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Sample records for hvcn1 modulates bcr

  1. HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species.

    Science.gov (United States)

    Capasso, Melania; Bhamrah, Mandeep K; Henley, Tom; Boyd, Robert S; Langlais, Claudia; Cain, Kelvin; Dinsdale, David; Pulford, Karen; Khan, Mahmood; Musset, Boris; Cherny, Vladimir V; Morgan, Deri; Gascoyne, Randy D; Vigorito, Elena; DeCoursey, Thomas E; MacLennan, Ian C M; Dyer, Martin J S

    2010-03-01

    Voltage-gated proton currents regulate generation of reactive oxygen species (ROS) in phagocytic cells. In B cells, stimulation of the B cell antigen receptor (BCR) results in the production of ROS that participate in B cell activation, but the involvement of proton channels is unknown. We report here that the voltage-gated proton channel HVCN1 associated with the BCR complex and was internalized together with the BCR after activation. BCR-induced generation of ROS was lower in HVCN1-deficient B cells, which resulted in attenuated BCR signaling via impaired BCR-dependent oxidation of the tyrosine phosphatase SHP-1. This resulted in less activation of the kinases Syk and Akt, impaired mitochondrial respiration and glycolysis and diminished antibody responses in vivo. Our findings identify unanticipated functions for proton channels in B cells and demonstrate the importance of ROS in BCR signaling and downstream metabolism.

  2. Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells.

    Science.gov (United States)

    Bucur, Octavian; Stancu, Andreea Lucia; Goganau, Ioana; Petrescu, Stefana Maria; Pennarun, Bodvael; Bertomeu, Thierry; Dewar, Rajan; Khosravi-Far, Roya

    2013-01-01

    Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.

  3. Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-kappaB and p53 modulation.

    Science.gov (United States)

    Monteghirfo, Stefano; Tosetti, Francesca; Ambrosini, Claudia; Stigliani, Sara; Pozzi, Sarah; Frassoni, Francesco; Fassina, Gianfranco; Soverini, Simona; Albini, Adriana; Ferrari, Nicoletta

    2008-09-01

    The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-kappaB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl+ myeloid leukemia cells. The hop flavonoid xanthohumol inhibits tumor growth by targeting the nuclear factor-kappaB and Akt pathways and angiogenesis. Here, we show that xanthohumol has in vitro activity against Bcr-Abl+ cells and clinical samples and retained its cytotoxicity when imatinib mesylate-resistant K562 cells were examined. Xanthohumol inhibition of K562 cell viability was associated with induction of apoptosis, increased p21 and p53 expression, and decreased survivin levels. We show that xanthohumol strongly inhibited Bcr-Abl expression at both mRNA and protein levels and show that xanthohumol caused elevation of intracellular reactive oxygen species and that the antioxidant N-acetylcysteine blunted xanthohumol-induced events. Further, we observed that xanthohumol inhibits leukemia cell invasion, metalloprotease production, and adhesion to endothelial cells, potentially preventing in vivo life-threatening complications of leukostasis and tissue infiltration by leukemic cells. As structural mutations and/or gene amplification in Bcr-Abl can circumvent an otherwise potent anticancer drug such as imatinib, targeting Bcr-Abl expression as well as its kinase activity could be a novel additional therapeutic approach for the treatment of Bcr-Abl+ myeloid leukemia.

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

    OpenAIRE

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

    2011-01-01

    Summary 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 hig...

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

    Science.gov (United States)

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

    2017-03-02

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

  6. BCR/ABL stimulates WRN to promote survival and genomic instability

    Science.gov (United States)

    Slupianek, Artur; Poplawski, Tomasz; Jozwiakowski, Stanislaw K.; Cramer, Kimberly; Pytel, Dariusz; Stoczynska, Ewelina; Nowicki, Michal O.; Blasiak, Janusz; Skorski, Tomasz

    2010-01-01

    BCR/ABL-transformed chronic myeloid leukemia (CML) cells accumulate numerous DNA double-strand breaks (DSBs) induced by reactive oxygen species (ROS) and genotoxic agents. To repair these lesions BCR/ABL stimulate unfaithful DSB repair pathways, homologous recombination repair (HRR), non-homologous end-joining (NHEJ) and single-strand annealing (SSA). Here we show that BCR/ABL enhances the expression and increase nuclear localization of WRN (mutated in Werner syndrome), which is required for processing DSB ends during the repair. Other fusion tyrosine kinases (FTKs) such as TEL/ABL, TEL/JAK2, TEL/PDGFβR, and NPM/ALK also elevate WRN. BCR/ABL induces WRN mRNA and protein expression in part by c-MYC -mediated activation of transcription and Bcl-xL –dependent inhibition of caspase-dependent cleavage, respectively. WRN is in complex with BCR/ABL resulting in WRN tyrosine phosphorylation and stimulation of its helicase and exonuclease activities. Activated WRN protects BCR/ABL-positive cells from the lethal effect of oxidative and genotoxic stresses, which causes DSBs. In addition, WRN promotes unfaithful recombination-dependent repair mechanisms HRR and SSA, and enhances the loss of DNA bases during NHEJ in leukemia cells. In summary, we postulate that BCR/ABL-mediated stimulation of WRN modulates the efficiency and fidelity of major DSB repair mechanisms to protect leukemia cells from apoptosis and to facilitate genomic instability. PMID:21123451

  7. BCR/ABL stimulates WRN to promote survival and genomic instability.

    Science.gov (United States)

    Slupianek, Artur; Poplawski, Tomasz; Jozwiakowski, Stanislaw K; Cramer, Kimberly; Pytel, Dariusz; Stoczynska, Ewelina; Nowicki, Michal O; Blasiak, Janusz; Skorski, Tomasz

    2011-02-01

    BCR/ABL-transformed chronic myeloid leukemia (CML) cells accumulate numerous DNA double-strand breaks (DSB) induced by reactive oxygen species (ROS) and genotoxic agents. To repair these lesions BCR/ABL stimulate unfaithful DSB repair pathways, homologous recombination repair (HRR), nonhomologous end-joining (NHEJ), and single-strand annealing (SSA). Here, we show that BCR/ABL enhances the expression and increase nuclear localization of WRN (mutated in Werner syndrome), which is required for processing DSB ends during the repair. Other fusion tyrosine kinases (FTK), such as TEL/ABL, TEL/JAK2, TEL/PDGFβR, and NPM/ALK also elevate WRN. BCR/ABL induces WRN mRNA and protein expression in part by c-MYC-mediated activation of transcription and Bcl-xL-dependent inhibition of caspase-dependent cleavage, respectively. WRN is in complex with BCR/ABL resulting in WRN tyrosine phosphorylation and stimulation of its helicase and exonuclease activities. Activated WRN protects BCR/ABL-positive cells from the lethal effect of oxidative and genotoxic stresses, which causes DSBs. In addition, WRN promotes unfaithful recombination-dependent repair mechanisms HRR and SSA, and enhances the loss of DNA bases during NHEJ in leukemia cells. In summary, we postulate that BCR/ABL-mediated stimulation of WRN modulates the efficiency and fidelity of major DSB repair mechanisms to protect leukemia cells from apoptosis and to facilitate genomic instability.

  8. BCR: a new target in resistance mediated by BCR/ABL-315I?

    Science.gov (United States)

    Haberbosch, Isabella; Rafiei, Anahita; Oancea, Claudia; Ottmann, Gerhart Oliver; Ruthardt, Martin; Mian, Afsar Ali

    2016-01-01

    Targeting BCR/ABL with Tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias but the “gatekeeper” mutation T315I confers resistance against all approved TKIs, with the only exception of ponatinib, a multi-targeted kinase inhibitor. Besides resistance to TKIs, T315I also confers additional features to the leukemogenic potential of BCR/ABL, involving endogenous BCR. Therefore we studied the role of BCR on BCR/ABL mutants lacking functional domains indispensable for the oncogenic activity of BCR/ABL. We used the factor independent growth of murine myeloid progenitor 32D cells and the transformation of Rat-1 fibroblasts both mediated by BCR/ABL. Here we report that T315I restores the capacity to mediate factor-independent growth and transformation potential of loss-of-function mutants of BCR/ABL. Targeting endogenous Bcr abrogated the capacity of oligomerization deficient mutant of BCR/ABL-T315I to mediate factor independent growth of 32D cells and strongly reduced their transformation potential in Rat-1 cells, as well as led to the up-regulation of mitogen activated protein kinase (MAPK) pathway. Our data show that the T315I restores the capacity of loss-of-function mutants to transform cells which is dependent on the transphosphorylation of endogenous Bcr, which becomes a putative therapeutic target to overcome resistance by T315I. PMID:27014420

  9. Synthetic antigens reveal dynamics of BCR endocytosis during inhibitory signaling.

    Science.gov (United States)

    Courtney, Adam H; Bennett, Nitasha R; Zwick, Daniel B; Hudon, Jonathan; Kiessling, Laura L

    2014-01-17

    B cells detect foreign antigens through their B cell antigen receptor (BCR). The BCR, when engaged by antigen, initiates a signaling cascade. Concurrent with signaling is endocytosis of the BCR complex, which acts to downregulate signaling and facilitate uptake of antigen for processing and display on the cell surface. The relationship between signaling and BCR endocytosis is poorly defined. Here, we explore the interplay between BCR endocytosis and antigens that either promote or inhibit B cell activation. Specifically, synthetic antigens were generated that engage the BCR alone or both the BCR and the inhibitory co-receptor CD22. The lectin CD22, a member of the Siglec family, binds sialic acid-containing glycoconjugates found on host tissues, inhibiting BCR signaling to prevent erroneous B cell activation. At low concentrations, antigens that can cocluster the BCR and CD22 promote rapid BCR endocytosis; whereas, slower endocytosis occurs with antigens that bind only the BCR. At higher antigen concentrations, rapid BCR endocytosis occurs upon treatment with either stimulatory or inhibitory antigens. Endocytosis of the BCR, in response to synthetic antigens, results in its entry into early endocytic compartments. Although the CD22-binding antigens fail to activate key regulators of antigen presentation (e.g., Syk), they also promote BCR endocytosis, indicating that inhibitory antigens can be internalized. Together, our observations support a functional role for BCR endocytosis in downregulating BCR signaling. The reduction of cell surface BCR levels in the absence of B cell activation should raise the threshold for BCR subsequent activation. The ability of the activating synthetic antigens to trigger both signaling and entry of the BCR into early endosomes suggests strategies for targeted antigen delivery.

  10. 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.

  11. 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.

  12. BCR/ABL positive thrombocythemia: a diagnostic dilemma

    Directory of Open Access Journals (Sweden)

    Lubna Zafar

    2017-01-01

    Full Text Available Both chronic myeloid leukemia and essential thrombocythemia are part of the spectrum of myeloproliferative neoplasm. Therefore, considerable overlap may occur in the clinical manifestations, and hematological and molecular findings in some patients. We report here a case of a 45-year-old men who presented with thrombocytosis. Bone marrow aspiration yielded small megakaryocytes with hypolobulated nuclei and positive BCR-ABL rearrangement. A diagnosis of BCR-ABL+ essential thrombocythemia was made and imatinib was advised.

  13. BCR-ABL DERIVED PEPTIDE VACCINES FOR CHRONIC MYELOID LEUKAEMIA

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    M. Bocchia

    2012-01-01

    Full Text Available Chronic Myeloid Leukemia (CML is a myeloproliferative pluripotent stem cell disorder characterized by the presence of a cytogenetic hallmark, the Philadelphia (Ph chromosome, and accounts for 15% of adult leukemias. The disease progresses from a chronic phase through an accelerated phase to a blast phase and its natural course accounts for a median 4 years survival1. The Ph chromosome is derived by a reciprocal translocation termed t(9;22 in which the c-abl oncogene has moved from chromosome 9 into the breakpoint cluster region (bcr, within the bcr gene on chromosome 22, resulting in a chimeric bcr-abl fusion gene that encodes a 210 KD protein (p210 with constitutive tyrosine kinase activity. Two major alternative chimeric p210 can result from this fusion gene: p210-b2a2 where the junction occurs between bcr exon 2 (b2 and abl exon 2 (a2 and p210-b3a2 where the the junction occurs between bcr exon 3 (b3 and abl exon 2 (a2. About 40% of CML patients harbor the p210-b2a2 and about 60% of them show the p210-b3a2.

  14. Conservation and distribution of the benzalkonium chloride resistance cassette bcrABC in Listeria monocytogenes.

    Science.gov (United States)

    Dutta, Vikrant; Elhanafi, Driss; Kathariou, Sophia

    2013-10-01

    Analysis of a panel of 116 Listeria monocytogenes strains of diverse serotypes and sources (clinical, environment of food processing plants, and food) revealed that all but one of the 71 benzalkonium chloride-resistant (BC(r)) isolates harbored bcrABC, previously identified on a large plasmid (pLM80) of the 1998-1999 hot dog outbreak strain H7858. In contrast, bcrABC was not detected among BC-susceptible (BC(s)) isolates. The bcrABC sequences were highly conserved among strains of different serotypes, but variability was noted in sequences flanking bcrABC. The majority of the BC(r) isolates had either the pLM80-type of organization of the bcrABC region or appeared to harbor bcrABC on the chromosome, adjacent to novel sequences. Transcription of bcrABC was induced by BC (10 μg/ml) in strains of different serotypes and diverse bcrABC region organization. These findings reveal widespread dissemination of bcrABC across BC(r) L. monocytogenes strains regardless of serotype and source, while also suggesting possible mechanisms of bcrABC dissemination across L. monocytogenes genomes.

  15. The Functional Interplay Between the t(9;22)-Associated Fusion Proteins BCR/ABL and ABL/BCR in Philadelphia Chromosome-Positive Acute Lymphatic Leukemia

    Science.gov (United States)

    Rafiei, Anahita; Mian, Afsar Ali; Döring, Claudia; Metodieva, Anna; Oancea, Claudia; Thalheimer, Frederic B.; Hansmann, Martin Leo; Ottmann, Oliver Gerhard; Ruthardt, Martin

    2015-01-01

    The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph+ leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. The co-expression of p96ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185BCR/ABL. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and Ph+ ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96ABL/BCR and p185BCR/ABL in hematopoietic stem cells. Co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph+ ALL. PMID:25919613

  16. The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia.

    Science.gov (United States)

    Rafiei, Anahita; Mian, Afsar Ali; Döring, Claudia; Metodieva, Anna; Oancea, Claudia; Thalheimer, Frederic B; Hansmann, Martin Leo; Ottmann, Oliver Gerhard; Ruthardt, Martin

    2015-04-01

    The hallmark of Philadelphia chromosome positive (Ph(+)) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph(+) leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96(ABL/BCR) for the pathogenesis of Ph(+) ALL. The co-expression of p96(ABL/BCR) enhanced the kinase activity and as a consequence, the transformation potential of p185(BCR/ABL). Targeting p96(ABL/BCR) by RNAi inhibited growth of Ph(+) ALL cell lines and Ph(+) ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96(ABL/BCR) and p185(BCR/AB)L in hematopoietic stem cells. Co-expression of p96(ABL/BCR) abolished the capacity of p185(BCR/ABL) to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96(ABL/BCR) for the pathogenesis of Ph(+) ALL.

  17. The functional interplay between the t(9;22-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia.

    Directory of Open Access Journals (Sweden)

    Anahita Rafiei

    2015-04-01

    Full Text Available The hallmark of Philadelphia chromosome positive (Ph(+ leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph(+ leukemia. The t(9;22 is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML and 100% of patients with Ph+ acute lymphatic leukemia (ALL. ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96(ABL/BCR for the pathogenesis of Ph(+ ALL. The co-expression of p96(ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185(BCR/ABL. Targeting p96(ABL/BCR by RNAi inhibited growth of Ph(+ ALL cell lines and Ph(+ ALL patient-derived long-term cultures (PD-LTCs. Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96(ABL/BCR and p185(BCR/ABL in hematopoietic stem cells. Co-expression of p96(ABL/BCR abolished the capacity of p185(BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96(ABL/BCR for the pathogenesis of Ph(+ ALL.

  18. Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.

    Science.gov (United States)

    Moens, Leen; Kane, Alisa; Tangye, Stuart G

    2016-09-01

    Immunological memory is characterized by the rapid reactivation of memory B cells that produce large quantities of high-affinity antigen-specific antibodies. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these diverse responses of naïve and memory B cells is incompletely resolved. Here we investigated the nature of B-cell receptor (BCR) signaling in human splenic naïve, IgM(+) memory and isotype-switched memory B cells following multivalent BCR crosslinking. We observed comparable rapid and transient phosphorylation kinetics for proximal (phosphotyrosine and spleen tyrosine kinase) and propagation (B-cell linker, phospholipase Cγ2) signaling components in these different B-cell subsets. However, the magnitude of activation of downstream components of the BCR signaling pathway were greater in memory compared with naïve cells. Although no differences were observed in the magnitude of Ca(2+) mobilization between subsets, IgM(+) memory B cells exhibited a more rapid Ca(2+) mobilization and a greater depletion of the Ca(2+) endoplasmic reticulum stores, while IgG(+) memory B cells had a prolonged Ca(2+) uptake. Collectively, our findings show that intrinsic signaling features of B-cell subsets contribute to the robust response of human memory B cells over naïve B cells. This has implications for our understanding of memory B-cell responses and provides a framework to modulate these responses in the setting of vaccination and immunopathologies, such as immunodeficiency and autoimmunity.

  19. INHIBITION OF APOPTOSIS BY bcr-abl FUSION GENE IN K562 CELLS

    Institute of Scientific and Technical Information of China (English)

    WANG Chun-hong; SUN Bing-zhong; YUAN Yue-chuan

    1999-01-01

    Objective: To investigate the effect of bcr-abl fusion gene on CML cell apoptosis. Methods: Apoptosis of exvivo cultured K562 cells were observed after exposure to synthetic 18 mer antisense oligodeoxynucleotide complementary to the bcr-abl junction (b3a2). Results: Apoptosis of K562 cells was significantly increased associated with inhibition of bcr-abl expression. Conclusion: bcr-abl fusion gene formation due to chromosome translocation may be the major mechanism of CML via inhibition of apoptosis.

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

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    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.

  1. BCR Routing for Intermittently Connected Mobile Ad hoc Networks

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    S. RAMESH

    2014-03-01

    Full Text Available The Wireless and the Mobile Networks appear to provide a wide range of applications. Following these, the Mobile Ad hoc Networks (MANET aid in wide development of many applications. The achievement of the real world applications are attained through effective routing. The Intermittently Connected Mobile Ad hoc Network (ICMANET is a sparse network where a full connectivity is never possible. ICMANET is a disconnected MANET and is also a Delay Tolerant Network (DTN that sustains for higher delays. The routing in a disseminated network is a difficult task. A new routing scheme called Bee Colony Routing (BCR is been proposed with a motto of achieving optimal result in delivering the data packet towards the destined node. BCR is proposed with the basis of Bee Colony Optimization technique (BCO. The routing in ICMNAET is done by means of Bee routing protocol. This paper enchants a novel routing methodology for data transmission in ICMANET.

  2. 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.

  3. Colorimetric assessment of BCR-ABL1 transcripts in clinical samples via gold nanoprobes.

    Science.gov (United States)

    Vinhas, Raquel; Correia, Cláudia; Ribeiro, Patricia; Lourenço, Alexandra; Botelho de Sousa, Aida; Fernandes, Alexandra R; Baptista, Pedro V

    2016-07-01

    Gold nanoparticles functionalized with thiolated oligonucleotides (Au-nanoprobes) have been used in a range of applications for the detection of bioanalytes of interest, from ions to proteins and DNA targets. These detection strategies are based on the unique optical properties of gold nanoparticles, in particular, the intense color that is subject to modulation by modification of the medium dieletric. Au-nanoprobes have been applied for the detection and characterization of specific DNA sequences of interest, namely pathogens and disease biomarkers. Nevertheless, despite its relevance, only a few reports exist on the detection of RNA targets. Among these strategies, the colorimetric detection of DNA has been proven to work for several different targets in controlled samples but demonstration in real clinical bioanalysis has been elusive. Here, we used a colorimetric method based on Au-nanoprobes for the direct detection of the e14a2 BCR-ABL fusion transcript in myeloid leukemia patient samples without the need for retro-transcription. Au-nanoprobes directly assessed total RNA from 38 clinical samples, and results were validated against reverse transcription-nested polymerase chain reaction (RT-nested PCR) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The colorimetric Au-nanoprobe assay is a simple yet reliable strategy to scrutinize myeloid leukemia patients at diagnosis and evaluate progression, with obvious advantages in terms of time and cost, particularly in low- to medium-income countries where molecular screening is not routinely feasible. Graphical abstract Gold nanoprobe for colorimetric detection of BCR-ABL1 fusion transcripts originating from the Philadelphia chromosome.

  4. UAP56 is a novel interacting partner of Bcr in regulating vascular smooth muscle cell DNA synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Sahni, Abha [Department of Pathology, University of Texas Medical Branch, Galveston, TX (United States); Wang, Nadan [Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (United States); Alexis, Jeffrey D., E-mail: jeffrey_alexis@urmc.rochester.edu [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (United States)

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer UAP56 is an important regulator of DNA synthesis in vascular smooth muscle cells. Black-Right-Pointing-Pointer UAP56 binds to Bcr. Black-Right-Pointing-Pointer Interaction between Bcr and UAP56 is critical for Bcr induced DNA synthesis. -- Abstract: Bcr is a serine/threonine kinase that is a critical regulator of vascular smooth muscle cell inflammation and proliferation. We have previously demonstrated that Bcr acts in part via phosphorylation and inhibition of PPAR{gamma}. We have identified the RNA helicase UAP56 as another substrate of Bcr. In this report we demonstrate that knockdown of UAP56 blocks Bcr induced DNA synthesis in vascular smooth muscle cells (VSMC). We also found that over expression of Bcr increased the expression of cyclin E and decreased the expression of p27. Knockdown of UAP56 reversed the effect of Bcr on cyclin E and p27 expression. Furthermore, we found that Bcr binds to UAP56 and demonstrate that binding of UAP56 to Bcr is critical for Bcr induced DNA synthesis in VSMC. Our data identify UAP56 as an important binding partner of Bcr and a novel target for inhibiting vascular smooth muscle cell proliferation.

  5. 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

    ) 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...

  6. Detection of p190BCR-ABL AND p210BCR-ABL fusion transcripts in patients with chronic myeloid leukemia (CML using qualitative RT-PCR

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    Aya Bonilla, Carlos Alberto

    2014-10-01

    Full Text Available Introduction: Chronic myelogenous leukemia (CML is characterized by the presence of the Philadelphia chromosome (Ph, resulting from the balanced reciprocal translocation t(9;22(q34;q11. This marker chromosome is found less frequently in patients suffering from acute lymphoblastic leukemia. Objective: To determine the frequency of BCR-ABL gene fusions encoding the p210BCR-ABL y p190 BCR-ABL transcripts in Colombian patients diagnosed with CML in different stages of the disease and/or its treatment. Materials and methods: Cross sectional, descriptive study of thirty one CML patients (aged 15-78. Analysis was carried out through qualitative nested PCR for the isoforms P210 BCR-ABL (b3a2 e b2a2 and P190 BCR-ABL (e1a2, and based on peripheral blood samples. Results: In 29 of the 31 patients (93.6% transcript p210BCR-ABL was detected; b2a2 and b3a2 gene fusions and the coexpression b3a2 y b2a2 were identified in 55.2% (16/29, 34.5% (10/29 and 10.3% (3/29 of the cases, respectively. Conclusion: b2a2 gene fusion was the most frequent in this CML population.

  7. p185BCR/ABL has a lower sensitivity than p210BCR/ABL to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia

    Science.gov (United States)

    Mian, Afsar A.; Metodieva, Anna; Najajreh, Yousef; Ottmann, Oliver G.; Mahajna, Jamal; Ruthardt, Martin

    2012-01-01

    Background The t(9;22) translocation leads to the formation of the chimeric breakpoint cluster region/c-abl oncogene 1 (BCR/ABL) fusion gene on der22, the Philadelphia chromosome. The p185BCR/ABL or the p210BCR/ABL fusion proteins are encoded as a result of the translocation, depending on whether a “minor” or “major” breakpoint occurs, respectively. Both p185BCR/ABL and p210BCR/ABL exhibit constitutively activated ABL kinase activity. Through fusion to BCR the ABL kinase in p185BCR/ABL and p210BCR/ABL “escapes” the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. A novel class of compounds including GNF-2 restores allosteric inhibition of the kinase activity and the transformation potential of BCR/ABL. Here we investigated whether there are differences between p185BCR/ABL and p210BCR/ABL regarding their sensitivity towards allosteric inhibition by GNF-2 in models of Philadelphia chromosome-positive acute lymphatic leukemia. Design and Methods We investigated the anti-proliferative activity of GNF-2 in different Philadelphia chromosome-positive acute lymphatic leukemia models, such as cell lines, patient-derived long-term cultures and factor-dependent lymphatic Ba/F3 cells expressing either p185BCR/ABL or p210BCR/ABL and their resistance mutants. Results The inhibitory effects of GNF-2 differed constantly between p185BCR/ABL and p210BCR/ABL expressing cells. In all three Philadelphia chromosome-positive acute lymphatic leukemia models, p210BCR/ABL-transformed cells were more sensitive to GNF-2 than were p185BCR/ABL-positive cells. Similar results were obtained for p185BCR/ABL and the p210BCR/ABL harboring resistance mutations. Conclusions Our data provide the first evidence of a differential response of p185BCR/ABL- and p210BCR/ABL- transformed cells to allosteric inhibition by GNF-2, which is of importance for the treatment of patients with Philadelphia chromosome-positive acute lymphatic leukemia. PMID:22058195

  8. Expression of BCR/ABL p210 from a Knockin Allele Enhances Bone Marrow Engraftment without Inducing Neoplasia

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    Samantha B. Foley

    2013-10-01

    Full Text Available Chronic myeloid leukemia (CML and some acute lymphoblastic leukemias are characterized by the t(9;22 chromosome, which encodes the BCR/ABL oncogene. Multiple mouse models of CML express BCR/ABL at high levels from non-Bcr promoters, resulting in the development of leukemias. In contrast, a significant fraction of healthy humans have been found to have BCR/ABL-positive hematopoietic cells. To bridge the gap between the information derived from current mouse models and nonleukemic humans with the BCR/ABL oncogene, we generated a knockin model with BCR/ABL p210 expressed from the Bcr locus. Unlike previous models, expression of BCR/ABL from the knockin allele did not induce leukemia. BCR/ABL mutant cells did exhibit favorable bone marrow engraftment compared to control cells. These data suggest that BCR/ABL expression alone is insufficient to induce disease. This model allows for inducible spatial and temporal control of BCR/ABL expression for analysis of early steps in the pathogenesis of BCR/ABL-expressing leukemias.

  9. The Study on BCR/ABL Fusion Gene in Adult Acute Lymphoblastic Leukemia

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    In order to assess the significance of BCR/ABC fusion gene in adult acute lymphoblastic Leukemia (ALL), 28 patients who were diagnosed as ALL were enrolled to detect BCR/ABC gene using nested-RT PCR. The results showed that 9 cases (31.25%) were BCR/ABL positive ,and expressed P210 subtype. A mong them 7 cases were B-ALL, and one was T-ALL. The diagnosis was proved by monoclonal antibodies recognition by indirect immunofluorescence. Adult patients with BCR/ABL positive ALL were significantly older (p<0. 01) and had higher WBC count (p<0. 01) as compared with BCR/ABL-negative patients. There was no significant difference in sex, hemoglobin and splenomegaly between two group (p>0. 05). The induc tion failure rate was high in BCR/ABL positive patients and those who achieved complete remission usually relapsed earlier. In conclusion, adult ALL patients with BCR/ABL-positive have poorer prognosis.

  10. A generalized quantitative antibody homeostasis model: regulation of B-cell development by BCR saturation and novel insights into bone marrow function

    Science.gov (United States)

    Prechl, József

    2017-01-01

    In a pair of articles, we present a generalized quantitative model for the homeostatic function of clonal humoral immune system. In this first paper, we describe the cycles of B-cell expansion and differentiation driven by B-cell receptor engagement. The fate of a B cell is determined by the signals it receives via its antigen receptor at any point of its lifetime. We express BCR engagement as a function of apparent affinity and free antigen concentration, using the range of 10−14–10−3 M for both factors. We assume that for keeping their BCR responsive, B cells must maintain partial BCR saturation, which is a narrow region defined by [Ag]≈KD. To remain in this region, B cells respond to changes in [Ag] by proliferation or apoptosis and modulate KD by changing BCR structure. We apply this framework to various niches of B-cell development such as the bone marrow, blood, lymphoid follicles and germinal centers. We propose that clustered B cells in the bone marrow and in follicles present antigen to surrounding B cells by exposing antigen captured on complement and Fc receptors. The model suggests that antigen-dependent selection in the bone marrow results in (1) effector BI cells, which develop in blood as a consequence of the inexhaustible nature of soluble antigens, (2) memory cells that survive in antigen rich niches, identified as marginal zone B cells. Finally, the model implies that memory B cells could derive survival signals from abundant non-cognate antigens. PMID:28265373

  11. Do nomograms designed to predict biochemical recurrence (BCR) do a better job of predicting more clinically relevant prostate cancer outcomes than BCR? A report from the SEARCH database group.

    Science.gov (United States)

    Teeter, Anna E; Presti, Joseph C; Aronson, William J; Terris, Martha K; Kane, Christopher J; Amling, Christopher L; Freedland, Stephen J

    2013-07-01

    To examine the ability of various postoperative nomograms to predict prostate cancer-specific mortality (PCSM) and to validate that they could predict aggressive biochemical recurrence (BCR). Prostate-specific antigen (PSA), grade, and stage are the classic triad used to predict BCR after radical prostatectomy (RP). Multiple nomograms use these to predict risk of BCR. A previous study showed that several nomograms could predict aggressive BCR (prostate-specific antigen doubling time [PSADT] SEARCH) database who underwent RP between 1990 and 2009. We also compared their ability to predict BCR and aggressive BCR in a subset of men. We calculated the c-index for each nomogram to determine its predictive accuracy for estimating actual outcomes. We found that each nomogram could predict aggressive BCR and PCSM in a statistically significant manner and that they all predicted PCSM more accurately than they predicted BCR (ie, with higher c-index values). Currently available nomograms used to predict BCR accurately predict PCSM and other more clinically relevant endpoints. Moreover, not only do they significantly predict PCSM, but do so with generally greater accuracy than BCR. Published by Elsevier Inc.

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

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    Costa Juliana

    2010-11-01

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

  13. Improved coiled-coil design enhances interaction with Bcr-Abl and induces apoptosis.

    Science.gov (United States)

    Dixon, Andrew S; Miller, Geoffrey D; Bruno, Benjamin J; Constance, Jonathan E; Woessner, David W; Fidler, Trevor P; Robertson, James C; Cheatham, Thomas E; Lim, Carol S

    2012-01-01

    The oncoprotein Bcr-Abl drives aberrant downstream activity through trans-autophosphorylation of homo-oligomers in chronic myelogenous leukemia (CML).(1, 2) The formation of Bcr-Abl oligomers is achieved through the coiled-coil domain at the N-terminus of Bcr.(3, 4) We have previously reported a modified version of this coiled-coil domain, CCmut2, which exhibits disruption of Bcr-Abl oligomeric complexes and results in decreased proliferation of CML cells and induction of apoptosis.(5) A major contributing factor to these enhanced capabilities is the destabilization of the CCmut2 homodimers, increasing the availability to interact with and inhibit Bcr-Abl. Here, we included an additional mutation (K39E) that could in turn further destabilize the mutant homodimer. Incorporation of this modification into CCmut2 (C38A, S41R, L45D, E48R, Q60E) generated what we termed CCmut3, and resulted in further improvements in the binding properties with the wild-type coiled-coil domain representative of Bcr-Abl [corrected]. A separate construct containing one revert mutation, CCmut4, did not demonstrate improved oligomeric properties and indicated the importance of the L45D mutation. CCmut3 demonstrated improved oligomerization via a two-hybrid assay as well as through colocalization studies, in addition to showing similar biologic activity as CCmut2. The improved binding between CCmut3 and the Bcr-Abl coiled-coil may be used to redirect Bcr-Abl to alternative subcellular locations with interesting therapeutic implications.

  14. A Requirement for SOCS-1 and SOCS-3 Phosphorylation in Bcr-Abl-Induced Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Xiaoxue Qiu

    2012-06-01

    Full Text Available Suppressors of cytokine signaling 1 and 3 (SOCS-1 and SOCS-3 are inhibitors of the Janus tyrosine kinase (JAK/signal transducers and activators of transcription (STAT pathway and function in a negative feedback loop during cytokine signaling. Abl transformation is associated with constitutive activation of JAK/STAT-dependent signaling. However, the mechanism by which Abl oncoproteins bypass SOCS inhibitory regulation remains poorly defined. Here, we demonstrate that coexpression of Bcr-Abl with SOCS-1 or SOCS-3 results in tyrosine phosphorylation of these SOCS proteins. Interestingly, SOCS-1 is highly tyrosine phosphorylated in one of five primary chronic myelogenous leukemia samples. Bcr-Abl-dependent tyrosine phosphorylation of SOCS-1 and SOCS-3 occurs mainly on Tyr 155 and Tyr 204 residues of SOCS-1 and on Tyr 221 residue of SOCS-3. We observed that phosphorylation of these SOCS proteins was associated with their binding to Bcr-Abl. Bcr-Abl-dependent phosphorylation of SOCS-1 and SOCS-3 diminished their inhibitory effects on the activation of JAK and STAT5 and thereby enhanced JAK/STAT5 signaling. Strikingly, disrupting the tyrosine phosphorylation of SOCS-1 or SOCS-3 impaired the expression of Bcl-XL protein and sensitized K562 leukemic cells to undergo apoptosis. Moreover, selective mutation of tyrosine phosphorylation sites of SOCS-1 or SOCS-3 significantly blocked Bcr-Abl-mediated tumorigenesis in nude mice and inhibited Bcr-Abl-mediated murine bone marrow transformation. Together, these results reveal a mechanism of how Bcr-Abl may overcome SOCS-1 and SOCS-3 inhibition to constitutively activate the JAK/STAT-dependent signaling, and suggest that Bcr-Abl may critically requires tyrosine phosphorylation of SOCS-1 and SOCS-3 to mediate tumorigenesis when these SOCS proteins are present in cells.

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

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    Min Yu

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS: 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.

  16. Increased BCR responsiveness in B cells from patients with chronic GVHD.

    Science.gov (United States)

    Allen, Jessica L; Tata, Prasanthi V; Fore, Matthew S; Wooten, Jenna; Rudra, Sharmistha; Deal, Allison M; Sharf, Andrew; Hoffert, Todd; Roehrs, Philip A; Shea, Thomas C; Serody, Jonathan S; Richards, Kristy L; Jagasia, Madan; Lee, Stephanie J; Rizzieri, David; Horwitz, Mitchell E; Chao, Nelson J; Sarantopoulos, Stefanie

    2014-03-27

    Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.

  17. Evaluation of Morpholino Antisense Oligos’ Role on BCR-ABL Gene Silencing in the K562 Cell Line

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    Bahman Delalat

    2010-01-01

    Full Text Available Objective: Chronic myeloid leukemia (CML develops when a hematopoietic stem cellacquires the BCR/ABL fusion gene. This causes these transformed hematopoietic cellsto have a greater than normal proliferation rate. Scientists attempt to improve the CMLtreatment process by silencing the BCR/ABL oncogene. In this work, we used morpholinoantisense oligos to silence the BCR/ABL oncogene.Materials and Methods: In this study, the K562 was used as a BCR/ABL fusion-genepositive cell line and the Jurkat cell line as a control. We explored the inhibiting capacityof morpholino antisense oligos in the the expression of the BCR/ABL oncogene andstudied their p210 BCR/ABL suppression, inhibition of cell proliferation and stimulation ofapoptosis in the K562 cells after 24 and 48 hours. Endo-Porter was used for delivery ofmorpholino antisense oligos into cell cytosols. Meanwhile, flow cytometric analysis wasperformed in order to determine the appropriate concentration of morpholino antisenseoligos.Results: Prolonged exposure of the K562 cell line to the morpholino antisense oligostargeted against the BCR-ABL gene showed proliferation inhibition as its main feature.After western blotting, we found that complete silencing of BCR/ABL was achieved, butflow cytometric analysis showed no broad apoptosis.Conclusion: The results indicate that the Morpholino antisense oligo is able to inhibitp210 BCR/ABL; however, it cannot induce broad apoptosis due to co-silencing of BCR.

  18. Role of Bcr1-activated genes Hwp1 and Hyr1 in Candida albicans oral mucosal biofilms and neutrophil evasion.

    Science.gov (United States)

    Dwivedi, Prabhat; Thompson, Angela; Xie, Zhihong; Kashleva, Helena; Ganguly, Shantanu; Mitchell, Aaron P; Dongari-Bagtzoglou, Anna

    2011-01-25

    Candida albicans triggers recurrent infections of the oropharyngeal mucosa that result from biofilm growth. Prior studies have indicated that the transcription factor Bcr1 regulates biofilm formation in a catheter model, both in vitro and in vivo. We thus hypothesized that Bcr1 plays similar roles in the formation of oral mucosal biofilms and tested this hypothesis in a mouse model of oral infection. We found that a bcr1/bcr1 mutant did not form significant biofilm on the tongues of immunocompromised mice, in contrast to reference and reconstituted strains that formed pseudomembranes covering most of the tongue dorsal surface. Overexpression of HWP1, which specifies an epithelial adhesin that is under the transcriptional control of Bcr1, partly but significantly rescued the bcr1/bcr1 biofilm phenotype in vivo. Since HWP1 overexpression only partly reversed the biofilm phenotype, we investigated whether additional mechanisms, besides adhesin down-regulation, were responsible for the reduced virulence of this mutant. We discovered that the bcr1/bcr1 mutant was more susceptible to damage by human leukocytes when grown on plastic or on the surface of a human oral mucosa tissue analogue. Overexpression of HYR1, but not HWP1, significantly rescued this phenotype. Furthermore a hyr1/hyr1 mutant had significantly attenuated virulence in the mouse oral biofilm model of infection. These discoveries show that Bcr1 is critical for mucosal biofilm infection via regulation of epithelial cell adhesin and neutrophil function.

  19. Reciprocal t(9;22 ABL/BCR fusion proteins: leukemogenic potential and effects on B cell commitment.

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    Xiaomin Zheng

    Full Text Available BACKGROUND: t(9;22 is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome--Ph+ determine formation of different fusion genes that are associated with either Ph+ acute lymphatic leukemia (Ph+ ALL or chronic myeloid leukemia (CML. The "minor" breakpoint in Ph+ ALL encodes p185(BCR/ABL from der22 and p96(ABL/BCR from der9. The "major" breakpoint in CML encodes p210(BCR/ABL and p40(ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96(ABL/BCR and p40(ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL. METHODOLOGY: All t(9;22 derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells and human umbilical cord blood cells (UCBC. Stem cell potential was determined by replating efficiency, colony forming--spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR. PRINCIPAL FINDINGS: Both p96(ABL/BCR and p40(ABL/BCR increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96(ABL/BCR and to a minor extent p40(ABL/BCR forced the B-cell commitment of SL-cells and UCBC. CONCLUSIONS/SIGNIFICANCE: Our here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22 in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their

  20. Fractionation of Heavy Metals in Fly Ash from Wood Biomass Using the BCR Sequential Extraction Procedure.

    Science.gov (United States)

    Jukić, Mirela; Ćurković, Lidija; Šabarić, Jasenka; Kerolli-Mustafa, Mihone

    2017-08-20

    The aim of this study was to extract the wood biomass fly ash fractions by a three-stage sequential extraction method for acetic acid and ion exchangeable (BCR 1), hydroxylamine hydrochloride reduction (BCR 2), and hydrogen peroxide oxidation (BCR 3) fractions in order to access the leaching behavior of this residue. The fly ash was collected as a by-product from the processing of mixed wood biomass in Udbina combustion facility, Croatia. Concentrations of several elements (As, Cd, Cr, Cu, Ni, Pb and Zn) in all extracts were determined by inductively coupled plasma atomic emission spectrometry. The acidic exchangeable form of the metals was used to evaluate the potential ecological risk of biomass fly ash. According to calculated potential ecological risk index, it is confirmed that mobility of Ni and As has major environmental impact. However the results of potential ecological risk show that biomass fly ash had a low risk.

  1. Oridonin Triggers Chaperon-mediated Proteasomal Degradation of BCR-ABL in Leukemia

    Science.gov (United States)

    Huang, Huilin; Weng, Hengyou; Dong, Bowen; Zhao, Panpan; Zhou, Hui; Qu, Lianghu

    2017-01-01

    Inducing degradation of oncoproteins by small molecule compounds has the potential to avoid drug resistance and therefore deserves to be exploited for new therapies. Oridonin is a natural compound with promising antitumor efficacy that can trigger the degradation of oncoproteins; however, the direct cellular targets and underlying mechanisms remain unclear. Here we report that oridonin depletes BCR-ABL through chaperon-mediated proteasomal degradation in leukemia. Mechanistically, oridonin poses oxidative stress in cancer cells and directly binds to cysteines of HSF1, leading to the activation of this master regulator of the chaperone system. The resulting induction of HSP70 and ubiquitin proteins and the enhanced binding to CHIP E3 ligase hence target BCR-ABL for ubiquitin-proteasome degradation. Both wild-type and mutant forms of BCR-ABL can be efficiently degraded by oridonin, supporting its efficacy observed in cultured cells as well as mouse tumor xenograft assays with either imatinib-sensitive or -resistant cells. Collectively, our results identify a novel mechanism by which oridonin induces rapid degradation of BCR-ABL as well as a novel pharmaceutical activator of HSF1 that represents a promising treatment for leukemia. PMID:28128329

  2. Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias.

    Science.gov (United States)

    Fei, Fei; Stoddart, Sonia; Groffen, John; Heisterkamp, Nora

    2010-05-01

    The emergence of resistance to tyrosine kinase inhibitors due to point mutations in Bcr/Abl is a challenging problem for Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) patients, especially for those with the T315I mutation, against which neither nilotinib or dasatinib shows significant activity. VX-680 is a pan-Aurora kinase inhibitor active against all Bcr/Abl proteins but has not been extensively examined in preclinical models of Ph-positive ALL. Here, we have tested VX-680 for the treatment of Bcr/Abl-positive ALL when leukemic cells are protected by the presence of stroma. Under these conditions, VX-680 showed significant effects on primary human Ph-positive ALL cells both with and without the T315I mutation, including ablation of tyrosine phosphorylation downstream of Bcr/Abl, decreased viability, and induction of apoptosis. However, drug treatment of human Ph-positive ALL cells for 3 days followed by drug removal allowed the outgrowth of abnormal cells 21 days later, and on culture of mouse Bcr/Abl ALL cells on stroma with lower concentrations of VX-680, drug-resistant cells emerged. Combined treatment of human ALL cells lacking the T315I mutation with both VX-680 and dasatinib caused significantly more cytotoxicity than each drug alone. We suggest that use of VX-680 together with a second effective drug as first-line treatment for Ph-positive ALL is likely to be safer and more useful than second-line treatment with VX-680 as monotherapy for drug-resistant T315I Ph-positive ALL.

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

    Directory of Open Access Journals (Sweden)

    Sulaf Farhat-Maghribi

    2016-01-01

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

  4. MicroRNA-320a acts as a tumor suppressor by targeting BCR/ABL oncogene in chronic myeloid leukemia.

    Science.gov (United States)

    Xishan, Zhu; Ziying, Lin; Jing, Du; Gang, Liu

    2015-01-01

    Accumulating evidences demonstrated that the induction of epithelial-mesenchymal transition (EMT) and aberrant expression of microRNAs (miRNAs) are associated with tumorigenesis, tumor progression, metastasis and relapse in cancers, including chronic myeloid leukemia (CML). We found that miR-320a expression was reduced in K562 and in CML cancer stem cells. Moreover, we found that miR-320a inhibited K562 cell migration, invasion, proliferation and promoted apoptosis by targeting BCR/ABL oncogene. As an upstream regulator of BCR/ABL, miR-320a directly targets BCR/ABL. The enhanced expression of miR-320a inhibited the phosphorylation of PI3K, AKT and NF-κB; however, the expression of phosphorylated PI3K, AKT and NF-κB were restored by the overexpression of BCR/ABL. In K562, infected with miR-320a or transfected with SiBCR/ABL, the protein levels of fibronectin, vimentin, and N-cadherin were decreased, but the expression of E-cadherin was increased. The expression of mesenchymal markers in miR-320a-expressing cells was restored to normal levels by the restoration of BCR/ABL expression. Generally speaking, miR-320a acts as a novel tumor suppressor gene in CML and miR-320a can decrease migratory, invasive, proliferative and apoptotic behaviors, as well as CML EMT, by attenuating the expression of BCR/ABL oncogene.

  5. BCR-mediated apoptosis associated with negative selection of immature B cells is selectively dependent on Pten

    Institute of Scientific and Technical Information of China (English)

    Shuhua Cheng; Constance Yu Hsia; Biao Feng; Me-Ling Liou; Xiaoying Fang; Pier Paolo Pandolfi; Hsiou-Chi Liou

    2009-01-01

    The molecular basis of B cell receptor (BCR)-induced apoptosis during the negative selection of immature B cells is largely unknown. We use transitional immature B cells that are highly susceptible to BCR-induced apoptosis to show that Pten is selectively required for BCR-mediated initiation of the mitochondrial death pathway. Specifically,deleting Pten, but not other pro-apoptotic molecules, abrogates BCR-elicited apoptosis and improves viability in wild-type immature B cells. We further identify a physiologically and significantly higher intracellular Pten level in immature B cells, as compared to mature B cells, which is responsible for low AKT activity and the propensity towards death in immature B cells. Restoration of AKT activity using a constitutive form of AKT or reduction of Pten to a level comparable with that seen in mature B cells rescues immature B cells from BCR-induced apoptosis. Thus,we provide evidence that Pten is an essential mediator of BCR-induced cell death, and that differential regulation of intracellular Pten levels determines whether BCR ligation promotes cell death or survival. Our findings provide a valuable insight into the mechanisms underlying negative selection and clonal deletion of immature B cells.

  6. Hematopoietic stem cell involvement in BCR-ABL1-positive ALL as potential mechanism of resistance to blinatumomab therapy.

    Science.gov (United States)

    Nagel, Inga; Bartels, Marius; Duell, Johannes; Oberg, Hans-Heinrich; Ussat, Sandra; Bruckmueller, Henrike; Ottmann, Oliver; Pfeifer, Heike; Trautmann, Heiko; Gökbuget, Nicola; Caliebe, Almuth; Kabelitz, Dieter; Kneba, Michael; Horst, Heinz-August; Hoelzer, Dieter; Topp, Max S; Cascorbi, Ingolf; Siebert, Reiner; Brüggemann, Monika

    2017-08-21

    The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19-antigen on leukemic cells which has been established as a novel escape mechanism to CD19-specific immunotherapies. Here, we provide evidence that CD19-negative relapse after CD19-directed therapy in BCP-ALL may be due to selection of preexisting CD19-negative malignant progenitor cells. We present two BCR-ABL1-fusion-positive BCP-ALL patients with CD19-negative myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1-positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. Using the same approach in 25 additional diagnostic samples of patients with BCR-ABL1-positive BCP-ALL, HSC involvement was identified in 40% of the patients. Patients with major-BCR-ABL1 transcript encoding P210(BCR-ABL1) mainly showed HSC involvement (6/8), whereas in most of the patients with minor-BCR-ABL1 transcript encoding P190(BCR-ABL1) only the CD19-positive leukemia compartments were BCR-ABL1-positive (9/12) (p=0.02). Our data are of clinical importance, because they indicate that not only CD19-positive cells, but also CD19-negative precursors should be targeted to avoid CD19-negative relapses in patients with BCR-ABL1-positive ALL. Copyright © 2017 American Society of Hematology.

  7. 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...... myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011......) 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....

  8. Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Churchman, Michelle L; Low, Jonathan; Qu, Chunxu; Paietta, Elisabeth M; Kasper, Lawryn H; Chang, Yunchao; Payne-Turner, Debbie; Althoff, Mark J; Song, Guangchun; Chen, Shann-Ching; Ma, Jing; Rusch, Michael; McGoldrick, Dan; Edmonson, Michael; Gupta, Pankaj; Wang, Yong-Dong; Caufield, William; Freeman, Burgess; Li, Lie; Panetta, John C; Baker, Sharyn; Yang, Yung-Li; Roberts, Kathryn G; McCastlain, Kelly; Iacobucci, Ilaria; Peters, Jennifer L; Centonze, Victoria E; Notta, Faiyaz; Dobson, Stephanie M; Zandi, Sasan; Dick, John E; Janke, Laura; Peng, Junmin; Kodali, Kiran; Pagala, Vishwajeeth; Min, Jaeki; Mayasundari, Anand; Williams, Richard T; Willman, Cheryl L; Rowe, Jacob; Luger, Selina; Dickins, Ross A; Guy, R Kiplin; Chen, Taosheng; Mullighan, Charles G

    2015-09-14

    Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

  9. 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.

  10. 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.

  11. LMC y detección del gen de fusión BCR/ABL

    Directory of Open Access Journals (Sweden)

    C. G. Artigas Allaire

    2006-04-01

    Full Text Available La anormalidad citogenética más común en la leucemia mieloide crónica (LMC es el cromosoma Philadelphia producida por la translocación t(9:22, cuya expresión molecular es el gen de fusión BCR-ABL, que codifica una proteína con actividad tirosinquinasa.

  12. On Tachyons in Generic Orbifolds of $\\BC^r$ and Gauged Linear Sigma Models

    OpenAIRE

    Sarkar, Tapobrata

    2006-01-01

    We study some aspects of Gauged Linear Sigma Models corresponding to orbifold singularities of the form $\\BC^r/\\Gamma$, for $r=2,3$ and $\\Gamma = \\BZ_n$ and $\\BZ_n\\times \\BZ_m$. These orbifolds might be tachyonic in general. We compute expressions for the multi parameter sigma model Lagrangians for these orbifolds, in terms of their toric geometry data. Using this, we analyze some aspects of the phases of generic orbifolds of $\\BC^r$.

  13. 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.

  14. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia

    Science.gov (United States)

    Fei, Fei; Stoddart, Sonia; Müschen, Markus; Kim, Yong-mi; Groffen, John; Heisterkamp, Nora

    2010-01-01

    Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Ph-positive leukemias. At a once-daily dose and a relatively short half-life of 3-5 hours, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective. PMID:20111071

  15. 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.

  16. shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance.

    Science.gov (United States)

    Khorashad, Jamshid S; Eiring, Anna M; Mason, Clinton C; Gantz, Kevin C; Bowler, Amber D; Redwine, Hannah M; Yu, Fan; Kraft, Ira L; Pomicter, Anthony D; Reynolds, Kimberly R; Iovino, Anthony J; Zabriskie, Matthew S; Heaton, William L; Tantravahi, Srinivas K; Kauffman, Michael; Shacham, Sharon; Chenchik, Alex; Bonneau, Kyle; Ullman, Katharine S; O'Hare, Thomas; Deininger, Michael W

    2015-03-12

    The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-09-07

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

  18. Acute promyelocytic leukaemia in patients originating in Latin America is associated with an increased frequency of the bcr1 subtype of the PML/RARalpha fusion gene.

