Akt, and ERK1/2Pathways and the Abrogation of VEGF Secretion.

    Science.gov (United States)

    Souid, Soumaya; Najjaa, Hanen; Riahi-Chebbi, Ichrak; Haoues, Meriam; Neffati, Mohamed; Arnault, Ingrid; Auger, Jacques; Karoui, Habib; Essafi, Makram; Essafi-Benkhadir, Khadija

    2017-01-01

    Use of plant extracts, alone or combined to the current chemotherapy as chemosensitizers, has emerged as a promising strategy to overcome tumor drug resistance. Here, we investigated the anticancer activity of Allium roseum L. extracts, a wild edible species in North Africa, on human Chronic Myeloid Leukemia (CML) K562 cells. The dehydrated aqueous extract (DAE) disturbed the cell cycle progression and induced the apoptosis of K562 cells. Chemical analysis of DAE showed a diversity of organosulfur compounds S-alk(en)yl-cysteine sulfoxides (RCSO) and high amount of allicin, suggesting that such molecule may be behind its antitumor effect. DAE was efficient in inhibiting K562 cell viability. DAE inhibitory effect was associated with the dephosphorylation of the BCR-ABL kinase and interfered with ERK 1/2 , Akt, and STAT5 pathways. Furthermore, we found that DAE-induced inactivation of Akt kinase led to the activation of its target FOXO3 transcription factor, enhancing the expression of FOXO3-regulated proapoptotic effectors, Bim and Bax, and cell cycle inhibitor p27. Finally, we found that DAE reduced the secretion of vascular endothelial growth factor. Overall, our data suggest that A. roseum extract has great potential as a nontoxic cheap and effective alternative to conventional chemotherapy.

  8. No influence of BCR-ABL1 transcript types e13a2 and e14a2 on long-term survival: results in 1494 patients with chronic myeloid leukemia treated with imatinib.

    Science.gov (United States)

    Pfirrmann, Markus; Evtimova, Dobromira; Saussele, Susanne; Castagnetti, Fausto; Cervantes, Francisco; Janssen, Jeroen; Hoffmann, Verena S; Gugliotta, Gabriele; Hehlmann, Rüdiger; Hochhaus, Andreas; Hasford, Joerg; Baccarani, Michele

    2017-05-01

    The genomic break on the major breakpoint cluster region of chromosome 22 results in two BCR-ABL1 transcripts of different sizes, e14a2 and e13a2. Favorable survival probabilities of patients with chronic myeloid leukemia (CML) in combination with too small patient samples may yet have obstructed the observation of differences in overall survival of patients according to transcript type. To overcome potential power problems, overall survival (OS) probabilities and probabilities of CML-related death were analyzed in 1494 patients randomized to first-line imatinib treatment. OS probabilities and probabilities of dying of CML were compared using the log-rank or Gray test whichever was appropriate. Both tests were stratified for the EUTOS long-term survival score. Between the groups with a single transcript, neither OS probabilities (stratified log-rank test: p = 0.106) nor probabilities of CML-related death were significantly different (stratified Gray test: p = 0.256). Regarding OS, the Cox hazard ratio (HR) of transcript type e13a2 (n = 565) to type e14a2 (n = 738) was 1.332 (95% CI 0.940-1.887). Considering probabilities of leukemia-related death, the corresponding subdistribution HR resulted in 1.284 (95% CI 0.758-2.176). Outcome did not change if patients with both transcripts (n = 191) were added to the 738 with type e14a2 only. The prognostic association of transcript type and long-term survival outcome was weak and without clinical relevance. However, earlier reported differences in the rate and the depth of molecular response could be relevant for the chance of successfully discontinuing TKI treatment. The effect of transcript type on molecular relapse after discontinuation is unknown, yet.

  9. Assessment of response to imatinib therapy in patients with chronic myeloid leukemia with e13a2 and e14a2 transcripts of BCR/ABL1 gene

    International Nuclear Information System (INIS)

    Dmitrenko, Yi.V.; Fedorenko, V.Yi.; Shlyakhtichenko, T.Yu.; And others

    2015-01-01

    The influence of e13a2 and e14a2 transcripts of BCR/ABL1 gene on the efficiency of imatinib therapy in patients with chronic myeloid leukemia was assessed. We examined 508 patients with the chronic phase of chronic myeloid leukemia without radiation in anamnesis as well as 13 patients with the similar diagnosis and with confirmed presence of radiation exposure due to the Chornobyl Nuclear Power Plant accident. No significant differences in hematologic parameters, rate of additional chromosomal aberrations and variant translocations were observed between patients with e13a2 and e14a2 transcript. The overall survival and progression-free survival rates were not statistically different between two groups with different transcripts. However, the rate of event-free survival was statistically lower for the patients with e13a2 transcript compared to the ones with e14a2 transcript (51 % versus 62.0 %, p = 0.039). The number of primary resistant patients was 40 % regardless of the transcript expressed. A significant prevalence in incidence either of lost complete cytogenetic response or failure of the major molecular response was shown in patients with e13a2 transcript compared to patients with e14a2 transcripts (43.5 % versus 24.8 %, p = 0.015). Imatinib therapy is more effective for CML patients with e14a2 transcript compared to patients with e13a2 transcript expression. The transcript e13a2 can be viewed as a adverse prognostic factor for imatinib therapy of chronic myeloid leukemia

  10. 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

  11. Identification of Qnr and AAC(6')-1b-cr plasmid-mediated fluoroquinolone resistance determinants in multidrug-resistant Enterobacter spp. isolated from extraintestinal infections in companion animals.

    Science.gov (United States)

    Gibson, Justine S; Cobbold, Rowland N; Heisig, Peter; Sidjabat, Hanna E; Kyaw-Tanner, Myat T; Trott, Darren J

    2010-07-14

    Fluoroquinolone resistance is becoming more common in veterinary medicine. Resistance is due to a combination of chromosomal and plasmid-mediated fluoroquinolone resistance (PMQR) mechanisms. The aim of the present study was to screen 17 multidrug-resistant Enterobacter isolates obtained from opportunistic infections in companion animals for chromosomal and plasmid-mediated fluoroquinolone resistance determinants and to determine if they are co-located with other antimicrobial resistance genes including beta-lactamases. Phenotypic tests (biochemical identification, organic solvent tolerance testing) were combined with genotypic analysis (PCR, pulsed field gel electrophoresis, sequencing, plasmid isolation and southern blot hybridization) to characterize the molecular basis for fluoroquinolone resistance. Antimicrobial susceptibility was determined by broth microdilution for fluoroquinolone antimicrobials (enrofloxacin, ciprofloxacin, moxifloxacin, marbofloxacin and pradofloxacin) and by disk diffusion for other antimicrobials. Sixteen isolates were resistant to at least one of the five fluoroquinolones tested. Fourteen isolates possessed PMQR determinants which were identified as qnrA1 (n=3) or qnrB2 (n=11), often in combination with aac(6')-1b-cr (n=6). The PMQR genes were localized to large, transferable MDR plasmids often associated with an extended-spectrum beta-lactamase and quinolone resistance was co-transferred with bla(SHV-12) for 10 of the 14 qnr-positive strains. Three isolates had wild-type topoisomerases, 11 had a single point mutation in gyrA (Ser83Phe or Tyr), and three had two mutations; one in gyrA (Ser83Ile) and one in parC (Ser80Ile). PMQR genes in clinical veterinary Enterobacter isolates are co-located with beta-lactamases and other resistance genes on large transferable plasmids. PMQR genes contribute to fluoroquinolone resistance when combined with topoisomerase mutations and efflux. (c) 2009 Elsevier B.V. All rights reserved.

  12. 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.

  13. 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.

  14. Molecular processes involved in B cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Malouf, Camille; Ottersbach, Katrin

    2018-02-01

    B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1.

  15. 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.

  16. 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

  17. Heavy metals and its chemical speciation in sewage sludge at different stages of processing.

    Science.gov (United States)

    Tytła, Malwina; Widziewicz, Kamila; Zielewicz, Ewa

    2016-01-01

    The analysis of heavy metal concentrations and forms in sewage sludge constitutes an important issue in terms of both health and environmental hazards the metals pose. The total heavy metals concentration enables only the assessment of its contamination. Hence the knowledge of chemical forms is required to determine their environmental mobility and sludge final disposal. Heavy metals speciation was studied by using four-stage sequential extraction BCR (Community Bureau of Reference). This study was aimed at determining the total concentration of selected heavy metals (Zn, Cu, Ni, Pb, Cd, Cr and Hg) and their chemical forms (except for Hg) in sludge collected at different stages of its processing at two municipal Wastewater Treatment Plants in southern Poland. Metals contents in sludge samples were determined by using flame atomic absorption spectrometry (FAAS) and electrothermal atomic absorption spectrometry (ETAAS). This study shows that Zn and Cu appeared to be the most abundant in sludge, while Cd and Hg were in the lowest concentrations. The sewage sludge revealed the domination of immobile fractions over the mobile ones. The oxidizable and residual forms were dominant for all the heavy metals. There was also a significant difference in metals speciation between sludges of different origin which was probably due to differences in wastewater composition and processes occurring in biological stage of wastewater treatment. The results indicate a negligible capability of metals to migrate from sludge into the environment. Our research revealed a significant impact of thickening, stabilization and hygienization on the distribution of heavy metals in sludge and their mobility.

  18. 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

  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...

  20. 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...... 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...... of odor formation and prediction • Details the WATS sewer process model • Highlights the importance of aerobic, anoxic, and anaerobic processes Sewer Processes: Microbial and Chemical Process Engineering of Sewer Networks, Second Edition, provides a basis for up-to-date understanding and modeling of sewer...

  1. 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

  2. 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

  3. 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...... advantages and challenges of agile processes in mobile software and web businesses are identified. The applicability of these agile processes is discussed in re- gards to design educations and product development in the domain of Industrial Design and is briefly seen in relation to the concept of dromology...

  4. 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...

  5. Image processing

    NARCIS (Netherlands)

    van der Heijden, Ferdinand; Spreeuwers, Lieuwe Jan; Blanken, Henk; Vries de, A.P.; Blok, H.E.; Feng, L; Feng, L.

    2007-01-01

    The field of image processing addresses handling and analysis of images for many purposes using a large number of techniques and methods. The applications of image processing range from enhancement of the visibility of cer- tain organs in medical images to object recognition for handling by

  6. 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

  7. 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...

  8. 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.

  9. 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

  10. 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...

  11. 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.

  12. IL-4Rα-Associated Antigen Processing by B Cells Promotes Immunity in Nippostrongylus brasiliensis Infection

    Science.gov (United States)

    Hoving, Jennifer C.; Nieuwenhuizen, Natalie; McSorley, Henry J.; Ndlovu, Hlumani; Bobat, Saeeda; Kimberg, Matti; Kirstein, Frank; Cutler, Anthony J.; DeWals, Benjamin; Cunningham, Adam F.; Brombacher, Frank

    2013-01-01

    In this study, B cell function in protective TH2 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. PMID:24204255

  13. 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

  14. 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...... galvanic industries....

  15. 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.

  16. Image processing

    OpenAIRE

    Rino, Franco

    2014-01-01

    An image segmentation method has a training phase, and a segmentation phase. In the training phase a frame of pixel lated data from a camera is processed using information on camera characteristics to render it camera-independent. The camera independent data are processed using a chosen value of illuminant spectral characteristics to derive reflectivity data of the items in the image. Pixels of high reflectivity are established. Then, using data from the high reflectivity pixels, the actual i...

  17. Image processing

    International Nuclear Information System (INIS)

    Kindler, M.; Radtke, F.; Demel, G.

    1986-01-01

    The book is arranged in seven sections, describing various applications of volumetric analysis using image processing systems, and various methods of diagnostic evaluation of images obtained by gamma scintigraphy, cardic catheterisation, and echocardiography. A dynamic ventricular phantom is explained that has been developed for checking and calibration for safe examination of patient, the phantom allowing extensive simulation of volumetric and hemodynamic conditions of the human heart: One section discusses the program development for image processing, referring to a number of different computer systems. The equipment described includes a small non-expensive PC system, as well as a standardized nuclear medical diagnostic system, and a computer system especially suited to image processing. (orig.) [de

  18. 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....

  19. 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

  20. 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...

  1. 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 and compu......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...

  2. 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...

  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. 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...

  5. 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

  6. 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.

  7. 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...

  8. 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

  9. 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

  10. Arobin process

    Energy Technology Data Exchange (ETDEWEB)

    Welz, H.

    1943-10-22

    The Arobin (Aromatenbenzin = aromatic gasoline) process was developed to operate on highly aromatic residues from various other processes (especially the HF process) for production of aviation gasoline and similar fuels. Those residues generally had boiling points from about 165/sup 0/ to 325/sup 0/C, so they were not included in the gasoline mde by the other processes. The Arobin process was able to split these residues into lower-boiling-point compounds which made up a high-performance gasoline containing 70% to 75% aromatics by volume. In order to accomplish this, it was necessary to choose the proper catalyst, one in which the splitting effect was much more pronounced than the hydrogenating effect. The catalyst which seemed to be most effective was an alkali-free aluminum silicate with small amounts (1%) molybdic acid (MoO/sub 3/) added. (An aluminum oxide catalyst used at about 500/sup 0/C produced even higher percentages of aromatics, but it seemed best suited for production of single pure compounds such as toluene.) The Arobin process was carried out at about 200 atm pressure and 400/sup 0/C, with a ratio of 1:1 for fresh starting material to recycled material and a throughput of 1 kg per liter of catalyst per hour. The overall yield of gasoline distilled up to 165/sup 0/C was 85% to 87%, and the time-yield was 0.43 kg per liter of catalyst per hour; the process used 360 m/sup 3/ hydrogen and 200 Calories of heat per (metric) ton of product gasoline. The Arobin gasoline could be blended with a lower-octane aviation gasoline to produce a blend with 50% aromatics; in this way, one (metric) ton of HF residue could give rise to 1.2 tons of such blended gasoline. The oxide catalyst could generally be regenerated by a heated steam of nitrogen diluted with air, unless damaged by certain nitrogen or oxygen compounds. 1 diagram, 3 tables.

  11. 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)

  12. 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.

  13. Restoration Process

    Science.gov (United States)

    1979-01-01

    In the accompanying photos, a laboratory technician is restoring the once-obliterated serial number of a revolver. The four-photo sequence shows the gradual progression from total invisibility to clear readability. The technician is using a new process developed in an applications engineering project conducted by NASA's Lewis Research Center in conjunction with Chicago State University. Serial numbers and other markings are frequently eliminated from metal objects to prevent tracing ownership of guns, motor vehicles, bicycles, cameras, appliances and jewelry. To restore obliterated numbers, crime laboratory investigators most often employ a chemical etching technique. It is effective, but it may cause metal corrosion and it requires extensive preparatory grinding and polishing. The NASA-Chicago State process is advantageous because it can be applied without variation to any kind of metal, it needs no preparatory work and number recovery can be accomplished without corrosive chemicals; the liquid used is water.

  14. Residue processing

    Energy Technology Data Exchange (ETDEWEB)

    Gieg, W.; Rank, V.

    1942-10-15

    In the first stage of coal hydrogenation, the liquid phase, light and heavy oils were produced; the latter containing the nonliquefied parts of the coal, the coal ash, and the catalyst substances. It was the problem of residue processing to extract from these so-called let-down oils that which could be used as pasting oils for the coal. The object was to obtain a maximum oil extraction and a complete removal of the solids, because of the latter were returned to the process they would needlessly burden the reaction space. Separation of solids in residue processing could be accomplished by filtration, centrifugation, extraction, distillation, or low-temperature carbonization (L.T.C.). Filtration or centrifugation was most suitable since a maximum oil yield could be expected from it, since only a small portion of the let-down oil contained in the filtration or centrifugation residue had to be thermally treated. The most satisfactory centrifuge at this time was the Laval, which delivered liquid centrifuge residue and centrifuge oil continuously. By comparison, the semi-continuous centrifuges delivered plastic residues which were difficult to handle. Various apparatus such as the spiral screw kiln and the ball kiln were used for low-temperature carbonization of centrifuge residues. Both were based on the idea of carbonization in thin layers. Efforts were also being made to produce electrode carbon and briquette binder as by-products of the liquid coal phase.

  15. Curing process

    International Nuclear Information System (INIS)

    Maruyama, Tsutomu; Watanabe, Tadashi.

    1969-01-01

    A process for the rapid curing of an electrophoretically applied coating with either compositions of aqueous dispersion or aqueous coating compositions thereof is provided by irradiating with ionizing radiations. The process comprises the steps of (a) neutralizing an aqueous alkyd resin with a base, in which the alkyd resin contains a conjugated unsaturated fatty acid or oil as one of its constituents, (b) dispersing the neutralized resin in water, (c) applying to an electroconductive material the varnishes of the dispersed composition or the dispersed coating composition, and (d) irradiating the coatings with ionizing radiations so as to harden them. The alkyd resins have an acid value of 30 to 100 and the bases are equivalent to 0.7 to 1.2. the process is suitable for coil coating. In examples, a semi-esterified product of acid value 54 was diluted with 440 parts of ethylene glycol monobutyl ether and 110 parts of butanol. Next, they were neutralized with 87 parts of dimethyl amino ethanol. Thereafter, they were mixed with 1,013 parts of water to produce an aqueous dispersion of alkyd resin varnish at a concentration of 40%. To 325 parts of the varnish were added 1.3 parts of cobalt naphthenate- 60% toluene solution and then 675 parts of water to produce water soluble varnish containing 13% of a nonvolatile substance. The varnish was applied by electrophoresis for 10 seconds. The time required for the irradiation was about 1 second. The total radiation dose was 3 Mrad of electron beams at an acceleration energy of 300 kV and 25 mA of current. (Iwakiri, K.)

  16. 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...

  17. Shared processes

    Directory of Open Access Journals (Sweden)

    María Auxiliadora Gálvez Pérez

    2015-05-01

    Full Text Available AbstractThe comparison between the creative processes in dance and architecture constitute a panorama, which is able to fi gure out reality with different and intense perceptive connotations. It is about a reality where the important thing is the immersion into the spatial-temporal phenomena, the contact of the space of our body and the spatial essence that is outside our skin limits. Under an architectonical point of view, dance would be a key  discipline, a laboratory where it is possible to freely explore the concepts related to the body-space system, consequently it is also a good frame to seek the necessary tools to work with them. One of the most important examples of this laboratory consolidated in the intersection of choreographical, and architectonical processes is the collaboration betweenLawrence Halprin, landscape architect, and Anna Halprin, choreographer. Through the direct experience of the body in space, they will develop notations and creative cycles able to work with the material of this expanded perception of reality. The review of these creative cycles tested mainly in the sixties is nowadays specially appropriated, when diverse branches of philosophy rooted in phenomenology are interested precisely in dance and architecture as key territories. It seems that it is the opportune moment to expand the architectonical tools, which have been implemented till now, following phenomenological concerns.

  18. 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.

  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. 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.

  1. 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.

  2. 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

  3. Image Processing

    Science.gov (United States)

    1993-01-01

    Electronic Imagery, Inc.'s ImageScale Plus software, developed through a Small Business Innovation Research (SBIR) contract with Kennedy Space Flight Center for use on space shuttle Orbiter in 1991, enables astronauts to conduct image processing, prepare electronic still camera images in orbit, display them and downlink images to ground based scientists for evaluation. Electronic Imagery, Inc.'s ImageCount, a spin-off product of ImageScale Plus, is used to count trees in Florida orange groves. Other applications include x-ray and MRI imagery, textile designs and special effects for movies. As of 1/28/98, company could not be located, therefore contact/product information is no longer valid.

  4. 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.

  5. 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

  6. 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

  7. Comparison of the fixation effects of heavy metals by cement rotary kiln co-processing and cement based solidification/stabilization.

    Science.gov (United States)

    Zhang, Junli; Liu, Jianguo; Li, Cheng; Jin, Yiying; Nie, Yongfeng; Li, Jinhui

    2009-06-15

    Cement rotary kiln co-processing of hazardous wastes and cement based solidification/stabilization could both immobilize heavy metals. The different retention mechanisms of the two technologies lead to different fixation effects of heavy metals. The same amount of heavy metal compounds were treated by the two types of fixation technologies. Long-term leaching test (160 days), the maximum availability leaching test (NEN 7341) and a modified three-step sequential extraction procedure, proposed by the Commission of the European Communities Bureau of Reference (BCR) were employed to compare the fixation effects of the two fixation technologies. The leaching concentrations in NEN 7341 and long-term leaching tests were compared with identification standard for hazardous wastes (GB5085.3-1996) and drinking water standard (GB5749-2005). The results indicate that the leaching concentrations of the long-term leaching test and NEN 7341 test were lower than the regulatory limits and the leached ratios were small. Both cement based solidification/stabilization and cement rotary kiln co-processing could effectively fix heavy metals. Calcination in a cement rotary kiln and the following hydration that follows during cement application could fix As, Cd, Pb and Zn more effectively and decrease the release to the environment. Cement solidification/stabilization technology has better effect in immobilizing Cr and Ni. Cr wastes are more fitful to be treated by cement solidification/stabilization.

  8. 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.

  9. The hierarchical process of differentiation of long-lived antibody-secreting cells is dependent on integrated signals derived from antigen and IL-17A.

    Directory of Open Access Journals (Sweden)

    Lidiane Zito Grund

    Full Text Available Switched CD19-positive memory B cells purified from mice with chronic immune response against Thalassophrynenattereri venom proteins were cultured with venom or cytokines. Our results confirm the existence of a hierarchic process of differentiation: activated memory B cells progressively acquire increasing levels of CD138 and decreasing levels of CD45R/B220 to finally arrive at ASC with B220(neg phenotype, which are IgG1-secreting cells. Only Bmem from peritoneal cavity or bone marrow of VTn immunized mice presented the capacity to generate ASC functionally active. IL-17A or IL-21/IL-23/IL-33 improves the ability of venom to induce intracellular IgG of peritoneal derived-ASC. Cognate stimulation with venom and IL-17A is sufficient to down-regulate the expression of CD45R/B220. BAFF-R is up-regulated in splenic or medullar derived-ASC stimulated by venom, CpG or cytokines. Only splenic derived-ASC up-regulate Bcl-2 expression after CpG or the combination of IL-21/IL-23/IL-33 stimulation. Finally, the activation of ASC for IgG1 secretion is triggered by venom proteins in peritoneal cavity and by IL-17A in medullar niche. These results show the importance of the integration of signals downstream of BCR and IL17-A receptors in modulating ASC differentiation, focusing in the microenvironment niche of their generation.

  10. 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.

  11. 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.

  12. 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.

  13. Thinning spatial point processes into Poisson processes

    DEFF Research Database (Denmark)

    Møller, Jesper; Schoenberg, Frederic Paik

    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......, 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...... 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....

  14. Thinning spatial point processes into Poisson processes

    DEFF Research Database (Denmark)

    Møller, Jesper; Schoenberg, Frederic Paik

    2010-01-01

    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...... 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......, 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....

  15. 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....

  16. 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...

  17. 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...

  18. SAR processing using SHARC signal processing systems

    Science.gov (United States)

    Huxtable, Barton D.; Jackson, Christopher R.; Skaron, Steve A.

    1998-09-01

    Synthetic aperture radar (SAR) is uniquely suited to help solve the Search and Rescue problem since it can be utilized either day or night and through both dense fog or thick cloud cover. Other papers in this session, and in this session in 1997, describe the various SAR image processing algorithms that are being developed and evaluated within the Search and Rescue Program. All of these approaches to using SAR data require substantial amounts of digital signal processing: for the SAR image formation, and possibly for the subsequent image processing. In recognition of the demanding processing that will be required for an operational Search and Rescue Data Processing System (SARDPS), NASA/Goddard Space Flight Center and NASA/Stennis Space Center are conducting a technology demonstration utilizing SHARC multi-chip modules from Boeing to perform SAR image formation processing.

  19. Drug Development Process

    Science.gov (United States)

    ... Approvals The Drug Development Process The Drug Development Process Share Tweet Linkedin Pin it More sharing options ... public. More Information More in The Drug Development Process Step 1: Discovery and Development Step 2: Preclinical ...

  20. 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,

  1. 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

    Cancer Research, a biochemist with a research focus on tumor suppressor and cell cycle checkpoint signaling pathways. For more information about...the treatment of cancer. Cell Cycle . 2004;3:779-788. 12. Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone...deacetylase inhibitors for the treatment of cancer. Cell Cycle . 2004;3:779-788. 26. Guo F, Sigua C, Tao J, et al. Cotreatment with histone deacetylase

  2. 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...

  3. 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

  4. 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....

  5. 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

  6. 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

  7. Recursive Markov Process

    OpenAIRE

    Hidaka, Shohei

    2015-01-01

    A Markov process, which is constructed recursively, arises in stochastic games with Markov strategies. In this study, we defined a special class of random processes called the recursive Markov process, which has infinitely many states but can be expressed in a closed form. We derive the characteristic equation which the marginal stationary distribution of an arbitrary recursive Markov process needs to satisfy.

  8. 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.

  9. 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

  10. 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.

  11. 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...

  12. DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma.

    Science.gov (United States)

    Amin, Rada; Mourcin, Frédéric; Uhel, Fabrice; Pangault, Céline; Ruminy, Philippe; Dupré, Loic; Guirriec, Marion; Marchand, Tony; Fest, Thierry; Lamy, Thierry; Tarte, Karin

    2015-10-15

    Follicular lymphoma (FL) results from the accumulation of malignant germinal center (GC) B cells leading to the development of an indolent and largely incurable disease. FL cells remain highly dependent on B-cell receptor (BCR) signaling and on a specific cell microenvironment, including T cells, macrophages, and stromal cells. Importantly, FL BCR is characterized by a selective pressure to retain surface immunoglobulin M (IgM) BCR despite an active class-switch recombination process, and by the introduction, in BCR variable regions, of N-glycosylation acceptor sites harboring unusual high-mannose oligosaccharides. However, the relevance of these 2 FL BCR features for lymphomagenesis remains unclear. In this study, we demonstrated that IgM(+) FL B cells activated a stronger BCR signaling network than IgG(+) FL B cells and normal GC B cells. BCR expression level and phosphatase activity could both contribute to such heterogeneity. Moreover, we underlined that a subset of IgM(+) FL samples, displaying highly mannosylated BCR, efficiently bound dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), which could in turn trigger delayed but long-lasting BCR aggregation and activation. Interestingly, DC-SIGN was found within the FL cell niche in situ. Finally, M2 macrophages induced a DC-SIGN-dependent adhesion of highly mannosylated IgM(+) FL B cells and triggered BCR-associated kinase activation. Interestingly, pharmacologic BCR inhibitors abolished such crosstalk between macrophages and FL B cells. Altogether, our data support an important role for DC-SIGN-expressing infiltrating cells in the biology of FL and suggest that they could represent interesting therapeutic targets. © 2015 by The American Society of Hematology.