    Science.gov (United States)

    Douer, Dan; Santillana, Sergio; Ramezani, Laleh; Samanez, Cesar; Slovak, Marilyn L; Lee, Ming S; Watkins, Kristy; Williams, Tony; Vallejos, Carlos

    2003-08-01

    The PML/RARalpha fusion gene in acute promyelocytic leukaemia (APL) has three subtypes based on the breakpoint site of the PML gene: long (bcr1), short (bcr3) and variable (bcr2) subtypes. The PML/RARalpha fusion protein is involved in the pathogenesis of APL and the breakpoint site of the PML gene might be associated with aetiological factor(s). Because APL is over-represented in patients that originate in Latin America (Latinos), we evaluated whether the distribution of the PML/RARalpha fusion mRNA in this population is different to that reported in non-Latinos. Among 52 APL patients (28 from Mexico and Central America diagnosed in Los Angeles and 24 from Peru, South America), bcr1, bcr2 and bcr3 expression was 75%, 10% and 15% respectively. However, bcr1 breakpoints were significantly higher compared with non-Latino patients (340/654, 52%) reported in four studies. Often bcr1 and bcr2 are reported together; 862 (60%) of 1429 non-Latino APL patients reported in nine studies were either bcr1 or bcr2, compared with 44 (85%) in our 52 Latino patients. This difference was also statistically significant when our patients were compared to each of the individual studies from USA and Europe, but not for a small series from China and Japan. These results suggest that the overrepresentation of APL among Latin American patients can be accounted for by an increase of a single subtype--bcr1, and the breakage sites in the PML gene may not be random but possibly influenced by genetic and/or environmental factor(s).

  19. 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 hemokinin-1during B-cell develop...ng) (.svg) (.html) (.csml) Show Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin-1during B-cell develop...ated by interleukin-7, the preBCR, and hemokinin-1during B-cell development. Authors Milne CD, Fleming HE, Z

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

    OpenAIRE

    Janusz Blasiak; Ewelina Synowiec; Sylwester Glowacki

    2013-01-01

    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 ...

  1. Inhibition of phosphotyrosine phosphatase 1B causes resistance in BCR-ABL-positive leukemia cells to the ABL kinase inhibitor STI571.

    Science.gov (United States)

    Koyama, Noriko; Koschmieder, Steffen; Tyagi, Sandhya; Portero-Robles, Ignacio; Chromic, Jörg; Myloch, Silke; Nürnberger, Heike; Rossmanith, Tanja; Hofmann, Wolf-Karsten; Hoelzer, Dieter; Ottmann, Oliver Gerhard

    2006-04-01

    Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of BCR-ABL-mediated transformation in vitro and in vivo. To investigate whether PTP1B modulates the biological effects of the abl kinase inhibitor STI571 in BCR-ABL-positive cells, we transfected Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cell-derived K562 cells with either wild-type PTP1B (K562/PTP1B), a substrate-trapping dominant-negative mutant PTP1B (K562/D181A), or empty vector (K562/mock). Cells were cultured with or without STI571 and analyzed for its effects on proliferation, differentiation, and apoptosis. In both K562/mock and K562/PTP1B cells, 0.25 to 1 mumol/L STI571 induced dose-dependent growth arrest and apoptosis, as measured by a decrease of cell proliferation and an increase of Annexin V-positive cells and/or of cells in the sub-G(1) apoptotic phase. Western blot analysis showed increased protein levels of activated caspase-3 and caspase-8 and induction of poly(ADP-ribose) polymerase cleavage. Low concentrations of STI571 promoted erythroid differentiation of these cells. Conversely, K562/D181A cells displayed significantly lower PTP1B-specific tyrosine phosphatase activity and were significantly less sensitive to STI571-induced growth arrest, apoptosis, and erythroid differentiation. Pharmacologic inhibition of PTP1B activity in wild-type K562 cells, using bis(N,N-dimethylhydroxamido)hydroxooxovanadate, attenuated STI571-induced apoptosis. Lastly, comparison of the STI571-sensitive Ph+ acute lymphoblastic leukemia cell line SupB15 with a STI571-resistant subline revealed significantly decreased PTP1B activity and enhanced BCR-ABL phosphorylation in the STI571-resistant SupB15 cells. In conclusion, functional PTP1B is involved in STI571-induced growth and cell cycle arrest, apoptosis, and differentiation, and attenuation of PTP1B function may contribute to resistance towards STI571.

  2. BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability

    Science.gov (United States)

    Slupianek, Artur; Falinski, Rafal; Znojek, Pawel; Stoklosa, Tomasz; Flis, Sylwia; Doneddu, Valentina; Pytel, Dariusz; Synowiec, Ewelina; Blasiak, Janusz; Bellacosa, Alfonso; Skorski, Tomasz

    2013-01-01

    Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of CML-CP. Unfortunately, 25% of TKI-naive patients and 50–90% of TKI-responding patients carry CML clones expressing TKI resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species (ROS), which may result in accumulation of uracil derivatives in genomic DNA. Unfaithful and/or inefficient repair of these lesions generates TKI resistant point mutations in BCR-ABL1 kinase. Using an array of specific substrates and inhibitors/blocking antibodies we found that uracil-DNA glycosylase UNG2 were inhibited in BCR-ABL1 –transformed cell lines and CD34+ CML cells. The inhibitory effect was not accompanied by downregulation of nuclear expression and/or chromatin association of UNG2. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI we found that reduction of UNG2 activity increased the number of uracil derivatives in genomic DNA detected by modified comet assay and facilitated accumulation of ouabain-resistant point mutations in reporter gene Na+/K+ATPase. In conclusion, we postulate that BCR-ABL1 kinase-mediated inhibition of UNG2 contributes to accumulation of point mutations responsible for TKI-resistance causing the disease relapse, and perhaps also other point mutations facilitating malignant progression of CML. PMID:23047475

  3. 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

  4. 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.

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

    Science.gov (United States)

    Larripa, Irene; Ruiz, María Sol; Gutiérrez, Marina; Bianchini, Michele

    2017-01-01

    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.

  6. Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia.

    Science.gov (United States)

    Zeng, Xian; Zhao, Hui; Li, Yubin; Fan, Jiajun; Sun, Yun; Wang, Shaofei; Wang, Ziyu; Song, Ping; Ju, Dianwen

    2015-01-01

    The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.

  7. Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.

    Science.gov (United States)

    Yeh, Yuh-Ying; Ozer, Hatice Gulcin; Lehman, Amy M; Maddocks, Kami; Yu, Lianbo; Johnson, Amy J; Byrd, John C

    2015-05-21

    Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by α-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes α-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile.

  8. NS-187 (INNO-406, a Bcr-Abl/Lyn Dual Tyrosine Kinase Inhibitor

    Directory of Open Access Journals (Sweden)

    Tomoko Niwa

    2007-01-01

    Full Text Available Protein kinases catalyze the transfer of the γ-phosphoryl group of adenosine triphosphate (ATP to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today’s drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (GleevecTM in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specifi city in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (SprycelTM or bosutinib (SKI-606. Our work has led to the development of NS-187 (INNO-406, a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profi ling of NS-187, including site-directed mutagenesis experiments.

  9. 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

  10. Molecular Imaging of Bcr-Abl Phosphokinase in a Xenograft Model*

    OpenAIRE

    Wu, Ji Yuan; David J. Yang; Angelo, Laura S.; Kohanim, Saady; Kurzrock, Razelle

    2009-01-01

    The purpose of this study was to determine whether the Bcr-Abl tyrosine kinase can be assessed by gamma imaging using an 111Indium-labeled anti-phosphotyrosine antibody, and if the response to treatment with imatinib could be detected using this imaging technique. Anti-phosphotyrosine antibody (APT) was labeled with indium (111In) using ethylenedicysteine (EC) as a chelator. To determine if 111In-EC-APT could assess a non-receptor tyrosine kinase, xenografts of the human chronic myelogenous l...

  11. Recent developments in the third generation inhibitors of Bcr-Abl for overriding T315I mutation.

    Science.gov (United States)

    Lu, X Y; Cai, Q; Ding, K

    2011-01-01

    In the treatment of chronic myeloid leukemia (CML) with Bcr-Abl kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents, such as imatinib, nilotinib and dasatinib, by discrupting important contact interactions between the inhibitors and the enzyme. To overcome this particular resistance, several different strategies have been explored and many molecules have been investigated as capable of potently inhibiting Bcr-Abl T315I. Herein, this review reports on some predominant examples of third generation inhibitors of Bcr-Abl active against the T315I mutation, and special attentions are paid to the "hybrid-design" strategy for creating type-II class ATP-competitive inhibitors.

  12. BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance.

    Science.gov (United States)

    Kuraoka, Masayuki; Snowden, Pilar B; Nojima, Takuya; Verkoczy, Laurent; Haynes, Barton F; Kitamura, Daisuke; Kelsoe, Garnett

    2017-02-14

    Activation-induced cytidine deaminase (AID) is required to purge autoreactive immature and transitional-1 (immature/T1) B cells at the first tolerance checkpoint, but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR) and endosomal Toll-like receptor (TLR) signals synergize to elicit high levels of AID expression in immature/T1 B cells. This synergy is restricted to ligands for endocytic TLR and requires phospholipase-D activation, endosomal acidification, and MyD88. The first checkpoint is significantly impaired in AID- or MyD88-deficient mice and in mice doubly heterozygous for AID and MyD88, suggesting interaction of these factors in central B cell tolerance. Moreover, administration of chloroquine, an inhibitor of endosomal acidification, results in a failure to remove autoreactive immature/T1 B cells in mice. We propose that a BCR/TLR pathway coordinately establishes central tolerance by hyper-activating AID in immature/T1 B cells that bind ligands for endosomal TLRs.

  13. Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia.

    Science.gov (United States)

    Trino, Stefania; De Luca, Luciana; Simeon, Vittorio; Laurenzana, Ilaria; Morano, Annalisa; Caivano, Antonella; La Rocca, Francesco; Pietrantuono, Giuseppe; Bianchino, Gabriella; Grieco, Vitina; Signorino, Elisabetta; Fragasso, Alberto; Bochicchio, Maria Teresa; Venturi, Claudia; Rosti, Gianantonio; Martinelli, Giovanni; Del Vecchio, Luigi; Cilloni, Daniela; Musto, Pellegrino

    2016-01-01

    Endocytosis is the major regulator process of tyrosine kinase receptor (RTK) functional activities. Bridging integrator 1 (BIN1) is a key protein involved in RTK intracellular trafficking. Here, we report, by studying 34 patients with chronic myeloid leukemia (CML) at diagnosis, that BIN1 gene is downregulated in CML as compared to healthy controls, suggesting an altered endocytosis of RTKs. Rab interactor 1 (RIN1), an activator of BIN1, displayed a similar behavior. Treatment of 57 patients by tyrosine kinase inhibitors caused, along with BCR-ABL1 inactivation, an increase of BIN1 and RIN1 expression, potentially restoring endocytosis. There was a significant inverse correlation between BIN1-RIN1 and BCR-ABL1 expression. In vitro experiments on both CML and nontumorigenic cell lines treated with Imatinib confirmed these results. In order to provide another proof in favor of BIN1 and RIN1 endocytosis function in CML, we demonstrated that Imatinib induced, in K562 cell line, BIN1-RIN1 upregulation accompanied by a parallel AXL receptor internalization into cytoplasmic compartment. This study shows a novel deregulated mechanism in CML patients, indicating BIN1 and RIN1 as players in the maintenance of the abnormal RTK signaling in this hematological disease.

  14. Janus kinase 2 mutations in cases with BCR-ABL-negative chronic myeloproliferative disorders from Turkey

    Science.gov (United States)

    Yildiz, Ismail; Yokuş, Osman; Gedik, Habip

    2017-01-01

    Objective: We aimed to investigate the frequency of Janus kinase 2 (JAK2) mutations in cases with chronic myeloproliferative disorders (CMDs), and the relationship between the presence of JAK2 mutation and leukocytosis and splenomegaly, retrospectively. Materials and Methods: Patients, who were diagnosed with BCR-ABL-negative CMDs according to diagnosis criteria of the World Health Organization and followed up at the hematology clinic between 2013 and 2015, were investigated in terms of the frequency of JAK2 mutation in cases with CMDs, and the relationship between the presence of JAK2 mutation and leukocytosis and splenomegaly, retrospectively. Results: In total, 100 patients, who were diagnosed with BCR-ABL-negative CMDs, were evaluated retrospectively. The mean age of the patients with JAK2 positivity was significantly higher compared to patients with negative. JAK2-positivity rates in the age groups were significantly different. Gender, diagnosis, splenomegaly, and leukocytosis were not statistically different for JAK2 positivity between the groups. Conclusion: JAK2 V617F mutation is more commonly seen in older age as a risk for complications related to CDMS. Splenomegaly and leukocytosis are not associated with JAK2 V617F mutation. PMID:28182037

  15. BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance

    Directory of Open Access Journals (Sweden)

    Masayuki Kuraoka

    2017-02-01

    Full Text Available Activation-induced cytidine deaminase (AID is required to purge autoreactive immature and transitional-1 (immature/T1 B cells at the first tolerance checkpoint, but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR and endosomal Toll-like receptor (TLR signals synergize to elicit high levels of AID expression in immature/T1 B cells. This synergy is restricted to ligands for endocytic TLR and requires phospholipase-D activation, endosomal acidification, and MyD88. The first checkpoint is significantly impaired in AID- or MyD88-deficient mice and in mice doubly heterozygous for AID and MyD88, suggesting interaction of these factors in central B cell tolerance. Moreover, administration of chloroquine, an inhibitor of endosomal acidification, results in a failure to remove autoreactive immature/T1 B cells in mice. We propose that a BCR/TLR pathway coordinately establishes central tolerance by hyper-activating AID in immature/T1 B cells that bind ligands for endosomal TLRs.

  16. Microstructure and Wear Analysis of FeBCr Based Coating Deposited by HVOF Method

    Directory of Open Access Journals (Sweden)

    M.S. Priyan

    2014-06-01

    Full Text Available Thermally sprayed coatings that are based on FeBCr-related alloy powders are widely used to improve properties such as the surface hardness and wear resistance of a variety of coated metal substrate materials. Gray cast iron is widely used in the automobile industry due to its low cost and performance. In this work Gray cast iron substrate is coated with FeBCr alloy powder to improve its performance. The microstructure and micro abrasive wear performance of both the uncoated substrates and the coated substrates were characterized by optical microscopy as well as by Scanning Electron Microscope (SEM. In addition, X-ray Diffraction (XRD was undertaken in the partial characterization of the coating. The densely layered coating had porosity levels that were below 2.5 % and a high surface hardness, of the order of 980 HV0.1. The coating exhibited excellent wear resistance when subjected to the ball-cratering test method. The low coefficients of friction of hard coating on the substrate were recorded. The wear performance of the coating was nearly 82 % better than that of the substrate, with a 0.05 N load, even under severe three body abrasive conditions.

  17. A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant Cmls

    Science.gov (United States)

    2008-05-01

    10% SDS-PAGE and analyzed for indicated proteins by infrared labeled secondary antibodies and scanning with Odyssey scanner ( LiCor Technology). pBcr...proteins by infrared labeled secondary antibodies and scanning with Odyssey scanner ( LiCor Technology). 10 treated 32D/T315I-BCR-ABL cells with increasing...with Odyssey scanner ( LiCor Technology). V G 0.5 1.0 2.5 5.0 0.5 1.0 2.5 5.0 (µM

  18. 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

  19. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.

    Science.gov (United States)

    Zabriskie, Matthew S; Eide, Christopher A; Tantravahi, Srinivas K; Vellore, Nadeem A; Estrada, Johanna; Nicolini, Franck E; Khoury, Hanna J; Larson, Richard A; Konopleva, Marina; Cortes, Jorge E; Kantarjian, Hagop; Jabbour, Elias J; Kornblau, Steven M; Lipton, Jeffrey H; Rea, Delphine; Stenke, Leif; Barbany, Gisela; Lange, Thoralf; Hernández-Boluda, Juan-Carlos; Ossenkoppele, Gert J; Press, Richard D; Chuah, Charles; Goldberg, Stuart L; Wetzler, Meir; Mahon, Francois-Xavier; Etienne, Gabriel; Baccarani, Michele; Soverini, Simona; Rosti, Gianantonio; Rousselot, Philippe; Friedman, Ran; Deininger, Marie; Reynolds, Kimberly R; Heaton, William L; Eiring, Anna M; Pomicter, Anthony D; Khorashad, Jamshid S; Kelley, Todd W; Baron, Riccardo; Druker, Brian J; Deininger, Michael W; O'Hare, Thomas

    2014-09-08

    Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph(+)) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph(+) leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.

  20. Application of BCR-ABL in chronic myelogenous leukemia%BCR-ABL探针在慢性粒细胞白血病中的应用

    Institute of Scientific and Technical Information of China (English)

    李娟; 陆莉; 蒲育栋; 杨柳; 赵丽

    2009-01-01

    目的 用常规细胞遗传学(conventional cytogenetics,CC)和荧光原位杂交(fluorescence chromosomal in situ hybridization,FISH)技术检测Ph染色体.方法 常规细胞遗传学分析(CC),荧光原位杂交(FISH)技术.结果 7例患者4例Ph染色体阴性,其中2例分别伴有t(18;22)和t(17;22)异常,其余2例为异基因造血干细胞移植后正常核型.一例培养后无中期分裂相.2例Ph染色体阳性,FISH结果bcr/abl(+)细胞检出率分别为63.87%,84.51%,7.56%,4.0%,74.45%,67%,47%.结论 常规细胞遗传学与荧光原位杂交技术相结合对CML患者诊断治疗过程中肿瘤负荷动态检测有显著意义.

  1. Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate.

    Directory of Open Access Journals (Sweden)

    C James Chou

    Full Text Available Chronic myeloid leukemia (CML is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.

  2. Growth Arrest of BCR-ABL Positive Cells with a Sequence-Specific Polyamide-Chlorambucil Conjugate

    Science.gov (United States)

    Chou, C. James; O'Hare, Thomas; Lefebvre, Sophie; Alvarez, David; Tyner, Jeffrey W.; Eide, Christopher A.; Druker, Brian J.; Gottesfeld, Joel M.

    2008-01-01

    Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model. PMID:18974832

  3. A multiple reaction monitoring (MRM method to detect Bcr-Abl kinase activity in CML using a peptide biosensor.

    Directory of Open Access Journals (Sweden)

    Tzu-Yi Yang

    Full Text Available The protein kinase Bcr-Abl plays a major role in the pathogenesis of chronic myelogenous leukemia (CML, and is the target of the breakthrough drug imatinib (Gleevec™. While most patients respond well to imatinib, approximately 30% never achieve remission or develop resistance within 1-5 years of starting imatinib treatment. Evidence from clinical studies suggests that achieving at least 50% inhibition of a patient's Bcr-Abl kinase activity (relative to their level at diagnosis is associated with improved patient outcomes, including reduced occurrence of resistance and longer maintenance of remission. Accordingly, sensitive assays for detecting Bcr-Abl kinase activity compatible with small amounts of patient material are desirable as potential companion diagnostics for imatinib. Here we report the detection of Bcr-Abl activity and inhibition by imatinib in the human CML cell line K562 using a cell-penetrating peptide biosensor and multiple reaction monitoring (MRM on a triple quadrupole mass spectrometer. MRM enabled reproducible, selective detection of the peptide biosensor at fmol levels from aliquots of cell lysate equivalent to ~15,000 cells. This degree of sensitivity will facilitate the miniaturization of the entire assay procedure down to cell numbers approaching 15,000, making it practical for translational applications in patient cells in which the limited amount of available patient material often presents a major challenge.

  4. Mutations of Cx43 that affect B cell spreading in response to BCR signaling

    Directory of Open Access Journals (Sweden)

    Letitia Falk

    2014-07-01

    Full Text Available The gap junction (GJ protein connexin 43 (Cx43 is both necessary and sufficient for B cell receptor (BCR-mediated cell spreading. To address how Cx43 mediates this effect, we blocked its function genetically, by expressing mutants of Cx43, and pharmacologically, by using chemical inhibitors. While various point mutations of Cx43 inhibited B cell spreading, treatment with channel blocking drugs did not, suggesting that this response was independent of channel function. The critical region of Cx43 appears to be the cytoplasmic carboxyl-terminal (CT domain, which has previously been shown to be important for B cell spreading. Consistent with this, mutations of either tyrosine 247 or 265 found in the CT were sufficient to inhibit spreading. Thus Cx43 may influence B cell spreading by mechanisms requiring protein binding to, or modification of, these sites in the CT tail.

  5. 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.

  6. 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.

  7. BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability.

    Science.gov (United States)

    Slupianek, A; Falinski, R; Znojek, P; Stoklosa, T; Flis, S; Doneddu, V; Pytel, D; Synowiec, E; Blasiak, J; Bellacosa, A; Skorski, T

    2013-03-01

    Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in chronic phase (CML-CP). Unfortunately, 25% of TKI-naive patients and 50-90% of patients developing TKI-resistance carry CML clones expressing TKI-resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species, which may result in accumulation of uracil derivatives in genomic DNA. Unfaithful and/or inefficient repair of these lesions generates TKI-resistant point mutations in BCR-ABL1 kinase. Using an array of specific substrates and inhibitors/blocking antibodies we found that uracil DNA glycosylase UNG2 were inhibited in BCR-ABL1-transformed cell lines and CD34(+) CML cells. The inhibitory effect was not accompanied by downregulation of nuclear expression and/or chromatin association of UNG2. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI, we found that reduction of UNG2 activity increased the number of uracil derivatives in genomic DNA detected by modified comet assay and facilitated accumulation of ouabain-resistant point mutations in reporter gene Na(+)/K(+)ATPase. In conclusion, we postulate that BCR-ABL1 kinase-mediated inhibition of UNG2 contributes to accumulation of point mutations responsible for TKI resistance causing the disease relapse, and perhaps also other point mutations facilitating malignant progression of CML.

  8. Transcription Factors Efg1 and Bcr1 Regulate Biofilm Formation and Virulence during Candida albicans-Associated Denture Stomatitis.

    Science.gov (United States)

    Yano, Junko; Yu, Alika; Fidel, Paul L; Noverr, Mairi C

    2016-01-01

    Denture stomatitis (DS) is characterized by inflammation of the oral mucosa in direct contact with dentures and affects a significant number of otherwise healthy denture wearers. The disease is caused by Candida albicans, which readily colonizes and form biofilms on denture materials. While evidence for biofilms on abiotic and biotic surfaces initiating Candida infections is accumulating, a role for biofilms in DS remains unclear. Using an established model of DS in immunocompetent animals, the purpose of this study was to determine the role of biofilm formation in mucosal damage during pathogenesis using C. albicans or mutants defective in morphogenesis (efg1-/-) or biofilm formation (bcr1-/-). For in vivo analyses, rats fitted with custom dentures, consisting of fixed and removable parts, were inoculated with wild-type C. albicans, mutants or reconstituted strains and monitored weekly for fungal burden (denture and palate), body weight and tissue damage (LDH) for up to 8 weeks. C. albicans wild-type and reconstituted mutants formed biofilms on dentures and palatal tissues under in vitro, ex vivo and in vivo conditions as indicated by microscopy demonstrating robust biofilm architecture and extracellular matrix (ECM). In contrast, both efg1-/- and bcr1-/- mutants exhibited poor biofilm growth with little to no ECM. In addition, quantification of fungal burden showed reduced colonization throughout the infection period on dentures and palates of rats inoculated with efg1-/-, but not bcr1-/-, compared to controls. Finally, rats inoculated with efg1-/- and bcr1-/- mutants had minimal palatal tissue damage/weight loss while those inoculated with wild-type or reconstituted mutants showed evidence of tissue damage and exhibited stunted weight gain. These data suggest that biofilm formation is associated with tissue damage during DS and that Efg1 and Bcr1, both central regulators of virulence in C. albicans, have pivotal roles in pathogenesis of DS.

  9. Transcription Factors Efg1 and Bcr1 Regulate Biofilm Formation and Virulence during Candida albicans-Associated Denture Stomatitis.

    Directory of Open Access Journals (Sweden)

    Junko Yano

    Full Text Available Denture stomatitis (DS is characterized by inflammation of the oral mucosa in direct contact with dentures and affects a significant number of otherwise healthy denture wearers. The disease is caused by Candida albicans, which readily colonizes and form biofilms on denture materials. While evidence for biofilms on abiotic and biotic surfaces initiating Candida infections is accumulating, a role for biofilms in DS remains unclear. Using an established model of DS in immunocompetent animals, the purpose of this study was to determine the role of biofilm formation in mucosal damage during pathogenesis using C. albicans or mutants defective in morphogenesis (efg1-/- or biofilm formation (bcr1-/-. For in vivo analyses, rats fitted with custom dentures, consisting of fixed and removable parts, were inoculated with wild-type C. albicans, mutants or reconstituted strains and monitored weekly for fungal burden (denture and palate, body weight and tissue damage (LDH for up to 8 weeks. C. albicans wild-type and reconstituted mutants formed biofilms on dentures and palatal tissues under in vitro, ex vivo and in vivo conditions as indicated by microscopy demonstrating robust biofilm architecture and extracellular matrix (ECM. In contrast, both efg1-/- and bcr1-/- mutants exhibited poor biofilm growth with little to no ECM. In addition, quantification of fungal burden showed reduced colonization throughout the infection period on dentures and palates of rats inoculated with efg1-/-, but not bcr1-/-, compared to controls. Finally, rats inoculated with efg1-/- and bcr1-/- mutants had minimal palatal tissue damage/weight loss while those inoculated with wild-type or reconstituted mutants showed evidence of tissue damage and exhibited stunted weight gain. These data suggest that biofilm formation is associated with tissue damage during DS and that Efg1 and Bcr1, both central regulators of virulence in C. albicans, have pivotal roles in pathogenesis of DS.

  10. Changes in the proteome associated with the action of Bcr-Abl tyrosine kinase are not related to transcriptional regulation.

    Science.gov (United States)

    Smith, Duncan L; Evans, Caroline A; Pierce, Andrew; Gaskell, Simon J; Whetton, Anthony D

    2002-11-01

    Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease, the hallmark of which is the Bcr-Abl protein tyrosine kinase (PTK). Without intervention the disease progresses from a benign chronic phase to a rapidly fatal blast crisis. To identify the molecular mechanisms underlying disease progression we used two-dimensional gel electrophoresis on a model we have previously described using the expression of a conditional mutant of Bcr-Abl PTK in a multipotent stem cell line, FDCP-Mix. Long term exposure of FDCP-Mix cells to Bcr-Abl mimics disease progression in CML. Four major differences were observed as a consequence of long term exposure to the Bcr-Abl PTK compared with cells exposed short term. The proteins were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry-generated peptide mass fingerprint data and liquid chromatography-tandem mass spectrometry-generated sequence information. Leukotriene A4 hydrolase, an enzyme known to be deregulated in CML, was found to be up-regulated. Annexin VI, vacuolar ATP synthase catalytic subunit A, and mortalin were found to be down-regulated. Poly(A) PCR cDNA analysis showed there was no correlation between the protein expression changes and mRNA levels. Western blot analysis also indicated no change in the levels of mortalin or leukotriene A4 hydrolase, indicating that post-translational events may modify protein content of the specific spots. Leukotriene B4 levels (product of leukotriene A4 hydrolase) were, however, reduced in cells exposed long term to Bcr-Abl activity. This study demonstrates the potential of proteomic analysis to define novel effects of oncogenes.

  11. CCR7 is involved in BCR-ABL/STAP-2-mediated cell growth in hematopoietic Ba/F3 cells.

    Science.gov (United States)

    Kubo, Kaori; Iwakami, Masashi; Muromoto, Ryuta; Inagaki, Takuya; Kitai, Yuichi; Kon, Shigeyuki; Sekine, Yuichi; Oritani, Kenji; Matsuda, Tadashi

    2015-08-07

    Chronic myeloid leukemia is a clonal disease characterized by the presence of the Philadelphia chromosome and its oncogenic product, BCR-ABL, which activates multiple pathways involved in cell survival, growth promotion, and disease progression. We previously reported that in murine hematopoietic Ba/F3 cells, signal transducing adaptor protein-2 (STAP-2) binds to BCR-ABL and up-regulates BCR-ABL phosphorylation, leading to enhanced activation of its downstream signaling molecules. The binding of STAP-2 to BCR-ABL also influenced the expression levels of chemokine receptors, such as CXCR4 and CCR7. For the induction of CCR7 expression, signals mediated by the MAPK/ERK pathway were critical in Ba/F3 cells expressing BCR-ABL and STAP-2. In addition, STAP-2 cooperated with BCR-ABL to induce the production of CCR7 ligands, CCL19 and CCL21. Our results demonstrate a contribution of CCR7 to STAP-2-dependent enhancement of BCR-ABL-mediated cell growth in Ba/F3 cells.

  12. Comparative study of DNA damage, cell cycle and apoptosis in human K562 and CCRF-CEM leukemia cells: role of BCR/ABL in therapeutic resistance.

    Science.gov (United States)

    Pytel, Dariusz; Wysocki, Tomasz; Majsterek, Ireneusz

    2006-09-01

    The Philadelphia translocation t(9;22) resulting in the bcr/abl fusion gene is the pathogenic principle of almost 95% of human chronic myelogenous leukemia (CML). Imatinib mesylate (STI571) is a specific inhibitor of the BCR/ABL fusion tyrosine kinase that exhibits potent antileukemic effects in CML. BCR/ABL-positive K562 and -negative CCRF-CEM human leukemia cells were investigated. MTT survival assay and clonogenic test of the cell proliferation ability were used to estimate resistance against idarubicin. DNA damage after cell treatment with the drug at the concentrations from 0.001 to 3 microM with or without STI571 pre-treatment were examined by the alkaline comet assay. We found that the level of DNA damages was lower in K562 cells after STI571 pre-treatment. It is suggested that BCR/ABL activity may promote genomic instability, moreover K562 cells were found to be resistant to the drug treatment. Further, we provided evidence of apoptosis inhibition in BCR/ABL-positive cells using caspase-3 activity colorimetric assay and DAPI nuclear staining for chromatin condensation. We suggest that these processes associated with cell cycle arrest in G2/M checkpoint detected in K562 BCR/ABL-positive compared to CCRF-CEM cells without BCR/ABL expression might promote clone selection resistance to drug treatment.

  13. Optimal Molecular Methods in Detecting p190BCR-ABL Fusion Variants in Hematologic Malignancies: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Rebecca J. Sonu

    2015-01-01

    Full Text Available Patients with BCR-ABL1 positive hematologic malignancies and Philadelphia-like B-lymphoblastic leukemia (B-ALL are potential candidates for targeted therapy with tyrosine kinase inhibitors (TKI. Before TKIs, patients with B-ALL had a much worse prognosis and current treatments with targeted TKI therapy have improved outcomes. Thus, the detection of BCR-ABL1 is crucial and a false negative BCR-ABL1 result may adversely affect patient care. We report a case of a 76-year-old male with a new diagnosis of B-ALL who was initially found to be BCR-ABL1 negative by quantitative polymerase chain reaction (PCR. A concurrent qualitative PCR was performed which detected a positive BCR-ABL1 result that was confirmed by a next generation sequencing (NGS based assay and identified as the rare fusion variant e1a3 of p190BCR-ABL. Based on this result, the patient was placed on dasatinib as a targeted therapy. In the era of molecular diagnostic medicine and targeted therapy, it is essential to have an understanding of the limitations of molecular assays and to follow a comprehensive diagnostic approach in order to detect common abnormalities and rare variants. Incorporating NGS methods in an algorithmic manner into the standard diagnostic PCR-based approach for BCR-ABL1 will aid in minimizing false negative results.

  14. The NDR/LATS kinase Cbk1 controls the activity of the transcriptional regulator Bcr1 during biofilm formation in Candida albicans.

    Directory of Open Access Journals (Sweden)

    Pilar Gutiérrez-Escribano

    Full Text Available In nature, many microorganisms form specialized complex, multicellular, surface-attached communities called biofilms. These communities play critical roles in microbial pathogenesis. The fungal pathogen Candida albicans is associated with catheter-based infections due to its ability to establish biofilms. The transcription factor Bcr1 is a master regulator of C. albicans biofilm development, although the full extent of its regulation remains unknown. Here, we report that Bcr1 is a phosphoprotein that physically interacts with the NDR kinase Cbk1 and undergoes Cbk1-dependent phosphorylation. Mutating the two putative Cbk1 phosphoacceptor residues in Bcr1 to alanine markedly impaired Bcr1 function during biofilm formation and virulence in a mouse model of disseminated candidiasis. Cells lacking Cbk1, or any of its upstream activators, also had reduced biofilm development. Notably, mutating the two putative Cbk1 phosphoacceptor residues in Bcr1 to glutamate in cbk1Δ cells upregulated the transcription of Bcr1-dependent genes and partially rescued the biofilm defects of a cbk1Δ strain. Therefore, our data uncovered a novel role of the NDR/LATS kinase Cbk1 in the regulation of biofilm development through the control of Bcr1.

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

    Directory of Open Access Journals (Sweden)

    Cao Qi

    2010-05-01

    Full Text Available Abstract 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

  16. Detection of BCR/ABL Fusion Gene by Fluorescence In Situ Hybridization and Its Clinical Application%荧光原位杂交技术检测BCR/ABL融合基因的临床应用

    Institute of Scientific and Technical Information of China (English)

    周瑞莲; 莫耀禧; 蓝梅; 林金盈

    2011-01-01

    This study was aimed to investigate the clinical value of detecting BCR/ABL fusion gene by fluorescence in situ hybridization (FISH). The conventional cytogenetic test and detection of BCR/ABL fusion gene by FISH for bone marrow of patients with newly diagnosed chronic myeloproliferative disease or myelodysplastic and myeloproliferative disorders, acute lymphocytic leukemia and chronic myelogeneous leukemia (CML) after allogeneic hematopoietic stem cell transplantation were carried out. The results showed that ( 1 ) out of 46 newly diagnosed as chronic myeloproliferative dsease or myelodysplastic and myeloproliferative disorders, 22 cases were diagnosed as CML, the FISH detection showed all positive (100% ), while cytogenetic test showed 86.4% (19/22) positive, in the other 24 patients who were diagnosed as other chronic myeloproliferative disease or myelodysplastic and myeloproliferative disorders, BCR/ABL fusion gene all were be detected as regative 100% by FISH, while the cytogenetic test of bone marrow in 3 cases supported the diagnosis of CML, and the diagnosis of myelodysplastic disorder in 1 case; (2) in 3 out of 7 acute lymphocytic leukemia cases the BCR/ABL fusion gene could not be detected by FISH; (3) the BCR/ABL fusion gene could be detected by FISH in 2 cases of CML received allogeneic hematopoietic stem cell transplantation, with abnormal threshold 6.5% and 1. 2% respectively. It is concluded that the detection of BCR/ABL fusion gene by FISH is sensitive and reliable, which is very important for the diagnosis and differential dignosis of chronic myeloproliferative disorders, myelodysplastic and myeloproliferative disease, as well as definite diagnosis of Ph* acute lymphoblastic leukemia. This method also has an important significance for monitor of minimal residual disease in CML patients received allogeneic hematopoietic stem cell transplantation.%本研究探讨应用荧光原位杂交技术( FISH)检测BCR/ABL融合基因在临床中的应用价

  17. Ability of 3 extraction methods (BCR, Tessier and protease K) to estimate bioavailable metals in sediments from Huelva estuary (Southwestern Spain).

    Science.gov (United States)

    Rosado, Daniel; Usero, José; Morillo, José

    2016-01-15

    The bioavailable fraction of metals (Zn, Cu, Cd, Mn, Pb, Ni, Fe, and Cr) in sediments of the Huelva estuary and its littoral of influence has been estimated carrying out the most popular methods of sequential extraction (BCR and Tessier) and a biomimetic approach (protease K extraction). Results were compared to enrichment factors found in Arenicola marina. The linear correlation coefficients (R(2)) obtained between the fraction mobilized by the first step of the BCR sequential extraction, by the sum of the first and second steps of the Tessier sequential extraction, and by protease K, and enrichment factors in A. marina, are at their highest for protease K extraction (0.709), followed by BCR first step (0.507) and the sum of the first and second steps of Tessier (0.465). This observation suggests that protease K represents the bioavailable fraction more reliably than traditional methods (BCR and Tessier), which have a similar ability.

  18. 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.

  19. Kriging analysis of geochemical data obtained by sequential extraction procedure (BCR)

    Science.gov (United States)

    Fajkovic, Hana; Pitarević Svedružić, Lovorka; Prohić, Esad; Rončević, Sanda; Nemet, Ivan

    2015-04-01

    Field examination and laboratory analysis were performed to establish whether nonsanitary landfill Bastijunski brig has a negative influence on Vransko Lake, situated only 1500 m away. Vransko Lake is Croatia's largest natural lake, and it is a part of the Nature Park and ornithological reserve, which indicates its high biodiversity. Therefore it is necessary to understand the environmental processes and complex sediment/water interface. Lake sediments are considered to be a good "sinkhole'and are often the final recipients of anthropogenic and natural pollutants through adsorption onto the organic or clay fraction in sediments. Geochemical investigation were obtained throughout more than 50 lake sediments cores situated in different parts of the lake Speciation of heavy metals by modified BCR sequential extraction procedure with the addition of a first step of sequential extraction procedure by Tessier and analysis of residual by aqua regia were used to determine the amounts of selected elements (Al, Cd, Cr, Co, Cu, Fe, Mn, Ni, Pb, Zn) in different fractions. With such approach it is possible to determine which element will be extracted from sediment/soil in a different environmental conditions and can be valuable tool for interpretation of the mobile fraction of the elements, considered bioavailability, that present threat to biota in a case of a contaminant concentration magnification. All sediment and soil samples were analyzed by inductively coupled plasma atomic emission spectrometry. More accurate interpretation of data is an advantage of BCR sequential extraction procedure while high number of the data together with point data type could be considered as a drawback. Due to high amount of data, graphical presentation is advisable while interpolation tool is a first choice for point type of data, as it makes predictions for defined area based on the measurements. Distribution maps of analysed elements were obtained by kriging as a geostatistical method and

  20. Quantification of BCR-ABL mRNA in Plasma/Serum of Patients with Chronic Myelogenous Leukemia

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    Miwako Narita, Anri Saito, Aya Kojima, Minami Iwabuchi, Naoya Satoh, Takayoshi Uchiyama, Akie Yamahira, Tatsuo Furukawa, Hirohito Sone, Masuhiro Takahashi

    2012-01-01

    Full Text Available Quantification of tumor-associated mRNA extracted from blood cells/tissues containing tumor cells is used for evaluation of treatment efficacy or residual tumor cell burden in tumors including leukemia. However, this method using tumor cell-containing blood/tissue is difficult to evaluate the whole tumor cell burden in the body. In order to establish an efficient method to evaluate the whole tumor cell burden in the body, we tried to quantify tumor-associated mRNA existing in plasma/serum instead of leukemia cell-containing blood cells in patients with chronic myelogenous leukemia (CML and compared the levels of BCR-ABL mRNA between plasma/serum and peripheral blood cells. mRNA of BCR-ABL, WT1 or GAPDH (control molecule was detected by real-time RT-PCR using RNA extracted from plasma/serum of almost all the patients with CML. Copy numbers of BCR-ABL mRNA were significantly correlated between plasma/serum and peripheral blood cells. However, levels of BCR-ABL mRNA extracted from serum were low compared with those extracted with peripheral blood cells. The present findings suggest that although real-time RT-PCR of mRNA existing in plasma/serum could be used for evaluating the whole tumor cell burden in the body, it's required to establish an efficient method to quantify plasma/serum mRNA by nature without degrading during the procedure.

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

    Science.gov (United States)

    2010-05-01

    diverse client proteins. Biopolymers 2009. 41. Tsuruma R, Ohbayashi N, Kamitani S, et al. Physical and functional interactions between STAT3 and...compounds to significantly inhibit the proliferation of K562 and Ba/F3:JAK2V617F cells suggests that this scaffold could be a promising lead for the... scaffold could be a promising lead for the development of anticancer agents that are able to block BCR-ABL phosphorylation in leuke- mic cells. 2010

  2. 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

    2014-01-01

    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 2nd 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. PMID:24598855

  3. 血液病患者bcr/abl融合基因、Ph染色体异同浅谈

    Institute of Scientific and Technical Information of China (English)

    王旭萍

    2011-01-01

    @@ CML特异性费城染色体(Philadephia,Ph)是由t(9:22)(q34:11)易位形成.9号染色体原癌基因abl(Abelson protooncogene)易位至22号染色体的断裂点簇集区(breakpoint duster region,ber),发生重排,产生bcr/abl融合基因,引起CML的始动突变.融合基因bcr/abl几乎见于所有的慢性粒细胞性白血病、25%-50%的急性B系淋巴细胞性白血病(ALL)和约5%的急性粒细胞性白血病中J,本文统计了进行染色体和bcr/abl融合基因检查的初诊血液病66例,对其骨髓细胞染色体核型及ber/~1融合基因进行分析.

  4. Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase.

    Science.gov (United States)

    Steinhardt, James J; Peroutka, Raymond J; Mazan-Mamczarz, Krystyna; Chen, Qing; Houng, Simone; Robles, Carol; Barth, Rolf N; DuBose, Joseph; Bruns, Brandon; Tesoriero, Ronald; Stein, Deborah; Fang, Raymond; Hanna, Nader; Pasley, Jason; Rodriguez, Carlos; Kligman, Mark D; Bradley, Matthew; Rabin, Joseph; Shackelford, Stacy; Dai, Bojie; Landon, Ari L; Scalea, Thomas; Livak, Ferenc; Gartenhaus, Ronald B

    2014-12-11

    Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5' untranslated region (UTR). Oncogenes with complex 5'UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5'UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G(+) splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM(+) B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.

  5. [Detection of BCR-ABL1 chimeric gene-positive neutrophils in a patient with mixed phenotype acute leukemia].

    Science.gov (United States)

    Nagasawa, Fusako; Nakamura, Yukitsugu; Tokita, Katsuya; Takahashi, Wataru; Iso, Hisako; Arai, Honoka; Tsurumi, Shigeharu; Handa, Tomoyuki; Nakamura, Yuko; Nakamura, Yuka; Sasaki, Ko; Mitani, Kinuko

    2013-11-01

    We experienced two patients with mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1 according to the WHO classification 2008. The type of BCR/ABL1 was major in both patients, and the chimeric gene was also detected in neutrophils from peripheral blood by the fluorescence in situ hybridization technique. Patient 1 was a 59-year-old Japanese woman, and patient 2 a 45-year-old Japanese man. They had both developed leukemia suddenly. Their leukemic blasts expressed B cell and myeloid cell antigens, but concomitantly in patient 1 (biphenotypic) and separately in patient 2 (biclonal). Percentages of BCR-ABL1-positive neutrophils were 98% and 89%, respectively. Both patients received an imatinib (600 mg/day)-combined Hyper-CVAD regimen as induction therapy, followed by treatment with dasatinib (140 mg/day). MEC therapy was also applied between these two treatments in patient 2. At present, patient 1 has obtained complete molecular remission quantitatively and qualitatively, and patient 2 only quantitatively. Considering their acute onsets with no prior history of chronic myelocytic leukemia (CML), they were both diagnosed as having acute leukemia with Ph1, but not blastic crisis of CML. In this tyrosine kinase inhibitor era, it has become more difficult to differentiate these two types of Ph1-positive leukemia development.

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

    Science.gov (United States)

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

    2016-04-15

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

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

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    Anna Grazia Recchia

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

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

    Science.gov (United States)

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

    2015-01-01

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

  10. Migration of antibody secreting cells towards CXCL12 depends on the isotype that forms the BCR

    Science.gov (United States)

    Achatz-Straussberger, Gertrude; Zaborsky, Nadja; Königsberger, Sebastian; Luger, Elke O.; Lamers, Marinus; Crameri, Reto; Achatz, Gernot

    2010-01-01

    Truncation of the cytoplasmic tail of membrane-bound IgE in vivo results in lower serum IgE levels, decreased numbers of IgE-secreting plasma cells and the abrogation of specific secondary immune responses. Here we present mouse strain KN1 that expresses a chimeric ε-γ1 BCR, consisting of the extracellular domains of the ε gene and the trans-membrane and cytoplasmic domains of the γ1 gene. Thus, differences in the IgE immune response of KN1 mice reflect the influence of the “γ1-mediated signalling” of mIgE bearing B cells. KN1 mice show an increased serum IgE level, resulting from an elevated number of IgE-secreting cells. Although the primary IgE immune response in KN1 mice is inconspicuous, the secondary response is far more robust. Most strikingly, IgE-antibody secreting cells with “γ1-signalling history” migrate more efficiently towards the chemokine CXCL12, which guides plasmablasts to plasma cell niches, than IgE-antibody secreting cells with WT “ε-signalling history”. We conclude that IgE plasmablasts have an intrinsic, lower chance to contribute to the long-lived plasma cell pool than IgG1 plasmablasts. PMID:18925577

  11. Papel da P190 BCR-ABL como parâmetro de recaída na leucemia mielóide crônica P190 BCR-ABL role in myeloid chronic leukemia relapse

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    Gabriela V. Andrade

    2008-08-01

    Full Text Available A leucemia mielóide crônica (LMC é uma desordem hematológica mieloproloferativa clonal causada por uma mutação em uma célula-tronco pluripotente, resultando na proliferação e acúmulo de células mielóides e seus progenitores. O cromossomo Philadelphia é o resultado de uma translocação recíproca de material genético entre os genes abl (Abelson murine leukemia no cromossomo 9, e o bcr (breakpoint cluster region no cromossomo 22, resultando na formação do gene quimérico BCR-ABL. Neste trabalho, 45 pacientes foram acompanhados de forma seqüencial, de acordo com as avaliações periódicas individuais, e 360 amostras foram selecionadas e analisadas pela técnica da reação em cadeia da polimerase (PCR através da técnica qualitativa para as isoformas características da P210BCR-ABL (b3a2 e b2a2 e P190BCR-ABL (e1a2. No nosso estudo no pré-TMO, observou-se uma prevalência das isoformas características da LMC (b3a2 e/ou b2a2, fato imprescindível para que o paciente fosse acompanhado dentro do protocolo da LMC. A isoforma e1a2, característica da LLA, foi detectada em 11 pacientes em conjunto com essas isoformas. A detecção do transcrito e1a2 foi avaliada quanto ao seu provável papel na LMC, e foi um dos parâmetros de avaliação deste estudo.Chronic myeloid leukemia (CML is a myeloproliferative clonal disorder caused by a mutation in a stem cell, resulting in the proliferation and accumulation of myeloid cells and their progenitors. The Philadelphia chromosome (Ph1 is a result of a mutual translocation of genetic material between the abl gene (Abelson murine leukemia in chromosome 9 and bcr gene (breakpoint cluster region in chromosome 22, resulting in the formation of the chimerical gene, BCR-ABL. In this work 45 patients were sequentially followed up in individual periodic evaluations, and 360 samples were selected and analyzed by PCR using the qualitative technique for isoforms characteristic of P210CR-ABL (b3a2 and b2a2

  12. Outcomes of Children With BCR-ABL1–Like Acute Lymphoblastic Leukemia Treated With Risk-Directed Therapy Based on the Levels of Minimal Residual Disease

    Science.gov (United States)

    Roberts, Kathryn G.; Pei, Deqing; Campana, Dario; Payne-Turner, Debbie; Li, Yongjin; Cheng, Cheng; Sandlund, John T.; Jeha, Sima; Easton, John; Becksfort, Jared; Zhang, Jinghui; Coustan-Smith, Elaine; Raimondi, Susana C.; Leung, Wing H.; Relling, Mary V.; Evans, William E.; Downing, James R.; Mullighan, Charles G.; Pui, Ching-Hon

    2014-01-01

    Purpose BCR-ABL1–like acute lymphoblastic leukemia (ALL) is a recently identified B-cell ALL (B-ALL) subtype with poor outcome that exhibits a gene expression profile similar to BCR-ABL1-positive ALL but lacks the BCR-ABL1 fusion protein. We examined the outcome of children with BCR-ABL1–like ALL treated with risk-directed therapy based on minimal residual disease (MRD) levels during remission induction. Patients and Methods Among 422 patients with B-ALL enrolled onto the Total Therapy XV study between 2000 and 2007, 344 had adequate samples for gene expression profiling. Next-generation sequencing and/or analysis of genes known to be altered in B-ALL were performed in patients with BCR-ABL1–like ALL who had available material. Outcome was compared between patients with and those without BCR-ABL1–like ALL. Results Forty (11.6%) of the 344 patients had BCR-ABL1–like ALL. They were significantly more likely to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction than did other patients with B-ALL. Among 25 patients comprehensively studied for genetic abnormalities, 11 harbored a genomic rearrangement of CRLF2, six had fusion transcripts responsive to ABL tyrosine kinase inhibitors or JAK inhibitors, and seven had mutations involving the Ras signaling pathway. There were no significant differences in event-free survival (90.0% ± 4.7% [SE] v 88.4% ± 1.9% at 5 years; P = .41) or in overall survival (92.5% ± 4.2% v 95.1% ± 1.3% at 5 years; P = .41) between patients with and without BCR-ABL1–like ALL. Conclusion Patients who have BCR-ABL1–like ALL with poor initial treatment response can be salvaged with MRD-based risk-directed therapy and may benefit from identification of kinase-activating lesions for targeted therapies. PMID:25049327

  13. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL– and mutant FLT3-expressing cells

    Science.gov (United States)

    Weisberg, Ellen; Banerji, Lolita; Wright, Renee D.; Barrett, Rosemary; Ray, Arghya; Moreno, Daisy; Catley, Laurence; Jiang, Jingrui; Hall-Meyers, Elizabeth; Sauveur-Michel, Maira; Stone, Richard; Galinsky, Ilene; Fox, Edward; Kung, Andrew L.

    2008-01-01

    Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo. PMID:18184863

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

    Science.gov (United States)

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

    2015-01-01

    BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1  negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated. PMID:25789185

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

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    A. N. Chamseddine

    2015-01-01

    Full Text Available BCR-ABL1 negative myeloproliferative neoplasms (MPNs are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24 that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U showing a t(9;22(p24;q11, which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT. To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1  negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.

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

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    Ilana de França Azevedo

    2014-10-01

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

  17. Fluorescent in-situ hybridization (FISH for BCR/ABL in chronic myeloid leukemia after bone marrow transplantation

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    Maria de Lourdes Lopes Ferrari Chauffaille

    2001-01-01

    Full Text Available CONTEXT: Identification of Philadelphia chromosome or BCR/ABL gene rearrangement in chronic myeloid leukemia is important at diagnosis as well as after treatment. OBJECTIVE: To compare the results of karyotyping using fluorescent in-situ hybridization (FISH upon diagnosis and 1 year after bone marrow transplantation in 12 patients. TYPE OF STUDY: Diagnostic test and residual disease detection. SETTING: Hematology and Hemotherapy Department, Federal University of São Paulo/Escola Paulista de Medicina, São Paulo, Brazil. SAMPLE: 12 patients with chronic myeloid leukemia at diagnosis and 1 year after bone marrow transplantation. DIAGNOSTIC TEST: Karyotyping was done in the usual way and the BCR/ABL gene-specific probe was used for FISH. MAIN MEASUREMENTS: Disease at diagnosis and residual. RESULTS: At diagnosis, 10 patients presented t(9;22(q34.1;q11 as well as positive FISH. Two cases did not have metaphases but FISH was positive. After bone marrow transplantation, 8 patients presented normal karyotype, 1 had persistence of identifiable Philadelphia chromosome and 3 had no metaphases. Two cases showed complete chimera and 2 had donor and host cells simultaneously. FISH was possible in all cases after bone marrow transplantation and confirmed the persistence of identifiable Philadelphia chromosome clone in one patient, and identified another that did not present metaphases for analysis. Cases that showed mixed chimera in karyotype were negative for BCR/ABL by FISH. CONCLUSION: The applicability of FISH is clear, particularly for residual disease detection. Classical and molecular cytogenetics are complementary methods.