  13. 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

  14. 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.

  15. 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...

  16. 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...

  17. Dairy processing, Improving quality

    NARCIS (Netherlands)

    Smit, G.

    2003-01-01

    This book discusses raw milk composition, production and quality, and reviews developments in processing from hygiene and HACCP systems to automation, high-pressure processing and modified atmosphere packaging.

  18. 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...

  19. Towards better process understanding

    DEFF Research Database (Denmark)

    Matero, Sanni Elina; van der Berg, Franciscus Winfried J; Poutiainen, Sami

    2013-01-01

    The manufacturing of tablets involves many unit operations that possess multivariate and complex characteristics. The interactions between the material characteristics and process related variation are presently not comprehensively analyzed due to univariate detection methods. As a consequence......, current best practice to control a typical process is to not allow process-related factors to vary i.e. lock the production parameters. The problem related to the lack of sufficient process understanding is still there: the variation within process and material properties is an intrinsic feature...... and cannot be compensated for with constant process parameters. Instead, a more comprehensive approach based on the use of multivariate tools for investigating processes should be applied. In the pharmaceutical field these methods are referred to as Process Analytical Technology (PAT) tools that aim...

  20. 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....

  1. 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

  2. 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

  3. 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...

  4. Secure Processing Lab

    Data.gov (United States)

    Federal Laboratory Consortium — The Secure Processing Lab is the center of excellence for new and novel processing techniques for the formation, calibration and analysis of radar. In addition, this...

  5. 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.

  6. GREENSCOPE: Sustainable Process Modeling

    Science.gov (United States)

    EPA researchers are responding to environmental problems by incorporating sustainability into process design and evaluation. EPA researchers are also developing a tool that allows users to assess modifications to existing and new chemical processes to determine whether changes in...

  7. 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...

  8. 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, ...

  9. Business Process innovation

    DEFF Research Database (Denmark)

    Møller, Charles; Hansen, Poul Kyvsgaard

    2016-01-01

    Most organizations today are required not only to establish effective business processes but they are required to accommodate for changing business conditions at an increasing rate. Many business processes extend beyond the boundary of the enterprise into the supply chain and the information...... infrastructure therefore is critical. Today nearly every business relies on their Enterprise System (ES) for process integration and the future generations of Enterprise Systems will increasingly be driven by business process models. Consequently process modelling and improvement will become vital for business...... process innovation (BPI) in future organizations. This paper explores the applicability of one particular methodology for Business Process Innovation to deal with the challenge that the LEGO organization is facing with the alignment of their product development process and their supply chain. The paper...

  10. 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

  11. 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

  12. 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...

  13. 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...

  14. 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.

  15. 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

  16. 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...

  17. 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

  18. Advances in Solidification Processing

    Indian Academy of Sciences (India)

    Unknown

    FOREWORD. Solidification phenomena are the heart of most of the product manufacturing processes. ... casting etc. to the latest technologies like crystal growth, near-net shape processing, laser processing, and ... paper is on one of the recent technological innovations in the steel industry, the thin-slab casting machine, to ...

  19. 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.

  20. Nonaqueous processing methods

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. [Inter-session-processes].

    Science.gov (United States)

    Zeeck, Almut; Hartmann, Armin; Orlinsky, David

    2004-06-01

    We do not know much about how patients internalize, remember or use psychotherapeutic experiences between psychotherapy sessions and how they use them for change. What happens with in-session-experiences after a session ("inter-session-process") is of main importance for outcome. The inter-session-process describes the work on psychotherapy between sessions. Although inter-session-processes are a central element connecting psychotherapy process and outcome, they remain a neglected area of research. Previous studies examined individual outpatient settings only. This paper gives an overview over theory, instruments for measurement, previous studies and relevance of inter-session-processes for the field of psychotherapy research.

  2. Auditory processing models

    DEFF Research Database (Denmark)

    Dau, Torsten

    2008-01-01

    The Handbook of Signal Processing in Acoustics will compile the techniques and applications of signal processing as they are used in the many varied areas of Acoustics. The Handbook will emphasize the interdisciplinary nature of signal processing in acoustics. Each Section of the Handbook...... will present topics on signal processing which are important in a specific area of acoustics. These will be of interest to specialists in these areas because they will be presented from their technical perspective, rather than a generic engineering approach to signal processing. Non-specialists, or specialists...

  3. Biomass process handbook

    Energy Technology Data Exchange (ETDEWEB)

    1983-01-01

    Descriptions are given of 42 processes which use biomass to produce chemical products. Marketing and economic background, process description, flow sheets, costs, major equipment, and availability of technology are given for each of the 42 processes. Some of the chemicals discussed are: ethanol, ethylene, acetaldehyde, butanol, butadiene, acetone, citric acid, gluconates, itaconic acid, lactic acid, xanthan gum, sorbitol, starch polymers, fatty acids, fatty alcohols, glycerol, soap, azelaic acid, perlargonic acid, nylon-11, jojoba oil, furfural, furfural alcohol, tetrahydrofuran, cellulose polymers, products from pulping wastes, and methane. Processes include acid hydrolysis, enzymatic hydrolysis, fermentation, distillation, Purox process, and anaerobic digestion.

  4. 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

  5. Evaluation of steelmaking processes

    Energy Technology Data Exchange (ETDEWEB)

    Fruehan, R.J. [Carnegie-Mellon Univ., Pittsburgh, PA (United States)

    1994-01-01

    Objective of the AISI Direct Steelmaking Program is to develop a process for producing steel directly from ore and coal; the process should be less capital intensive, consume less energy, and have higher productivity. A task force was formed to examine available processes: trough, posthearth, IRSID, Electric Arc Furnace, energy optimizing furnace. It is concluded that there is insufficient incentive to replace a working BOF with any of these processes to refine hot metal; however, if new steelmaking capacity is required, IRSID and EOF should be considered. A fully continuous process should not be considered until direct ironmaking and continuous refining are perfected.

  6. 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

  7. 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.

  8. Process innovation laboratory

    DEFF Research Database (Denmark)

    Møller, Charles

    2007-01-01

    will increasingly be driven by business process models. Consequently business process modelling and improvement is becoming a serious challenge. The aim of this paper is to establish a conceptual framework for business process innovation (BPI) in the supply chain based on advanced EIS. The challenge is thus....... 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...

  9. Gas processing handbook

    Energy Technology Data Exchange (ETDEWEB)

    1982-04-01

    Brief details are given of processes including: BGC-Lurgi slagging gasification, COGAS, Exxon catalytic coal gasification, FW-Stoic 2-stage, GI two stage, HYGAS, Koppers-Totzek, Lurgi pressure gasification, Saarberg-Otto, Shell, Texaco, U-Gas, W-D.IGI, Wellman-Galusha, Westinghouse, and Winkler coal gasification processes; the Rectisol process; the Catacarb and the Benfield processes for removing CO/SUB/2, H/SUB/2s and COS from gases produced by the partial oxidation of coal; the selectamine DD, Selexol solvent, and Sulfinol gas cleaning processes; the sulphur-tolerant shift (SSK) process; and the Super-meth process for the production of high-Btu gas from synthesis gas.

  10. Processes and process development in Japan

    Science.gov (United States)

    Noda, T.

    1986-01-01

    The commercialization of solar power generation necessitates the development of low cost manufacturing method of silicon suitable for solar cells. The manufacturing methods of semiconductor grade silicon (SEG-Si) and the development of solar grade silicon (SOG-Si) in foreign countries was investigated. It was concluded that the most efficient method of developing such materials was the hydrogen reduction process of trichlorosilane (TCS), using a fluidized bed reactor. The low cost reduction of polysilicon requires cost reductions of raw materials, energy, labor, and capital. These conditions were carefully reviewed. The overall conclusion was that a development program should be based on the TCS-FBR process and that the experimental program should be conducted in test facilities capable of producing 10 tons of silicon granules per year.

  11. Rumor Processes on and Discrete Renewal Processes

    Science.gov (United States)

    Gallo, Sandro; Garcia, Nancy L.; Junior, Valdivino Vargas; Rodríguez, Pablo M.

    2014-05-01

    We study two rumor processes on , the dynamics of which are related to an SI epidemic model with long range transmission. Both models start with one spreader at site and ignorants at all the other sites of , but differ by the transmission mechanism. In one model, the spreaders transmit the information within a random distance on their right, and in the other the ignorants take the information from a spreader within a random distance on their left. We obtain the probability of survival, information on the distribution of the range of the rumor and limit theorems for the proportion of spreaders. The key step of our proofs is to show that, in each model, the position of the spreaders on can be related to a suitably chosen discrete renewal process.

  12. 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

  13. Thin Film Processes

    CERN Document Server

    Vossen, John L.

    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 several key topics presented in the original volume are updated * Emphasizes practical applications of major thin film deposition and etching processes * Helps readers find the appropriate technology for a particular application

  14. 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.

  15. Technology or Process First?

    DEFF Research Database (Denmark)

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

    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......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...

  16. Spitzer Telemetry Processing System

    Science.gov (United States)

    Stanboli, Alice; Martinez, Elmain M.; McAuley, James M.

    2013-01-01

    The Spitzer Telemetry Processing System (SirtfTlmProc) was designed to address objectives of JPL's Multi-mission Image Processing Lab (MIPL) in processing spacecraft telemetry and distributing the resulting data to the science community. To minimize costs and maximize operability, the software design focused on automated error recovery, performance, and information management. The system processes telemetry from the Spitzer spacecraft and delivers Level 0 products to the Spitzer Science Center. SirtfTlmProc is a unique system with automated error notification and recovery, with a real-time continuous service that can go quiescent after periods of inactivity. The software can process 2 GB of telemetry and deliver Level 0 science products to the end user in four hours. It provides analysis tools so the operator can manage the system and troubleshoot problems. It automates telemetry processing in order to reduce staffing costs.

  17. Process Analytical Chemistry

    OpenAIRE

    Trevisan, Marcello G.; Poppi, Ronei J.

    2006-01-01

    Process Analytical Chemistry (PAC) is an important and growing area in analytical chemistry, that has received little attention in academic centers devoted to the gathering of knowledge and to optimization of chemical processes. PAC is an area devoted to optimization and knowledge acquisition of chemical processes, to reducing costs and wastes and to making an important contribution to sustainable development. The main aim of this review is to present to the Brazilian community the developmen...

  18. Natural Language Processing

    OpenAIRE

    Preeti; BrahmaleenKaurSidhu

    2013-01-01

    Natural language processing (NLP) work began more than sixty years ago; it is a field of computer science and linguistics devoted to creating computer systems that use human (natural) language. Natural Language Processing holds great promise for making computer interfaces that are easier to use for people, since people will be able to talk to the computer in their own language, rather than learn a specialized language of computer commands. Natural Language processing techniques can make possi...

  19. 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.

  20. 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

  1. Polygon mesh processing

    CERN Document Server

    Botsch, Mario; Pauly, Mark; Alliez, Pierre; Levy, Bruno

    2010-01-01

    Geometry processing, or mesh processing, is a fast-growing area of research that uses concepts from applied mathematics, computer science, and engineering to design efficient algorithms for the acquisition, reconstruction, analysis, manipulation, simulation, and transmission of complex 3D models. Applications of geometry processing algorithms already cover a wide range of areas from multimedia, entertainment, and classical computer-aided design, to biomedical computing, reverse engineering, and scientific computing. Over the last several years, triangle meshes have become increasingly popular,

  2. Transnational Learning Processes

    DEFF Research Database (Denmark)

    Nedergaard, Peter

    , 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......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...

  3. Business process trends

    OpenAIRE

    von Rosing, Mark; Polovina, Simon

    2015-01-01

    Business process and business process management (BPM) concepts have matured over the years and new technology, concepts, standards and solutions appear. In this chapter\\ud we will therefore focus on the current and future process trends. We will elaborate on the importance of trends, the maturity of the subject, giving a perspective on what emerging trends, industry trends, mega trends are, what is hyped at the moment, and what has reached a market adoption where it has started to become the...

  4. 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.

  5. 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.

  6. 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)

  7. 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

  8. The Recruitment Process:

    DEFF Research Database (Denmark)

    Holm, Anna

    The aim of this research was to determine whether the introduction of e-recruitment has an impact on the process and underlying tasks, subtasks and activities of recruitment. Three large organizations with well-established e-recruitment practices were included in the study. The three case studies......, which were carried out in Denmark in 2008-2009 using qualitative research methods, revealed changes in the sequence, divisibility and repetitiveness of a number of recruitment tasks and subtasks. The new recruitment process design was identified and presented in the paper. The study concluded...... that the main task of the process shifted from processing applications to communicating with candidates....

  9. 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....

  10. 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...

  11. Living olefin polymerization processes

    Science.gov (United States)

    Schrock, Richard R.; Baumann, Robert

    2003-08-26

    Processes for the living polymerization of olefin monomers with terminal carbon-carbon double bonds are disclosed. The processes employ initiators that include a metal atom and a ligand having two group 15 atoms and a group 16 atom or three group 15 atoms. The ligand is bonded to the metal atom through two anionic or covalent bonds and a dative bond. The initiators are particularly stable under reaction conditions in the absence of olefin monomer. The processes provide polymers having low polydispersities, especially block copolymers having low polydispersities. It is an additional advantage of these processes that, during block copolymer synthesis, a relatively small amount of homopolymer is formed.

  12. 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

  13. 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...

  14. Living olefin polymerization processes

    Science.gov (United States)

    Schrock, Richard R.; Bauman, Robert

    2006-11-14

    Processes for the living polymerization of olefin monomers with terminal carbon-carbon double bonds are disclosed. The processes employ initiators that include a metal atom and a ligand having two group 15 atoms and a group 16 atom or three group 15 atoms. The ligand is bonded to the metal atom through two anionic or covalent bonds and a dative bond. The initiators are particularly stable under reaction conditions in the absence of olefin monomer. The processes provide polymers having low polydispersities, especially block copolymers having low polydispersities. It is an additional advantage of these processes that, during block copolymer synthesis, a relatively small amount of homopolymer is formed.

  15. 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.

  16. Visual processing in migraine

    OpenAIRE

    OHare, Louise; Hibbard, Paul

    2016-01-01

    Background Migraine is a common neurological condition that often involves differences in visual processing. These sensory processing differences provide important information about the underlying causes of the condition, and for the development of treatments. Review of Psychophysical Literature Psychophysical experiments have shown consistent impairments in contrast sensitivity, orientation acuity, and the perception of global form and motion. They have also established ...

  17. Technologies for Optical Processing

    DEFF Research Database (Denmark)

    Stubkjær, Kristian

    2008-01-01

    The article consists of a Powerpoint presentation on technologies for optical processing. The paper concludes that the nonlinear elements based on SOA, fibers and waveguide structures have capabilities of simple processing at data rates of 100-600 Gb/s. Switching powers comparable to electronics...

  18. 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

  19. 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…

  20. 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...

  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. 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

  3. 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

  4. 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

  5. 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…

  6. Image processing mini manual

    Science.gov (United States)

    Matthews, Christine G.; Posenau, Mary-Anne; Leonard, Desiree M.; Avis, Elizabeth L.; Debure, Kelly R.; Stacy, Kathryn; Vonofenheim, Bill

    1992-01-01

    The intent is to provide an introduction to the image processing capabilities available at the Langley Research Center (LaRC) Central Scientific Computing Complex (CSCC). Various image processing software components are described. Information is given concerning the use of these components in the Data Visualization and Animation Laboratory at LaRC.

  7. 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...

  8. How honey is processed

    Science.gov (United States)

    This month's column follows the "How Is It Processed?" theme. Honey has been called "the nectar of the gods" because of its rich histor and contribution to foods. This column will explore the properties of honey as well as how honey is processed - from flower to food....

  9. How cheese is processed

    Science.gov (United States)

    This column continues the theme of "How Is It Processed?" with a focus on cheese. A fun fact is that it takes 10 pounds of milk to make one pound of cheese. Production of cheese is described in this column, as well as the effects of processing on the final properties of this popular food....

  10. 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.

  11. Suppliers solve processing problems

    Science.gov (United States)

    The year's IFT food expo showcased numerous companies and organizations offering solutions to food processing needs and challenges. From small-scale unit operations to commercial-scale equipment lines, exhibitors highlighted both traditional and novel food processing operations fro food product dev...

  12. 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

  13. Process, Product, and Playmaking

    Science.gov (United States)

    Fisher, Maisha T.; Purcell, Susie Spear; May, Rachel

    2009-01-01

    This article examines relationships among process, product, and playmaking in a southeastern playwriting and performance program for teen girls, Playmaking for Girls (PFG). The authors have chosen to focus on tensions between process and product. Such tensions are present in the challenges teachers experience when privileging student-centered…

  14. Positron annihilation processes update

    Science.gov (United States)

    Guessoum, Nidhal; Skibo, Jeffrey G.; Ramaty, Reuven

    1997-01-01

    The present knowledge concerning the positron annihilation processes is reviewed, with emphasis on the data of the cross sections of the various processes of interest in astrophysical applications. Recent results are presented including results on reaction rates and line widths, the validity of which is verified.

  15. 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...

  16. 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.

  17. 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)

  18. Radiation processing in Australia

    International Nuclear Information System (INIS)

    West, G.

    2003-01-01

    Australia is a true pioneer in commercial irradiation processing as the first commercial irradiation processing plant in the world was commissioned in Melbourne in 1959. This talk will briefly discuss the establishment of the process in Australia. Steritech's three irradiation plants will be discussed in detail, especially the different engineering aspects and the effect that those differences have on irradiation performance and flexibility of operation.Steritech's new state of the art 'pallet irradiator' will be featured. The transportation and loading of Cobalt 60 into the plants will be demonstrated, and public opposition, and security issues since September 11th 2001, will be highlighted. The wide variety of products that are routinely processed at Steritechs plants will be revealed including some 'world firsts' for Australia. Finally, the talk will address the future of irradiation processing in Australia including the potential, or otherwise, of the irradiation of food items

  19. 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)

  20. Conceptualizing operations strategy processes

    DEFF Research Database (Denmark)

    Rytter, Niels Gorm; Boer, Harry; Koch, Christian

    2007-01-01

    Purpose - The purpose of this paper is to present insights into operations strategy (OS) in practice. It outlines a conceptualization and model of OS processes and, based on findings from an in-depth and longitudinal case study, contributes to further development of extant OS models and methods......; taking place in five dimensions of change - technical-rational, cultural, political, project management, and facilitation; and typically unfolding as a sequential and parallel, ordered and disordered, planned and emergent as well as top-down and bottom-up process. The proposed OS conceptualization...... outcomes for an OS process in practice, change agents may need to moderate their outcome ambitions, manage process dimensions and agendas in a situational manner, balance inherent process paradoxes, strive at bridging both language and reality, as well as mobilizing key stakeholders, especially middle...

  1. 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...

  2. 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.

  3. 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...

  4. Manufacturing processes 4 forming

    CERN Document Server

    Klocke, Fritz

    2013-01-01

    This book provides essential information on metal forming, utilizing a practical distinction between bulk and sheet metal forming. In the field of bulk forming, it examines processes of cold, warm and hot bulk forming, as well as rolling and a new addition, the process of thixoforming. As for the field of sheet metal working, on the one hand it deals with sheet metal forming processes (deep drawing, flange forming, stretch drawing, metal spinning and bending). In terms of special processes, the chapters on internal high-pressure forming and high rate forming have been revised and refined. On the other, the book elucidates and presents the state of the art in sheet metal separation processes (shearing and fineblanking). Furthermore, joining by forming has been added to the new edition as a new chapter describing mechanical methods for joining sheet metals. The new chapter “Basic Principles” addresses both sheet metal and bulk forming, in addition to metal physics, plastomechanics and computational basics; ...

  5. Formed HIP Can Processing

    Energy Technology Data Exchange (ETDEWEB)

    Clarke, Kester Diederik [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-07-27

    The intent of this report is to document a procedure used at LANL for HIP bonding aluminum cladding to U-10Mo fuel foils using a formed HIP can for the Domestic Reactor Conversion program in the NNSA Office of Material, Management and Minimization, and provide some details that may not have been published elsewhere. The HIP process is based on the procedures that have been used to develop the formed HIP can process, including the baseline process developed at Idaho National Laboratory (INL). The HIP bonding cladding process development is summarized in the listed references. Further iterations with Babcock & Wilcox (B&W) to refine the process to meet production and facility requirements is expected.

  6. Beyond the search process

    DEFF Research Database (Denmark)

    Hyldegård, Jette

    2009-01-01

    This paper reports on the findings from a longitudinal case study exploring Kuhlthau's information search process (ISP)-model in a group based academic setting. The research focus is on group members' activities and cognitive and emotional experiences during the task process of writing an assignm......This paper reports on the findings from a longitudinal case study exploring Kuhlthau's information search process (ISP)-model in a group based academic setting. The research focus is on group members' activities and cognitive and emotional experiences during the task process of writing...... seeking, the cognitive pattern associated with focus formulation and the tendency towards an increase in writing activities while searching activities decreased. Differences in behavior were also found, which were associated with contextual and social factors beyond the mere search process...

  7. Improving Healthcare Logistics Processes

    DEFF Research Database (Denmark)

    Feibert, Diana Cordes

    provision whilst providing high quality care. Logistics activities in hospitals provide a significant opportunity for cost containment in healthcare through the implementation of best practices. Literature provides little guidance on how to improve healthcare logistics processes. This study investigates...... 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...... at hospitals in Denmark and the US investigating three different types of processes: bed logistics, hospital cleaning, and pharmaceutical distribution. Based on an analysis and comparison of the case studies, a set of factors were identified influencing the decision on how to improve healthcare logistics...

  8. 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...... 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...... into the process of a logistics innovation in an oriental healthcare supply chain context. The study is, however, still limited in disclosing end-to-end supply chain benefits including concrete performance improvements at the suppliers. Examining logistics innovation processes should result not only...

  9. Euglena Transcript Processing.

    Science.gov (United States)

    McWatters, David C; Russell, Anthony G

    2017-01-01

    RNA transcript processing is an important stage in the gene expression pathway of all organisms and is subject to various mechanisms of control that influence the final levels of gene products. RNA processing involves events such as nuclease-mediated cleavage, removal of intervening sequences referred to as introns and modifications to RNA structure (nucleoside modification and editing). In Euglena, RNA transcript processing was initially examined in chloroplasts because of historical interest in the secondary endosymbiotic origin of this organelle in this organism. More recent efforts to examine mitochondrial genome structure and RNA maturation have been stimulated by the discovery of unusual processing pathways in other Euglenozoans such as kinetoplastids and diplonemids. Eukaryotes containing large genomes are now known to typically contain large collections of introns and regulatory RNAs involved in RNA processing events, and Euglena gracilis in particular has a relatively large genome for a protist. Studies examining the structure of nuclear genes and the mechanisms involved in nuclear RNA processing have revealed that indeed Euglena contains large numbers of introns in the limited set of genes so far examined and also possesses large numbers of specific classes of regulatory and processing RNAs, such as small nucleolar RNAs (snoRNAs). Most interestingly, these studies have also revealed that Euglena possesses novel processing pathways generating highly fragmented cytosolic ribosomal RNAs and subunits and non-conventional intron classes removed by unknown splicing mechanisms. This unexpected diversity in RNA processing pathways emphasizes the importance of identifying the components involved in these processing mechanisms and their evolutionary emergence in Euglena species.

  10. Prognostic significance of BCR-ABL rearrangement in childhood acute lymphoblastic leukemia

    OpenAIRE

    Styczyński, Jan; Jatczak-Gaca, Agnieszka; Matiakowska, Karolina; Bartoszewska-Kubiak, Alicja; Kołtan, Andrzej; Dębski, Robert; Pogorzała, Monika; Skonieczka, Katarzyna; Morgut-Klimkiewicz, Małgorzata; Soszyńska, Krystyna; Wysocki, Mariusz

    2015-01-01

    B a c k g r o u n d. Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy. Presence of adverse risk factors determines risk group stratification in this disease. O b j e c t i v e. The aim of study was the analysis of results of therapy and role of prognostic risk factors in treatment of childhood ALL in kujawsko-pomorskie region in 1995-2010. P a t i e n t s a n d m e t h o d s. During this period, ALL was diagnosed in 223 patients. With respect to time period and the...

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

    African Journals Online (AJOL)

    The disease status of CML patients was categorized according to the European Leukemia Net [10]. RNA extraction procedure,. Peripheral blood samples of study subjects were collected in ethylenediaminetetraacetate (EDTA) tubes. Plasma was separated from blood cells by centrifugation at 1200 x g for 10 minutes. RNA.

  12. 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

  13. 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

  14. 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 ...

  15. 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.

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

    Science.gov (United States)

    2008-02-01

    PA) as a series of tagged image files. All images were then constructed in Adobe Photoshop 6.0 (Adobe, San Jose, CA). Antibodies and Western blot...hereby marked ‘‘ advertisement ’’ in accordance with 18 USC section 1734. © 2007 by The American Society of Hematology 678 BLOOD, 15 JULY 2007 ! VOLUME 110

  17. 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.

  18. 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

  19. 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)

  20. 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.

  1. 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

  2. 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.

    ° 53.03'N 83° 29.21'E BHM 4 19 5 17° 52.42'N 83° 30.04'E VSP 1 12 1 17° 42.01'N 83° 14.26'E Visakhapatnam VSP 2 25 3 17° 41.27'N 83° 20.18'E VSP 3 35 5 17° 38.94'N 83° 19.11'E GVM 1 20 0.5 17° 36.83'N 83° 14.84'E GVM 2 23 1 17° 36.36'N 83...

  3. 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

  4. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.

    Science.gov (United States)

    Boisson, Bertrand; Wang, Yong-Dong; Bosompem, Amma; Ma, Cindy S; Lim, Annick; Kochetkov, Tatiana; Tangye, Stuart G; Casanova, Jean-Laurent; Conley, Mary Ellen

    2013-11-01

    Approximately 90% of patients with isolated agammaglobulinemia and failure of B cell development have mutations in genes required for signaling through the pre–B cell and B cell receptors. The nature of the gene defect in the majority of remaining patients is unknown. We recently identified 4 patients with agammaglobulinemia and markedly decreased numbers of peripheral B cells. The B cells that could be detected had an unusual phenotype characterized by the increased expression of CD19 but the absence of a B cell receptor. Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47. The mutant protein (E555K) was stable in patient-derived EBV-transformed cell lines and cell lines transfected with expression vectors. E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47. Mutant E47 did permit DNA binding by a tissue-specific heterodimeric DNA-binding partner, myogenic differentiation 1 (MYOD). These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia. Further, they indicate that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors.