  18. Speciation of heavy metals by modified BCR sequential extraction procedure in different depths of sediments from Sungai Buloh, Selangor, Malaysia

    Energy Technology Data Exchange (ETDEWEB)

    Nemati, Keivan, E-mail: keivan_nemati@yahoo.com [Environmental Research Group, Department of Chemistry, University of Malaya (UM), Kuala Lumpur 50603 (Malaysia); Bakar, Nor Kartini Abu; Abas, Mhd. Radzi; Sobhanzadeh, Elham [Environmental Research Group, Department of Chemistry, University of Malaya (UM), Kuala Lumpur 50603 (Malaysia)

    2011-08-15

    Highlights: {yields} A BCR sequential extraction procedure was applied for measurement of heavy metals in Sungai Buloh sediments in different depths. {yields} The amounts of CF and percentage of RAC was measured in this study too. {yields} Highest CF was obtained for Cd, Co, Pb and Zn in these samples. {yields} Zn at S3 and Cd at S3-S7 showed a high risk for the sediment samples. There were no elements of very high risk conditions in the selected samples. - Abstract: The sequential extraction procedure proposed by the European Standard, Measurements and Testing (SM and T) program, formerly the Community Bureau of Reference (BCR), was applied for partitioning of heavy metals (HMs) in river sediments collected along the course of Sungai Buloh and the Straits of Malacca in Selangor, Malaysia. Eight elements (V, Pb, Cd, Cr, Co, Ni, Cu and Zn) from seven stations (S1-S7) and at different depths were analyzed using the modified BCR Sequential Extraction Procedure (SEP) in combination with ICP-MS to obtain the metal distribution patterns in this region. The results showed that heavy metal contaminations at S2 and S3 was more severe than at other sampling sites, especially for Zn, Cu, Ni and Pb. Nevertheless, the element concentrations from top to bottom layers decreased predominantly. The samples from the Straits of Malacca (S4-S7) the highest contamination factors obtained were for Co, Zn and Pb while the lowest were found for V and Cr, similar to Sungai Buloh sediments. The sediments showed a low risk for V, Cr, Cu and Pb with RAC values of less than 10%, but medium risk for Co, Zn (except S3), Cd at S1 and S2 and Ni at S1, S3 and S5. Zn at S3 and Cd at S3-S7 showed high risk to our sediment samples. There is not any element of very high risk conditions in the selected samples.

  19. PESV对K562细胞BCR/ABL融合基因及凋亡调控因子Bcl-2、Bad表达的影响%The Effects of PESV on the Expression of BCR/ABL Fusion Gene and Bcl-2, Bad of Apoptosis Regulators on the K562 Cells

    Institute of Scientific and Technical Information of China (English)

    于文俊; 杨文华; 杨向东; 史哲新; 王兴丽; 郝征; 张佳

    2012-01-01

    Objective: To investigate the PESV of K562 cells BCR / ABL fusion gene and apoptosis regulators bcl-2 and bad expression. Methods: K562 cells were cultured in vitro, by PESV for different times, the apoptosis rate by flow cytometry, fluorescence quantitative RT-PCR detection of BCR / ABL, Bcl-2, Bad mRNA level changes. Results: Compared with the control group, PESV treated K562 cells, apoptosis increased, BCR / ABL fusion gene reduced expression, anti-apoptotic gene Bcl-2 mRNA expression decreased, pro-apoptotic gene Bad mRNA expression. Conclusion: PESV reduced in K562 cells can reduce the BCR / ABL fusion gene, may regulate the expression of Bcl-2 and Bad, inhibit proliferation of K562 cells and promote their apoptosis.%目的:探讨PESV对K562细胞BCR/ABL融合基因及凋亡调控因子bcl-2和bad表达的影响.方法:将体外培养K562细胞,经PESV处理不同时间后,流式细胞术检测细胞凋亡率,荧光定量RT-PCR检测BCR/ABL、Bcl-2、Bad mRNA水平变化.结果:与对照组相比,PESV处理后K562细胞,凋亡率增加,BCR/ABL融合基因表达降低,抗凋亡相关基因Bcl-2 mRNA表达降低,促凋亡基因Bad mRNA表达增加.结论:PESV能降低降低K562细胞BCR/ABL融合基因的表达,可能通过调节Bcl-2和Bad表达,抑制K562细胞增殖,促进其凋亡.

  20. Molecular monitoring of BCR-ABL transcripts in patients with chronic myelogenous leukemia: is high sensitivity of clinical value?

    Science.gov (United States)

    Norkin, Maxim; Schiffer, Charles A

    2010-04-01

    Monitoring of disease response during treatment with tyrosine kinase inhibitors of patients with chronic myelogenous leukemia dramatically changed after the introduction of real-time PCR, which allows quantification of BCR-ABL transcript levels with high sensitivity and precision. However, its role in patients who have achieved complete cytogenetic response is not entirely clear; incorrect interpretation of results could lead to unnecessary changes from an effective treatment. This review discusses the current evidence regarding the benefits, uncertainties, and potential drawbacks of molecular monitoring in patients with chronic myelogenous leukemia in chronic phase.

  1. 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.

  2. Detection of residual bcr/abl translocation by polymerase chain reaction in chronic myeloid leukaemia patients after bone-marrow transplantation.

    Science.gov (United States)

    Gabert, J; Thuret, I; Lafage, M; Carcassonne, Y; Maraninchi, D; Mannoni, P

    1989-11-11

    The polymerase chain reaction was used to evaluate minimum residual disease in chronic myelogenous leukaemia (CML) patients after bone-marrow transplantation, by amplification of the transcript of the specific bcr/abl hybrid gene. Strict precautions were taken to avoid contamination. Peripheral blood cells from 22 patients transplanted for haematological malignant disorders were analysed. The results were clearcut for positive controls (patients with CML in relapse) and negative controls (patients with malignant disorders other than CML). In 11 of 12 CML patients in clinical and cytogenetic remission the bcr/abl transcript was detected 3 months to 6 years after transplantation. Thus, it appears that cells expressing the bcr/abl mRNA are not eradicated from the blood of CML patients in complete clinical remission even years after bone-marrow transplantation.

  3. Dasatinib treatment can overcome imatinib and nilotinib resistance in CML patient carrying F359I mutation of BCR-ABL oncogene.

    Science.gov (United States)

    Barańska, Marta; Lewandowski, Krzysztof; Gniot, Michał; Iwoła, Małgorzata; Lewandowska, Maria; Komarnicki, Mieczysław

    2008-01-01

    Point mutations of bcr-abl tyrosine kinase are the most frequent causes of imatinib resistance in chronic myeloid leukaemia (CML) patients. In most CML cases with BCR-ABL mutations leading to imatinib resistance the second generation of tyrosine kinase inhibitors (TKI- e.g. nilotinib or dasatinib) may be effective. Here, we report a case of a CML patient who during imatinib treatment did not obtain clinical and cytogenetic response within 12 months of therapy. The sequencing of BCR-ABL kinase domains was performed and revealed the presence of a F359I point mutation (TTC-to-ATC nucleotide change leading to Phe-to-Ile amino acid substitution). After 1 month of nilotinib therapy a rapid progression of clinical symptoms was observed. In the presence of the F359I point mutation only dasatinib treatment overcame imatinib and nilotinib resistance.

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

    Directory of Open Access Journals (Sweden)

    Janusz Blasiak

    2013-08-01

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

  5. 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.

  6. 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.

  7. Speciation of heavy metals by modified BCR sequential extraction procedure in different depths of sediments from Sungai Buloh, Selangor, Malaysia.

    Science.gov (United States)

    Nemati, Keivan; Abu Bakar, Nor Kartini; Abas, Mhd Radzi; Sobhanzadeh, Elham

    2011-08-15

    The sequential extraction procedure proposed by the European Standard, Measurements and Testing (SM&T) program, formerly the Community Bureau of Reference (BCR), was applied for partitioning of heavy metals (HMs) in river sediments collected along the course of Sungai Buloh and the Straits of Malacca in Selangor, Malaysia. Eight elements (V, Pb, Cd, Cr, Co, Ni, Cu and Zn) from seven stations (S1-S7) and at different depths were analyzed using the modified BCR Sequential Extraction Procedure (SEP) in combination with ICP-MS to obtain the metal distribution patterns in this region. The results showed that heavy metal contaminations at S2 and S3 was more severe than at other sampling sites, especially for Zn, Cu, Ni and Pb. Nevertheless, the element concentrations from top to bottom layers decreased predominantly. The samples from the Straits of Malacca (S4-S7) the highest contamination factors obtained were for Co, Zn and Pb while the lowest were found for V and Cr, similar to Sungai Buloh sediments. The sediments showed a low risk for V, Cr, Cu and Pb with RAC values of less than 10%, but medium risk for Co, Zn (except S3), Cd at S1 and S2 and Ni at S1, S3 and S5. Zn at S3 and Cd at S3-S7 showed high risk to our sediment samples. There is not any element of very high risk conditions in the selected samples.

  8. Implication of the Autologous Immune System in BCR-ABL Transcript Variations in Chronic Myelogenous Leukemia Patients Treated with Imatinib.

    Science.gov (United States)

    Clapp, Geoffrey D; Lepoutre, Thomas; El Cheikh, Raouf; Bernard, Samuel; Ruby, Jérémy; Labussière-Wallet, Hélène; Nicolini, Franck E; Levy, Doron

    2015-10-01

    Imatinib and other tyrosine kinase inhibitors (TKI) have improved treatment of chronic myelogenous leukemia (CML); however, most patients are not cured. Deeper mechanistic understanding may improve TKI combination therapies to better control the residual leukemic cell population. In analyzing our patients' data, we found that many patients who otherwise responded well to imatinib therapy still showed variations in their BCR-ABL transcripts. To investigate this phenomenon, we applied a mathematical model that integrates CML and an autologous immune response to the patients' data. We define an immune window or a range of leukemic loads for which the autologous immune system induces an improved response. Our modeling results suggest that, at diagnosis, a patient's leukemic load is able to partially or fully suppress the autologous immune response developed in a majority of patients, toward the CML clone(s). Imatinib therapy drives the leukemic population into the "immune window," allowing the patient's autologous immune cells to expand and eventually mount an efficient recognition of the residual leukemic burden. This response drives the leukemic load below this immune window, allowing the leukemic population to partially recover until another weaker immune response is initiated. Thus, the autologous immune response may explain the oscillations in BCR-ABL transcripts regularly observed in patients on imatinib. ©2015 American Association for Cancer Research.

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

    Science.gov (United States)

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

    2016-01-01

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

  10. 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.

  11. A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL.

    Directory of Open Access Journals (Sweden)

    Uwe Rix

    Full Text Available Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL is in part driven by the tyrosine kinase bcr-abl, but imatinib does not produce long-term remission. Therefore, second-generation ABL inhibitors are currently in clinical investigation. Considering different target specificities and the pronounced genetic heterogeneity of Ph+ ALL, which contributes to the aggressiveness of the disease, drug candidates should be evaluated with regard to their effects on the entire Ph+ ALL-specific signaling network. Here, we applied an integrated experimental and computational approach that allowed us to estimate the differential impact of the bcr-abl inhibitors nilotinib, dasatinib, Bosutinib and Bafetinib. First, we determined drug-protein interactions in Ph+ ALL cell lines by chemical proteomics. We then mapped those interactions along with known genetic lesions onto public protein-protein interactions. Computation of global scores through correlation of target affinity, network topology, and distance to disease-relevant nodes assigned the highest impact to dasatinib, which was subsequently confirmed by proliferation assays. In future, combination of patient-specific genomic information with detailed drug target knowledge and network-based computational analysis should allow for an accurate and individualized prediction of therapy.

  12. Role of the three-dimensional distribution of abl and bcr genes in the formation of bcr/abl fusion gene in interphase neucleus%间期细胞核中abl和bcr基因的三维空间分布在bcr/abl融合基因形成中的作用

    Institute of Scientific and Technical Information of China (English)

    张青; 周淑芸; 刘晓力; 牛超; 徐岚; 陈赛娟

    2002-01-01

    目的从生物体视学角度分析bcr/abl融合基因的形成机制.方法应用荧光原位杂交和激光共聚焦扫描显微镜技术,观察γ-射线对IM9细胞中的bcr和abl基因在间期核内三维空间分布的影响.结果abl和bcr基因在间期核内有其特定的分布区域,且该分布区域在细胞周期中呈规律性的动态变化.放射性照射会使abl和bcr基因之间的距离缩短.结论abl和bcr基因在间期细胞核内的易接近性是bcr/abl融合基因形成的因素之一.

  13. The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders.

    Science.gov (United States)

    Nithianantharajah, Jess; Hannan, Anthony J

    2009-12-01

    The concept of 'cognitive reserve', and a broader theory of 'brain reserve', were originally proposed to help explain epidemiological data indicating that individuals who engaged in higher levels of mental and physical activity via education, occupation and recreation, were at lower risk of developing Alzheimer's disease and other forms of dementia. Subsequently, behavioral, cellular and molecular studies in animals (predominantly mice and rats) have revealed dramatic effects of environmental enrichment, which involves enhanced levels of sensory, cognitive and motor stimulation via housing in novel, complex environments. Furthermore, increasing levels of voluntary physical exercise, via ad libitum access to running wheels, can have significant effects on brain and behavior, thus informing the relative effects of mental and physical activity. More recently, animal models of brain disorders have been compared under environmentally stimulating and standard housing conditions, and this has provided new insights into environmental modulators and gene-environment interactions involved in pathogenesis. Here, we review animal studies that have investigated the effects of modifying mental and physical activity via experimental manipulations, and discuss their relevance to brain and cognitive reserve (BCR). Recent evidence suggests that the concept of BCR is not only relevant to brain aging, neurodegenerative diseases and dementia, but also to other neurological and psychiatric disorders. Understanding the cellular and molecular mechanisms mediating BCR may not only facilitate future strategies aimed at optimising healthy brain aging, but could also identify molecular targets for novel pharmacological approaches aimed at boosting BCR in 'at risk' and symptomatic individuals with various brain disorders.

  14. Detection of BCR/ABL Fusion Gene in Interphase Cens with Bi-labelling Hybridization in Situ%双标记原位杂交法检测间期细胞BCR/ABL融合基因

    Institute of Scientific and Technical Information of China (English)

    袁长吉; 王建伟; 李舜华; 易永林

    2003-01-01

    目的:应用双标记原位杂交方法检测BCR/ABL融合基因.方法:BCR基因探针用地高辛标记,碱性磷酸酶显色;ABL基因用3H-dATP标记,核子乳胶放射自显影.结果:检测9例初治的慢性粒细胞白血病(CML)病人均为阳性,阳性细胞比例为93%;检测CML来源的K562细胞株阳性细胞占98.8%;正常人假阳性率为0.75%.结论:该方法简便、快速,适用于CML微小残留病的检测.

  15. 66例血液病患者bcr/abl融合基因、Ph染色体结果分析

    Institute of Scientific and Technical Information of China (English)

    刘永林; 虞玉群; 陈益民; 张丽; 彭来君; 施丽华; 谈潘莉; 钱丽丽; 胡正军; 陈婷停

    2011-01-01

    @@ CML特异性费城染色体(Philadephia,Ph)是由t(9:22)(q34:11)易位形成.9号染色体原癌基因abl(Abelson protooncogene)易位至22号染色体的断裂点簇集区(breakpointcluster region,bcr),发生重排,产生ber/abl融合基因,引起CML的始动突变.融合基因bcr/abl几乎见于所有的慢性粒细胞性白血病、25%~50%的急性B系淋巴细胞性白血病(ALL)和约5%的急性粒细胞性白血病中,本文统计了进行染色体和bcr/abl融合基因检查的初诊血液病66例,对其骨髓细胞染色体核型及bcr/abl融合基因进行分析.

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

    Directory of Open Access Journals (Sweden)

    Sarah L. McCarron

    2013-01-01

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

  17. A novel Lyn-protein kinase Cδ/ε-protein kinase D axis is activated in B cells by signalosome-independent alternate pathway BCR signaling.

    Science.gov (United States)

    Guo, Benchang; Rothstein, Thomas L

    2013-06-01

    BCR signaling initiates multiple activities critical for B-cell function. Recently, we identified an alternate BCR signaling pathway, induced by IL-4, that is signalosome-independent, unlike the classical signalosome-dependent pathway, and that leads to activation of the MAP kinase, ERK. Here we questioned whether alternate pathway signaling extends to other key downstream events, especially protein kinase D (PKD) activation. We found that in murine spleen-derived B cells the IL-4-induced alternate pathway for BCR signaling results in PKD and PKD substrate phosphorylation, and that alternate pathway phosphorylation of HDAC5/7 and other key substrates requires PKD. Furthermore, we found that tyrosine phosphorylation of PKCδ/ε occurs as a result of alternate but not classical pathway signaling and is required for phosphorylation of PKD and PKD substrates. This result identifies PKCδ/ε tyrosine phosphorylation as a unique outcome of the alternate pathway. The alternate pathway is mediated by Lyn that is not required for classical pathway signaling and we found that Lyn associates directly with PKCδ/ε and is required for phosphorylation of PKCδ/ε and of PKD. These findings indicate that IL-4 influences B-cell activation by inducing a novel signaling pathway from BCR to Lyn to PKCδ/ε to PKD.

  18. The role of Bruton's tyrosine kinase in the development and BCR/TLR-dependent activation of AM14 rheumatoid factor B cells

    Science.gov (United States)

    Nündel, Kerstin; Busto, Patricia; Debatis, Michelle; Marshak-Rothstein, Ann

    2013-01-01

    The protein kinase Btk has been implicated in the development, differentiation, and activation of B cells through its role in the BCR and TLR signaling cascades. These receptors and in particular, the BCR and either TLR7 or TLR9 also play a critical role in the activation of autoreactive B cells by RNA- or DNA-associated autoantigens. To explore the role of Btk in the development of autoreactive B cells, as well as their responses to nucleic acid-associated autoantigens, we have now compared Btk-sufficient and Btk-deficient mice that express a prototypic RF BCR encoded by H- and L-chain sdTgs. These B cells bind autologous IgG2a with low affinity and only proliferate in response to IgG2a ICs that incorporate DNA or RNA. We found that Btk-sufficient RF+ B cells mature into naïve FO B cells, all of which express the Tg BCR, despite circulating levels of IgG2a. By contrast, a significant proportion of Btk-deficient RF+ B cells acquires a MZ or MZ precursor phenotype. Remarkably, despite the complete inability of RF+ Xid/y B cells to respond to F(ab′)2 anti-IgM, RF+ Xid/y B cells could respond well to autoantigen-associated ICs. These data reveal unique features of the signaling cascades responsible for the activation of autoreactive B cells. PMID:23804807

  19. Efficacy of Dasatinib in Treatment of Imatinib-Resistant BCR/ABL Positive Leukemia%达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的临床研究

    Institute of Scientific and Technical Information of China (English)

    朱雨; 潘良琴; 钱思轩; 宋萍; 于慧; 张苏江; 葛峥; 洪鸣; 田甜

    2013-01-01

    本研究评价达沙替尼治疗原发或继发伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性.对27例原发或继发伊马替尼耐药的慢性髓系白血病(CML)或Ph阳性急性淋巴细胞白血病(Ph+ ALL)患者,给予达沙替尼100-140 mg/d口服治疗,评估疗效、总体生存和耐受情况.结果表明:27例伊马替尼耐药的BCR/ABL阳性白血病中位达沙替尼治疗时间8(1-66)个月,中位随访时间54(3-75)个月.27例接受达沙替尼治疗的患者中,88.8%获得完全血液学反应(CHR),44.4%获得主要细胞遗传学反应(mCyR),37%获得完全遗传学反应(CCyR),18.5%获得主要分子学反应(MMR).伊马替尼耐药的进展期(CML-AP、CML-BC、骨髓复发Ph+ ALL)患者接受达沙替尼治疗获CCyR率低于疾病稳定期(CML-CP、骨髓缓解Ph+ ALL)患者(P=0.0377),且3-4级不良反应发生率明显增高.达沙替尼治疗后获得CCyR的患者生存期(OS)较未达CCyR者明显延长(63个月vs9个月,P=0.0126).达沙替尼治疗后最常见的3-4级不良反应包括血液学反应如血小板减少(51.8%)、中性粒细胞减少(48.1%)、贫血(33.3%)和非血液学反应如胸腔积液(18.5%)、肺部感染(18.5%)、心包积液(11.1%).3-4级不良反应主要发生在疾病进展期时改服达沙替尼者,均发生于服药12个月内.结论:达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病有效,且在疾病稳定期改服达沙替尼疗效和耐受性更好.%This study was aimed to evaluate the efficacy and safety of dasatinib in BCR/ABL positive leukemia patients with primary or secondary resistance to imatinib.27 patients with primary or secondary imatinib-resistant chronic myelogenous leukemia (CML) or Philadelphia chromosome positive acute lymphocytic leukemia (Ph + ALL) received 100-140 mg/d dasatinib orally.Their overall survival and tolerance were evaluated.The results showed that the median duration of dasatinib therapy was 8 (1-66) months in the 27

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

    Directory of Open Access Journals (Sweden)

    Zafar Iqbal

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

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

    Directory of Open Access Journals (Sweden)

    Qianyin Li

    2017-03-01

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

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

    Science.gov (United States)

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

    2017-03-02

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

  3. Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression.

    Science.gov (United States)

    Akram, Afia Muhammad; Iqbal, Zafar; Akhtar, Tanveer; Khalid, Ahmed Mukhtar; Sabar, Muhammad Farooq; Qazi, Mahmood Hussain; Aziz, Zeba; Sajid, Nadia; Aleem, Aamer; Rasool, Mahmood; Asif, Muhammad; Aloraibi, Saleh; Aljamaan, Khaled; Iqbal, Mudassar

    2017-04-03

    BCR-ABL kinase domain (KD) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-KD mutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders. Direct sequencing analysis was used for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which 8 (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-KD. Occurrence of mutations was found associated with elevated platelet count (p = 0.037) and patients of male sex (p = 0.049). The median overall survival and event free survival of CML patients (n = 90) was 6.98 and 5.8 y respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-KD mutation screening in late chronic phase CML patients for improved clinical management of disease.

  4. A Non-ATP-Competitive Dual Inhibitor of JAK2 and BCR-ABL Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition.

    Science.gov (United States)

    Jatiani, Shashidhar S; Cosenza, Stephen C; Reddy, M V Ramana; Ha, Ji Hee; Baker, Stacey J; Samanta, Ajoy K; Olnes, Matthew J; Pfannes, Loretta; Sloand, Elaine M; Arlinghaus, Ralph B; Reddy, E Premkumar

    2010-04-01

    Here we report the discovery of ON044580, an α-benzoyl styryl benzyl sulfide that possesses potent inhibitory activity against two unrelated kinases, JAK2 and BCR-ABL, and exhibits cytotoxicity to human tumor cells derived from chronic myelogenous leukemia (CML) and myelodysplasia (MDS) patients or cells harboring a mutant JAK2 kinase. This novel spectrum of activity is explained by the non-ATP-competitive inhibition of JAK2 and BCR-ABL kinases. ON044580 inhibits mutant JAK2 kinase and the proliferation of JAK2(V617F)-positive leukemic cells and blocks the IL-3-mediated phosphorylation of JAK2 and STAT5. Interestingly, this compound also directly inhibits the kinase activity of both wild-type and imatinib-resistant (T315I) forms of the BCR-ABL kinase. Finally, ON044580 effectively induces apoptosis of imatinib-resistant CML patient cells. The apparently unrelated JAK2 and BCR-ABL kinases share a common substrate, STAT5, and such substrate competitive inhibitors represent an alternative therapeutic strategy for development of new inhibitors. The novel mechanism of kinase inhibition exhibited by ON044580 renders it effective against mutant forms of kinases such as the BCR-ABL(T315I) and JAK2(V617F). Importantly, ON044580 selectively reduces the number of aneuploid cells in primary bone marrow samples from monosomy 7 MDS patients, suggesting another regulatory cascade amenable to this agent in these aberrant cells. Data presented suggest that this compound could have multiple therapeutic applications including monosomy 7 MDS, imatinib-resistant CML, and myeloproliferative neoplasms that develop resistance to ATP-competitive agents.

  5. Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response.

    Science.gov (United States)

    Cazzaniga, Giovanni; Lanciotti, Marina; Rossi, Vincenzo; Di Martino, Daniela; Aricò, Maurizio; Valsecchi, Maria Grazia; Basso, Giuseppe; Masera, Giuseppe; Micalizzi, Concetta; Biondi, Andrea

    2002-11-01

    Children with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) represent a subgroup at very high risk for treatment failure, despite intensive chemotherapy. However, recent retrospective studies showed that Ph+ childhood ALL is a heterogeneous disease with regard to treatment response. We have prospectively monitored, by reverse transcription polymerase chain reaction (RT-PCR) during follow-up, the presence of the BCR/ABL fusion transcript in Ph+ ALL children diagnosed in the Italian multicentre Associazione Italiana Ematologia Oncologia Pediatrica ALL-AIEOP-95 therapy protocol. To our knowledge, this is the first report on the evaluation of minimal residual disease (MRD) in childhood Ph+ ALL prospectively enrolled in an intensive, Berlin-Frankfurt-Munster (BFM)-type treatment protocol. Twenty-seven of 36 (75.0%) Ph+ patients consecutively enrolled into the high-risk group of the AIEOP-ALL protocol between May 1995 and October 1999 were successfully analysed. Twenty were good responders to the pre-phase of prednisone/intrathecal methotrexate treatment (PGR) and seven were poor responders (PPR). Within the PPR group, the RT-PCR monitoring constantly showed positivity for the BCR/ABL fusion transcript and all the patients died of disease progression. In contrast, highly sensitive qualitative RT-PCR monitoring revealed heterogeneity within the PGR group of Ph+ childhood ALL patients. Three different subgroups could be defined, according to the clearance of Ph+ cells within the first 5 months of treatment. This provides useful information on the capability of chemotherapy to reduce the leukaemic clone, with prognostic implications.

  6. The synaptic recruitment of lipid rafts is dependent on CD19-PI3K module and cytoskeleton remodeling molecules.

    Science.gov (United States)

    Xu, Liling; Auzins, Arturs; Sun, Xiaolin; Xu, Yinsheng; Harnischfeger, Fiona; Lu, Yun; Li, Zhanguo; Chen, Ying-Hua; Zheng, Wenjie; Liu, Wanli

    2015-08-01

    Sphingolipid- and cholesterol-rich lipid raft microdomains are important in the initiation of BCR signaling. Although it is known that lipid rafts promote the coclustering of BCR and Lyn kinase microclusters within the B cell IS, the molecular mechanism of the recruitment of lipid rafts into the B cell IS is not understood completely. Here, we report that the synaptic recruitment of lipid rafts is dependent on the cytoskeleton-remodeling proteins, RhoA and Vav. Such an event is also efficiently regulated by motor proteins, myosin IIA and dynein. Further evidence suggests the synaptic recruitment of lipid rafts is, by principle, an event triggered by BCR signaling molecules and second messenger molecules. BCR-activating coreceptor CD19 potently enhances such an event depending on its cytoplasmic Tyr421 and Tyr482 residues. The enhancing function of the CD19-PI3K module in synaptic recruitment of lipid rafts is also confirmed in human peripheral blood B cells. Thus, these results improve our understanding of the molecular mechanism of the recruitment of lipid raft microdomains in B cell IS.

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

    Science.gov (United States)

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

    2017-04-01

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

  8. 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.

  9. Problems in the application of the three-step BCR sequential extraction to low amounts of sediments: an alternative validated route.

    Science.gov (United States)

    Ciceri, Elena; Giussani, Barbara; Pozzi, Andrea; Dossi, Carlo; Recchia, Sandro

    2008-07-30

    Poor recoveries are obtained if the BCR three-step sequential extraction is applied to 100 mg specimens rather than to 1 g. It is observed that analytes are lost during each phase separation which is carried out via centrifugation and can be hardly quantitatively performed on 100 mg sediment specimens. An alternative procedure, which is carried out on a single empty SPE column and involves separation by filtration, is developed to solve this problem. The proposed method is validated on 100 mg samples of certified sediment (BCR-701), but could be potentially used for even lower sediment specimens. Problems related to pH stability during step 2 and its influence on recoveries is also reported.

  10. Multidimensional single-cell analysis of BCR signaling reveals proximal activation defect as a hallmark of chronic lymphocytic leukemia B cells.

    Directory of Open Access Journals (Sweden)

    M Lia Palomba

    Full Text Available PURPOSE: Chronic Lymphocytic Leukemia (CLL is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation. EXPERIMENTAL DESIGN: We developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR. Results from multidimensional modeling were validated using an independent test cohort of 38 patients. RESULTS: We identified a dynamic and variable imbalance between proximal (pSYK, pBTK and distal (pPLCγ2, pBLNK, ppERK phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness. CONCLUSION: Single-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets.

  11. Modeling the influence of stromal microenvironment in the selection of ENU-induced BCR-ABL1 mutants by tyrosine kinase inhibitors.

    Science.gov (United States)

    Aggoune, Djamel; Tosca, Lucie; Sorel, Nathalie; Bonnet, Marie-Laure; Dkhissi, Fatima; Tachdjian, Gérard; Bennaceur-Griscelli, Annelise; Chomel, Jean-Claude; Turhan, Ali G

    2014-01-01

    Tyrosine kinase inhibitors (TKIs) have profoundly changed the natural history of chronic myeloid leukemia (CML). However, acquired resistance to imatinib, dasatinib or nilotinib (1(st) and 2(nd) generation TKIs), due in part to BCR-ABL1 kinase mutations, has been largely described. These drugs are ineffective on the T315I gatekeeper substitution, which remains sensitive to 3(rd) generation TKI ponatinib. It has recently been suggested that the hematopoietic niche could protect leukemic cells from targeted therapy. In order to investigate the role of a stromal niche in mutation-related resistance, we developed a niche-based cell mutagenesis assay. For this purpose, ENU (N-ethyl-N-nitrosourea)-exposed UT-7 cells expressing non-mutated or T315I-mutated BCR-ABL1 were cultured with or without murine MS-5 stromal cells and in the presence of imatinib, dasatinib, nilotinib, or ponatinib. In the assays relative to 1(st) and 2(nd) generation TKIs, which were performed on non-mutated BCR-ABL1 cells, our data highlighted the increasing efficacy of the latter, but did not reveal any substantial effect of the niche. In ponatinib assays performed on both non-mutated and T315I-mutated BCR-ABL1 cells, an increased number of resistant clones were observed in the presence of MS-5. Present data suggested that T315I mutants need either compound mutations (e.g. E255K/T315I) or a stromal niche to escape from ponatinib. Using array-comparative genomic hybridization experiments, we found an increased number of variations (involving some recurrent chromosome regions) in clones cultured on MS-5 feeder. Overall, our study suggests that the hematopoietic niche could play a crucial role in conferring resistance to ponatinib, by providing survival signals and favoring genetic instability.

  12. Rapid detection of BCR-ABL fusion genes using a novel combined LUX primer, in-cell RT-PCR and flow cytometric method.

    Science.gov (United States)

    Shi, Yan; Li, Li-Zhen; Sun, Jian-Zhi; Zhang, Ti; Peng, Jun; Xu, Cong-Gao

    2008-01-01

    Currently, quantitative and semiquantitative assays for minimal residual disease detection include fluorescence in situ hybridisation, multiparameter flow cytometric immunophenotyping and real-time quantitative polymerase chain reaction (RQ-PCR). We have developed a new approach to detect hybrid breakpoint cluster region and Abelson proto-oncogene (BCR-ABL) transcripts inside suspension cells using in situ RT-PCR and light upon extension (LUX) primer, followed by rapid quantitative analysis with flow cytometry. After cellular permeabilization and fixation of single cell suspension, the neoplastic mRNA was reverse transcribed and amplified by PCR with LUX primer. The results demonstrated that a strong positive yellow-green signal was observed in 99-100% cells of K562 cell line, only the red nucleus was detected in NB4 cell line and normal controls. The technique has been utilised to study 12 patients with chronic myeloid leukemia, and the results were compared with those of BCR-ABL fusion mRNA by RT-PCR and BCR-ABL fusion gene of the interphase cells by fluorescence in situ hybridization (FISH). In the five diagnosed patients, 90-98% cells were strongly positive. Four patients, including three patients treated with interferon-alpha and hydroxyurea and one patient treated with imatinib mesylate, had 26-82.5% positive cells. Three patients treated with imatinib mesylate were negative. The in situ RT-PCR results demonstrated complete concordance with the results of I-FISH and RT-PCR. A fluorescence signal was detectable at 1/10(4) cells and became negative below this threshold with flow cytometry. The results of the present study suggest that (1) LUX primers can be used to efficiently detect BCR-ABL fusion mRNA by in-cell RT-PCR; (2) the novel technique is a specific and sensitive way of detecting fusion gene with potential clinical usefulness.

  13. Targeting of heme oxygenase-1 attenuates the negative impact of Ikaros isoform 6 in adult BCR-ABL1-positive B-ALL.

    Science.gov (United States)

    Lin, Xiaojing; Zou, Xingli; Wang, Ziming; Fang, Qin; Chen, Shuya; Huang, Jun; Zhe, Nana; Yu, Meisheng; Zhang, Yaming; Wang, Jishi

    2016-08-16

    The correlation between Heme oxygenase-1 (HO-1) and dominant-negative Ikaros isoform 6 (IK6) is unclear. Firstly, we detected that IK6 existed in 20 of 42 (47.6%) adult BCR-ABL1-positive B-lineage acute lymphoblastic leukemia (BCR-ABL1-positive B-ALL) by using reverse transcribed polymerase chain reaction (PCR) and nucleotide sequencing. IK6-positive patients had an unfavorable outcome compared with IK6-negative ones. Further study showed that the level of HO-1 expression was higher in IK6-positive patients' samples than that in IK6-negative ones. And there was a strong correlation between the expression of IK6 and HO-1. The growth of primary CD34+ leukemic cells derived from our IK6-positive patients' pool was prohibited by silencing HO-1, further promoting their apoptosis. Furthermore, primary CD34+ leukemic cells derived from IK6-positive patients shown poor responses to imatinib in comparison with wild-type (IK1) patients, suggesting that the expression of IK6 resisted to imatinib in adult BCR-ABL1-positive B-ALL. Importantly, inhibition of HO-1 also increased their sensitivity to tyrosine kinase inhibitors (TKIs). Finally, we found that IK6 activated downstream STAT5, and HO-1 was one of the downstream target genes of STAT5. In conclusion, HO-1 is an essential survival factor in BCR-ABL1-positive B-ALL with IK6, and targeting HO-1 can attenuate the negative impact of IK6.

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

    Directory of Open Access Journals (Sweden)

    Ewelina Synowiec

    2015-08-01

    Full Text Available 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.

  15. 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.

  16. Evaluating the mobility of toxic metals in untreated industrial wastewater sludge using a BCR sequential extraction procedure and a leaching test.

    Science.gov (United States)

    Kazi, T G; Jamali, M K; Kazi, G H; Arain, M B; Afridi, H I; Siddiqui, A

    2005-09-01

    The distribution and speciation of toxic metals in industrial wastewater sludge (IWS) was investigated. In this work, the modified BCR three-stage sequential extraction procedure was applied to the fractionation of Cr Pb Ni, and Cd in untreated industrial wastewater sludge from industrial sites in Hyderabad (Pakistan). The extracts were analyzed using electrothermal atomic absorption spectrometry. The procedure was evaluated using a certified reference material for soil mixed with sewage sludge BCR 483. The results from the partitioning study indicate that more easily mobilized forms (acid exchangeable) of Cd were dominant. The oxidizable fraction was dominant for all four toxic metals. Metal recovery was good, with metal recovered through the extractant steps and the total metal determined after microwave digestion. Lixiviation tests (DIN 38414-S4) were used to evaluate the leaching of toxic species from IWS, and it was observed that levels of leachable toxic metals were low compared to the amount of metal extracted in the exchangeable fraction of the BCR protocol.

  17. An appraisal of conventional, microwave and ultrasound BCR extraction methods for the analysis of metals in sediments of Pančevo, Serbia

    Directory of Open Access Journals (Sweden)

    Relić D.

    2013-04-01

    Full Text Available We use conventional, microwave and ultrasound assisted sequential extraction, of defined time and power, techniques for extractions of Cd, Cu, Cr, Ni, Pb and Zn in sediments and certified material. We did not change the conditions of extractions through steps, cause we what to see is there difference in extraction results for the certified material and sediments. We use lower powers and time from microwave and ultrasound extraction in order to avoid additional heating and boiling of the samples. Steps 1–3 of the BCR (Community Bureau of Reference, excluding the hydrogen peroxide digestion in step 3, were completed in 16 h in the conventional, in 120 s with 90 W power of microwave and in 30 min of 42 kHz of an ultrasonic frequency. Digestion of organic matter with hydrogen peroxide was performed the same for all techniques. The fourth step, the pseudo-total content, was performed the same on samples remaining after performing the extraction of the previous three phases either conventionally, microwave-assisted or with ultrasound. The precision and accuracy of the proposed procedures were evaluated using a certified reference material BCR701. Acceptable accuracy for most of the metals was observed for all three steps of BCR protocol applying a 16 h total shaking period. Metals were determined with an acceptable accuracy after the pseudo-total step; expect Cr. Results obtained after the application of different techniques on sediments were comparable with ANOVA test for the 95 % of confidence level.

  18. [Standardization of quantitative detection of BCR-ABL gene expression by RQ-PCR in patients with chronic myeloid leukemia in cooperation with European Leukemia Net].

    Science.gov (United States)

    Sacha, Tomasz; Zawada, Magdalena; Czekalska, Sylwia; Florek, Izabela; Mueller, Martin; Gniot, Michał; Jaźwiec, Bozena; Kyrcz-Krzemień, Sławomira; Leszczyńska, Aleksandra; Lewandowski, Krzysztof; Matiakowska, Karolina; Solarska, Iwona; Stokłosa, Tomasz; Skotnicki, Aleksander B

    2010-01-01

    Monitoring of chronic myeloid leukemia treatment efficacy requires very sensitive methods of BCR-ABL gene detection based on polymerase chain reaction (PCR). The lack of comparability of BCR-ABL mRNA quantification results generated by various methodologies in different laboratories was the cause of an international multicenter trial initiation with the participation of 133 laboratories in 24 European countries cooperating within the "EUTOS for CML" project. Pracownia Diagnostyki Molekularnej Kliniki Hematologii is taking part in standardisation rounds organised since 2005. The compatibility of methodology used in Pracownia with European Leukemia Net (ELN) standards was confirmed, and correction factor for the expression of RQ-PCR results in an international scale was calculated. Pracownia was charge by ELN with a task of conducting the standardisation in polish molecular biology laboratories. Test probes were prepared and sent to eight cooperating laboratories. The results obtained in six laboratories were concordant with results from laboratory in Krakow after conversion to international scale, therefore it was possible to calculate individual correction factors. The participation of polish laboratories in international standardization process created the opportunity for unification of BCR-ABL quantification methodologies with recommendations of international experts, and showed that the quality of analyses performed in majority of them was satisfactory enough to calculate correction factor and to express the RQ-PCR results in widely accepted international scale.

  19. 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.

  20. Immunologic evaluation of peptides derived from BCR/ABL-out-of-frame fusion protein in HLA A2.1 transgenic mice.

    Science.gov (United States)

    Casnici, Claudia; Volpe, Gisella; Crotta, Katia; Lattuada, Donatella; Saglio, Giuseppe; Marelli, Ornella

    2012-05-01

    Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphocytic leukemia express, besides the main BCR/ABL transcripts, novel BCR/ABL transcripts derived from alternative splicing between BCR exons 1, 13, or 14 with ABL exons 4 and 5. Their translational products present at C-terminus an amino acid portion derived from out-of-frame (OOF) reading of the ABL gene. The presence of OOF-peptide-specific T cells in chronic myelogenous leukemia patients was demonstrated and a first study in in vivo model demonstrated that OOF ABL portion was immunogenic in human leukcocyte antigen (HLA)-A2.1 transgenic mice. Here we immunized HLA A2.1 mice with novel peptides designed on the ABL OOF sequence, containing epitopes with high affinity for HLA A2.1 molecule. The specific immune response, cellular and humoral, obtained ex vivo against HLA A2.1-positive human chronic myelogenous leukemia cells using peptide 22-53 and the cytotoxic activity induced by peptide 32mer confirm the possibility to use the ABL OOF portion as target to evoke a specific and multiple immune response in Philadelphia positive leukemic patients in cytogenetic remission.

  1. 自身淬灭荧光定量PCR检测慢性粒细胞白血病bcr/abl mRNA%Quantification of bcr/abl mRNA in patients with chronic myeloid leukemia by using real-time quantitative fluorescence PCR with self-quenched primer

    Institute of Scientific and Technical Information of China (English)

    彭辉; 冯文莉; 王小中; 曾建明; 肖青; 潘健; 曹唯希; 罗云萍; 黄宗干

    2007-01-01

    目的 利用自身淬灭探针技术建立一种能检测慢性粒细胞白血病(CML)bcr/abl融合基因mRNA的实时荧光定量PCR方法,为CML的诊断、疗效观察以及微量残留白血病(MRD)的监测提供有效手段.方法 用逆转录PCR方法(RT-PCR)扩增K562细胞的bcr/abl融合基因,A-T克隆法构建定量标准模板;设计自身淬灭荧光引物(探针),建立自身淬灭荧光定量逆转录PCR方法(FQRT-PCR),并对该方法的线性检测范围、灵敏度、重复性、稳定性进行检测;然后检测临床白血病患者骨髓标本bcr/abl mRNA.结果 建立的FQ-RT-PCR方法可检测10 copies/μl的bcr/abl重组质粒,并能从105个正常细胞中检出1个白血病细胞,该方法的批内、批间变异系数(CV)分别为2.1%、6.1%,线性检测范围为102~109 copies/μl.25例CML患者bcr/abl融合基因mRNA表达量中位数为4.50×104[(0.45~89.00)×104]copies/μg RNA,其中11例慢性期初诊患者bcr/abl mRNA表达量中位数为5.45×104[(2.95~19.30)×104]copies/μg RNA,6例急变期患者bcr/abl mRNA表达量中位数为13.00×104[(4.10~89.00)×104]copies/μg RNA,8例慢性期治疗后复查患者bcr/ablmRNA表达量中位数为2.35×104[(0.45~5.12)×104]copies/μg RNA,CML急变期患者bcr/abl融合基因表达水平与慢性期患者之间差异有统计学意义(q=3.41,P<0.05).PCR产物经电泳分析,其中21例CML患者为b3a2型,4例CML患者为b2a2型;3例急性淋巴细胞白血病(ALL)患者中,1例有bcr/abl mRNA表达,为b2a2型.结论 所建立的基于自身淬灭探针技术的实时荧光定量PCR检测方法灵敏、特异、重复性好,结果用拷贝数表示,准确可靠,利于标准统一.可广泛用于CML的诊断、疗效观察以及MRD的监测.

  2. 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

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

    Directory of Open Access Journals (Sweden)

    Maria Luiza F. M. Kede

    2014-11-01

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

  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; Junior, Sidney F Salles; Marques, Marcia; Moreira, Josino C; Pérez, Daniel V

    2014-11-07

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

  5. BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: using guidelines to make rational treatment choices.

    Science.gov (United States)

    Kantarjian, Hagop; Cortes, Jorge

    2008-03-01

    The success of the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib in improving prognosis in chronic myeloid leukemia (CML) has led to its wide use as first-line therapy at a standard dose of 400 mg daily. As more patients have undergone therapy, the development of molecular and clinical resistance to imatinib has raised further therapeutic challenges. The 2 main approaches to overcoming resistance are imatinib dose escalation and the use of alternative more potent TKIs, such as dasatinib or nilotinib. The phase II SRC/ABL Tyrosine Kinase Inhibition Activity Research Trials (START) of dasatinib have established dasatinib as potent and effective in overcoming imatinib resistance or intolerance in all phases of CML. The most recent treatment guidelines by the National Comprehensive Cancer Network now contain recommendations for using dasatinib in this setting. The issue of when to change from imatinib to an alternative agent in preference to imatinib dose escalation is keenly debated, particularly as new clinical evidence emerges, which highlights the importance of achieving early cytogenetic and molecular responses for a good long-term outcome. Identifying patients in whom a change to dasatinib or nilotinib is more appropriate than imatinib dose escalation is therefore important.

  6. Effects of modified zeolite on the removal and stabilization of heavy metals in contaminated lake sediment using BCR sequential extraction.

    Science.gov (United States)

    Wen, Jia; Yi, Yuanjie; Zeng, Guangming

    2016-08-01

    Sediment can be applied on land as a soil conditioner. However, toxic substances such as heavy metals within the sediment often lead to soil contamination if no proper management is conducted prior to land application. In order to reduce the bioavailable portion of heavy metals such as Pb, Cu, Zn and Cd, zeolite as a kind of stabilizer was investigated on the effect of metal stabilization in sediment. Zeolite was firstly modified and screened to get the best condition for removal of heavy metals. Results showed that the granulated zeolite with NaCl conditioning had the highest CEC and metal sorption. Using BCR sequential extraction, the selected modified zeolite effectively stabilized Pb, Cu, Zn and Cd in sediment to different extents. It was most suitable for Cd stabilization by reducing its acid exchangeable fraction while increasing the contents of the reducible and residual fractions. Modified zeolite also immobilized Cu, Zn and Pb in sediment by enhancing one stable fraction while decreasing the acid exchangeable fraction.

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

    Science.gov (United States)

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

    2014-02-15

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

  8. Speciation of Heavy Metals by Modified BCR Sequential Extraction in Soils Contaminated by Phosphogypsum in Sfax, Tunisia

    Directory of Open Access Journals (Sweden)

    Ahmed Wali

    2015-01-01

    Full Text Available The accumulation of trace metals in soil is a serious environmental problem that creates a hazard when metals are transferred to water or plants. To understand the mobility and bioavailability of trace metals, the concentrations and distributions of trace metals must be established for different physical and chemical phases of the soil. We determined the concentrations of trace metals (Zn, Pb, Cu, Cr, Co, Ni, Mn, and Fe in soil using the sequential extraction method recommended by Community Bureau of Reference (BCR and analysed chemical properties, such as the pH, cation exchange capacity, total organic carbon, electrical conductivity, and calcium carbonate. Our results revealed higher concentrations of trace metals in topsoil samples (0–20 cm than in subsoil samples (20–40 cm and 40–60 cm for most metals at four sites. Zn in the topsoil was mostly associated with the non-resistant fraction at all sites. Approximately 60% more Pb was bound to the non-residual, exchangeable and reducible fractions at all sites, and soil depths. Cr, Cu, Ni and Fe were mainly in the residual fraction, whereas Mn was largely present in the non-resistant fraction. The global contamination factor of trace metals decreased with soil depth. The mobility and bioavailability were greatest for Zn, followed by Cu and Pb. DOI: http://dx.doi.org/10.5755/j01.erem.70.4.7807

  9. A BCR-ABL1 cutoff of 1.5% at 3 months, determined by the GeneXpert system, predicts an optimal response in patients with chronic myeloid leukemia

    Science.gov (United States)

    García-Gutiérrez, Valentín; Gómez-Casares, María T.; Puerta, José M.; Alonso-Domínguez, Juan M.; Osorio, Santiago; Hernández-Boluda, Juan C.; Collado, Rosa; Ramírez, María J.; Ibáñez, Fátima; Martín, María L.; Rodríguez-Gambarte, Juan D.; Martínez-Laperche, Carolina; Gómez, Montse; Fiallo, Dolly V.; Redondo, Sara; Rodríguez, Alicia; Ruiz-Nuño, Concepción; Steegmann, Juan L.

    2017-01-01

    In chronic myeloid leukemia (CML) patients, 3-month BCR-ABL1 levels have consistently been correlated with further outcomes. Monitoring molecular responses in CML using the GeneXpert (Cepheid) platform has shown an optimal correlation with standardized RQ-PCR (IS) when measuring BCR-ABL1 levels lower than 10%, as it is not accurate for values over 10%. The aim of the present study was to determine the predictive molecular value at three months on different outcome variables using the Xpert BCR-ABL1 MonitorTM assay (Xpert BCR-ABL1). We monitored 125 newly diagnosed consecutive CML patients in the chronic phase (CML-CP) using an automated method: Xpert BCR-ABL1. Only 5% of patients did not achieve an optimal response at 3 months, and the 10% BCR-ABL1 cutoff defined by RQ-PCR (IS) methods was unable to identify significant differences in the probabilities of achieving a complete cytogenetic response (CCyR) (50% vs. 87%, p = 0.1) or a major molecular response (MMR) (60% vs. 80%, p = 0.29) by 12 months. In contrast, a cutoff of 1.5% more accurately identified differences in the probabilities of achieving CCyR (98% vs. 54%, p<0.001) and MMR (88% vs. 56%, p<0.001) by 12 months, as well as probabilities of treatment changes (p = 0.005). Therefore, when using the Xpert BCR-ABL1 assay, a cutoff of 1.5% at 3 months could with high probability identify patients able to achieve an optimal response at 12 months. PMID:28278193

  10. miR-29b suppresses CML cell proliferation and induces apoptosis via regulation of BCR/ABL1 protein

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yajuan; Wang, Haixia; Tao, Kun [Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated of Ministry of Education, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 (China); Xiao, Qing [Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 (China); Huang, Zhenglan; Zhong, Liang; Cao, Weixi [Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated of Ministry of Education, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 (China); Wen, Jianping [Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5 (Canada); Feng, Wenli, E-mail: fengwlcqmu@sina.com [Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated of Ministry of Education, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 (China)

    2013-05-01

    MicroRNAs (miRNAs) are small RNAs that regulate gene expression posttranscriptionally and are critical for many cellular pathways. Recent evidence has shown that aberrant miRNA expression profiles and unique miRNA signaling pathways are present in many cancers. Here, we demonstrate that miR-29b is markedly lower expressed in CML patient samples. Bioinformatics analysis reveals a conserved target site for miR-29b in the 3′-untranslated region (UTR) of ABL1. miR-29b significantly suppresses the activity of a luciferase reporter containing ABL1-3′UTR and this activity is not observed in cells transfected with mutated ABL1-3′UTR. Enforced expression of miR-29b in K562 cells inhibits cell growth and colony formation ability thereby inducing apoptosis through cleavage of procaspase 3 and PARP. Furthermore, K562 cells transfected with a siRNA targeting ABL1 show similar growth and apoptosis phenotypes as cells overexpression of miR-29b. Collectively, our results suggest that miR-29b may function as a tumor suppressor by targeting ABL1 and BCR/ABL1. - Highlights: ► miR-29b expression was downregulated in CML patients. ► ABL1 was identified as a direct target gene of miR-29b. ► Enforced expression of miR-29b inhibits cell proliferation and induces apoptosis. ► miR-29b might be a therapeutic target to CML.

  11. Pharmacophore modeling of nilotinib as an inhibitor of ATP-binding cassette drug transporters and BCR-ABL kinase using a three-dimensional quantitative structure-activity relationship approach.

    Science.gov (United States)

    Shukla, Suneet; Kouanda, Abdul; Silverton, Latoya; Talele, Tanaji T; Ambudkar, Suresh V

    2014-07-07

    Nilotinib (Tasigna) is a tyrosine kinase inhibitor approved by the FDA to treat chronic phase chronic myeloid leukemia patients. It is also a transport substrate of the ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which may have an effect on the pharmacokinetics and toxicity of this drug. The goal of this study was to identify pharmacophoric features of nilotinib in order to potentially develop specific inhibitors of BCR-ABL kinase with minimal interactions with ABC drug transporters. Three-dimensional pharmacophore modeling and quantitative structure-activity relationship (QSAR) studies were carried out on a series of nilotinib analogues to identify chemical features that contribute to inhibitory activity of nilotinib against BCR-ABL kinase activity, P-gp, and ABCG2. Twenty-five derivatives of nilotinib were synthesized and were then tested to measure their activity to inhibit BCR-ABL kinase and to inhibit the function of ABC drug transporters. A set of in vitro experiments including kinase activity and cell-based transport assays and photolabeling of P-gp and ABCG2 with a transport substrate, [(125)I]-iodoarylazido-prazosin (IAAP), were carried out in isolated membranes to evaluate the potency of the derivatives to inhibit the function of ABC drug transporters and BCR-ABL kinase. Sixteen, fourteen, and ten compounds were selected as QSAR data sets, respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL kinase, ABCG2, and P-gp inhibitors. The IC50 values of these derivatives against P-gp, ABCG2, or BCR-ABL kinase were used to generate pharmacophore features required for optimal interactions with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for ABCG2 inhibitory activity, and a seven-point pharmacophore (AADDRRR) for P-gp inhibitory activity were generated. The derived models clearly demonstrate high predictive power

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

    Directory of Open Access Journals (Sweden)

    Eduardo Vinícius Vieira Varejão

    2009-08-01

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

  13. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

    Science.gov (United States)

    Pfeifer, Heike; Wassmann, Barbara; Pavlova, Anna; Wunderle, Lydia; Oldenburg, Johannes; Binckebanck, Anja; Lange, Thoralf; Hochhaus, Andreas; Wystub, Silvia; Brück, Patrick; Hoelzer, Dieter; Ottmann, Oliver G

    2007-07-15

    Acquired imatinib resistance in advanced Philadelphia-positive acute lymphoblastic leukemia (Ph(+) ALL) has been associated with mutations in the kinase domain (KD) of BCR-ABL. We examined the prevalence of KD mutations in newly diagnosed and imatinib-naive Ph(+) ALL patients and assessed their clinical relevance in the setting of uniform frontline therapy with imatinib in combination with chemotherapy. Patients enrolled in the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) trial ADE10 for newly diagnosed elderly Ph(+) ALL were retrospectively examined for the presence of BCR-ABL KD mutations by denaturing high-performance liquid chromatography (D-HPLC), cDNA sequencing, and allele-specific polymerase chain reaction (PCR). A KD mutation was detected in a minor subpopulation of leukemic cells in 40% of newly diagnosed and imatinib-naive patients. At relapse, the dominant cell clone harbored an identical mutation in 90% of cases, the overall prevalence of mutations at relapse was 80%. P-loop mutations predominated and were not associated with an inferior hematologic or molecular remission rate or shorter remission duration compared with unmutated BCR-ABL. BCR-ABL mutations conferring high-level imatinib resistance are present in a substantial proportion of patients with de novo Ph(+) ALL and eventually give rise to relapse. This provides a rationale for the frontline use of kinase inhibitors active against these BCR-ABL mutants.