  5. 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

  6. 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)

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

    African Journals Online (AJOL)

    2015-05-12

    May 12, 2015 ... 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.

  8. 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

  9. Adventures in SAR processing

    Science.gov (United States)

    Fiedler, Ralph; Jansen, Robert

    2000-04-01

    The image formation process associated with coherent imaging sensor is particularly sensitive to and is often corrupted by non-stationary processes. In the case of SAR, non- stationary processes result from motion within the scene, variable radar cross section, multi-path, topographic variations, sensor anomalies, and deficiencies in the image formation processing chain. Conversely, stationary processes result in image signatures that appear literal to the eye, e.g., urban infrastructure, vegetation, and natural terrain. In analyzing SAR signal history two objectives unfold. One is to obtain a well-focused image devoid of distortions and non-literal artifacts. The second objective is the detection and value-added exploitation of the non-stationary signatures. Note that the roles of signal and clutter are reversed for these two objectives. The notion that joint time-frequency (JTF) techniques may prove useful in accomplishing these objectives has spurred limited investigations into the field of coherent radar imaging systems. This paper addresses SAR image formation processing, the complex response function for a point source, and SAR JTF image formation implementations. Each of these topics is described within the context of applying JTF processing to all aspects of SAR image formation and analysis.

  10. 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)

  11. 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...

  12. 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.

  13. Biological process linkage networks.

    Directory of Open Access Journals (Sweden)

    Dikla Dotan-Cohen

    Full Text Available The traditional approach to studying complex biological networks is based on the identification of interactions between internal components of signaling or metabolic pathways. By comparison, little is known about interactions between higher order biological systems, such as biological pathways and processes. We propose a methodology for gleaning patterns of interactions between biological processes by analyzing protein-protein interactions, transcriptional co-expression and genetic interactions. At the heart of the methodology are the concept of Linked Processes and the resultant network of biological processes, the Process Linkage Network (PLN.We construct, catalogue, and analyze different types of PLNs derived from different data sources and different species. When applied to the Gene Ontology, many of the resulting links connect processes that are distant from each other in the hierarchy, even though the connection makes eminent sense biologically. Some others, however, carry an element of surprise and may reflect mechanisms that are unique to the organism under investigation. In this aspect our method complements the link structure between processes inherent in the Gene Ontology, which by its very nature is species-independent. As a practical application of the linkage of processes we demonstrate that it can be effectively used in protein function prediction, having the power to increase both the coverage and the accuracy of predictions, when carefully integrated into prediction methods.Our approach constitutes a promising new direction towards understanding the higher levels of organization of the cell as a system which should help current efforts to re-engineer ontologies and improve our ability to predict which proteins are involved in specific biological processes.

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Staging Collaborative Innovation Processes

    DEFF Research Database (Denmark)

    Pedersen, Signe; Clausen, Christian

    Organisations are currently challenged by demands for increased collaborative innovation internally as well as with external and new entities - e.g. across the value chain. The authors seek to develop new approaches to managing collaborative innovative processes in the context of open innovation...... and public private innovation partnerships. Based on a case study of a collaborative design process in a large electronics company the paper points to the key importance of staging and navigation of collaborative innovation process. Staging and navigation is presented as a combined activity: 1) to translate...

  1. 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

  2. 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...

  3. The image processing handbook

    CERN Document Server

    Russ, John C

    2006-01-01

    Now in its fifth edition, John C. Russ's monumental image processing reference is an even more complete, modern, and hands-on tool than ever before. The Image Processing Handbook, Fifth Edition is fully updated and expanded to reflect the latest developments in the field. Written by an expert with unequalled experience and authority, it offers clear guidance on how to create, select, and use the most appropriate algorithms for a specific application. What's new in the Fifth Edition? ·       A new chapter on the human visual process that explains which visual cues elicit a response from the vie

  4. 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...

  5. 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....

  6. 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

  7. 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

  8. 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

  9. Multiple beam optical processing

    Science.gov (United States)

    Gibbs, Hyatt M.; Peyghambarian, N.; Khitrova, G.; Koch, S.; Kostuk, R.; MacLeod, A.; Wagner, K.; Roude, D.; Warren, M.

    1989-12-01

    The objective of this effort was to develop optical processing technology required to implement high performance signal processing systems. The work concentrated on the evaluation and characterization of GaAs nonlinear etalons and methods of using these etalons in optical processing functions. Experiments included the implementation of a one bit adder using symbolic substitution, a pattern recognizer that can distinguish between simple three spot patterns, an associative memory which can discriminate against two different input objects, and an all optical compare and exchange module which can compare the magnitude of two digital input signals and make an appropriate exchange decision. These experiments, although rudimentary, may be extendable to larger scales upon further development of the optical processing technology.

  10. 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...

  11. 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,...

  12. 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...

  13. 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...

  14. 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

  15. 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...

  16. 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...

  17. 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...

  18. Processing composite materials

    Science.gov (United States)

    Baucom, R. M.

    1982-01-01

    The fabrication of several composite structural articles including DC-10 upper aft rudders, L-1011 vertical fins and composite biomedical appliances are discussed. Innovative composite processing methods are included.

  19. 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...

  20. 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...

  1. 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.

  2. 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....

  3. 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.

  4. Staging Collaborative Innovation Processes

    DEFF Research Database (Denmark)

    Pedersen, Signe; Clausen, Christian

    Organisations are currently challenged by demands for increased collaborative innovation internally as well as with external and new entities - e.g. across the value chain. The authors seek to develop new approaches to managing collaborative innovative processes in the context of open innovation...... and public private innovation partnerships. Based on a case study of a collaborative design process in a large electronics company the paper points to the key importance of staging and navigation of collaborative innovation process. Staging and navigation is presented as a combined activity: 1) to translate...... the diverse matters of concern into a coherent product or service concept, and 2) in the same process move these diverse holders of the matters of concern into a translated actor network which carry or support the concept....

  5. 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)

  6. Product and Process Modelling

    DEFF Research Database (Denmark)

    Cameron, Ian T.; Gani, Rafiqul

    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....... 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...... 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....

  7. Processes and beyond

    CSIR Research Space (South Africa)

    Goncalves, D

    2008-06-01

    Full Text Available of unprecedented or innovative systems and attempts to focus some attention on important social issues relating to how work gets done. A framework of coordination mechanisms is developed. Coordination can be performed using processes, work products, skill...

  8. 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...

  9. Business Model Process Configurations

    DEFF Research Database (Denmark)

    Taran, Yariv; Nielsen, Christian; Thomsen, Peter

    2015-01-01

    strategic preference, as part of their business model innovation activity planned. Practical implications – This paper aimed at strengthening researchers and, particularly, practitioner’s perspectives into the field of business model process configurations. By insuring an [abstracted] alignment between......Purpose – The paper aims: 1) To develop systematically a structural list of various business model process configuration and to group (deductively) these selected configurations in a structured typological categorization list. 2) To facilitate companies in the process of BM innovation......, by developing (inductively) an ontological classification framework, in view of the BM process configurations typology developed. Design/methodology/approach – Given the inconsistencies found in the business model studies (e.g. definitions, configurations, classifications) we adopted the analytical induction...

  10. 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.)

  11. 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.

  12. Interpersonal processes in depression.

    Science.gov (United States)

    Hames, Jennifer L; Hagan, Christopher R; Joiner, Thomas E

    2013-01-01

    Humans have an intrinsic need for social connection; thus, it is crucial to understand depression in an interpersonal context. Interpersonal theories of depression posit that depressed individuals tend to interact with others in a way that elicits rejection, which increases their risk for future depression. In this review, we summarize the interpersonal characteristics, risk factors, and consequences of depression in the context of the relevant theories that address the role of interpersonal processes in the onset, maintenance, and chronicity of depression. Topics reviewed include social skills, behavioral features, communication behaviors, interpersonal feedback seeking, and interpersonal styles as they relate to depression. Treatment implications are discussed in light of the current research on interpersonal processes in depression, and the following future directions are discussed: developing integrative models of depression, improving measurement of interpersonal constructs, examining the association between interpersonal processes in depression and suicide, and tailoring interventions to target interpersonal processes in depression.

  13. Instrumentation for Microwave Processing

    National Research Council Canada - National Science Library

    Lloyd, Isabel

    2000-01-01

    ...) Optical extensometer system to be used as a non-contact optical dilatomer. Includes table to facilitate focusing on sample and computer and software to allow the extensometer to be used for closed loop process control; (c...

  14. 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)

  15. EDITORIAL: Process Tomography

    Science.gov (United States)

    Wang, Mi

    2006-08-01

    Process tomography (PT) refers to a methodology by which the internal characteristics of process vessel reaction or pipeline flows are acquired from measurements on or outside the domain of interest in a non-invasive fashion. As a generic 'tool' PT is extremely useful in improving, for example, the modelling and design of many complex processes, in understanding the dynamic mechanisms of flowing and mixing of colloidal dispersions, and in multiphase flow phenomena, hydraulic transport and process control. Over two decades of research worldwide, PT has become a routine research tool in many research laboratories and is being accepted for process measurement and control in some industrial applications. This is the fourth special feature on process tomography after previous publications in this journal in 1996, 2001 and 2002. In this issue, recent developments in sensors, measurements and algorithms with new features for specific distinctive applications are addressed, such as the high temporal resolutions of 1000 frames/s and beyond obtained by both x-ray and impedance tomography for flow measurement and fast process reaction; interferometric tomography combining the Mach Zehnder interferometer and tomography to utilize the phase difference in propagation for visualization of particular features in a process and new three-dimensional image reconstruction algorithms in process applications. The important aspect of this issue is that it demonstrates current developments focusing on the improvement of performance at the temporal resolution, phase information and 3D algorithms for specific application. Looking back over two decades of research, we can see that the process tomography technique is maturing and its applications in industrial manufacture are being deployed as a result of the determined efforts of researchers worldwide. As Guest Editor of this special feature, I would like to thank my colleagues at the Virtual Centre for Industrial Process Tomography (VCIPT

  16. 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...

  17. Laser Processed Heat Exchangers

    Science.gov (United States)

    Hansen, Scott

    2017-01-01

    The Laser Processed Heat Exchanger project will investigate the use of laser processed surfaces to reduce mass and volume in liquid/liquid heat exchangers as well as the replacement of the harmful and problematic coatings of the Condensing Heat Exchangers (CHX). For this project, two scale unit test articles will be designed, manufactured, and tested. These two units are a high efficiency liquid/liquid HX and a high reliability CHX.

  18. Cauchy cluster process

    DEFF Research Database (Denmark)

    Ghorbani, Mohammad

    2013-01-01

    In this paper we introduce an instance of the well-know Neyman–Scott cluster process model with clusters having a long tail behaviour. In our model the offspring points are distributed around the parent points according to a circular Cauchy distribution. Using a modified Cramér-von Misses test...... statistic and the simulated pointwise envelopes it is shown that this model fits better than the Thomas process to the frequently analyzed long-leaf pine data-set....

  19. 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

  20. Research in Stochastic Processes.

    Science.gov (United States)

    1984-10-01

    description, from the stochastic point of view, of the celebrated Hodgkin - Huxley equations. Ph.D. students under Gopinath Kallianpur Victor Perez-Abreu...optimal filter in the general white noise model is shown to be a Markov process. More precisely, it is shown that Ft( Y ) and rt( y ) - the normalized...and unnormalized conditional distribution (where y is the white noise observation) regards as measure-valued processes either on the quasi- P

  1. 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.)

  2. 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.

  3. Image Processing Software

    Science.gov (United States)

    1992-01-01

    To convert raw data into environmental products, the National Weather Service and other organizations use the Global 9000 image processing system marketed by Global Imaging, Inc. The company's GAE software package is an enhanced version of the TAE, developed by Goddard Space Flight Center to support remote sensing and image processing applications. The system can be operated in three modes and is combined with HP Apollo workstation hardware.

  4. Poststroke neuroplasticity processes

    Directory of Open Access Journals (Sweden)

    I. V. Damulin

    2014-01-01

    Full Text Available The paper considers different aspects of neuroplasticity in patients with stroke. It underlines the dynamism of this process and the ambiguity of involvement of the structures of the contralateral cerebral hemisphere in the restorative process. It considers the periods after onset of stroke and the activation of different brain regions (of both the involved and intact hemisphere in the poststroke period. Particular emphasis is placed on the issues of neurorehabilitation in this category of patients. Delay in rehabilitation measures leads to a worse outcome, the patients must be at hospital longer. It is emphasized that the neurorehabilitaton measures should use strategies aimed at improving plasticity processes at the level of synaptic transmission and neuronal communications. At the same time, of great importance are the processes of structural and functional remodeling of neuronal communications with the involvement of surviving neurons that are located in the peri-infarct area and partially damaged during ischemia. To recover stroke-induced lost motor functions, measures are implemented to modulate the ipsilateral motor cortex, contralateral motor cortex, and sensory afferentation. Remodeling processes, one of the manifestations of neuroplasticity, vary with the size and location of an ischemic focus. The specific features of this process with subcortical and cortical foci are considered. It is stressed that there are genetically determined neurotrophic factors that may enhance remodeling processes in the peri-infarct area, as well as factors that inhibit these processes. The sensory system is noted to have a high potential of compensation, which is appreciably associated with the considerable extent of sensory fibers even at the level of the cerebral cortex.

  5. Personal sale process

    Directory of Open Access Journals (Sweden)

    Gašović Milan

    2002-01-01

    Full Text Available Experience from prior successful sale of many companies from different business activities, tells us that it is necessary to create approach system, flexible to different buyers and environment. The base of this system is a belief that salesmen can stimulate big buyers to make buying decisions, if the selling process is done well. Emphasis is made on practical selling techniques which are used in the whole selling process.

  6. Biomedical signal processing

    CERN Document Server

    Akay, Metin

    1994-01-01

    Sophisticated techniques for signal processing are now available to the biomedical specialist! Written in an easy-to-read, straightforward style, Biomedical Signal Processing presents techniques to eliminate background noise, enhance signal detection, and analyze computer data, making results easy to comprehend and apply. In addition to examining techniques for electrical signal analysis, filtering, and transforms, the author supplies an extensive appendix with several computer programs that demonstrate techniques presented in the text.

  7. 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

  8. Pennsylvania's partnering process

    International Nuclear Information System (INIS)

    Latham, J.W.

    1996-01-01

    Pennsylvania is committed to finding a site for a low-level radioactive waste (LLRW) disposal facility through an innovative voluntary process. The Pennsylvania Department of Environmental Protection (DEP) and Chem-Nuclear Systems, Inc. (CNSI) developed the Community Partnering Plan with extensive public participation. The Community Partnering Plan outlines a voluntary process that empowers municipalities to evaluate the advantages and disadvantages of hosting the facility. DEP and CNSI began developing the Community Partnering Plan in July 1995. Before then, CNSI was using a screening process prescribed by state law and regulations to find a location for the facility. So far, approximately 78 percent of the Commonwealth has been identified as disqualified as a site for the LLRW disposal facility. The siting effort will now focus on identifying volunteer host municipalities in the remaining 22 percent of the state. This combination of technical screening and voluntary consideration makes Pennsylvania's process unique. A volunteered site will have to meet the same tough requirements for protecting people and the environment as a site chosen through the screening process. Protection of public health and safety continues to be the foundation of the state's siting efforts. The Community Partnering Plan offers a window of opportunity. If Pennsylvania does not find volunteer municipalities with suitable sites by the end of 1997, it probably will return to a technical screening process

  9. Process Management Plans

    Directory of Open Access Journals (Sweden)

    Tomasz Miksa

    2014-07-01

    Full Text Available In the era of research infrastructures and big data, sophisticated data management practices are becoming essential building blocks of successful science. Most practices follow a data-centric approach, which does not take into account the processes that created, analysed and presented the data. This fact limits the possibilities for reliable verification of results. Furthermore, it does not guarantee the reuse of research, which is one of the key aspects of credible data-driven science. For that reason, we propose the introduction of the new concept of Process Management Plans, which focus on the identification, description, sharing and preservation of the entire scientific processes. They enable verification and later reuse of result data and processes of scientific experiments. In this paper we describe the structure and explain the novelty of Process Management Plans by showing in what way they complement existing Data Management Plans. We also highlight key differences, major advantages, as well as references to tools and solutions that can facilitate the introduction of Process Management Plans.

  10. 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 by intern......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. Several dosimeter systems like calorimetry, perspex, and radiochromic dye films are being improved and new systems have emerged, e.g. spectrophotometry of dichromate solution for reference...... 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...

  11. Studsvik Processing Facility Update

    Energy Technology Data Exchange (ETDEWEB)

    Mason, J. B.; Oliver, T. W.; Hill, G. M.; Davin, P. F.; Ping, M. R.

    2003-02-25

    Studsvik has completed over four years of operation at its Erwin, TN facility. During this time period Studsvik processed over 3.3 million pounds (1.5 million kgs) of radioactive ion exchange bead resin, powdered filter media, and activated carbon, which comprised a cumulative total activity of 18,852.5 Ci (6.98E+08 MBq). To date, the highest radiation level for an incoming resin container has been 395 R/hr (3.95 Sv/h). The Studsvik Processing Facility (SPF) has the capability to safely and efficiently receive and process a wide variety of solid and liquid Low Level Radioactive Waste (LLRW) streams including: Ion Exchange Resins (IER), activated carbon (charcoal), graphite, oils, solvents, and cleaning solutions with contact radiation levels of up to 400 R/hr (4.0 Sv/h). The licensed and heavily shielded SPF can receive and process liquid and solid LLRWs with high water and/or organic content. This paper provides an overview of the last four years of commercial operations processing radioactive LLRW from commercial nuclear power plants. Process improvements and lessons learned will be discussed.

  12. Continuous Correctness of Business Processes Against Process Interference

    NARCIS (Netherlands)

    van Beest, Nick; Bucur, Doina

    2013-01-01

    In distributed business process support environments, process interference from multiple stakeholders may cause erroneous process outcomes. Existing solutions to detect and correct interference at runtime employ formal verification and the automatic generation of intervention processes at runtime.

  13. Radiation processing of polysaccharides

    International Nuclear Information System (INIS)

    2004-11-01

    Radiation processing is a very convenient tool for imparting desirable effects in polymeric materials and it has been an area of enormous interest in the last few decades. The success of radiation technology for processing of synthetic polymers can be attributed to two reasons namely, their ease of processing in various shapes and sizes, and secondly, most of these polymers undergo crosslinking reaction upon exposure to radiation. In recent years, natural polymers are being looked at with renewed interest because of their unique characteristics, such as inherent biocompatibility, biodegradability and easy availability. Traditionally, the commercial exploitation of natural polymers like carrageenans, alginates or starch etc. has been based, to a large extent, on empirical knowledge. But now, the applications of natural polymers are being sought in knowledge - demanding areas such as pharmacy and biotechnology, which is acting as a locomotive for further scientific research in their structure-function relationship. Selected success stories concerning radiation processed natural polymers and application of their derivatives in the health care products industries and agriculture are reported. This publication will be of interest to individuals at nuclear institutions worldwide that have programmes of R and D and applications in radiation processing technologies. New developments in radiation processing of polymers and other natural raw materials give insight into converting them into useful products for every day life, human health and environmental remediation. The book will also be of interest to other field specialists, readers including managers and decision makers in industry (health care, food and agriculture) helping them to understand the important role of radiation processing technology in polysaccharides

  14. Novel food processing techniques

    Directory of Open Access Journals (Sweden)

    Vesna Lelas

    2006-12-01

    Full Text Available Recently, a lot of investigations have been focused on development of the novel mild food processing techniques with the aim to obtain the high quality food products. It is presumed also that they could substitute some of the traditional processes in the food industry. The investigations are primarily directed to usage of high hydrostatic pressure, ultrasound, tribomechanical micronization, microwaves, pulsed electrical fields. The results of the scientific researches refer to the fact that application of some of these processes in particular food industry can result in lots of benefits. A significant energy savings, shortening of process duration, mild thermal conditions, food products with better sensory characteristics and with higher nutritional values can be achieved. As some of these techniques act also on the molecular level changing the conformation, structure and electrical potential of organic as well as inorganic materials, the improvement of some functional properties of these components may occur. Common characteristics of all of these techniques are treatment at ambient or insignificant higher temperatures and short time of processing (1 to 10 minutes. High hydrostatic pressure applied to various foodstuffs can destroy some microorganisms, successfully modify molecule conformation and consequently improve functional properties of foods. At the same time it acts positively on the food products intend for freezing. Tribomechanical treatment causes micronization of various solid materials that results in nanoparticles and changes in structure and electrical potential of molecules. Therefore, the significant improvement of some rheological and functional properties of materials occurred. Ultrasound treatment proved to be potentially very successful technique of food processing. It can be used as a pretreatment to drying (decreases drying time and improves functional properties of food, as extraction process of various components

  15. Due process traditionalism.

    Science.gov (United States)

    Sunstein, Cass R

    2008-06-01

    In important cases, the Supreme Court has limited the scope of "substantive due process" by reference to tradition, but it has yet to explain why it has done so. Due process traditionalism might be defended in several distinctive ways. The most ambitious defense draws on a set of ideas associated with Edmund Burke and Friedrich Hayek, who suggested that traditions have special credentials by virtue of their acceptance by many minds. But this defense runs into three problems. Those who have participated in a tradition may not have accepted any relevant proposition; they might suffer from a systematic bias; and they might have joined a cascade. An alternative defense sees due process traditionalism as a second-best substitute for two preferable alternatives: a purely procedural approach to the Due Process Clause, and an approach that gives legislatures the benefit of every reasonable doubt. But it is not clear that in these domains, the first-best approaches are especially attractive; and even if they are, the second-best may be an unacceptably crude substitute. The most plausible defense of due process traditionalism operates on rule-consequentialist grounds, with the suggestion that even if traditions are not great, they are often good, and judges do best if they defer to traditions rather than attempting to specify the content of "liberty" on their own. But the rule-consequentialist defense depends on controversial and probably false assumptions about the likely goodness of traditions and the institutional incapacities of judges.

  16. Coal processing plants

    Science.gov (United States)

    Bitterlich, W.; Bohn, T.; Eickhoff, H. G.; Geldmacher, H.; Mengis, W.; Oomatia, H.; Stroppel, K. G.

    1980-08-01

    The efficient design of processing plants which combine various coal based technologies in order to maximize the effectiveness of coal utilization is considered. The technical, economical and ecological virtues which compound plants for coal conversion offer are assayed. Twenty-two typical processes of coal conversion and product refinement are selected and described by a standardized method of characterization. An analysis of product market and a qualitative assessment of plant design support six different compound plant propositions. The incorporation of such coal conversion schemes into future energy supply systems was simulated by model calculations. The analysis shows that byproducts and nonconverted materials from individual processes can be processed in a compound plant in a profitable manner. This leads to an improvement in efficiencies. The product spectrum can be adapted to a certain degree to demand variations. Furthermore, the integration of fluidized bed combustion can provide an efficient method of desulfurization. Compound plants are expected to become economic in the 1990's. A necessary condition to compound technologies is high reliability in the functioning of all individual processes.

  17. Customer Innovation Process Leadership

    DEFF Research Database (Denmark)

    Lindgren, Peter; Jørgensen, Jacob Høj; Goduscheit, René Chester

    2007-01-01

    Innovation leadership has traditionally been focused on leading the companies' product development fast, cost effectively and with an optimal performance driven by technological inventions or by customers´ needs. To improve the efficiency of the product development process focus has been on diffe......Innovation leadership has traditionally been focused on leading the companies' product development fast, cost effectively and with an optimal performance driven by technological inventions or by customers´ needs. To improve the efficiency of the product development process focus has been...... to handle shorter and faster product life cycles. Continuously changing customer needs are pushing companies' competence of continuous innovation to a maximum - but still this seems not to be enough to stay competitive on the global market and reach the goals of growth. This article therefore suggests...... another outlook to future innovation leadership - Customer Innovation Process Leadership - CIP-leadership. CIP-leadership moves the company's innovation process closer to the customer innovation process and discusses how companies can be involved and innovate in customers' future needs and lead...

  18. VLSI signal processing technology

    CERN Document Server

    Swartzlander, Earl

    1994-01-01

    This book is the first in a set of forthcoming books focussed on state-of-the-art development in the VLSI Signal Processing area. It is a response to the tremendous research activities taking place in that field. These activities have been driven by two factors: the dramatic increase in demand for high speed signal processing, especially in consumer elec­ tronics, and the evolving microelectronic technologies. The available technology has always been one of the main factors in determining al­ gorithms, architectures, and design strategies to be followed. With every new technology, signal processing systems go through many changes in concepts, design methods, and implementation. The goal of this book is to introduce the reader to the main features of VLSI Signal Processing and the ongoing developments in this area. The focus of this book is on: • Current developments in Digital Signal Processing (DSP) pro­ cessors and architectures - several examples and case studies of existing DSP chips are discussed in...

  19. 21 CFR 1271.220 - Processing and process controls.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Processing and process controls. 1271.220 Section... process controls. (a) General. If you are an establishment that processes HCT/Ps, you must process each... mixed in a single receptacle) during manufacturing. (c) In-process control and testing. You must ensure...

  20. 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...... consistency with suggested kinetic parameter values of the literature. A large amount of information about the two plants and their performances is obtained from the models, of which the variations of the influent ammonia load, and the autotrophic and heterotrophic biomass activity have particular interest...

  1. Radiation processes in astrophysics

    CERN Document Server

    Tucker, Wallace H

    1975-01-01

    The purpose of this book is twofold: to provide a brief, simple introduction to the theory of radiation and its application in astrophysics and to serve as a reference manual for researchers. The first part of the book consists of a discussion of the basic formulas and concepts that underlie the classical and quantum descriptions of radiation processes. The rest of the book is concerned with applications. The spirit of the discussion is to present simple derivations that will provide some insight into the basic physics involved and then to state the exact results in a form useful for applications. The reader is referred to the original literature and to reviews for rigorous derivations.The wide range of topics covered is illustrated by the following table of contents: Basic Formulas for Classical Radiation Processes; Basic Formulas for Quantum Radiation Processes; Cyclotron and Synchrotron Radiation; Electron Scattering; Bremsstrahlung and Collision Losses; Radiative Recombination; The Photoelectric Effect; a...