  14. The CRISPR/Cas9 system efficiently reverts the tumorigenic ability of BCR/ABL in vitro and in a xenograft model of chronic myeloid leukemia.

    Science.gov (United States)

    García-Tuñón, Ignacio; Hernández-Sánchez, María; Ordoñez, José Luis; Alonso-Pérez, Veronica; Álamo-Quijada, Miguel; Benito, Rocio; Guerrero, Carmen; Hernández-Rivas, Jesús María; Sánchez-Martín, Manuel

    2017-02-09

    CRISPR/Cas9 technology was used to abrogate p210 oncoprotein expression in the Boff-p210 cell line, a pro-B line derived from interlukin-3-dependent Baf/3, that shows IL-3-independence arising from the constitutive expression of BCR-ABL p210. Using this approach, pools of Boff-p210-edited cells and single edited cell-derived clones were obtained and functionally studied in vitro. The loss of p210 expression in Boff-p210 cells resulted in the loss of ability to grow in the absence of IL-3, as the Baf/3 parental line, showing significantly increased apoptosis levels. Notably, in a single edited cell-derived clone carrying a frame-shift mutation that prevents p210 oncoprotein expression, the effects were even more drastic, resulting in cell death. These edited cells were injected subcutaneously in immunosuppressed mice and tumor growth was followed for three weeks. BCR/ABL-edited cells developed smaller tumors than those originating from unedited Boff-p210 parental cells. Interestingly, the single edited cell-derived clone was unable to develop tumors, similar to what is observed with the parental Baf/3 cell line.CRISPR/Cas9 genomic editing technology allows the ablation of the BCR/ABL fusion gene, causing an absence of oncoprotein expression, and blocking its tumorigenic effects in vitro and in the in vivo xenograft model of CML. The future application of this approach in in vivo models of CML will allow us to more accurately assess the value of CRISPR/Cas9 technology as a new therapeutic tool that overcomes resistance to the usual treatments for CML patients.

  15. 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 (RCT) 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.

  16. Comparative quantitative analysis of BCR-ABL transcripts with the T315I mutant clone by polymerase chain reaction (PCR)-Invader method.

    Science.gov (United States)

    Tadokoro, Kenichi; Ishikawa, Maho; Suzuki, Makoto; Saito, Tomoyoshi; Suzuki, Yoshie; Yamaguchi, Toshikazu; Yagasaki, Fumiharu

    2011-09-01

    Drug resistance is a serious complication in the treatment of chronic myeloid leukemia (CML). The most common and best-characterized mechanism of secondary imatinib resistance in CML is the development of kinase domain mutations in the BCR-ABL gene. Second-generation tyrosine kinase inhibitors, such as dasatinib or nilotinib, overcome most of these mutations, but they are not effective against the T315I mutant. To determine whether these mutations contribute to clinical resistance, it is necessary to monitor the ratio of the mutant and wild-type forms. Here, we developed a polymerase chain reaction (PCR)-Invader assay for comparative quantitative analysis (qPI assay) of BCR-ABL transcripts with the T315I mutant clone. T315I ratios were calculated for the wild-type and mutant fold-over-zero (FOZ) values. In examination with 2 kinds of plasmids containing wild-type or T315I mutant PCR amplicons, mutant FOZ values were detected down to 1% of the total. The results of 12 serial samples from 2 patients (case A: Philadelphia-positive acute lymphoblastic leukemia and case B: CML) with the T315I mutant clone were compared with those of direct sequencing or 2 kinds of allele-specific oligonucleotide (ASO)-PCR. All samples showed the T315I mutation by qPI assay and ASO-PCR, and 10 samples showed it by direct sequencing. Significant correlation (correlation coefficient; r2 = 0.951) was noted between the qPI assay and quantitative ASO-PCR to analyze T315I mutant ratios. Thus, the qPI assay is a useful method for evaluating the T315I mutant clone in BCR-ABL transcripts.

  17. BCR/ABL DCDF-FISH信号特征与染色体核型的关系及其在慢性粒细胞白血病中的意义%Significance of BCR/ABL DCDF-FISH signal pattern and karyotype in chronic myeloid leukemia

    Institute of Scientific and Technical Information of China (English)

    杜庆华; 应逸; 陈晓燕

    2010-01-01

    目的 探讨慢性粒细胞白血病(CML)BCR/ABL DCCF-FISH的信号特点及其与染色体核型的关系.结果 使用BCR/ABL的DCDF探针对65例慢性粒细胞白血病骨髓标本进行荧光原位杂交及染色体核型检查.结果 65例CML核型43例Ph阳性,1例阴性,其余21例未行核性检查或无可分析分裂相;FISH结果65例均为BCR/ABL阳性,其中9例伴ASS基因缺失,5例复杂易位,1例+Ph伴ASS基因缺失.结论 传统核型与DCDF-FISH,应互相结合,方可对遗传学特征作出更准确分析.%Objective To investigate the relation between the BCR/ABL DCDF-FISH signal pattern and karyotype in chronic myeloid leukemia(CML). Methods 65 cases of CML were performed FISH and karyotyping. Results In 65 cases CML. 43 cases were Ph positive, 1 case was Ph negative, 21 cases had no performed karyotyping analysis. All of 65 cases were FISH positive,9 cases with ASS gene deletion, 5 cases with complex variant translocation, 1 case with (+) Ph and ASS gene deletion. Conclusion More precise analysis can be got by combining the result of FISH and karyotyping.

  18. 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

  19. 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

    ), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation......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...

  20. Study of the water-rock interaction in Tsengwenshi groundwater system (southern Taiwan) using BCR sequential extraction procedure

    Science.gov (United States)

    Teng, J. Y.

    2012-04-01

    The heavy metals in groundwater seriously risk the human wealth, agriculture and the aquaculture, especially, if the water is the major source of daily use. Generally, in spite of anthropogenic source, the heavy metals in groundwater are released during water-rock interaction. However, there are many mineral phases being capable of releasing heavy metals. It would need a sequential extraction procedure to identify the source mineral phase in the aquifer. In addition, the geochemical reactions after the release of heavy metals are also important to modify the concentrations. In this study, the rare earth elements are used to be a natural tracer for this purpose. The study area, Tsengwenshi watershed in southern Taiwan, is an alluvial fan with all kinds of land uses and is notorious of arsenic contamination. The groundwaters sampled in this study show that arsenic is enriched in deep aquifer (depth>150m), which is composed of sediments deposited in the last glacial period (18 ka). Based on this conceptual model, the results of BCR sequential extraction procedure are categorized into shallow aquifer (depthheavy metals in two groups can be subsequently obtained to take account of extensive water-rock interaction in the groundwater system. The results show that arsenic and other heavy metals are mostly binding with Fe-Mn oxides. To compare the ratios between deep and shallow aquifers for all heavy metals, the pattern of groundwaters does not show the similar type with those of extracted phases from soils. It is believed that the released heavy metals were strongly modified by the geochemical reactions during the transportation in the groundwater system. In addition, the analysis results of the rare earth elements demonstrates that almost all groundwaters with high arsenic do not have Ce negative anomaly; and, on the contrary, those with low arsenic are generally characterized by strong negative anomaly. Generally, the Ce negative anomaly is a prominent indicator of

  1. 伴不典型BCR-ABL融合基因的慢性髓性白血病的临床和实验研究%A clinical and laboratory study of chronic myeloid leukemia with atypical BCR-ABL fusion gene subtypes

    Institute of Scientific and Technical Information of China (English)

    桂晓敏; 潘金兰; 仇惠英; 岑建农; 薛永权; 陈苏宁; 沈宏杰; 姚利; 张俊

    2014-01-01

    目的 探讨伴不典型BCR-ABL融合基因亚型el4a3和e19a2型慢性髓性白血病(CML)的临床和实验室特点.方法 对2004至2012年染色体核型分析有t(9;22) (q34;q11),荧光原位杂交(FISH)证实为BCR-ABL融合基因阳性,而常规实时定量PCR(RQ-PCR)检测常见BCR-ABL融合基因(b3a2、b2a2和e1a2)阴性的6例CML患者,重新设计引物进行PCR扩增,并将扩增产物测序,以明确不典型BCR-ABL融合基因类型.对BCR-ABL融合基因扩增产物进行突变检测.对患者的临床资料进行回顾性分析.结果 6例患者PCR扩增产物经测序分析,其中5例为e14a3型,1例为e19a2型.5例e14a3型CML患者中,男4例,女1例,中位年龄48岁,慢性期4例,加速期1例;1例e19a2型患者为女性,40岁,CML慢性期,PLT>1 000× 109/L.5例e14a3型CML患者中4例在羟基脲或IFN治疗无效后予以伊马替尼(IM)治疗,1例行造血干细胞移植(HSCT).前4例患者中1例因有E255K突变而对IM耐药,改用达沙替尼后获完全细胞遗传学反应(CCyR);1例在IM治疗获CCyR后3个月复发并急变,最终死亡;2例IM治疗后获CCyR,目前状态稳定,仍处于CCyR,尽管其中1例伴有I293T突变.行HSCT治疗患者目前处于CCyR.1例e19a2型CML患者羟基脲治疗后获得完全血液学反应,后改用IM治疗,很快获得CCyR.结论 伴不典型BCR-ABL融合基因的CML发病率极低,酪氨酸激酶抑制剂或HSCT都可以取得疗效,常规RQ-PCR可能漏检少见的不典型BCR-ABL融合基因亚型.%Objective To explore the clinical and laboratory features of chronic myeloid leukemia (CML) with atypical e14a3 and e19a2 BCR-ABL fusion gene subtypes.Methods We retrospectively analyzed a cohort of CML patients with Ph chromosome positive confirmed by cytogenetic and FISH but classical el3a3 (b2a2),e14a2 (b3a2)and ela2 fusion transcripts negative identified by conventional realtime quantification RT-PCR (RQ-PCR).Further RQ-PCR was done with the forward primer and reverse primer designed to

  2. 荧光原位杂交在慢性粒细胞白血病细胞BCR/ABL融合基因检测中的应用及其意义%The detection of BCR/ABL fusion gene by interphase fluorescence in situ hybridization in patients with chronic myeloid leukemia and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    张济; 李君君; 颜家运; 邹礼衡; 刘静

    2012-01-01

    目的:探讨荧光原位杂交(FISH)技术检测慢性粒细胞白血病(CML)骨髓和外周血细胞的BCR /ABL融合基因的临床价值.方法:应用FISH 对正常对照组及CML患者骨髓和外周血细胞BCR/ ABL融合基因进行检测和分析.结果:慢性期CML 患者骨髓和外周血细胞该融合基因阳性细胞率分别为(61.9 ± 22.3)%和(68.4 ± 19.8)%,加速期为(77.2 ± 16.7)% 和(86.8 ± 12.1)%,急变期为(80.6 ± 17.5)%和(81.4 ± 18.0)%,两者细胞中BCR/ABL 基因的阳性率未见统计学差异(P>0.05),且骨髓和外周血细胞之间融合基因阳性细胞比率呈直线正相关.同时发现在完全临床缓解患者中,经伊马替尼治疗的CML 患者(71.4%)较经干扰素和羟基脲联合治疗者(10.0%)有更高的分子生物学缓解(P 0.05). A significant correlation was found between the BCR/ABL positive cells in peripheral blood and in bone marrow samples. Moreover, the higher rate of complete molecular remission was achieved by treating with imatinib than with interferon and hydroxyurea during complete remission phase (P < 0.05). Conclusions Detecting BCR/ABL fusion gene in peripheral blood and bone marrow samples by FISH are beneficial to diagnosis, treatment and minimal residual disease monitor in CML.

  3. Comparison between BCR sequential extraction and geo-accumulation method to evaluate metal mobility in sediments of Dongting Lake, Central China

    Science.gov (United States)

    Yao, Zhigang

    2008-02-01

    The form in which a metal exists strongly influences its mobility and thus, the effects on the environment. Operational methods of speciation analysis, such as the use of sequential extraction procedures, are commonly applied. The Dongting Lake, the second largest fresh-water lake in China, contains three China wetlands of international importance, the East Dongting Lake, South Dongting Lake, and West Dongting Lake. In this work, an optimized BCR sequential extraction procedure was used to assess the environmental risk of Cd, Cr, Cu, Ni, Pb and Zn in contaminated sediment of the Dongting Lake. The procedure was evaluated by using a certified reference material, BCR701. The results of the partitioning study indicated that in the lake sediments, more easily mobilized forms (acid exchangeable) were predominant for Cd, particularly in the samples from the East Dongting Lake. In contrast, the largest amount of Pb was associated with the iron and manganese oxide fractions and Cu, Zn, Cr, and Ni analyzed were mainly distributed in residual phase at an average percentage greater than 60% of the total metals. The potential risk to the lake’s water contamination was highest in the East Dongting Lake based on the calculated contamination factors. On the other hand, the total metal content was determined as well by inductively coupled plasma and mass spectrometry (ICP-MS) and assessed by using geo-accumulation index. The assessment results using geo-accumulation index were compared with the information on metal speciation. Both were correspondent with each other.

  4. Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage.

    Directory of Open Access Journals (Sweden)

    Mingqiang Ren

    Full Text Available Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19(+ IgM(- CD43(+ immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19(+ IgM(- CD43(+ were also either B220(+ or B220(-, suggesting a block in differentiation at the pro-B cell stage. The B220(- phenotype was retained in one of the cell lines while the other was B220(+. When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease.

  5. Fractionation of heavy metals in liquefied chromated copper arsenate 9-treated wood sludge using a modified BCR-sequential extraction procedure.

    Science.gov (United States)

    Pan, Hui; Hse, Chung-Yun; Gambrell, Robert; Shupe, Todd F

    2009-09-01

    Chromated copper arsenate (CCA)-treated wood was liquefied with polyethylene glycol/glycerin and sulfuric acid. After liquefaction, most CCA metals (98% As, 92% Cr, and 83% Cu) were removed from liquefied CCA-treated wood by precipitation with calcium hydroxide. The original CCA-treated wood and liquefied CCA-treated wood sludge were fractionated by a modified Community Bureau of Reference (BCR) sequential extraction procedure. The purpose of the BCR-sequential extraction used in this study was to examine the availability of CCA metals in treated wood for reuse. Both As and Cr had a slightly higher concentration in the sludge sample than in original CCA-treated wood. The sequential extraction showed that As and Cr were principally existed in an oxidizable fraction (As, 67%; Cr, 88%) in original CCA-treated wood. Only 1% of both As and Cr were extracted by hot nitric acid with the last extraction step. The distribution of As and Cr changed markedly in liquefied CCA-treated wood sludge. The amount of As in the exchangeable/acid extractable fraction increased from 16% to 85% while the amount of Cr increased from 3% to 54%. Only about 3% of As was present in the oxidizable fraction. However, there was still about 34% of Cr in the same fraction. Based on these results from sequential extraction procedures, it can be concluded that the accessibilities of CCA metals increase markedly by the liquefaction-precipitation process.

  6. 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.

  7. INFLUENCE OF CHEMOTHERAPEUTANTS AND CYTOKINES ON GROWTH AND TRANSGENE EXPRESSION OF BONE MARROW CELLS FROM MT/P210bcr-ab1 TRANSGENIC MICE

    Institute of Scientific and Technical Information of China (English)

    CHEN Hanchun; Andrew Pierce; Tony Whetton

    1999-01-01

    Objective: To investigate the influence of chemotherapeutic agents and cytokines on growth of bone marrow cells from MT/p210 bcr-ab1 transgenic mice.Methods: The bone marrow cells of transgenic chronic myelogenous leukemia (CML) model mice carrying metallothionein (MT) promoter/enhancer, bcr-abl (p210)cDNA and SV40 splicing/poly (A) signal sequences were cultured in liquid and soft agar with hydroxyurea (Hu),5-fluorouracil (5-Fu), mouse stem cell factor (mSCF)and mouse interleukin-3 (mIL-3) independently or collectively. The cells and colonies were counted. The levels of transgene expression were detected by reverse transcriptase-polymerase chain reaction (RT-PCR).Results: The cell proliferation, colony formation and transgene expression of the bone marrow cells were stimulated with mSCF and mIL-3, but there was little growth without any growth factors, or when mSCF,mIL-3 and Hu or 5-Fu were added. Conclusion: The combined utilization of chemotherapeutants and cytokines is a potentially effective strategy of clinical treatment for CML.

  8. Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment.

    Science.gov (United States)

    Oaxaca, Derrick M; Yang-Reid, Sun Ah; Ross, Jeremy A; Rodriguez, Georgialina; Staniswalis, Joan G; Kirken, Robert A

    2016-09-01

    Tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients suffering from chronic myeloid leukemia (CML); however, patients will eventually develop resistance to TKI therapy or adverse side effects due to secondary off-target mechanisms associated with TKIs. CML patients exhibiting TKI resistance are at greater risk of developing an aggressive and drug-insensitive disease. Drug-resistant CML typically arises in response to spontaneous mutations within the drug binding sites of the targeted oncoproteins. To better understand the mechanism of drug resistance in TKI-resistant CML patients, the BCR-ABL transformed cell line KCL22 was grown with increasing concentrations of imatinib for a period of 6 weeks. Subsequently, a drug-resistant derivative of the parental KCL22 cell line harboring the T315I gatekeeper mutation was isolated and investigated for TKI drug sensitivity via multi-agent drug screens. A synergistic combination of ponatinib- and forskolin-reduced cell viability was identified in this clinically relevant imatinib-resistant CML cell line, which also proved efficacious in other CML cell lines. In summary, this study provides new insight into the biological underpinnings of BCR-ABL-driven CML and potential rationale for investigating novel treatment strategies for patients with T315I CML.

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

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    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.

  10. 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.

  11. -Regular Modules

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    Areej M. Abduldaim

    2013-01-01

    Full Text Available We introduced and studied -regular modules as a generalization of -regular rings to modules as well as regular modules (in the sense of Fieldhouse. An -module is called -regular if for each and , there exist and a positive integer such that . The notion of -pure submodules was introduced to generalize pure submodules and proved that an -module is -regular if and only if every submodule of is -pure iff   is a -regular -module for each maximal ideal of . Many characterizations and properties of -regular modules were given. An -module is -regular iff is a -regular ring for each iff is a -regular ring for finitely generated module . If is a -regular module, then .

  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. BCR/ABL阴性骨髓增生性疾病患者JAK2-V617F点突变与外周血三系变化的相关性%Correlation between JAK2-V617F mutations and variation of peripheral blood cells among BCR/ABL-negative MPD patients

    Institute of Scientific and Technical Information of China (English)

    叶远馨; 宋兴勃; 周易; 应斌武; 陆小军

    2012-01-01

    目的 探讨BCR/ABL阴性骨髓增生性疾病患者JAK2-V617F突变的阳性率以及突变量与外周血三系变化的相关性.方法 对191例确诊为BCR/ABL阴性的骨髓增生性疾病患者进行JAK2-V617F突变检测,分别以外周血中红细胞、白细胞、血小板计数进行分类统计,分析不同类型的标本JAK2-V617F基因点突变的发生率及相对定量变化.结果 外周血红细胞、白细胞、血小板计数不同范围的标本JAK2-V617F突变阳性率有统计学差异.随着外周血红细胞、血小板计数增高,JAK2-V617F突变阳性率也随之增高,且以三系均增多者JAK2-V617F突变率为最高(92.86%).结论 BCR/ABL阴性的骨髓增生性疾病JAK2-V617F点突变发生率与外周血三系变化存在明显的相关性.外周血三系变化、尤其是红细胞计数与BCR/ABL阴性的骨髓增生性疾病JAK2-V617F突变的阳性率以及突变相对定量存在一定的相关性.%Objective To assess the correlation between JAK2-V617F mutation and complete blood counts among patients with BCR/ABL-negative myeloproliferative diseases (MPD).Methods One hundred and ninety one patients were recruited.Retrospectively,their laboratory data were analyzed for the counts of red blood cells (RBC),white blood cells (WBC) and platelets (PLT).And the incidence of JAK2-V617F mutation was determined.Results There was significant difference in the incidence of JAK2-V617F mutation between patients with different cell counts (P<0.01).The incidence of JAK2-V617F mutation has increased with the counts of RBC and PLT,which was the highest (92.86%) among those featuring simultaneous increase in all three series.Conclusion The incidence of JAK2-V617F mutation seems to be strongly associated with variation of peripheral blood cell counts among patients with BCR/ABL-negative MPD.Variation of peripheral blood cells,particularly RBC,may be correlated with the rate of JAK2-V617F mutation.

  14. 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?

    Science.gov (United States)

    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.

  15. BCR ligation antagonizes the IL-21 enhancement of anti-CD40/IL-4 plasma cell differentiation and IgE production found in low density human B cell cultures.

    Science.gov (United States)

    Caven, Timothy H; Sturgill, Jamie L; Conrad, Daniel H

    2007-05-01

    We sought to discover the mechanisms explaining increased IgE production seen at low cell densities when IL-21 is added to human B cell cultures activated with anti-CD40 and IL-4. When cells were cultured in the absence of BCR ligation, qPCR demonstrated dramatic increases in mRNA for the plasma cell transcription factors BLIMP1 and XBP1. Furthermore, a majority of viable cells expressed high levels of CD38 while losing expression of surface IgD. In contrast, in the presence of BCR stimulation, both the XBP1 mRNA levels and CD38 cell surface expression were markedly reduced, and a large population of cells retained IgD expression, indicating reduced plasma cell differentiation. IgE levels were reduced in the BCR stimulated cultures by 90%, while IgG4 levels remained unchanged. In summary, IL-21 enhances IgE production at low densities through stimulating cell division and plasma cell differentiation and this activity is reduced upon BCR cross-linking.

  16. Expression patterns of WT-1 and Bcr-Abl measured by TaqMan quantitative real-time RT-PCR during follow-up of leukemia patients with the Ph chromosome

    Institute of Scientific and Technical Information of China (English)

    CHEN Zi-xing陈子兴; Jaspal Kaeda; Sue Saunders; John M Goldman

    2004-01-01

    Background This study was designed to quantitatively measure WT-1 expression levels in patients with chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) during follow-up and to clarify the value of WT-1 as a molecular marker in minimal residual disease monitoring.Methods The TaqMan quantitative real-time RT-PCR method was established by using cloned WT-1 cDNA or synthesized oligonucleotides resembling WT-1 cDNA fragments in limit dilution as template until a stable and reliable standard curve was obtained. In a 25-month follow-up, the transcriptional levels of WT-1, Bcr-Abl, and Abl gene, were quantitatively measured in bone marrow cells from 25 CML or acute lymphoblastic leukemia (ALL) patients with the Ph chromosome. In addition, the expression of these genes in 40 samples of normal peripheral blood was also examined using the same method. The ratios of WT-1/Abl and Bcr-Abl/Abl were both plotted, and the two expression patterns were compared as well as their clinical significance.Results The levels of WT-1 expression in normal peripheral blood were detectable. In CML and Ph positive ALL patients, WT-1 expression levels changed in parallel with the Bcr-Abl expression pattern as the disease progressed or responded to effective treatment.Conclusion WT-1 expression provides a novel molecular marker in addition to Bcr-Abl for monitoring minimal residual disease (MRD) and targeting therapy in Ph chromosome-positive leukemia patients.

  17. 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.

  18. 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

    2012-01-01

    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

  19. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036

    Science.gov (United States)

    Chan, Wayne W.; Wise, Scott C.; Kaufman, Michael D.; Ahn, Yu Mi; Ensinger, Carol L.; Haack, Torsten; Hood, Molly M.; Jones, Jennifer; Lord, John W.; Lu, Wei Ping; Miller, David; Patt, William C.; Smith, Bryan D.; Petillo, Peter A.; Rutkoski, Thomas J.; Telikepalli, Hanumaiah; Vogeti, Lakshminarayana; Yao, Tony; Chun, Lawrence; Clark, Robin; Evangelista, Peter; Gavrilescu, L. Cristina; Lazarides, Katherine; Zaleskas, Virginia M.; Stewart, Lance J.; Van Etten, Richard A.; Flynn, Daniel L.

    2011-01-01

    Summary Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for chronic myeloid leukemia (CML) patients. Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead “switch-control” inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1T315I-expressing cell lines, prolongs survival in mouse models of T315I-mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph+ leukemia. PMID:21481795

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

    Directory of Open Access Journals (Sweden)

    Marianna Greco

    2013-01-01

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

  1. Patan hospital experience in treating philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients with gleevec (imatinib mesylate; the first generation specific tyrosine kinase inhibitor

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    Zimmerman Mark

    2010-12-01

    Full Text Available Abstract Background Chronic Myeloid Leukemia (CML is caused by the abnormal fusion protein BCR-ABL1, a constitutively active tyrosine kinase and product of the Philadelphia chromosome. Gleevec (Imatinib mesylate is a selective inhibitor of this kinase. Treatment with this agent is known to result in hematologic, cytogenetic, and molecular responses. Patan hospital (Patan, Nepal is one of the Gleevec International Patient Assistance Program (GIPAP centers for patients with CML. Methods A total of 106 Philadelphia positive CML patients were enrolled in our center between Feb 2003 and Jun 2008, and 103 of them were eligible for cytogenetic and/or hematologic response analyses. Results Out of 103 patients, 27% patients underwent cytogenetic analysis. Imatinib induced major cytogenetic responses in 89% and complete hematologic responses in almost 100% of the patients with confirmed CML. After a mean follow up of 27 months, an estimated 90% of the patients on imatinib remained in hematologic remission and more than 90% of the patients are still alive. About 30% of patients developed some form of manageable myelosuppression. A few patients developed non-hematologic toxic side effects such as edema and hepatotoxicity. Conclusions Our study demonstrates that imatinib is safe to use in a developing country. Furthermore, we demonstrate that imatinib is very effective and induced long lasting responses in a high proportion of patients with Ph chromosome/BCR-ABL1 positive CML. Imatinib is well tolerated by our patients. The lack of cytogenetic analysis in the majority of our patients hindered our ability to detect inadequate responses to imatinib and adjust therapy appropriately.

  2. Fitness conferred by BCR-ABL kinase domain mutations determines the risk of pre-existing resistance in chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Kevin Leder

    Full Text Available Chronic myeloid leukemia (CML is the first human malignancy to be successfully treated with a small molecule inhibitor, imatinib, targeting a mutant oncoprotein (BCR-ABL. Despite its successes, acquired resistance to imatinib leads to reduced drug efficacy and frequent progression of disease. Understanding the characteristics of pre-existing resistant cells is important for evaluating the benefits of first-line combination therapy with second generation inhibitors. However, due to limitations of assay sensitivity, determining the existence and characteristics of resistant cell clones at the start of therapy is difficult. Here we combined a mathematical modeling approach using branching processes with experimental data on the fitness changes (i.e., changes in net reproductive rate conferred by BCR-ABL kinase domain mutations to investigate the likelihood, composition, and diversity of pre-existing resistance. Furthermore, we studied the impact of these factors on the response to tyrosine kinase inhibitors. Our approach predicts that in most patients, there is at most one resistant clone present at the time of diagnosis of their disease. Interestingly, patients are no more likely to harbor the most aggressive, pan-resistant T315I mutation than any other resistance mutation; however, T315I cells on average establish larger-sized clones at the time of diagnosis. We established that for patients diagnosed late, the relative benefit of combination therapy over monotherapy with imatinib is significant, while this benefit is modest for patients with a typically early diagnosis time. These findings, after pre-clinical validation, will have implications for the clinical management of CML: we recommend that patients with advanced-phase disease be treated with combination therapy with at least two tyrosine kinase inhibitors.

  3. SPR Detection and Discrimination of the Oligonucleotides Related to the Normal and the Hybrid bcr-abl Genes by Two Stringency Control Strategies

    Science.gov (United States)

    Matsishin, M. J.; Ushenin, Iu. V.; Rachkov, A. E.; Solatkin, A. P.

    2016-01-01

    In this study, we applied two stringency control strategies for surface plasmon resonance (SPR) detection of DNA hybridization and discrimination of completely and partially complementary 24-mer sequences. These sequences are specific to the human normal bcr and the hybrid bcr-abl genes, protein products of which are responsible for some leukemia. SPR sensors based on resonance phenomena in nanoscale gold films are well suited for label-free, real-time investigations of the macromolecule interactions. Thermodynamic parameters obtained using the web server DINAMelt allowed supposing the possibility for realization (a) stringency control based on the ionic strength of the hybridization buffer and (b) stringency control based on the temperature elevation. The first one resulted in that the discrimination index of completely complementary and partially complementary oligonucleotides depending on the target concentration varied from 1.3 to 1.8 in 2 × SSC and from 2.0 to 2.9 in 0.5 × SSC. For implementation of the second stringency control strategy, SPR spectrometer measuring flow cell with built-in high-precision temperature control and regulation as well as corresponding software was created. It is shown that the duplexes formed by the immobilized probes mod-Ph and completely complementary oligonucleotides P1 remained without significant changes until ~50 °C, while the duplexes formed with partially complementary oligonucleotide Bcrex14 almost entirely disrupted at 40 °C. Thus, the absolutely effective thermodiscrimination of this pair of oligonucleotides was achieved in this temperature range (40-50 °C).

  4. Cell sorting enables interphase fluorescence in situ hybridization detection of low BCR-ABL1 producing stem cells in chronic myeloid leukaemia patients beyond deep molecular remission.

    Science.gov (United States)

    van Kooten Niekerk, Peter B; Petersen, Charlotte C; Nyvold, Charlotte G; Ommen, Hans B; Roug, Anne S; Nederby, Line; Hokland, Peter; Kjeldsen, Eigil

    2014-01-01

    The exact disease state of chronic myeloid leukaemia (CML) patients in deep molecular remission is unknown, because even the most sensitive quantitative reverse transcription polymerase chain reaction (qPCR) methods cannot identify patients prone to relapse after treatment withdrawal. To elucidate this, CD34(+) stem cell and progenitor cell subpopulations were isolated by fluorescence-activated cell sorting (FACS), and their content of residual Philadelphia positive (Ph(+) ) cells was evaluated in 17 CML patients (major molecular response, n = 6; 4-log reduction in BCR-ABL1 expression (MR(4) ), n = 11) using both sensitive qPCR and interphase fluorescence in situ hybridization (iFISH). Despite evaluating fewer cells, iFISH proved superior to mRNA-based qPCR in detecting residual Ph(+) stem cells (P = 0·005), and detected Ph(+) stem- and progenitor cells in 9/10 patients at frequencies of 2-14%. Moreover, while all qPCR(+) samples also were iFISH(+) , 9/33 samples were qPCR-/iFISH(+) , including all positive samples from MR(4) patients. Our findings show that residual Ph(+) cells are low BCR-ABL1 producers, and that DNA-based methods are required to assess the content of persisting Ph(+) stem cells in these patients. This approach demonstrates a clinically applicable manner of assessing residual disease at the stem cell level in CML patients in MR(4) , and may enable early and safe identification of candidates for tyrosine kinase inhibitor withdrawal.

  5. 用COLD-PCR方法提高BCR-ABL1激酶区耐药突变检测灵敏度%Application of COLD-PCR for improved detection of BCR-ABL1 kinase domain drug-resistant mutation

    Institute of Scientific and Technical Information of China (English)

    李庆; 刘红星; 孙慧; 王倩; 张之芬; 武焕玲; 李元堂; 陈永金; 田文君

    2013-01-01

    Objective To evaluate the feasibility of the co-amplification using a low denaturation temperature PCR (COLD-PCR) method in improving the detection of BCR-ABL1 fusion gene kinase domain drug-resistant mutation.Methods Conventional nested PCR (CN-PCR) and COLD-PCR protocol were designed to amplify full-length of BCR-ABL1 kinase domain.PCR products were purified and then Sanger sequenced to detect BCR-ABL1 kinase domain mutation (KDM).20 newly diagnosed CML patients and 32 Imatinib (IM) resistant patients were chosen and peripheral blood or bone marrow samples were collected.PCR products of the clinical specimens were purified and then cloned to evaluate the proportion of the KDM allele.Standard samples with different proportion of KDMs were prepared using T-A vectors with KDM and wild type BCR-ABL1 kinase domain sequence,and then CN-PCR,COLD-PCR and Sanger sequencing were performed to compare the detection sensitivity.Results In the 32 IM-resistant patients,23 were identified KDM-positive using CN-PCR and 28 KDM-positive using COLD-PCR.In the 20 newly diagnosed CML patients,none was identified KDM-positive using CN-PCR and 1 was identified carrying a lower proportion of KDM using COLD-PCR.For 16 different types of KDMs,COLD-PCR method could improve the detection sensitivity 4-12 times.Conclusion Detection sensitivity of BCR-ABL1 drug-resistant kinase domain mutation can be effectively improved by using COLD-PCR method and may contribute to early detection of resistance KDMs.%目的 探讨用低变性温度共扩增PCR(COLD-PCR)方法提高BCR-ABL1融合基因激酶区耐药突变检测灵敏度的可行性.方法 本研究为实验诊断研究.设计常规巢式PCR(CN-PCR)和COLD-PCR方案扩增BCR-ABL1激酶区全长,扩增产物纯化后用Sanger测序法检测激酶区突变(KDM).采集32例经伊马替尼(IM)治疗并出现耐药的慢性粒细胞性白血病(CML)患者和20例初诊CML患者外周血或骨髓标本,用上述2种方案检测标本中的KDM.

  6. 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

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

    Directory of Open Access Journals (Sweden)

    Thiago Cezar Fujita

    2010-09-01

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

  8. Overexpression or knock-down of runt-related transcription factor 1 affects BCR-ABL-induced proliferation and migration in vitro and leukemogenesis in vivo in mice

    Institute of Scientific and Technical Information of China (English)

    YANG Li-jun; YU Wei-dong; DU Jun-bao; CHAO Shuang; CHEN Min-xia; ZHAO He-hua; GUO Jing-zhu

    2009-01-01

    Background Runt-related transcription factor 1 (Runx1) plays a crucial role in hematogenesis and its dysfunction may contribute to leukemogenesis. However, it is not clear whether or not abnormal expression of Runx1 will induce leukemia and how the change of Runx1 expression level could affect BCR-ABL-induced leukemogenesis. In the present study, we aimed to analyze if abnormal expression of Runx1 in BaF3 cells alone would induce leukemogenesis. And we also wanted to know if abnormal expression of Runx1 in leukemic cells would affect leukemogenesis. Furthermore, we investigated whether overexpression or knock-down of Runx1 in BaF3 cells would induce leukemogenesis.Methods Plasmids containing full-length Runx1 cDNA were transduced into BaF3 cells and BaF3-P185wt cells (BCR-ABL transformed BaF3 cells) by electroporation. Plasmids containing a short hairpin RNA of Runx1 were transduced into BaF3 cells and BaF3-P185wt cells by electroporation. Runx1 expression level was quantified by Western blotting and quantitative real-time PCR. The effects of overexpression or knock-down of Runx1 on proliferation, apoptosis and migration of cells were detected in vitro. Then, using MSCV-P185wt-FGFP as a control, we transplanted MSCV-P185wt-Runx1 cells or MSCV-P185wt-shRNA cells into Balb/c mice through tail vein and observed tumorgenesis of the different phenotypes.Results In vitro analysis revealed that overexpression of Runx1 in P185wt cells could inhibit cell proliferation and slow down cell migration; while knock-down of Runx1 could promote cell proliferation and speed up cell migration. In vivo analysis indicated that mice transplanted with MSCV-P185wt-Runx1 survived longer than controls. In contrast, mice transplanted with MSCV-P185wt-shRNA survived shorter than the control group. Gross pathological analysis revealed that the MSCV-P185wt-Runx1 group had less severe splenomegaly and hepatomegaly compared to the control group, and the MSCV-P185wt-shRNA group had more severe

  9. 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.

    Science.gov (United States)

    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.

  10. Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status.

    Science.gov (United States)

    Kawajiri, Chika; Tanaka, Hiroaki; Hashimoto, Shinichiro; Takeda, Yusuke; Sakai, Shio; Takagi, Toshiyuki; Takeuchi, Masahiro; Ohwada, Chikako; Sakaida, Emiko; Shimizu, Naomi; Nakaseko, Chiaki

    2014-04-01

    Philadelphia chromosome-positive mixed phenotype acute leukemia (Ph(+)MPAL) is a rare type of acute leukemia having myeloid and lymphoid features. In the present study, we describe the successful treatment of a 71-year-old Japanese female patient with Ph(+)MPAL by the alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutations. The patient survived in her third complete remission (CR) for over 4 years. In her first CR, the patient was treated with multiple-agent chemotherapy and underwent maintenance therapy with imatinib and monthly vincristine and prednisolone (VP). At the first relapse, an examination of the bone marrow revealed a transformation into acute lymphoblastic leukemia and an F317L mutation in BCR-ABL1 gene, which responded preferentially to nilotinib over dasatinib. She achieved second CR, and nilotinib with VP therapy was selected for maintenance treatment. At second relapse, BCR-ABL1 mutational analysis revealed Y253H mutation instead of F317L mutation, resulting in resistance to nilotinib. The patient achieved third CR with dasatinib and VP therapy, and maintained CR with this treatment. This suggests that appropriate alternation of TKIs may contribute to long-term survival in elderly patients with Ph(+)MPAL.

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

    Science.gov (United States)

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

    2014-01-01

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

  12. DFT+ U study of electronic structure and Curie temperature of A2 B ReO6 (A=Sr, Ca and B=Cr, Fe)

    Science.gov (United States)

    Lee, Alex; Marianetti, Chris

    Re-based double perovskites (DPs) have attracted much attention due to their high Curie temperature (TC) and colossal magneto resistance with large potential for spintronic applications. Here we investigate the electronic and magnetic properties of the Re-based DPs A2 B ReO6 (A=Sr, Ca and B=Cr, Fe) using density functional theory + U (DFT+ U) calculations. While monoclinic Ca2CrReO6 and Ca2FeReO6 (monoclinic) are insulating within GGA+ U, tetragonal Sr2CrReO6 (a0a0c0) and Sr2FeReO6 (a0a0c-) remain metallic. We show that both on-site interaction U and octahedral tilting are critical to obtain the insulating phases. The a0a0c- -phase of Sr2CrReO6 is most stable and insulating with nonzero U, suggesting that the high quality Sr2CrReO6 film on STO substrate can be a semiconductor as reported in recent experiments. We explain that the insulator-to-metal transition (MIT) of Ca2FeReO6 at 140K is predominantly due to a structural phase transition which drives the insulating state. Curie temperatures of Re-based DPs are calculated using the classical Monte Carlo simulations based on the Heisenberg model.

  13. Doxorubicin Differentially Induces Apoptosis, Expression of Mitochondrial Apoptosis-Related Genes, and Mitochondrial Potential in BCR-ABL1-Expressing Cells Sensitive and Resistant to Imatinib

    Directory of Open Access Journals (Sweden)

    Ewelina Synowiec

    2015-01-01

    Full Text Available Imatinib resistance is an emerging problem in the therapy of chronic myeloid leukemia (CML. Because imatinib induces apoptosis, which may be coupled with mitochondria and DNA damage is a prototype apoptosis-inducing factor, we hypothesized that imatinib-sensitive and -resistant CML cells might differentially express apoptosis-related mitochondrially encoded genes in response to genotoxic stress. We investigated the effect of doxorubicin (DOX, a DNA-damaging anticancer drug, on apoptosis and the expression of the mitochondrial NADH dehydrogenase 3 (MT-ND3 and cytochrome b (MT-CYB in model CML cells showing imatinib resistance caused by Y253H mutation in the BCR-ABL1 gene (253 or culturing imatinib-sensitive (S cells in increasing concentrations of imatinib (AR. The imatinib-resistant 253 cells displayed higher sensitivity to apoptosis induced by 1 μM DOX and this was confirmed by an increased activity of executioner caspases 3 and 7 in those cells. Native mitochondrial potential was lower in imatinib-resistant cells than in their sensitive counterparts and DOX lowered it. MT-CYB mRNA expression in 253 cells was lower than that in S cells and 0.1 μM DOX kept this relationship. In conclusion, imatinib resistance may be associated with altered mitochondrial response to genotoxic stress, which may be further exploited in CML therapy in patients with imatinib resistance.

  14. Chemical and physiological metal bioaccessibility assessment in surface bottom sediments from the Deba River urban catchment: Harmonization of PBET, TCLP and BCR sequential extraction methods.

    Science.gov (United States)

    Unda-Calvo, Jessica; Martínez-Santos, Miren; Ruiz-Romera, Estilita

    2017-04-01

    In the present study, the physiologically based extraction test PBET (gastric and intestinal phases) and two chemical based extraction methods, the toxicity characteristic leaching procedure (TCLP) and the sequential extraction procedure BCR 701 (Community Bureau of Reference of the European Commission) have been used to estimate and evaluate the bioaccessibility of metals (Fe, Mn, Zn, Cu, Ni, Cr and Pb) in sediments from the Deba River urban catchment. The statistical analysis of data and comparison among physiological and chemical methods have highlighted the relevance of simulate the gastrointestinal tract environment since metal bioaccessibility seems to depend on water and sediment properties such as pH, redox potential and organic matter content, and, primordially, on the form in which metals are present in the sediment. Indeed, metals distributed among all fractions (Mn, Ni, Zn) were the most bioaccessible, followed by those predominantly bound to oxidizable fraction (Cu, Cr and Pb), especially near major urban areas. Finally, a toxicological risk assessment was also performed by determining the hazard quotient (HQ), which demonstrated that, although sediments from mid- and downstream sampling points presented the highest metal bioaccessibilities, were not enough to have adverse effects on human health, Cr being the most potentially toxic element. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Xi Zhang

    Full Text Available ABSTRACT CONTEXT: Acute promyelocytic leukemia (APL accounts for 8% to 10% of cases of acute myeloid leukemia (AML. Remission in cases of high-risk APL is still difficult to achieve, and relapses occur readily. CASE REPORT: Here, we describe a case of APL with high white blood cell counts in blood tests and hypogranular variant morphology in bone marrow, together with fms-like tyrosine kinase-3 with internal tandem duplication mutations (FLT3-ITD, and bcr-3 isoform of PML-RARα. Most importantly, we detected high level of Wilms’ tumor gene (WT1 in marrow blasts, through the reverse transcription polymerase chain reaction (RT-PCR. To date, no clear conclusions about an association between WT1 expression levels and APL have been reached. This patient successively received a combined treatment regimen consisting of hydroxycarbamide, arsenic trioxide and idarubicin plus cytarabine, which ultimately enabled complete remission. Unfortunately, he subsequently died of sudden massive hemoptysis because of pulmonary infection. CONCLUSION: Based on our findings and a review of the literature, abnormal functioning of WT1 may be a high-risk factor in cases of APL. Further studies aimed towards evaluating the impact of WT1 expression on the prognosis for APL patients are of interest.

  16. Generation of T-follicular helper cells in vitro: requirement for BCR cross-linking and cognate B- and T-cell interaction.

    Science.gov (United States)

    Kolenbrander, Anne; Grewe, Bastian; Nemazee, David; Überla, Klaus; Temchura, Vladimir

    2017-09-07

    The minimal requirements for in vitro modeling of the natural CD4(+) T-cell differentiation into T follicular helper (TFH) cells are still under investigation. We co-cultured wild type and TCR-transgenic CD4(+) T-cells from naïve mice with dendritic cells and BCR-transgenic B-cells in the presence of HIV-derived virus-like particles containing matched B- and T-cell epitopes. This co-culturing induced co-expression of TFH-master regulator transcription factor BCL-6 and CXCR5 in up to 10% of the wild type and up to 40% of the TCR-transgenic CD4(+) T-cells. Phenotypic markers, production of IL-21 and isotype switching of the B-cells to IgG1 further indicated a helper function of the induced TFH-cells in vitro. Dendritic cells supported the generation of functional TFH-cells, but were unable to induce them without cognate B-cells. Thus, our study presents a robust experimental system for efficient generation of functionally active TFH-cells in vitro and confirms the importance of cognate B- and T-cell cross-talk for the TFH differentiation process. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  17. Induction of apoptosis by shikonin through a ROS/JNKmediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    This study examined the signaling events induced by shikonin that lead to the induction of apoptosis in Bcr/ Abl-positive chronic myelogenous leukemia (CML) cells (e.g., K562, LAMA84). Treatment of K562 cells with shikonin (e.g., 0.5 μM) resulted in profound induction of apoptosis accompanied by rapid generation of reactive oxygen species (ROS), striking activation of c-Jun-N-terminai kinase (JNK) and p38, marked release of the mitochondrial proteins cytochrome c and Smac/DIABLO, activation of caspase-9 and -3, and cleavage of PARP. Scavenging of ROS completely blocked all of the above-mentioned events (i.e., JNK and p38 phosphorylation, cytochrome c and Smac/DIABLO release, caspase and PARP cleavage, as well as the induction of apoptosis) following shikonin treatment. Inhibition of JNK and knock-down of JNKI significantly attenuated cytochrome c release, caspase cleavage and apoptosis, but did not affect shikonin-mediated ROS production. Additionally, inhibition of caspase activation completely blocked shikonin-induced apoptosis, but did not appreciably modify shikonin-mediated cytochrome c release or ROS generation. Altogether, these findings demonstrate that shikonin-induced oxidative injury operates at a proximal point in apoptotic signaling cascades, and subsequently activates the stress-related JNK pathway, triggers mitochondrial dysfunction, cytochrome c release, and caspase activation, and leads to apoptosis. Our data also suggest that shikonin may be a promising agent for the treatment of CML, as a generator of ROS.

  18. Dasatinib treatment based on BCR-ABL mutation detection in imatinib-resistant patients with chronic myeloid leukemia%BCR-ABL突变检测指导下的达沙替尼治疗伊马替尼耐药的慢性髓性白血病疗效分析

    Institute of Scientific and Technical Information of China (English)

    江倩; 秦亚溱; 赖悦云; 江浩; 石红霞

    2016-01-01

    Objective To evaluate the efficiency of dasatinib as the second-or third-line tyrosine kinase inhibitor(TKI)in imatinib-resistant patients with chronic myeloid leukemia(CML)based on BCR-ABL mutation detection. Methods 122 CML patients received dasatinib treatment, including 83 with imatinib-resistance and 39 with both imatinib-and nilotinib-resistance, 55 in the chronic-phase(CP), 21 in the accelerated-phase (AP) and 46 in the blast-phase (BP). Those harboring dasatinib highly-resistant mutations(T315I/A, F317L/V/C and V299L)were excluded based on BCR-ABL kinase domain mutation screening by Sanger sequencing at baseline. Hematologic, cytogenetic and molecular responses were evaluated regularly, and rates of progression-free-survival(PFS)and overall survival(OS)were analyzed. BCR-ABL mutation detection was performed once the patients failed on dasatinib. Results In the CP patients, the rates of complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response(MMR)and molecular response 4.5(MR4.5)were 92.7%, 53.7%, 29.6%and 14.8%, respectively. 4-year PFS and OS rates were 84.4%and 89.5%, respectively. In the AP patients, HR and CCyR rates were 81.0%and 35.0%;and 3-year PFS and OS rates were 56.1%and 59.3%, respectively. In the BP patients, HR and CCyR rates were 63.0%and 21.4%;and 1-year PFS and OS rates were 43.6%and 61.8%, respectively. Outcomes were similar when dasatinib was used as the second-line TKI or thethird-line TKI. Of the 75 patients who were resistant to dasatinib, 37(48.7%)developed new mutation(s), and T315I(59.5%)was the most common mutation type. The patients who already harbored mutation(s) before dasatinib therapy achieved similar responses and outcomes to those with no mutation at baseline. However, they had higher likelihood of developing additional mutations associated with resistance to dasatinib(65.7%vs 34.1%, P=0.006). Conclusions Dasatinib was proved to be effective in the treatment of imatinib

  19. Signal transduction factors on the modulation of radiosusceptibility in K562 cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Kwang Mo; Jeong, Soo Jin [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Youn, Seon Min [College of Medicine, Eulji Univ., Daejeon (Korea, Republic of)

    2003-09-01

    The human chronic myelogenous leukemia cell line, K562, expresses the chimeric bcr-abl oncoprotein, whose deregulated protein tyrosine kinase activity antagonizes the induction of apoptosis via DNA damaging agents. Previous experiments have shown that nanomolar concentrations of herbimycin A [HMA] coupled with X-irradiation have a synergistic effect in inducing apoptosis in the Ph-positive K562 leukemia cell line, but genistein, a PTK inhibitor, is non selective for the radiation-induced apoptosis of p210{sup bcr}/{sup abl} protected K562 cells. In these experiments, the cytoplasmic signal transduction pathways, the induction of a number of transcription factors and the differential gene expression in this model were investigated. K562 cells in the exponential growth phase were used in this study. The cells were irradiated with 0.5-12 Gy, using a 6 MeV Linac (Clinac 1800, Varian, USA). Immediately after irradiation, the cells were treated with 0.25{mu}M of HMA and 25{mu}M of genistein, and the expressions and the activities of ablkinase, MAPK family, NF-KB, c-fos, c-myc, and thymidine kinase1 (TK1) were examined. The differential gene expressions induced by PTK inhibitors were also investigated. The modulating effects of herbimycin A and genistein on the radiosensitivity of K562 cells were not related to the bcr-abl kinase activity. The signaling responses through the MAPK family of proteins, were not involved either. In association with the radiation-induced apoptosis, which is accelerated by HMA, the expression of c-myc was increased. The combined treatment of genistein, with irradiation, enhanced NF-KB activity and the TK 1 expression and activity. The effects of HMA and genistein on the radiosensitivity of the K562 cells were not related to the bcr-abl kinase activity. In this study, another signaling pathway, besides the MAPK family responses to radiation to K562 cells, was found. Further evaluation using this model will provide valuable information for the

  20. Irreducible Specht modules are signed Young modules

    OpenAIRE

    Hemmer, David J.

    2005-01-01

    Recently Donkin defined signed Young modules as a simultaneous generalization of Young and twisted Young modules for the symmetric group. We show that in odd characteristic, if a Specht module $S^\\lambda$ is irreducible, then $S^\\lambda$ is a signed Young module. Thus the set of irreducible Specht modules coincides with the set of irreducible signed Young modules. This provides evidence for our conjecture that the signed Young modules are precisely the class of indecomposable self-dual module...

  1. *-Modules, co-*-modules and cotilting modules over Noetherian rings

    Institute of Scientific and Technical Information of China (English)

    汪明义; 许永华

    1996-01-01

    Let R be a Noetherian ring. The projectivity and injectivity of modules over R are discussed. The concept of modules is introduced and the descriptions for co-*-modules over R are given. At last, cotilting modules over R are characterized by means of co-*-modules.

  2. Thruster Module

    Science.gov (United States)

    Andersson, G.

    2015-09-01

    The thruster module described in this paper provides a low but controlled acceleration in a mission which would normally be labelled “microgravity”. The first mission was Cryofenix, where tanks containing liquid hydrogen were used in the experiment. The experiment utilizing the low acceleration is using liquids and requires a precise acceleration profile throughout the mission. Acceleration obtained by payload rotation is not feasible due to that the transversal forces required to change the acceleration will cause undesired liquid turbulence. In order to satisfy the experiment requirements a thruster module was developed by SSC for the Cryofenix mission funded by CNES. The Cryofenix mission had a payload weight of 380 kg and an apogee of about 260 km. The module produces a controlled thrust in flight direction by means of a cold gas system.

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

    Directory of Open Access Journals (Sweden)

    Linglong Cao

    2015-04-01

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

  4. Copper and zinc fractionation in apple orchard soil in the village of Bukevje (Croatia) using the revised four-step BCR extraction procedure.

    Science.gov (United States)

    Medunić, Gordana; Juranović Cindrić, Iva; Lovrenčić Mikelić, Ivanka; Tomašić, Nenad; Balen, Dražen; Oreščanin, Višnja; Kampić, Štefica; Ivković, Ivana

    2013-12-01

    The aim of this study was to establish the fractionation of copper and zinc in a small apple orchard using the revised (four-step) Bureau Communautaire de Référence (BCR) sequential extraction procedure and assess their potential mobility in soil. Soil samples were collected at the depth of 10 cm to 25 cm, sixteen from the orchard and five control samples from a meadow located some 200 m away from the orchard. As the distribution of trace-element concentrations in the control samples was normal, they were used for comparison as background levels. We also determined soil mineralogical composition, carbonate content, soil pH, cation exchange capacity, and soil organic matter. The extraction yields of Cu and Zn from the control soil were lower than from the orchard soil (25% vs. 34% and 47% vs. 52%, respectively), which pointed to natural processes behind metal bonding in the control soil and greater influence of man-made activities in the orchard soil. Compared to control, the orchard soil had significantly higher concentrations of total Cu (P=0.0009), possibly due to the application of Cu-based fungicides. This assumption was further supported by greater speciation variability of Cu than of zinc, which points to different origins of the two, Cu from pesticides and Zn from the parent bedrock. Copper levels significantly better (P=0.01) correlated with the oxidisable fraction of the orchard soil than of control soil. Residual and organically bound copper and zinc constituted the most important fractions in the studied soils. However, the use of Cu-based fungicides in the apple orchard did not impose environmental and health risk from Cu exposure.

  5. Reproducibility of the BCR sequential extraction procedure in a long-term study of the association of heavy metals with soil components in an upland catchment in Scotland.

    Science.gov (United States)

    Bacon, Jeffrey R; Hewitt, Irene J; Cooper, Patricia

    2005-01-20

    Humic iron podzol soils from three different plots at the Glensaugh Research Station, Aberdeenshire have been sampled on an annual basis since 1990 and analysed using both total digestion and the original BCR sequential extraction procedure. Particular care was required during the oxidation of these organic soils to prevent loss of material. The residue from the sequential extraction was analysed so that the values for total concentration derived from the total digestion and from the sum of the concentrations in the fractions of the extraction procedure could be compared. The comparison was good for all three soils indicating that not only did the sequential extraction give good recovery but that this was reproducible over a period of several years. The proportion of metals extractable at each step remained relatively constant thereby demonstrating the reproducibility of the procedure and the stability of the metals in the soils over the time scale of the sampling used. Whereas the total concentrations of Cr, Cu and Ni were highest in the soil from a roadside plot, this was not the case for Cd, Pb and Zn. In the case of Pb, concentrations in soils (0-25-cm depth) well away from the road were over 100 mg/kg and well above the expected background level. The distribution of metals between each of the extracted fractions varied not only between each metal but also between each of the three soils indicating that both metal and soil influenced the measured distribution. The distribution of Pb in the roadside soil was different from those in the other two soils and over 10% was extracted in the first, acetic acid soluble, fraction.

  6. Signed Young Modules and Simple Specht Modules

    OpenAIRE

    Danz, Susanne; Lim, Kay Jin

    2015-01-01

    By a result of Hemmer, every simple Specht module of a finite symmetric group over a field of odd characteristic is a signed Young module. While Specht modules are parametrized by partitions, indecomposable signed Young modules are parametrized by certain pairs of partitions. The main result of this article establishes the signed Young module labels of simple Specht modules. Along the way we prove a number of results concerning indecomposable signed Young modules that are of independent inter...

  7. Memory Modulation

    NARCIS (Netherlands)

    Roozendaal, Benno; McGaugh, James L.

    2011-01-01

    Our memories are not all created equally strong: Some experiences are well remembered while others are remembered poorly, if at all. Research on memory modulation investigates the neurobiological processes and systems that contribute to such differences in the strength of our memories. Extensive evi

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

    Directory of Open Access Journals (Sweden)

    Shuit-Mun Wong

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

  9. 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.

  10. 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

  11. 达沙替尼治疗伊马替尼耐药的 BCR/ABL阳性白血病%Dasatinib in treatment of imatinib-resistant BCR/ABL positive leukemia

    Institute of Scientific and Technical Information of China (English)

    严红; 赵海军

    2014-01-01

    This study was aimed to evaluate the efficacy and safety of dasatinib in BCR /ABL positive leukemia patients with resistance to imatinib.Method 9 patients with imatinib -resistant chronic myelogenous leukemia ( CML) or Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ALL) received 100~140 mg· d-1 dasatinib orally.Their overall survival and tolerance were evalua-ted.Results After the dasatinib treatment ,2 patients with CML in chronic phase achieved complete hematologic response ( CHR) ,one of them achieved complete cytogenetic response (CCyR);4 of 5 patients with CML in blast crisis achieved CHR and partly cytogenetic response (PCyR);one patient had no response .Treated with dasatinib,one patient with Ph +ALL,presented with E255V mutation,a-chieved CHR and PCyR .The other died of infection .Conlusion Receiving therapy of dasatinib , patients with resistance to imatinib could achieve CHR ,even PCyR .%目的:评价达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性。方法对9例伊马替尼耐药的慢性髓系白血病( CML)或Ph阳性急性淋巴细胞白血病( Ph+ALL)患者,给予达沙替尼100~140 mg· d-1口服治疗,评估疗效和耐受情况。结果9例伊马替尼耐药的BCR/ABL阳性白血病,2例CML-CP患者均获得CHR,1例达CCyR;5例CML-BC患者中4例获得CHR和PCyR,1例NR;2例Ph+ALL患者中1例检测到E255V突变,采用达沙替尼治疗达CHR和PCyR,1例诱导缓解时,同时行VDP方案化疗,继发严重感染死亡。结论达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病患者可获得血液学甚至细胞遗传学缓解,且耐受性好。

  12. Module Evaluation

    Science.gov (United States)

    2006-02-01

    MODULES IN LIFE TEST CHAMBER (LEFT SIDE) 68 MODULE TRANSMIT TEMP CA1 54.8°C CB1 65.3°C CC1 70.5°C CD1 75.2°C CE1 68.5°C CA2 72.1°C CB2 ...NO. PA (Contractor) PA (MELTS) DRV (Contractor) DRV (MELTS) CA1 058 +11.0 VOLTS +10.3 VOLTS + 7.5 VOLTS + 3.64 VOLTS CB1 085 +11.0 VOLTS +10.13...CE1 032 +11.0 VOLTS + 7.02 VOLTS + 7.5 VOLTS + 4.23 VOLTS CA2 065 +11.0 VOLTS +11.03 VOLTS + 7.5 VOLTS + 7.53 VOLTS CB2 057 +11.0 VOLTS + 9.49

  13. Module descriptor

    DEFF Research Database (Denmark)

    Vincenti, Gordon; Klausen, Bodil; Kjær Jensen, Jesper

    2016-01-01

    The Module Descriptor including a Teacher’s Guide explains and describes how to work innovatively and co-creatively with wicked problems and young people. The descriptor shows how interested educators and lecturers in Europe can copy the lessons of the Erasmus+ project HIP when teaching their own...... students how to include marginalized young people and practitioners in the education of future social workers and social educators....

  14. Module descriptor

    DEFF Research Database (Denmark)

    Vincenti, Gordon; Klausen, Bodil; Kjær Jensen, Jesper

    2016-01-01

    The Module Descriptor including a Teacher’s Guide explains and describes how to work innovatively and co-creatively with wicked problems and young people. The descriptor shows how interested educators and lecturers in Europe can copy the lessons of the Erasmus+ project HIP when teaching their own...... students how to include marginalized young people and practitioners in the education of future social workers and social educators....

  15. Polymorphism Analysis of 5′ Promotor Region of BCR Gene%BCR基因5′启动子区多态性分析

    Institute of Scientific and Technical Information of China (English)

    田红; 郑维扬; 付永贵; 林蒋海; 吕凤娟; 周淑芸

    2004-01-01

    背景与目的:bcr-abl融合基因被认为是慢性髓系白血病(chronic myelogenous leukemia,CML)的分子标志,该融合基因的表达受 bcr基因启动子的调控.本实验目的是研究 bcr基因启动子区的多态性,并探讨其与 CML之间可能存在的联系.方法:采用 PCR方法扩增 bcr基因 5′启动子区 1.13 kb的序列范围,通过测序获得了 30例 CML和 19例对照的启动子区序列.应用软件和在线工具对启动子序列进行转录因子结合位点分析和重复序列分析.结果:在所研究片段范围内共发现 4处新的单核苷酸多态性(single nucleotide polymorphism,SNP)和 3处与参考序列不一致的碱基变异.其中 2处 SNPs和 1处碱基插入位于转录因子结合位点中或邻近几个碱基内.各多态性基因频率在 CML和对照人群中无统计学差异.结论:bcr基因的 5′启动子区存在一定的序列多态性,主要为 SNPs,未能证实其与 CML之间存在相关性,但部分 SNPs的定位使其有可能对基因的转录和表达产生影响.

  16. Simultaneous N, C, S isotopic analyses using purge and trap EA technology. Application to δ34S analyses of natural phosphate material NBS120c and BCR32

    Science.gov (United States)

    Fourel, F. P.; Lecuyer, C.; Martineau, F.

    2013-12-01

    The first example of stable isotope analyses in continuous flow mode by Preston et al in 19861 involved Elemental Analyser Isotopic Ratio Mass Spectrometry (EA-IRMS) dedicated to carbon isotopes in combustion mode. EA-IRMS has since then evolved to allow 34S/32S determinations still in combustion mode and mainly to access pyrolysis reaction for O and H isotopes. As far as combustion EA-IRMS is concerned the technique itself has remained unchanged since the development of 'purge and trap' separation techniques online with IRMS instruments. Here we have used a high-precision, easy, low-cost and rapid method of simultaneous carbon, nitrogen and sulphur isotope analysis using this new type of elemental analyser based on 'purge and trap' technology 2,3. Simultaneous determinations, performed on the same aliquot of 13C, 15N and 34S are demonstrated. Emphasis is put on the high quality of 34S/32S determinations. First concentrating on peak shapes, yields of conversion and preliminary results. Then the reliability and accuracy of such a technique is illustrated using analyses from various international reference materials. Alongside international reference material working NCS calibrated material has been selected and characterized prior to apply this technology to calibrate natural phosphate material used as compositional reference material BCR32 and NBS120c. δ34S values of respectively 15.62×0.32‰ and 16.5×0.17‰ are proposed for those samples with sulphur concentrations below the 1% level. The possibility to reliably measure S isotopes on that kind of samples opens up new fields of investigation especially for paleoenvironmental reconstructions. Keywords: carbon, nitrogen, sulfur, isotope, combustion, phosphate, elemental-analyser 1. T. Preston, N.J.P. Owens: Preliminary 13C Measurements using a Gas Chromatograph Interfaced to an Isotope Ratio Mass Spectrometer. Biomedical. Mass Spectrom. 1985, 12-9, 510. 2. H.P. Sieper, H.J. Kupka, L. Lange, A. Rossmann, N. Tanz

  17. Photovoltaic module and module arrays

    Science.gov (United States)

    Botkin, Jonathan; Graves, Simon; Lenox, Carl J. S.; Culligan, Matthew; Danning, Matt

    2012-07-17

    A photovoltaic (PV) module including a PV device and a frame. The PV device has a PV laminate defining a perimeter and a major plane. The frame is assembled to and encases the laminate perimeter, and includes leading, trailing, and side frame members, and an arm that forms a support face opposite the laminate. The support face is adapted for placement against a horizontal installation surface, to support and orient the laminate in a non-parallel or tilted arrangement. Upon final assembly, the laminate and the frame combine to define a unitary structure. The frame can orient the laminate at an angle in the range of 3.degree.-7.degree. from horizontal, and can be entirely formed of a polymeric material. Optionally, the arm incorporates integral feature(s) that facilitate interconnection with corresponding features of a second, identically formed PV module.

  18. BCR-ABL1: Test

    Science.gov (United States)

    ... molecular genetic test, and/or fluorescence in situ hybridization (FISH) . These help establish the initial diagnosis of ... Health Professionals ©2001 - by American Association for Clinical Chemistry • Contact Us | Terms of Use | Privacy We comply ...

  19. Persistence of BCR/ABL mRNA-expressing bone-marrow cells in patients with chronic myelogenous leukemia in complete cytogenetic remission induced by interferon-alpha therapy.

    Science.gov (United States)

    Eberlé, F; Toiron, Y; Camerlo, J; Lafage, M; Sainty, D; Arnoulet, C; Raineri, V; Gabert, J; Maraninchi, D; Mannoni, P

    1995-06-01

    Complete hematologic and cytogenetic responses can be obtained with interferon-alpha (IFN-alpha) in 15-25% of the patients with chronic myelogenous leukemia (CML). In these patients, reverse-transcription polymerase chain reaction (RT-PCR) can be used to evaluate minimal residual disease. We studied 12 patients who remained Philadelphia-negative for a median period of 21 months on IFN-alpha therapy. Using RT-PCR, the specific transcript was found in all bone marrow (BM) samples. Ten patients still exhibiting a persistent residual clone remained in cytogenetic remission for a median period of 14 months. As we observed a dissociation between bcr-abl expression in BM and peripheral blood (PB) cells, and given the known fluctuations of the bcr-abl PCR results, we suggest that PB negative results should be confirmed on BM specimens. Alternatively, it remains to be demonstrated whether longitudinal monitoring of residual disease would benefit from quantitative PCR or double fluorescence in situ hybridization.

  20. 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.

  1. High frequency and poor prognosis of late childhood BCR-ABL-positive and MLL-AF4-positive ALL define the need for advanced molecular diagnostics and improved therapeutic strategies in pediatric B-ALL in Pakistan.

    Science.gov (United States)

    Iqbal, Zafar; Akhtar, Tanveer; Awan, Tashfin; Aleem, Aamer; Sabir, Noreen; Rasool, Mahmood; Absar, Muhammad; Akram, Afia M; Shammas, Masood A; Shah, Ijaz H; Khalid, Muhammad; Taj, Abid S; Jameel, Abid; Alanazi, Abdullah; Gill, Ammara T; Hashmi, Jamil Amjad; Hussain, Akhtar; Sabar, Muhammad Farooq; Khalid, Ahmad M; Qazi, Mehmood Hussain; Karim, Sajjad; Siddiqi, Muhammad Hassan; Mahmood, Aamir; Iqbal, Mudassar; Saeed, Anjum; Irfan, Muhammad Imran

    2015-10-01

    Fusion oncogenes (FOs) resulting from chromosomal abnormalities have an important role in leukemogenesis in pediatric B cell acute lymphoblastic leukemia (ALL). The most common FOs are BCR-ABL, MLL-AF4, ETV6-RUNX1, and TCF3-PBX1, all of which have important prognostic and drug selection implications. Moreover, frequencies of FOs have ethnic variations. We studied Pakistani frequencies of FOs, clinical pattern, and outcome in pediatric B-ALL. FOs were studied in 188 patients at diagnosis using reverse transcriptase-polymerase chain reaction (RT-PCR) and interphase fluorescent in situ hybridization (FISH). Data were analyzed using SPSS version 17 (SPSS Inc., Chicago, IL, USA). FOs were detected in 87.2 % of patients. Mean overall survival was 70.9 weeks, 3-year survival was 31.9 %, and 3-year relapse-free survival was 18.1 %. Four patients died of drug toxicities. ETV6-RUNX1 (19.14 %) had better survival (110.9 weeks; p = 0.03); TCF3-PBX1 (2.1 %) was associated with inferior outcome and higher central nervous system (CNS) relapse risk; MLL-AF4 (18.1 %) was more common in the 8- to 15-year age group (24/34; p = 0.001) and was associated with organomegaly, low platelet count, and poor survival; and BCR-ABL (47.9 %) was associated with older age (7-15 years, 52/90), lower remission rates, shorter survival (43.73 ± 4.24 weeks) and higher white blood cell count. Overall, MLL-AF4 and BCR-ABL were detected in 66 % of B-ALL, presented in later childhood, and were associated with poor prognosis and inferior survival. This study reports the highest ethnic frequency of BCR-ABL FO in pediatric ALL, and is consistent with previous reports from our region. Poor prognosis BCR-ABL and MLL-AF4 was detected in two-thirds of pediatric B-ALL and is likely to be the reason for the already reported poor survival of childhood ALL in South-East Asia. Furthermore, MLL-AF4, usually most common in infants, presented in later childhood in most of the ALL patients, which was

  2. MEMORY MODULATION

    Science.gov (United States)

    Roozendaal, Benno; McGaugh, James L.

    2011-01-01

    Our memories are not all created equally strong: Some experiences are well remembered while others are remembered poorly, if at all. Research on memory modulation investigates the neurobiological processes and systems that contribute to such differences in the strength of our memories. Extensive evidence from both animal and human research indicates that emotionally significant experiences activate hormonal and brain systems that regulate the consolidation of newly acquired memories. These effects are integrated through noradrenergic activation of the basolateral amygdala which regulates memory consolidation via interactions with many other brain regions involved in consolidating memories of recent experiences. Modulatory systems not only influence neurobiological processes underlying the consolidation of new information, but also affect other mnemonic processes, including memory extinction, memory recall and working memory. In contrast to their enhancing effects on consolidation, adrenal stress hormones impair memory retrieval and working memory. Such effects, as with memory consolidation, require noradrenergic activation of the basolateral amygdala and interactions with other brain regions. PMID:22122145

  3. Module theory, extending modules and generalizations

    CERN Document Server

    Tercan, Adnan

    2016-01-01

    The main focus of this monograph is to offer a comprehensive presentation of known and new results on various generalizations of CS-modules and CS-rings. Extending (or CS) modules are generalizations of injective (and also semisimple or uniform) modules. While the theory of CS-modules is well documented in monographs and textbooks, results on generalized forms of the CS property as well as dual notions are far less present in the literature. With their work the authors provide a solid background to module theory, accessible to anyone familiar with basic abstract algebra. The focus of the book is on direct sums of CS-modules and classes of modules related to CS-modules, such as relative (injective) ejective modules, (quasi) continuous modules, and lifting modules. In particular, matrix CS-rings are studied and clear proofs of fundamental decomposition results on CS-modules over commutative domains are given, thus complementing existing monographs in this area. Open problems round out the work and establish the...

  4. Cofinitely weak supplemented modules

    OpenAIRE

    Alizade, Rafail; Büyükaşık, Engin

    2003-01-01

    We prove that a module M is cofinitely weak supplemented or briefly cws (i.e., every submodule N of M with M/N finitely generated, has a weak supplement) if and only if every maximal submodule has a weak supplement. If M is a cws-module then every M-generated module is a cws-module. Every module is cws if and only if the ring is semilocal. We study also modules, whose finitely generated submodules have weak supplements.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-08-15

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

  6. 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.

  7. On generalized extending modules

    Institute of Scientific and Technical Information of China (English)

    ZENG Qing-yi

    2007-01-01

    A module M is called generalized extending if for any submodule N of M, there is a direct summand K of M such that N≤K and K/N is singular. Any extending module and any singular module are generalized extending. Any homomorphic image of a generalized extending module is generalized extending. Any direct sum of a singular (uniform) module and a semi-simple module is generalized extending. A ring R is a right Co-H-ring ifand only ifall right R modules are generalized extending modules.

  8. Identification of plasmid-mediated quinolone resistance genes qnrA1, qnrB1 and aac(6′-1b-cr in a multiple drug-resistant isolate of Klebsiella pneumoniae from Chennai

    Directory of Open Access Journals (Sweden)

    H Magesh

    2011-01-01

    Full Text Available Purpose: Resistance to fluoroquinolones, a commonly prescribed antimicrobial for Gram-negative and Gram-positive microorganisms, is of importance in therapy. The purpose of this study was to screen for the presence of Plasmid-Mediated Quinolone Resistance (PMQR determinants in clinical isolates of Klebsiella pneumoniae. Materials and Methods: Extended-Spectrum Beta-Lactamase (ESBL isolates of K. pneumoniae collected during October 2009 were screened by the antimicrobial susceptibility test. The plasmids from these isolates were analysed by specific Polymerase chain Reaction (PCR for qnrA, qnrB and aac(6′-1b. The amplified products were sequenced to confirm the allele. Results: Our analysis showed that 61% out of the 23 ESBL K. pneumoniae isolates were resistant to ciprofloxacin and 56% to levofloxacin. The PMQR was demonstrated by transforming the plasmids from two isolates P12 and P13 into E. coli JM109. The PMQR gene qnrA was found in 16 isolates and qnrB in 11 isolates. The plasmid pKNMGR13 which conferred an minimum inhibitory concentration (MIC of more than 240 ΅g/ml in sensitive E. coli was found to harbour the qnrA1 and qnrB1 allele. Furthermore, the gene aac(6′-1b-cr encoding a variant aminoglycoside 6′-N Acetyl transferase which confers resistance to fluoroquinolones was found in the same plasmid. Conclusions: Our report shows the prevalence of PMQR mediated by qnrA and qnrB in multidrug-resistant K. pneumoniae isolates from Chennai. A multidrug-resistant plasmid conferring high resistance to ciprofloxacin was found to harbour another PMQR gene, aac(6′-1b-cr mutant gene. This is the first report screening for PMQR in K. pneumoniae isolates from India.

  9. Monitoring of bcr/abl Fusion Gene by Interphase-Dual-Color and Dual-Fusion Fluorescence in situ Hybridization in CML after Allo-HSCT%间期双色双融合荧光原位杂交监测慢性髓系白血病异基因造血干细胞移植后bcr/abl融合基因

    Institute of Scientific and Technical Information of China (English)

    钱思轩; 李建勇; 张闰; 洪鸣; 仇海荣; 李丽; 徐卫; 盛瑞兰; 吴汉新

    2006-01-01

    本研究探讨bcr/abl双色双融合荧光原位杂交(DD-FISH)的敏感性及临床应用价值.对19例慢性髓细胞白血病(CML)异基因造血干细胞移植(allo-HSCT)后微小残留病灶(MRD)用DD-FISH进行监测,同时与常规细胞遗传学(CC)、逆转录-聚合酶链反应(RT-PCR)结果相比较.样本取自骨髓,少数来源于骨髓片或外周血.结果表明:14例CML患者在Allo-HSCT后CC显示持续正常供者核型,RT-PCR转为阴性,移植2月后均为完全供者嵌合(DC),DD-FISH检测结果持续为阴性,平均随访11.25月,MRD无增加.1例CC及RT-PCR阴性,而性染色体FISH为混合嵌合,DD-FISH阳性,监测无MRD增加,临床未治疗,疾病稳定.3例骨髓复发患者的DD-FISH及性染色体FISH均提示MRD明显增加,RT-PCR转为阳性,却只有1例CC异常,供者淋巴细胞输注(DLI)及甲磺酸伊马替尼治疗后均为DC,DD-FISH阴性,RT-PCR阴性.1例骨活检证实髓外复发患者骨髓或外周血样本的DD-FISH、CC及PCR均阴性,供受者完全嵌合.结论:间期双色双融合FISH可应用于CML异基因造血干细胞移植后MRD的监测,其操作简易快速,灵敏度高,且骨髓或外周血均可采用.动态监测能及时发现扩大的白血病细胞克隆.

  10. Ballasted photovoltaic module and module arrays

    Science.gov (United States)

    Botkin, Jonathan; Graves, Simon; Danning, Matt

    2011-11-29

    A photovoltaic (PV) module assembly including a PV module and a ballast tray. The PV module includes a PV device and a frame. A PV laminate is assembled to the frame, and the frame includes an arm. The ballast tray is adapted for containing ballast and is removably associated with the PV module in a ballasting state where the tray is vertically under the PV laminate and vertically over the arm to impede overt displacement of the PV module. The PV module assembly can be installed to a flat commercial rooftop, with the PV module and the ballast tray both resting upon the rooftop. In some embodiments, the ballasting state includes corresponding surfaces of the arm and the tray being spaced from one another under normal (low or no wind) conditions, such that the frame is not continuously subjected to a weight of the tray.

  11. Measurement of thermal conductivity and thermal diffusivity using a thermoelectric module

    Science.gov (United States)

    Beltrán-Pitarch, Braulio; Márquez-García, Lourdes; Min, Gao; García-Cañadas, Jorge

    2017-04-01

    A proof of concept of using a thermoelectric module to measure both thermal conductivity and thermal diffusivity of bulk disc samples at room temperature is demonstrated. The method involves the calculation of the integral area from an impedance spectrum, which empirically correlates with the thermal properties of the sample through an exponential relationship. This relationship was obtained employing different reference materials. The impedance spectroscopy measurements are performed in a very simple setup, comprising a thermoelectric module, which is soldered at its bottom side to a Cu block (heat sink) and thermally connected with the sample at its top side employing thermal grease. Random and systematic errors of the method were calculated for the thermal conductivity (18.6% and 10.9%, respectively) and thermal diffusivity (14.2% and 14.7%, respectively) employing a BCR724 standard reference material. Although errors are somewhat high, the technique could be useful for screening purposes or high-throughput measurements at its current state. This new method establishes a new application for thermoelectric modules as thermal properties sensors. It involves the use of a very simple setup in conjunction with a frequency response analyzer, which provides a low cost alternative to most of currently available apparatus in the market. In addition, impedance analyzers are reliable and widely spread equipment, which facilities the sometimes difficult access to thermal conductivity facilities.

  12. BCR-ABL融合基因T315I突变的白血病行异基因HSCT的疗效及复发后的治疗分析%Curative effectiveness of allogeneic stem cell transplantation and treatment of recurrence in patients harboring T315I BCR-ABL mutated leukemias

    Institute of Scientific and Technical Information of China (English)

    桂晓敏; 仇惠英; 潘金兰; 周敏; 鲍协炳; 陈苏宁; 孙爱宁; 吴德沛; 岑建农

    2014-01-01

    Objective To retrospectively analyze the curative effectiveness of allogeneic stem cell transplantation (allo-SCT) for the leukemia patients with the T315I mutation,and to discuss the treatments for the relapsing patients after allo-SCT.Method Through observing 10 leukemia patients harboring a T315I BCR-ABL mutation who underwent allo-SCT,we analyzed the remission rate,recurrence rate and long-term survival situation of these patients and explored the treatments for relapsing patients after allo-SCT.Result Of 10 patients,4 patients were female and 6 were male.The median age was 29 years (range,18-49).Before HSCT,5 were given imatinib,3 nilotinib and 2 dasatinib,respectively.Ten patients (100%) obtained complete remission (CR) and the median remission time was 23 days (range,14-56).During the follow-up period,1 case of CML and 3 cases of Ph+-ALL (40%) obtained CR.The survival time was 75 to 741 days.In the 6 dead patients,1 died of upper gastrointestinal hemorrhage on the day 137 after allo-SCT; 2 died of graft versus host disease on the day 53 and 617 respectively after allo-SCT; 1 case of CML and 2 cases of Ph+ ALL relapsed on the day 27,50 and 130 respectively after allo-SCT,and 2 of them died on the day 5 and 40 respectively after relapse,and 1 recurrent case did not obtain remission after chemotherapy and died on the day 97 after relapse.Conclusion The allo-SCT can be used to treat the leukemia patients with T315I mutation,and high remission rate can be obtained,tut there is the high risk of recurrence.The patients with recurrent leukemia can take further relevant treatment to prolong survival time.%目的 分析BCR-ABL融合基因T315I突变的白血病患者接受异基因造血干细胞移植(HSCT)的资料,探讨移植疗效及复发后的治疗.方法 观察10例伴T315I突变的费城染色体阳性(Ph+)的急性淋巴细胞白血病(ALL)和慢性粒细胞白血病(CML)接受异基因HSCT后缓解率、复发率以及长期存活情况,分析这

  13. Module utilization committee

    Science.gov (United States)

    Volkmer, K.; Praver, G.

    1984-01-01

    Photovoltaic collector modules were declared surplus to the needs of the U.S. Dept. of Energy. The Module Utilization Committee was formed to make appropriate disposition of the surplus modules on a national basis and to act as a broker for requests for these modules originating outside of the National Photovoltaics Program.

  14. MI 4010 Thermoelectric Modules.

    Science.gov (United States)

    The report covers the design justification, physical specification and characterization of the MI 4010 module . The purpose of the contract was to...demonstrate the capability to fabricate pieceparts, process into assemblies, and test thermoelectric modules equivalent to the module used in the Hand...Held Thermal Viewer. The completed modules were also subjected to limited demonstration tests of reliability and useful life.

  15. Modulation properties of VCSEL with intracavity modulator

    Science.gov (United States)

    van Eisden, J.; Yakimov, M.; Tokranov, V.; Varanasi, M.; Mohammed, E. M.; Young, I. A.; Oktyabrsky, S.

    2007-02-01

    We have studied the modulation properties of VCSEL with intracavity multiple quantum well (MQW) electroabsorption modulator integrated into the top distributed Bragg reflector (DBR) [1]. Small signal analysis of rate equations for loss modulation shows an intrinsic high-frequency roll-off slope of 1/ω instead of 1/ω2 in directly modulated laser diodes, and consequently bandwidths in excess of 40 GHz are obtainable with this configuration [2]. Possible limiting factors to high bandwidth were examined by fitting high frequency characteristics to a multi-pole transfer function, and include RC delay and carrier drift-limited time of flight (TOF) in the modulator intrinsic region. Intracavity loss modulation shows a strong (+20dB) relaxation oscillation resonant feature in both theory and experiment. As demonstrated, this feature can be significantly reduced in amplitude using parasitics. We have extracted relative contribution of TOF and parasitic capacitance by varying the modulator intrinsic region width (105 and 210 nm) and lateral size of the modulator (18 and 12μm). It was estimated that the small size modulator exhibits parasitics f -3dB at 8GHz. To estimate the carrier TOF contribution to bandwidth limits, low temperature growth of a 210 nm absorber i-region and MQW was employed to reduce photogenerated carrier lifetime. Bandwidth limitations were found to be mostly due to diode and metallization capacitances, in addition to one pole set by the optoelectronic resonance frequency. We have used p-modulation doping of the gain region to increase the relaxation frequency. Pronounced active Q-switching was observed, yielding pulse widths of 40 ps at a 4 GHz rate.

  16. CDC 7600 module slice

    CERN Multimedia

    Each module contained 8 circuit cards for a total of about 300-500 uncovered transistors packaged with face plates so the Freon plates wouldn't touch the circuits. (cooling plates that surrounded each module).

  17. Koszul differential graded modules

    Institute of Scientific and Technical Information of China (English)

    HE JiWei; WU QuanShui

    2009-01-01

    The concept of Koszulity for differential graded (DG, for short) modules is introduced. It is shown that any bounded below DG module with bounded Ext-group to the trivial module over a Koszul DG algebra has a Koszul DG submodule (up to a shift and truncation), moreover such a DG module can be approximated by Koszul DG modules (Theorem 3.6). Let A be a Koszul DG algebra, and Dc (A) be the full triangulated subcategory of the derived category of DG A-modules generated by the object AA. If the trivial DG module kA lies in Dc(A), then the heart of the standard t-structure on Dc(A) is anti-equivalent to the category of finitely generated modules over some finite dimensional algebra. As a corollary, Dc(A) is equivalent to the bounded derived category of its heart as triangulated categories.

  18. Koszul differential graded modules

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The concept of Koszulity for differential graded (DG, for short) modules is introduced. It is shown that any bounded below DG module with bounded Ext-group to the trivial module over a Koszul DG algebra has a Koszul DG submodule (up to a shift and truncation), moreover such a DG module can be approximated by Koszul DG modules (Theorem 3.6). Let A be a Koszul DG algebra, and Dc(A) be the full triangulated subcategory of the derived category of DG A-modules generated by the object AA. If the trivial DG module kA lies in Dc(A), then the heart of the standard t-structure on Dc(A) is anti-equivalent to the category of finitely generated modules over some finite dimensional algebra. As a corollary, Dc(A) is equivalent to the bounded derived category of its heart as triangulated categories.

  19. CDC 6600 Cordwood Module

    CERN Multimedia

    1964-01-01

    The CDC 6600 cordwood module containing 64 silicon transistors. The module was mounted between two plates that were cooled conductive by a refrigeration unit via the front panel. The construction of this module uses the cord method, so called because the resistors seem to be stacked like cord between the two circuit boards in order to obtain a high density. The 6600 model contained nearly 6,000 such modules.

  20. On Matlis dualizing modules

    Directory of Open Access Journals (Sweden)

    Edgar E. Enochs

    2002-01-01

    Full Text Available We consider rings admitting a Matlis dualizing module E. We argue that if R admits two such dualizing modules, then a module is reflexive with respect to one if and only if it is reflexive with respect to the other. Using this fact we argue that the number (whether finite or infinite of distinct dualizing modules equals the number of distinct invertible (R,R-bimodules. We show by example that this number can be greater than one.

  1. Modulating lignin in plants

    Science.gov (United States)

    Apuya, Nestor; Bobzin, Steven Craig; Okamuro, Jack; Zhang, Ke

    2013-01-29

    Materials and methods for modulating (e.g., increasing or decreasing) lignin content in plants are disclosed. For example, nucleic acids encoding lignin-modulating polypeptides are disclosed as well as methods for using such nucleic acids to generate transgenic plants having a modulated lignin content.

  2. Relatively Endocoherent Modules

    Institute of Scientific and Technical Information of China (English)

    Lixin Mao

    2007-01-01

    Let MR be a right R-module over a ring R with S= End(MR)We study the coherence of the left S-module sM relative to a torsion theory for the category of right R-modules.Various results are developed, many extending known results.

  3. Polarization modulators for CMBPol

    Energy Technology Data Exchange (ETDEWEB)

    Ade, P A R; Savini, G [Cardiff University, School of Physics and Astronomy, Queens Buildings, The Parade, Cardiff, CF24 3AA (United Kingdom); Chuss, D T [NASA Goddard Space Flight Center, Code 665, Greenbelt, MD, 20771 (United States); Hanany, S [School of Physics and Astronomy, University of Minnesota/Twin Cities, Minneapolis, MN, 55455 (United States); Haynes, V; Pisano, G [University of Manchester, School of Physics and Astronomy - Alan Turing Building, Upper Brooke street, Manchester, M13 4PL (United Kingdom); Keating, B G [Department of Physics, University of California, San Diego, La Jolla, CA 92093-0424 (United States); Kogut, A [Code 665 Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Ruhl, J E [Physics Department, Case Western Reserve University, Cleveland, OH, 44106 (United States); Wollack, E J [Observational Cosmology Laboratory, NASA/GSFC, Greenbelt, MD 20771 (United States)

    2009-03-01

    We review a number of technologies that are candidates for active polarization modulators for CMBPol. The technologies are appropriate for instruments that use bolometric detectors and include birefringent crystal-based and metal-mesh-based half-wave plates, variable phase polarization modulator, Faraday rotator, and photolithographed modulators. We also give a current account of the status of millimeter-wave orthomode transducers.

  4. MI 6040 Thermoelectric Modules.

    Science.gov (United States)

    The report covers the design justification, physical specification and characterization of the MI 6040 module . The purpose of the thermoelectric... modules is the cooling of infrared detector arrays to temperature of 170K or colder. The completed modules were also subjected to limited demonstration tests of reliability and useful life.

  5. Gigahertz optical modulation.

    Science.gov (United States)

    Riesz, R P; Biazzo, M R

    1969-07-01

    Light pulses from a mode-locked He-Ne laser have been modulated by a LiTaO(3) electrooptic crystal mounted on a thin film substrate. The crystal was driven by pulses from a GaAs Gunn effect diode. Amplitude modulation of 20% has been achieved at 2 GHz for a single pass through the modulator.

  6. A systems toxicology approach identifies Lyn as a key signaling phosphoprotein modulated by mercury in a B lymphocyte cell model

    Energy Technology Data Exchange (ETDEWEB)

    Caruso, Joseph A.; Stemmer, Paul M. [Institute of Environmental Health Sciences, Wayne State University, Detroit, MI (United States); Dombkowski, Alan [Department of Pediatrics, Wayne State University, Detroit, MI (United States); Caruthers, Nicholas J. [Institute of Environmental Health Sciences, Wayne State University, Detroit, MI (United States); Gill, Randall [Department of Immunology and Microbiology, Wayne State University, Detroit, MI (United States); Rosenspire, Allen J., E-mail: arosenspire@wayne.edu [Department of Immunology and Microbiology, Wayne State University, Detroit, MI (United States)

    2014-04-01

    Network and protein–protein interaction analyses of proteins undergoing Hg{sup 2+}-induced phosphorylation and dephosphorylation in Hg{sup 2+}-intoxicated mouse WEHI-231 B cells identified Lyn as the most interconnected node. Lyn is a Src family protein tyrosine kinase known to be intimately involved in the B cell receptor (BCR) signaling pathway. Under normal signaling conditions the tyrosine kinase activity of Lyn is controlled by phosphorylation, primarily of two well known canonical regulatory tyrosine sites, Y-397 and Y-508. However, Lyn has several tyrosine residues that have not yet been determined to play a major role under normal signaling conditions, but are potentially important sites for phosphorylation following mercury exposure. In order to determine how Hg{sup 2+} exposure modulates the phosphorylation of additional residues in Lyn, a targeted MS assay was developed. Initial mass spectrometric surveys of purified Lyn identified 7 phosphorylated tyrosine residues. A quantitative assay was developed from these results using the multiple reaction monitoring (MRM) strategy. WEHI-231 cells were treated with Hg{sup 2+}, pervanadate (a phosphatase inhibitor), or anti-Ig antibody (to stimulate the BCR). Results from these studies showed that the phosphoproteomic profile of Lyn after exposure of the WEHI-231 cells to a low concentration of Hg{sup 2+} closely resembled that of anti-Ig antibody stimulation, whereas exposure to higher concentrations of Hg{sup 2+} led to increases in the phosphorylation of Y-193/Y-194, Y-501 and Y-508 residues. These data indicate that mercury can disrupt a key regulatory signal transduction pathway in B cells and point to phospho-Lyn as a potential biomarker for mercury exposure. - Highlights: • Inorganic mercury (Hg{sup 2+}) induces changes in the WEHI-231 B cell phosphoproteome. • The B cell receptor (BCR) signaling pathway was the pathway most affected by Hg{sup 2+}. • The Src family phosphoprotein kinase Lyn was the

  7. Alkylglycerols modulate the proliferation and differentiation of non-specific agonist and specific antigen-stimulated splenic lymphocytes.

    Directory of Open Access Journals (Sweden)

    Linxi Qian

    Full Text Available Alkylglycerols (AKGs are ether-linked glycerols derived from shark liver oil and found in small amounts in human milk. Previous studies showed that oral AKGs administration significantly increased the immune response in mice. The aim of the present study was to investigate the in vitro immunomodulatory effect of AKGs on stimulating splenic lymphocyte responses. C57BL/6 mice were immunized with hepatitis B surface antigen (HBsAg. Splenic B cells were purified and stimulated with anti-BCR and anti-CD38. Meanwhile, splenic CD4+ T cells were purified and stimulated with anti-CD3 and anti-CD28. For antigen specific stimulation, the purified CD4+ T cells were cocultured with HBsAg -pulsed dendritic cells. The stimulated lymphocytes were treated with different concentrations of AKGs. The cell proliferation was assessed by [3H]-thymidine incorporation assay. The maturation of B cells was assessed by examining the germline (GL transcription of IgG (γ1 mRNA expression, and the surface expressions of CD80/CD86 markers were examined by flow cytometry analysis. Th1/Th2 polarity was assessed by T-BET (Th1/GATA-3 (Th2 flow cytometry assay and by characteristic cytokines ELISA assay (TNF-α and IFN-γ for Th1; IL-4 and IL-10 for Th2. It was found that AKGs significantly increased the BCR/CD38 -stimulated B cell proliferation. The T cell proliferation in response to CD3/CD28 or specific antigen stimulation was also increased by AKGs. The transcriptional level of IgG (γ1 and the expressions of CD80/CD86 molecules were markedly increased by AKGs in BCR/CD38 -stimulated B cells. Meanwhile, the results showed that AKGs increased the expression of T-BET transcriptional factor and the production of Th1 cytokines (TNF-α and IFN-γ upon CD3/CD28 stimulation; whereas, levels of Th2 cytokines (IL-4 and IL-10 were decreased by AKGs. Our study demonstrated that AKGs can modulate immune responses by boosting the proliferation and maturation of murine lymphocytes in vitro.

  8. 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.

  9. 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.

  10. Switching to second-generation tyrosine kinase inhibitor improves the response and outcome of frontline imatinib-treated patients with chronic myeloid leukemia with more than 10% of BCR-ABL/ABL ratio at 3 months

    Science.gov (United States)

    Casado, Luis-Felipe; García-Gutiérrez, José-Valentín; Massagué, Isabel; Giraldo, Pilar; Pérez-Encinas, Manuel; de Paz, Raquel; Martínez-López, Joaquín; Bautista, Guiomar; Osorio, Santiago; Requena, María-José; Palomera, Luis; Peñarrubia, María-Jesús; Calle, Carmen; Hernández-Rivas, José-Ángel; Burgaleta, Carmen; Maestro, Begoña; García-Ormeña, Nuria; Steegmann, Juan-Luis

    2015-01-01

    Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar. PMID:25756742

  11. Divisible ℤ-modules

    Directory of Open Access Journals (Sweden)

    Futa Yuichi

    2016-03-01

    Full Text Available In this article, we formalize the definition of divisible ℤ-module and its properties in the Mizar system [3]. We formally prove that any non-trivial divisible ℤ-modules are not finitely-generated.We introduce a divisible ℤ-module, equivalent to a vector space of a torsion-free ℤ-module with a coefficient ring ℚ. ℤ-modules are important for lattice problems, LLL (Lenstra, Lenstra and Lovász base reduction algorithm [15], cryptographic systems with lattices [16] and coding theory [8].

  12. Reduced Multiplication Modules

    Indian Academy of Sciences (India)

    Karim Samei

    2011-05-01

    An -module is called a multiplication module if for each submodule of , = for some ideal of . As defined for a commutative ring , an -module is said to be reduced if the intersection of prime submodules of is zero. The prime spectrum and minimal prime submodules of the reduced module are studied. Essential submodules of are characterized via a topological property. It is shown that the Goldie dimension of is equal to the Souslin number of Spec (). Also a finitely generated module is a Baer module if and only if Spec () is an extremally disconnected space; if and only if it is a -module. It is proved that a prime submodule is minimal in if and only if for each $x\\in N,\\mathrm{Ann}(x)\

  13. Solar cell module. Taiyo denchi module

    Energy Technology Data Exchange (ETDEWEB)

    Nakano, Akihiko.

    1990-01-24

    This invention concerns a module frame of solar cell and a solar cell module using this frame. In particular, it concerns a frame and a module useful for the CdS/CdTe or CdS/CuInSe {sub 2} based cell. In the existing solar cell module, sealant is packed in between the edges of a glass substrate, a resin layer and a back protective thin film, etc. and a grooved frame of U-shaped section. For the sealant, silicon based resin and butyl rubber based resin are used many times, but either resin has defects such as their overflow from the module structure. In order to solve these defects, this invention proposes to provide stair-shaped protrusions along the four sides of the bottom of the box frame (herein after called the lower frame) of the module and at the same time, provide a groove for pooling the sealant at the portion where such protrusion meets the side wall, furthermore to provide depressions for pooling the sealant at the upper edge inside the side wall of the lower frame or to punch holes at the corners of the bottom of the lower frame. 9 figs.

  14. A photovoltaic module

    OpenAIRE

    Krebs, Frederik C.; Sommer-Larsen, Peter

    2013-01-01

    The present invention relates to a photovoltaic module comprising a carrier substrate, said carrier substrate carrying a purely printed structure comprising printed positive and negative module terminals, a plurality of printed photovoltaic cell units each comprising one or more printed photovoltaic cells, wherein the plurality of printed photovoltaic cell units are electrically connected in series between the positive and the negative module terminals such that any two neighbouring photovolt...

  15. Investigating Quantum Modulation States

    Science.gov (United States)

    2016-03-01

    3. DATES COVERED (From - To) OCT 2012 – SEP 2015 4. TITLE AND SUBTITLE INVESTIGATING QUANTUM MODULATION STATES 5a. CONTRACT NUMBER IN-HOUSE 5b...Coherent states are the most classical of quantum states. Generation and detection of their polarization and phase modulations are well...stream cipher maps message bits onto random blocks of bits producing modulated states that are intrinsically noisy. The ciphertext so generated is

  16. Model theory and modules

    CERN Document Server

    Prest, M

    1988-01-01

    In recent years the interplay between model theory and other branches of mathematics has led to many deep and intriguing results. In this, the first book on the topic, the theme is the interplay between model theory and the theory of modules. The book is intended to be a self-contained introduction to the subject and introduces the requisite model theory and module theory as it is needed. Dr Prest develops the basic ideas concerning what can be said about modules using the information which may be expressed in a first-order language. Later chapters discuss stability-theoretic aspects of module

  17. Delphi Accounts Receivable Module -

    Data.gov (United States)

    Department of Transportation — Delphi accounts receivable module contains the following data elements, but are not limited to customer information, cash receipts, line of accounting details, bill...

  18. THERMOELECTRIC POWER MODULES.

    Science.gov (United States)

    MODULES (ELECTRONICS), GENERATORS, THERMOELECTRICITY, PERFORMANCE(ENGINEERING), TABLES(DATA), HEAT, ALUMINUM, WEIGHT, SEMICONDUCTORS, SILICON, GERMANIUM, MEASUREMENT, VOLTAGE, ELECTRICAL RESISTANCE, POWER, TEMPERATURE, TIME.

  19. The synthetic heat shock protein 90 (Hsp90) inhibitor EC141 induces degradation of Bcr-Abl p190 protein and apoptosis of Ph-positive acute lymphoblastic leukemia cells.

    Science.gov (United States)

    Tong, Wei-Gang; Estrov, Zeev; Wang, Yongtao; O'Brien, Susan; Faderl, Stefan; Harris, David M; Van Pham, Quin; Hazan-Halevy, Inbal; Liu, Zhiming; Koch, Patricia; Kantarjian, Hagop; Keating, Michael J; Ferrajoli, Alessandra

    2011-12-01

    The prognosis of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is poor. Chemotherapy is rarely curative and tyrosine kinase inhibitors (TKIs) induce only transient responses. Heat shock protein 90 (Hsp90) is a chaperone protein that is important in signal transduction, cell cycle control, and transcription regulation in both normal and leukemia cells. In the current study, we tested the growth inhibitory and apoptotic effects of a novel Hsp90 inhibitor, EC141 on the Ph+ ALL lines Z-119, Z-181, and Z-33, as well as primary bone marrow-derived blasts from patients with newly diagnosed Ph+ ALL. We found that EC141 inhibited the growth of Ph+ ALL cells in a concentration-dependent manner with IC(50) ranged from 1 to 10 nM. EC141 also inhibited the proliferation of primary bone marrow-derived blasts using the ALL blast colony assay. EC141 down-regulated Hsp90 and up-regulated Hsp70 protein levels, inhibited CrkL phosphorylation, and induced degradation of Bcr-Abl p190 protein through ubiquitin-dependent proteasomal pathway. Furthermore, exposure of Ph+ ALL cells to EC141 resulted in activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and induction of apoptosis. In conclusion, our data suggest that EC141 is a potent Hsp90 inhibitor with activity against Ph+ ALL. Further studies to investigate the anticancer effect of EC141 either as a single agent, or in combination in Ph+ ALL and other hematological malignancies are warranted.

  20. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib

    Science.gov (United States)

    Shah, Neil P.; Kim, Dong-Wook; Kantarjian, Hagop; Rousselot, Philippe; Llacer, Pedro Enrique Dorlhiac; Enrico, Alicia; Vela-Ojeda, Jorge; Silver, Richard T.; Khoury, Hanna Jean; Müller, Martin C.; Lambert, Alexandre; Matloub, Yousif; Hochhaus, Andreas

    2010-01-01

    Background Dasatinib 100 mg once daily achieves intermittent BCR-ABL kinase inhibition and is approved for chronic-phase chronic myeloid leukemia patients resistant or intolerant to imatinib. To better assess durability of response to and tolerability of dasatinib, data from a 2-year minimum follow-up for a dose-optimization study in chronic-phase chronic myeloid leukemia are reported here. Design and Methods In a phase 3 study, 670 chronic-phase chronic myeloid leukemia patients with resistance, intolerance, or suboptimal response to imatinib were randomized to dasatinib 100 mg once-daily, 50 mg twice-daily, 140 mg once-daily, or 70 mg twice-daily. Results Data from a 2-year minimum follow-up demonstrate that dasatinib 100 mg once daily achieves major cytogenetic response and complete cytogenetic response rates comparable to those in the other treatment arms, and reduces the frequency of key side effects. Comparable 2-year progression-free survival and overall survival rates were observed (80% and 91%, respectively, for 100 mg once daily, and 75%–76% and 88%–94%, respectively, in other arms). Complete cytogenetic responses were achieved rapidly, typically by 6 months. In patients treated with dasatinib 100 mg once daily for 6 months without complete cytogenetic response, the likelihood of achieving such a response by 2 years was 50% for patients who had achieved a partial cytogenetic response, and only 8% or less for patients with minor, minimal, or no cytogenetic response. Less than 3% of patients suffered disease transformation to accelerated or blast phase. Conclusions Intermittent kinase inhibition can achieve rapid and durable responses, indistinguishable from those achieved with more continuous inhibition. PMID:20139391

  1. Parabolic Dish Stirling Module

    Science.gov (United States)

    Washom, B.

    1984-01-01

    The design, manufacture, and assembly of a commercially designed parabolic dish Stirling 25 kWe module is examined. The cost, expected performance, design uniquenesses, and future commercial potential of this module, which is regarded as the most technically advanced in the parabolic dish industry is discussed.

  2. Synthetic Space Vector Modulation

    Science.gov (United States)

    2013-06-01

    Modulation RF Radio Frequency SVM Space Vector Modulation VCO Voltage Controlled Oscillator VSI Voltage Source Inverter xvi THIS PAGE...examining the literature, an NE566 voltage controlled oscillator ( VCO ) chip as seen in Figure 10 was used to design a circuit that produced the

  3. Cosmetology. Computerized Learning Modules.

    Science.gov (United States)

    Finnerty, Kathy, Ed.

    Intended to help reading-limited students meet course objectives, these 11 modules are based on instructional materials in cosmetology that have a higher readability equivalent. Modules cover bacteriology, chemical waving, scalp and hair massage, chemistry, hair shaping, hairstyling, chemical hair relaxing, hair coloring, skin and scalp,…

  4. The Structure of Modules

    Institute of Scientific and Technical Information of China (English)

    陈焕艮; 佟文廷

    1994-01-01

    In this paper,we introduce two concepts:projective radical and semi-reflexive radical of a module,and establish some elementary relations among subprojective,semi-reflexive and torsion-free modules Using these properties,ws give classifications of some rings.

  5. Solar energy modulator

    Science.gov (United States)

    Hale, R. R. (Inventor); Mcdougal, A. R.