  2. The Nursing Process

    Directory of Open Access Journals (Sweden)

    M. Hammond

    1978-09-01

    Full Text Available The essence of the nursing process can be summed up in this quotation by Sir Francis Bacon: “Human knowledge and human powers meet in one; for where the cause is not known the effect cannot be produced.” Arriving at a concise, accurate definition of the nursing process was, for me, an impossible task. It is altogether too vast and too personal a topic to contract down into a niftylooking, we-pay-lip-service-to-it cliché. So what I propose to do is to present my understanding of the nursing process throughout this essay, and then to leave the reader with some overall, general impression of what it all entails.

  3. Laser Processing and Chemistry

    CERN Document Server

    Bäuerle, Dieter

    2011-01-01

    This book gives an overview of the fundamentals and applications of laser-matter interactions, in particular with regard to laser material processing. Special attention is given to laser-induced physical and chemical processes at gas-solid, liquid-solid, and solid-solid interfaces. Starting with the background physics, the book proceeds to examine applications of lasers in “standard” laser machining and laser chemical processing (LCP), including the patterning, coating, and modification of material surfaces. This fourth edition has been enlarged to cover the rapid advances in the understanding of the dynamics of materials under the action of ultrashort laser pulses, and to include a number of new topics, in particular the increasing importance of lasers in various different fields of surface functionalizations and nanotechnology. In two additional chapters, recent developments in biotechnology, medicine, art conservation and restoration are summarized. Graduate students, physicists, chemists, engineers, a...

  4. Quantum independent increment processes

    CERN Document Server

    Franz, Uwe

    2005-01-01

    This volume is the first of two volumes containing the revised and completed notes 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 during the period March 9 – 22, 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 first volume contains the following lectures: "Lévy Processes in Euclidean Spaces and Groups" by David Applebaum, "Locally Compact Quantum Groups" by Johan Kustermans, "Quantum Stochastic Analysis" by J. Martin Lindsay, and "Dilations, Cocycles and Product Systems" by B.V. Rajarama Bhat.

  5. 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...... structured and holistic method of decision making toward nearly zero-energy building renovation. The methodology is evolutive, implementable on a large scale, and allows an optimal integration of nonexpert decision makers. In practice, such a scheme allowed most behavioral barriers to sustainable home....... 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....

  6. Topological signal processing

    CERN Document Server

    Robinson, Michael

    2014-01-01

    Signal processing is the discipline of extracting information from collections of measurements. To be effective, the measurements must be organized and then filtered, detected, or transformed to expose the desired information.  Distortions caused by uncertainty, noise, and clutter degrade the performance of practical signal processing systems. In aggressively uncertain situations, the full truth about an underlying signal cannot be known.  This book develops the theory and practice of signal processing systems for these situations that extract useful, qualitative information using the mathematics of topology -- the study of spaces under continuous transformations.  Since the collection of continuous transformations is large and varied, tools which are topologically-motivated are automatically insensitive to substantial distortion. The target audience comprises practitioners as well as researchers, but the book may also be beneficial for graduate students.

  7. Stochastic processes inference theory

    CERN Document Server

    Rao, Malempati M

    2014-01-01

    This is the revised and enlarged 2nd edition of the authors’ original text, which was intended to be a modest complement to Grenander's fundamental memoir on stochastic processes and related inference theory. The present volume gives a substantial account of regression analysis, both for stochastic processes and measures, and includes recent material on Ridge regression with some unexpected applications, for example in econometrics. The first three chapters can be used for a quarter or semester graduate course on inference on stochastic processes. The remaining chapters provide more advanced material on stochastic analysis suitable for graduate seminars and discussions, leading to dissertation or research work. In general, the book will be of interest to researchers in probability theory, mathematical statistics and electrical and information theory.

  8. Radiation processing of wastewater

    International Nuclear Information System (INIS)

    2007-01-01

    Rapid population growth and increased agricultural and industrial development have led to the generation of large quantities of polluted industrial and municipal wastewaters. The recognition that these polluted waters may pose a serious threat to humans has led technologists to seek cost effective technologies for their treatment. A variety of methods based on biological. chemical. photochemical and electrochemical processes are being explored for decomposing the chemical and biological contaminants present in these wastewaters. Radiation technologists have been investigating the use of high energy radiation for their treatment. The primary advantage of radiation processing over alternatives is that the reactive species are generated in situ during the radiolysis process without the addition of any chemicals. Several pilot scale and a number of industrial scale wastewater treatment plants based on radiation technology are in operation or under construction. The results of practical applications have confirmed that radiation technology can be easily and effectively utilized for treating large quantities ol wastewater

  9. Process planning at Sikorsky

    Science.gov (United States)

    Waldman, H.

    The software program is called Computer Managed Process Planning, (CMPP). This system employs computer technology to speed and simplify process planning of cylindrical parts. It is aimed at the machining of expensive materials requiring tight tolerances and complex manufacturing processes. Thus far, the program has resulted in a 75 percent reduction in manpower and a 70 percent increase in productivity. The software performs four tasks: (1) it manipulates the manufacturing database, accepting input information from a central CAD system or from an interactive display; (2) it finds the dimensioning reference surfaces, clamping surfaces, and locating surfaces for each machining operation; (3) it analyzes dimensions, tolerances, and stock removals in all cuts for each operation to ensure that bluprint specifications can be achieved; and (4) it prints a summary of operations or a routing sheet.

  10. Plasma processing of nanomaterials

    CERN Document Server

    Sankaran, R Mohan

    2014-01-01

    CRC Press author R. Mohan Sankaran is the winner of the 2011 Peter Mark Memorial Award "… for the development of a tandem plasma synthesis method to grow carbon nanotubes with unprecedented control over the nanotube properties and chirality." -2011 AVS Awards Committee"Readers who want to learn about how nanomaterials are processed, using the most recent methods, will benefit greatly from this book. It contains very recent technical details on plasma processing and synthesis methods used by current researchers developing new nano-based materials, with all the major plasma-based processing techniques used today being thoroughly discussed."-John J. Shea, IEEE Electrical Insulation Magazine, May/June 2013, Vol. 29, No. 3.

  11. Quartz resonator processing system

    Science.gov (United States)

    Peters, Roswell D. M.

    1983-01-01

    Disclosed is a single chamber ultra-high vacuum processing system for the oduction of hermetically sealed quartz resonators wherein electrode metallization and sealing are carried out along with cleaning and bake-out without any air exposure between the processing steps. The system includes a common vacuum chamber in which is located a rotatable wheel-like member which is adapted to move a plurality of individual component sets of a flat pack resonator unit past discretely located processing stations in said chamber whereupon electrode deposition takes place followed by the placement of ceramic covers over a frame containing a resonator element and then to a sealing stage where a pair of hydraulic rams including heating elements effect a metallized bonding of the covers to the frame.

  12. WWTP Process Tank Modelling

    DEFF Research Database (Denmark)

    Laursen, Jesper

    solution of the Navier-Stokes equations in a multiphase scheme. After a general introduction to the activated sludge tank as a system, the activated sludge tank model is gradually setup in separate stages. The individual sub-processes that are often occurring in activated sludge tanks are initially......-process models, the last part of the thesis, where the integrated process tank model is tested on three examples of activated sludge systems, is initiated. The three case studies are introduced with an increasing degree of model complexity. All three cases are take basis in Danish municipal wastewater treatment...... plants. The first case study involves the modeling of an activated sludge tank undergoing a special controlling strategy with the intention minimizing the sludge loading on the subsequent secondary settlers during storm events. The applied model is a two-phase model, where the sedimentation of sludge...

  13. Foundations of signal processing

    CERN Document Server

    Vetterli, Martin; Goyal, Vivek K

    2014-01-01

    This comprehensive and engaging textbook introduces the basic principles and techniques of signal processing, from the fundamental ideas of signals and systems theory to real-world applications. Students are introduced to the powerful foundations of modern signal processing, including the basic geometry of Hilbert space, the mathematics of Fourier transforms, and essentials of sampling, interpolation, approximation and compression. The authors discuss real-world issues and hurdles to using these tools, and ways of adapting them to overcome problems of finiteness and localisation, the limitations of uncertainty and computational costs. Standard engineering notation is used throughout, making mathematical examples easy for students to follow, understand and apply. It includes over 150 homework problems and over 180 worked examples, specifically designed to test and expand students' understanding of the fundamentals of signal processing, and is accompanied by extensive online materials designed to aid learning, ...

  14. Total process surveillance: (TOPS)

    International Nuclear Information System (INIS)

    Millar, J.H.P.

    1992-01-01

    A Total Process Surveillance system is under development which can provide, in real-time, additional process information from a limited number of raw measurement signals. This is achieved by using a robust model based observer to generate estimates of the process' internal states. The observer utilises the analytical reduncancy among a diverse range of transducers and can thus accommodate off-normal conditions which lead to transducer loss or damage. The modular hierarchical structure of the system enables the maximum amount of information to be assimilated from the available instrument signals no matter how diverse. This structure also constitutes a data reduction path thus reducing operator cognitive overload from a large number of varying, and possibly contradictory, raw plant signals. (orig.)

  15. NTP comparison process

    Science.gov (United States)

    Corban, Robert

    The systems engineering process for the concept definition phase of the program involves requirements definition, system definition, and consistent concept definition. The requirements definition process involves obtaining a complete understanding of the system requirements based on customer needs, mission scenarios, and nuclear thermal propulsion (NTP) operating characteristics. A system functional analysis is performed to provide a comprehensive traceability and verification of top-level requirements down to detailed system specifications and provides significant insight into the measures of system effectiveness to be utilized in system evaluation. The second key element in the process is the definition of system concepts to meet the requirements. This part of the process involves engine system and reactor contractor teams to develop alternative NTP system concepts that can be evaluated against specific attributes, as well as a reference configuration against which to compare system benefits and merits. Quality function deployment (QFD), as an excellent tool within Total Quality Management (TQM) techniques, can provide the required structure and provide a link to the voice of the customer in establishing critical system qualities and their relationships. The third element of the process is the consistent performance comparison. The comparison process involves validating developed concept data and quantifying system merits through analysis, computer modeling, simulation, and rapid prototyping of the proposed high risk NTP subsystems. The maximum amount possible of quantitative data will be developed and/or validated to be utilized in the QFD evaluation matrix. If upon evaluation of a new concept or its associated subsystems determine to have substantial merit, those features will be incorporated into the reference configuration for subsequent system definition and comparison efforts.

  16. Lasers in Materials Processing

    Science.gov (United States)

    Kukreja, L. M.; Paul, C. P.; Kumar, Atul; Kaul, R.; Ganesh, P.; Rao, B. T.

    Laser is undoubtedly one of the most important inventions of the twentieth century. Today, it is widely deployed for a cornucopia of applications including materials processing. Different lasers such as CO2, Nd:YAG, excimer, copper vapor, diode, fiber lasers, etc., are being used extensively for various materials processing applications like cutting, welding, brazing, surface treatment, peening, and rapid manufacturing by adopting conventional and unconventional routes with unprecedented precision. In view of its potential for providing solution to the emerging problems of the industrial materials processing and manufacturing technologies, a comprehensive program on laser materials processing and allied technologies was initiated at our laboratory. A novel feature-based design and additive manufacturing technologies facilitated the laser rapid manufacturing of complex engineering components with superior performance. This technology is being extended for the fabrication of anatomically shaped prosthetics with internal heterogeneous architectures. Laser peening of spring steels brought significant improvement in its fatigue life. Laser surface treatments resulted in enhanced intergranular corrosion resistance of AISI 316(N) and 304 stainless steel. Parametric dependence of laser welding of dissimilar materials, AISI 316M stainless steel with alloy D9, was established for avoiding cracks under optimum processing conditions. In the domain of laser cutting and piercing, the development of a power ramped pulsed mode with high pulse repetition frequency and low duty cycle scheme could produce highly circular, narrow holes with minimum spattered pierced holes. A review of these experimental and some theoretical studies is presented and discussed in this chapter. These studies have provided deeper insight of fascinating laser-based materials processing application for industrial manufacturing technologies.

  17. NTP comparison process

    Science.gov (United States)

    Corban, Robert

    1993-01-01

    The systems engineering process for the concept definition phase of the program involves requirements definition, system definition, and consistent concept definition. The requirements definition process involves obtaining a complete understanding of the system requirements based on customer needs, mission scenarios, and nuclear thermal propulsion (NTP) operating characteristics. A system functional analysis is performed to provide a comprehensive traceability and verification of top-level requirements down to detailed system specifications and provides significant insight into the measures of system effectiveness to be utilized in system evaluation. The second key element in the process is the definition of system concepts to meet the requirements. This part of the process involves engine system and reactor contractor teams to develop alternative NTP system concepts that can be evaluated against specific attributes, as well as a reference configuration against which to compare system benefits and merits. Quality function deployment (QFD), as an excellent tool within Total Quality Management (TQM) techniques, can provide the required structure and provide a link to the voice of the customer in establishing critical system qualities and their relationships. The third element of the process is the consistent performance comparison. The comparison process involves validating developed concept data and quantifying system merits through analysis, computer modeling, simulation, and rapid prototyping of the proposed high risk NTP subsystems. The maximum amount possible of quantitative data will be developed and/or validated to be utilized in the QFD evaluation matrix. If upon evaluation of a new concept or its associated subsystems determine to have substantial merit, those features will be incorporated into the reference configuration for subsequent system definition and comparison efforts.