    1984-01-01

    A module is described with a receiver having a solar energy acceptance opening and supported by a mounting ring along the optic axis of a parabolic mirror in coaxial alignment for receiving solar energy from the mirror, and a solar flux modulator plate for varying the quantity of solar energy flux received by the acceptance opening of the module. The modulator plate is characterized by an annular, plate-like body, the internal diameter of which is equal to or slightly greater than the diameter of the solar energy acceptance opening of the receiver. Slave cylinders are connected to the modulator plate for supporting the plate for axial displacement along the axis of the mirror, therby shading the opening with respect to solar energy flux reflected from the surface of the mirror to the solar energy acceptance opening.

  6. On Modules Whose Singular Subgenerated Modules Are Weakly Injective

    Institute of Scientific and Technical Information of China (English)

    S. Dhompongsa; J. Sanwong; S.Plubtieng; H.Tansee

    2001-01-01

    Rings over which every singular right module is injective (briefly,right SI-rings) were introduced and investigated by Goodearl. Weakly injective modules, as a generalization of injective modules, were introduced by Jain and modules are weakly injective, which we call SwI-rings. This concept is extended to SwI-modules, i.e., modules whose singular subgenerated modules are weakly injective. Several characterizations and properties of SwI-rings and SwI-modules are obtained which generalize some earlier known results on SI-rings and weakly semisimple rings.

  7. Photovoltaic module and interlocked stack of photovoltaic modules

    Science.gov (United States)

    Wares, Brian S.

    2014-09-02

    One embodiment relates to an arrangement of photovoltaic modules configured for transportation. The arrangement includes a plurality of photovoltaic modules, each photovoltaic module including a frame. A plurality of individual male alignment features and a plurality of individual female alignment features are included on each frame. Adjacent photovoltaic modules are interlocked by multiple individual male alignment features on a first module of the adjacent photovoltaic modules fitting into and being surrounded by corresponding individual female alignment features on a second module of the adjacent photovoltaic modules. Other embodiments, features and aspects are also disclosed.

  8. Essentially normal Hilbert modules and Khomology Ⅲ: Homogenous quotient modules of Hardy modules on the bidisk

    Institute of Scientific and Technical Information of China (English)

    Kun-yu GUO; Peng-hui WANG

    2007-01-01

    In this paper, we study the homogenous quotient modules of the Hardy module on the bidisk. The essential normality of the homogenous quotient modules is completely characterized. We also describe the essential spectrum for a general quotient module. The paper also considers K-homology invariant defined in the case of the homogenous quotient modules on the bidisk.

  9. Solar cell module. Taiyo denchi module

    Energy Technology Data Exchange (ETDEWEB)

    Nakano, Akihiko; Matsumoto, Hitoshi; Komatsu, Yasumitsu; Shirai, Sadaharu.

    1989-09-29

    In the solar cell module of this invention, such junctions as CdS/CdTe or CdS/CuInSe {sub 2} are contained as a photoelectromotive force part coexists with air in a closed space which consists of glass, metal parts and a bonding resin layer; the photoelectromotive force part is coated either with a fluorine resin or a silicone resin. The fluorine resin contains a fundamental skeleton of an alternative copolymer of fluoroolefin and a hydrocarbon-based vinyl monomer; the silicone resin has three types, i.e., addition-reacted, condensated or UV-curing type, and the released oxygen is sealed in the closed space. The resin layer which adheres the glass and the metal plate is a thermoplastic resin which is polyethylene modified by copolymerization of acid anhydride. By this, the reliability of the solar cell module was enhanced. 3 figs.

  10. Optical modulator including grapene

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ming; Yin, Xiaobo; Zhang, Xiang

    2016-06-07

    The present invention provides for a one or more layer graphene optical modulator. In a first exemplary embodiment the optical modulator includes an optical waveguide, a nanoscale oxide spacer adjacent to a working region of the waveguide, and a monolayer graphene sheet adjacent to the spacer. In a second exemplary embodiment, the optical modulator includes at least one pair of active media, where the pair includes an oxide spacer, a first monolayer graphene sheet adjacent to a first side of the spacer, and a second monolayer graphene sheet adjacent to a second side of the spacer, and at least one optical waveguide adjacent to the pair.

  11. Analytic Hilbert modules

    CERN Document Server

    Chen, Xiaoman

    2003-01-01

    The seminal 1989 work of Douglas and Paulsen on the theory of analytic Hilbert modules precipitated a number of major research efforts. This in turn led to some intriguing and valuable results, particularly in the areas of operator theory and functional analysis. With the field now beginning to blossom, the time has come to collect those results under one cover. Written by two of the most active and often-cited researchers in the field, Analytic Hilbert Modules reports on the progress made by the authors and others, including the characteristic space theory, rigidity, the equivalence problem, the Arveson modules, extension theory, and reproducing Hilbert spaces on n-dimensional complex space.

  12. The ANTARES Optical Module

    CERN Document Server

    Amram, P; Anvar, S; Ardellier-Desages, F E; Aslanides, Elie; Aubert, Jean-Jacques; Azoulay, R; Bailey, D; Basa, S; Battaglieri, M; Bellotti, R; Benhammou, Ya; Bernard, F; Berthier, R; Bertin, V; Billault, M; Blaes, R; Bland, R W; Blondeau, F; De Botton, N R; Boulesteix, J; Brooks, B; Brunner, J; Cafagna, F; Calzas, A; Capone, A; Caponetto, L; Cârloganu, C; Carmona, E; Carr, J; Carton, P H; Cartwright, S L; Cassol, F; Cecchini, S; Ciacio, F; Circella, M; Compere, C; Cooper, S; Coyle, P; Croquette, J; Cuneo, S; Danilov, M; Van Dantzig, R; De Marzo, C; De Vita, R; Deck, P; Destelle, J J; Dispau, G; Drougou, J F; Druillole, F; Engelen, J; Feinstein, F; Festy, D; Fopma, J; Gallone, J M; Giacomelli, G; Goret, P; Gosset, L G; Gournay, J F; Heijboer, A; Hernández-Rey, J J; Herrouin, G; Hubbard, John R; Jacquet, M; De Jong, M; Karolak, M; Kooijman, P M; Kouchner, A; Kudryavtsev, V A; Lachartre, D; Lafoux, H; Lamare, P; Languillat, J C; Laubier, L; Laugier, J P; Le Guen, Y; Le Provost, H; Le Van-Suu, A; Lemoine, L; Lo Nigro, L; Lo Presti, D; Loucatos, Sotirios S; Louis, F; Lyashuk, V I; Magnier, P; Marcelin, M; Margiotta, A; Massol, A; Masullo, R; Mazéas, F; Mazeau, B; Mazure, A; McMillan, J E; Michel, J L; Migneco, E; Millot, C; Mols, P; Montanet, François; Montaruli, T; Morel, J P; Moscoso, L; Navas, S; Nezri, E; Nooren, G J L; Oberski, J; Olivetto, C; Oppelt-pohl, A; Palanque-Delabrouille, Nathalie; Payre, P; Perrin, P; Petruccetti, M; Petta, P; Piattelli, P; Poinsignon, J; Popa, V; Potheau, R; Queinec, Y; Racca, C; Raia, G; Randazzo, N; Rethore, F; Riccobene, G; Ricol, J S; Ripani, M; Roca-Blay, V; Rolin, J F; Rostovtsev, A A; Russo, G V; Sacquin, Yu; Salusti, E; Schuller, J P; Schuster, W; Soirat, J P; Suvorova, O; Spooner, N J C; Spurio, M; Stolarczyk, T; Stubert, D; Taiuti, M; Tao, Charling; Tayalati, Y; Thompson, L F; Tilav, S; Triay, R; Valente, V; Varlamov, I; Vaudaine, G; Vernin, P; De Witt-Huberts, P K A; De Wolf, E; Zakharov, V; Zavatarelli, S; De Dios-Zornoza-Gomez, Juan; Zúñiga, J

    2002-01-01

    The ANTARES collaboration is building a deep sea neutrino telescope in the Mediterranean Sea. This detector will cover a sensitive area of typically 0.1 km-squared and will be equipped with about 1000 optical modules. Each of these optical modules consists of a large area photomultiplier and its associated electronics housed in a pressure resistant glass sphere. The design of the ANTARES optical module, which is a key element of the detector, has been finalized following extensive R & D studies and is reviewed here in detail.

  13. The ANTARES optical module

    Energy Technology Data Exchange (ETDEWEB)

    Amram, P.; Anghinolfi, M.; Anvar, S.; Ardellier-Desages, F.E.; Aslanides, E.; Aubert, J.-J.; Azoulay, R.; Bailey, D.; Basa, S.; Battaglieri, M.; Bellotti, R.; Benhammou, Y.; Bernard, F.; Berthier, R.; Bertin, V.; Billault, M.; Blaes, R.; Bland, R.W.; Blondeau, F.; Botton, N. de; Boulesteix, J.; Brooks, C.B.; Brunner, J.; Cafagna, F.; Calzas, A.; Capone, A.; Caponetto, L.; Carloganu, C.; Carmona, E.; Carr, J.; Carton, P.-H.; Cartwright, S.L.; Cassol, F.; Cecchini, S.; Ciacio, F.; Circella, M.; Compere, C.; Cooper, S.; Coyle, P.; Croquette, J.; Cuneo, S.; Danilov, M.; Dantzig, R. van; De Marzo, C.; DeVita, R.; Deck, P.; Destelle, J.-J.; Dispau, G.; Drougou, J.F.; Druillole, F.; Engelen, J.; Feinstein, F.; Festy, D.; Fopma, J.; Gallone, J.-M.; Giacomelli, G.; Goret, P.; Gosset, L.; Gournay, J.-F.; Heijboer, A.; Hernandez-Rey, J.J.; Herrouin, G.; Hubbard, J.R.; Jaquet, M.; Jong, M. de; Karolak, M.; Kooijman, P.; Kouchner, A.; Kudryavtsev, V.A.; Lachartre, D.; Lafoux, H. E-mail: lafoux@cea.fr; Lamare, P.; Languillat, J.-C.; Laubier, L.; Laugier, J.-P.; Le Guen, Y.; Le Provost, H.; Le Van Suu, A.; Lemoine, L.; Lo Nigro, L.; Lo Presti, D.; Loucatos, S.; Louis, F.; Lyashuk, V.; Magnier, P.; Marcelin, M.; Margiotta, A.; Massol, A.; Masullo, R.; Mazeas, F.; Mazeau, B.; Mazure, A.; McMillan, J.E.; Michel, J.L.; Migneco, E.; Millot, C.; Mols, P.; Montanet, F.; Montaruli, T.; Morel, J.P.; Moscoso, L.; Musumeci, M.; Navas, S.; Nezri, E.; Nooren, G.J.; Oberski, J.; Olivetto, C.; Oppelt-Pohl, A.; Palanque-Delabrouille, N.; Papaleo, R.; Payre, P.; Perrin, P.; Petruccetti, M.; Petta, C.; Piattelli, P.; Poinsignon, J.; Potheau, R.; Queinec, Y.; Racca, C.; Raia, G.; Randazzo, N.; Rethore, F.; Riccobene, G.; Ricol, J.-S.; Ripani, M.; Roca-Blay, V.; Rolin, J.F.; Rostovstev, A.; Russo, G.V.; Sacquin, Y.; Salusti, E.; Schuller, J.-P.; Schuster, W.; Soirat, J.-P.; Souvorova, O.; Spooner, N.J.C.; Spurio, M.; Stolarczyk, T.; Stubert, D.; Taiuti, M.; Tao, C.; Tayalati, Y.; Thompson, L.F.

    2002-05-21

    The ANTARES collaboration is building a deep sea neutrino telescope in the Mediterranean Sea. This detector will cover a sensitive area of typically 0.1 km{sup 2} and will be equipped with about 1000 optical modules. Each of these optical modules consists of a large area photomultiplier and its associated electronics housed in a pressure resistant glass sphere. The design of the ANTARES optical module, which is a key element of the detector, has been finalized following extensive R and D studies and is reviewed here in detail.

  14. Microlensing modulation by binaries

    CERN Document Server

    Dubath, F; Durrer, R; Dubath, Florian; Gasparini, Maria Alice; Durrer, Ruth

    2006-01-01

    We compute the effect of the lens quadrupole on microlensing. The time dependence of the quadrupole can lead to specific modulations of the amplification signal. We study especially binary system lenses in our galaxy. The modulation is observable if the rotation period of the system is smaller than the time over which the amplification is significant and if the impact parameter of the passing light ray is sufficiently close to the Einstein radius so that the amplification is very large. Observations of this modulation can reveal important information on the quadrupole and thus on the gravitational radiation emitted by the lens.

  15. Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice.

    Directory of Open Access Journals (Sweden)

    Laure B Bindels

    Full Text Available We tested the hypothesis that changing the gut microbiota using pectic oligosaccharides (POS or inulin (INU differently modulates the progression of leukemia and related metabolic disorders. Mice were transplanted with Bcr-Abl-transfected proB lymphocytes mimicking leukemia and received either POS or INU in their diet (5% for 2 weeks. Combination of pyrosequencing, PCR-DGGE and qPCR analyses of the 16S rRNA gene revealed that POS decreased microbial diversity and richness of caecal microbiota whereas it increased Bifidobacterium spp., Roseburia spp. and Bacteroides spp. (affecting specifically B. dorei to a higher extent than INU. INU supplementation increased the portal SCFA propionate and butyrate, and decreased cancer cell invasion in the liver. POS treatment did not affect hepatic cancer cell invasion, but was more efficient than INU to decrease the metabolic alterations. Indeed, POS better than INU delayed anorexia linked to cancer progression. In addition, POS treatment increased acetate in the caecal content, changed the fatty acid profile inside adipose tissue and counteracted the induction of markers controlling β-oxidation, thereby hampering fat mass loss. Non digestible carbohydrates with prebiotic properties may constitute a new nutritional strategy to modulate gut microbiota with positive consequences on cancer progression and associated cachexia.

  16. Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice.

    Science.gov (United States)

    Bindels, Laure B; Neyrinck, Audrey M; Salazar, Nuria; Taminiau, Bernard; Druart, Céline; Muccioli, Giulio G; François, Emmanuelle; Blecker, Christophe; Richel, Aurore; Daube, Georges; Mahillon, Jacques; de los Reyes-Gavilán, Clara G; Cani, Patrice D; Delzenne, Nathalie M

    2015-01-01

    We tested the hypothesis that changing the gut microbiota using pectic oligosaccharides (POS) or inulin (INU) differently modulates the progression of leukemia and related metabolic disorders. Mice were transplanted with Bcr-Abl-transfected proB lymphocytes mimicking leukemia and received either POS or INU in their diet (5%) for 2 weeks. Combination of pyrosequencing, PCR-DGGE and qPCR analyses of the 16S rRNA gene revealed that POS decreased microbial diversity and richness of caecal microbiota whereas it increased Bifidobacterium spp., Roseburia spp. and Bacteroides spp. (affecting specifically B. dorei) to a higher extent than INU. INU supplementation increased the portal SCFA propionate and butyrate, and decreased cancer cell invasion in the liver. POS treatment did not affect hepatic cancer cell invasion, but was more efficient than INU to decrease the metabolic alterations. Indeed, POS better than INU delayed anorexia linked to cancer progression. In addition, POS treatment increased acetate in the caecal content, changed the fatty acid profile inside adipose tissue and counteracted the induction of markers controlling β-oxidation, thereby hampering fat mass loss. Non digestible carbohydrates with prebiotic properties may constitute a new nutritional strategy to modulate gut microbiota with positive consequences on cancer progression and associated cachexia.

  17. Module bay with directed flow

    Science.gov (United States)

    Torczynski, John R.

    2001-02-27

    A module bay requires less cleanroom airflow. A shaped gas inlet passage can allow cleanroom air into the module bay with flow velocity preferentially directed toward contaminant rich portions of a processing module in the module bay. Preferential gas flow direction can more efficiently purge contaminants from appropriate portions of the module bay, allowing a reduced cleanroom air flow rate for contaminant removal. A shelf extending from an air inlet slit in one wall of a module bay can direct air flowing therethrough toward contaminant-rich portions of the module bay, such as a junction between a lid and base of a processing module.

  18. HIGHER FREQUENCY ULTRASONIC LIGHT MODULATORS.

    Science.gov (United States)

    LIGHT), (* MODULATORS , (*ULTRASONIC RADIATION, MODULATORS ), OPTICAL COMMUNICATIONS, BANDWIDTH, TRANSDUCERS, HIGH FREQUENCY, VERY HIGH FREQUENCY, ATTENUATION, DATA PROCESSING, OPTICAL EQUIPMENT, ANALOG COMPUTERS, THEORY.

  19. A photovoltaic module

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to a photovoltaic module comprising a carrier substrate, said carrier substrate carrying a purely printed structure comprising printed positive and negative module terminals, a plurality of printed photovoltaic cell units each comprising one or more printed...... photovoltaic cells, wherein the plurality of printed photovoltaic cell units are electrically connected in series between the positive and the negative module terminals such that any two neighbouring photovoltaic cell units are electrically connected by a printed interconnecting electrical conductor....... The carrier substrate comprises a foil and the total thickness of the photovoltaic module is below 500 [mu]m. Moreover, the nominal voltage level between the positive and the negative terminals is at least 5 kV DC....

  20. Ultrasound Modulated Bioluminescence Tomography

    CERN Document Server

    Bal, Guillaume

    2013-01-01

    We propose a method to reconstruct the density of a luminescent source in a highly-scattering medium from ultrasound modulated optical measurements. Our approach is based on the solution to a hybrid inverse source problem for the diffusion equation.

  1. Isothermal Containment Module

    Science.gov (United States)

    1999-01-01

    Isothermal Containment Modules are the temperature-controlling carrier that BioServe built to carry Commercial Generic Bioprocessing Apparatus (CGBA) and in the future, Space Automated Bioproduct Lab (SABL) to the International Space Station.

  2. GREET Pretreatment Module

    Energy Technology Data Exchange (ETDEWEB)

    Adom, Felix K.; Dunn, Jennifer B.; Han, Jeongwoo

    2014-09-01

    A wide range of biofuels and biochemicals can be produced from biomass via different pretreatment technologies that yield sugars. This report documents the material and energy flows that occur when fermentable sugars from four lignocellulosic feedstocks (corn stover, miscanthus, switchgrass, and poplar) are produced via dilute acid pretreatment and ammonia fiber expansion. These flows are documented for inclusion in the pretreatment module of the Greenhouses Gases, Regulated Emissions, and Energy Use in Transportation (GREET) model. Process simulations of each pretreatment technology were developed in Aspen Plus. Material and energy consumption data from Aspen Plus were then compiled in the GREET pretreatment module. The module estimates the cradle-to-gate fossil energy consumption (FEC) and greenhouse gas (GHG) emissions associated with producing fermentable sugars. This report documents the data and methodology used to develop this module and the cradle-to-gate FEC and GHG emissions that result from producing fermentable sugars.

  3. Top Local Cohomology Modules

    Institute of Scientific and Technical Information of China (English)

    Mohammad T. Dibaei; Siamak Yassemi

    2007-01-01

    For a finitely generated module M over a commutative Noetherian local ring (R, m), it is shown that there exist only a finite number of non-isomorphic top localeohomology modules Hdim(M) (M) for all ideals a of RIt is also shown that for a giveninteger r ≥ 0, if Hra(R/p) is zero for all p in Supp(M), then Hia(M)=0 for all I ≥ r.

  4. Groups, rings, modules

    CERN Document Server

    Auslander, Maurice

    2014-01-01

    This classic monograph is geared toward advanced undergraduates and graduate students. The treatment presupposes some familiarity with sets, groups, rings, and vector spaces. The four-part approach begins with examinations of sets and maps, monoids and groups, categories, and rings. The second part explores unique factorization domains, general module theory, semisimple rings and modules, and Artinian rings. Part three's topics include localization and tensor products, principal ideal domains, and applications of fundamental theorem. The fourth and final part covers algebraic field extensions

  5. Absolutely Indecomposable Modules

    CERN Document Server

    Göbel, Rüdiger

    2007-01-01

    A module is called absolutely indecomposable if it is directly indecomposable in every generic extension of the universe. We want to show the existence of large abelian groups that are absolutely indecomposable. This will follow from a more general result about R-modules over a large class of commutative rings R with endomorphism ring R which remains the same when passing to a generic extension of the universe. It turns out that `large' in this context has the precise meaning, namely being smaller then the first omega-Erdos cardinal defined below. We will first apply result on large rigid trees with a similar property established by Shelah in 1982, and will prove the existence of related ` R_omega-modules' (R-modules with countably many distinguished submodules) and finally pass to R-modules. The passage through R_omega-modules has the great advantage that the proofs become very transparent essentially using a few `linear algebra' arguments accessible also for graduate students. The result gives a new constru...

  6. Photovoltaic module reliability workshop

    Energy Technology Data Exchange (ETDEWEB)

    Mrig, L. (ed.)

    1990-01-01

    The paper and presentations compiled in this volume form the Proceedings of the fourth in a series of Workshops sponsored by Solar Energy Research Institute (SERI/DOE) under the general theme of photovoltaic module reliability during the period 1986--1990. The reliability Photo Voltaic (PV) modules/systems is exceedingly important along with the initial cost and efficiency of modules if the PV technology has to make a major impact in the power generation market, and for it to compete with the conventional electricity producing technologies. The reliability of photovoltaic modules has progressed significantly in the last few years as evidenced by warranties available on commercial modules of as long as 12 years. However, there is still need for substantial research and testing required to improve module field reliability to levels of 30 years or more. Several small groups of researchers are involved in this research, development, and monitoring activity around the world. In the US, PV manufacturers, DOE laboratories, electric utilities and others are engaged in the photovoltaic reliability research and testing. This group of researchers and others interested in this field were brought together under SERI/DOE sponsorship to exchange the technical knowledge and field experience as related to current information in this important field. The papers presented here reflect this effort.

  7. Yetter-Drinfel‘d Module and Convolution Module

    Institute of Scientific and Technical Information of China (English)

    张良云; 王栓宏

    2002-01-01

    In this paper,we first give a sufficent and necessary condition for a Hopf algebra to be a Yetter-Drinfel'd module,and prove that the finite dual of a Yetter-Drinfel'd module is still a Yetter-Drinfel'd module,Finally,we introduce a concept of convolution module.

  8. Superstability for Generalized Module Left Derivations and Generalized Module Derivations on a Banach Module (I

    Directory of Open Access Journals (Sweden)

    Rassias JM

    2009-01-01

    Full Text Available We discuss the superstability of generalized module left derivations and generalized module derivations on a Banach module. Let be a Banach algebra and a Banach -module, and . The mappings , and are defined and it is proved that if (resp., is dominated by then is a generalized (resp., linear module- left derivation and is a (resp., linear module- left derivation. It is also shown that if (resp., is dominated by then is a generalized (resp., linear module- derivation and is a (resp., linear module- derivation.

  9. Universal enveloping crossed module of Leibniz crossed modules and representations

    Science.gov (United States)

    Casado, Rafael F.; García-Martínez, Xabier; Ladra, Manuel

    2016-03-01

    The universal enveloping algebra functor UL: Lb → Alg, defined by Loday and Pirashvili [1], is extended to crossed modules. Then we construct an isomorphism between the category of representations of a Leibniz crossed module and the category of left modules over its universal enveloping crossed module of algebras. Note that the procedure followed in the proof for the Lie case cannot be adapted, since the actor in the category of Leibniz crossed modules does not always exist.

  10. Batch Covariance Relaxation (BCR) Adaptive Processing.

    Science.gov (United States)

    1981-08-01

    IR&D Final Report 7263-001F, March 15, 1980. [2] Hestenes, M. R. and Steifel, E., "Methods of Conjugate Gradients for Solving Linear Systems," Journal ...Wilkinson, J. H., "Notes on the Solution of Algebraic Linear Simultaneous Equations," Quarterly Journal of Mechanics and Applied Mathematics, pp. 149-173...00 0 In F- P0 -a -- -~e -2 - - -4 - o 0 p.. to I ~ a I I PzN N oin g I ’ l g 1 C 0I ~ Nw c gL Il* . a* . * p. 4r I-in a a4i * Csea OCI I2e Co , lk. lX

  11. Characterizations of Graded Distributive Modules

    Institute of Scientific and Technical Information of China (English)

    Qinghua Chen; Chang'an Li

    2002-01-01

    In this paper, we give some characterizations of graded distributive modules, prove some interesting results between graded rings (modules) and lattices under finiteness conditions, and investigate the direct sum of graded distributive modules in terms of orders of graded submodules and homomorphisms of graded factor modules.

  12. Integrated unaligned resonant modulator tuning

    Energy Technology Data Exchange (ETDEWEB)

    Zortman, William A.; Lentine, Anthony L.

    2017-10-03

    Methods and systems for tuning a resonant modulator are disclosed. One method includes receiving a carrier signal modulated by the resonant modulator with a stream of data having an approximately equal number of high and low bits, determining an average power of the modulated carrier signal, comparing the average power to a predetermined threshold, and operating a tuning device coupled to the resonant modulator based on the comparison of the average power and the predetermined threshold. One system includes an input structure, a plurality of processing elements, and a digital control element. The input structure is configured to receive, from the resonant modulator, a modulated carrier signal. The plurality of processing elements are configured to determine an average power of the modulated carrier signal. The digital control element is configured to operate a tuning device coupled to the resonant modulator based on the average power of the modulated carrier signal.

  13. Spatial Terahertz Modulator

    Science.gov (United States)

    Xie, Zhenwei; Wang, Xinke; Ye, Jiasheng; Feng, Shengfei; Sun, Wenfeng; Akalin, Tahsin; Zhang, Yan

    2013-11-01

    Terahertz (THz) technology is a developing and promising candidate for biological imaging, security inspection and communications, due to the low photon energy, the high transparency and the broad band properties of the THz radiation. However, a major encountered bottleneck is lack of efficient devices to manipulate the THz wave, especially to modulate the THz wave front. A wave front modulator should allow the optical or electrical control of the spatial transmission (or reflection) of an input THz wave and hence the ability to encode the information in a wave front. Here we propose a spatial THz modulator (STM) to dynamically control the THz wave front with photo-generated carriers. A computer generated THz hologram is projected onto a silicon wafer by a conventional spatial light modulator (SLM). The corresponding photo-generated carrier spatial distribution will be induced, which forms an amplitude hologram to modulate the wave front of the input THz beam. Some special intensity patterns and vortex beams are generated by using this method. This all-optical controllable STM is structure free, high resolution and broadband. It is expected to be widely used in future THz imaging and communication systems.

  14. Superconducting optical modulator

    Science.gov (United States)

    Bunt, Patricia S.; Ference, Thomas G.; Puzey, Kenneth A.; Tanner, David B.; Tache, Nacira; Varhue, Walter J.

    2000-12-01

    An optical modulator based on the physical properties of high temperature superconductors has been fabricated and tested. The modulator was constructed form a film of Yttrium Barium Copper Oxide (YBCO) grown on undoped silicon with a buffer layer of Yttria Stabilized Zirconia. Standard lithographic procedures were used to pattern the superconducting film into a micro bridge. Optical modulation was achieved by passing IR light through the composite structure normal to the micro bridge and switching the superconducting film in the bridge region between the superconducting and non-superconducting states. In the superconducting state, IR light reflects from the superconducting film surface. When a critical current is passed through the micro bridge, it causes the film in this region to switch to the non-superconducting state allowing IR light to pass through it. Superconducting materials have the potential to switch between these two states at speeds up to 1 picosecond using electrical current. Presently, fiber optic transmission capacity is limited by the rate at which optical data can be modulated. The superconducting modulator, when combined with other components, may have the potential to increase the transmission capacity of fiber optic lines.

  15. NREL module energy rating methodology

    Energy Technology Data Exchange (ETDEWEB)

    Whitaker, C.; Newmiller, J.; Kroposki, B. [National Renewable Energy Laboratory, Golden, CO (United States)] [and others

    1995-11-01

    The goals of this project were to develop a tool for: evaluating one module in different climates; comparing different modules; provide a Q&D method for estimating periodic energy production; provide an achievable module rating; provide an incentive for manufacturers to optimize modules to non-STC conditions; and to have a consensus-based, NREL-sponsored activity. The approach taken was to simulate module energy for five reference days of various weather conditions. A performance model was developed.

  16. Thin film module development

    Science.gov (United States)

    Jester, T.

    1985-01-01

    The design of ARCO Solar, Inc.'s Genesis G100 photovoltaic module was driven by several criteria, including environmental stability (both electrical and mechanical), consumer aesthetics, low materials costs, and manufacturing ease. The module circuitry is designed as a 12 volt battery charger, using monolithic patterning techniques on a glass superstrate. This patterning and interconnect method proves amenable to high volume, low cost production throughput, and the use of glass serves the dual role of handling ease and availability. The mechanical design of the module centers on environmental stability. Packaging of the glass superstrate circuit must provide good resistance to thermal and humidity exposure along with hi-pot insulation and hailstone impact resistance. The options considered are given. Ethylene vinyl acetate (EVA) is chosen as the pottant material for its excellent weatherability.

  17. Space Experiment Module (SEM)

    Science.gov (United States)

    Brodell, Charles L.

    1999-01-01

    The Space Experiment Module (SEM) Program is an education initiative sponsored by the National Aeronautics and Space Administration (NASA) Shuttle Small Payloads Project. The program provides nationwide educational access to space for Kindergarten through University level students. The SEM program focuses on the science of zero-gravity and microgravity. Within the program, NASA provides small containers or "modules" for students to fly experiments on the Space Shuttle. The experiments are created, designed, built, and implemented by students with teacher and/or mentor guidance. Student experiment modules are flown in a "carrier" which resides in the cargo bay of the Space Shuttle. The carrier supplies power to, and the means to control and collect data from each experiment.

  18. GREET Pretreatment Module

    Energy Technology Data Exchange (ETDEWEB)

    Adom, Felix K. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Dunn, Jennifer B. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Han, Jeongwoo [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division

    2014-09-01

    A wide range of biofuels and biochemicals can be produced from cellulosic biomass via different pretreatment technologies that yield sugars. Process simulations of dilute acid and ammonia fiber expansion pretreatment processes and subsequent hydrolysis were developed in Aspen Plus for four lignocellulosic feedstocks (corn stover, miscanthus, switchgrass, and poplar). This processing yields sugars that can be subsequently converted to biofuels or biochemical. Material and energy consumption data from Aspen Plus were then compiled in a new Greenhouses Gases, Regulated Emissions, and Energy Use in Transportation (GREETTM) pretreatment module. The module estimates the cradle-to-gate fossil energy consumption (FEC) and greenhouse gas (GHG) emissions associated with producing fermentable sugars. This report documents the data and methodology used to develop this module and the cradle-to-gate FEC and GHG emissions that result from producing fermentable sugars.

  19. Quantitative velocity modulation spectroscopy

    Science.gov (United States)

    Hodges, James N.; McCall, Benjamin J.

    2016-05-01

    Velocity Modulation Spectroscopy (VMS) is arguably the most important development in the 20th century for spectroscopic study of molecular ions. For decades, interpretation of VMS lineshapes has presented challenges due to the intrinsic covariance of fit parameters including velocity modulation amplitude, linewidth, and intensity. This limitation has stifled the growth of this technique into the quantitative realm. In this work, we show that subtle changes in the lineshape can be used to help address this complexity. This allows for determination of the linewidth, intensity relative to other transitions, velocity modulation amplitude, and electric field strength in the positive column of a glow discharge. Additionally, we explain the large homogeneous component of the linewidth that has been previously described. Using this component, the ion mobility can be determined.

  20. Models for Modules

    CERN Document Server

    Troost, Jan

    2012-01-01

    We recall the structure of the indecomposable sl(2) modules in the Bernstein-Gelfand-Gelfand category O. We show that all these modules can arise as quantized phase spaces of physical models. In particular, we demonstrate in a path integral discretization how a redefined action of the sl(2) algebra over the complex numbers can glue finite dimensional and infinite dimensional highest weight representations into indecomposable wholes. Furthermore, we discuss how projective cover representations arise in the tensor product of finite dimensional and Verma modules and give explicit tensor product decomposition rules. The tensor product spaces can be realized in terms of product path integrals. Finally, we discuss relations of our results to brane quantization and cohomological calculations in string theory.

  1. Power module assembly

    Science.gov (United States)

    Campbell, Jeremy B [Torrance, CA; Newson, Steve [Redondo Beach, CA

    2011-11-15

    A power module assembly of the type suitable for deployment in a vehicular power inverter, wherein the power inverter has a grounded chassis, is provided. The power module assembly comprises a conductive base layer electrically coupled to the chassis, an insulating layer disposed on the conductive base layer, a first conductive node disposed on the insulating layer, a second conductive node disposed on the insulating layer, wherein the first and second conductive nodes are electrically isolated from each other. The power module assembly also comprises a first capacitor having a first electrode electrically connected to the conductive base layer, and a second electrode electrically connected to the first conductive node, and further comprises a second capacitor having a first electrode electrically connected to the conductive base layer, and a second electrode electrically connected to the second conductive node.

  2. Hollow dimension of modules

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    In this paper, we are interested in the following general question: Given a module Mwhich has finite hollow dimension and which has a finite collection of submodules Ki (1≤i≤n) such that M=K1+... +Kn, can we find an expression for the hollow dimension of Min terms of hollow dimensions of modules built up in some way from K1 Kn? We prove the following theorem:Let Mbe an amply supplemented module having finite hollow dimension and let Ki (1≤i≤n) be a finite collection of submodules of Msuch that M=K1+...+Kn. Then the hollow dimension h(M) of Mis the sum of the hollow dimensions of Ki (1≤i≤n) ifand only if Ki is a supplement of K1+...+Ki-1+Ki+1+...+Kn in Mfor each 1≤i≤n.

  3. Flat covers of modules

    CERN Document Server

    Xu, Jinzhong

    1996-01-01

    Since the injective envelope and projective cover were defined by Eckmann and Bas in the 1960s, they have had great influence on the development of homological algebra, ring theory and module theory. In the 1980s, Enochs introduced the flat cover and conjectured that every module has such a cover over any ring. This book provides the uniform methods and systematic treatment to study general envelopes and covers with the emphasis on the existence of flat cover. It shows that Enochs' conjecture is true for a large variety of interesting rings, and then presents the applications of the results. Readers with reasonable knowledge in rings and modules will not have difficulty in reading this book. It is suitable as a reference book and textbook for researchers and graduate students who have an interest in this field.

  4. Stirling Module Development Overview

    Science.gov (United States)

    Livingston, F. R.

    1984-01-01

    The solar parabolic dish Stirling engine electrically generating module consists of a solar collector coupled to a Stirling engine powered electrical generator. The module is designed to convert solar power to electrical power in parallel with numerous identical units coupled to an electrical utility power grid. The power conversion assembly generates up to 25 kilowatts at 480 volts potential/3 phase/alternating current. Piston rings and seals with gas leakage have not occurred, however, operator failures resulted in two burnt out receivers, while material fatigue resulted in a broken piston rod between the piston rod seal and cap seal.

  5. The Strip Module

    DEFF Research Database (Denmark)

    Pedersen, Tommy

    1996-01-01

    When the behaviour of a ship in waves is to be predicted it is convenient to have a tool which includes different approaches to the problem.The aim of this project is to develop such a tool named the strip theory module. The strip theory module will consist of submodules dependent on the I......-ship code available at the department. It will be structured as a general preprocessor mainly to determine the hydrodynamic mass and damping. A strip processor including three different theories: A linear frequency domain strip theory, a quadratic strip theory and a nonlinear time domain strip theory...

  6. Flexible programmable logic module

    Energy Technology Data Exchange (ETDEWEB)

    Robertson, Perry J. (Albuquerque, NM); Hutchinson, Robert L. (Albuquerque, NM); Pierson, Lyndon G. (Albuquerque, NM)

    2001-01-01

    The circuit module of this invention is a VME board containing a plurality of programmable logic devices (PLDs), a controlled impedance clock tree, and interconnecting buses. The PLDs are arranged to permit systolic processing of a problem by offering wide data buses and a plurality of processing nodes. The board contains a clock reference and clock distribution tree that can drive each of the PLDs with two critically timed clock references. External clock references can be used to drive additional circuit modules all operating from the same synchronous clock reference.

  7. Instant node package module

    CERN Document Server

    Ali, Juzer

    2013-01-01

    Get to grips with a new technology, understand what it is and what it can do for you, and then get to work with the most important features and tasks. A practical exploration of the lifecycle of creating node modules as well as learning all of the top features that npm has to offer.Intended for readers who want to create their first node.js modules. The programming paradigm of JavaScript is not covered so a foundation in these concepts would be beneficial.

  8. Lunar Module Illustration

    Science.gov (United States)

    1969-01-01

    This concept is a cutaway illustration of the Lunar Module (LM) with detailed callouts. The LM was a two part spacecraft. Its lower or descent stage had the landing gear, engines, and fuel needed for the landing. When the LM blasted off the Moon, the descent stage served as the launching pad for its companion ascent stage, which was also home for the two astronauts on the surface of the Moon. The LM was full of gear with which to communicate, navigate, and rendezvous. It also had its own propulsion system, and an engine to lift it off the Moon and send it on a course toward the orbiting Command Module.

  9. Pain and modulation processes

    Directory of Open Access Journals (Sweden)

    Ghaffarpoor M

    1997-08-01

    Full Text Available Pain is one of the most important and sometimes difficult problems, that patients and physicians are encountered. It may be clinically acute or chronic, acute pain has usually definite cause and favourable response to treatment. On the other hand there are difficulties in diagnosis and management of chronic pain. Peripheral and cranial nerves convey pain impulses toward central nervous system, and modulations take place at several levels. Diagnosis of different pains, including nociceptive, nerve trunk pain and deafferentation types is essential to acceptable management. In this article we review pain pathway, neurotransmitters and modulation.

  10. Photovoltaic module and interlocked stack of photovoltaic modules

    Science.gov (United States)

    Wares, Brian S.

    2012-09-04

    One embodiment relates to an arrangement of photovoltaic modules configured for transportation. The arrangement includes a plurality of photovoltaic modules, each photovoltaic module including a frame having at least a top member and a bottom member. A plurality of alignment features are included on the top member of each frame, and a plurality of alignment features are included on the bottom member of each frame. Adjacent photovoltaic modules are interlocked by the alignment features on the top member of a lower module fitting together with the alignment features on the bottom member of an upper module. Other embodiments, features and aspects are also disclosed.

  11. Paratransit: An Instructional Module.

    Science.gov (United States)

    Scalici, Anthony

    A concept-based introduction to paratransit is provided in this instructional module for undergraduate and graduate transportation-related courses for disciplines such as engineering, business, marketing, and technology. The concept of paratransit generally refers to modes of transportation other than mass transit and solo-driven automobiles. The…

  12. An Integrated Teaching Module.

    Science.gov (United States)

    Samuel, Marie R.; Seiferth, Berniece B.

    This integrated teaching module provides elementary and junior high school teachers with a "hands-on" approach to studying the Anasazi Indian. Emphasis is on creative exploration that focuses on integrating art, music, poetry, writing, geography, dance, history, anthropology, sociology, and archaeology. Replicas of artifacts,…

  13. Modelling the Photovoltaic Module

    DEFF Research Database (Denmark)

    Katsanevakis, Markos

    2011-01-01

    This paper refers into various ways in simulation the Photovoltaic (PV) module behaviour under any combination of solar irradiation and ambient temperature. There are three different approaches presented here briefly and one of them is chosen because of its good accuracy and relatively low...

  14. Multicultural Education Module.

    Science.gov (United States)

    Campbell-Whatley, Gloria D.

    The purpose of this multicultural education module is to provide faculty, teachers, and administrators with a resource that will aid them in creating an environment that is amenable to diverse social and cultural groups within U.S. school systems. The guide identifies current resources for addressing issues with respect to cultural diversity and…

  15. Transparent solar cell module

    Science.gov (United States)

    Antonides, G. J.; Dillard, P. A.; Fritz, W. M.; Lott, D. P.

    1979-01-01

    Modified solar cell module uses high transmission glass and adhesives, and heat dissipation to boost power per unit area by 25% (9.84% efficiency based on cell area at 60 C and 100 mW/sq cm flux). Design is suited for automatic production and is potentially more cost effective.

  16. Semi-projective modules

    Directory of Open Access Journals (Sweden)

    D. Döman

    1984-03-01

    Full Text Available It is well-known that the submodules of a projective module need not be projective. In this article we investigate a certain projectivity which is preserved under the taking of submodules. This property is used to characterize hereditary rings and QF rings.

  17. ALICE silicon strip module

    CERN Multimedia

    Maximilien Brice

    2006-01-01

    This small silicon detector strip will be inserted into the inner tracking system (ITS) on the ALICE detector at CERN. This detector relies on state-of-the-art particle tracking techniques. These double-sided silicon strip modules have been designed to be as lightweight and delicate as possible as the ITS will eventually contain five square metres of these devices.

  18. Scaling: An Items Module

    Science.gov (United States)

    Tong, Ye; Kolen, Michael J.

    2010-01-01

    "Scaling" is the process of constructing a score scale that associates numbers or other ordered indicators with the performance of examinees. Scaling typically is conducted to aid users in interpreting test results. This module describes different types of raw scores and scale scores, illustrates how to incorporate various sources of…

  19. Coplanar interconnection module

    Science.gov (United States)

    Steward, R. D.; Windsor, H. F.

    1970-01-01

    Module for interconnecting a semiconductor array to external leads or components incorporates a metal external heat sink for cooling the array. Heat sink, extending down from the molded block that supports the array, is immersed in a liquid nitrogen bath which is designed to maintain the desired array temperature.

  20. Fundamentals of spread spectrum modulation

    CERN Document Server

    Ziemer, Rodger E

    2007-01-01

    This lecture covers the fundamentals of spread spectrum modulation, which can be defined as any modulation technique that requires a transmission bandwidth much greater than the modulating signal bandwidth, independently of the bandwidth of the modulating signal. After reviewing basic digital modulation techniques, the principal forms of spread spectrum modulation are described. One of the most important components of a spread spectrum system is the spreading code, and several types and their characteristics are described. The most essential operation required at the receiver in a spread spect

  1. Lunar Module 5 mated with Spacecraft Lunar Module Adapter (SLA)

    Science.gov (United States)

    1969-01-01

    Interior view of the Kennedy Space Center's (KSC) Manned Spacecraft Operations Building showing Lunar Module 5 mated to its Spacecraft Lunar Module Adapter (SLA). LM-5 is scheduled to be flown on the Apollo 11 lunar landing mission.

  2. Prime Submodules and Flat Modules

    Institute of Scientific and Technical Information of China (English)

    A.AZIZI

    2007-01-01

    In this paper, some characterizations of prime submodules in fiat modules and, particularly,in free modules are given. Furthermore, the height of prime submodules and some saturated chain of prime submodules are also given.

  3. Generic ISIS Transport Module Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The purpose of the Generic ISIS Transport Module is to provide a means to bring living specimens to and from orbit. In addition to living specimens, the module can...

  4. Bent Electro-Absorption Modulator

    DEFF Research Database (Denmark)

    2002-01-01

    components and the applied electric field in relation to the frequency of the modulated radiation, the bending losses (and possibly coupling losses) will provide extinction of light guided by the bent waveguide section. The refractive index contract may be modulated while keeping the absorption coefficient...... substantially constant and small, whereby the guided light can be modulated only by bending losses. Alternatively, the invention may be applied to enhance the extinction ratio of existing absorption modulators such as Electro-Absorption Modulators (EAMs) in which case extinction by absorption and extinction......The present invention relates to a method and a device for modulating optical signals based on modulating bending losses in bend, quantum well semiconductor waveguide sections. The complex refractive index of the optical active semiconducting components of the waveguide section is modulated...

  5. Modulational instability of nematic phase

    Indian Academy of Sciences (India)

    T Mithun; K Porsezian

    2014-02-01

    We numerically observe the effect of homogeneous magnetic field on the modulationally stable case of polar phase in = 2 spinor Bose–Einstein condensates (BECs). Also we investigate the modulational instability of uniaxial and biaxial (BN) states of polar phase. Our observations show that the magnetic field triggers the modulational instability and demonstrate that irrespective of the magnetic field effect the uniaxial and biaxial nematic phases show modulational instability.

  6. On closed weak supplemented modules

    Institute of Scientific and Technical Information of China (English)

    ZENG Qing-yi; SHI Mei-hua

    2006-01-01

    A module M is called closed weak supplemented if for any closed submodule N of M, there is a submodule K of M such that M=K+N and K(c)N<<M. Any direct summand of closed weak supplemented module is also closed weak supplemented.Any nonsingular image of closed weak supplemented module is closed weak supplemented. Nonsingular V-rings in which all nonsingular modules are closed weak supplemented are characterized in Section 4.

  7. Stable local oscillator module.

    Energy Technology Data Exchange (ETDEWEB)

    Brocato, Robert Wesley

    2007-11-01

    This report gives a description of the development of a Stable Local Oscillator (StaLO) multi-chip module (MCM). It is a follow-on report to SAND2006-6414, Stable Local Oscillator Microcircuit. The StaLO accepts a 100MHz input signal and produces output signals at 1.2, 3.3, and 3.6 GHz. The circuit is built as a multi-chip module (MCM), since it makes use of integrated circuit technologies in silicon and lithium niobate as well as discrete passive components. This report describes the development of an MCM-based version of the complete StaLO, fabricated on an alumina thick film hybrid substrate.

  8. Silicon photonics: optical modulators

    Science.gov (United States)

    Reed, G. T.; Gardes, F. Y.; Hu, Youfang; Thomson, D.; Lever, L.; Kelsall, R.; Ikonic, Z.

    2010-01-01

    Silicon Photonics has the potential to revolutionise a whole raft of application areas. Currently, the main focus is on various forms of optical interconnects as this is a near term bottleneck for the computing industry, and hence a number of companies have also released products onto the market place. The adoption of silicon photonics for mass production will significantly benefit a range of other application areas. One of the key components that will enable silicon photonics to flourish in all of the potential application areas is a high performance optical modulator. An overview is given of the major Si photonics modulator research that has been pursued at the University of Surrey to date as well as a worldwide state of the art showing the trend and technology available. We will show the trend taken toward integration of optical and electronic components with the difficulties that are inherent in such a technology.

  9. Modulators of decision making.

    Science.gov (United States)

    Doya, Kenji

    2008-04-01

    Human and animal decisions are modulated by a variety of environmental and intrinsic contexts. Here I consider computational factors that can affect decision making and review anatomical structures and neurochemical systems that are related to contextual modulation of decision making. Expectation of a high reward can motivate a subject to go for an action despite a large cost, a decision that is influenced by dopamine in the anterior cingulate cortex. Uncertainty of action outcomes can promote risk taking and exploratory choices, in which norepinephrine and the orbitofrontal cortex appear to be involved. Predictable environments should facilitate consideration of longer-delayed rewards, which depends on serotonin in the dorsal striatum and dorsal prefrontal cortex. This article aims to sort out factors that affect the process of decision making from the viewpoint of reinforcement learning theory and to bridge between such computational needs and their neurophysiological substrates.

  10. Silicon Optical Modulator Simulation

    Directory of Open Access Journals (Sweden)

    Soon Thor LIM

    2015-04-01

    Full Text Available We developed a way of predicting and analyzing high speed optical modulator. Our research adopted a bottom-up approach to consider high-speed optical links using an eye diagram. Our method leverages on modular mapping of electrical characteristics to optical characteristics, while attaining the required accuracy necessary for device footprint approaching sub-micron scales where electrical data distribution varies drastically. We calculate for the bias dependent phase shift (2pi/mm and loss (dB/mm for the optical modulator based on the real and imaginary part of complex effective indices. Subsequently, combine effectively both the electrical and optical profiles to construct the optical eye diagram which is the essential gist of signal integrity of such devices.

  11. NEUROBIOLOGICAL MODULATORS OF ANXIETY

    Directory of Open Access Journals (Sweden)

    Mohale Deepak S.

    2012-01-01

    Full Text Available Anxiety can be a core symptom of various mental/ behavioral disorders such as major depressive disorders, obsessive-compulsive disorders, panic disorder, adaptive disorder, post-traumatic stress disorder, social withdrawal disorder, and various phobias. The neuroanatomic circuits that support fear and anxiety behavior are modulated by a variety of neurochemicals, these include the peptidergic neurotransmitters, Corticotrophin releasing factor (CRF, neuropeptide Y (NPY, and substance P, the monoaminergic transmitters, Norepinephrine (NE, serotonin (5-hydroxytryptamine or 5-HT, and dopamine (DA, and the amino acid transmitters, Gamma Aminobuteric Acid (GABA and glutamate and many more. These neurochemical systems subserve important adaptive functions in preparing the organism for responding to threat or stress, by increasing vigilance, modulating memory, mobilizing energy stores, and elevating cardiovascular function. Nevertheless, these biological responses to threat and stress can become maladaptive if they are chronically or inappropriately activated.

  12. Silicon optical modulators

    Directory of Open Access Journals (Sweden)

    Graham T. Reed

    2005-01-01

    Full Text Available Ever since the earliest research on optical circuits, dating back to the 1970s, there have been visions of an optical superchip (see for example1,2, containing a variety of integrated optical components to carry out light generation, modulation, manipulation, detection, and amplification (Fig. 1. The early work was associated with ferroelectric materials such as lithium niobate (LiNbO3, and III-V semiconductors such as gallium arsenide (GaAs and indium phosphide (InP based systems. LiNbO3 was interesting almost solely because of the fact that it possesses a large electro-optic coefficient3, enabling optical modulation via the Pockels effect. Alternatively, the III-V compounds were interesting because of the relative ease of laser fabrication and the prospect of optical and electronic integration.

  13. Modulation instability: The beginning

    Science.gov (United States)

    Noskov, Roman; Belov, Pavel; Kivshar, Yuri

    2012-11-01

    The study of metal nanoparticles plays a central role in the emerging novel technologies employing optics beyond the diffraction limit. Combining strong surface plasmon resonances, high intrinsic nonlinearities and deeply subwavelength scales, arrays of metal nanoparticles offer a unique playground to develop novel concepts for light manipulation at the nanoscale. Here we suggest a novel principle to control localized optical energy in chains of nonlinear subwavelength metal nanoparticles based on the fundamental nonlinear phenomenon of modulation instability. In particular, we demonstrate that modulation instability can lead to the formation of long-lived standing and moving nonlinear localized modes of several distinct types such as bright and dark solitons, oscillons, and domain walls. We analyze the properties of these nonlinear localized modes and reveal different scenarios of their dynamics including transformation of one type of mode to another. We believe this work paves a way towards the development of nonlinear nanophotonics circuitry.

  14. Digital Communication and Modulation

    DEFF Research Database (Denmark)

    Sørensen, John Aasted

    2011-01-01

    The course presents the fundamental principles for digital communication, e.g. fixed-wire modems or wireless communication channels, as applied in mobile phones, wireless computer networks or wireless systems in intelligent houses. Based on the functional blocks of a digital communication system...... system. Having passed the course, the student will be able to accomplish the following, within the areas shown below: Model for Communication System. Prepare and explain the functional block in a digital communication system, corresponding to the specific course contents. Model for Communication Channel....... Prepare and explain a model for a communication channel, corresponding to the specific course contents. Modulation Methods. Explain the properties of digital modulation methods, corresponding to the specific course contents. Intersymbol Interference. Explain intersymbol inteference, corresponding...

  15. A Scalable Module System

    CERN Document Server

    Rabe, Florian

    2011-01-01

    Symbolic and logic computation systems ranging from computer algebra systems to theorem provers are finding their way into science, technology, mathematics and engineering. But such systems rely on explicitly or implicitly represented mathematical knowledge that needs to be managed to use such systems effectively. While mathematical knowledge management (MKM) "in the small" is well-studied, scaling up to large, highly interconnected corpora remains difficult. We hold that in order to realize MKM "in the large", we need representation languages and software architectures that are designed systematically with large-scale processing in mind. Therefore, we have designed and implemented the MMT language -- a module system for mathematical theories. MMT is designed as the simplest possible language that combines a module system, a foundationally uncommitted formal semantics, and web-scalable implementations. Due to a careful choice of representational primitives, MMT allows us to integrate existing representation l...