  18. The process of entrepreneurship:

    DEFF Research Database (Denmark)

    Neergaard, Helle

    2003-01-01

    . In general, the data show that entrepreneurial managers are aware of the need to change. More specifically the data supports that hiring of employees necessitates change. Bringing in CEOs from the outside also affects the need for role transition. The chapter concludes by offering a framework......Growing a technology-based new venture is a complex process because these ventures are embedded in turbulent environments that require fast organisational and managerial transformation. This chapter addresses the evolutionary process of such ventures. It seeks to provide insight into the link...

  19. Industrial Information Processing

    DEFF Research Database (Denmark)

    Svensson, Carsten

    2002-01-01

    This paper demonstrates, how cross-functional business processes may be aligned with product specification systems in an intra-organizational environment by integrating planning systems and expert systems, thereby providing an end-to-end integrated and an automated solution to the “build-to-order......This paper demonstrates, how cross-functional business processes may be aligned with product specification systems in an intra-organizational environment by integrating planning systems and expert systems, thereby providing an end-to-end integrated and an automated solution to the “build...

  20. A grieving process illustrated?

    Science.gov (United States)

    Hutchinson, Rory

    2018-03-01

    The sudden death of Pablo Picasso's closest friend Carlos Casagemas in 1901 came as a great shock to the young Picasso. From a young age, Picasso had ruminated on life and death; however, this was his first experience of bereavement. Following the death of Casagemas, Picasso's paintings can be seen as a diary of his grieving process and clearly illustrate the five stages of the grieving process as outlined by Kubler-Ross in ' On Death and Dying ' (1969). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  1. Thermal stir welding process

    Science.gov (United States)

    Ding, R. Jeffrey (Inventor)

    2012-01-01

    A welding method is provided for forming a weld joint between first and second elements of a workpiece. The method includes heating the first and second elements to form an interface of material in a plasticized or melted state interface between the elements. The interface material is then allowed to cool to a plasticized state if previously in a melted state. The interface material, while in the plasticized state, is then mixed, for example, using a grinding/extruding process, to remove any dendritic-type weld microstructures introduced into the interface material during the heating process.

  2. Solar industrial process heat

    Energy Technology Data Exchange (ETDEWEB)

    Lumsdaine, E.

    1981-04-01

    The aim of the assessment reported is to candidly examine the contribution that solar industrial process heat (SIPH) is realistically able to make in the near and long-term energy futures of the United States. The performance history of government and privately funded SIPH demonstration programs, 15 of which are briefly summarized, and the present status of SIPH technology are discussed. The technical and performance characteristics of solar industrial process heat plants and equipment are reviewed, as well as evaluating how the operating experience of over a dozen SIPH demonstration projects is influencing institutional acceptance and economoc projections. Implications for domestic energy policy and international implications are briefly discussed. (LEW)

  3. Hard exclusive QCD processes

    Energy Technology Data Exchange (ETDEWEB)

    Kugler, W.

    2007-01-15

    Hard exclusive processes in high energy electron proton scattering offer the opportunity to get access to a new generation of parton distributions, the so-called generalized parton distributions (GPDs). This functions provide more detailed informations about the structure of the nucleon than the usual PDFs obtained from DIS. In this work we present a detailed analysis of exclusive processes, especially of hard exclusive meson production. We investigated the influence of exclusive produced mesons on the semi-inclusive production of mesons at fixed target experiments like HERMES. Further we give a detailed analysis of higher order corrections (NLO) for the exclusive production of mesons in a very broad range of kinematics. (orig.)

  4. Reversible brazing process

    Science.gov (United States)

    Pierce, Jim D.; Stephens, John J.; Walker, Charles A.

    1999-01-01

    A method of reversibly brazing surfaces together. An interface is affixed to each surface. The interfaces can be affixed by processes such as mechanical joining, welding, or brazing. The two interfaces are then brazed together using a brazing process that does not defeat the surface to interface joint. Interfaces of materials such as Ni-200 can be affixed to metallic surfaces by welding or by brazing with a first braze alloy. The Ni-200 interfaces can then be brazed together using a second braze alloy. The second braze alloy can be chosen so that it minimally alters the properties of the interfaces to allow multiple braze, heat and disassemble, rebraze cycles.

  5. Genomic signal processing

    CERN Document Server

    Shmulevich, Ilya

    2007-01-01

    Genomic signal processing (GSP) can be defined as the analysis, processing, and use of genomic signals to gain biological knowledge, and the translation of that knowledge into systems-based applications that can be used to diagnose and treat genetic diseases. Situated at the crossroads of engineering, biology, mathematics, statistics, and computer science, GSP requires the development of both nonlinear dynamical models that adequately represent genomic regulation, and diagnostic and therapeutic tools based on these models. This book facilitates these developments by providing rigorous mathema

  6. Actinide metal processing

    International Nuclear Information System (INIS)

    Sauer, N.N.; Watkin, J.G.

    1992-01-01

    A process for converting an actinide metal such as thorium, uranium, or plutonium to an actinide oxide material by admixing the actinide metal in an aqueous medium with a hypochlorite as an oxidizing agent for sufficient time to form the actinide oxide material and recovering the actinide oxide material is described together with a low temperature process for preparing an actinide oxide nitrate such as uranyl nitrate. Additionally, a composition of matter comprising the reaction product of uranium metal and sodium hypochlorite is provided, the reaction product being an essentially insoluble uranium oxide material suitable for disposal or long term storage

  7. PROCESS OF RECOVERING URANIUM

    Science.gov (United States)

    Carter, J.M.; Larson, C.E.

    1958-10-01

    A process is presented for recovering uranium values from calutron deposits. The process consists in treating such deposits to produce an oxidlzed acidic solution containing uranium together with the following imparities: Cu, Fe, Cr, Ni, Mn, Zn. The uranium is recovered from such an impurity-bearing solution by adjusting the pH of the solution to the range 1.5 to 3.0 and then treating the solution with hydrogen peroxide. This results in the precipitation of uranium peroxide which is substantially free of the metal impurities in the solution. The peroxide precipitate is then separated from the solution, washed, and calcined to produce uranium trioxide.

  8. Lasers in materials processing

    International Nuclear Information System (INIS)

    Davis, J.I.; Rockower, E.B.

    1981-01-01

    A status report on the uranium Laser Isotope Separation (LIS) Program at the Lawrence Livermore National Laboratory is presented. Prior to this status report, process economic analysis is presented so as to understand how the unique properties of laser photons can be best utilized in the production of materials and components despite the high cost of laser energy. The characteristics of potential applications that are necessary for success are identified, and those factors that have up to now frustrated attempts to find commercially viable laser induced chemical and physical process for the production of new or existing materials are pointed out

  9. Biomedical Image Processing

    CERN Document Server

    Deserno, Thomas Martin

    2011-01-01

    In modern medicine, imaging is the most effective tool for diagnostics, treatment planning and therapy. Almost all modalities have went to directly digital acquisition techniques and processing of this image data have become an important option for health care in future. This book is written by a team of internationally recognized experts from all over the world. It provides a brief but complete overview on medical image processing and analysis highlighting recent advances that have been made in academics. Color figures are used extensively to illustrate the methods and help the reader to understand the complex topics.

  10. Normal modified stable processes

    DEFF Research Database (Denmark)

    Barndorff-Nielsen, Ole Eiler; Shephard, N.

    2002-01-01

    This paper discusses two classes of distributions, and stochastic processes derived from them: modified stable (MS) laws and normal modified stable (NMS) laws. This extends corresponding results for the generalised inverse Gaussian (GIG) and generalised hyperbolic (GH) or normal generalised inverse...... Gaussian (NGIG) laws. The wider framework thus established provides, in particular, for added flexibility in the modelling of the dynamics of financial time series, of importance especially as regards OU based stochastic volatility models for equities. In the special case of the tempered stable OU process...

  11. Uranium ore dressing process

    International Nuclear Information System (INIS)

    Floter, W.; Schoning, G.; Landsiedel, K.

    1982-01-01

    A process for dressing uranium ore containing water-soluble substances is claimed. In a mixture of crushed ore and water the solid material and water are partly separated. The first fraction, which contains the smaller grain-size portion of the solid material and the major part of the water is passed through a water softening means for removal of undesired ions. The second fraction, which contains the coarser grain-size portion of the solid material and most of the solids of the first fraction from which undesired ions have been at least partly removed is leached. The liquid is processed to obtain the dissolved uranium compounds

  12. Cell production process

    OpenAIRE

    Salas Bacalla, Julio; FII-UNMSM

    2014-01-01

    The Cellular production consists on containing the components and machines in cells, combining the production for process with the online productión, to obtain the advantages  that offer both processes, in this case the company can offer variety of products and low costs. La producción celular, consiste en agrupar los componentes y máquinas en células, combinando la producción por proceso con la producción en línea, para obtener las ventajas que ofrecen ambos métodos, como son la variedad ...

  13. Stochastic Process Creation

    Science.gov (United States)

    Esparza, Javier

    In many areas of computer science entities can “reproduce”, “replicate”, or “create new instances”. Paramount examples are threads in multithreaded programs, processes in operating systems, and computer viruses, but many others exist: procedure calls create new incarnations of the callees, web crawlers discover new pages to be explored (and so “create” new tasks), divide-and-conquer procedures split a problem into subproblems, and leaves of tree-based data structures become internal nodes with children. For lack of a better name, I use the generic term systems with process creation to refer to all these entities.

  14. Advanced Polymer Processing Facility

    Energy Technology Data Exchange (ETDEWEB)

    Muenchausen, Ross E. [Los Alamos National Laboratory

    2012-07-25

    Some conclusions of this presentation are: (1) Radiation-assisted nanotechnology applications will continue to grow; (2) The APPF will provide a unique focus for radiolytic processing of nanomaterials in support of DOE-DP, other DOE and advanced manufacturing initiatives; (3) {gamma}, X-ray, e-beam and ion beam processing will increasingly be applied for 'green' manufacturing of nanomaterials and nanocomposites; and (4) Biomedical science and engineering may ultimately be the biggest application area for radiation-assisted nanotechnology development.

  15. Symbolic signal processing

    International Nuclear Information System (INIS)

    Rechester, A.B.; White, R.B.

    1993-01-01

    Complex dynamic processes exhibit many complicated patterns of evolution. How can all these patterns be recognized using only output (observational, experimental) data without prior knowledge of the equations of motion? The powerful method for doing this is based on symbolic dynamics: (1) Present output data in symbolic form (trial language). (2) Topological and metric entropies are constructed. (3) Develop algorithms for computer optimization of entropies. (4) By maximizing entropies, find the most appropriate symbolic language for the purpose of pattern recognition. (5) Test this method using a variety of dynamical models from nonlinear science. The authors are in the process of applying this method for analysis of MHD fluctuations in tokamaks

  16. Radiation processed polysaccharide products

    International Nuclear Information System (INIS)

    Nguyen, Quoc Hien

    2007-01-01

    Radiation crosslinking, degradation and grafting techniques for modification of polymeric materials including natural polysaccharides have been providing many unique products. In this communication, typical products from radiation processed polysaccharides particularly plant growth promoter from alginate, plant protector and elicitor from chitosan, super water absorbent containing starch, hydrogel sheet containing carrageenan/CM-chitosan as burn wound dressing, metal ion adsorbent from partially deacetylated chitin were described. The procedures for producing those above products were also outlined. Future development works on radiation processing of polysaccharides were briefly presented. (author)

  17. Data processing on FPGAs

    CERN Document Server

    Teubner, Jens

    2013-01-01

    Roughly a decade ago, power consumption and heat dissipation concerns forced the semiconductor industry to radically change its course, shifting from sequential to parallel computing. Unfortunately, improving performance of applications has now become much more difficult than in the good old days of frequency scaling. This is also affecting databases and data processing applications in general, and has led to the popularity of so-called data appliances-specialized data processing engines, where software and hardware are sold together in a closed box. Field-programmable gate arrays (FPGAs) incr

  18. Validation Process Methods

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, John E. [National Renewable Energy Lab. (NREL), Golden, CO (United States); English, Christine M. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Gesick, Joshua C. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Mukkamala, Saikrishna [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2018-01-04

    This report documents the validation process as applied to projects awarded through Funding Opportunity Announcements (FOAs) within the U.S. Department of Energy Bioenergy Technologies Office (DOE-BETO). It describes the procedures used to protect and verify project data, as well as the systematic framework used to evaluate and track performance metrics throughout the life of the project. This report also describes the procedures used to validate the proposed process design, cost data, analysis methodologies, and supporting documentation provided by the recipients.

  19. Water And Waste Water Processing

    International Nuclear Information System (INIS)

    Yang, Byeong Ju

    1988-04-01

    This book shows US the distribution diagram of water and waste water processing with device of water processing, and device of waste water processing, property of water quality like measurement of pollution of waste water, theoretical Oxygen demand, and chemical Oxygen demand, processing speed like zero-order reactions and enzyme reactions, physical processing of water and waste water, chemical processing of water and waste water like neutralization and buffering effect, biological processing of waste water, ammonia removal, and sludges processing.

  20. Modeling of biopharmaceutical processes. Part 2: Process chromatography unit operation

    DEFF Research Database (Denmark)

    Kaltenbrunner, Oliver; McCue, Justin; Engel, Philip

    2008-01-01

    Process modeling can be a useful tool to aid in process development, process optimization, and process scale-up. When modeling a chromatography process, one must first select the appropriate models that describe the mass transfer and adsorption that occurs within the porous adsorbent. The theoret......Process modeling can be a useful tool to aid in process development, process optimization, and process scale-up. When modeling a chromatography process, one must first select the appropriate models that describe the mass transfer and adsorption that occurs within the porous adsorbent...