  16. Lightweight Trauma Module - LTM

    Science.gov (United States)

    Hatfield, Thomas

    2008-01-01

    Current patient movement items (PMI) supporting the military's Critical Care Air Transport Team (CCATT) mission as well as the Crew Health Care System for space (CHeCS) have significant limitations: size, weight, battery duration, and dated clinical technology. The LTM is a small, 20 lb., system integrating diagnostic and therapeutic clinical capabilities along with onboard data management, communication services and automated care algorithms to meet new Aeromedical Evacuation requirements. The Lightweight Trauma Module is an Impact Instrumentation, Inc. project with strong Industry, DoD, NASA, and Academia partnerships aimed at developing the next generation of smart and rugged critical care tools for hazardous environments ranging from the battlefield to space exploration. The LTM is a combination ventilator/critical care monitor/therapeutic system with integrated automatic control systems. Additional capabilities are provided with small external modules.

  17. Module Utilization Committee. Final report

    Energy Technology Data Exchange (ETDEWEB)

    None

    1984-03-01

    Photovoltaic collector modules were declared surplus to the needs of the US Department of Energy. The Module Utilization Committee was formed to make appropriate disposition of the surplus modules. The final report of that committee accounts for that disposition. The membership and activities of the committee are set forth and the results of its activities are reported.

  18. -k-torsionfree modules and

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The notion of ω-k-torsionfree modules with respect to a bimoduleω is introduced, which is characterized in terms of left addR ω-approximations. The notion of ω-left approximation dimension is introduced, and the forms of k-syzygy modules being k-torsionfree modules are described.

  19. Security Requirements for Cryptographic Modules

    Science.gov (United States)

    1999-01-01

    module interfaces; roles, services, and authentication; finite state machine model ; physical security; operating system security; cryptographic key...15 4.4 Finite State Machine Model .......................................................................................................... 17...These areas include cryptographic module specification; module interfaces; roles, services, and authentication; finite state machine model ; physical

  20. Higher Level Orderings on Modules

    Institute of Scientific and Technical Information of China (English)

    Min WU; Guang Xing ZENG

    2005-01-01

    The aim of this paper is to investigate higher level orderings on modules over commutative rings. On the basis of the theory of higher level orderings on fields and commutative rings, some results involving existence of higher level orderings are generalized to the category of modules over commutative rings. Moreover, a strict intersection theorem for higher level orderings on modules is established.

  1. FERMI multi-chip module

    CERN Multimedia

    This FERMI multi-chip module contains five million transistors. 25 000 of these modules will handle the flood of information through parts of the ATLAS and CMS detectors at the LHC. To select interesting events for recording, crucial decisions are taken before the data leaves the detector. FERMI modules are being developed at CERN in partnership with European industry.

  2. of Banach modules

    Directory of Open Access Journals (Sweden)

    Anousheh Fatemeh

    2015-10-01

    Full Text Available Let A be a Banach algebra, E be a Banach A-bimodule and Δ E → A be a bounded Banach A-bimodule homomorphism. It is shown that under some mild conditions, the weakΔ''-amenability of E'' (as an A''-bimodule necessitates weak Δ-amenability of E (as an A-bimodule. Some examples of weak-amenable Banach modules are provided as well.

  3. NEUROBIOLOGICAL MODULATORS OF ANXIETY

    OpenAIRE

    Mohale Deepak S.; Tripathi Alok S.; Wadhwani Paresh J.; Shrirao Abhijit V.; Chandewar Anil V.

    2012-01-01

    Anxiety can be a core symptom of various mental/ behavioral disorders such as major depressive disorders, obsessive-compulsive disorders, panic disorder, adaptive disorder, post-traumatic stress disorder, social withdrawal disorder, and various phobias. The neuroanatomic circuits that support fear and anxiety behavior are modulated by a variety of neurochemicals, these include the peptidergic neurotransmitters, Corticotrophin releasing factor (CRF), neuropeptide Y (NPY), and substance P, the ...

  4. Sparx PCA Module

    Energy Technology Data Exchange (ETDEWEB)

    2017-04-25

    Sparx, a new environment for Cryo-EM image processing; Cryo-EM, Single particle reconstruction, principal component analysis; Hardware Req.: PC, MAC, Supercomputer, Mainframe, Multiplatform, Workstation. Software Req.: operating system is Unix; Compiler C++; type of files: source code, object library, executable modules, compilation instructions; sample problem input data. Location/transmission: http://sparx-em.org; User manual & paper: http://sparx-em.org;

  5. Modulation instability: The beginning

    Science.gov (United States)

    Zakharov, V. E.; Ostrovsky, L. A.

    2009-03-01

    We discuss the early history of an important field of “sturm and drang” in modern theory of nonlinear waves. It is demonstrated how scientific demand resulted in independent and almost simultaneous publications by many different authors on modulation instability, a phenomenon resulting in a variety of nonlinear processes such as envelope solitons, envelope shocks, freak waves, etc. Examples from water wave hydrodynamics, electrodynamics, nonlinear optics, and convection theory are given.

  6. Packaging the MAMA module

    Science.gov (United States)

    Seals, J. Dennis

    1994-10-01

    The MAMA (Mixed Arithmetic, Multiprocessing Array) module is being developed to evaluate new packaging technologies and processing paradigms for advanced military processing systems. The architecture supports a tight mix of signal, data,and I/O processing at GFLOP throughput rates. It is fabricated using only commercial-on-the-sehlf (COTS) chips and will provide a high level of durability. Its attributes are largely the result of two new interconnection and packaging technologies. Chip-in-board packaging is used to reduce local x-y communication delays and solder joints, while significantly improving board-level packaging density. A unique 3-D interconnection technology called a cross-over cell has been developed to reduce board-to-board communication delays, drive power, glue logic, and card-edge pin-outs. These technologies enable true 3-D structures that are form, fit and connector compatible with conventional line-replacable modules. The module's design rational, packaging technology, and basic architecture will be presented in this paper.

  7. Solar Module Fabrication

    Directory of Open Access Journals (Sweden)

    A. El Amrani

    2007-01-01

    Full Text Available One of the most important steps in the photovoltaic industry is the encapsulation of the solar cells. It consists to connect the cells in order to provide useful power for any application and also protect them from environmental damages which cause corrosion, and mechanical shocks. In this paper, we present the encapsulation process we have developed at Silicon Technology Unit (UDTS for monocrystalline silicon solar cells. We will focus particularly on the thermal treatment, the most critical step in the process, which decides on the quality and the reliability of the module. This thermal treatment is conducted in two steps: the lamination and the polymerization. Several tests of EVA reticulation have been necessary for setting technological parameters such as the level of vacuum, the pressure, the temperature, and the time. The quality of our process has been confirmed by the tests conducted on our modules at the European Laboratory of Joint Research Centre (JRC of ISPRA (Italy. The electrical characterization of the modules has showed that after the encapsulation the current has been improved by a factor of 4% to 6% and the power gain by a factor of 4% to 7%. This is mainly due to the fact of using a treated glass, which reduces the reflection of the light at a level as low as 8%.

  8. Modulation masking produced by complex-tone modulators

    DEFF Research Database (Denmark)

    Ewert, Stephan; Verhey, J.L.; Dau, Torsten

    2003-01-01

    Thresholds were measured for detecting sinusoidal amplitude modulation in the presence of a complex-tone masker modulation. Both modulations were applied to the same sinusoidal carrier. Two different masker modulations were used: (i) a pair of components beating at the difference frequency and (ii......) a three-tone complex producing a sinusoidal amplitude modulation of the modulation depth at the difference frequency between adjacent components. Both maskers show a periodicity in the waveform that is not contained in the envelope spectrum itself but can be observed when the envelope of the envelope......, referred to as the "venelope" [Ewert et al., J. Acoust. Soc. Am. 112. 2921-2931 (2002)], is calculated. For a signal frequency equal to the masker-venelope periodicity, modulation depth at threshold was measured as a function of the signal phase relative to the phase of the masker-venelope component...

  9. WAVELET ANALYSIS OF MODULATED SIGNALS

    Institute of Scientific and Technical Information of China (English)

    Hu Jianwei; Yang Shaoquan

    2006-01-01

    The relationship between Haar wavelet decomposition coefficients and modulated signal parameters is discussed. A new modulation classification method is presented. The new method uses the amplitude,frequency and phase information derived from Haar wavelet decomposition as feature vectors to distinguish the modulation types of M-ary Frequency-Shift Keying (MFSK), M-ary Phase-Shift Keying (MPSK) and Quadrature Amplitude Modulation (QAM) modulation types. A parallel combined classifier is designed based on these feature vectors. The overall successful recognition rate of 92.4% can be achieved even at a low Signal-to-Noise Ratio (SNR) of 5dB.

  10. Extension closure of relative syzygy modules

    Institute of Scientific and Technical Information of China (English)

    HUANG; Zhaoyong(黄兆泳)

    2003-01-01

    In this paper we introduce the notion of relative syzygy modules. We then study the extensionclosure of the category of modules consisting of relative syzygy modules (resp. relative k-torsionfree modules).

  11. On staggered indecomposable Virasoro modules

    Energy Technology Data Exchange (ETDEWEB)

    Kytoelae, Kalle [Geneve Univ. (Switzerland); Ridout, David [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2009-06-15

    In this article, certain indecomposable Virasoro modules are studied. Specifically, the Virasoro mode L0 is assumed to be non-diagonalisable, possessing Jordan blocks of rank two. Moreover, the module is further assumed to have a highest weight submodule, the ''left module'', and that the quotient by this submodule yields another highest weight module, the ''right module''. Such modules, which have been called staggered, have appeared repeatedly in the logarithmic conformal field theory literature, but their theory has not been explored in full generality. Here, such a theory is developed for the Virasoro algebra using rather elementary techniques. The focus centres on two different but related questions typically encountered in practical studies: How can one identify a given staggered module, and how can one demonstrate the existence of a proposed staggered module. Given just the values of the highest weights of the left and right modules, themselves subject to simple necessary conditions, invariants are defined which together with the knowledge of the left and right modules uniquely identify a staggered module. The possible values of these invariants form a vector space of dimension zero, one or two, and the structures of the left and right modules limit the isomorphism classes of the corresponding staggered modules to an affine subspace (possibly empty). The number of invariants and affine restrictions is purely determined by the structures of the left and right modules. Moreover, in order to facilitate applications, the expressions for the invariants and restrictions are given by formulae as explicit as possible (they generally rely on expressions for Virasoro singular vectors). Finally, the text is liberally peppered throughout with examples illustrating the general concepts. These have been carefully chosen for their physical relevance or for the novel features they exhibit. (orig.)

  12. On staggered indecomposable Virasoro modules

    Science.gov (United States)

    Kytölä, Kalle; Ridout, David

    2009-12-01

    In this article, certain indecomposable Virasoro modules are studied. Specifically, the Virasoro mode L0 is assumed to be nondiagonalizable, possessing Jordan blocks of rank 2. Moreover, the module is further assumed to have a highest weight submodule, the "left module," and that the quotient by this submodule yields another highest weight module, the "right module." Such modules, which have been called staggered, have appeared repeatedly in the logarithmic conformal field theory literature, but their theory has not been explored in full generality. Here, such a theory is developed for the Virasoro algebra using rather elementary techniques. The focus centers on two different but related questions typically encountered in practical studies: How can one identify a given staggered module, and how can one demonstrate the existence of a proposed staggered module. Given just the values of the highest weights of the left and right modules, themselves subject to simple necessary conditions, invariants are defined which together with the knowledge of the left and right modules uniquely identify a staggered module. The possible values of these invariants form a vector space of dimension 0, 1, or 2, and the structures of the left and right modules limit the isomorphism classes of the corresponding staggered modules to an affine subspace (possibly empty). The number of invariants and affine restrictions is purely determined by the structures of the left and right modules. Moreover, in order to facilitate applications, the expressions for the invariants and restrictions are given by formulas as explicit as possible (they generally rely on expressions for Virasoro singular vectors). Finally, the text is liberally peppered throughout with examples illustrating the general concepts. These have been carefully chosen for their physical relevance or for the novel features they exhibit.

  13. DEMODULATION OF FREQUENCY OR SPACE MODULATED LIGHT.

    Science.gov (United States)

    LIGHT , DEMODULATION), (*OPTICAL COMMUNICATIONS, FREQUENCY MODULATION), (*FREQUENCY MODULATION, LIGHT ), OPTICAL TRACKING, BEAMS(ELECTROMAGNETIC), DEFLECTION, MICROWAVE FREQUENCY, ELECTRON BEAMS, PHOTOCATHODES

  14. Perfusion Bioreactor Module

    Science.gov (United States)

    Morrison, Dennis R.

    1990-01-01

    Perfusion bioreactor module, self-contained, closed-loop cell-culture system that operates in microgravity or on Earth. Equipment supports growth or long-term maintenance of cultures of human or other fragile cells for experiments in basic cell biology or process technology. Designed to support proliferation (initially at exponential rates of growth) of cells in complex growth medium and to maintain confluent cells in defined medium under conditions optimized to permit or encourage selected functions of cells, including secretion of products of cells into medium.

  15. Modulation of whistlers

    Science.gov (United States)

    Sivokon', V. P.; Bogdanov, V. V.; Druzhin, G. I.; Cherneva, N. V.; Kubyshkin, A. V.; Sannikov, D. V.; Agranat, I. V.

    2014-11-01

    Analysis of the experimental data obtained at Paratunka observatory (53.02° N, 158.65° E; L = 2.3) has revealed a nonstandard form of whistlers involving spectral lines that are symmetric with respect to the whistler. We have shown that this form is most likely due to the amplitude modulation of whistlers by electromagnetic pulses with a length of around 1 s and carrier frequency of around 1.1 kHz. We have suggested that these pulses could be emitted by the auroral electrojet modified by heating radiation from the HAARP facility (62.30° N, 145.30° W; L > 4.2).

  16. Galois module structure

    CERN Document Server

    Snaith, Victor P

    1994-01-01

    Galois module structure deals with the construction of algebraic invariants from a Galois extension of number fields with group G. Typically these invariants lie in the class-group of some group-ring of G or of a related order. These class-groups have "Hom-descriptions" in terms of idèlic-valued functions on the complex representations of G. Following a theme pioneered by A. Frölich, T. Chinburg constructed several invariants whose Hom-descriptions are (conjecturally) given in terms of Artin root numbers. For a tame extension, the second Chinburg invariant is given by the ring of integers, and

  17. CDC 7600 Module

    CERN Multimedia

    1970-01-01

    The CDC 7600 has been created by Seymour Cray. It was designed to be compatible with the 6600, which allows for a substantial increase in performance. Furthermore the rise of new technologies has enabled this performance by reducing the minor cycle clock period from 100 ns to 27.5 ns (4 time faster). A very large machine, the 7600 had over 120 miles of hand-wired interconnections. It was the most powerful computer of its time. However, this speed caused a ground-loop problem causing intermittent faults, and eventually requiring all modules to be fitted with sheathed rubber bands. The CDC 7600 was replaced in 1983 by CRAY-1A.

  18. Rigidity of tilting modules

    DEFF Research Database (Denmark)

    Let $U_q$ denote the quantum group associated with a finite dimensional semisimple Lie algebra. Assume that $q$ is a complex root of unity of odd order and that $U_q$ is %the quantum group version obtained via Lusztig's $q$-divided powers construction. We prove that all regular projective (tilting......$ and in this case as well as for type $A_2$ we calculate explicitly the Loewy structure for all regular Weyl modules. We also demonstrate that these results carry over to the modular case when the highest weights in question are in the so-called Jantzen region. At the same time we show by examples that as soon...

  19. On indecomposable modules over the Virasoro algebra

    Institute of Scientific and Technical Information of China (English)

    苏育才

    2001-01-01

    It is proved that an indecomposable Harish-Chandra module over the Virasoro algebra must be (i) a uniformly bounded module, or (ii) a module in Category , or (iii) a module in Category , or (iv) a module which contains the trivial module as one of its composition factors.

  20. Modulation masking produced by second-order modulators

    DEFF Research Database (Denmark)

    Füllgrabe, Christian; Moore, Brian C.J.; Demany, Laurent;

    2005-01-01

    Recent studies suggest that an auditory nonlinearity converts second-order sinusoidal amplitude modulation (SAM) (i.e., modulation of SAM depth) into a first-order SAM component, which contributes to the perception of second-order SAM. However, conversion may also occur in other ways......-carrier modulation frequency, phase relationship between the probe and masker modulator, and probe modulation depth. In experiment 1, the carrier was a 5-kHz sinusoid presented either alone or within a notched-noise masker in order to restrict off-frequency listening. In experiment 2, the carrier was a white noise....... The data obtained in both carrier conditions are consistent with the existence of a modulation distortion component. However, the phase yielding poorest detection performance varied across experimental conditions between 0° and 180°, confirming that, in addition to nonlinear mechanisms, cochlear filtering...

  1. Observation of Modulation Transfer Spectroscopy in the Deep Modulation Regime

    Institute of Scientific and Technical Information of China (English)

    ZHOU Zi-Chao; WEI Rong; SHI Chun-Yan; WANG Yu-Zhu

    2010-01-01

    @@ We observe the modulation transfer spectroscopy on the D2 line of87 Rb in a rubidium cell with acoustic-optic modulator in the deep modulation regime.In this regime,the sidebands of the pump beam are involved in the four-wave mixing processes,which increase the signM gradients and the peak-to-peak amplitudes of both the absorption and dispersion components.

  2. Emissivity modulating electrochromic device

    Science.gov (United States)

    Demiryont, Hulya; Shannon, Kenneth C., III; Sheets, Judd

    2009-05-01

    The IR-ECDTM (Infra-Red ElectroChromic Device) variable emitance device (VED) is an all-solid-state monolithic vacuum deposited thin film system with a unique metamaterial IR transparent-electrode system which functions as an electrically controlled dimmable mirror in the IR region. The maximum reflectance corresponding to the bleached condition of the system is around 90% (low-e condition, e=0.1). The minimum reflectance reaches nearly zero in the colored condition of the system (high emittance, e=1). The average emissivity modulation of the IRECDTM is 0.7 in the 8-12 micron region, and at 9.7 micron (room temperature) it reaches a value of 0.9. Half and full emissivity modulations occur within 2 and10 minutes respectively. Because of its light weight (5g/m2), low voltage requirement (+/- 1 Volts), extremely good emissivity control properties (from 0 to 0.9 at 300K) and highly repeatable deposition process, the IR-ECDTM technology is very attractive for satellite thermal control applications. The IR-ECDTM has been under evaluation in a real space environment since March 8, 2007. This paper presents recent achievements of the IR-ECDTM including space test results.

  3. Photodynamic immune modulation (PIM)

    Science.gov (United States)

    North, John R.; Hunt, David W. C.; Simkin, Guillermo O.; Ratkay, Leslie G.; Chan, Agnes H.; Lui, Harvey; Levy, Julia G.

    1999-09-01

    Photodynamic Therapy (PDT) is accepted for treatment of superficial and lumen-occluding tumors in regions accessible to activating light and is now known to be effective in closure of choroidal neovasculature in Age Related Macular Degeneration. PDT utilizes light absorbing drugs (photosensitizers) that generate the localized formation of reactive oxygen species after light exposure. In a number of systems, PDT has immunomodulatory effects; Photodynamic Immune Modulation (PIM). Using low- intensity photodynamic regimens applied over a large body surface area, progression of mouse autoimmune disease could be inhibited. Further, this treatment strongly inhibited the immunologically- medicated contact hypersensitivity response to topically applied chemical haptens. Immune modulation appears to result from selective targeting of activated T lymphocytes and reduction in immunostimulation by antigen presenting cells. Psoriasis, an immune-mediated skin condition, exhibits heightened epidermal cell proliferation, epidermal layer thickening and plaque formation at different body sites. In a recent clinical trial, approximately one-third of patients with psoriasis and arthritis symptoms (psoriatic arthritis) displayed a significant clinical improvement in several psoriasis-related parameters after four weekly whole-body PIM treatments with verteporfin. The safety profile was favorable. The capacity of PIM to influence other human immune disorders including rheumatoid arthritis is under extensive evaluation.

  4. OH Module Assembly Stand

    Energy Technology Data Exchange (ETDEWEB)

    Bolan, P.J.; /Fermilab

    1990-10-16

    There is an OR module assembly stand in use at IB4. This design has been approved by safety, as presented by Mike Foley, and has been successfully used. Another one is needed at the D-zero assembly building, but some modifications need to be made. This report will show that the new modified design is at least as strong, if not stronger, than the older IB4 design in every aspect. Since the weight distribution of the OR modules on the sling is indeterminate, this report compares three cases of support for the entire assembly: the lowest two beams only, the lowest four beams only, and all six beams. In each of these cases, the new design is stronger than the old design in maximum allowable weight. The ability of the the cradle to support the weight is also shown. For all of the failure conditions except for two, the cradle is stronger than the beams that it supports. In the two excepted situations, the calculated limit of the cradle is less than the beams it supports. This is because no credit is taken for the sling and strongback, which in reality will relieve much of the horizontal load.

  5. Apparatuses to support photovoltaic modules

    Energy Technology Data Exchange (ETDEWEB)

    Ciasulli, John; Jones, Jason

    2017-08-22

    Methods and apparatuses to support photovoltaic ("PV") modules are described. A saddle bracket has a mounting surface to support one or more PV modules over a tube, a gusset coupled to the mounting surface, and a mounting feature coupled to the gusset to couple to the tube. A grounding washer has a first portion to couple to a support; and a second portion coupled to the first portion to provide a ground path to a PV module. A PV system has a saddle bracket; a PV module over the saddle bracket; and a grounding washer coupled to the saddle bracket and the PV module. Saddle brackets can be coupled to a torque tube at predetermined locations. PV modules can be coupled to the saddle brackets.

  6. Polarisation Encryption/Decryption Module

    DEFF Research Database (Denmark)

    2002-01-01

    A polarisation encryption/decryption module comprising at least two array based modulating devices, preferably spatial light modulators (SLMs), at least one array based intensity detector, and at least one source of electromagnetic radiation. A local region of information displayed on a first of ...... rapidly. May be used for real time encryption/decryption of motion pictures. Further, a method of polarisation encrypting and decrypting information. The encryption/decryption is performed optically while the communication is performed electronically....

  7. Photovoltaic concentrator module improvements study

    Energy Technology Data Exchange (ETDEWEB)

    Levy, S.L.; Kerschen, K.A. (Black and Veatch, Kansas City, MO (United States)); Hutchison, G. (Solar Kinetics, Inc., Dallas, TX (United States)); Nowlan, M.J. (Spire Corp., Bedford, MA (United States))

    1991-08-01

    This report presents results of a project to design and fabricate an improved photovoltaic concentrator module. Using previous work as a baseline, this study conducted analyses and testing to select major module components and design features. The lens parquet and concentrator solar cell were selected from the highest performing, available components. A single 185X point-focus module was fabricated by the project team and tested at Sandia. Major module characteristics include a 6 by 4 compression-molded acrylic lens parquet (0.737 m{sup 2} area), twenty-four 0.2 ohms-cm, FZ, p-Si solar cells (1.56 cm{sup 2} area) soldered to ceramic substrates and copper heat spreaders, and an aluminized steel housing with corrugated bottom. This project marked the first attempt to use prismatic covers on solar cells in a high-concentration, point-focus application. Cells with 15 percent metallization were obtained, but problems with the fabrication and placement of prismatic covers on these cells lead to the decision not to use covers in the prototype module. Cell assembly fabrication, module fabrication, and module optical design activities are presented here. Test results are also presented for bare cells, cell assemblies, and module. At operating conditions of 981 watts/m{sup 2} DNI and an estimated cell temperature of 65{degrees}C, the module demonstrated an efficiency of 13.9 percent prior to stressed environmental exposure. 12 refs., 56 figs., 7 tabs.

  8. PENGEMBANGAN MODUL KEWIRAUSAHAAN DI SMK

    Directory of Open Access Journals (Sweden)

    Wening Patmi Rahayu

    2016-02-01

    Abstrak: Pengembangan Modul Kewirausahaan di SMK. Penelitian ini bertujuan untuk menghasilkan modul kewirausahaan SMK yang siap pakai. Penelitian pengembangan dilakukan di empat SMK negeri dan swasta, kabupaten dan kota Malang dalam dua tahap. Hasilnya menunjukkan bahwa modul kewirausahaan untuk siswa dan panduan pembelajaran kewirausahaan untuk guru kelas satu dan kelas dua SMK telah siap pakai, karena memenuhi unsur  efektif, efisien, layak, individualized, dan aplicable. Modul dan panduan ini dapat digunakan sebagai salah satu media peningkatan kemampuan guru pengajar mata diklat kewirausahaan, dan sebagai salah satu metode pembelajaran modular yang sesuai dengan tuntutan kurikulum.

  9. Strongly Irreducible Submodules of Modules

    Institute of Scientific and Technical Information of China (English)

    A. KHAKSARI; M. ERSHAD; H. SHARIF

    2006-01-01

    Strongly irreducible submodules of modules are defined as follows: A submodule N of an R-module M is said to be strongly irreducible if for submodules L and K of M, the inclusion L ∩ K (∈) TV implies that either L (∈) N or K (∈) N. The relationship among the families of irreducible, strongly irreducible, prime and primary submodules of an .R-module M is considered, and a characterization of Noetherian modules which contain a non-prime strongly irreducible submodule is given.

  10. Multichip module technology development

    Energy Technology Data Exchange (ETDEWEB)

    Kapustinsky, J.S.; Boissevain, J.G.; Muck, R.C.; Smith, G.D.; Wong-Swanson, B.G.; Ziock, H.J.

    1997-10-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). A Multichip Module (MCM) was designed and submitted for fabrication to the Lockheed Martin foundry using a licensed process called High Density Interconnect (HDI). The HDI process uses thin film techniques to create circuit interconnect patterns on multiple layers of dielectric film which are deposited directly on top of unpackaged electronic die. This results in an optimally small package that approaches the area of the bare die themselves. This project tested the capability of the Lockheed Martin foundry to produce, in an HDI process, a complex mixed-mode (analog and digital) circuit on a single MCM substrate.

  11. Neuroinflammatory modulators of oligodendrogenesis

    Directory of Open Access Journals (Sweden)

    Ana Armada-Moreira

    2015-01-01

    Full Text Available Oligodendrocytes are key neural cells that are responsible for producing myelin sheaths that wrap around neuronal axons in the central nervous system. Myelin is essential to insulate neurons and maintain a fast and saltatory propagation of action potentials along the axon. However, oligodendrocytes are very susceptible to damage, and thus demyelination may arise from a brain lesion or a neurodegenerative disorder. Consequently, demyelination produces a loss of axonal insulation leading to sensory or motor neuron failure. During adulthood, there are two main sources of oligodendrocytes: parenchymal oligodendrocyte precursor cells (OPCs and subventricular zone derived OPCs. In this review, we will discuss oligodendrogenesis derived from these two sources, and also highlight their main extrinsic and intrinsic modulators. In addition, the neuroinflammatory mediators of oligodendrogenesis will also be assessed.

  12. Modulating aging and longevity

    DEFF Research Database (Denmark)

    Rattan, Suresh

    Provides information and an evaluation of a variety of approaches tried for modulating aging and longevity, including dietary supplementation with antioxidants, vitamins and hormones, genetic engineering, life-style alterations, and hormesis through mild stress. After decades of systematic...... collection of data describing age-related changes in organisms, organs, tissues, cells and macromolecules, biogerontologists are now in a position to construct general principles of ageing and explore various possibilities of intervention using rational approaches. While not giving serious consideration...... to the claims made by charlatans, it cannot be ignored that several researchers are making genuine attempts to test and develop various means of intervention for the prevention and treatment of age-related diseases, for regaining the functional abilities and for prolonging the lifespan of experimental organisms...

  13. Terrestrial solar modules

    Science.gov (United States)

    Sampson, W.; Olah, S.

    Processing methods and materials for the fabrication of solar cell modules are reviewed. It is noted that current production favors copper, particularly in mesh form, as the cell interconnect material due to suitability for stress relief configurations to offset the effects of thermal expansion and deficiencies in the bond between copper and Si. Ethylene vinyl/acetate is preferred to polyvinyl butyral as an encapsulant because it is also a dry film and adheres at low temperature without requiring a pressure bond. The thermal cycling parameters have been set at -40 to 90 C, and tempered low iron, high transmission, water white glass is used as the superstrate. A conceptual design for an automated production of the encapsulated cells is outlined, including the ability to make front and back interconnects and achieve accurate soldering due to the precise location of the solar cells in the process.

  14. Digital Communication and Modulation

    DEFF Research Database (Denmark)

    Sørensen, John Aasted

    2011-01-01

    system.   Sessions in class with active participation by the students. The time will be divided between lectures and the students solving problems, including simulating digital communication building blocks in Matlab. Combines lectures and hands-on work. Semester: E2011 Extent: 7.5 ects......The course presents the fundamental principles for digital communication, e.g. fixed-wire modems or wireless communication channels, as applied in mobile phones, wireless computer networks or wireless systems in intelligent houses. Based on the functional blocks of a digital communication system......, the fundamental principles for modulation and detection in Gaussian noise is treated. This includes the principles for the determination of the bit-error rate for a digital communication system. During the course, a selection of small Matlab exercises are prepared, for simulation of parts of a communication...

  15. Digital Communication and Modulation

    DEFF Research Database (Denmark)

    Sørensen, John Aasted

    2011-01-01

    The course presents the fundamental principles for digital communication, e.g. fixed-wire modems or wireless communication channels, as applied in mobile phones, wireless computer networks or wireless systems in intelligent houses. Based on the functional blocks of a digital communication system......, the fundamental principles for modulation and detection in Gaussian noise is treated. This includes the principles for the determination of the bit-error rate for a digital communication system. During the course, a selection of small Matlab exercises are prepared, for simulation of parts of a communication...... system. Having passed the course, the student will be able to accomplish the following, within the areas shown below: Model for Communication System. Prepare and explain the functional block in a digital communication system, corresponding to the specific course contents. Model for Communication Channel...

  16. Photovoltaic module mounting system

    Science.gov (United States)

    Miros, Robert H. J.; Mittan, Margaret Birmingham; Seery, Martin N.; Holland, Rodney H.

    2012-04-17

    A solar array mounting system having unique installation, load distribution, and grounding features, and which is adaptable for mounting solar panels having no external frame. The solar array mounting system includes flexible, pedestal-style feet and structural links connected in a grid formation on the mounting surface. The photovoltaic modules are secured in place via the use of attachment clamps that grip the edge of the typically glass substrate. The panel mounting clamps are then held in place by tilt brackets and/or mid-link brackets that provide fixation for the clamps and align the solar panels at a tilt to the horizontal mounting surface. The tilt brackets are held in place atop the flexible feet and connected link members thus creating a complete mounting structure.

  17. Digital Communication and Modulation

    DEFF Research Database (Denmark)

    Sørensen, John Aasted

    2011-01-01

    The course presents the fundamental principles for digital communication, e.g. fixed-wire modems or wireless communication channels, as applied in mobile phones, wireless computer networks or wireless systems in intelligent houses. Based on the functional blocks of a digital communication system......, the fundamental principles for modulation and detection in Gaussian noise is treated. This includes the principles for the determination of the bit-error rate for a digital communication system. During the course, a selection of small Matlab exercises are prepared, for simulation of parts of a communication...... system. Having passed the course, the student will be able to accomplish the following, within the areas shown below: Model for Communication System. Prepare and explain the functional block in a digital communication system, corresponding to the specific course contents. Model for Communication Channel...

  18. Modulation frequency and modulation level owing to vocal microtremor.

    Science.gov (United States)

    Schoentgen, Jean

    2002-08-01

    Vocal microtremor designates a normal slow modulation of the vocal cycle lengths of speakers who do not suffer from pathological tremor of the limbs and whose voices are not perceived as tremulous. Vocal microtremor is therefore distinct from pathological vocal tremor. The objective is to report data about the modulation frequency and modulation level owing to vocal microtremor. The modulation data have been obtained for vowels [a], [i], and [u] sustained by normophonic and mildly dysphonic male and female speakers. The results are the following. First, modulation frequencies and relative modulation levels do not differ significantly for male and female speakers, normophonic and mildly dysphonic speakers, as well as for vowel timbres [a], [i], and [u]. Second, the typical interquartile intervals of the modulation frequency and modulation level are equal to 2.0-4.7 Hz and 0.4%-1.3%, respectively. Third, dissimilarities between data reported by different studies are due to different cutoff frequencies below which spectral peaks are considered not to contribute to vocal microtremor.

  19. Transient heliosheath modulation

    Science.gov (United States)

    Quenby, J. J.; Webber, W. R.

    2015-10-01

    Voyager 1 has explored the solar wind-interstellar medium interaction region between the terminal shock and heliopause, following the intensity distribution of Galactic cosmic ray protons above 200 MeV energy. Before this component reached the expected galactic flux level at 121.7 au from the Sun, four episodes of rapid intensity change occurred with a behaviour similar to that found in Forbush Decreases in the inner Solar system, rather than that expected from a mechanism related to models for the long-term modulation found closer to the Sun. Because the mean solar wind flow is both expected and observed to be perpendicular to the radial direction close to the heliopause, an explanation is suggested in terms of transient radial flows related to possible heliopause boundary flapping. It is necessary that the radial flows are of the order either of the sound speed found for conditions downstream of the terminal shock or of the fluctuations found near the boundary by the Voyager 1 Low Energy Charged Particle detector and that the relevant cosmic ray diffusion perpendicular to the mean field is controlled by `slab' fluctuations accounting for about 20 per cent of the total power in the field variance. However, additional radial drift motion related to possible north to south gradients in the magnetic field may allow the inclusion of some diffusion according to the predictions of a theory based upon the presence of 2D turbulence. The required field gradients may arise due to field variation in the field carried by solar plasma flow deflected away from the solar equatorial plane. Modulation amounting to a total 30 per cent drop in galactic intensity requires explanation by a combination of transient effects.

  20. New pulse modulator with low switching frequency

    Directory of Open Access Journals (Sweden)

    Golub V. S.

    2014-12-01

    Full Text Available The author presents an integrating pulse modulator (analog signal converter with the pulse frequency and duration modulation similar to sigma-delta modulation (with low switching frequency, without quantization. The modulator is characterized by the absence of the quantization noise inherent in sigma-delta modulator, and a low switching frequency, unlike the pulse-frequency modulator. The modulator is recommended, in particular, to convert signals at the input of the class D power amplifier.

  1. Essentially normal Hilbert modules and K-homology Ⅲ:Homogenous quotient modules of Hardy modules on the bidisk

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In this paper, we study the homogenous quotient modules of the Hardy module on the bidisk. The essential normality of the homogenous quotient modules is completely characterized. We also describe the essential spectrum for a general quotient module. The paper also considers K-homology invariant defined in the case of the homogenous quotient modules on the bidisk.

  2. Aligned natural inflation with modulations

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Kiwoon, E-mail: kchoi@ibs.re.kr [Center for Theoretical Physics of the Universe, Institute for Basic Science (IBS), Daejeon, 34051 (Korea, Republic of); Kim, Hyungjin, E-mail: hjkim06@kaist.ac.kr [Center for Theoretical Physics of the Universe, Institute for Basic Science (IBS), Daejeon, 34051 (Korea, Republic of); Department of Physics, KAIST, Daejeon, 305-701 (Korea, Republic of)

    2016-08-10

    The weak gravity conjecture applied for the aligned natural inflation indicates that generically there can be a modulation of the inflaton potential, with a period determined by sub-Planckian axion scale. We study the oscillations in the primordial power spectrum induced by such modulation, and discuss the resulting observational constraints on the model.

  3. Aligned natural inflation with modulations

    Directory of Open Access Journals (Sweden)

    Kiwoon Choi

    2016-08-01

    Full Text Available The weak gravity conjecture applied for the aligned natural inflation indicates that generically there can be a modulation of the inflaton potential, with a period determined by sub-Planckian axion scale. We study the oscillations in the primordial power spectrum induced by such modulation, and discuss the resulting observational constraints on the model.

  4. Small Molecular as SIRT Modulators.

    Science.gov (United States)

    Yao, Lei; Xu, Xiangming; Chen, Kai

    2016-06-19

    Sirtuins are class III histone deacetylases, they involve in many important biological functions. Small molecules that can modulate sirtuin activity have been shown to have potential for treating many human diseases. In the article, recent development of small molecular as SIRT modulators has been reviewed.

  5. Environmental Microbiology Modules. Final Report.

    Science.gov (United States)

    Walke, Raymond H.; Walke, Jayne G.

    This publication is the result of a project to develop microbiology instructional materials for vocational college students. These materials are a series of self-paced modules. Each module includes a pre-test, an introduction and historical packet, an organizational packet to set the framework for in-depth study, one or more in-depth packets, a…

  6. Input/output interface module

    Science.gov (United States)

    Ozyazici, E. M.

    1980-01-01

    Module detects level changes in any of its 16 inputs, transfers changes to its outputs, and generates interrupts when changes are detected. Up to four changes-in-state per line are stored for later retrieval by controlling computer. Using standard TTL logic, module fits 19-inch rack-mounted console.

  7. Diagnosis And Prescription: Reinforcement Module.

    Science.gov (United States)

    Fair, George W.

    This learning module has been designed to aid the teacher trainee in identifying ways in which he influences student behavior in the classroom and also explores means of selecting more meaningful reinforcers and their application. Terminal objectives of the module are the ability to (1) define the terms "reinforcement,""positive…

  8. Modular crystals as modulated structures

    DEFF Research Database (Denmark)

    Elcoro, L.; Perez-Mato, J.M.; Friese, K.;

    2008-01-01

    The use of the superspace formalism is extended to the description and refinement of the homologous series of modular structures with two symmetry-related modules with different orientations. The lillianite homologous series has been taken as a study case. Starting from a commensurate modulated c...

  9. Photovoltaic module parameters acquisition model

    Science.gov (United States)

    Cibira, Gabriel; Koščová, Marcela

    2014-09-01

    This paper presents basic procedures for photovoltaic (PV) module parameters acquisition using MATLAB and Simulink modelling. In first step, MATLAB and Simulink theoretical model are set to calculate I-V and P-V characteristics for PV module based on equivalent electrical circuit. Then, limited I-V data string is obtained from examined PV module using standard measurement equipment at standard irradiation and temperature conditions and stated into MATLAB data matrix as a reference model. Next, the theoretical model is optimized to keep-up with the reference model and to learn its basic parameters relations, over sparse data matrix. Finally, PV module parameters are deliverable for acquisition at different realistic irradiation, temperature conditions as well as series resistance. Besides of output power characteristics and efficiency calculation for PV module or system, proposed model validates computing statistical deviation compared to reference model.

  10. Modulation field induces universe rotation

    CERN Document Server

    Chen, Chien Yu

    2008-01-01

    Noncommutative field theory is a theory concerning a background field on the string world sheet. Whole of the universe is survived on background field situation. In this paper, we consider a module field on spacetime expansion without modifying commutative relation, and omit the deformed effects by $\\star$ production. Lorentz symmetry is conserved on module and unmodule coordinate, the violation point is under the translation between each others by module expansion. However, considering a background field on spacetime geodesic we could understand that even magnetic force could not be generated by putting a module $Poincar\\check{e}$ boost due to CPT conservation. Which phenomenon, each particle field will be rotated and expanded. Assembling the commutative and anti-commutative null vector by putting an operated coefficients on three orthogonal states. Spacetime is homogeneous but anisotropic, since the energy fluid is not uniformed by a distribution of modulation field. Therefore, concentrating on which signif...

  11. Acceleration Recorder and Playback Module

    Science.gov (United States)

    Bozeman, Richard J., Jr. (Inventor)

    1996-01-01

    The present invention is directed to methods and apparatus relating to an accelerometer electrical signal recorder and playback module. The recorder module may be manufactured in lightweight configuration and includes analog memory components to store data. Signal conditioning circuitry is incorporated into the module so that signals may be connected directly from the accelerometer to the recorder module. A battery pack may be included for powering both the module and the accelerometer. Timing circuitry is included to control the time duration within which data is recorded or played back so as to avoid overloading the analog memory components. Multiple accelerometer signal recordings may be taken simultaneously without analog to digital circuits, multiplexing circuitry or software to compensate for the effects of multiplexing the signals.

  12. Force Modulator System

    Energy Technology Data Exchange (ETDEWEB)

    Redmond Clark

    2009-04-30

    Many metal parts manufacturers use large metal presses to shape sheet metal into finished products like car body parts, jet wing and fuselage surfaces, etc. These metal presses take sheet metal and - with enormous force - reshape the metal into a fully formed part in a manner of seconds. Although highly efficient, the forces involved in forming metal parts also damage the press itself, limit the metals used in part production, slow press operations and, when not properly controlled, cause the manufacture of large volumes of defective metal parts. To date, the metal-forming industry has not been able to develop a metal-holding technology that allows full control of press forces during the part forming process. This is of particular importance in the automotive lightweighting efforts under way in the US automotive manufacturing marketplace. Metalforming Controls Technology Inc. (MC2) has developed a patented press control system called the Force Modulator that has the ability to control these press forces, allowing a breakthrough in stamping process control. The technology includes a series of hydraulic cylinders that provide controlled tonnage at all points in the forming process. At the same time, the unique cylinder design allows for the generation of very high levels of clamping forces (very high tonnages) in very small spaces; a requirement for forming medium and large panels out of HSS and AHSS. Successful production application of these systems testing at multiple stamping operations - including Ford and Chrysler - has validated the capabilities and economic benefits of the system. Although this technology has been adopted in a number of stamping operations, one of the primary barriers to faster adoption and application of this technology in HSS projects is system cost. The cost issue has surfaced because the systems currently in use are built for each individual die as a custom application, thus driving higher tooling costs. This project proposed to better

  13. Biological modulation of tectonics

    Science.gov (United States)

    Sleep, N. H.; Bird, D. K.

    2008-12-01

    Photosynthesis has had geologic consequences over the Earth's history. In addition to modifying Earth's atmosphere and ocean chemistry, it has also modulated tectonic processes through enhanced weathering and modification of the nature and composition of sedimentary rocks within fold mountain belts and convergent margins. Molecular biological studies indicate that bacterial photosynthesis evolved just once and that most bacterial clades descend from this photosynthetic common ancestor. Iron-based photosynthesis (ideally 4FeO + CO2 + H2O = 2Fe2O3 + CH2O) was the most bountiful anoxygenic niche on land. The back reaction provided energy to heterotrophic microbes and returned FeO to the photosynthetic microbes. Bacterial land colonists evolved into ecosystems that effectively weathered FeO-bearing minerals and volcanic glass. Clays, sands, and dissolved cations from the weathering process entered the ocean and formed our familiar classes sedimentary rocks: shales, sandstones, and carbonates. Marine photosynthesis caused organic carbon to accumulate in black shales. In contrast, non-photosynthetic ecosystems do not cause organic carbon to accumulate in shale. These evolutionary events occurred before 3.8 Ga as black shales are among the oldest rock types (Rosing and Frei, Earth Planet. Sci. Lett. 217, 237-244, 2004). Thick sedimentary sequences deformed into fold mountain belts. They remelted at depth to form granitic rocks (Rosing et al., Palaeoclimatol. Palaeoecol. 232, 99-11, 2006). Regions of outcropping low-FeO rocks including granites, quartzites, and some shales were a direct result. This dearth of FeO favored the evolution of oxic photosynthesis of cyanobacteria from photosynthetic soil bacteria. Black shales have an additional modulation effect on tectonics as they concentrate radioactive elements, particularly uranium (e.g. so that the surface heat flow varies by a factor of ca. 2). Thick sequences of black shales at continental rises of passive margins are

  14. Programmable Thermostat Module Upgrade for the Multipurpose Logistics Module

    Science.gov (United States)

    Clark, D. W.; Glasgow, S. d.; Reagan, S. E.; Presson, K. H.; Howard, D. E.; Smith, D. A.

    2007-01-01

    The STS-121/ULF 1.1 mission was the maiden flight of the programmable thermostat module (PTM) system used to control the 28 V shell heaters on the multi-purpose logistics module (MPLM). These PTMs, in conjunction with a data recorder module (DRM), provide continuous closed loop temperature control and data recording of MPLM on-orbit heater operations. This Technical Memorandum discusses the hardware design, development, test, and verification (DDT&V) activities performed at the Marshall Space Flight Center as well as the operational implementation and mission performance.

  15. Wavelet modulation: An alternative modulation with low energy consumption

    Science.gov (United States)

    Chafii, Marwa; Palicot, Jacques; Gribonval, Rémi

    2017-02-01

    This paper presents wavelet modulation, based on the discrete wavelet transform, as an alternative modulation with low energy consumption. The transmitted signal has low envelope variations, which induces a good efficiency for the power amplifier. Wavelet modulation is analyzed and compared for different wavelet families with orthogonal frequency division multiplexing (OFDM) in terms of peak-to-average power ratio (PAPR), power spectral density (PSD) properties, and the impact of the power amplifier on the spectral regrowth. The performance in terms of bit error rate and complexity of implementation are also evaluated, and several trade-offs are characterized. xml:lang="fr"

  16. Living Systems Energy Module

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-09-26

    The Living Systems Energy Module, renamed Voyage from the Sun, is a twenty-lesson curriculum designed to introduce students to the major ways in which energy is important in living systems. Voyage from the Sun tells the story of energy, describing its solar origins, how it is incorporated into living terrestrial systems through photosynthesis, how it flows from plants to herbivorous animals, and from herbivores to carnivores. A significant part of the unit is devoted to examining how humans use energy, and how human impact on natural habitats affects ecosystems. As students proceed through the unit, they read chapters of Voyage from the Sun, a comic book that describes the flow of energy in story form (Appendix A). During the course of the unit, an ``Energy Pyramid`` is erected in the classroom. This three-dimensional structure serves as a classroom exhibit, reminding students daily of the importance of energy and of the fragile nature of our living planet. Interactive activities teach students about adaptations that allow plants and animals to acquire, to use and to conserve energy. A complete list of curricular materials and copies of all activity sheets appear in Appendix B.

  17. OCGen Module Mooring Project

    Energy Technology Data Exchange (ETDEWEB)

    McEntee, Jarlath [Ocean Renewable Power Company, LLC, Portland, ME (United States)

    2015-02-06

    Ocean Renewable Power Company's OCGen Module Mooring Project provided an extensive research, design, development, testing and data collection effort and analysis conducted with respect to a positively buoyant, submerged MHK device secured to the seabed using a tensioned mooring system. Different analytic tools were evaluated for their utility in the design of submerged systems and their moorings. Deployment and testing of a prototype OCGen® system provided significant data related to mooring line loads and system attitude and station keeping. Mooring line loads were measured in situ and reported against flow speeds. The Project made a significant step in the development of designs, methodologies and practices related to floating and mooring of marine hydrokinetic (MHK) devices. Importantly for Ocean Renewable Power Company, the Project provided a sound basis for advancing a technically and commercially viable OCGen® Power System. The OCGen® Power System is unique in the MHK industry and, in itself, offers distinct advantages of MHK devices that are secured to the seabed using fixed structural frames. Foremost among these advantages are capital and operating cost reductions and increased power extraction by allowing the device to be placed at the most energetic level of the water column.

  18. Superstability for Generalized Module Left Derivations and Generalized Module Derivations on a Banach Module (I

    Directory of Open Access Journals (Sweden)

    Huai-Xin Cao

    2009-01-01

    Full Text Available We discuss the superstability of generalized module left derivations and generalized module derivations on a Banach module. Let 𝒜 be a Banach algebra and X a Banach 𝒜-module, f:X→X and g:𝒜→𝒜. The mappings Δf,g1, Δf,g2, Δf,g3, and Δf,g4 are defined and it is proved that if ∥Δf,g1(x,y,z,w∥ (resp., ∥Δf,g3(x,y,z,w,α,β∥ is dominated by φ(x,y,z,w, then f is a generalized (resp., linear module-𝒜 left derivation and g is a (resp., linear module-X left derivation. It is also shown that if ∥Δf,g2(x,y,z,w∥ (resp., ∥Δf,g4(x,y,z,w,α,β∥ is dominated by φ(x,y,z,w, then f is a generalized (resp., linear module-𝒜 derivation and g is a (resp., linear module-X derivation.

  19. ABSOLUTELY E-PURE MODULES AND E-PURE SPLIT MODULES

    Institute of Scientific and Technical Information of China (English)

    Yan Hangyu

    2011-01-01

    We first introduce the concepts of absolutely E-pure modules and Epure split modules. Then, we characterize the IF rings in terms of absolutely E-pure modules. The E-pure split modules are also characterized.

  20. Quadratic and 2-Crossed Modules of Algebras

    Institute of Scientific and Technical Information of China (English)

    Z. Arvasi; E. Ulualan

    2007-01-01

    In this work, we define the quadratic modules for commutative algebras and give relations among 2-crossed modules, crossed squares, quadratic modules and simplicial commutative algebras with Moore complex of length 2.

  1. Reachability modules for the description logic SRIQ

    CSIR Research Space (South Africa)

    Nortje, R

    2013-12-01

    Full Text Available In this paper we investigate module extraction for the Description Logic SRIQ. We formulate modules in terms of the reachability problem for directed hypergraphs. Using inseperability relations, we investigate the module-theoretic properties...

  2. Modulation of B-cell receptor and microenvironment signaling by a guanine exchange factor in B-cell malignancies

    Institute of Scientific and Technical Information of China (English)

    Wei Liao; Sanjai Sharma

    2016-01-01

    Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-1 over-expressing and a control transfected cell line. Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.

  3. Tree modules and counting polynomials

    CERN Document Server

    Kinser, Ryan

    2011-01-01

    We give a formula for counting tree modules for the quiver S_g with g loops and one vertex in terms of tree modules on its universal cover. This formula, along with work of Helleloid and Rodriguez-Villegas, is used to show that the number of d-dimensional tree modules for S_g is polynomial in g with the same degree and leading coefficient as the counting polynomial A_{S_g}(d, q) for absolutely indecomposables over F_q, evaluated at q=1.

  4. Photovoltaic module with adhesion promoter

    Science.gov (United States)

    Xavier, Grace

    2013-10-08

    Photovoltaic modules with adhesion promoters and methods for fabricating photovoltaic modules with adhesion promoters are described. A photovoltaic module includes a solar cell including a first surface and a second surface, the second surface including a plurality of interspaced back-side contacts. A first glass layer is coupled to the first surface by a first encapsulating layer. A second glass layer is coupled to the second surface by a second encapsulating layer. At least a portion of the second encapsulating layer is bonded directly to the plurality of interspaced back-side contacts by an adhesion promoter.

  5. High-performance electroabsorption modulator

    Science.gov (United States)

    Wei, Zhang; Jiaoqing, Pan; Hongliang, Zhu; Huan, Wang; Wei, Wang

    2009-09-01

    A 100-μm-long electroabsorption modulator monolithically integrated with passive waveguides at the input and output ports is fabricated through ion implantation induced quantum well intermixing, using only a two-step low-pressure metal-organic vapor phase epitaxial process. An InGaAsP/InGaAsP intra-step quantum well is introduced to the active region to improve the modulation properties. In the experiment high modulation speed and high extinction ratio are obtained simultaneously, the electrical-to-optical frequency response (E/O response) without any load termination reaches to 22 GHz, and extinction ration is as high as 16 dB.

  6. Matching polytopes and Specht modules

    CERN Document Server

    Liu, Ricky Ini

    2009-01-01

    We prove that the dimension of the Specht module of a forest $G$ is the same as the normalized volume of the matching polytope of $G$. We also associate to $G$ a symmetric function $s_G$ (analogous to the Schur symmetric function $s_\\lambda$ for a partition $\\lambda$) and investigate its combinatorial and representation-theoretic properties in relation to the Specht module and Schur module of $G$. We then use this to define notions of standard and semistandard tableaux for forests.

  7. Ammonia corrodes solar modules; Salmiakgeist greift Module an

    Energy Technology Data Exchange (ETDEWEB)

    Petzold, Katrin

    2011-07-01

    Ammonia is an aggressive gas produced in animal shelters, which may cause corrosion of solar modules. Various institutions, e.g. DLG and TUeV Rheinland, therefore offer an ammonia test for solar modules. The TUeV Rheinland recently commissioned a walk-in test chamber and now issues an official seal of approval, while the DLG doubts the practical value of the test.

  8. Modulation of lymphopoiesis

    Energy Technology Data Exchange (ETDEWEB)

    Rosse, C.

    1990-01-01

    Ongoing experiments contribute to the four specific aims in our current 3-year project period studying lymphopoiesis using CE mammary adenocarcinoma (CE maca) mice. Specific Aim 1: Function of Bone Marrow Stroma in CE Maca Bearing Mice. We have concluded that bone marrow stromal cells from tumor bearing animals are as effective as bone marrow stromal cells from normal animals at supporting B lymphopoiesis in culture. If stromal cell disfunction occurs in tumor bearing animals, the effect is not long lasting. Specific Aim 2: Factors Elaborated by CE Maca. Conditioned medium from CE maca cultures induces bone resorbing activity in bone organ cultures. We have identified a 32 kDa protein that meets the criteria for an osteoclast specific growth factor in this medium. However, we have also found that even though an osteoclast specific growth factor exists, a growth factor whose primary targets are granulocyte precursors will also stimulate osteoclast activity. Specific Aim 3: In Vitro Systems for Investigating Modulation of NK Lymphopoiesis by CE Maca. CE maca is shown to inhibit NK all production as well as B all production. In the course of the these experiments, we have established conditions for enriching NK precursors and have established a prototype long term bone marrow culture system which shows NK cell production. Specific Aim 4: Relationship Between Myclogenic and Intrathymic T Cell Precursors. There is evidence for a stream of T all maturation in both host (or intrathymic) cells and non-host (both hematogenous and intrathymic) cells. If thymic atrophy is induced by cortisone (a depopulation equivalent to that caused by 1000 rad) our data conclusively show thymic recovery is effected almost exclusively by intrathymic cells. This assigns a much greater importance to intrathymic T all progenitors in the maintenance of T cell production in the thymus than has been hitherto recognized. (MHB)

  9. Modulation of lymphopoiesis

    Energy Technology Data Exchange (ETDEWEB)

    Rosse, C.

    1991-01-01

    During the current project period we have demonstrated correspondence between animal models and in vitro models of modulated lymphopoiesis. Our finding that G-CSF, a growth factor for neutrophil granulocytes, suppresses lymphopoiesis in long term bone marrow cultures (LTBMC) has important implications both for understanding the regulatory mechanisms of hemopoiesis and for clinical use of recombinant growth factors that are beginning to be widely used for the treatment of a variety of diseases. During the present project period we adopted LTBMC systems developed by others for the purposes of our specific aims. Also we developed a novel long term culture system for NK cells. The discovery of a new growth factor, O-CSF, specific for osteoclasts and the establishment of a clonal assay system that provides evidence for a new class of hemopoietic progenitor cells, the osteoclast progenitor, are important contributions. Given the important role T cells play in the immune response and in the regulation of other lymphohemopoietic cell lineages through the lymphokines they secrete, the need for an in vitro system that lends itself to the analysis of T cell maturation and to the testing of factors that may adversely affect T lymphopoiesis cannot be overemphasized. We believe that we can exploit an advantageous set of circumstances that present an excellent opportunity for initiating a focused experimental program for developing such a system. By a systematic and selective analysis of molecular interactions between heterogenous thymic stromal cells and T cell progenitors at different stages of maturation, it will be possible for our program to define the complement of critical cellular interactions on which successive stages of T lymphopoiesis depend. The experiments we propose will lay a rational foundation for the development of a long term culture system for T lymphopoiesis. 24 refs., 7 figs.

  10. Cosmic ray modulation

    Science.gov (United States)

    Agarwal Mishra, Rekha; Mishra, Rajesh Kumar

    2016-07-01

    Propagation of cosmic rays to and inside the heliosphere, encounter an outward moving solar wind with cyclic magnetic field fluctuation and turbulence, causing convection and diffusion in the heliosphere. Cosmic ray counts from the ground ground-based neutron monitors at different cut of rigidity show intensity changes, which are anti-correlated with sunspot numbers. They also lose energy as they propagate towards the Earth and experience various types of modulations due to different solar activity indices. In this work, we study the first three harmonics of cosmic ray intensity on geo-magnetically quiet days over the period 1965-2014 for Beijing, Moscow and Tokyo neutron monitoring stations located at different cut off rigidity. The amplitude of first harmonic remains high for low cutoff rigidity as compared to high cutoff rigidity on quiet days. The diurnal amplitude significantly decreases during solar activity minimum years. The diurnal time of maximum significantly shifts to an earlier time as compared to the corotational direction having different cutoff rigidities. The time of maximum for first harmonic significantly shifts towards later hours and for second harmonic it shifts towards earlier hours at low cutoff rigidity station as compared to the high cut off rigidity station on quiet days. The amplitude of second/third harmonics shows a good positive correlation with solar wind velocity, while the others (i.e. amplitude and phase) have no significant correlation on quiet days. The amplitude and direction of the anisotropy on quiet days does not show any significant dependence on high-speed solar wind streams for these neutron monitoring stations of different cutoff rigidity threshold. Keywords: cosmic ray, cut off rigidity, quiet days, harmonics, amplitude, phase.

  11. Multilevel Modulation formats for Optical Communication

    DEFF Research Database (Denmark)

    Jensen, Jesper Bevensee

    2008-01-01

    This thesis studies the use of multilevel modulation formats for optical communication systems. Multilevel modulation is an attractive method of increasing the spectral efficiency of optical communication systems. Various modulation formats employing phase modulation, amplitude modulation...... or a combination of the two have been studied. The use of polarization multiplexing (PolMux) to double the bit rate has also been investigated. The impact of transmission impairments such as chromatic dispersion, self phase modulation and cross phase modulation has been investigated. The feasibility of multilevel...... modulation for network oriented scenarios has been demonstrated....

  12. RELIABILITY OF PRINTED WIRING CORDWOOD MODULES,

    Science.gov (United States)

    MODULES (ELECTRONICS), *RELIABILITY(ELECTRONICS), RELIABILITY(ELECTRONICS), MODULES (ELECTRONICS), PRINTED CIRCUITS, ENVIRONMENTAL TESTS, LIFE EXPECTANCY(SERVICE LIFE), TEST METHODS, ENCAPSULATION, SOLDERED JOINTS.

  13. Ultrasound-modulated bioluminescence tomography

    Science.gov (United States)

    Bal, Guillaume; Schotland, John C.

    2014-03-01

    We propose a method to reconstruct the density of a luminescent source in a highly scattering medium from ultrasound-modulated optical measurements. Our approach is based on the solution to a hybrid inverse source problem for the diffusion equation.

  14. CIM—Compact intensity modulation

    Science.gov (United States)

    Bleuel, M.; Lang, E.; Gähler, R.; Lal, J.

    2008-07-01

    Compact intensity modulation (CIM), a new method to modulate the intensity of a neutron beam is demonstrated. CIM allows the production of arbitrary signals where the focus point can be chosen and changed without any constraints. A novel feature in this technique compared to spin echo techniques is that the neutron polarization is kept parallel or anti-parallel to the static fields during the passage through the magnetic fields and the beating pattern at the detector is produced by an amplitude modulation (AM) of the adiabatic RF-spin flippers rather than Larmor precession like in neutron spin echo (NSE) instruments; thus, the achievable contrast is very high and the instrument resolution can be changed very quickly. This gives the fascinating possibility at pulsed neutron sources to sweep the modulation frequency of the flippers in order to increase dynamic resolution range during the same neutron pulse.

  15. Compact energy conversion module Project

    Data.gov (United States)

    National Aeronautics and Space Administration — This STTR project delivers a compact vibration-based Energy Conversion Module (ECM) that powers sensors for purposes like structural health monitoring (SHM). NASA...

  16. Photovoltaic Module Qualification Plus Testing

    Energy Technology Data Exchange (ETDEWEB)

    Kurtz, S.; Wohlgemuth, J.; Kempe, M.; Bosco, N.; Hacke, P.; Jordan, D.; Miller, D. C.; Silverman, T. J.; Phillips, N.; Earnest, T.; Romero, R.

    2013-12-01

    This report summarizes a set of test methods that are in the midst of being incorporated into IEC 61215 for certification of a module design or other tests that go beyond certification to establish bankability.

  17. Second-order temporal modulation transfer functions.

    Science.gov (United States)

    Lorenzi, C; Soares, C; Vonner, T

    2001-08-01

    Detection thresholds were measured for a sinusoidal modulation applied to the modulation depth of a sinusoidally amplitude-modulated (SAM) white noise carrier as a function of the frequency of the modulation applied to the modulation depth (referred to as f'm). The SAM noise acted therefore as a "carrier" stimulus of frequency fm, and sinusoidal modulation of the SAM-noise modulation depth generated two additional components in the modulation spectrum: fm-f'm and fm+f'm. The tracking variable was the modulation depth of the sinusoidal variation applied to the "carrier" modulation depth. The resulting "second-order" temporal modulation transfer functions (TMTFs) measured on four listeners for "carrier" modulation frequencies fm of 16, 64, and 256 Hz display a low-pass segment followed by a plateau. This indicates that sensitivity to fluctuations in the strength of amplitude modulation is best for fluctuation rates f'm below about 2-4 Hz when using broadband noise carriers. Measurements of masked modulation detection thresholds for the lower and upper modulation sideband suggest that this capacity is possibly related to the detection of a beat in the sound's temporal envelope. The results appear qualitatively consistent with the predictions of an envelope detector model consisting of a low-pass filtering stage followed by a decision stage. Unlike listeners' performance, a modulation filterbank model using Q values > or = 2 should predict that second-order modulation detection thresholds should decrease at high values of f'm due to the spectral resolution of the modulation sidebands (in the modulation domain). This suggests that, if such modulation filters do exist, their selectivity is poor. In the latter case, the Q value of modulation filters would have to be less than 2. This estimate of modulation filter selectivity is consistent with the results of a previous study using a modulation-masking paradigm [S. D. Ewert and T. Dau, J. Acoust. Soc. Am. 108, 1181

  18. Modulation corticale de la locomotion

    OpenAIRE

    Tard, Céline

    2015-01-01

    Patients with Parkinson 's disease present gait impairments, sometimes sudden and unexpected, either improved or deteriorated with environmental stimuli. Attention focalization, either on external stimuli or on gait, could then modulate locomotion.The main objective was to better characterize how environmental stimuli would modulate locomotion, via attentional networks, in healthy subjects and in parkinsonian patients, with or without freezing of gait.At first, we precisely defined the attent...

  19. Defining Modules, Modularity and Modularization

    DEFF Research Database (Denmark)

    Miller, Thomas Dedenroth; Pedersen, Per Erik Elgård

    The paper describes the evolution of the concept of modularity in a historical perspective. The main reasons for modularity are: create variety, utilize similarities, and reduce complexity. The paper defines the terms: Module, modularity, and modularization.......The paper describes the evolution of the concept of modularity in a historical perspective. The main reasons for modularity are: create variety, utilize similarities, and reduce complexity. The paper defines the terms: Module, modularity, and modularization....

  20. ABOUT SOLIDWORKS COSTING MODULE FEATURES

    Directory of Open Access Journals (Sweden)

    Catalin IANCU

    2016-05-01

    Full Text Available In this paperwork is presented the SolidWorks analysis of costing, using Simulation Costing module. There are presented the settings that have to be done for such analysis and the results shown by this software module. The elements that are taken into account are specific to costing templates in SolidWorks, but can be adjusted for the specific costs of a given factory.

  1. Intelligent spacecraft module

    Science.gov (United States)

    Oungrinis, Konstantinos-Alketas; Liapi, Marianthi; Kelesidi, Anna; Gargalis, Leonidas; Telo, Marinela; Ntzoufras, Sotiris; Paschidi, Mariana

    2014-12-01

    The paper presents the development of an on-going research project that focuses on a human-centered design approach to habitable spacecraft modules. It focuses on the technical requirements and proposes approaches on how to achieve a spatial arrangement of the interior that addresses sufficiently the functional, physiological and psychosocial needs of the people living and working in such confined spaces that entail long-term environmental threats to human health and performance. Since the research perspective examines the issue from a qualitative point of view, it is based on establishing specific relationships between the built environment and its users, targeting people's bodily and psychological comfort as a measure toward a successful mission. This research has two basic branches, one examining the context of the system's operation and behavior and the other in the direction of identifying, experimenting and formulating the environment that successfully performs according to the desired context. The latter aspect is researched upon the construction of a scaled-model on which we run series of tests to identify the materiality, the geometry and the electronic infrastructure required. Guided by the principles of sensponsive architecture, the ISM research project explores the application of the necessary spatial arrangement and behavior for a user-centered, functional interior where the appropriate intelligent systems are based upon the existing mechanical and chemical support ones featured on space today, and especially on the ISS. The problem is set according to the characteristics presented at the Mars500 project, regarding the living quarters of six crew-members, along with their hygiene, leisure and eating areas. Transformable design techniques introduce spatial economy, adjustable zoning and increased efficiency within the interior, securing at the same time precise spatial orientation and character at any given time. The sensponsive configuration is

  2. Steganalysis of stochastic modulation steganography

    Institute of Scientific and Technical Information of China (English)

    HE Junhui; HUANG Jiwu

    2006-01-01

    Stochastic modulation steganography embeds secret message within the cover image by adding stego-noise with a specific probabilistic distribution. No method is known to be applicable to the estimation of stochastic modulation steganography. By analyzing the distributions of the horizontal pixel difference of images before and after stochastic modulation embedding, we present a new steganalytic approach to accurately estimate the length of secret message in stochastic modulation steganography. The proposed method first establishes a model describing the statistical relationship among the differences of the cover image, stego-image and stego-noise. In the case of stego- image-only steganalysis, rough estimate of the distributional parameters of the cover image's pixel difference is obtained with the use of the provided stego-image. And grid search and Chi-square goodness of fit test are exploited to estimate the length of the secret message embedded with stochastic modulation steganography. The experimental results demonstrate that our new approach is effective for steganalyzing stochastic modulation steganography and accurately estimating the length of the secret message.

  3. Customized PEC modules. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Soerensen, Martin B. (DTI, Taastrup (Denmark))

    2012-07-01

    The purpose of the project ''Customized PEC modules'' was to move from the production hand-made individual DSCs (dye-sensitized solar cells) in the laboratory to the production of DSC modules in a semi-automated process. At the same time allowing sufficient variation in the product's specification for real tailoring of the product to the application. The tailoring can be related to the module's electrical output and size, but also to the possibility of designing patterns for decoration or communication purposes by playing around with the shape, size and layout of the individual cells forming the module. This was to be accomplished mainly by screen printing of DSC components on glass substrates at Mekoprint. For reaching this goal the work was divided into a number of steps. The central part of the work done was in the initial conception activity and the following manufacturing activity. An activity regarding optimization included several tasks of optimization and adaptation of the existing laboratory process for manufacturing of the DSCs. Finally, work focused on international activities was done. All the steps needed for the production of customized DSC modules have been demonstrated in this project. In combination with the development of a high performing printable sealant and sealing method all the prerequisites for producing customized DSC modules have been demonstrated. (LN)

  4. Essentially finitely indecomposable QTAG-Modules

    Directory of Open Access Journals (Sweden)

    Alveera Mehdi

    2016-01-01

    Full Text Available A right module $M$ over an associative ring with unity is a $QTAG$-module if every finitely generated submodule of any homomorphic image of $M$ is a direct sum of uniserial modules. There are many fascinating results related to these modules and essentially indecomposable modules are extensively researched. Motivated by these modules we generalize them as essentially finitely indecomposable modules whose every direct decomposition $M=\\bigoplus\\limits_{k\\in I} M_k$ implies that there exists a positive integer $n$ such that $H_n(M_i=0$ for all $M_i$'s except for a finite number of $M_i$'s. Here we investigate these modules and their relationship with $HT$-modules. The cases when the modules are not $HT$-modules are especially highlighted.

  5. ITER Central Solenoid Module Fabrication

    Energy Technology Data Exchange (ETDEWEB)

    Smith, John [General Atomics, San Diego, CA (United States)

    2016-09-23

    The fabrication of the modules for the ITER Central Solenoid (CS) has started in a dedicated production facility located in Poway, California, USA. The necessary tools have been designed, built, installed, and tested in the facility to enable the start of production. The current schedule has first module fabrication completed in 2017, followed by testing and subsequent shipment to ITER. The Central Solenoid is a key component of the ITER tokamak providing the inductive voltage to initiate and sustain the plasma current and to position and shape the plasma. The design of the CS has been a collaborative effort between the US ITER Project Office (US ITER), the international ITER Organization (IO) and General Atomics (GA). GA’s responsibility includes: completing the fabrication design, developing and qualifying the fabrication processes and tools, and then completing the fabrication of the seven 110 tonne CS modules. The modules will be shipped separately to the ITER site, and then stacked and aligned in the Assembly Hall prior to insertion in the core of the ITER tokamak. A dedicated facility in Poway, California, USA has been established by GA to complete the fabrication of the seven modules. Infrastructure improvements included thick reinforced concrete floors, a diesel generator for backup power, along with, cranes for moving the tooling within the facility. The fabrication process for a single module requires approximately 22 months followed by five months of testing, which includes preliminary electrical testing followed by high current (48.5 kA) tests at 4.7K. The production of the seven modules is completed in a parallel fashion through ten process stations. The process stations have been designed and built with most stations having completed testing and qualification for carrying out the required fabrication processes. The final qualification step for each process station is achieved by the successful production of a prototype coil. Fabrication of the first

  6. On generalized k-syzygy modules

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In this paper, we first introduce the notion of generalized k-syzygy modules, and then give an equivalent characterization that the class of generalized k-syzygy modules coincides with that ofω-k-torsionfree modules. We further study the extension closure of the category consisting of generalized k-syzygy modules. Some known results are obtained as corollaries.

  7. Australia: round module handling and cotton classing

    Science.gov (United States)

    Round modules of seed cotton produced via on-board module building harvesters are the reality of the cotton industry, worldwide. Although round modules have been available to the industry for almost a decade, there is still no consensus on the best method to handle the modules, particularly when th...

  8. Weight modules over some Block algebras

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    In this paper, the Harish-Chandra modules and Verma modules over Block algebra L[G] are investigated. More precisely, the irreducibility of the Verma modules over L[G] is completely determined, and the Harish-Chandra modules over L[Z] are classified.

  9. On Sequentially Co-Cohen-Macaulay Modules

    Institute of Scientific and Technical Information of China (English)

    Nguyen Thi Dung

    2007-01-01

    In this paper,we define the notion of dimension filtration of an Artinian module and study a class of Artinian modules,called sequentially co-Cohen-Macaulay modules,which contains strictly all co-Cohen-Macaulay modules.Some characterizations of co-Cohen-Macaulayness in terms of the Matlis duality and of local homology are also given.

  10. Weight modules over some Block algebras

    Institute of Scientific and Technical Information of China (English)

    L(U) RenCai

    2009-01-01

    In this paper,the Harish-Chandra modules and Verma modules over Block algebra (e)[G]are investigated.More precisely,the irreducibility of the Verma modules over (e)[G]is completely determined,and the Harish-Chandra modules over (e)[Z]are classified.

  11. On generalized k-syzygy modules

    Institute of Scientific and Technical Information of China (English)

    Chong-hui HUANG; Zhao-yong HUANG

    2007-01-01

    In this paper, we first introduce the notion of generalized k-syzygy modules, and then give an equivalent characterization that the class of generalized k-syzygy modules coincides with that of ω- k-torsionfree modules. We further study the extension closure of the category consisting of generalized k-syzygy modules. Some known results are obtained as corollaries.

  12. Induced Modules of Restricted Lie Superalgebras

    Institute of Scientific and Technical Information of China (English)

    刘文德

    2005-01-01

    In this paper we first prove the PBW theorem for reduced universal enveloping algebras of restricted Lie superalgebras. Then the notion of an induced module is introduced and the dimension formula of induced modules is established.Finally, using the results above, we obtain a property of induced modules pertaining to automorphisms of Lie superalgebras and isomorphisms of modules.

  13. Health Occupations Module. The Integumentary System.

    Science.gov (United States)

    Temple Univ., Philadelphia, PA. Div. of Vocational Education.

    This module on the integumentary system is one of eight modules designed for individualized instruction in health occupations education programs at both the secondary and postsecondary levels. This module contains an introduction to the module topic, objectives (e.g., list and describe the types of glands formed in the skin, and explain the…

  14. Laser frequency modulator for modulating a laser cavity

    Science.gov (United States)

    Erbert, Gaylen V.

    1992-01-01

    The present invention relates to a laser frequency modulator for modulating a laser cavity. It is known in the prior art to utilize a PZT (piezoelectric transducer) element in combination with a mirror to change the cavity length of a laser cavity (which changes the laser frequency). Using a PZT element to drive the mirror directly is adequate at frequencies below 10 kHz. However, in high frequency applications (100 kHz and higher) PZT elements alone do not provide a sufficient change in the cavity length. The present invention utilizes an ultrasonic concentrator with a PZT element and mirror to provide modulation of the laser cavity. With an ultrasonic concentrator, the mirror element at the end of a laser cavity can move at larger amplitudes and higher frequencies.

  15. Unconventional role of voltage-gated proton channels (VSOP/Hv1) in regulation of microglial ROS production.

    Science.gov (United States)

    Kawai, Takafumi; Okochi, Yoshifumi; Ozaki, Tomohiko; Imura, Yoshio; Koizumi, Schuichi; Yamazaki, Maya; Abe, Manabu; Sakimura, Kenji; Yamashita, Toshihide; Okamura, Yasushi

    2017-09-01

    It has been established that voltage-gated proton channels (VSOP/Hv1), encoded by Hvcn1, support reactive oxygen species (ROS) production in phagocytic activities of neutrophils (El Chemaly et al. ) and antibody production in B lymphocytes (Capasso et al. ). VSOP/Hv1 is a potential therapeutic target for brain ischemia, since Hvcn1 deficiency reduces microglial ROS production and protects brain from neuronal damage (Wu et al. ). In the present study, we report that VSOP/Hv1 has paradoxical suppressive role in ROS production in microglia. Extracellular ROS production was lower in neutrophils of Hvcn1(-/-) mice than WT mice as reported. In contrast, it was drastically enhanced in isolated Hvcn1(-/-) microglia as compared with cells from WT mice. Actin dynamics was altered in Hvcn1(-/-) microglia and intracellular distribution of cytosolic NADPH oxidase subunit, p67, was changed. When expression levels of oxidative stress responsive antioxidant genes were compared between WT and Hvcn1(-/-) in cerebral cortex at different ages of animals, they were slightly decreased in Hvcn1(-/-) mice at younger stage (1 day, 5 days, 3 weeks old), but drastically increased at aged stage (6 months old), suggesting that the regulation of microglial ROS production by VSOP/Hv1 is age-dependent. We also performed brain ischemic stroke experiments and found that the neuroprotective effect of VSOP/Hv1deficiency on infarct volume depended on the age of animals. Taken together, regulation of ROS production by VSOP/Hv1 is more complex than previously thought and significance of VSOP/Hv1 in microglial ROS production depends on age. © 2017 International Society for Neurochemistry.

  16. On a Class of Semicommutative Modules

    Indian Academy of Sciences (India)

    Nazim Agayev; Tahire Özen; Abdullah Harmanci

    2009-04-01

    Let be a ring with identity, a right -module and $S=\\mathrm{End}_R(M)$. In this note, we introduce -semicommutative, -Baer, $S-q.$-Baer and $S-p.q.$-Baer modules. We study the relations between these classes of modules. Also we prove if is an -semicommutative module, then is an $S-p.q.$-Baer module if and only if $M[x]$ is an $S[x]-p.q.$-Baer module, is an -Baer module if and only if $M[x]$ is an $S[x]$-Baer module, is an $S-q.$-Baer module if and only if $M[x]$ is an $S[x]-q.$-Baer module.

  17. Automated solar module assembly line

    Science.gov (United States)

    Bycer, M.

    1980-01-01

    The solar module assembly machine which Kulicke and Soffa delivered under this contract is a cell tabbing and stringing machine, and capable of handling a variety of cells and assembling strings up to 4 feet long which then can be placed into a module array up to 2 feet by 4 feet in a series of parallel arrangement, and in a straight or interdigitated array format. The machine cycle is 5 seconds per solar cell. This machine is primarily adapted to 3 inch diameter round cells with two tabs between cells. Pulsed heat is used as the bond technique for solar cell interconnects. The solar module assembly machine unloads solar cells from a cassette, automatically orients them, applies flux and solders interconnect ribbons onto the cells. It then inverts the tabbed cells, connects them into cell strings, and delivers them into a module array format using a track mounted vacuum lance, from which they are taken to test and cleaning benches prior to final encapsulation into finished solar modules. Throughout the machine the solar cell is handled very carefully, and any contact with the collector side of the cell is avoided or minimized.

  18. Printed interconnects for photovoltaic modules

    Energy Technology Data Exchange (ETDEWEB)

    Fields, J. D.; Pach, G.; Horowitz, K. A. W.; Stockert, T. R.; Woodhouse, M.; van Hest, M. F. A. M.

    2017-01-01

    Film-based photovoltaic modules employ monolithic interconnects to minimize resistance loss and enhance module voltage via series connection. Conventional interconnect construction occurs sequentially, with a scribing step following deposition of the bottom electrode, a second scribe after deposition of absorber and intermediate layers, and a third following deposition of the top electrode. This method produces interconnect widths of about 300 um, and the area comprised by interconnects within a module (generally about 3%) does not contribute to power generation. The present work reports on an increasingly popular strategy capable of reducing the interconnect width to less than 100 um: printing interconnects. Cost modeling projects a savings of about $0.02/watt for CdTe module production through the use of printed interconnects, with savings coming from both reduced capital expense and increased module power output. Printed interconnect demonstrations with copper-indium-gallium-diselenide and cadmium-telluride solar cells show successful voltage addition and miniaturization down to 250 um. Material selection guidelines and considerations for commercialization are discussed.

  19. Automated solar module assembly line

    Science.gov (United States)

    Bycer, M.

    1980-08-01

    The solar module assembly machine which Kulicke and Soffa delivered under this contract is a cell tabbing and stringing machine, and capable of handling a variety of cells and assembling strings up to 4 feet long which then can be placed into a module array up to 2 feet by 4 feet in a series of parallel arrangement, and in a straight or interdigitated array format. The machine cycle is 5 seconds per solar cell. This machine is primarily adapted to 3 inch diameter round cells with two tabs between cells. Pulsed heat is used as the bond technique for solar cell interconnects. The solar module assembly machine unloads solar cells from a cassette, automatically orients them, applies flux and solders interconnect ribbons onto the cells. It then inverts the tabbed cells, connects them into cell strings, and delivers them into a module array format using a track mounted vacuum lance, from which they are taken to test and cleaning benches prior to final encapsulation into finished solar modules. Throughout the machine the solar cell is handled very carefully, and any contact with the collector side of the cell is avoided or minimized.

  20. Mechanical models of amplitude and frequency modulation

    Energy Technology Data Exchange (ETDEWEB)

    Bellomonte, L; Guastella, I; Sperandeo-Mineo, R M [GRIAF - Research Group on Teaching/Learning Physics, DI.F.TE.R. -Dipartimento di Fisica e Tecnologie Relative, University of Palermo, Viale delle Scienze, Edificio 18, 90128 Palermo (Italy)

    2005-05-01

    This paper presents some mechanical models for amplitude and frequency modulation. The equations governing both modulations are deduced alongside some necessary approximations. Computer simulations of the models are carried out by using available educational software. Amplitude modulation is achieved by using a system of two weakly coupled pendulums, whereas the frequency modulation is obtained by using a pendulum of variable length. Under suitable conditions (small oscillations, appropriate initial conditions, etc) both types of modulation result in significantly accurate and visualized simulations.

  1. Quantification of modulation degree for VMAT

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong Min; Park, So Yeon; Wu, Hong Gyun; Kim, Jin Ho; Ye, Sung Joon [Dept. of Radiation Oncology, Seoul National University Hospital, Seoul (Korea, Republic of); Carkson, Joel [Program in Biomedical Radiation Sciences, Dept. of Transdisciplinary Studies, Seoul National University Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of)

    2014-11-15

    The aim of this study is to quantify the degree of modulation by presenting a modulation index (MI) for volumetric modulated arc therapy (VMAT) based on the speed and acceleration analysis of modulating-parameters such as multi-leaf collimator (MLC) movements, gantry rotation and dose-rate, comprehensively, as well as by performing texture analysis on fluence maps. The MIt showed good performance for the evaluation of the modulation-degree of VMAT plans showing highest correlations to the plan deliverability.

  2. Solid-state membrane module

    Science.gov (United States)

    Gordon, John Howard; Taylor, Dale M.

    2011-06-07

    Solid-state membrane modules comprising at least one membrane unit, where the membrane unit has a dense mixed conducting oxide layer, and at least one conduit or manifold wherein the conduit or manifold comprises a dense layer and at least one of a porous layer and a slotted layer contiguous with the dense layer. The solid-state membrane modules may be used to carry out a variety of processes including the separating of any ionizable component from a feedstream wherein such ionizable component is capable of being transported through a dense mixed conducting oxide layer of the membrane units making up the membrane modules. For ease of construction, the membrane units may be planar.

  3. Modulation classification based on spectrogram

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The aim of modulation classification (MC) is to identify the modulation type of a communication signal. It plays an important role in many cooperative or noncooperative communication applications. Three spectrogram-based modulation classification methods are proposed. Their reccgnition scope and performance are investigated or evaluated by theoretical analysis and extensive simulation studies. The method taking moment-like features is robust to frequency offset while the other two, which make use of principal component analysis (PCA) with different transformation inputs,can achieve satisfactory accuracy even at low SNR (as low as 2 dB). Due to the properties of spectrogram, the statistical pattern recognition techniques, and the image preprocessing steps, all of our methods are insensitive to unknown phase and frequency offsets, timing errors, and the arriving sequence of symbols.

  4. Unity connecting module in SSPF

    Science.gov (United States)

    1998-01-01

    In the Space Station Processing Facility, the Unity connecting module, part of the International Space Station, is shown with Pressurized Mating Adapters 1 (left) and 2 (right) attached. Unity is scheduled to undergo testing of the common berthing mechanism to which other space station elements will dock. Unity is the primary payload on mission STS-88, targeted to launch Dec. 3, 1998. Other testing includes the Pad Demonstration Test to verify the compatibility of the module with the Space Shuttle as well as the ability of the astronauts to send and receive commands to Unity from the flight deck of the orbiter. Unity is expected to be ready for installation into the payload canister on Oct. 25, and transported to Launch Pad 39-A on Oct. 27. The Unity will be mated to the Russian-built Zarya control module which should already be in orbit at that time.

  5. Acoustic field modulation in regenerators

    Science.gov (United States)

    Hu, J. Y.; Wang, W.; Luo, E. C.; Chen, Y. Y.

    2016-12-01

    The regenerator is a key component that transfers energy between heat and work. The conversion efficiency is significantly influenced by the acoustic field in the regenerator. Much effort has been spent to quantitatively determine this influence, but few comprehensive experimental verifications have been performed because of difficulties in modulating and measuring the acoustic field. In this paper, a method requiring two compressors is introduced and theoretically investigated that achieves acoustic field modulation in the regenerator. One compressor outputs the acoustic power for the regenerator; the other acts as a phase shifter. A RC load dissipates the acoustic power out of both the regenerator and the latter compressor. The acoustic field can be modulated by adjusting the current in the two compressors and opening the RC load. The acoustic field is measured with pressure sensors instead of flow-field imaging equipment, thereby greatly simplifying the experiment.

  6. Kummer Theory for Drinfeld Modules

    CERN Document Server

    Pink, Richard

    2012-01-01

    Let {\\phi} be a Drinfeld A-module of characteristic p0 over a finitely generated field K. Previous articles determined the image of the absolute Galois group of K up to commensurability in its action on all prime-to-p0 torsion points of {\\phi}, or equivalently, on the prime-to-p0 adelic Tate module of {\\phi}. In this article we consider in addition a finitely generated torsion free A-submodule M of K for the action of A through {\\phi}. We determine the image of the absolute Galois group of K up to commensurability in its action on the prime-to-p0 division hull of M, or equivalently, on the extended prime-to-p0 adelic Tate module associated to {\\phi} and M.

  7. CAMAC 488 module: 68,000 based GPIB interface module

    Energy Technology Data Exchange (ETDEWEB)

    Seino, K.C.

    1985-03-01

    What kind of hardware and software should be used to interface GPIB devices with the existing computer system. One idea was to use a commercially available Multibus card, BLC 8488 from National Semiconductor, whose on-board Z80 would manage the GPIB read/write functions and handshakes. With this card, one could make a hardware system which would consist of (1) CAMAC 080, (2) Multibus crate, (3) M. Shea's M68000, (4) M080, (5) BLC 8488 and (6) memory board. And the software considered for such a hardware package was GAS, which had been an established software package for communication between the ACNET computer system and smart CAMAC modules. However, a second idea was to put everything on a two-wide CAMAC module. The author pursued the second idea and came up with a two-wide CAMAC module called C488. The author describes the hardware - block diagrams, circuit blocks, front panel and hardware tests. He also refers to the software - system, modules and applications.

  8. Equivalence of Quotient Hilbert Modules

    Indian Academy of Sciences (India)

    Ronald G Douglas; Gadadhar Misra

    2003-08-01

    Let $\\mathcal{M}$ be a Hilbert module of holomorphic functions over a natural function algebra $\\mathcal{A}()$, where $ \\subseteq \\mathbb{C}^m$ is a bounded domain. Let $\\mathcal{M}_0 \\subseteq \\mathcal{M}$ be the submodule of functions vanishing to order on a hypersurface $\\mathcal{Z} \\subseteq $. We describe a method, which in principle may be used, to construct a set of complete unitary invariants for quotient modules $\\mathcal{Q} = \\mathcal{M} \\ominus \\mathcal{M}_0$. The invariants are given explicitly in the particular case of = 2.

  9. DELPHI Barrel Muon Chamber Module

    CERN Multimedia

    1989-01-01

    The module was used as part of the muon identification system on the barrel of the DELPHI detector at LEP, and was in active use from 1989 to 2000. The module consists of 7 individual muons chambers arranged in 2 layers. Chambers in the upper layer are staggered by half a chamber width with respect to the lower layer. Each individual chamber is a drift chamber consisting of an anode wire, 47 microns in diameter, and a wrapped copper delay line. Each chamber provided 3 signal for each muon passing through the chamber, from which a 3D space-point could be reconstructed.

  10. Programmable Multi-Chip Module

    Science.gov (United States)

    Kautz, David; Morgenstern, Howard; Blazek, Roy J.

    2004-11-16

    A multi-chip module comprising a low-temperature co-fired ceramic substrate having a first side on which are mounted active components and a second side on which are mounted passive components, wherein this segregation of components allows for hermetically sealing the active components with a cover while leaving accessible the passive components, and wherein the passive components are secured using a reflow soldering technique and are removable and replaceable so as to make the multi-chip module substantially programmable with regard to the passive components.

  11. Deriving and Manipulating Module Interfaces

    Science.gov (United States)

    1992-05-01

    psation by providing a meaw form p ad mmaging this interactin though it module system [42]. In this examp1 ft two modules for character and line operations...possibility of further transformations that could specialfrt the screen in the context of the buffer state (a,., incremental update). Keep in mind that...G)) oWsAbS(a)) 4- a end Soase Of the expressiveness of the geneao may be lost since it is filtered out by 0 but this does not matter since other

  12. Heegner modules and elliptic curves

    CERN Document Server

    Brown, Martin L

    2004-01-01

    Heegner points on both modular curves and elliptic curves over global fields of any characteristic form the topic of this research monograph. The Heegner module of an elliptic curve is an original concept introduced in this text. The computation of the cohomology of the Heegner module is the main technical result and is applied to prove the Tate conjecture for a class of elliptic surfaces over finite fields; this conjecture is equivalent to the Birch and Swinnerton-Dyer conjecture for the corresponding elliptic curves over global fields.

  13. Lattice of ℤ-module

    Directory of Open Access Journals (Sweden)

    Futa Yuichi

    2016-03-01

    Full Text Available In this article, we formalize the definition of lattice of ℤ-module and its properties in the Mizar system [5].We formally prove that scalar products in lattices are bilinear forms over the field of real numbers ℝ. We also formalize the definitions of positive definite and integral lattices and their properties. Lattice of ℤ-module is necessary for lattice problems, LLL (Lenstra, Lenstra and Lovász base reduction algorithm [14], and cryptographic systems with lattices [15] and coding theory [9].

  14. LISA propulsion module separation study

    Energy Technology Data Exchange (ETDEWEB)

    Merkowitz, S M [NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Ahmad, A [NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Hyde, T T [NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Sweetser, T [Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109 (United States); Ziemer, J [Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109 (United States); Conkey, S [Swales Aerospace, 5050 Powder Mill Road, Beltsville, MD 20705 (United States); III, W Kelly [Swales Aerospace, 5050 Powder Mill Road, Beltsville, MD 20705 (United States); Shirgur, B [Swales Aerospace, 5050 Powder Mill Road, Beltsville, MD 20705 (United States)

    2005-05-21

    The Laser Interferometer Space Antenna (LISA) mission is a space-borne gravitational wave detector consisting of three sciencecraft in heliocentric orbit. Each sciencecraft is delivered to its operational orbit by a propulsion module. Because of the strict thermal and mass balancing requirements of LISA, the baseline mission concept requires that the propulsion module separate from the sciencecraft after delivery. The only propulsion system currently included in the sciencecraft design are micronewton level thrusters, such as field emission electric propulsion (FEEP) or colloid thrusters, that are used to balance the 30-40 {mu}N of solar radiation pressure and provide the drag-free and attitude control of the sciencecraft. Due to these thrusters' limited authority, the separation of the propulsion module from the sciencecraft must be well controlled to not induce a large tip-off rotation of the sciencecraft. We present here the results of a study of the propulsion module separation system requirements that are necessary to safely deliver the three LISA sciencecraft to their final operational orbits.

  15. Bidirectional reachability-based modules

    CSIR Research Space (South Africa)

    Nortje, R

    2011-07-01

    Full Text Available The authors introduce an algorithm for MinA extraction in EL based on bidirectional reachability. They obtain a significant reduction in the size of modules extracted at almost no additional cost to that of extracting standard reachability...

  16. Automated Accounting. Payroll. Instructor Module.

    Science.gov (United States)

    Moses, Duane R.

    This teacher's guide was developed to assist business instructors using Dac Easy Accounting Payroll Version 3.0 edition software in their accounting programs. The module contains assignment sheets and job sheets designed to enable students to master competencies identified in the area of automated accounting--payroll. Basic accounting skills are…

  17. A simple, inexpensive photoelastic modulator

    Science.gov (United States)

    Braun, Kyle J.; Lytle, Christian R.; Kavanaugh, James A.; Thielen, James A.; Green, Adam S.

    2009-01-01

    A block of birefringent gelatin acts as a variable retarder when driven harmonically by a speaker coil and can be used to vary the polarization of a laser beam sinusoidally. We model this effect with Mueller matrices and show that the gelatin behaves much like a commercial photoelastic modulator and is suitable for a variety of polarimetry experiments in an advanced undergraduate optics course.

  18. Market Segmentation: An Instructional Module.

    Science.gov (United States)

    Wright, Peter H.

    A concept-based introduction to market segmentation is provided in this instructional module for undergraduate and graduate transportation-related courses. The material can be used in many disciplines including engineering, business, marketing, and technology. The concept of market segmentation is primarily a transportation planning technique by…

  19. WRAP module 1 treatment plan

    Energy Technology Data Exchange (ETDEWEB)

    Mayancsik, B.A.

    1995-05-01

    This document provides the methodology to treat waste in the Waste Receiving and Processing Module 1 facility to meet the Resource Conservation and Recovery Act (RCRA) land disposal restrictions or the Waste Isolation and Pilot Plant waste acceptance criteria. This includes Low-Level Mixed Waste, Transuranic Waste, and Transuranic Mixed Waste.

  20. Exercises in modules and rings

    CERN Document Server

    Lam, TY

    2009-01-01

    This volume offers a compendium of exercises of varying degree of difficulty in the theory of modules and rings. All exercises are solved in full detail. Each section begins with an introduction giving the general background and the theoretical basis for the problems that follow.

  1. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  2. Radio frequency modulation made easy

    CERN Document Server

    Faruque, Saleh

    2017-01-01

    This book introduces Radio Frequency Modulation to a broad audience. The author blends theory and practice to bring readers up-to-date in key concepts, underlying principles and practical applications of wireless communications. The presentation is designed to be easily accessible, minimizing mathematics and maximizing visuals.

  3. OMV--Propulsion Module Changeout

    Science.gov (United States)

    1986-01-01

    In this 1986 artist's concept, the Orbital Maneuvering Vehicle (OMV), undergoes changeout of the Propulsion Module outside the Space Shuttle Cargo Bay. As envisioned by Marshall Space Flight Center plarners, the OMV would be a remotely-controlled free-flying space tug which would place, rendezvous, dock, and retrieve orbital payloads.

  4. Weakly Distributive Modules. Applications to Supplement Submodules

    Indian Academy of Sciences (India)

    Engin Büyükaşik; Yilmaz M Demirci

    2010-11-01

    In this paper, we define and study weakly distributive modules as a proper generalization of distributive modules. We prove that, weakly distributive supplemented modules are amply supplemented. In a weakly distributive supplemented module every submodule has a unique coclosure. This generalizes a result of Ganesan and Vanaja. We prove that -projective duo modules, in particular commutative rings, are weakly distributive. Using this result we obtain that in a commutative ring supplements are unique. This generalizes a result of Camillo and Lima. We also prove that any weakly distributive $\\oplus$-supplemented module is quasi-discrete.

  5. Reliability and Energy Output of Bifacial Modules

    Energy Technology Data Exchange (ETDEWEB)

    Van Aken, B.B.; Jansen, M.J.; Dekker, N.J.J. [ECN Solar Energy, Petten (Netherlands)

    2013-06-15

    Although flash tests under standard test conditions yields lower power due to transmittance of the back sheet, bifacial modules are expected to outperform their monofacial equivalents in terms of yearly energy output in the field. We compare flash tests for bifacial modules with and without a light scattering panel directly behind the modules: 3% more power output is obtained. We also report on the damp-heat reliability of modules with transparent back sheet. Finally we will present the results of an outdoor study comparing modules with transparent back sheet and modules with state-of-the-art AR coating on the front glass.

  6. A UNIVERSAL ALGORITHM OF MODULATION AND DEMODULATION

    Institute of Scientific and Technical Information of China (English)

    Zhang Rui; Li Jiandong; Wu Jie

    2002-01-01

    A new universal algorithm of modulation and demodulation is presented to process most signals of digital phase-related modulation schemes such as M-DPSK, MSK and even some M-FSK with low modulation level. It can easily deal with modulation and demodulation of the signals with different modulation schemes and data rates by only setting a few input arguments of the versatile software modules. The computational complexity of the algorithm is far less than that of conventional methods. The average processing capacity of the algorithm is about 15instructions per symbol when processing DQPSK signals. It can be applied to software radios.

  7. Earth System Science Education Modules

    Science.gov (United States)

    Hall, C.; Kaufman, C.; Humphreys, R. R.; Colgan, M. W.

    2009-12-01

    The College of Charleston is developing several new geoscience-based education modules for integration into the Earth System Science Education Alliance (ESSEA). These three new modules provide opportunities for science and pre-service education students to participate in inquiry-based, data-driven experiences. The three new modules will be discussed in this session. Coastal Crisis is a module that analyzes rapidly changing coastlines and uses technology - remotely sensed data and geographic information systems (GIS) to delineate, understand and monitor changes in coastal environments. The beaches near Charleston, SC are undergoing erosion and therefore are used as examples of rapidly changing coastlines. Students will use real data from NASA, NOAA and other federal agencies in the classroom to study coastal change. Through this case study, learners will acquire remotely sensed images and GIS data sets from online sources, utilize those data sets within Google Earth or other visualization programs, and understand what the data is telling them. Analyzing the data will allow learners to contemplate and make predictions on the impact associated with changing environmental conditions, within the context of a coastal setting. To Drill or Not To Drill is a multidisciplinary problem based module to increase students’ knowledge of problems associated with nonrenewable resource extraction. The controversial topic of drilling in the Arctic National Wildlife Refuge (ANWR) examines whether the economic benefit of the oil extracted from ANWR is worth the social cost of the environmental damage that such extraction may inflict. By attempting to answer this question, learners must balance the interests of preservation with the economic need for oil. The learners are exposed to the difficulties associated with a real world problem that requires trade-off between environmental trust and economic well-being. The Citizen Science module challenges students to translate scientific

  8. Green card for solar modules; Die Green Card fuer Module

    Energy Technology Data Exchange (ETDEWEB)

    Petzold, Katrin

    2010-07-01

    Manufacturers intending to export solar modules must have them tested according to international safety standards. However, the world ends at the doors of North America. The USA have national safety standards which necessitate a separate test by the US test institute 'Underwriters Laboratories'. Some claim that this is important, while others view this as a strategy to protect the US industry. Now, another test institute has been commissioned near Frankfurt, Germany. (orig.)

  9. Realization of DVCCTA Based Versatile Modulator

    Directory of Open Access Journals (Sweden)

    Neeta Pandey

    2014-01-01

    Full Text Available A Differential Voltage Current Conveyor Transconductance Amplifier (DVCCTA based versatile modulator is proposed which can work as an amplitude modulator, frequency modulator, delta modulator, and sigma delta modulator. The modulator operational scheme uses pulse generator as a core and its output is used as carrier signal. A DVCCTA based pulse generator is proposed first and subsequently configured as different modulators. Compact realization is the key feature of the proposed circuit as it uses two DVCCTA; a grounded resistor and a grounded capacitor hence are appropriate for IC realization. The functionality of the proposed circuit is verified through SPICE simulations using TSMC 0.25 μm CMOS process model parameters. The performance parameters such as power dissipation and noise for various modulator schemes are also obtained.

  10. Index modulation for 5G wireless communications

    CERN Document Server

    Wen, Miaowen; Yang, Liuqing

    2017-01-01

    This book presents a thorough examination of index modulation, an emerging 5G modulation technique. It includes representative transmitter and receiver design, optimization, and performance analysis of index modulation in various domains. First, the basic spatial modulation system for the spatial domain is introduced. Then, the development of a generalized pre-coding aided quadrature spatial modulation system as well as a virtual spatial modulation system are presented. For the space-time domain, a range of differential spatial modulation systems are examined, along with the pre-coding design. Both basic and enhanced index modulated OFDM systems for the frequency domain are discussed, focusing on the verification of their strong capabilities in inter-carrier interference mitigation. Finally, key open problems are highlighted and future research directions are considered. Designed for researchers and professionals, this book is essential for anyone working in communications networking, 5G, and system design. A...

  11. Generalized Green Correspondence of Graded Modules

    Institute of Scientific and Technical Information of China (English)

    Salah El-Din; S.HUSSEIN

    2009-01-01

    The author studies the Green correspondence and quasi-Green correspondence for indecomposable modules over strongly graded rings.The motivation is to investigate the influence of induction and restriction processes on indecomposability of graded modules.

  12. Reliability Issues for Photovoltaic Modules (Presentation)

    Energy Technology Data Exchange (ETDEWEB)

    Kurtz, S.

    2009-10-01

    Si modules good in field; new designs need reliability testing. CdTe & CIGS modules sensitive to moisture; carefully seal. CPV in product development stage; benefits from expertise in other industries.

  13. Fiber Acousto-Electro-Optic Modulator

    Institute of Scientific and Technical Information of China (English)

    Anen; Jiang

    2003-01-01

    A new kind of fiber acousto-electro-optic modulator is made by using Lithium Niobate crystal. This kind of modulator can be used in fiber communication, and its center frequency can be changed by directed current voltages.

  14. Pulse shaping using a spatial light modulator

    CSIR Research Space (South Africa)

    Botha, N

    2009-07-01

    Full Text Available Femtosecond pulse shaping can be done by different kinds of pulse shapers, such as liquid crystal spatial light modulators (LC SLM), acousto optic modulators (AOM) and deformable and movable mirrors. A few applications where pulse shaping...

  15. Modularity for Modulating Exercises and Levels

    DEFF Research Database (Denmark)

    Lund, Henrik Hautop; Nielsen, Camilla Balslev

    2011-01-01

    The modular interactive tiles aim at engaging anybody (elderly, carer, hospital personnel, children) in performing playful and motivating physical activities. Inspired by modular robotics, each tile is a self-contained module with processing power and communication to neighbouring modules...

  16. Complex light modulation for lensless image projection

    Institute of Scientific and Technical Information of China (English)

    M. Makowski; A. Kolodziejczyk; A. Siemion; I. Ducin; K. Kakarenko; M. Sypek; A. M. Siemion; J. Suszek; D. Wojnowski; Z. Jaroszewicz

    2011-01-01

    We present a lensless projection of color images based on computer-generated Fourier holograms. Amplitude and phase modulation of three primary-colored laser beams is performed by a matched pair of spatial light modulators. The main advantage of the complex light modulation is the lack of iterative phase retrieval techniques. The advantage is the lack of speckles in the projected images. Experimental results are given and compared with the outcome of classical phase-only modulation.%We present a lensless projection of color images based on computer-generated Fourier holograms.Amplitude and phase modulation of three primary-colored laser beams is performed by a matched pair of spatial light modulators.The main advantage of the complex light modulation is the lack of iterative phase retrieval techniques.The advantage is the lack of speckles in the projected images.Experimental results are given and compared with the outcome of classical phase-only modulation.

  17. Direct current modulation of a photomixing signal

    Science.gov (United States)

    Constantin, Florin L.

    2016-04-01

    Direct modulation of the bias voltage of a LTG-GaAs photomixer is exploited to modulate the signal generated at the frequency of the optical beat between two diode lasers at 820 nm. The photomixing signal is calculated from an expansion in power series of the amplitude of the modulation voltage and displays amplitude modulation sidebands equidistantly spaced to the frequency of the optical beat by integer multiples of the modulation frequency. Modulation at harmonics of the modulation frequency is allowed by the electrical nonlinear response of the photomixer, driven at low voltage by the saturation of the electron drift velocity. Coupling of an alternative voltage to the photomixer operated at zero-bias leads to bifrequency operation. Modulation of the photomixing signal and bifrequency operation of the photomixer are observed experimentally with an optical beat in the microwave regime.

  18. Mounting support for a photovoltaic module

    Science.gov (United States)

    Brandt, Gregory Michael; Barsun, Stephan K.; Coleman, Nathaniel T.; Zhou, Yin

    2013-03-26

    A mounting support for a photovoltaic module is described. The mounting support includes a foundation having an integrated wire-way ledge portion. A photovoltaic module support mechanism is coupled with the foundation.

  19. Plasma optical modulators for intense lasers

    CERN Document Server

    Yu, Lu-Le; Qian, Lie-Jia; Chen, Min; Weng, Su-Ming; Sheng, Zheng-Ming; Jaroszynski, D A; Mori, W B; Zhang, Jie

    2016-01-01

    Optical modulators can be made nowadays with high modulation speed, broad bandwidth, while being compact, owing to the recent advance in material science and microfabrication technology. However, these optical modulators usually work for low intensity light beams. Here, we present an ultrafast, plasma-based optical modulator, which can directly modulate high power lasers with intensity up to 10^16 W/cm^2 level to produce an extremely broad spectrum with a fractional bandwidth over 100%, extending to the mid-infrared regime in the low-frequency side. This concept relies on two co-propagating laser beams in a sub-mm-scale underdense plasma, where a drive laser pulse first excites an electron plasma wave in its wake while a following carrier laser beam is modulated by the plasma wave. The laser and plasma parameters suitable for the modulator to work are presented. Such optical modulators may enable new applications in the high field physics.

  20. CMOS Compatible Ultra-Compact Modulator

    DEFF Research Database (Denmark)

    Babicheva, Viktoriia; Kinsey, Nathaniel; Naik, Gururaj V.

    2014-01-01

    A planar layout for an ultra-compact plasmonic modulator is proposed and numerically investigated. Our device utilizes potentially CMOS compatible materials and can achieve 3-dB modulation in just 65nm and insertion loss <1dB at telecommunication wavelengths.......A planar layout for an ultra-compact plasmonic modulator is proposed and numerically investigated. Our device utilizes potentially CMOS compatible materials and can achieve 3-dB modulation in just 65nm and insertion loss